diff --git "a/약학_dataset.txt" "b/약학_dataset.txt" new file mode 100644--- /dev/null +++ "b/약학_dataset.txt" @@ -0,0 +1,164598 @@ + +The first two editions of Harrison’s Neurology in Clinical +Medicine were unqualified successes. +For many physicians, neurologic diseases represent +particularly challenging problems. +By the second edition, the section was +considerably enlarged by Raymond D. +Adams, whose +influence on the textbook was profound. +The third +neurology editor, Joseph B. +Thanks also to Dr. +This new volume was championed by James Shanahan +and impeccably managed by Kim Davis. +We live in an electronic, wireless age. +Information +is downloaded rather than pulled from the shelf. +Some +have questioned the value of traditional books in this +new era. +Stephen L. +Hauser, MD +Preface xiv +NOTICE +Medicine is an ever-changing science. +Readers are encouraged +to confirm the information contained herein with other sources. +This recommendation is of particular importance in connection with +new or infrequently used drugs. +The genetic icons identify a clinical issue with an explicit genetic relationship. +Harrison’s Self-Assessment and Board Review, 18th ed. +New York, McGraw-Hill, 2012, ISBN 978-0-07-177195-5. +This page intentionally left blank +SECTION I + +INTRODUCTION TO +NEUROLOGY + Daniel H. +Lowenstein ■ Joseph B. +Martin ■ Stephen L. +Hauser +2 + Neurologic diseases are common and costly. +Are the pain-sensitive meninges +involved? +A more detailed examina- +tion of a particular region of the CNS or PNS is often +indicated. +In addition, this strategy safeguards against +making serious errors. +The history also helps to bring a focus to the neuro- +logic examination that follows. +For example, a patient complains +of weakness of the right arm. +What are the associated +features? +Negative +associations may also be crucial. +Other pertinent features of the +history include the following: +1. +Temporal course of the illness. +2. +Patients’ descriptions of the complaint. +The same words +often mean different things to different patients. +“Dizziness” may imply impending syncope, a +sense of disequilibrium, or true spinning vertigo. +3. +Corroboration of the history by others. +4. +Family history. +Many neurologic disorders have an +underlying genetic component. +5. +Medical illnesses. +Many neurologic diseases occur in +the context of systemic disorders. +Patients with malig- +nancy may also present with a neurologic paraneo- +plastic syndrome (Chap. +44) or complications from +chemotherapy or radiotherapy. +Various neurologic disorders occur +with dysthyroid states or other endocrinopathies. +Most patients with coma in a hospital setting have a +metabolic, toxic, or infectious cause. +6. +Drug use and abuse and toxin exposure. +It is essential to +inquire about the history of drug use, both prescribed +and illicit. +7. +Formulating an impression of the patient. +Use the +opportunity while taking the history to form an +impression of the patient. +Is the information forth- +coming, or does it take a circuitous course? +Is there +evidence of anxiety, depression, or hypochondriasis? +Are there any clues to defects in language, memory, +insight, or inappropriate behavior? +A screening examination done +in this way can be completed in 3–5 min. +Several additional points about the examination are +worth noting. +A single small-amplitude movement of the finger is +sufficient for a normal response. +CN VII (facial) +Look for facial asymmetry at rest and with spontaneous +movements. +Test eyebrow elevation, forehead wrin- +kling, eye closure, smiling, and cheek puff. +Any suspected problem should +be followed up with formal audiometry. +11, +17, and 24, respectively. +MOTOR EXAMINATION +• The bare minimum: Look for muscle atrophy and check +extremity tone. +Tap the biceps, patellar, and Achilles reflexes. +Test +for lower extremity strength by having the patient walk +normally and on heels and toes. +The motor examination includes observations of mus- +cle appearance, tone, strength, and reflexes. +Check for muscle fasciculations, tenderness, and atrophy +or hypertrophy. +Tone +Muscle tone is tested by measuring the resistance to +passive movement of a relaxed limb. +Decreased +tone is most commonly due to lower motor neuron or +peripheral nerve disorders. +It is also helpful to palpate accessible muscles +as they contract. +The +normal reflex consists of plantar flexion of the toes. +Normally, the umbilicus +will pull toward the stimulated quadrant. +With upper +motor neuron lesions, these reflexes are absent. +In many instances stroking the +back of the hand will lead to its release. +Check double simultaneous stimulation using +light touch on the hands. +With patients +who are uncooperative or lack an understanding of +the tests, it may be useless. +The examination should be +focused on the suspected lesion. +The Romberg +maneuver is primarily a test of proprioception. +A loss of balance +with the eyes closed is an abnormal response. +Coordination refers to the orchestration and fluid- +ity of movements. +Part of this integration +relies on normal function of the cerebellar and basal +ganglia systems. +In the lower limb, the patient rapidly taps the foot +against the floor or the examiner’s hand. +For all these +movements, the accuracy, speed, and rhythm are noted. +Watching the patient walk is the most important part +of the neurologic examination. +4); or (4) elec- +trophysiologic studies (Chap. +5). +17. +Daniel H. +Lowenstein +11 + Knowledge of the basic neurologic examination is +an essential clinical skill. +THE NEUROLOGIC SCREENING EXAM + CHAPTER 2 + Martin A. +VIDEO ATLAS OF THE DETAILED NEUROLOGIC +EXAMINATION + CHAPTER 3 + William P. +A computer calculates a “back projection” image from +the 360° x-ray attenuation profi le. +Multidetector CT (MDCT) is now standard in most +radiology departments. +4-1B and C). +CTA images are +postprocessed for display in three dimensions to yield +angiogram-like images (Fig. +4-1C, 4-2 E and F, and +see Fig. +27-4). +CTA has proved useful in assessing the +cervical and intracranial arterial and venous anatomy. +COMPLICATIONS +CT is safe, fast, and reliable. +Care must be taken to reduce exposure when imaging +children. +Advanced soft- +ware that permits noise reduction may permit lower +radiation doses. +The most frequent complications are +associated with use of intravenous contrast agents. +Two +broad categories of contrast media, ionic and non- +ionic, are in use. +As a result, ionic +agents have been largely replaced by safer nonionic +compounds. +A. +Noncontrast CT demonstrates subarachnoid hemorrhage +and mild obstructive hydrocephalus. +B. +C. +A. +B. +C. +D. +E. +G. +H and I. +Field strength of the +magnet is directly related to signal-to-noise ratio. +Rf pulses transiently excite the energy state of +the hydrogen protons in the body. +Rf is administered +at a frequency specific for the field strength of the mag- +net. +The echo is transformed +by Fourier analysis into the information used to form +an MR image. +The relaxation rate varies among +normal and pathologic tissues. +Two relaxation rates, T1 and T2, influence the +signal intensity of the image. +So-called +T1-weighted (T1W) images are produced by keeping +the TR and TE relatively short. +T2-weighted (T2W) +images are produced by using longer TR and TE times. +4-6B). +Many different MR pulse sequences exist, and each +can be obtained in various planes (Figs. +4-2, 4-3, 4-4). +4-6B). +4-5C). +MR images +can be generated in any plane without changing the +patient’s position. +Each sequence, however, must be +obtained separately and takes 1–10 min on average to +complete. +FIGURE 4-3 +Cerebral abscess in a patient with fever and a right +hemiparesis. +A. +B. +Approximately 0.2 mL/kg body weight +is administered intravenously; the cost is ∼$60 per +dose. +4-3A) and areas of the brain that +normally are devoid of the BBB (pituitary, choroid +plexus). +Renal failure does not occur. +A and B. +C. +The suspected diagnosis of herpes sim- +plex encephalitis was confirmed by CSF PCR analysis. +Renal disease (including solitary kidney, renal trans- +plant, renal tumor) +2. +Age >60 years +3. +History of hypertension +4. +History of diabetes +5. +The incidence of NSF in patients with severe renal +dysfunction (GFR <30) varies from 0.19 to 4%. +A. +Noncontrast CT scan shows +one hyperdense lesion in the right hemisphere (arrow). +B. +T2-weighted fast spin echo image shows subtle low-intensity +lesions (arrows). +C. +Caution is advised for patients +with a GFR below 45. +The patient lies on a table +A B +C +that is moved into a long, narrow gap within the mag- +net. +Approximately 5% of the population experiences +severe claustrophobia in the MR environment. +This can +be reduced by mild sedation but remains a problem for +some. +A. +B. +Coronal T2 FLAIR image demonstrates +high signal glioma in left temporal lobe. +C. +MRI is considered safe for patients, even at very high +field strengths (>3–4 T). +These provide a vascular flow map rather than the ana- +tomic map shown by conventional angiography. +spin echo MR images. +4-2G). +MRA can also be acquired during infusion of + contrast material. +Advantages include faster imaging +times (1–2 min vs. +10 min), fewer flow-related arti- +facts, and higher-resolution images. +Recently, con- +trast-enhanced MRA has become the standard for +extracranial vascular MRA. +Proper technique and timing +of acquisition relative to bolus arrival are critical for +success. +In rou- +tine spin echo imaging, images of the brain can be +obtained in 5–10 min. +Fast MRI reduces patient and +organ motion, permitting diffusion imaging and tractog- +raphy (Figs. +4-2H, 4-3, 4-4C, 4-6; and see Fig. +27-16), +perfusion imaging during contrast infusion, fMRI, and +kinematic motion studies. +4-3B). +4-6). +Irritated or infiltrated nerves will +demonstrate high signal on T2W imaging. +Multiple images of glucose uptake +activity are formed after 45–60 min. +A lower activity +of FDG in the parietal lobes has been associated with +Alzheimer’s disease. +FDG PET is used primarily for the +detection of extracranial metastatic disease. +In patients with a suspected spinal block, MR is the +preferred technique. +Adequate hydration before and +after myelography will reduce the incidence of this +complication. +Management of post–lumbar puncture headache is + discussed in Chap. +8. +Hearing loss is a rare complication of myelog- +raphy. +Intrathecal +contrast reactions are rare, but aseptic meningitis and +encephalopathy may occur. +Seizures occur follow- +ing myelography in 0.1–0.3% of patients. +CT and plain films are +obtained following the procedure. +Angiography has been replaced for many indications by +CT/CTA or MRI/MRA. +The most feared complication of cerebral angiography is +stroke. +35) prior to aortic aneurysm repair. +Many of these disorders place +the patient at high risk of cerebral hemorrhage, stroke, +or death. +Michael J. +The characteristics of the +normal EEG depend on the patient’s age and level of +arousal. +5-1 ) . +Digital systems are now widely used for recording +the EEG. +With generalized tonic-clonic sei- +zures, the EEG is always abnormal during the episode. +Thus, +the EEG cannot establish the diagnosis of epilepsy in +many cases. +5-2). +Normal EEG showing a posteriorly situated 9-Hz alpha +rhythm that attenuates with eye opening. +B. +Abnormal EEG +showing irregular diffuse slow activity in an obtunded patient +with encephalitis. +C. +D. +Periodic complexes occurring once +every second in a patient with Creutzfeldt-Jakob disease. +Hori- +zontal calibration: 1 s; vertical calibration: 200 μV in A, 300 μV +in other panels. +(From MJ Aminoff, ed: Electrodiagnosis in Clini- +cal Neurology, 5th ed. +A, earlobe; C, central; F, frontal; Fp, frontal polar; P, pari- +etal; T, temporal; O, occipital. +5-1). +The EEG generally slows +in metabolic encephalopathies, and triphasic waves may +be present. +5-1). +A. +B. +C. +Horizontal calibration: 1 s; verti- +cal calibration: 400 mV in A, 200 mV in B, and 750 mV in C. +(From MJ Aminoff, ed: Electrodiagnosis in Clinical Neurology, +5th ed. +5-1) or subacute scle- +rosing panencephalitis. +Its presence, latency, and symmetry +over the two sides of the scalp are noted. +The VEP findings are therefore +helpful in indicating previous or subclinical optic neuri- +tis. +Normal VEPs +may be elicited by flash stimuli in patients with cortical +blindness. +The EP findings are sometimes of prognostic rel- +evance. +The procedure is painless and apparently +safe. +Nevertheless, it is not used widely for clinical +purposes. +Within each motor unit, all of the +muscle fibers are of the same type. +Slight voluntary contraction of a muscle leads to acti- +vation of a small number of motor units. +5-3). +The number +of units activated depends on the degree of voluntary +activity. +A. +Spontaneous fibrillation +potentials and positive sharp waves. +B. +Complex repetitive +discharges recorded in partially denervated muscle at rest. +C. +Normal triphasic motor unit action potential. +D. +E. +Long-duration polyphasic motor unit action potential such as +may be seen in neuropathic disorders. +SECTION I +Introduction to Neurology +32 of voluntary activity. +5-3). +Such +information is important for prognostic purposes. +Various quantitative EMG approaches have been +developed. +The technique of single- +fiber EMG is discussed separately below. +They may suggest the underlying pathologic basis +in individual cases. +H-REFLEX STUDIES +The H reflex is easily recorded only from the soleus +muscle (S1) in normal adults. +In disorders of neu- +romuscular transmission this safety factor is reduced. +Elizabeth Robbins ■ Stephen L. +Hauser +35 + In experienced hands, lumbar puncture (LP) is usually +a safe procedure. +Bleeding com- +plications rarely occur in patients with platelet counts +≥50,000/μL and an INR ≤1.5. +ANALGESIA + Anxiety and pain can be minimized prior to begin- +ning the procedure. +Topi- +cal anesthesia can be achieved by the application of a +lidocaine-based cream. +POSITIONING + Proper positioning of the patient is essential. +6-1 ). +The spinal cord terminates +at approximately the L1 vertebral level in 94% of indi- +viduals. +In the remaining 6%, the conus extends to the +L2-L3 interspace. +LP is therefore performed at or below +the L3-L4 interspace. +An alternative to the lateral recumbent position is the +seated position. +The patient sits at the side of the bed, +with feet supported on a chair. +The patient is instructed +to curl forward, trying to touch the nose to the umbi- +licus. +LP +is sometimes more easily performed in obese patients if +they are sitting. +A pause of ∼15 s +between injections helps to minimize the pain of the +subsequent injection. +Approximately +5–10 mini-boluses are injected, using a total of ∼5 mL +of lidocaine. +Even a delay of 5 min will help to +reduce pain. +If there is still no fluid, +the stylet is reinserted and the needle is advanced slightly. +The needle can then be reinserted at the same +level or at an adjacent one. +Once the SAS is reached, a manometer is attached +to the needle and the opening pressure measured. +CSF is allowed to drip into collection tubes; it should +not be withdrawn with a syringe. +Note that the shoulders and hips are in a vertical +plane; the torso is perpendicular to the bed. +(From RP Simon +et al [eds]: Clinical Neurology, 7th ed. +In general 20–30 mL +may be safely removed from adults. +POST-LP HEADACHE +The principal complication of LP is headache, occur- +ring in 10–30% of patients. +Younger age and female +gender are associated with an increased risk of post-LP +headache. +Headache usually begins within 48 h but +may be delayed for up to 12 days. +The longer the patient is upright, the +longer the latency before head pain subsides. +The pain +is usually a dull ache but may be throbbing; its location +is occipitofrontal. +7]) and antiemetics. +For +some patients, beverages with caffeine can provide tem- +porary pain relief. +This procedure is most often performed by +a pain specialist or anesthesiologist. +The acute benefit may be due to compression of the CSF +space by the clot, increasing CSF pressure. +Strategies to decrease the incidence of post-LP head- +ache are listed in Table 6-1. +6-2). +There is a low risk of needle dam- +age, e.g., breakage, with the Sprotte atraumatic needle. +CSF glu- +cose concentrations <2.2 mmol/L (<40 mg/dL) are +abnormal. +bIgG index = CSF IgG (mg/dL) × serum albumin (g/dL)/serum IgG (g/ +dL) × CSF albumin (mg/dL). +SECTION II +CLINICAL +MANIFESTATIONS OF +NEUROLOGIC DISEASE + James P. +Rathmell ■ Howard L. +Fields +40 + The task of medicine is to preserve and restore health +and to relieve suffering. +Understanding pain is essen- +tial to both of these goals. +The function of the pain sensory system is +to protect the body and maintain homeostasis. +It is the +physician’s responsibility to provide rapid and effective +pain relief. +THE PAIN SENSORY SYSTEM + Pain is an unpleasant sensation localized to a part of the +body. +These properties illustrate the duality of pain: it +is both sensation and emotion. +7-1 ) . +In normal individuals, +the activity of these fi bers does not produce pain. +7-1 ). +These fi bers are present +in nerves to the skin and to deep somatic and visceral +structures. +Some tissues, such as the cornea, are inner- +vated only by Aδ and C fi ber afferents. +Individual primary afferent nociceptors can respond +to several different types of noxious stimuli. +Following injury and resultant sensitization, nor- +mally innocuous stimuli can produce pain. +Sensitization is of particular importance for pain and +tenderness in deep tissues. +Nociceptor-induced inflammation +Primary afferent nociceptors also have a neuroeffec- +tor function. +7-2). +An example +is substance P, an 11-amino-acid peptide. +Substance P +is released from primary afferent nociceptors and has +multiple biologic activities. +ganglion. +All sympathetic postganglionic fibers are +unmyelinated. +They terminate in the +dorsal horn of the spinal gray matter (Fig. +7-3). +The major neurotransmitter released is gluta- +mate, which rapidly excites dorsal horn neurons. +A. +Direct activation by intense pressure and consequent cell +damage. +B. +Secondary activation. +Thus, inflam- +mation near the central diaphragm is usually reported as +shoulder discomfort. +The spinothalamic path- +way is crucial for pain sensation in humans. +Interruption +of this pathway produces permanent deficits in pain and +temperature discrimination. +Spinothalamic tract axons ascend to several regions +of the thalamus. +7-4). +One of the thalamic pro- +jections is to the somatosensory cortex. +This affective +dimension of pain produces suffering and exerts potent +control of behavior. +Because of this dimension, fear is a +constant companion of pain. +7-4). +7-5). +A. +Trans- +mission system for nociceptive messages. +B. +Pain- +modulation network. +Pain-modulating circuits can enhance as well as sup- +press pain. +Paradoxically, damage to or dysfunction of these +pathways can also produce pain. +These features are rare in +other types of pain. +On examination, a sensory deficit +is characteristically present in the area of the patient’s +pain. +A variety of mechanisms contribute to neuropathic +pain. +Damaged pri- +mary afferents may also develop sensitivity to norepineph- +rine. +Thus, both CNS and peripheral nervous +system hyperactivity contribute to neuropathic pain. +This pain is often described as having a burning quality. +33). +Sometimes, treat- +ing the underlying condition does not immediately +relieve pain. +Older age and history of +gastrointestinal disease increase the risks of aspirin and +NSAIDs. +NSAIDs can also +increase blood pressure in some individuals. +Food and Drug Administration (FDA) for the +treatment of pain. +bGabapentin in doses up to 1800 mg/d is FDA approved for postherpetic neuralgia. +Note: 5-HT, serotonin; NE, norepinephrine. +CHAPTER 7 +Pain: Pathophysiology and Management +47 of NSAIDs, excluding aspirin. +OPIOID ANALGESICS Opioids are the most potent +pain-relieving drugs currently available. +Respiratory depres- +sion is uncommon at standard analgesic doses, but can +be life-threatening. +Opioid-related side effects can be +reversed rapidly with the narcotic antagonist naloxone. +The physician should not hesitate to use opioid analgesics +in patients with acute severe pain. +Table 7-1 lists the most +commonly used opioid analgesics. +Opioids produce analgesia by actions in the CNS. +They activate pain-inhibitory neurons and directly +inhibit pain-transmission neurons. +One striking example of this is norme- +peridine, a metabolite of meperidine. +Normeperidine +produces hyperexcitability and seizures that are not +reversible with naloxone. +Normeperidine accumulation +is increased in patients with renal failure. +Common side effects include +nausea, vomiting, constipation, and sedation. +The most +serious side effect is respiratory depression. +Because of this, initiation of therapy requires titra- +tion to optimal dose and interval. +The most important +principle is to provide adequate pain relief. +Because many patients are reluc- +tant to complain, this practice leads to needless suffering. +The +patient can then titrate the dose to the optimal level. +The availability of new routes of administration has +extended the usefulness of opioid analgesics. +Most +important is the availability of spinal administration. +Opioids can be infused through a spinal catheter placed +either intrathecally or epidurally. +In this way, side effects +such as sedation, nausea, and respiratory depression can +be minimized. +However, +fixed-ratio combinations of an opioid with acetaminophen +carry a special risk. +CHRONIC PAIN +Managing patients with chronic pain is intellectually +and emotionally challenging. +The traditional +medical approach of seeking an obscure organic pathol- +ogy is usually unhelpful. +There are several factors that can cause, perpetuate, +or exacerbate chronic pain. +Finally, +a variety of psychological conditions can exacerbate or +even cause pain. +There are certain areas to which special attention +should be paid in a patient’s medical history. +Relief of the pain with a sympathetic block +is diagnostic. +Optimal therapy requires that each of +these factors be looked for and treated. +There are no set criteria for predicting which +patients will respond to these procedures. +Such referrals are +clearly not necessary for all chronic pain patients. +For +some, pharmacologic management alone can provide +adequate relief. +Table 7-2 lists some of the painful conditions +that respond to TCAs. +The TCAs that have been shown to relieve pain have +significant side effects (Table 7-1; Chap. +53). +bControlled studies indicate benefit but not analgesia. +This pain has a characteristic brief, +shooting, electric shock–like quality. +Transdermal fentanyl is another +excellent option. +In contrast, opioid medications should +be used as a second- or third-line drug class. +Drugs of dif- +ferent classes can be used in combination to optimize +pain control. +Peter J. +Goadsby ■ Neil H. +Raskin +51 + Headache is among the most common reasons patients +seek medical attention. +7 ). +Headache may originate from either or +both mechanisms. +Philadelphia, Lippin- +cott, Williams & Wilkins, 2005. +SECTION II +Clinical Manifestations of Neurologic Disease +52 also be seen in migraine. +Migraine is a brain disorder, and best understood and +managed as such. +Patients with recent onset of pain +require prompt evaluation and appropriate treatment. +A complete neurologic examination is an essen- +tial first step in the evaluation. +Serious underlying conditions that are associated with +headache are described next. +Brain tumor is a rare cause +of headache and even less commonly a cause of severe +pain. +The vast majority of patients presenting with +severe headache have a benign cause. +MENINGITIS +Acute, severe headache with stiff neck and fever sug- +gests meningitis. +Lumbar puncture is mandatory. +Often +there is striking accentuation of pain with eye move- +ment. +Meningitis is discussed in Chaps. +40 and 41. +Rarely, if the hemorrhage is small or below the +foramen magnum, the head CT scan can be normal. +Intracranial hemorrhage is discussed in Chap. +28. +This pattern of symptoms +results from migraine far more often than from brain +tumor. +The headache of brain tumor disturbs sleep in +about 10% of patients. +Brain tumors are discussed in Chap. +37. +TEMPORAL ARTERITIS +(See also Chap. +The average +age of onset is 70 years, and women account for 65% +of cases. +Headache is the dominant symptom and +often appears in association with malaise and muscle +aches. +Headache is usually worse at night and often +aggravated by exposure to cold. +GLAUCOMA +Glaucoma may present with a prostrating headache +associated with nausea and vomiting. +The headache +often starts with severe eye pain. +On physical exami- +nation, the eye is often red with a fixed, moderately +dilated pupil. +Glaucoma is discussed in Chap. +21. +The most common are +migraine, tension-type headache, and cluster headache. +Migraine +can often be recognized by its activators, referred to as +triggers. +8-1). +CGRP receptor antagonists have now +been shown to be effective in the acute treatment of +migraine. +Data also support a role for dopamine in the patho- +physiology of migraine. +Most migraine symptoms +can be induced by dopaminergic stimulation. +Mutations in the neuronal voltage-gated sodium +channel SCN1A cause FHM 3. +Functional neuroim- +aging has suggested that brainstem regions in migraine +(Fig. +8-3) are good candidates for specific involvement +in primary headache. +Diagnosis and clinical features +Diagnostic criteria for migraine headache are listed in +Table 8-4. +New York, Churchill +Livingston, 1988; with permission. +FIGURE 8-2 +Positron emission tomography (PET) activation in +migraine. +Most patients with disabling head- +ache probably have migraine. +The Migraine Disability Assessment Score +(MIDAS) is a well-validated, easy-to-use tool (Fig. +8-4). +Patient education is an important aspect of migraine +management. +Most patients +benefit by the identification and avoidance of spe- +cific headache triggers. +For most patients, this approach +is, at best, an adjunct to pharmacotherapy. +Nonphar- +macologic measures are unlikely to prevent all migraine +attacks. +Mild migraine attacks can usually be man- +aged by oral agents; the average efficacy rate is 50–70%. +Severe migraine attacks may require parenteral therapy. +Migraine therapy must be individualized; +a standard approach for all patients is not possible. +Indeed, +many undiagnosed migraineurs are self-treated with +nonprescription NSAIDs. +A general consensus is that +NSAIDs are most effective when taken early in the +migraine attack. +The +combination of acetaminophen, aspirin, and caffeine +has been approved for use by the U.S. +On how many days in the last 3 months did you not do household work +because of your headaches? +On how many days in the last 3 months did you have a headache? +2. +3. +4. +5. +A. +B. +............................ +................................................................................ +..................... +................................................................. +......................................... +.......................................... +Write zero if you did not do the activity in the last 3 months. +*MIDAS Questionnaire +FIGURE 8-4 +MIDAS Questionnaire. +Local regulations and guidelines should be consulted. +Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; 5-HT, 5-hydroxytryptamine. +CHAPTER 8 +Headache +59 tans are selective 5-HT1B/1D receptor agonists. +Side effects are common though often mild and tran- +sient. +Ergotamine preparations offer a nonselective means +of stimulating 5-HT1 receptors. +The +average oral ergotamine dose for a migraine attack is +2 mg. +Important side effects of NSAIDs +include dyspepsia and gastrointestinal irritation. +5-HT1 RECEPTOR AGONISTS +Oral Stimulation of 5-HT1B/1D receptors can stop an +acute migraine attack. +Sumatriptan, 6 mg SC, is +effective in ∼70–80% of patients. +Drug absorption +is impaired during migraine because of reduced gas- +trointestinal motility. +In +addition, dopamine antagonists decrease nausea/vom- +iting and restore normal gastric motility. +Nasal A nasal preparation of butorphanol is available +for the treatment of acute pain. +Parenteral Narcotics are effective in the acute treat- +ment of migraine. +For example, IV meperidine (50–100 +mg) is given frequently in the emergency room. +This +regimen “works” in the sense that the pain of migraine is +eliminated. +However, this regimen is clearly suboptimal +for patients with recurrent headache. +Narcotic craving and/or withdrawal can +aggravate and accentuate migraine. +Drugs that have the capacity to stabilize migraine are +listed in Table 8-7. +In addition, +a number of other drugs appear to display prophylactic +efficacy. +bNot available in the United States. +The probability of success with any one of the anti- +migraine drugs is 50–75%. +The headache may +be episodic or chronic (present >15 days per month). +Pathophysiology +The pathophysiology of TTH is incompletely under- +stood. +Behavioral approaches including relaxation can also be +effective. +There is no evidence for +the efficacy of acupuncture. +Placebo-controlled trials +of onabotulinum toxin type A in chronic TTH have not +shown benefit. +Pain is usually severe and may occur more than once a +day. +A core feature of cluster headache is periodicity. +Patients are generally perfectly well between episodes. +This +phenomenon of unilateral photophobia/phonophobia is +characteristic of TACs. +8-3). +cIndicates complete response to indomethacin. +However, treatment of acute attacks is required for all +cluster headache patients at some time. +Many patients with acute clus- +ter headache respond very well to oxygen inhalation. +This should be given as 100% oxygen at 10–12 L/min for +15–20 min. +It appears that high flow and high oxygen +content are important. +Oral +sumatriptan is not effective for prevention or for acute +treatment of cluster headache. +When ergotamine (1–2 mg) is used, it is most +effective when given 1–2 h before an expected attack. +Lithium (600–900 mg qd) appears to be particularly useful +for the chronic form of the disorder. +The initial dose range is +40–80 mg twice daily; effective doses may be as high +as 960 mg/d. +Side effects such as constipation and leg +swelling can be problematic. +A baseline ECG is recom- +mended for all patients. +Dose increases +are usually made in 80-mg increments. +For patients on +long-term verapamil, ECG monitoring every 6 months +is advised. +Topira- +mate is helpful in some cases. +Piroxicam has been used, +although it is not as effective as indomethacin. +Vera- +pamil, an effective treatment for cluster headache, does +not appear to be useful for PH. +Secondary PH is more likely if the patient +requires high doses (>200 mg/d) of indomethacin. +In +patients with apparent bilateral PH, raised CSF pressure +should be suspected. +It is important to note that indo- +methacin reduces CSF pressure. +When a diagnosis of +PH is considered, MRI is indicated to exclude a pitu- +itary lesion. +Diagnosis +The pain of SUNCT/SUNA is unilateral and may be +located anywhere in the head. +Each pattern may be seen +in the context of an underlying continuous head pain. +Apart from trigeminal sensory disturbance, the neuro- +logic examination is normal in primary SUNCT. +34). +Secondary (Symptomatic) SUNCT +SUNCT can be seen with posterior fossa or pituitary +lesions. +However, IV lidocaine, which arrests +the symptoms, can be used in hospitalized patients. +The most effective treatment for prevention is +lamotrigine, 200–400 mg/d. +Topiramate and gabapentin +may also be effective. +Carbamazepine, 400–500 mg/d, +has been reported by patients to offer modest benefit. +Greater occipital nerve injection has produced limited +benefit in some patients. +Occipital nerve stimulation +is probably helpful in an important subgroup of these +patients. +Popula- +tion-based estimates suggest that about 4% of adults +have daily or near-daily headache. +For patients with primary headaches, diagnosis of the +headache type will guide therapy. +Anticonvulsants, such as topiramate, valproate, +and gabapentin, are also useful in migraineurs. +Flunari- +zine can also be very effective for some patients, as can +methysergide or phenelzine. +The residual +symptoms probably represent the underlying headache +disorder. +bSome patients may have headache >4 h/d. +One approach is to reduce the medication dose by 10% +every 1–2 weeks. +IM chlor- +promazine can be helpful at night; patients must be ade- +quately hydrated. +The first priority +is to distinguish between a primary and a secondary +cause of this syndrome. +28). +The pain, which is occipitofrontal, is usually a dull +ache but may be throbbing. +Post-LP headache usually begins within +48 h but may be delayed for up to 12 days. +Its inci- +dence is between 10 and 30%. +Beverages with caffeine +may provide temporary relief. +Postural orthostatic tachycardia syndrome (POTS +[Chap. +8-5). +Initial treatment for low CSF volume headache is +bed rest. +An ECG to screen for arrhythmia should +be performed before administration. +If unsuccessful, an abdominal binder may be help- +ful. +If a leak can be identified, an autologous blood patch +is usually curative. +Raised CSF Pressure Headache Raised CSF +pressure is well recognized as a cause of headache. +Brain imaging can often reveal the cause, such as a +space-occupying lesion. +Persistently raised intracranial pres- +sure can trigger chronic migraine. +It is generally worse with recumbency. +Visual +obscurations are frequent. +Evaluation of patients suspected to have raised CSF +pressure requires brain imaging. +It is most efficient to +obtain an MRI, including an MR venogram, as the initial +study. +An elevated opening pressure and +improvement in headache following removal of CSF is +diagnostic. +Initial treatment is with acetazolamide (250–500 mg +bid); the headache may improve within weeks. +Complaints of dizziness, +vertigo, and impaired memory can accompany the head- +ache. +Symptoms may remit after several weeks or persist +for months and even years after the injury. +Typically the +neurologic examination is normal and CT or MRI stud- +ies are unrevealing. +Chronic subdural hematoma may on +occasion mimic this disorder. +Evaluation +reveals no apparent cause for the headache. +Treatment is largely empirical. +The MAOI phenelzine may also be +useful in carefully selected patients. +The headache usually +resolves within 3–5 years, but it can be quite disabling. +Primary NDPH Primary NDPH occurs in both males +and females. +Nausea, photophobia, and/or phonophobia +occur in about half of patients. +At 24 months, ∼86% of patients are headache-free. +Featureless NDPH is one of the primary headache forms +most refractory to treatment. +Standard preventive thera- +pies can be offered but are often ineffective. +The age of onset ranges from 11 to 58 years; women are +affected twice as often as men. +The cause is unknown. +Topiramate can be +helpful in some patients. +The mecha- +nism of this response is unclear. +It may be pre- +cipitated by any form of exercise; it often has the pul- +satile quality of migraine. +The mechanism of primary exertional headache is +unclear. +The link to exercise is the +main clinical clue that headache is of cardiac origin. +Pheochromocytoma may occasionally cause exertional +headache. +Intracranial lesions and stenosis of the carotid +arteries are other possible etiologies. +The +pain usually begins as a dull bilateral headache that sud- +denly becomes intense at orgasm. +The headache can +be prevented or eased by ceasing sexual activity before +orgasm. +The latter arises from vigor- +ous sexual activity and is a form of low CSF pressure +headache. +In +about half of patients, sex headache will subside within +6 months. +Migraine is probably more +common in patients with sex headache. +TREATMENT Primary Sex Headache +Benign sex headaches recur irregularly and infrequently. +An alter- +native is the calcium channel–blocking agent diltiazem, +60 mg tid. +Hypnic headache +This headache syndrome typically begins a few hours +after sleep onset. +Daytime naps can also precipitate head pain. +Most patients are female, and the onset is usually after +age 60 years. +Headaches are bilateral in most, but may +be unilateral. +Photophobia or phonophobia and nausea +are usually absent. +Case reports suggest that flunari- +zine, 5 mg nightly, can be effective. +John W. +Engstrom ■ Richard A. +population is chronically disabled +because of back pain. +9-1 and 9-2) . +The posterior portion of the spine consists of the ver- +tebral arches and processes. +Each arch consists of paired +cylindrical pedicles anteriorly and paired laminae poste- +riorly. +The apposition of a superior and inferior facet consti- +tutes a facet joint . +15-2 and 15-3 ). +The cervical nerve roots follow a short +intraspinal course before exiting. +9-3 ) . +The nucleus +pulposus of the intervertebral disk is not pain-sensitive +under normal circumstances. +( From A Gauthier Cornuelle, DH Gronefeld: Radiographic Anatomy Posi- +tioning. +(From A Gauthier Cornuelle, DH Gronefeld: +Radiographic Anatomy Positioning. +The site of the pain is near the affected part of the back. +Pain referred to the back may arise from abdominal or +pelvic viscera. +The patient may +occasionally complain of back pain only. +Pain of spine origin may be located in the back or +referred to the buttocks or legs. +The pain may increase in +postures that stretch the nerves and nerve roots. +The normal spine has a cervical and lumbar lordosis, +and a thoracic kyphosis. +(From Adams and Victor’s +Principles of Neurology, 9th ed. +Pain from hip disease may mimic the pain of lumbar +spine disease. +Passive dorsiflexion of the foot during the maneu- +ver adds to the stretch. +Eliciting the SLR +sign in the sitting position can help determine if the +finding is reproducible. +The crossed SLR sign is less sensitive but more +specific for disk herniation than the SLR sign. +The nerve +or nerve root lesion is always on the side of the pain. +Breakaway weakness may be due +to pain or a combination of pain and underlying true +weakness. +Breakaway weakness without pain is almost +always due to a lack of effort. +In the absence of risk factors, these imaging +studies are rarely helpful in nonspecific ALBP. +5). +It occurs in +up to 6% of adolescents. +The trunk may be shortened and the abdomen pro- +tuberant as a result. +A dimple or small lipoma may overlie +the defect. +Most cases are asymptomatic and discovered +incidentally during an evaluation for back pain. +MRI +studies reveal a low-lying conus (below L1-L2) and a +short and thickened filum terminale. +These +terms are used loosely and do not clearly describe a spe- +cific anatomic lesion. +The pain is usually confined to +the lower back, and there is no radiation to the buttocks +or legs. +Patients with paraspinal muscle spasm often +assume unusual postures. +Neurologic impairment is com- +mon, and early surgical treatment is indicated. +LUMBAR DISK DISEASE +This is a common cause of chronic or recurrent low +back and leg pain (Figs. +9-3 and 9-4). +The +cause is often unknown; the risk is increased in over- +weight individuals. +Disk herniation is unusual prior +to age 20 years and is rare in the fibrotic disks of the +elderly. +Genetic factors may play a role in predisposing +some patients to disk disease. +The pain may be located +in the low back only or referred to a leg, buttock, or +hip. +The mechanism by which intervertebral disk injury +causes back pain is controversial. +The inner annulus +fibrosus and nucleus pulposus are normally devoid of +innervation. +Clinical manifestations of specific nerve root +lesions are summarized in Table 9-2. +For example, an absent knee +reflex may be due to a femoral neuropathy or an L4 +nerve root injury. +Spine +MRIs yield exquisite views of intraspinal and adjacent +soft tissue anatomy. +The correlation of neuroradiologic findings +to symptoms, particularly pain, is not simple. +Asymptomatic disk +protrusions are also common and may enhance with +contrast. +The correla- +tion between CT and EMG for localization of nerve +root injury is between 65 and 73%. +Up to one-third +of asymptomatic adults have a lumbar disk protrusion +detected by CT or MRI scans. +Management of lumbar disk disease is discussed later +in the chapter. +35), +and Guillain-Barré syndrome (Chap. +46). +Combi- +ned involvement of the conus medullaris and cauda +equina can occur. +CES is commonly due to a ruptured +FIGURE 9-4 +Left L5 radiculopathy. +A. +Sagittal T2-weighted image on +the left reveals disk herniation at the L4-L5 level. +B. +37). +Symptoms in the legs are usu- +ally bilateral. +Unlike vascular claudication, symptoms are often +provoked by standing without walking. +Unlike lum- +bar disk disease, symptoms are usually relieved by sit- +ting. +Severe neurologic deficits, including paralysis +and urinary incontinence, occur only rarely. +LSS can be acquired (75%), congenital, or due to a +combination of these factors. +MRI provides the best definition of +the abnormal anatomy (Fig. +9-5). +There is insufficient evi- +dence to support the use of epidural glucocorticoid +injections. +Patients treated nonoperatively improve uncommonly. +A. +The image +shows a normal thecal sac within the lumbar spinal canal. +The +thecal sac is bright. +The lumbar roots are dark punctuate dots +in the posterior thecal sac with the patient supine. +B. +The usefulness of therapeutic facet joint blocks for pain +has not been rigorously studied. +Patients are often males below age 40. +Onset at a +young age and back pain improving with exercise are +characteristic. +Cancer- +related back pain tends to be constant, dull, unrelieved +by rest, and worse at night. +By contrast, mechanical low +back pain usually improves with rest. +MRI, CT, and +CT-myelography are the studies of choice when spi- +nal metastasis is suspected. +A. +B. +Axial +T2-weighted image. +SECTION II +Clinical Manifestations of Neurologic Disease +80 diagnosis is crucial. +The management of spinal metasta- +sis is discussed in detail in Chap. +37. +The primary source of infection is usu- +ally the urinary tract, skin, or lungs. +Intravenous drug +use is a well-recognized risk factor. +Fever or an elevated white +blood cell count is found in a minority of patients. +The intervertebral disk can also +be affected by infection (diskitis), and very rarely by +tumor. +Spinal epidural abscess (Chap. +The abscess may track over multiple spinal +levels and is best delineated by spine MRI. +The MRI shows clumped nerve roots or loculations +of cerebrospinal fluid within the thecal sac. +Clumped +nerve roots may also occur with demyelinating poly- +neuropathy or neoplastic infiltration. +Treatment is usu- +ally unsatisfactory. +Dorsal column stimulation for pain relief has produced +varying results. +Up to two-thirds +of compression fractures seen on radiologic imaging are +asymptomatic. +The risk of an additional vertebral fracture +at 1 year following a first vertebral fracture is 20%. +If tumor is suspected, a bone biopsy or diagnostic search +for a primary tumor is indicated. +The role of NSAIDs is controversial. +Both pain and disability are improved with bracing. +Spinal cord or nerve root compression +can result from bony encroachment. +Occasionally, back pain + +CHAPTER 9 +Back and Neck Pain +81 may be the first and only manifestation. +Fatty foods occaionally induce +back pain associated with biliary disease. +The classic clinical triad of abdomi- +nal pain, shock, and back pain occurs in <20% of +patients. +The typical patient at risk is an elderly male +smoker with back pain. +Frequently, the diagnosis is +initially missed because the symptoms and signs can +be nonspecific. +Patients with suspected +AAA should be evaluated with abdominal ultrasound, +CT, or MRI. +The pain is referred to the sacral region. +Endo- +metriosis or uterine cancers may invade the uterosacral +ligaments. +Menstrual pain may be felt in the sacral region. +Poorly localized, cramping pain can radiate down the +legs. +Low back pain that radiates into +one or both thighs is common in the last weeks of +pregnancy. +Lesions +of the bladder and testes do not often produce back +pain. +Paraspinal lumbar +pain may be a symptom of ureteral obstruction due to +nephrolithiasis. +Exercises to strengthen the paraspinal and abdomi- +nal muscles are sometimes helpful. +IDIOPATHIC +The cause of low back pain occasionally remains +unclear. +Full recovery can be expected in 85% +of adults with ALBP without leg pain. +Risk factors for a +serious cause of ALBP are shown in Table 9-1. +Labora- +tory and imaging studies are unnecessary if risk factors +are absent. +The prognosis is generally excellent. +Many patients +do not seek medical care and apparently improve on +their own. +Edu- +cation is an important part of treatment. +Several randomized trials +suggest that bed rest does not accelerate the pace of +recovery. +Application of heat by heating pads +or heated blankets is sometimes helpful. +Limiting the use of muscle relaxants to nighttime +only may be an option for some patients. +In this setting, how- +ever, the benefit of opioid therapy or muscle relaxants is +less clear. +In general, activity tolerance is +the primary goal, while pain relief is secondary. +Trials of the latter suggest some benefit even for +patients without evidence of depression. +Trials do not +support the efficacy of selective serotonin reuptake +inhibitors for back pain. +Behav- +ioral treatments may have effects similar in magnitude +to exercise therapy. +Back pain is the most common reason for seeking +complementary and alternative treatments. +The most +common of these for back pain are spinal manipulation, +acupuncture, and massage. +Biofeedback has not +been studied rigorously. +Simi- +larly, there is little evidence to support the use of trigger +point injections. +A few small trials have +resulted in conflicting results for facet joint pain. +Each of these studies included patients with back pain +and a degenerative disk, but no sciatica. +Both U.S. +These are generally designed as metal plates with a +polyethylene cushion sandwiched in between. +This treat- +ment remains controversial for low back pain. +Systematic +reviews suggest that the evidence is limited and effects +are moderate. +Some observers have raised concern that chronic +back pain may often be overtreated. +On the other hand, exercise therapy +and treatment of depression appear to be underused. +Resumption of normal activity as much as possible +is usually the best activity recommendation. +The utility of diagnostic nerve root blocks +remains a subject of debate. +son for recommending spine surgery. +Some patients will want the fastest +possible relief and find surgical risks acceptable. +The usual surgical procedure is a partial hemilami- +nectomy with excision of the prolapsed disk. +The costs associated with +lumbar interbody fusion have increased dramatically in +recent years. +35). +The decision to obtain imag- +ing should be based upon the nature of the injury. +A CT scan is the diagnostic procedure +of choice for detection of acute fractures. +Up to 50% of persons reporting whip- +lash injury acutely have persistent neck pain 1 year later. +Severe initial symptoms have been associated +with a poor long-term outcome. +Neck +pain, stiffness, and a range of motion limited by pain +are the usual manifestations. +A herniated cervical disk +is responsible for ∼25% of cervical radiculopathies. +Cervical disk herniations are +usually posterolateral near the lateral recess. +The cervi- +cal nerve roots most commonly affected are C7 and C6. +9-6); this compres- +sion accounts for 75% of cervical radiculopathies. +The +roots most commonly affected are C7 and C6. +Combinations of radiculopathy and myelopathy +may be present. +32), multiple +sclerosis (Chap. +39), spinal cord tumors, or syringomy- +elia (Chap. +35). +EMG +and nerve conduction studies can localize and assess +the severity of the nerve root injury. +In advanced RA, synovitis of the atlantoaxial +joint (C1-C2; Fig. +Radio- +logic evidence of atlantoaxial subluxation occurs in 30% +of patients with RA. +Not surprisingly, the degree of +subluxation correlates with the severity of erosive dis- +ease. +Surgery should be considered when myelopa- +thy or spinal instability is present. +MRI is the imaging +modality of choice. +Pain is mild +or absent. +Treatment consists of surgical resec- +tion of the anomalous band. +Blood pressure is +reduced in the affected limb, and signs of emboli may be +present in the hand. +Neurologic signs are absent. +Ultra- +sound can confirm the diagnosis noninvasively. +Venous TOS +is due to subclavian vein thrombosis resulting in swell- +ing of the arm and pain. +The vein may be compressed by +a cervical rib or anomalous scalene muscle. +Venography +is the diagnostic test of choice. +The role of surgery in disputed TOS is controver- +sial. +The onset is +often preceded by an infection. +The long thoracic nerve +may be affected; the latter results in a winged scapula. +Recovery is generally good but may +take up to 3 years to be complete. +Lesions of the radial or ulnar nerve can mimic a radic- +ulopathy at C7 or C8, respectively. +For further discussion of peripheral nerve disorders, +see Chap. +45. +SHOULDER +Pain arising from the shoulder can on occasion mimic +pain from the spine. +Exercises often include +shoulder rolls and neck stretches. +Comparison to other conservative treatment +measures is needed. +Fusions can be performed with a vari- +ety of techniques. +The durability of disk prosthe- +ses is uncertain. +Available data do not strongly support +one surgical technique over another. +The onset is rapid, duration brief, and recovery spon- +taneous and complete. +The annual cost +for syncope-related hospitalization in the United States +is ∼$2 billion. +Syncope has a lifetime cumulative inci- +dence of up to 35% in the general population. +Neurally +mediated syncope is the etiology in the vast majority of +these cases. +In elderly adults, there is a sharp rise in the +incidence of syncope after 70 years. +In population-based studies, neurally mediated syn- +cope is the most common cause of syncope. +The inci- +dence is slightly higher in females than males. +In young +subjects there is often a family history in fi rst-degree +relatives. +The prognosis after a single syncopal event for all +age groups is generally benign. +10-1). +28). +10-2). +Blue denotes sympathetic neu- +rons and green parasympathetic neurons. +These include +diaphoresis, pallor, palpitations, nausea, hyperventila- +tion, and yawning. +The +eyes typically remain open and usually deviate upward. +Urinary but not fecal incontinence may occur. +Postictal +confusion is rare, although visual and auditory halluci- +nations are sometimes reported. +B. +The same tracing expanded to show 80 s of the +episode (from 80 to 200 s). +BP, blood pressure; bpm, beats +per minute; HR, heart rate. +syncope. +Randomized controlled trials support this inter- +vention. +In these +patients, dual-chamber pacing may be helpful. +10-3). +bHyperventilation (20 breaths) in a squatting position, rapid rise to standing, then Valsalva. +Visual blur- +ring may occur, likely due to retinal or occipital lobe +ischemia. +33). +33), Parkinson’s disease (Chap. +30), demen- +tia with Lewy bodies (Chap. +29), and pure auto- +nomic failure (Chap. +33). +B. +The same tracing expanded to +show 40 s of the episode (from 180 to 220 s). +BP, blood pres- +sure; bpm, beats per minute; HR, heart rate. +46 and +47). +The mechanism of postprandial syncope +is not fully elucidated. +Orthostatic hypotension is often iatrogenic. +Syncope due to bradycardia or +asystole is referred to as a Stokes-Adams attack. +Ventricular tachyarrhythmias frequently cause syn- +cope. +Next, nonphar- +macologic interventions should be introduced. +Intravascular volume should be expanded +by increasing dietary fluid and salt. +33). +SECTION II +Clinical Manifestations of Neurologic Disease +96 sudden death. +Structural disease may also contribute to other +pathophysiologic mechanisms of syncope. +TREATMENT Cardiac Syncope +Treatment of cardiac disease depends upon the under- +lying disorder. +These +disorders are best managed by physicians with special- +ized skills in this area. +Myoclonic jerks associated with syncope may +be multifocal or generalized. +They are typically arrhyth- +mic and of short duration (<30 s). +Mild flexor and exten- +sor posturing also may occur. +These phenomena should be differentiated from +the premonitory features of syncope. +Seizures, unlike syncope, are rarely pro- +voked by emotions or pain. +These symptoms are due to autonomic activation +to counter the falling blood glucose. +Hunger, in par- +ticular, is not a typical premonitory feature of syncope. +There are +no premonitory symptoms. +Cataplexy occurs in 60–75% +of patients with narcolepsy. +Such patients are rarely injured despite numerous +falls. +Autonomic Nervous System Testing (Chap. +33) Autonomic testing including tilt table testing can be +performed in specialized centers. +The hemodynamic +abnormalities demonstrated on tilt table test (Figs. +Currently, this test is rarely performed to evaluate +patients with syncope. +Mark F. +Walker ■ Robert B. +Faintness and syncope, which are +discussed in detail in Chap. +They may be paroxysmal or due to a fi xed unilateral or +bilateral vestibular defi cit. +Bilateral lesions cause imbal- +ance and instability of vision when the head moves +( oscillopsia ). +(2) +is it vestibular? +and (3) if vestibular, is it peripheral or +central? +Symmetric bilateral vestibular hypo- +function causes imbalance but no vertigo. +Causes of dizziness can be divided into episodes +that last for seconds, minutes, hours, or days. +Attacks of migrainous vertigo and +Ménière’s disease often last hours. +The range of eye movements and whether +they are equal in each eye should be observed. +If the VOR is deficient, a +catch-up saccade is seen at the end of the rotation. +bCombined vertical-torsional nystagmus suggests BPPV. +Dynamic visual acuity is a functional test that can +be useful in assessing vestibular function. +The choice of ancillary tests should be guided by the +history and examination findings. +Audiometry should +be performed whenever a vestibular disorder is sus- +pected. +Pre- +dominantly low-frequency hearing loss is characteristic +of Ménière’s disease. +TREATMENT Dizziness +Treatment of vestibular symptoms should be driven by +the underlying diagnosis. +The pattern of spontaneous nystagmus, if pres- +ent, may be helpful (Table 11-1). +If the head impulse test +is normal, an acute peripheral vestibular lesion is unlikely. +Benign paroxysmal positional vertigo +BPPV is a common cause of recurrent vertigo. +Superior +(also called anterior) canal involvement is rare. +For +posterior canal BPPV, the Epley maneuver is the most +commonly used procedure. +Unlike BPPV, the vertigo persists +even when the head is not moving. +Antiemetics may be helpful to +relieve symptoms at the time of an attack. +Diuretics and sodium restriction are the +initial treatments. +Full ablative procedures (vestibular nerve sec- +tion, labyrinthectomy) seldom are required. +The diagnosis often is not made until there is +sufficient hearing loss to be noticed. +In the laboratory, responses to caloric testing are +reduced. +Vestibular suppressant medications should not be used, +as they will increase the imbalance. +Psychosomatic dizziness +Psychological factors play an important role in chronic +dizziness. +Vestibular suppressant medications +generally should be avoided. +Food and Drug Adminis- +tration, but most are not approved for the treatment of vertigo. +cFor motion sickness only. +dFor benign paroxysmal positional vertigo. +eFor Ménière’s disease. +fFor vestibular migraine. +gFor acute vestibular neuritis (started within three days of onset). +hFor psychosomatic vertigo. +Michael J. +31 ) or abnormal movements ( Chap. +30 ). +The +mode of onset, distribution, and accompaniments of +weakness help suggest its cause. +Weakness is a reduction in the power that can be +exerted by one or more muscles. +18 ), sometimes is mis- +taken for weakness. +The suffi x +“-plegia” signifi es severe weakness or paralysis. +The distribution of weakness helps to indicate the +site of the underlying lesion. +Tone is the resistance of a muscle to passive stretch. +Spasticity is distinct from rigidity and paratonia, +two other types of hypertonia. +Rigidity occurs with +certain extrapyramidal disorders, such as Parkinson’s +disease. +1) and, in +particular, by an extensor plantar (Babinski) response. +47). +12-1). +These +lesions produce weakness through decreased activation +of the lower motor neurons. +Spasticity accompanies upper motor neuron weak- +ness but may not be present in the acute phase. +Upper +motor neuron lesions also affect the ability to perform +rapid repetitive movements. +Such movements are slow +and coarse, but normal rhythmicity is maintained. +Finger-nose-finger and heel-knee-shin maneuvers are +performed slowly but adequately. +12-2). +An absent +stretch reflex suggests involvement of spindle afferent +fibers. +Pyramidal neurons make direct monosynaptic +connections with lower motor neurons. +Cor- +ticobulbar neurons are similar to corticospinal neurons but +innervate brainstem motor nuclei. +The bulbospinal system +sometimes is referred to as the extrapyramidal upper motor +neuron system. +distribution and is influenced by preceding activity of the +affected muscle. +The presence of other +neurologic deficits helps localize the lesion. +Homon- +ymous visual field defects reflect either a cortical or a +subcortical hemispheric lesion. +27). +Evaluation (Fig. +12-3) +begins immediately with a CT scan of the brain and +laboratory studies. +Subacute hemiparesis that evolves over days or weeks +has an extensive differential diagnosis. +Loss of α +motor neurons or disruption of their axons produces lower +motor neuron weakness. +A tendon reflex requires the function of all the illustrated +structures. +CHAPTER 12 +Weakness and Paralysis +107 +over days to weeks. +AIDS may present with subacute +hemiparesis due to toxoplasmosis or primary CNS lym- +phoma. +35], and peripheral +neuropathies). +It is important to image the spinal +cord (Fig. +12-3). +35). +‡ If no abnormality detected, consider myelogram or brain MRI. +46), or myopathy (Chap. +48). +Subacute or chronic paraparesis with spasticity is caused +by upper motor neuron disease. +35). +If an +MRI of the spinal cord is normal, MRI of the brain +may be indicated. +The major causes of intermittent weakness are listed +in Table 12-2. +52). +Guillain-Barré +syndrome (Chap. +In obtunded patients, evaluation begins with a CT +scan of the brain. +An MRI is obtained of the clinically suspected site +of pathology. +Myopathic weakness rarely is limited to one limb. +27); diagnostic possibilities are similar to those +for acute hemiparesis. +Muscle disorders + a. +Channelopathies (periodic paralyses) + b. +Neuromuscular junction disorders + a. +Myasthenia gravis + b. +Lambert-Eaton myasthenic syndrome +4. +Central nervous system disorders + a. +Transient ischemic attacks of the brainstem + b. +Transient global cerebral ischemia + c. +Multiple sclerosis + +CHAPTER 12 +Weakness and Paralysis +109 reflects plexus involvement. +In either case, an electrodiagnostic study +is indicated. +45). +32). +Rarely, myopathies present with dis- +tal weakness (Chap. +48). +Electrodiagnostic studies help +localize the disorder (Fig. +12-3). +48). +Diseases +of the neuromuscular junction (such as myasthenia +gravis [Chap. +Numbness does not occur with any of these diseases. +48) or neuromuscular junction dis- +order (Chap. +47). +Bilateral facial palsy with areflexia +suggests Guillain-Barré syndrome (Chap. +46). +Asymmetric bulbar weakness usually is due to motor +neuron disease. +49). +Gait dis- +orders have been described in 15% of individuals older +than age 65 years. +By age 80 years, one person in four +will use a mechanical aid to assist ambulation. +Among +those 85 and older, the prevalence of gait abnormality +approaches 40%. +Each year, 8% of individ- +uals age >75 years suffer a serious fall-related injury. +Hip fractures often result in hospitalization and nursing +home admission. +Nearly +one in fi ve elderly individuals voluntarily limits activity +because of fear of falling. +These func- +tions are widely distributed in the central nervous sys- +tem. +Human patients with damage to +these structures have impaired balance with standing +and walking. +Boston, Little +Brown, 1995. +prone to falls and injury. +Frailty, muscle weakness, +and deconditioning also contribute to the risk. +There is a +growing literature on the use of attentional resources +to manage gait and balance. +Walking is vulnerable to neurologic +disease at every level. +One problem with this approach is that +many failing gaits look fundamentally similar. +Unique features of +the failing gait are often overwhelmed by the adaptive +response. +Some of the common patterns of abnormal gait +are summarized next. +Gait disorders can also be classified +by etiology, as listed in Table 13-1. +This disorder is +both common and nonspecific. +It is, in essence, an adap- +tation to a perceived postural threat. +There may be an +associated fear of falling. +The disorder reflects compro- +mise of corticospinal command and overactivity of spi- +nal reflexes. +The patient may walk on his or her toes. +In +extreme instances, the legs cross due to increased tone +in the adductors. +Upper motor neuron signs are present +on physical examination. +Shoes often reflect an uneven +pattern of wear across the outside. +The disorder may be +cerebral or spinal in origin. +Myelopathy from cervical spondylosis is a common +cause of spastic or spastic-ataxic gait. +Demyelinating dis- +ease and trauma are the leading causes of myelopathy in +younger patients. +A family history +should suggest hereditary spastic paraplegia (HSP; Chap. +32). +Genetic testing is now available for some of the +common HSP mutations. +Spinal cord disor- +ders are discussed in detail in Chap. +35. +Other stiff-legged gaits include dystonia (Chap. +48) +and stiff-person syndrome. +It +often has a genetic basis. +In autoimmune stiff-person syn- +drome (Chap. +30) is common, affecting +1% of the population age >55 years. +The stooped pos- +ture and shuffling gait are characteristic and distinctive +features. +Patients sometimes accelerate (festinate) with +walking or display retropulsion. +There may be difficulty +with gait initiation (freezing) and a tendency to turn +en bloc. +Imbalance and falls may develop as the disease +progresses over years. +Falls within the first year suggest the possibility of pro- +gressive supranuclear palsy. +In Hun- +tington’s disease (Chap. +29), the unpredictable occur- +rence of choreic movements gives the gait a dancing +quality. +The term lower +body parkinsonism is also used to describe such patients. +18). +Lesions are frequently found in the deep fron- +tal white matter and centrum ovale. +Communicating hydrocephalus in adults also pres- +ents with a gait disorder of this type. +A lumbar puncture or dynamic test is +necessary to confirm the presence of hydrocephalus. +Cerebellar gait ataxia +Disorders of the cerebellum have a dramatic impact on +gait and balance. +Difficulty main- +taining balance when turning is often an early feature. +They show considerable variation in their tendency to +fall in daily life. +30 and 33) +and various forms of hereditary cerebellar degenera- +tion (Chap. +31). +Alcoholic cer- +ebellar degeneration can be screened by history and +often confirmed by MRI. +In patients with ataxia, MRI +demonstrates the extent and topography of cerebellar +atrophy. +The sensory ataxia of tabetic +neurosyphilis is a classic example. +The contemporary +equivalent is the patient with neuropathy affecting +large fibers. +Joint position and vibration sense +are diminished in the lower limbs. +Table 13-2 compares sensory +ataxia with cerebellar ataxia and frontal gait disorder. +Neuropathy may be associated with a degree +of sensory imbalance, as described earlier. +Patients +with myopathy or muscular dystrophy more typically +exhibit proximal weakness. +Weakness of the hip gir- +dle may result in a degree of excess pelvic sway during +locomotion. +Chronic toxicity from medi- +cations and metabolic disturbances can impair motor +function and gait. +Mental status changes may be pres- +ent, and examination may reveal asterixis or myoclonus. +Static equilibrium is disturbed, and such patients are +easily thrown off balance. +These disorders are important +to recognize because they are often treatable. +Hysterical gait disorders are among +the most spectacular encountered. +Initial awareness +of an unsteady gait often follows a fall. +Stepwise evolu- +tion or sudden progression suggests vascular disease. +It is always important +to review the use of alcohol and medications that affect +gait and balance. +Gait observation provides an immediate sense of the +patient’s degree of disability. +Watching the patient +get out of a chair provides a good functional assess- +ment of balance. +Brain imaging studies may be informative in patients +with an undiagnosed disorder of gait. +Patients with recurrent falls are at risk for subdural +hematoma. +Imbalance implies a disturbance of equilibrium. +Neurologic examination +will reveal a variety of cerebellar signs. +Vestibular +disorders (Chap. +Not every patient +has all manifestations. +Laboratory testing is available to explore vestibulo-ocu- +lomotor and vestibulospinal deficits. +Somatosensory deficits also produce imbalance and +falls. +There is often a subjective sense of insecure bal- +ance and fear of falling. +44). +There may be reduced awareness of bal- +ance impairment. +Patients on sedating medications are +also in this category. +Some of these are frail older persons with chronic dis- +eases. +Recurrent falls sometimes indicate the presence +of serious balance impairment. +10 and 26). +Unlike gait problems that are apparent on observation, +falls are rarely observed in the office. +The patient and +family may have limited information about what trig- +gered the fall. +Injuries can complicate the physical +examination. +While there is no standard nosology of +falls, common patterns can be identified. +Boston, Little +Brown, 1995. +They occasionally occur in healthy indi- +viduals with good balance compensation. +Frequent trip- +ping falls raise suspicion about an underlying neurologic +deficit. +Patients with spasticity, leg weakness, or footdrop +experience tripping falls. +Deconditioning of this sort is often +treatable. +Patients who collapse from lack of pos- +tural tone present a diagnostic challenge. +Asterixis or epilepsy may impair postural sup- +port. +There may be a consistent direction to such +falls. +The patient with cerebellar pathology may lean +and topple over toward the side of the lesion. +Patients with progressive supranuclear palsy often fall +over backward. +This sequence of events can result +in a forward fall. +Gait freezing can also occur as the +patient attempts to turn and change direction. +These patients often express subjective +imbalance, apprehension, and fear of falling. +Deficits in +joint position and vibration sense are apparent on physi- +cal examination. +Standing blood +pressure should be recorded. +Specific treatment may +be possible, once a diagnosis is established. +A home visit to look for environmental haz- +ards can be helpful. +Sensory balance training is another approach +to improve balance stability. +Gail Kang ■ Nicholas B. +VIDEO LIBRARY OF GAIT DISORDERS + CHAPTER 14 + Michael J. +Aminoff ■ Arthur K. +Pain is considered sepa- +rately in Chap. +7 . +Such symptoms are often painful. +This thresh- +old varies in accordance with how rapidly function is +lost in sensory nerve fi bers. +5 ). +Paresthesias and +dysesthesias are general terms used to denote posi- +tive sensory symptoms. +Another set of terms refers to sensory abnormalities +found on examination. +Hyperesthesia means pain or increased +sensitivity in response to touch. +An example is elicitation of a painful sensation +by application of a vibrating tuning fork. +It is possible not only to record from but also +to stimulate single fibers in isolation. +15-1). +7). +This is the spinothalamic +pathway or anterolateral system. +Some general principles pertain. +Further, examination +may be limited in some patients. +Comparison of response +on one side of the body to that on the other is essential. +Discretion must be used in pur- +suing this possibility. +Evaluation of stance +and gait also tests the integrity of motor and cerebellar +systems. +Areas of hypal- +gesia should be mapped by proceeding radially from the +most hypalgesic site (Figs. +15-2, 15-3 and 15-4). +(From AH +Ropper, RH Brown, in Adams and Victor’s Principles of Neu- +rology, 9th ed. +This is impractical in most settings. +Great auricular n. +Ant. +cut. +n. +of neck +Ant. +cut. +rami +of + thor. +n’s. +T2 +3 +4 +5 +6 +7 +8 +9 +10 +11 +12 +Lat. +cut. +rami +Supraclavicular n’s. +Med. +cut. +n. +of arm + & intercostobrachial n. +Med. +cut. +n. +of forearm +Iliohypo- +gastric n. +Genital +branch of +genitofem. +n. +Dorsal n. +of penis +Scrotal branch of perineal n. +Obturator n. +Lat.cut. +n. +of calf +(from common peroneal n.) +Superficial peroneal n. +(from common peroneal n.) +Deep peroneal n. +(from common peroneal n.) +Intermed. +& med. +cut. +n’s. +of thigh (from femoral n.) +Lat. +cut. +n. +of thigh +Lat. +cut. +of forearm +(from musculocut. +n.) +Lower lat.cut. +n. +of arm +(from radial n.) +Axillary n. +(circumflex) +I +II +III +Ilio- +inguinal n. +Femoral +branch +of genito- +femoral n. +(lumbo-inguinal n.) +Saphenous n. +(from femoral n.) +Med. +& lat. +plantar n’s. +(from posttibial n.) +Sural n. +(from tibial n.) +Radial n. +Median n. +Ulnar n. +Great auricular n. +Greater +Lesser n.} occipital nerves +Ant. +cut. +n. +of neck +T2 +3 +4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 + 12 +T1 +L1 +S1 +Post. +rami of +lumbar sacral +& coccygeal n’s. +Lat. +cut. +rami +Post. +cut. +rami +of +thor. +n’s. +C5 +C6 Supraclavicular n’s. +Med. +cut. +n. +of arm + & intercostobrachial n. +Post. +cut. +n. +of forearm + (from radial n.) +Lat. +cut. +n. +of forearm + (from musculocut n.) Med. +cut. +n. +of + forearm +Obturator n. +Superficial peroneal n. +(from common peroneal n.) +Lat. +cut. +n.of calf +(from common femoral n.) +Inf. +med. +cluneal n. +Inf. +lat. +cluneal n’s. +Lat. +plantar n. +Saphenous n. +Sural n. +Calcanean branches +of tibial & sural n’s. +Med. +plantar n. +Lat. +plantar n. +Superficial +peroneal +n. +Inf. +med. +n. +of thigh +Post cut. +n. +of thigh +Lower +Lat. +cut. +of arm +(from radial n.) +Post cut. +n. +of arm +(from radial n.) +Axillary n. +(circumflex) +Iliohypo- +gastric n. +Saphenous n. +(from femoral n.) +Med. +cut. +n. +of thigh +(from femoral n.) +Calcanean branches of +sural & tibial n’s. +Sural n. +(from tibial n.) +Radial n. +Median n. +Ulnar n. +FIGURE 15-2 +The cutaneous fields of peripheral nerves. +(Reproduced by permission from W Haymaker, B Woodhall: Peripheral Nerve Inju- +ries, 2nd ed. +Touch usually is tested with a wisp of cotton or a +fine camel hair brush. +Normal individuals can do +this accurately, with errors of 1 cm or less. +The sense of vibration is tested with a tuning fork +that vibrates at 128 Hz. +If abnormal- +ities are found, more proximal sites can be examined. +(From D Sinclair: Mechanisms of +Cutaneous Sensation. +Oxford, UK, Oxford University Press, +1981; with permission from Dr. +Interside comparisons are important for all cor- +tical sensory testing. +The phenomenon +is referred to as extinction or neglect. +Once again, interside comparison is +of prime importance. +Inability to recognize numbers or +letters is termed agraphesthesia. +Common standard objects such as keys, paper +clips, and coins are best used. +Patients should be allowed to feel the object with only +one hand at a time. +If they are unable to identify it in +one hand, it should be placed in the other for compari- +son. +Their +extent, configuration, symmetry, quality, and severity +are the key observations. +Dysesthesias without sensory findings by examination +may be difficult to interpret. +Sometimes distal dyses- +thesias have no definable basis. +15-2, 15-3 and +15-4). +9). +45). +When dysesthesias reach the knees, they +usually also have appeared in the fingertips. +12). +Sensory dissociation may occur with +spinal cord lesions as well as small-fiber neuropathies. +Dysesthesias, if +present at all, tend to be tingling or bandlike in quality. +Pain and numbness +progress to sensory ataxia and impairment of all sensory +modalities with time. +This condition is usually paraneo- +plastic or idiopathic in origin (Chaps. +44 and 45). +Spinal cord +(See also Chap. +35) If the spinal cord is transected, all +sensation is lost below the level of transection. +Bladder +and bowel function also are lost, as is motor function. +15-1 and 35-1). +The presence of upper motor +neuron signs (Chap. +27-10). +The per- +sistent, unrelenting unilateral pain often is described in +dramatic terms. +Dysesthesias or a sense of numbness may +also occur and, rarely, a painful state. +S. +Andrew Josephson ■ Bruce L. +Delirium is a clinical diagnosis that can be made only +at the bedside. +However, the +long-term cognitive effects of delirium remain largely +unknown and understudied. +Some episodes of delirium +continue for weeks, months, or even years. +Even after an episode of +delirium resolves, there may be lingering effects of the +disorder. +The two most consistently identified risks are older +age and baseline cognitive dysfunction. +Whether age +and baseline cognitive dysfunction are truly indepen- +dent risk factors is uncertain. +Avoiding such risks remains a key compo- +nent of delirium prevention as well as treatment. +The relationship between delirium and demen- +tia (Chap. +Older patients in the ICU have especially high +rates of delirium that range from 70 to 87%. +PATHOGENESIS +The pathogenesis and anatomy of delirium are incom- +pletely understood. +Deficiency of acetylcholine often plays a key role in +delirium pathogenesis. +Other neurotransmitters are also likely to be +involved in this diffuse cerebral disorder. +For example, +increases in dopamine can also lead to delirium. +Not all individuals exposed to the same insult will +develop signs of delirium. +Unfortunately, these scales do not identify +the full spectrum of patients with delirium. +Baseline cogni- +tive impairment is common in patients with delirium. +The neurologic examination requires a careful assess- +ment of mental status. +In these cases, assessment only +during morning rounds may be falsely reassuring. +Attention can be assessed while +taking a history from the patient. +Common etiolo- +gies are listed in Table 16-1. +Prescribed, over-the-counter, and herbal medica- +tions are common precipitants of delirium. +In younger patients especially, illicit drugs and tox- +ins are common causes of delirium. +Systemic infections often cause delirium, especially +in the elderly. +Pneumonia, skin infections such as cellulitis, +and frank sepsis also can lead to delirium. +As a result, LP should be consid- +ered in any delirious patient with a negative workup. +These treatments often lead to prompt reso- +lution of delirium. +At night, a quiet, dark environment with +limited interruptions by staff can assure proper rest. +ACKNOWLEDGMENT +In the 16th edition of Harrison’s Principles of Internal Medi- +cine, Allan H. +Allan H. +Ropper +132 + Coma is among the most common and striking prob- +lems in general medicine. +Coma demands immediate +attention and requires an organized approach. +Drowsiness +and stupor are usually accompanied by some degree of +confusion ( Chap. +16 ). +In the vegeta- +tive state, the eyelids may open, giving the appearance +of wakefulness. +Respiratory and autonomic functions +are retained. +28 ). +It is also usually +the result of damage to the frontal lobes and its connec- +tions ( Chap. +18 ). +The special problem of coma in brain death is discussed +later in this chapter. +The pupils are normally reactive. +Such individuals have +written entire treatises using Morse code. +46), critical illness neuropathy (Chap. +28), and +pharmacologic neuromuscular blockade. +17-1). +17-1A). +( A) Uncal; (B) central; (C) +transfalcial; (D) foraminal. +17-2). +The distor- +tions may also entrap portions of the ventricular system, +resulting in hydrocephalus. +17-1B). +Miotic pupils and drowsi- +ness are the heralding signs. +The result is a sequence of neurologic signs +that corresponds to each affected level. +17-1D), which causes compression of the medulla, +respiratory arrest, and death. +This +lateral shift may be quantified on axial images of CT +and MRI scans (Fig. +17-2). +Thus, in metabolic enceph- +alopathies, clouded consciousness and coma are in a +continuum. +Simultaneous hypoxia and ischemia exhaust glucose +more rapidly. +Apart from hyperammonemia, +which of these mechanisms is of critical importance is +not clear. +The mechanism of the encephalopathy of +renal failure is also not known. +In hyperosmolar coma, the serum osmolarity +is generally >350 mosmol/L. +Many +drugs and toxins are capable of depressing nervous sys- +tem function. +The +approach to the patient with coma from cranial trauma +is discussed in Chap. +36. +Hypothermia itself causes +coma only when the temperature is <31°C (87.8°F). +Aberrant respiratory patterns that reflect brainstem +disorders are discussed later. +Lack of restless movements on one side or +an outturned leg suggests a hemiplegia. +43). +The results of testing may vary from minute to +minute, and serial examinations are most useful. +17-3). +Enlargement of the +pupil contralateral to a hemispheral mass may occur +but is infrequent. +Horizontal divergence of +the eyes at rest is normal in drowsiness. +As coma deep- +ens, the ocular axes may become parallel again. +Spontaneous eye movements in coma often take +the form of conjugate horizontal roving. +17-3). +The corneal (and pharyngeal) +response may be lost for a time on the side of an acute +hemiplegia. +Respiratory Patterns These are of less localiz- +ing value in comparison to other brainstem signs. +Shal- +low, slow, but regular breathing suggests metabolic or +drug depression. +Tachy- +pnea occurs with lymphoma of the CNS. +A number of other cyclic +breathing variations have been described but are of +lesser significance. +calcium, osmolarity, and renal (blood urea nitrogen) +and hepatic (NH3) function. +Nevertheless, if +the source of coma remains unknown, a scan should be +obtained. +The EEG (Chap. +The amount of background slowing of the +EEG is a reflection of the severity of an encephalopa- +thy. +Arterial blood gas analysis is helpful in patients +with lung disease and acid-base disorders. +6). +When cerebrovascular disease is the cause of coma, +diagnosis can be difficult (Chap. +27). +The majority of medical causes of +coma can be established without a neuroimaging study. +TABLE 17-1 +DIFFERENTIAL DIAGNOSIS OF COMA +1. +Intoxications: alcohol, sedative drugs, opiates, etc. +b. +Shock from any cause + e. +Postseizure states, status epilepticus, subclinical +epilepsy + f. +Hypertensive encephalopathy, eclampsia + g. +Severe hyperthermia, hypothermia + h. +Concussion + i. +Acute hydrocephalus +2. +Subarachnoid hemorrhage from ruptured aneurysm, +arteriovenous malformation, trauma +b. +Acute bacterial meningitis +c. +Viral encephalitis +d. +Miscellaneous: fat embolism, cholesterol embolism, +carcinomatous and lymphomatous meningitis, etc. +3. +Brainstem infarction due to basilar artery +thrombosis or embolism +c. +Brain abscess, subdural empyema +d. +Epidural and subdural hemorrhage, brain contusion +e. +Brain tumor with surrounding edema +f. +Cerebellar and pontine hemorrhage and infarction +g. +Widespread traumatic brain injury +h. +Metabolic coma (see earlier) with preexisting focal +damage +i. +Abbreviations: CSF, cerebrospinal fluid; RBCs, red blood cells; +WBCs, white blood cells. +It is the only type +of brain damage recognized as equivalent to death. +The heart rate is +invariant and unresponsive to atropine. +The +pupils are usually midsized but may be enlarged; they +should not, however, be small. +Loss of deep tendon +reflexes is not required because the spinal cord remains +functional. +Babinski signs are generally absent and the +toe response is often flexor. +co2 ten- +sion increases ∼0.3–0.4 kPa/min (2–3 mmHg/min) +during apnea. +The test is usually stopped if there is serious cardiovas- +cular instability. +An isoelectric EEG may be used as a confirmatory test +for total cerebral damage. +Fever and meningismus +indicate an urgent need for examination of the CSF to +diagnose meningitis. +The manage- +ment of raised ICP is discussed in Chap. +28. +The +uniformly poor outcome of the persistent vegetative +state has already been mentioned. +Metabolic comas have a far better prognosis +than traumatic ones. +28-4). +In one case, a rudimen- +tary form of one-way communication could be estab- +lished. +It is prudent to avoid generalizations from these +experiments. +The primary sensory and motor areas constitute 10% of +the cerebral cortex. +18-1 ). +Dysarthria and mutism do not +by themselves lead to a diagnosis of aphasia. +A deficit of nam- +ing (anomia) is the single most common finding in apha- +sic patients. +This is known as a one-way (or retrieval- +based) naming deficit. +FIGURE 18-1 +Lateral (top) and medial (bottom) views of the cerebral +hemispheres. +The numbers refer to the Brodmann cyto- +architectonic designations. +The rest of the cerebral cortex contains asso- +ciation areas. +Reading should be assessed for defi- +cits in reading aloud as well as comprehension. +Writing +is assessed for spelling errors, word order, and gram- +mar. +The syndromes outlined next +are idealizations; pure syndromes occur rarely. +Language +output is fluent but is highly paraphasic and circumlo- +cutious. +The output is +therefore voluminous but uninformative. +And with +it when that was downstairs was my teeth-tick…a… +den…dentith…my dentist. +And they happened to be +in that bag…see? +How could this have happened? +Where my two…two little pieces +of dentist that I use…that I…all gone. +This aphasia therefore has expressive as well +as receptive components. +Repetition, naming, reading, +and writing also are impaired. +Intracerebral hemorrhage, severe head +trauma, and neoplasm are other causes. +In most other patients, prognosis for recovery of +language function is guarded. +It is impov- +erished in function words but enriched in meaning- +appropriate nouns and verbs. +Speech is +telegraphic and pithy but quite informative. +Go to hospital. +Dotor…kept me beside. +In +addition to fluency, naming and repetition are impaired. +Patients +with Broca’s aphasia can be tearful, easily frustrated, and +profoundly depressed. +Insight into their condition is pre- +served, in contrast to Wernicke’s aphasia. +Visual fields are intact. +Mass +lesions, including tumor, intracerebral hemorrhage, and +abscess, also may be responsible. +Naming, repetition, +reading, and writing also are impaired. +Naming and writing also are impaired. +Reading aloud is impaired, but reading comprehension +is preserved. +Associated neurologic signs +in conduction aphasia vary according to the primary +lesion site. +The neurologic examination may be other- +wise intact, but a right hemiparesis also can exist. +Associated neu- +rologic findings may include hemianopia. +Isolation aphasia +This rare syndrome represents a combination of the +two transcortical aphasias. +Comprehension is severely +impaired, and there is no purposeful speech output. +Language output is fluent but parapha- +sic, circumlocutious, and uninformative. +Fluency may +be interrupted by word-finding hesitations. +Patients cannot repeat spo- +ken language but have no difficulty naming objects. +Cerebrovascular lesions are the most common cause. +Pure alexia without agraphia +This is the visual equivalent of pure word deafness. +There is usu- +ally a right hemianopia, but the core language network +remains unaffected. +This is known +as a color anomia. +Recovery is the rule and involves an intermediate stage +of hoarse whispering. +Writing, reading, and comprehen- +sion are intact, and so this is not a true aphasic syndrome. +The form that is encountered most frequently +in clinical practice is known as ideomotor apraxia. +Buccofa- +cial apraxia involves apraxic deficits in movements of +the face and mouth. +Limb apraxia encompasses apraxic +deficits in movements of the arms and legs. +Its presence cannot be ascertained in patients +with language comprehension deficits. +This aspect of language is known as prosody. +These are the “classic” aphasias +described earlier in this chapter. +Language in PPA +The language impairment in PPA varies from patient +to patient. +Distinct forms of agramma- +tism and/or word comprehension deficits also can arise. +The agrammatism consists of inappropriate word order +and misuse of small grammatical words. +However, dysarthria is usually +absent. +Alzheimer’s pathology is seen most fre- +quently in the logopenic variant. +The clinical subtyping +of PPA thus may help predict the nature of the underly- +ing neuropathology. +18-2). +Subcortical com- +ponents of this network include the striatum and the +thalamus. +The red +and black areas show regions of task-related significant +activation. +(Top) The subjects were asked to determine if +two words were synonymous. +The activations are exclusively in the left hemisphere. +(Bot- +tom) The subjects were asked to shift spatial attention to a +peripheral target. +The activations are predominantly in the +right hemisphere. +18-3A). +Movement and distracting +stimuli greatly exacerbate the difficulties of visual per- +ception. +Simultanagnosia sometimes can occur without +the other two components of Bálint’s syndrome. +2.5 cm [3 to 4 in. +vs. +1 in.] +in height), and all targets are embedded among foils. +18-3B). +Depending on the site of the lesion, a patient +A +FIGURE 18-3 +A. +Only targets +on the right are circled. +This is +a manifestation of left hemis- +patial neglect. +B. +This is a manifestation of simul- +tanagnosia. +It is important to distinguish visual object agno- +sia from anomia. +A patient with anomia cannot name +the object but can describe its use. +Rarely, the responsible lesion +is unilateral. +A disturbance in this function is known as an +amnestic state. +Memories are stored in widely +distributed form throughout the cerebral cortex. +This is known as confabula- +tion. +Adequate recall at the end +of this interval requires offline storage, retention, and +retrieval. +The assessment of memory can be quite challenging. +Bedside evaluations may detect only the most severe +impairments. +Tem- +poral disorientation and poor recall of recent conver- +sations are early manifestations. +Transient global amnesia is a distinctive syndrome usually +seen in late middle age. +Recurrences are noted in approximately +20% of patients. +These syndromes tend to arise almost exclusively after +bilateral lesions. +In these +patients, the anterior temporal lobe and caudate nucleus +are also atrophic. +Appropri- +ate intervention may be delayed while a treatable tumor +keeps expanding. +Reactive depression is common in patients with +higher cerebral dysfunction and should be treated. +In many cases, agitation may be controlled with reas- +surance. +Spontaneous improvement of cognitive deficits due +to acute neurologic lesions is common. +The mechanisms for this recovery are incom- +pletely understood. +Prognosis for recovery from aphasia is best +when Wernicke’s area is spared. +Cognitive rehabilita- +tion procedures have been used in the treatment of +higher cortical deficits. +Some types +of deficits may be more prone to recovery than others. +This is true only at the terminal +stages. +There are other dementias in which memory is intact. +Maria Luisa Gorno-Tempini ■ Jennifer Ogar ■ Joel Kramer +■ Bruce L. +Czeisler ■ John W. +Winkelman ■ Gary S. +For most, it is an occasional +night of poor sleep or daytime sleepiness. +In addition, such problems may +contribute to or exacerbate medical or psychiatric con- +ditions. +Since then, a distinct class of sleep and +arousal disorders has been identifi ed. +At the extremes, infants and the elderly +have frequent interruptions of sleep. +The EOG shows bursts of REM similar to +those seen during eyes-open wakefulness. +20-1 ) . +After +sleep onset, sleep usually progresses through NREM +stages N1–N3 sleep within 45–60 min. +The percentage of +slow-wave sleep is infl uenced by several factors, most +notably age (see later). +The fi rst REM sleep episode usually occurs in +the second hour of sleep. +Overall, REM sleep constitutes 20–25% of total sleep, +and NREM stages N1 and N2 are 50–60%. +Age has a profound impact on sleep state organi- +zation (Fig. +20-1). +A different age profile exists for REM sleep than for +slow-wave sleep. +Specific regions in the pons are associated with the +neurophysiologic correlates of REM sleep. +These +experimental manipulations are mimicked by patho- +logic conditions in humans and animals. +20-2). +? +(Copyright +Charles J. +Awakenings from REM sleep are associated with +recall of vivid dream imagery >80% of the time. +The +reliability of dream recall increases with REM sleep epi- +sodes occurring later in the night. +Cardiac dysrhyth- +mias may occur selectively during REM sleep. +Respi- +ratory function also changes. +Endocrine function also varies with sleep. +A careful history is essential. +Similarly, the duration of +the symptom influences diagnostic and therapeutic con- +siderations. +Short-term insomnia lasts from a few days to 3 +weeks. +Clocks can heighten the anxiety about +the time it has taken to fall asleep. +Consistent, regular bedtimes +and rising times should be maintained daily, including +weekends. +A variety of sedative +compounds are used for this purpose. +Alcohol and anti- +histamines are the most commonly used nonprescrip- +tion sleep aids. +The broad range of half-lives allows flexibility in +the duration of sedative action. +The risk of priapism is small (~1 in +10,000). +Behavioral therapies are the treatment modality of +choice, with intermittent use of medications. +Time in bed can then be +gradually expanded. +Recovery is generally +rapid, usually within a few weeks. +Both hypoxia +and hypocapnia are thought to be involved in the +development of periodic breathing. +54). +Depressed patients +also show decreased slow-wave sleep and reduced sleep +continuity. +In mania and hypomania, sleep latency is increased +and total sleep time can be reduced. +This is associated with impaired daytime alert- +ness. +Epilepsy may rarely present as a sleep complaint +(Chap. +26). +Often the history is of abnormal behavior, +at times with convulsive movements during sleep. +Diagnosis requires +nocturnal polysomnography with a full EEG montage. +30), +are also associated with disrupted sleep, presumably +through secondary mechanisms. +However, the abnor- +mal movements themselves are greatly reduced during +sleep. +Headache syndromes (migraine or cluster headache) +may show sleep-associated exacerbations (Chap. +8) by +unknown mechanisms. +Insomnia is a prominent early +symptom. +The pathogenesis is a mutation in the prion gene +(Chap. +43). +Treat- +ment of the underlying medical problem is the most +useful approach. +Sleep disruption can also result from +the use of medications such as glucocorticoids (see +later). +One prominent association is between sleep disrup- +tion and asthma. +Cardiac ischemia may also be associated with sleep dis- +ruption. +The ischemia itself may result from increases in +sympathetic tone as a result of sleep apnea. +Caffeine is perhaps the most com- +mon pharmacologic cause of insomnia. +Withdrawal leads to an REM +sleep rebound. +A number of prescribed medications can +produce insomnia. +Antidepressants, sympathomimet- +ics, and glucocorticoids are common causes. +The symptoms appear +with inactivity and are temporarily relieved by move- +ment. +In contrast, paresthesias secondary to peripheral +neuropathy persist with activity. +The +prevalence is 1–5% of young to middle-age adults and +10–20% of those aged >60 years. +Iron +deficiency and renal failure may cause RLS, which is +then considered secondary RLS. +Opioids, +benzodiazepines, and gabapentin may also be of thera- +peutic value. +20-3). +It is often unclear whether it is an incidental finding +or the cause of disturbed sleep. +When deemed to be +the latter, PLMS is called PLMD. +Treat- +ment options include dopaminergic medications or +benzodiazepines. +First, patients may be +unaware of the extent of sleep deprivation. +Second, subjective descriptions of wak- +ing impairment vary from patient to patient. +Driving is particularly hazardous for patients with +increased sleepiness. +Reaction time is equally impaired +by 24 h of sleep loss as by a blood alcohol level of +0.10 g/dL. +More than half of Americans admit to having +fallen asleep while driving. +Each of +those steps should be documented in the patient’s medi- +cal record. +RAT, right anterior tibialis; LAT, left anterior +tibialis. +52), or +endocrine deficiencies such as hypothyroidism or Addi- +son’s disease. +Some patients with +objectively confirmed narcolepsy (see later) may show +no evidence of cataplexy. +Once established, +the disease is chronic without remissions. +Secondary +forms of narcolepsy have been described (e.g., after +head trauma). +The +inheritance pattern of narcolepsy in humans is more +complex than in the canine model. +Diagnosis +The diagnostic criteria continue to be a matter of +debate. +The +REM-related symptoms of the classic narcolepsy tetrad +are variably present. +Chicago, Matrix Communications, 1989. +However, a history +of cataplexy can be difficult to establish reliably. +Nocturnal sleep disruption is commonly observed in +narcolepsy but is also a nonspecific symptom. +TREATMENT Narcolepsy +The treatment of narcolepsy is symptomatic. +Somno- +lence is treated with wake-promoting therapeutics. +20-3). +This is unfortunate since effective treatments are +available. +Episodes +are usually isolated but may be recurrent in 1–6% of +patients. +The cause is unknown, though it has a familial +basis in roughly one-third of cases. +Both sleep terrors and sleepwalking +represent abnormalities of arousal. +The +patient is usually unaware of the problem. +The typical +age of onset is 17–20 years, and spontaneous remission +usually occurs by age 40. +Sex distribution appears to be +equal. +There are anecdotal reports of ben- +efit using benzodiazepines. +Approxi- +mately one-half of patients with RBD will develop +Parkinson’s disease (Chap. +30) within 10–20 years. +Gastrointestinal discomfort is common. +Many more begin work between 4 A.M. +Sleep disturbance nearly doubles the risk +of a fatal work accident. +TREATMENT Shift-Work Disorder +Caffeine is frequently used to promote wakefulness. +Properly timed exposure to bright light can facilitate +rapid adaptation to night-shift work. +Modafinil +(200 mg, taken 30–60 min before the start of each night +shift) is approved by the U.S. +The goal should be to minimize +both sleep deprivation and circadian disruption. +Patients tend to be young +adults. +Typically, patients awaken from +3 to 5 A.M. +each day, often several hours before their +desired wake times. +20-2) that +altered the circadian period. +The inter- +vals between symptomatic periods may last several +weeks to several months. +Blood pressure of +night workers with sleep apnea is higher than that of +day workers. +In addition, both the toxicity and effective- +ness of drugs can vary during the day. +Anes- +thetic agents are particularly sensitive to time-of-day +effects. +Jonathan C. +Light is absorbed +by photopigment in two types of receptors: rods and +cones. +In the human retina there are 100 million rods +and 5 million cones. +The rods operate in dim (scoto- +pic) illumination. +The cones function under daylight +(photopic) conditions. +The cone system is specialized +for color perception and high spatial resolution. +There are a million ganglion +cells in each retina and hence a million fi bers in each +optic nerve. +The majority of fi bers synapse on cells in the +lateral geniculate body, a thalamic relay station. +Cells +in the lateral geniculate body project in turn to the +primary visual cortex. +Pupil responses are medi- +ated by input to the pretectal olivary nuclei in the +midbrain. +Circadian rhythms +are timed by a retinal projection to the suprachiasmatic +nucleus. +Visual orientation and eye movements are +served by retinal input to the superior colliculus. +This activity, called foveation , or looking, is +governed by an elaborate efferent motor system. +In emmetropia, parallel rays from infinity are focused per- +fectly on the retina. +Sadly, this condition is enjoyed by +only a minority of the population. +In myopia, the globe +is too long, and light rays come to a focal point in front +of the retina. +To +compensate for presbyopia, an emmetropic patient must +use reading glasses. +A patient already wearing glasses +for distance correction usually switches to bifocals. +Testing vision through a +pinhole aperture is a useful way to screen quickly for +refractive error. +VISUAL ACUITY +The Snellen chart is used to test acuity at a distance of +6 m (20 ft). +21-1). +If 6/6 (20/20) +acuity is not present in each eye, the deficiency in vision +must be explained. +Patients with a homonymous hemi- +anopia should not drive. +However, it is +important to test the near response if the light response +is poor or absent. +An eye with no light perception has no pupillary +response to direct light stimulation. +21-2). +Subtle inequality in pupil size, up to 0.5 mm, is a +fairly common finding in normal persons. +Anisocoria that increases in dim light +indicates a sympathetic paresis of the iris dilator muscle. +Anisocoria that increases in bright light suggests a +parasympathetic palsy. +The first concern is an oculo- +motor nerve paresis. +Acute pupillary dilation (mydriasis) can result +from damage to the ciliary ganglion in the orbit. +The diagnosis is confirmed by placing a drop of dilute +(0.125%) pilocarpine into each eye. +In this situation, normal strength (1%) pilo- +carpine causes no constriction. +A. +With dim background lighting, the pupils +are equal and relatively large. +B. +Shining a flashlight into the +right eye evokes equal, strong constriction of both pupils. +C. +(From P Levatin: Arch Oph- +thalmol 62:768, 1959. +Copyright © 1959 American Medical +Association. +They are small with narcotic use (morphine, +heroin) and large with anticholinergics (scopolamine). +Parasympathetic agents (pilocarpine, demecarium bro- +mide) used to treat glaucoma produce miosis. +The eyes +should move rapidly and accurately in a single jump to +their target. +If the eyes are straight, the corneal light reflex will be +centered in the middle of each pupil. +To test eye align- +ment more precisely, the cover test is useful. +The patient +is instructed to gaze upon a small fixation target in the +distance. +One eye is covered suddenly while the second +eye is observed. +If the second eye shifts to fixate on the +target, it was misaligned. +If it does not move, the first eye +is uncovered and the test is repeated on the second eye. +If neither eye moves, the eyes are aligned orthotropically. +The most popular office tests measure a +range of thresholds from 800–40 s of arc. +Normal ste- +reoacuity is 40 s of arc. +Mutations of the blue cone pigment are +exceedingly rare. +Ishihara color plates can be used to +detect red-green color blindness. +Because color blindness is almost exclusively X-linked, +it is worth screening only male children. +Acquired +defects in color vision frequently result from disease +of the macula or optic nerve. +Infarcts of the domi- +nant occipital lobe sometimes give rise to color anomia. +Affected patients can discriminate colors but cannot +name them. +21-3). +21-3A). +Retinal lesions produce scotomas +that correspond optically to their location in the fundus. +For example, a superior-nasal retinal detachment results +in an inferior-temporal field cut. +Damage to the macula +causes a central scotoma (Fig. +21-3B). +Optic nerve disease produces characteristic patterns +of visual field loss. +21-3C). +This type of field +defect mirrors the arrangement of the nerve fiber layer +in the temporal retina. +It plots the retinal sensitivity to light in the central +30° by using a gray scale format. +Areas of visual field loss +are shown in black. +The examples of common monocular, +prechiasmal field defects are all shown for the right eye. +21-3D). +About half the fibers in the optic nerve originate +from ganglion cells serving the macula. +21-3E). +Pallor of the nasal rim of the optic +disc is a less equivocal sign of optic atrophy. +At the optic chiasm, fibers from nasal ganglion cells +decussate into the contralateral optic tract. +Crossed +fibers are damaged more by compression than are +uncrossed fibers. +As a result, mass lesions of the sel- +lar region cause a temporal hemianopia in each eye. +21-3G). +More symmetric compression of the optic chi- +asm by a pituitary adenoma (Fig. +21-3H). +21-3I). +21-3K). +Lesions of the primary visual cortex give rise to +dense, congruous hemianopic field defects. +21-3L). +Destruction of both occipital lobes produces corti- +cal blindness. +A penlight with a blue filter will suf- +fice if a slit lamp is not available. +It is important to check for foreign bodies. +The +eye should be reexamined the next day. +Minor abrasions +may not require patching and cycloplegia. +Occa- +sionally it is a clue to an underlying bleeding disorder. +Pinguecula +Pinguecula is a small, raised conjunctival nodule at +the temporal or nasal limbus. +Blepharitis +This refers to inflammation of the eyelids. +The most +common form occurs in association with acne rosa- +cea or seborrheic dermatitis. +The eyelid margins usu- +ally are colonized heavily by staphylococci. +It can +be incised and drained or injected with glucocorticoids. +Gentle pressure over the lacrimal sac evokes +pain and reflux of mucus or pus from the tear puncta. +Dacryocystitis usually occurs after obstruction of the +lacrimal system. +Conjunctivitis +Conjunctivitis is the most common cause of a red, irri- +tated eye. +Pain is minimal, and visual acuity is reduced +only slightly. +The most common viral etiology is ade- +novirus infection. +It causes a watery discharge, a mild +foreign-body sensation, and photophobia. +Bacterial +infection tends to produce a more mucopurulent exu- +date. +Itching, redness, and +epiphora are typical. +Atopic conjunctivitis occurs in sub- +jects with atopic dermatitis or asthma. +Patients may develop dry eye after radiation +therapy if the treatment field includes the orbits. +Prob- +lems with ocular drying are also common after lesions +affecting cranial nerve V or VII. +Dry eye is managed by frequent +and liberal application of artificial tears and ocular lubri- +cants. +In severe cases the tear puncta can be plugged or +cauterized to reduce lacrimal outflow. +In the United States, +contact lenses play a major role in corneal infection and +ulceration. +They should not be worn by anyone with +an active eye infection. +The latter is accompanied by greater visual loss, +pain, photophobia, redness, and discharge. +In severe cases, pus settles at the bottom of the anterior +chamber, giving rise to a hypopyon. +A fungal etiology should always be considered +in a patient with keratitis. +Herpes simplex +The herpesviruses are a major cause of blindness from +keratitis. +Primary ocular infection generally is caused +by herpes simplex type 1 rather than type 2. +Recurrent ocular infection arises +from reactivation of the latent herpesvirus. +Viral erup- +tion in the corneal epithelium may result in the char- +acteristic herpes dendrite. +Involvement of the corneal +stroma produces edema, vascularization, and iridocy- +clitis. +Herpes keratitis is treated with topical antiviral +agents, cycloplegics, and oral acyclovir. +Topical gluco- +corticoids also carry the risk of prolonging infection and +inducing glaucoma. +Herpes zoster ophthalmicus is +treated with antiviral agents and cycloplegics. +Episcleritis resembles conjunctivitis, but it is a +more localized process and discharge is absent. +The inflam- +mation and thickening of the sclera can be diffuse or +nodular. +Episcleritis and scleritis should be treated with +NSAIDs. +Dilatation +of the pupil reduces pain and prevents the formation of +synechiae. +It is more likely than anterior uveitis to be associated +with an identifiable systemic disease. +21-4). +It usu- +ally is acquired by hematogenous seeding from a remote +site. +Although +most patients have ocular pain and injection, visual loss +is sometimes the only symptom. +27). +Note that the veins are +frosted with a white exudate. +Visual acuity improved from +20/400 to 20/20 after treatment with intravenous methylpred- +nisolone. +CHAPTER 21 +Disorders of Vision +183 +an embolus that becomes stuck within a retinal arte- +riole (Fig. +21-5). +With prolonged interrup- +tion of blood flow, the inner retina suffers infarction. +21-6). +Emboli are composed +of cholesterol (Hollenhorst plaque), calcium, or platelet- +fibrin debris. +21-7). +In addition, acute hypertension may pro- +duce visual loss from ischemic swelling of the optic disc. +Patients with acute hypertensive retinopathy should be +treated by lowering the blood pressure. +The +veins appear engorged and phlebitic, with numer- +ous retinal hemorrhages (Fig. +21-8). +The optic disc appears swollen and surrounded +by nerve fiber layer splinter hemorrhages (Fig. +21-9). +AION is divided into two forms: arteritic and nonar- +teritic. +The nonarteritic form is most common. +No +specific cause can be identified, although diabetes and +hypertension are common risk factors. +No treatment is +available. +Glucocorticoids should be started immediately, without +waiting for the biopsy to be completed. +Vision can be salvaged in +some patients by prompt blood transfusion and reversal +of hypotension. +Optic neuritis +This is a common inflammatory disease of the optic +nerve. +21-10), although optic disc pallor slowly +developed over subsequent months. +For some patients, optic neuritis remains an isolated +event. +CHAPTER 21 +Disorders of Vision +185 +multiple sclerosis after optic neuritis is 50%. +In summary, an MR scan is recommended in every +patient with a first attack of optic neuritis. +Eventually +optic atrophy ensues. +In toxic optic +neuropathy, visual loss also can develop gradually and +produce optic atrophy (Fig. +21-11) without a phase of +acute optic disc edema. +Papilledema +This connotes bilateral optic disc swelling from raised +intracranial pressure (Fig. +21-12). +Headache is a com- +mon but not invariable accompaniment. +Transient visual obscurations +are a classic symptom of papilledema. +They can occur +in only one eye or simultaneously in both eyes. +They +usually last seconds but can persist longer. +Obscurations +follow abrupt shifts in posture or happen spontaneously. +When obscurations are prolonged or spontaneous, the +papilledema is more threatening. +SECTION II +Clinical Manifestations of Neurologic Disease +186 +hemorrhage. +Visual field testing shows enlarged blind +spots and peripheral constriction (Fig. +21-3F). +Evaluation of papilledema requires neuroimaging to +exclude an intracranial lesion. +The majority of patients are young, +female, and obese. +Weight +reduction is vital but often unsuccessful. +Occasionally, emergency surgery is required for sud- +den blindness caused by fulminant papilledema. +Optic disc drusen +These are refractile deposits within the substance of the +optic nerve head (Fig. +21-13). +They are unrelated to +drusen of the retina, which occur in age-related macu- +lar degeneration. +Optic disc drusen are most common in +people of northern European descent. +However, in many patients they +are hidden beneath the surface, producing pseudopapill- +edema. +It is important to recognize optic disc drusen to +avoid an unnecessary evaluation for papilledema. +No +treatment is available. +Opacities develop in the vitre- +ous, casting annoying shadows on the retina. +This process, known as vitreous +detachment, is a common involutional event in the elderly. +It is not harmful unless it damages the retina. +If such a lesion is found, laser +application can forestall a retinal detachment. +FIGURE 21-13 +Optic disc drusen are calcified deposits of unknown etiol- +ogy within the optic disc. +They sometimes are confused with +papilledema. +CHAPTER 21 +Disorders of Vision +187 haze of blood. +Ultrasound is required to examine the +interior of the eye for a retinal tear or detachment. +If the +hemorrhage does not resolve spontaneously, the vitre- +ous can be removed surgically. +21-14). +The diagnosis is confirmed by oph- +thalmoscopic examination of the dilated eye. +Classic migraine +(See also Chap. +8) This usually occurs with a visual aura +lasting about 20 min. +Migraine phenomena also remain visible in the dark +or with the eyes closed. +Patients often +have a long history of stereotypic attacks. +After the visual +symptoms recede, headache develops in most patients. +Factitious (functional, nonorganic) visual loss +This is claimed by hysterics or malingerers. +CHRONIC VISUAL LOSS +Cataract +Cataract is a clouding of the lens sufficient to reduce +vision. +Radiation therapy and glucocorticoid +treatment can induce cataract as a side effect. +The only treatment for cataract is surgical extraction +of the opacified lens. +Over a million cataract opera- +tions are performed each year in the United States. +The +operation generally is done under local anesthesia on an +outpatient basis. +More than 95% of patients who +undergo cataract extraction can expect an improvement +in vision. +A small open- +ing is made in the lens capsule with a laser to restore +clarity. +In African Americans it is the +leading cause of blindness. +The mechanism by which +raised intraocular pressure injures the optic nerve is not +understood. +21-15). +Careful documentation of serial examinations is +helpful. +Detection of visual +field loss by computerized perimetry also contributes to +the diagnosis. +Finally, most patients with glaucoma have +raised intraocular pressure. +Glaucoma is usually painless (except in angle-closure +glaucoma). +Foveal acuity is spared until end-stage dis- +ease is reached. +The cup-to-disc ratio is about 0.7/1.0 in this patient. +CHAPTER 21 +Disorders of Vision +189 nonexudative (dry) form and an exudative (wet) form. +21-16). +With time they become larger, +more numerous, and confluent. +Treatment with vitamins C and E, beta-caro- +tene, and zinc may retard dry macular degeneration. +Central serous chorioretinopathy +This primarily affects males between the ages of 20 and +50. +The cause of central serous chorioretinopathy is +unknown. +Symptoms may resolve spontaneously if the +retina reattaches, but recurrent detachment is common. +Laser photocoagulation has benefited some patients +with this condition. +The retinopathy takes years to develop but eventually +appears in nearly all cases. +Regular surveillance of the +dilated fundus is crucial for any patient with diabetes. +It +occurs sporadically or in an autosomal recessive, domi- +nant, or X-linked pattern. +They appear as scat- +tered yellow subretinal deposits. +21-17). +The name is actually a misnomer because reti- +nitis pigmentosa is not an inflammatory process. +A +crinkled, cellophane-like membrane is visible on the +retinal examination. +Epiretinal membrane is most com- +mon in patients over 50 years of age and is usually uni- +lateral. +Contraction of an epiretinal +membrane sometimes gives rise to a macular hole. +Most +macular holes, however, are caused by local vitreous +traction within the fovea. +Vitrectomy can improve acu- +ity in selected cases. +Melanoma and other tumors +Melanoma is the most common primary tumor of the +eye (Fig. +21-18). +It causes photopsia, an enlarging sco- +toma, and loss of vision. +A small melanoma is often diffi- +cult to differentiate from a benign choroidal nevus. +Serial +examinations are required to document a malignant pat- +tern of growth. +Treatment of melanoma is controversial. +Options include enucleation, local resection, and irra- +diation. +Metastatic tumors to the eye outnumber primary +tumors. +Breast and lung carcinomas have a special pro- +pensity to spread to the choroid or iris. +Leukemia and +lymphoma also commonly invade ocular tissues. +PROPTOSIS +When the globes appear asymmetric, the clinician must +first decide which eye is abnormal. +CHAPTER 21 +Disorders of Vision +191 Horner’s syndrome can give the appearance of enoph- +thalmos. +A proptosis of only 2 mm +in one eye is detectable from this perspective. +Graves’ ophthalmopathy +This is the leading cause of proptosis in adults. +The pro- +ptosis is often asymmetric and can even appear to be +unilateral. +Radiation therapy is +not effective. +Symptoms are pain, limited eye movements, +proptosis, and congestion. +Imaging often shows swollen eye muscles +(orbital myositis) with enlarged tendons. +By contrast, in +Graves’ ophthalmopathy the tendons of the eye muscles +usually are spared. +The diagnosis of orbital pseudotumor is dif- +ficult. +Blood cultures should be obtained, but +they are usually negative. +Most patients respond to empiri- +cal therapy with broad-spectrum IV antibiotics. +Tumors +Tumors of the orbit cause painless, progressive proptosis. +Metastatic tumor to the orbit occurs frequently in breast +carcinoma, lung carcinoma, and lymphoma. +Direct fistulas usually +result from trauma. +The signs are more subtle, +and the diagnosis frequently is missed. +Imaging shows an enlarged superior ophthalmic vein in +the orbits. +Carotid cavernous shunts can be eliminated +by intravascular embolization. +PTOSIS +Blepharoptosis +This is an abnormal drooping of the eyelid. +Acquired +ptosis can develop so gradually that the patient is +unaware of the problem. +Inspection of old photographs +is helpful in dating the onset. +Fluctuating +ptosis that worsens late in the day is typical of myasthe- +nia gravis. +The extra weight of these sagging +tissues causes the lid to droop. +It occurs commonly in +older patients, presumably from loss of connective tissue +elasticity. +Myogenic ptosis +The causes of myogenic ptosis include myasthenia gra- +vis (Chap. +47) and a number of rare myopathies that +manifest with ptosis. +In general, diplopia is a late symptom +because all eye movements are reduced equally. +Patients have muscle wasting, +myotonia, frontal balding, and cardiac abnormalities. +Examination +of the pupil helps distinguish between these two pos- +sibilities. +In Horner’s syndrome, the eye with ptosis has +a smaller pupil and the eye movements are full. +In an +oculomotor nerve palsy, the eye with the ptosis has a +larger or a normal pupil. +If it does, +the diagnosis is monocular diplopia. +Occasionally it is a symptom of malingering or psychi- +atric disease. +However, subtle limitation of ocular excursions is often +difficult to detect. +To avoid diplopia, vision is suppressed from the +nonfixating eye. +In some children, this leads to impaired +vision (amblyopia, or “lazy” eye) in the deviated eye. +Myasthenia gravis +(See also Chap. +47) This is a major cause of diplopia. +The pupils are always normal. +Fluctuating ptosis may be +present. +Negative results from these tests do +not exclude the diagnosis. +Botulism from food or wound +poisoning can mimic ocular myasthenia. +This combination of findings is obvious. +More challeng- +ing is the diagnosis of early or partial oculomotor nerve +palsy. +Neu- +roimaging should be obtained, along with a CT or MR +angiogram. +Occasionally, a catheter arteriogram must be +done to exclude an aneurysm. +Occasionally +both superior recti are weak. +Isolated nuclear oculomo- +tor palsy is rare. +Oculomotor palsy +also can result from midbrain torsion and hemorrhages +during herniation. +Usually the patient complains of pain. +Diabetes, hypertension, and vascular disease are major +risk factors. +Spontaneous recovery over a period of +months is the rule. +The pupil also constricts upon +attempted adduction, elevation, or depression of the +globe. +Fibers +exit the brainstem dorsally and cross to innervate the +contralateral superior oblique. +The principal actions of +this muscle are to depress and intort the globe. +A palsy +therefore results in hypertropia and excyclotorsion. +The +cyclotorsion seldom is noticed by patients. +Instead, they +complain of vertical diplopia, especially upon reading +or looking down. +This “head tilt +test” is a cardinal diagnostic feature. +The trochlear nerve is particularly apt to suf- +fer injury after closed head trauma. +The free edge of the +tentorium is thought to impinge on the nerve during +a concussive blow. +Abducens nerve +The sixth cranial nerve innervates the lateral rectus +muscle. +A palsy produces horizontal diplopia, worse +on gaze to the side of the lesion. +Millard-Gubler syndrome from ventral pontine +injury is similar except for the eye findings. +Unilateral or bilateral abducens palsy is a classic sign +of raised intracranial pressure. +The diagnosis can be con- +firmed if papilledema is observed on fundus examina- +tion. +Treatment of abducens palsy is aimed at prompt cor- +rection of the underlying cause. +However, the cause +remains obscure in many instances despite diligent eval- +uation. +Some cases may develop as a postinfectious mononeu- +ritis (e.g., after a viral flu). +Skull base +tumors are easily missed even on contrast-enhanced +neuroimaging studies. +In a patient +with systemic malignancy, carcinomatous meningitis is +a likely diagnosis. +Cytologic examination may be nega- +tive despite repeated sampling of the cerebrospinal fluid. +The cancer-associated Lambert-Eaton myasthenic syn- +drome also can produce ophthalmoplegia. +Often the +ataxia is mild, and the reflexes are normal. +Antiganglio- +side antibodies (GQ1b) can be detected in about 50% of +cases. +Supranuclear disorders of gaze +These are often mistaken for multiple ocular motor +nerve palsies. +The disorder occurs in +malnourished or alcoholic patients and can be reversed +by thiamine. +Smooth pursuit is affected later in the course of the +disease. +With time, +this deficit resolves. +Parietal lesions disrupt smooth pursuit +of targets moving toward the side of the lesion. +They project directly to the ipsilateral abdu- +cens nucleus. +21-19). +A patient with bilateral injury +to the medial longitudinal fasciculus will have bilateral +INO. +The +patient’s only horizontal eye movement is abduction of +the eye on the other side. +Vertical gaze +This is controlled at the level of the midbrain. +Dis- +tal basilar artery ischemia is the most common etiology. +It is a classic sign of +hydrocephalus from aqueductal stenosis. +Pineal region +tumors, cysticercosis, and stroke also cause Parinaud’s +syndrome. +11). +This nystagmus is com- +monly referred to as congenital sensory nystagmus. +By convention, the +nystagmus is named after the quick phase. +Jerk nystag- +mus can be downbeat, upbeat, horizontal (left or right), +and torsional. +The pattern of nystagmus may vary with +gaze position. +Some patients will be oblivious to their +nystagmus. +Fine nys- +tagmus may be difficult to see on gross examination +of the eyes. +Gaze-evoked nystagmus +This is the most common form of jerk nystagmus. +The subject compensates by making a cor- +rective saccade to maintain the deviated eye position. +Many normal patients have mild gaze-evoked nys- +tagmus. +There may be associated tinni- +tus and hearing loss. +Sudden shifts in head position may +provoke or exacerbate symptoms. +Upbeat nystagmus is +FIGURE 21-19 +Left internuclear ophthalmoplegia (INO). +A. +In primary posi- +tion of gaze the eyes appear normal. +B. +Horizontal gaze to +the left is intact. +C. +On attempted horizontal gaze to the right, +the left eye fails to adduct. +In mildly affected patients the eye +may adduct partially or more slowly than normal. +Nystagmus +is usually present in the abducted eye. +D. +When +the saccades are confined to the horizontal plane, the +term ocular flutter is preferred. +It +has also been reported as a benign, transient phenom- +enon in otherwise healthy patients. +Shirley H. +VIDEO LIBRARY OF NEURO-OPHTHALMOLOGY + CHAPTER 22 + Richard L. +Doty ■ Steven M. +23-1 ). +When damaged, the +receptor cells can be replaced by stem cells near the +basement membrane. +Unfortunately, such replacement +is often incomplete. +23-2 ). +The axons of the mitral and tufted cells synapse +within the primary olfactory cortex (POC) ( Fig. +23-3 ). +23-4). +Each receptor type (red, green, blue) projects to a common +glomerulus. +The neural activity within each glomerulus is +modulated by periglomerular cells. +The number of taste receptor +cells per taste bud ranges from zero to well over 100. +T2Rs sense a wide +range of bitter substances but do not distinguish among +them. +23-5). +TRC, taste receptor +cell. +23-5). +This brain region is involved in +the conscious recognition of taste qualities. +23-6). +The cribriform plate does not have to be fractured +or show pathology for smell loss to be present. +Fewer than 10% of posttraumatic anosmic patients +recover age-related normal function over time. +Numbers by each data point indicate sample sizes. +Note that +women identify odorants better than men at all ages. +(From +Doty et al: Science 226:1421, 1984. +Olfactory impairment in PD often +predates the clinical diagnosis by at least 4 years. +The smell loss seen in iRBD is of the same magni- +tude as that found in PD. +iRBD may actually repre- +sent an early associated condition of PD. +Bell’s palsy +is among the most common causes of CN VII injury +that results in taste disturbance. +Indeed, over 250 medications +have been reported to alter the ability to taste. +As with olfaction, a number of systemic disorders +can affect taste. +Intermittent loss suggests the likelihood +of an inflammatory process. +Pending litigation and the possibility of +malingering should be considered. +The ORL examina- +tion should thoroughly assess the intranasal architecture +and mucosal surfaces. +As with other sensory disorders, quantitative sen- +sory testing is advised. +A number of standardized olfactory and taste +tests are commercially available. +Most evaluate the abil- +ity of patients to detect and identify odors or tastes. +In addi- +tion to electrogustometers, commercial chemical taste +tests are now available. +Most employ filter paper strips +impregnated with tastants, so no stimulus preparation +is required. +Like the UPSIT, these tests have published +norms for establishing the degree of dysfunction. +Other methods to improve sali- +vary flow include the use of mints, lozenges, or sugarless +gum. +Treatments are limited for patients with chemosen- +sory loss or primary injury to neural pathways. +None- +theless, spontaneous recovery can occur. +A major and often overlooked element of therapy +comes from chemosensory testing itself. +Importantly, quantitative testing places +the patient’s problem into overall perspective. +Anil K. +24-1 ) . +A. +B. +High-resolution +view of inner ear. +24-2). +Tympanoplasty +is highly effective (>90%) in the repair of tympanic +membrane perforations. +This is a slowly growing +lesion that destroys bone and normal ear tissue. +Conductive hearing loss secondary to ossic- +ular erosion is common. +Surgery is required to remove +this destructive process. +Hearing +impairment usually presents between the late teens +and the forties. +Fluoride therapy +to prevent hearing loss from cochlear otosclerosis is of +uncertain value. +Congenital malformations of the +inner ear may be the cause of hearing loss in some +adults. +With +progression, the hearing loss involves all frequencies. +More importantly, the hearing impairment is associated +with significant loss in clarity. +Although hearing aids are able +to amplify sounds, they cannot restore the clarity of hearing. +Therapy is directed toward the +control of vertigo. +A 2-g/d low-salt diet is the mainstay +of treatment for control of rotatory vertigo. +Both lab- +yrinthectomy and vestibular nerve section abolish rota- +tory vertigo in >90% of cases. +Primary diseases of the central nervous system can +also present with hearing impairment. +27). +A finding of conductive and sensory hearing loss in +combination is termed mixed hearing loss. +These abnormalities can be surgically corrected. +An associated facial nerve injury is not +uncommon. +Tinnitus is defined as the perception of a sound when +there is no sound in the environment. +Tinnitus is often +associated with either a conductive or sensorineural +hearing loss. +The pathophysiology of tinnitus is not well +understood. +Tinnitus may be the first symptom of a serious +condition such as a vestibular schwannoma. +Nearly two-thirds of HHIs are +nonsyndromic, and the remaining one-third are syn- +dromic. +Less than 5% is X-linked or maternally +inherited via the mitochondria. +The contribution of genetics to presbycusis +is also becoming better understood. +Susceptibility +to noise-induced hearing loss may also be genetically +determined. +There are >400 syndromic forms of hearing loss. +sensorineural vs. +bilateral involvement, nature of onset +(sudden vs. +insidious), and rate of progression (rapid vs. +slow). +Hearing loss with otorrhea is most +likely due to chronic otitis media or cholesteatoma. +Examination should include the auricle, external ear +canal, and tympanic membrane. +Insuf- +flation of the ear canal is necessary to assess tympanic +membrane mobility and compliance. +Careful inspection +of the nose, nasopharynx, and upper respiratory tract +is indicated. +The patient is asked to +indicate whether the tone is louder by air conduction +or bone conduction. +With a unilateral conductive hear- +ing loss, the tone is perceived in the affected ear. +With +a unilateral sensorineural hearing loss, the tone is per- +ceived in the unaffected ear. +A 5-dB difference in hear- +ing between the two ears is required for lateralization. +Pure tone audiometry assesses hearing acuity for pure +tones. +The test is administered by an audiologist and is +performed in a sound-attenuated chamber. +Air- and bone-conduction thresholds +are established for each ear. +The responses are measured in decibels. +An audiogram +is a plot of intensity in decibels of hearing threshold +versus frequency. +Pitch, on the other hand, does +not directly correlate with frequency. +The percep- +tion of pitch changes slowly in the low and high fre- +quencies. +Pure tone audiometry establishes the presence and +severity of hearing impairment, unilateral vs. +bilateral +involvement, and the type of hearing loss. +Speech audiometry tests the clarity with which one +hears. +The inten- +sity at which the patient can repeat 50% of the words +correctly is the SRT. +Patients with a +sensorineural hearing loss have variable loss of discrimi- +nation. +Compliance that does not change with change in +pressure suggests middle-ear effusion (type B). +A reduction +in the maximal compliance peak can be seen in otoscle- +rosis (type As). +During tympanometry, an intense tone elicits con- +traction of the stapedius muscle. +Assessment of acoustic reflex decay helps differentiate sen- +sory from neural hearing losses. +In neural hearing loss, +the reflex adapts or decays with time. +The emissions may be +spontaneous or evoked with sound stimulation. +CT is also ideal for the detection +of bone erosion with chronic otitis media and choles- +teatoma. +Hearing aids are effective and well tolerated in patients +with conductive hearing losses. +Hearing aids +have been improved to provide greater fidelity and have +been miniaturized. +This arrange- +ment is not possible with a self-contained, cosmetically +acceptable device. +Unfortunately, CROS and +BAHA devices are often judged by patients to be unsat- +isfactory. +Hearing aids with telecoils can also +be used with properly equipped telephones in the same +way. +Worldwide, nearly 200,000 +hearing impaired children and adults have received +cochlear implants. +Tinnitus often accompanies hearing loss. +Therapy +for tinnitus is usually directed toward minimizing the +appreciation of tinnitus. +Relief of the tinnitus may be +obtained by masking it with background music. +The use of a tinnitus masker is often followed +by several hours of inhibition of the tinnitus. +Antide- +pressants have been shown to be beneficial in helping +patients cope with tinnitus. +SECTION III +DISEASES OF THE +NERVOUS SYSTEM + Stephen L. +Hauser ■ M. +NEUROGENETICS + The landscape of neurology has been transformed by +modern molecular genetics. +45). +Interestingly, +the 16p deletion also is associated with epilepsy. +The understanding of +the role of copy-number variation in human disease is +still in its infancy. +Numerous diseases are known to result from +abnormalities in alternative splicing. +Increased inclusion +of exon 10–containing transcripts of MAPT can cause +frontotemporal dementia. +Epigenetic processes appear +to be dynamically active even in postmitotic neurons. +REF. +Iono- +tropic receptors are direct ion channels that open after +engagement by the neurotransmitter. +53-1). +Addictive drugs share the property of increasing dopamine +release in the nucleus accumbens. +Cocaine binds to dopamine trans- +porters and inhibits dopamine reuptake. +Not all cell-to-cell communication in the nervous +system occurs via neurotransmission. +Mecha- +nisms that involve gap junctions have been related to a +variety of neurologic disorders. +24). +25-1). +25-2). +The illus- +tration represents a composite of CNS and PNS myelin. +45). +39). +46). +The neurotrophins act at TrK and +p75 receptors to promote survival of neurons. +However, in phase 3 clini- +cal trials, growth factors were ineffective in human ALS. +The new neurons made connec- +tions and improved performance in a memory task. +A major advance has been the development of +induced pluripotent stem cells. +The establishment of appropriate +neural connections and afferent control is also critical. +Sialidase, which cleaves +one class of receptors for MAG, enhances axonal out- +growth. +25-3). +Experimental brain damage induced by hypoglyce- +mia also is attenuated by NMDA antagonists. +Excitotoxicity is not a single event but rather a cas- +cade of cell injury. +These channels offer a potential new therapeutic +target for stroke. +Mitochondria are essential in controlling specific +apoptosis pathways. +Deposition of β-amyloid is strongly implicated +in the pathogenesis of Alzheimer’s disease. +Parkin, which causes autosomal +recessive early-onset Parkinson’s disease, is a ubiqui- +tin ligase. +These two proteins are involved in transcription +regulation as well as RNA metabolism. +Autophagy is the degradation of cystolic components +in lysosomes. +Agents that upregulate gene transcription are neuropro- +tective in animal models of these diseases. +Familial +frontotemporal degeneration (Chap. +This has allowed insights into how networks of neu- +rons operate to produce behavior. +These techniques have been +used reliably in both behavioral and cognitive sciences. +25-4). +Other examples of the use of fMRI include the +study of memory. +A. +In red, activation during right hand imita- +tion. +In blue, activation during left hand imitation. +B. +C. +Daniel H. +The meaning of the term seizure needs to be carefully +distinguished from that of epilepsy. +A fundamental principle is that seizures may be either +focal or generalized. +Focal seizures are +usually associated with structural abnormalities of the +brain. +There are clear +exceptions in both cases, however. +SEIZURES AND EPILEPSY + CHAPTER 26 +TABLE 26-1 + CLASSIFICATION OF SEIZURES +1. +Generalized seizures + a. +Absence + Typical + Atypical + b. +Tonic clonic + c. +Clonic + d. +Tonic + e. +Atonic +f. +Myoclonic +3. +Focal seizures can also evolve into generalized +seizures. +Three additional features of focal motor seizures +are worth noting. +Third, in +rare instances the seizure may continue for hours or +days. +This condition, termed epilepsia partialis continua, is +often refractory to medical therapy. +In such +cases additional, detailed EEG studies may be helpful. +Contrac- +tion of the jaw muscles may cause biting of the tongue. +Bladder or bowel incon- +tinence may occur at this point. +Patients subsequently complain of headache, fatigue, and +muscle ache that can last for many hours. +The postictal EEG +shows diffuse slowing that gradually recovers as the +patient awakens. +Consciousness is briefly +impaired, but there is usually no postictal confusion. +28). +Epileptic spasms are such an example. +Abbreviations: GABA, γ-aminobutyric acid; PME, progressive myoclonus epilepsy. +and can be provoked by sleep deprivation. +Conscious- +ness is preserved unless the myoclonus is especially severe. +26-1). +The EEG suggested a right +temporal lobe focus. +1. +However, febrile seizures occur only in a +relatively small proportion of children. +2. +3. +Seizures are episodic. +The over- +all prevalence is 3–5% and even higher in some parts +of the world such as Asia. +Patients often have a fam- +ily history of febrile seizures or epilepsy. +A simple febrile sei- +zure is a single, isolated event, brief, and symmetric in +appearance. +Recurrences are much more +likely when the febrile seizure occurs in the first year +of life. +Childhood marks the age at which many of the well- +defined epilepsy syndromes present. +Head trauma is a common cause of epilepsy in ado- +lescents and adults. +Certain recognized causes of seizures are explained +by these mechanisms. +The general physical examination includes a search +for signs of infection or systemic illness. +Signs of head trauma and use of +alcohol or illicit drugs should be sought. +1). +Testing of visual +fields will help screen for lesions in the optic pathways +and occipital lobes. +Details +about the EEG are covered in Chap. +5. +26-2). +HISTORY AND EXAMINATION +The first goal is to determine whether the event was +truly a seizure. +The history should also focus on risk factors and pre- +disposing events. +The EEG is always abnormal +during generalized tonic-clonic seizures. +Thus, the +EEG cannot establish the diagnosis of epilepsy in many +cases. +Magnetoencephalography (MEG) provides another +way of looking noninvasively at cortical activity. +MSI can be +useful to localize potential seizure foci. +DIFFERENTIAL DIAGNOSIS OF +SEIZURES +Disorders that may mimic seizures are listed in +Table 26-6. +Two of +the more common nonepileptic syndromes in the dif- +ferential diagnosis are detailed next. +SYNCOPE +(See also Chap. +from the lying or sitting position. +Headache or incon- +tinence usually suggests a seizure but may on occasion +also occur with syncope. +Rarely, a syncopal episode can induce +a full tonic-clonic seizure. +PSYCHOGENIC SEIZURES +Psychogenic seizures are nonepileptic behaviors that +resemble seizures. +They are often part of a conver- +sion reaction precipitated by underlying psychological +distress. +Video-EEG monitor- +ing is very useful when historic features are nondiagnos- +tic. +Whether to +initiate therapy in a patient with a single seizure is contro- +versial. +Most +patients with one or more of these risk factors should be +treated. +Long-term use of some agents in adults, +especially the elderly, can lead to osteoporosis. +Close +follow-up is required to ensure these side effects are +promptly recognized and reversed. +Oxcarbazepine also has fewer drug +interactions than carbamazepine. +Lamotrigine tends +to be well tolerated in terms of side effects. +This risk can be +reduced by slow introduction and titration. +This is one of the main +causes of acute phenytoin toxicity. +Topiramate can be used +for both focal and generalized seizures. +bExtended-release product available. +This drug should generally +be avoided in patients with preexisting bone marrow or +liver disease. +Topiramate, +zonisamide, phenytoin, and carbamazepine are suitable +alternatives. +Topiramate, zonisamide, and felbamate may have +similar broad efficacy. +This process may take months or longer if the baseline +seizure frequency is low. +Starting doses are usually the lowest value listed +under the dosage column in Table 26-9. +It is also useful to monitor free drug levels in such +patients. +This is usually done by maintain- +ing the patient on the first drug while a second drug is +added. +The dose of the second drug is then further opti- +mized based on seizure response and side effects. +Mono- +therapy should be the goal whenever possible. +In most cases it is +preferable to reduce the dose of the drug gradually over +2–3 months. +If there is no improvement, a +third drug can be added while the first two are main- +tained. +Not all medically refractory patients are suitable +candidates for resective surgery. +For +GCSE, this is typically when seizures last beyond +5 min. +GCSE is obvious when the patient is having overt +convulsions. +However, after 30–45 min of uninter- +rupted seizures, the signs may become increasingly +subtle. +Patients may have mild clonic movements of +only the fingers or fine, rapid movements of the eyes. +There may be paroxysmal episodes of tachycardia, +hypertension, and pupillary dilation. +In such cases, the +EEG may be the only method of establishing the diag- +nosis. +Anticonvulsant therapy should then begin without delay; a +treatment approach is shown in Fig. +26-3. +Depression should be +treated through counseling or medication. +The horizontal bars indicate the approxi- +mate duration of drug infusions. +IV, intravenous; PE, phenytoin equivalents. +Loss of driving privileges is one of the most disrup- +tive social consequences of epilepsy. +Some patients may benefit from increases +in antiepileptic drug dosages during menses. +Natural +progestins or intramuscular medroxyprogesterone may +be of benefit to a subset of women. +However, epilepsy poses some important risks +to a pregnancy. +Valproic acid is strongly associated with an +increased risk of adverse fetal outcomes (7–20%). +BREAST-FEEDING +Antiepileptic medications are excreted into breast milk +to a variable degree. +Wade S. +Smith ■ Joey D. +English ■ S. +They cause ∼200,000 deaths each year in the +United States and are a major cause of disability. +Cerebral ischemia is caused by a +reduction in blood fl ow that lasts longer than several +seconds. +10 ). +28 ). +Tumors may present with acute neuro- +logic symptoms due to hemorrhage, seizure, or hydro- +cephalus. +Surprisingly, migraine can mimic stroke, even +in patients without a significant migraine history. +When +it develops without head pain (acephalgic migraine), the +diagnosis may remain elusive. +Patients without any prior +history of migraine may develop acephalgic migraine +even after age 65. +8). +The metabolic process serves to +“unmask” a prior deficit. +27-1). +SAH is discussed in Chap. +28. +anatomy, the site of occlusion, and likely systemic +blood pressure. +27-15 and 27-16). +Focal cerebral infarction occurs via two distinct path- +ways (Fig. +Rounded boxes +are diagnoses; rectangles are interventions. +Numbers are +percentages of stroke overall. +SECTION III +Diseases of the Nervous System +258 +to produce ATP. +Free radicals are produced by +membrane lipid degradation and mitochondrial dys- +function. +Induced moderate hypothermia +to mitigate stroke is the subject of continuing clinical +research. +27-1). +The first goal is to prevent or reverse brain injury. +See text for details. +iNOS, inducible nitric oxide synthase; PARP, poly-A +ribose polymerase. +Fever is detrimental and +should be treated with antipyretics and surface cooling. +Edema peaks on the second or third day but can +cause mass effect for ∼10 days. +Special vigilance is warranted for patients with cer- +ebellar infarction. +One-half of the patients were treated +within 90 min. +Symptomatic intracerebral hemorrhage +occurred in 6.4% of patients on rtPA and 0.6% on pla- +cebo. +Unlike the NINDS study, +patients older than 85 years of age and diabetic +patients were excluded. +Patients who awaken +with stroke have the onset defined as when they went +to bed. +Table 27-1 summarizes eligibility criteria and +instructions for administration of IV rtPA. +Intraarterial treatment of basilar artery occlusions may also +be beneficial for selected patients. +27-15). +Clopidogrel is being +tested as a way to prevent stroke following TIA and +minor ischemic stroke. +The U.S. +Use of SC unfraction- +ated heparin versus aspirin was tested in IST. +Heparin +given SC afforded no additional benefit over aspirin +and increased bleeding rates. +Several trials of LMWHs +have also shown no consistent benefit in AIS. +Hypothermia is a powerful neuroprotective treatment in +patients with cardiac arrest (Chap. +Use of clinical +pathways and staff dedicated to the stroke patient can +improve care. +ETIOLOGY OF ISCHEMIC STROKE +(Figs. +Judicious use of laboratory testing and imag- +ing studies completes the initial evaluation. +Neverthe- +less, nearly 30% of strokes remain unexplained despite +extensive evaluation. +A com- +plete neurologic examination is performed to localize +the site of stroke. +An ECG may demonstrate arrhythmias or reveal +evidence of recent myocardial infarction (MI). +Cardioembolic stroke +Cardioembolism is responsible for ∼20% of all ischemic +strokes. +These +thrombi then detach and embolize into the arterial cir- +culation. +The thrombus may fragment or lyse quickly, +producing only a TIA. +Alternatively, the arterial occlu- +sion may last longer, producing stroke. +Embolic strokes +tend to be sudden in onset, with maximum neuro- +logic deficit at once. +A smaller embolus may occlude +a small cortical or penetrating arterial branch. +A few pertinent aspects are highlighted here. +Nonrheumatic atrial fibrillation is the most com- +mon cause of cerebral embolism overall. +Patients with atrial fibrillation have an average +annual risk of stroke of ∼5%. +The risk of stroke can be +estimated by calculating the CHADS2 score (see Table +27-3). +Left atrial enlargement is an additional risk factor +for formation of atrial thrombi. +A. +B and C. +Diagram and reformatted CT angiogram +of the common, internal, and external carotid arteries. +CHAPTER 27 +Cerebrovascular Diseases +263 +reduce stroke risk. +Mitral valve prolapse is not usually a +source of emboli unless the prolapse is severe. +Both techniques are highly sensitive +for detection of right-to-left shunts. +Bacterial endocarditis can cause valvular vegetations +that can give rise to septic emboli. +Mycotic aneurysms caused +by septic emboli give rise to SAH or intracerebral +hemorrhage. +Less commonly, a diseased vessel +may acutely thrombose. +bMay be associated with any hypercoagulable disorder. +Abbreviations: CNS, central nervous system; PAN, polyarteritis +nodosa. +Abbreviations: Dose of aspirin is 50–325 mg/d; target INR for VKA is 2.5 unless otherwise specified. +Sources: Modified from DE Singer et al: Chest 133:546S, 2008; DN Salem et al: Chest 133:593S, 2008. +CHAPTER 27 +Cerebrovascular Diseases +265 also vulnerable to atherosclerosis. +Carotid atheroscle- +rosis produces an estimated 10% of ischemic stroke. +It is more common in patients of Asian +and African-American descent. +Recurrent stroke risk +is ∼15% per year, similar to symptomatic untreated +carotid atherosclerosis. +The dissection is usually painful and precedes +the stroke by several hours or days. +Treating asymptomatic pseudoaneurysms following dis- +section is controversial. +The cause of dissection is usu- +ally unknown and recurrence is rare. +Most dissec- +tions heal spontaneously, and stroke or TIA is uncom- +mon beyond 2 weeks. +Small-vessel +strokes account for ∼20% of all strokes. +27-4). +Prevention of other cardiovascular outcomes is not considered here. +Abbreviation: N/A, not applicable. +SECTION III +Diseases of the Nervous System +266 +lipohyalinotic thickening. +These infarcts +range in size from 3 mm to 2 cm in diameter. +Hyper- +tension and age are the principal risk factors. +Anterior cerebral a. +Internal carotid a. +Basilar a. +Basilar a. +Vertebral a. +Vertebral a. +Internal +carotid a. +Middle cerebral a. +Deep branches +of the basilar a. +Middle cerebral a. +Deep branches of the +middle cerebral a. +Note that these vessels are too small to be visualized +on CT angiography. +Protein S deficiency and +homocysteinemia may cause arterial thromboses as well. +Systemic lupus erythematosus with Libman-Sacks endo- +carditis can be a cause of embolic stroke. +Heparin prevents further thrombosis +and reduces venous hypertension and ischemia. +Anticoagulation is often continued indefinitely if +thrombophilia is diagnosed. +Sickle cell anemia (SS disease) is a common cause of +stroke in children. +Fibromuscular dysplasia affects the cervical arteries +and occurs mainly in women. +Occlusion is usually incom- +plete. +Involvement of the renal arteries is common and may +cause hypertension. +The cause and natural history of +fibromuscular dysplasia are unknown. +TIA or stroke +generally occurs only when the artery is severely nar- +rowed or dissects. +Anticoagulation or antiplatelet ther- +apy may be helpful. +It +rarely causes stroke as the internal carotid artery is usu- +ally not inflamed. +The cerebro- +spinal fluid (CSF) often shows pleocytosis, and the pro- +tein level is elevated. +Some cases follow the postpartum +period and are self-limited. +27-5). +An inflammatory profile found on +lumbar puncture favors an inflammatory cause. +With prompt recognition and treatment, many patients +can make an excellent recovery. +No data exist +on the value of any treatment. +Vascular inflammation +is absent. +Areas of +lacunar infarction are often seen also. +29). +Onset is +usually in the fourth or fifth decade of life. +TIAs may arise +from emboli to the brain or from in situ thrombosis of +an intracranial vessel. +With a TIA, the occluded blood +vessel reopens and neurologic function is restored. +Dramatic beading (arrows) +typical of vasculopathy is seen. +This may indicate carotid stenosis as the cause +or local ophthalmic artery disease. +This risk can be directly estimated using the +well-validated ABCD2 method (Table 27-5). +There- +fore, urgent evaluation and treatment are justified. +27-1 +and 27-3). +The improvement characteristic of TIA +is a contraindication to thrombolysis. +Risk of stroke is much greater in those with prior stroke +or TIA. +Many cardiac conditions predispose to stroke, +including atrial fibrillation and recent MI. +Also, the value of treating +systolic hypertension in older patients has been clearly +established. +Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood +pressure. +Lancet +369: 283, 2007. +Therefore, a statin +should be considered in all patients with prior ischemic +stroke. +Tobacco smoking should be discouraged in all +patients. +Aspirin is the most widely studied antiplatelet +agent. +This effect is permanent and +lasts for the usual 8-day life of the platelet. +This effect is transient. +Clopidogrel rarely causes TTP +but does not cause neutropenia. +Ongoing studies are currently addressing +this question. +The accumu- +lated adenosine is an inhibitor of aggregation. +The resulting elevation +in cyclic AMP inhibits aggregation of platelets. +This combination drug was +studied in three trials. +Telmisartan also had no effect +on these outcomes. +The principal side effect +of dipyridamole is headache. +The absolute reduc- +tion varies considerably, depending on the particular +patient’s risk. +Clearly, the likelihood of benefit far outweighs the risks +of treatment. +However, there are no definitive +data, and opinions vary. +Most physicians in North America recommend 81–325 +mg/d, while most Europeans recommend 50–100 mg. +Two doses of dabigatran were used: 110 mg/d and +150 mg/d. +These patients generally should +receive long-term anticoagulation. +VKAs +are recommended long-term if atrial fibrillation persists. +A recent +European study confirmed this finding. +Anticoagulation +has not been directly compared with antiplatelet ther- +apy for carotid disease. +Both showed a substantial benefit for +surgery in patients with a stenosis of ≥70%. +ECST found harm for +patients with stenosis <30% treated surgically. +Nearly one-half of the strokes in the sur- +gery group were caused by preoperative angiograms. +It +is possible that with longer follow-up, a clear benefit +in women will emerge. +At present, carotid endarterec- +tomy in asymptomatic women remains particularly +controversial. +This is of particular importance when the +patient presents with a TIA and a normal examination. +27-4, and 27-6 through 27-14. +Occlusion +of each major intracranial vessel has distinct clinical +manifestations. +27-6, 27-7, 27-8, and 27-9). +27-6). +27-7). +Dysarthria is common because of facial +weakness. +18). +Complete MCA syndromes occur most often when +an embolus occludes the stem of the artery. +18), with or without arm +weakness (frontal opercular syndrome). +27-7). +Deep branches of ant. +cerebral a. +Deep branches of middle cerebral a. +Middle cerebral a. +Anterior cerebral a. +KEY +Anterior +cerebral a. +Internal carotid a. +Middle cerebral a. +27-6). +This produces pure motor stroke or sen- +sory-motor stroke contralateral to the lesion. +Prerolandic a. +Sup. +division +middle cerebral a. +Lateral +orbitofrontal a. +Temporopolar a. +Inf. +division +middle cerebral a. +Ant. +temporal a. +Post. +temporal a. +Angular a. +Post. +parietal a. +Ant. +parietal a. +Note +the bifurcation of the middle cerebral artery into a superior +and inferior division. +27-4, 27-6, +and 27-8). +27-6). +Occlusion of a single A2 segment results in the +contralateral symptoms noted in Fig. +27-8. +27-9). +The cortex +supplied by the MCA territory is affected most often. +With a competent circle of Willis, occlusion may go +Secondary +motor area +Medial +prerolandic a. +Callosomarginal a. +Frontopolar a. +Medial orbitofrontal a. +Ant. +cerebral a. +Post. +communicating a. +Penetrating +thalamosubthalamic +paramedian As. +Calcarine a. +Parietooccipital a. +Medial posterior choroidal a. +Pericallosal a. +Post. +parietal a. +Splenial a. +Post. +thalamic a. +Lateral posterior +choroidal a. +Post. +temporal a. +Ant. +temporal a. +Post. +cerebral +stem +Visual +cortex +Sensory +cortex +Motor +cortex +Hippocampal As. +Medial +rolandic a. +Sometimes there is massive infarction of the entire deep +white matter and cortical surface. +27-8 and 27-9). +Patients typically +describe a horizontal shade that sweeps down or up across +the field of vision. +In most cases, these symptoms +last only a few minutes. +Jaw claudication may result from low +flow in the external carotid branches. +Bilateral common +carotid artery occlusions at their origin may occur in +Takayasu’s arteritis. +The vertebral arteries join to form +the basilar artery at the pontomedullary junction. +27-4, 27-8, and +27-9). +Occlusion of each +vessel produces its own distinctive syndrome. +cerebral a. +Post. +communicating a. +Post. +cerebral a. +Medial posterior +choroidal a. +Ant. +temporal a. +Hippocampal a. +Post. +temporal a. +Post. +thalamic a. +Lateral posterior +choroidal a. +Visual +cortex +Internal +carotid a. +Ant. +choroidal a. +Mesencephalic +paramedian As. +Splenial a. +Parietooccipital a. +Calcarine a. +Signs and symptoms: Structures involved + Peripheral territory (see also Fig. +27-12). +Homonymous hemi- +anopia (often upper quadrantic): Calcarine cortex or optic radia- +tion nearby. +Memory defect: Hippocampal lesion +bilaterally or on the dominant side only. +Simultanagnosia, hemivisual neglect: Dominant +visual cortex, contralateral hemisphere. +Complex hallucinations: Usually nondominant +hemisphere. +Central territory. +Contralateral hemiplegia: Cerebral +peduncle. +27-8 +and 27-9). +The precommunal, or P1, segment of the +true posterior cerebral artery is atretic in such cases. +27-9 and 27-14). +2 7-14). +If the subthalamic nucleus is involved, con- +tralateral hemiballismus may occur. +It is persistent and +responds poorly to analgesics. +Anticonvulsants (carbam- +azepine or gabapentin) or tricyclic antidepressants may +be beneficial. +P2 syndromes +(See also Figs. +Contralateral homonymous hemiano- +pia with macula sparing is the usual manifestation. +Occasionally, only the upper quadrant of visual field is +involved. +The defect usually clears because memory +has bilateral representation. +The patient is often unaware of the blindness +or may even deny it (Anton’s syndrome). +The second segment (V2) traverses +the vertebral foramina from C6 to C2. +Atherothrombotic lesions have a predilection for +V1 and V4 segments of the vertebral artery. +27-4 and 27-9). +Embolic occlusion or thrombosis of a V4 segment +causes ischemia of the lateral medulla. +27-10). +Typically, lesions +occlude either the proximal basilar and one or both +vertebral arteries. +27-11, 27-12, +27-13, and 27-14). +The pattern suggests +12th n. +Descending +sympathetic +tract +Dorsal +spinocerebellar tract +10th n. +Note that in Figs. +Approximate regions involved +in medial and lateral medullary stroke syndromes are shown. +Signs and symptoms: Structures involved + 1. +Many neurologists treat +with heparin to prevent clot propagation. +More often, unequivocal +signs of bilateral pontine disease are present. +Complete +basilar thrombosis carries a high mortality. +As long as symptoms remain unilateral, con- +cern over pending basilar occlusion should be reduced. +6th n. +8th n. +Middle cerebellar +peduncle + Restiform body +6th n. +nucleus +complex +Corticospinal and +corticobulbar tract + 7th n. +nucleus +Dorsal +cochlear +nucleus +Descending tract +and nucleus of +5th n. +Approximate regions involved in medial and lateral +inferior pontine stroke syndromes are shown. +Signs and symptoms: Structures involved + 1. +Partial +syndromes occur frequently (Fig. +27-13). +Neurosurgical intervention may be +lifesaving in such cases. +An occlusion close to the origin of the +artery may cause corticospinal tract signs (Fig. +27-11). +27-11 through 27-13). +IMAGING STUDIES +See also Chap. +4. +sensory nucleus +5th n. +Approximate regions involved in medial and lateral +midpontine stroke syndromes are shown. +Signs and symptoms: Structures involved + 1. +Carotid disease and intracranial vascular occlusions are +readily identified with this method (Fig. +27-3). +28). +Approximate regions involved in medial and lateral +superior pontine stroke syndromes are shown. +Signs and symptoms: Structures involved + 1. +27-1), and CTA and CT per- +fusion imaging may also be useful and convenient +adjuncts. +MRI +scanners with magnets of higher field strength produce +more reliable and precise images. +27-16), as +is fluid-attenuated inversion recovery (FLAIR) imaging +(Chap. +4). +Using IV administration of gadolinium con- +trast, MR perfusion studies can be performed. +This +sensitive technique images clotted blood within the +dissected vessel wall. +Claustrophobia also limits its application. +Most acute stroke protocols use CT because of these +limitations. +MRI may have particular utility in patients with +Midbrain syndrome: +Lateral Medial +3rd n. +Approximate regions involved in medial and lateral +midbrain stroke syndromes are shown. +Signs and symptoms: Structures involved + 1. +A. +CT perfusion +mean-transit time map showing delayed perfusion of the left +MCA distribution (blue). +B. +Predicted region of infarct (red) +and penumbra (green) based on CT perfusion data. +C. +D. +The clot removed with +a thrombectomy device (L5, Concentric Medical, Inc.). +E. +27-15). +27-16). +Bleeding into sub- +dural and epidural spaces is principally produced by +trauma. +SAHs are produced by trauma and rupture of +intracranial aneurysms (Chap. +28). +Intraparenchymal +and intraventricular hemorrhage will be considered +here. +27-1). +The +location of the hemorrhage narrows the differential +diagnosis to a few entities. +Table 27-6 lists the causes +and anatomic spaces involved in hemorrhages. +FIGURE 27-16 +MRI of acute stroke. +A. +B. +C. +The occlusion is within the carotid terminus. +D. +The initial blood pressure +should be maintained until the results of the CT scan +are reviewed. +Whether these reductions +in hematoma growth will translate to clinical benefit +is unclear. +28). +It accounts for ∼10% of all strokes and is asso- +ciated with a 50% case fatality rate. +Incidence rates are +particularly high in Asians and blacks. +Hypertension, +trauma, and cerebral amyloid angiopathy cause the +majority of these hemorrhages. +The small arteries in these areas seem +most prone to hypertension-induced vascular injury. +Within 48 h macrophages begin to phago- +cytize the hemorrhage at its outer surface. +The hemorrhage gen- +erally presents as the abrupt onset of focal neurologic +deficit. +Seizures are uncommon. +27-17). +Contralateral hemi- +paresis is therefore the sentinel sign. +The +paralysis may worsen until the affected limbs become +flaccid or extend rigidly. +In +milder cases, edema in adjacent brain tissue may cause +progressive deterioration over 12–72 h. +A prominent +sensory deficit involving all modalities is usually present. +There may also be +a homonymous visual field defect. +Patients may later develop a +chronic, contralateral pain syndrome (Déjérine-Roussy +syndrome). +In pontine hemorrhages, deep coma with quadriple- +gia usually occurs over a few minutes. +There is often +prominent decerebrate rigidity and “pinpoint” (1 mm) +pupils that react to light. +There is impairment of reflex +FIGURE 27-17 +Hypertensive hemorrhage. +17). +Hyperpnea, +severe hypertension, and hyperhidrosis are common. +Death often occurs within a few hours, but small hem- +orrhages are compatible with survival. +In mild cases there +may be no other neurologic signs other than gait ataxia. +Dizziness or vertigo may be prominent. +Dys- +arthria and dysphagia may occur. +If the deep cerebellar +nuclei are spared, full recovery is common. +Lobar hemorrhage +Symptoms and signs appear over several minutes. +Stiff neck and seizures are +uncommon. +It accounts for some +intracranial hemorrhages associated with IV throm- +bolysis given for MI. +Cocaine and methamphetamine are frequent causes of +stroke in young (age <45 years) patients. +ICH, ischemic +stroke, and SAH are all associated with stimulant use. +In cases of SAH, a saccular +aneurysm is usually identified. +Presumably, acute hyper- +tension causes aneurysmal rupture. +Head injury often causes intracranial bleeding. +36). +Anticoagulant-related ICHs may evolve +slowly, over 24–48 h. +Coagulopathy and thrombocyto- +penia should be reversed rapidly, as discussed later. +Skin and mucous +membrane bleeding is usually evident and offers a diag- +nostic clue. +Hemorrhage into a brain tumor may be the first mani- +festation of neoplasm. +Glioblastoma multiforme in adults +and medulloblastoma in children may also have areas of +ICH. +Hypertensive encephalopathy is a complication of malig- +nant hypertension. +Microscopically, +there are necrosis of arterioles, minute cerebral infarcts, +and hemorrhages. +Primary intraventricular hemorrhage is rare. +Alternatively, bleeding +can arise from periependymal veins. +Sepsis can cause small petechial hemorrhages throughout +the cerebral white matter. +35). +Spinal +hemorrhages usually present with sudden back pain and +some manifestation of myelopathy. +Specific attention to the platelet +count and PT/PTT are important to identify coagu- +lopathy. +CT imaging reliably detects acute focal hemor- +rhages in the supratentorial space. +Mass effect and +edema may remain. +Images of flowing blood +on MRI scan may identify AVMs as the cause of the +hemorrhage. +Any identified coagulopathy +should be reversed as soon as possible. +At present, little can be done about the hemorrhage +itself. +Evacuation of supratentorial hematomas does not +appear to improve outcome. +Tissue surrounding hematomas is displaced and +compressed but not necessarily infarcted. +Surprisingly, ICP is often normal even with large +intraparenchymal hemorrhages. +28). +These maneu- +vers will provide enough time to place a ventricu- +lostomy or ICP monitor. +Glu- +cocorticoids are not helpful for the edema from intra- +cerebral hematoma. +PREVENTION Hypertension is the leading cause +of primary ICH. +Patients with amyloid angiopathy should avoid +antithrombotic agents. +Abbreviation: ICH, intracerebral hemorrhage. +Sources: JC Hemphill et al: Stroke 32:891, 2001; JC Hemphill et al: +Neurology 73:1088, 2009. +AVMs are prob- +ably congenital but cases of acquired lesions have been +reported. +AVMs are more frequent in men, and rare +familial cases have been described. +Headache (without bleeding) may be hemicranial +and throbbing, like migraine, or diffuse. +Focal seizures, +with or without generalization, occur in ∼30% of cases. +One-half of AVMs become evident as ICHs. +The risk of rerupture +is ∼2–4% per year and is particularly high in the first +few weeks. +This is seen most often with large +AVMs in the territory of the MCA. +Headache at the onset of AVM rupture is +not generally as explosive as with aneurysmal rupture. +Patients with asymptomatic AVMs have about an +∼2–4% per year risk for hemorrhage. +Several angio- +graphic features can be used to help predict future +bleeding risk. +Paradoxically, smaller lesions seem to +have a higher hemorrhage rate. +A large-scale randomized trial is currently +addressing this question. +These structures, unlike AVMs, are functional +venous channels. +Surgical resection of these anoma- +lies may result in venous infarction and hemorrhage. +If resection of a cavernous malformation is +attempted, the venous anomaly should not be disturbed. +If bleeding does occur, it rarely produces mass +effect or significant symptoms. +No treatment options +exist. +The pathogenesis is unclear. +Both KRIT1 and CCM2 have roles +in blood vessel formation while PDCD10 is an apop- +totic gene. +Bleeding is usually of small volume, causing slight +mass effect only. +Seizures may occur if the malformation +is located near the cerebral cortex. +Radiation treatment has not been shown +to be of benefit. +Dural arteriovenous fistulas are acquired connections +usually from a dural artery to a dural sinus. +Patients +may complain of a pulse-synchronous cephalic bruit +(“pulsatile tinnitus”) and headache. +Surgical and endovascular techniques +are usually curative. +These fistulas may form because +of trauma, but most are idiopathic. +There is an associa- +tion between fistulas and dural sinus thrombosis. +J. +Claude Hemphill, III ■ Wade S. +Smith ■ Daryl R. +The two principal types of edema +are vasogenic and cytotoxic. +The +BBB may be compromised in ischemia, trauma, infec- +tion, and metabolic derangements. +Typically, vasogenic +edema develops rapidly following injury. +Early astrocytic swelling is a hallmark of ischemia. +17 ). +27-2 ). +Cytotoxic edema +ensues, and ultimately necrotic cell death and tissue +infarction occur. +An alternative pathway of cellular injury is apoptosis. +Excitotoxic- +ity and mechanisms of cell death are discussed in more +detail in Chap. +25. +28-1). +CBF is also +strongly influenced by pH and Paco2. +CBF increases +with hypercapnia and acidosis and decreases with hypo- +capnia and alkalosis. +Significant +increases in volume eventually result in increased ICP. +Elevated ICP diminishes cerebral perfu- +sion and can lead to tissue ischemia. +28-2). +An impaired level of consciousness is common in +critically ill patients. +The approach to the comatose patient is discussed in +Chap. +17; etiologies are listed in Table 17-1. +Cerebral +perfusion is constant over a wide range of systemic blood +pressure. +Perfusion is increased in the setting of hypoxia or +hypercarbia. +BP, blood pressure; CBF, cerebral blood flow. +(Reprinted with permission from HM Shapiro: Anesthesiology +43:447, 1975. +The +EEG of metabolic encephalopathy typically reveals gen- +eralized slowing. +Monitoring of ICP can be an important tool in +selected patients. +In gen- +eral, ICP should be maintained at <20 mmHg and CPP +should be maintained at ≥60 mmHg. +In this setting, ventricular drainage of +CSF is likely to be sufficient and most appropriate. +Fiberoptic ICP +and brain tissue oxygen monitors are usually secured using +a screwlike skull bolt. +Drain CSF via ventriculostomy (if in place) +2. +Elevate head of the bed; midline head position +3. +Hyperventilation—to PaCO2 30–35 mmHg +7. +Consider second-tier therapies for refractory ele- +vated ICP +a. +High-dose barbiturate therapy (“pentobarb coma”) +b. +Aggressive hyperventilation to PaCO2 <30 mmHg +c. +Hypothermia +d. +require immediate intervention. +If a +ventriculostomy device is in place, direct drainage of +CSF to reduce ICP is possible. +Early signs of elevated ICP include drowsiness and +a diminished level of consciousness. +Neuroimaging +studies may reveal evidence of edema and mass effect. +Hypotonic IV fluids should be avoided, and elevation of +the head of the bed is recommended. +are grave prognostic signs. +17), dementia, visual +agnosia (Chap. +In some circumstances, hypoxia +may predominate. +28-4). +Numbers in parentheses are +95% confidence intervals. +Tests denoted with an +asterisk (*) may not be available in a timely and standard- +ized manner. +SSEP, somatosensory evoked potentials; NSE, +neuron-specific enolase; FPR, false-positive rate. +28-5), with +almost invariable involvement of the hippocampus. +Diagnosis +Diagnosis is based upon the history of a hypoxic- +ischemic event such as cardiac arrest. +Potential complications of hypothermia include coagu- +lopathy and an increased risk of infection. +Carbon monoxide and cyanide intoxication can also +cause a delayed encephalopathy. +CHAPTER 28 +Neurologic Critical Care +301 and sleep disturbance. +This is often attributed to medi- +cation effects, sleep deprivation, pain, and anxiety. +Current strategies focus on limiting the use of sedative +medications when this can be done safely. +In the ICU setting, several metabolic causes of an +altered level of consciousness predominate. +Hypercar- +bic encephalopathy can present with headache, confu- +sion, stupor, or coma. +This condition +is broadly termed sepsis-associated encephalopathy. +Confusion, disorientation, agitation, and fluc- +tuations in level of alertness are typical. +Hyperreflexia and frontal +release signs such as a grasp or snout reflex (Chap. +18) +can be seen. +Abnormal movements such as myoclonus, +tremor, or asterixis can occur. +MRI is useful in estab- +lishing the diagnosis (Fig. +Occasional cases present with lesions outside of the +brainstem. +The characteristic clinical triad is that of ophthalmoplegia, +ataxia, and global confusion. +If the disease is not treated, stupor, coma, and death may +ensue. +The pupils are usually spared, but they may become +miotic with advanced disease. +Rarely, amblyopia or myelopathy occurs. +Ataxia improves +more slowly than the ocular motor abnormalities. +Apathy, drowsiness, and confusion +improve more gradually. +There is frequently endothe- +lial proliferation, demyelination, and some neuronal loss. +These changes may be detected by MRI scanning (Fig. +28-7). +The amnestic defect is related to lesions in the +dorsal medial nuclei of the thalamus. +FIGURE 28-6 +Central pontine myelinolysis. +FIGURE 28-7 +Wernicke’s disease. +The former include acute polyneuropathies such as +Guillain-Barré syndrome (Chap. +46), neuromuscular +junction disorders including myasthenia gravis (Chap. +47) and botulism, and primary muscle disorders such +as polymyositis (Chap. +49). +The latter result either +from the systemic disease itself or as a consequence of +interventions. +Neurologic findings +include diffuse weakness, decreased reflexes, and distal +sensory loss. +Prolonged neuromuscular blockade does not appear +to produce permanent damage to the PNS. +Muscle biopsy shows type II fiber atrophy. +Panfascicular +muscle fiber necrosis may also occur in the setting of +profound sepsis. +There may be associated ele- +vations in serum creatine kinase and urine myoglobin. +Acute quadriplegic myopathy has a good +prognosis. +Some patients do have residual long-term weakness, +with atrophy and fatigue limiting ambulation. +Monitoring with a peripheral nerve +stimulator can help to avoid the overuse of these agents. +Excluding head trauma, the most common cause of +SAH is rupture of a saccular aneurysm. +For patients who arrive alive at +hospital, the mortality rate over the next month is about +45%. +Unruptured, asymptomatic aneurysms are much +less dangerous than a recently ruptured aneurysm. +Their risk of rupture is ∼6% in the first year +after identi���cation and may remain high indefinitely. +They often cause symptoms by compressing the adja- +cent brain or cranial nerves. +Approximately 85% +of aneurysms occur in the anterior circulation, mostly on +the circle of Willis. +About 20% of patients have multiple +aneurysms, many at mirror sites bilaterally. +As an aneu- +rysm develops, it typically forms a neck with a dome. +The arte- +rial internal elastic lamina disappears at the base of the +neck. +The media thins, and connective tissue replaces +smooth-muscle cells. +Aneurysm size and site are +important in predicting risk of rupture. +Clinical manifestations +Most unruptured intracranial aneurysms are completely +asymptomatic. +At the moment of aneurysmal rup- +ture with major SAH, the ICP suddenly rises. +In ∼45% of cases, +severe headache associated with exertion is the present- +ing complaint. +The headache is usually generalized, often +with neck stiffness, and vomiting is common. +The deficits that result can include hemiparesis, aphasia, +and abulia. +27). +Pain in or behind the +eye and in the low temple can occur with an expanding +MCA aneurysm. +Thunderclap headache is a variant of +migraine that simulates an SAH. +For ruptured aneurysms, prognosis for good +outcomes falls as the grade increases. +1. +Rerupture. +Rerupture is asso- +ciated with a 60% mortality rate and poor outcome. +SECTION III +Diseases of the Nervous System +306 +Early treatment eliminates this risk. +2. +Hydrocephalus. +Hydrocephalus may clear spontaneously or +require temporary ventricular drainage. +Subtle signs may be a lack +of initiative in conversation or a failure to recover +independence. +3. +Vasospasm. +Signs +of ischemia appear 4–14 days after the hemorrhage, +most often at 7 days. +The severity and distribution of +vasospasm determine whether infarction will occur. +Spasm +of major arteries produces symptoms referable to the +appropriate vascular territory (Chap. +27). +All of these +focal symptoms may present abruptly, fluctuate, or +develop over a few days. +In most cases, focal spasm is +preceded by a decline in mental status. +CT angiography is another method that +can detect vasospasm. +4. +Hyponatremia. +Hyponatremia may be profound and +can develop quickly in the first 2 weeks following +SAH. +Laboratory evaluation and imaging +(Fig. +28-8) The hallmark of aneurysmal rupture is +blood in the CSF. +CHAPTER 28 +Neurologic Critical Care +307 +thick in the cerebral fissures. +28-8C). +An +asymptomatic troponin elevation is common. +Serious +ventricular dysrhythmias are unusual. +An aneu- +rysm can be “clipped” by a neurosurgeon or “coiled” +by an endovascular surgeon. +28-8D). +Risk of rebleeding was low, but more +common in the coiling group. +A. +CT angiography revealing +an aneurysm of the left superior cerebellar artery. +B. +C. +D. +High ICP refractory to treatment is a +poor prognostic sign. +If headache or neck pain is severe, mild sedation and +analgesia are prescribed. +Extreme sedation is avoided +because it can obscure changes in neurologic status. +Seizures are uncommon at the onset of aneurysmal +rupture. +Vasospasm remains the leading cause of morbidity +and mortality following aneurysmal SAH. +This method is called “triple-H” (hypertension, hemodi- +lution, and hypervolemic) therapy. +Acute hydrocephalus can cause stupor or coma. +It +may clear spontaneously or require temporary ventric- +ular drainage. +When chronic hydrocephalus develops, +ventricular shunting is the treatment of choice. +All patients should have pneumatic compression +stockings applied to prevent pulmonary embolism. +William W. +Seeley ■ Bruce L. +Focal cerebral +disorders are discussed in Chap. +18 and illustrated in a +video library in Chap. +19 . +18 ). +Lesions of cortical-striatal pathways produce specifi c +effects on behavior. +The dorsolateral prefrontal cortex +bears connections with a central band of the caudate. +The +lateral orbital frontal cortex connects with the ventrome- +dial caudate. +Lesions of this system cause impulsiveness, +distractibility, and disinhibition. +THE CAUSES OF DEMENTIA + The single strongest risk factor for dementia is increasing +age. +Whether +dementia is an inevitable consequence of normal human +aging remains controversial. +The many causes of dementia are listed in Table 29-1. +In patients under the age of 65, FTD rivals AD +as the most common cause of dementia. +Other disorders listed in the table are uncom- +mon but important because many are reversible. +Subtle cumulative decline in episodic memory is a +natural part of aging. +HISTORY The history should concentrate on the +onset, duration, and tempo of progression. +A per- +sonality change, disinhibition, and weight gain or com- +pulsive eating suggest FTD, not AD. +A history of stroke with irregular stepwise progres- +sion suggests vascular dementia. +(2) Is there a treat- +able or reversible component to the dementia? +(3) Can +the physician help to alleviate the burden on caregivers? +A broad overview of the approach to dementia is shown +in Table 29-3. +Rapid pro- +gression with motor rigidity and myoclonus suggests +CJD. +Gait dis- +turbance is common in vascular dementia, PD/DLB, or +normal-pressure hydrocephalus (NPH). +Alcoholism creates risk for +malnutrition and thiamine deficiency. +Hemiparesis or other focal neurologic deficits sug- +gest vascular dementia or brain tumor. +Dementia with a +myelopathy and peripheral neuropathy suggests vitamin +B12 deficiency. +thyroid dysfunction, Lyme disease, or vasculitis. +Dry, cool +skin, hair loss, and bradycardia suggest hypothyroidism. +Neuropsychiatric assessment is important for diag- +nosis, prognosis, and treatment. +LABORATORY TESTS The choice of laboratory +tests in the evaluation of dementia is complex. +Table 29-3 lists most screening tests for +dementia. +They also help to establish a regional pat- +tern of atrophy. +Focal frontal and/or anterior tem- +poral atrophy suggests FTD. +Extensive white +matter abnormalities correlate with a vascular etiology +for dementia. +29-1). +The disease also exacts a heavy +emotional toll on family members and caregivers. +AD, Alzheim- +er’s disease; MCI, mild cognitive impairment; PET, positron +emission tomography. +Social graces, routine behavior, and +superficial conversation may be surprisingly intact. +Lan- +guage becomes impaired—first naming, then compre- +hension, and finally fluency. +In some patients, aphasia is +an early and prominent feature. +Apraxia emerges, and patients have trouble performing +learned sequential motor tasks. +Simple calculations and clock reading become +difficult in parallel. +In the late stages of the disease, some persons remain +ambulatory but wander aimlessly. +Loss of judgment and +reasoning is inevitable. +Loss of inhibitions and aggres- +sion may occur and alternate with passivity and with- +drawal. +Sleep-wake patterns are disrupted, and night- +time wandering becomes disturbing to the household. +Patients often look parkinsonian (Chap. +30) but rarely have a high-amplitude, rhythmic, resting +tremor. +In end-stage AD, patients become rigid, mute, +incontinent, and bedridden. +Help is needed with eating, +dressing, and toileting. +Gener- +alized seizures may also occur. +The typical +duration of AD is 8–10 years, but the course can range +from 1 to 25 years. +29-2A, B). +29-2C, D). +The EEG in AD is normal or shows nonspecific slow- +ing. +Routine spinal fluid examination is also normal. +Simple clinical clues are useful in the differential diag- +nosis. +Resting tremor with stooped posture, brady- +kinesia, and masked facies suggest PD (Chap. +30). +35). +Early onset of a focal seizure suggests a metastatic or +primary brain neoplasm (Chap. +37). +43). +43), or rare hereditary +ataxias (Chap. +31). +EPIDEMIOLOGY +The most important risk factors for AD are old age and +a positive family history. +Female sex may also be a risk factor indepen- +dent of the greater longevity of women. +Some AD patients +have a past history of head trauma with concussion. +Diabetes +increases the risk of AD threefold. +The characteris- +tic microscopic findings are neuritic plaques and NFTs. +Eventually, further amy- +loid polymerization and fibril formation lead to neuritic +plaques (Fig. +Fluorodeoxyglucose PET scans of a normal control (C) and +a patient with AD (D). +AD, Alzheimer’s disease; PET, positron emission +tomography. +The normal function of +Aβ is unknown. +APP has neurotrophic and neuroprotec- +tive properties. +The accumulation of Aβ in +cerebral arterioles is termed amyloid angiopathy. +Finally, patients with AD often show comor- +bid DLB and vascular pathology. +One is the APP gene on +chromosome 21. +Many +develop a progressive dementia superimposed on their base- +line mental retardation. +Aβ peptide +results from cleavage of APP by β and γ secretases +(Fig. +29-4). +Presenilin-1 (PS-1) is on chromo- +some 14 and encodes a protein called S182. +Presenilin-2 (PS-2) is on chromosome 1 and +encodes a protein called STM2. +Mutations in +PS-1 are much more common than those in PS-2. +(Image +courtesy of S. +Excess production of Aβ42 is a key ini- +tiator of cellular damage in Alzheimer’s disease. +Genetic testing for these uncommon +mutations is now commercially available. +Apo +ε participates in cholesterol transport and has three alleles: +ε2, ε3, and ε4. +Conversely, many AD patients have no ε4 allele, +and ε4 carriers may never develop AD. +Therefore, ε4 is +neither necessary nor sufficient to cause AD. +Use of Apo ε testing in AD diagnosis remains +controversial. +Loss of independence and change of environment may +worsen confusion, agitation, and anger. +Communication +and repeated calm reassurance are necessary. +Use of adult day care centers can be helpful. +Due to hepa- +totoxicity, tacrine is no longer used. +Memantine appears to act by blocking overex- +cited N-methyl-D-aspartate (NMDA) glutamate receptors. +Each of these compounds has +only modest efficacy for AD. +This study +seemed to confirm the results of two earlier case-con- +trolled studies. +This study +markedly dampened enthusiasm for hormonal treat- +ments to prevent dementia. +Additionally, no benefit has +been found in the treatment of AD with estrogen alone. +of multi-infarct dementia. +Euphoria, elation, depression, or aggres- +sive behaviors are common as the disease progresses. +Both +pyramidal and cerebellar signs may be present. +A gait +disorder is present in at least half of these patients. +Seizures and myoclonic +jerks appear in a minority of patients. +Patients +typically report previous discrete episodes of sudden neu- +rologic deterioration. +Recur- +rent strokes result in a stepwise disease progression. +Neu- +roimaging reveals multiple areas of infarction. +29-5). +Skin +biopsy may show pathognomonic osmophilic gran- +ules in the media of arterioles. +The frequency of this disorder is +unknown, and there are no effective treatments. +Unlike +in AD, behavioral symptoms predominate in the early stages +of FTD. +Progranulin is a growth factor that binds to +tumor necrosis factor (TNF) receptors. +How progranu- +lin mutations lead to FTD is unknown. +In contrast, +familial FTD with ALS has been linked to chromosome +9. +Cognitive test- +ing typically reveals spared memory but impaired planning, +judgment, or language. +Patients with FTD often +show an absence of insight into their condition. +Findings at the bedside are dictated by the anatomic +localization of the disorder. +29-6 and +29-7). +29-8). +Loss of cortical serotonergic inner- +vation is seen in many patients. +In contrast to AD, the +cholinergic system is relatively spared in FTD. +29-9). +Many +FIGURE 29-6 +Frontotemporal dementia (FTD). +Areas of early and severe atrophy in each +syndrome are highlighted (white arrowheads). +Semantic dementia shows prominent temporopolar atro- +phy, more often on the left. +These fea- +tures are common at presentation and often precede the +motor syndrome. +Response to L-dopa is limited or absent; no other +treatments exist. +Death occurs within 5–10 years of onset. +At autopsy, accumulation of hyperphosphorylated tau is +seen within neurons and glia. +Furthermore, the behavioral syndromes +seen with DLB differ from PSP (see later). +Patients with PD who +develop dementia also show cortical atrophy on brain +imaging. +Parkinson’s disease is discussed in detail +in Chap. +30. +Some patients begin +with a progressive nonfluent aphasia or a progressive +motor speech disorder. +Classical Pick’s disease is +seen in only 10–20% of patients with frontotemporal dementia. +Scale bar represents 50 microns. +(CP-13 antibody courtesy of P. +Davies.) +SECTION III +Diseases of the Nervous System +326 coiled bodies. +The condition is rarely familial, the cause is +unknown, and there is no specific treatment. +Dementia can precede or follow +the appearance of parkinsonism. +Exercise programs maximize motor function and protect +against fall-related injury. +Antidepressants are often nec- +essary. +Prion diseases are discussed in +detail in Chap. +43. +Huntington’s disease (HD) (Chap. +30) is an autoso- +mal dominant, degenerative brain disorder. +Depression, apathy, social with- +drawal, irritability, and intermittent disinhibition are +common. +Delusions and obsessive-compulsive behavior +may occur. +Disease duration is typically around 15 years +but is quite variable. +Normal-pressure hydrocephalus (NPH) is a relatively +uncommon but treatable syndrome. +This syndrome is a +communicating hydrocephalus with a patent aqueduct +of Sylvius (Fig. +29-10), in contrast to aqueductal ste- +nosis, in which the aqueduct is small. +None has proven to be spe- +cific or consistently useful. +A. +B. +Axial T2-weighted MR images demonstrate dilation of the +lateral ventricles. +This patient underwent successful ventricu- +loperitoneal shunting. +SECTION III +Diseases of the Nervous System +328 during, and after lumbar CSF drainage. +Short-lasting improve- +ment is common. +Dementia can accompany chronic alcoholism (Chap. +56) +and may result from associated malnutrition, especially of +B vitamins, particularly thiamine. +Other poorly defined +aspects of chronic alcoholism may, however, also pro- +duce cerebral damage. +Thiamine (vitamin B1) deficiency causes Wernicke’s +encephalopathy (Chap. +28). +Dam- +age to the dorsomedial thalamus correlates most closely +with the memory loss. +Confabulation is common, although not always present. +Mammil- +lary body atrophy may be visible on MRI in the chronic +phase (Fig. +28-7). +35). +Damage to myelinated +axons may also cause dementia. +CNS infections usually cause delirium and other acute +neurologic syndromes. +41), may produce a dementing illness. +Between +20 and 30% of patients in the advanced stages of HIV +infection become demented (Chap. +42). +Cardinal features +include psychomotor retardation, apathy, and impaired +memory. +Primary and metastatic neoplasms of the CNS (Chap. +44). +If recurrent or persistent, the condition may be termed +complex partial status epilepticus. +The cognitive disturbance +often responds to anticonvulsant therapy. +The etiology +may be previous small strokes or head trauma; some cases +are idiopathic. +Such conditions include hypothyroidism; vas- +culitis; and hepatic, renal, or pulmonary disease. +Isolated vasculitis of the CNS (CNS granulomatous angi- +itis) (Chap. +Headache is common, and +strokes and cranial neuropathies may occur. +Brain imag- +ing studies may be normal or nonspecifically abnormal. +CSF analysis reveals a mild pleocytosis or protein eleva- +tion. +The progno- +sis is often poor, although the disorder may remit spon- +taneously. +Some patients respond to glucocorticoids or +chemotherapy. +Chronic metal exposure represents a rare cause of demen- +tia. +The key to diagnosis is to elicit a history of exposure +at work or home. +Chronic lead poisoning from inad- +equately fire-glazed pottery has been reported. +The treatment is chelation therapy with +agents such as ethylenediamine tetraacetic acid (EDTA). +Treatment is chelation therapy with dimercaprol +(BAL). +The condition has been eliminated by the +use of deionized water for dialysis. +Also, there may be loss of neurons in the substan- +tia nigra. +Chronic subdural hematoma (Chap. +Often +the amnesia occurs in the setting of an emotional stimu- +lus or physical exertion. +The patient may seem confused and repeatedly ask +about his or her location in place and time. +MLD is diagnosed by measur- +ing arylsulfatase A enzyme activity in white blood cells. +Adrenoleukodystrophy is diagnosed with measure- +ment of plasma very long chain fatty acids. +Diagnosis is made by +finding curvilinear inclusions within white blood cells or +neuronal tissue. +Psychogenic amnesia for personally important memories +can be seen. +On recovery, there +is a residual amnesia gap for the period of the fugue. +Psychiatric diseases may mimic dementia. +Patients in this condition may feel confused and unable +to accomplish routine tasks. +Such patients respond to +treatment of the underlying psychiatric illness. +Memory loss may also be part of a +conversion disorder. +Discontinuation of the offending medication +often improves mentation. +A proactive strategy has been shown to reduce the +occurrence of delirium in hospitalized patients. +Nondrug behavior therapy has an important place in +dementia management. +The primary goals are to make +the patient’s life comfortable, uncomplicated, and safe. +Preparing lists, schedules, calendars, and labels can be +helpful in the early stages. +Attempts to help +or take over may be greeted with complaints, depression, +or anger. +Hostile responses on the part of the caretaker +are useless and sometimes harmful. +These areas need to be monitored, +supervised, and made as safe as possible. +Antidepressants, such as SSRIs (Chap. +Anti- +convulsants are used to control seizures. +Agitation, hallucinations, delusions, and confusion are +difficult to treat. +Caregiver guilt +and burnout are common. +Caregivers should be encouraged to take advantage +of day-care facilities and respite breaks. +Education and +counseling about dementia are important. +C. +Warren Olanow ■ Anthony H.V. +PD affects men +and women of all races, all occupations, and all coun- +tries. +30-1 ) . +These studies suggest +that dopamine neurons are affected in midstage disease. +30-2 ) . +The basal ganglia play +an important role in regulating normal motor behavior. +Among +the different forms of parkinsonism, PD is the most com- +mon (approximately 75% of cases). +However, +postmortem studies found a 24% error rate when these +criteria were used. +With these revised criteria (known +as the U.K. +brain bank criteria), the clinical diagnosis of +PD is confirmed pathologically in 99% of cases. +30-3). +The penetrance +of the most common LRRK2 mutation ranges from 28 +to 74%, depending on age. +SNc, substantia nigra pars compacta. +33). +SNc, substantia nigra pars compacta; STN, +subthalamic nucleus. +33-2]) in MSA-c. +Patients frequently experience hyperextension of the +neck with early gait disturbance and falls. +In later stages, +speech and swallowing difficulty and dementia become +evident. +Dementia may occur at any stage of +the disease. +MRI frequently shows asymmetric cortical +atrophy. +Other drugs that +can cause secondary parkinsonism include tetrabenazine, +amiodarone, and lithium. +ETIOLOGY AND PATHOGENESIS +Most PD cases occur sporadically (∼85–90%) and are of +unknown cause. +However, no environ- +mental factor has yet been determined to cause PD. +(Courtesy of +Dr. +However, MPTP or MPTP-like compounds have +not been linked to sporadic PD. +MPTP has, however, +proved useful for generating an animal model of the dis- +ease. +Each of these +mechanisms offer potential targets for neuroprotective +drugs. +30-4). +30-1). +Increased lev- +els of unwanted proteins could also result from impaired +clearance. +Collectively, these findings implicate abnormal +protein accumulation in the etiology of PD. +Mitochondrial dysfunction has also been implicated +in familial PD. +Six different LRRK2 mutations have been linked to +PD, with the Gly2019Ser being the commonest. +Whole-genome association studies have provided +conflicting results. +30-5. +30-5). +There are, however, important limitations of levo- +dopa therapy. +Acute dopaminergic side effects include +nausea, vomiting, and orthostatic hypotension. +These +are usually transient and can generally be avoided by +gradual titration. +Inhibitory connections are shown +as blue arrows and excitatory connections as red arrows. +The striatum is the major input region and receives its major +input from the cortex. +The striatum and GPi/SNr are con- +nected by direct and indirect pathways. +This concept led to the rationale for +surgical therapies for PD. +30-6). +This loss of benefit is known as +the wearing-off effect. +At the same time, many patients +develop dyskinesias. +The cause of levodopa-induced motor complications +is not precisely known. +30-5). +Striatal dopamine +levels are normally maintained at a relatively constant +level. +Levodopa-induced motor complica- +tions. +Behavioral alterations can be encountered in levodopa- +treated patients. +In general, dopamine agonists do not have comparable +efficacy to levodopa. +Rotigotine is +administered as a once-daily transdermal patch. +It is generally administered SC as a +rescue agent for the treatment of severe “off” episodes. +However, +infusions are cumbersome, and this approach has not +been approved in the United States. +Acute side effects of dopamine agonists include +nausea, vomiting, and orthostatic hypotension. +As +with levodopa, these can usually be avoided by slow +titration. +Patients should be informed about this poten- +tial problem and should not drive when tired. +Selegiline and rasagiline are relatively +selective suicide inhibitors of the MAO-B enzyme. +MAO-B +inhibitors are generally safe and well tolerated. +Two COMT inhibitors have been +approved, tolcapone and entacapone. +There is also a +combination tablet of levodopa, carbidopa, and enta- +capone (Stalevo). +This problem has +not been encountered with entacapone. +Still, they can be helpful in indi- +vidual patients. +Amantadine also has historical importance. +Side effects include +livido reticularis, weight gain, and impaired cognitive +function. +A list of the major drugs and available dosage +strengths is provided in Table 30-5. +SURGICAL TREATMENT Surgical treatments for +PD have been employed for more than a century. +Most surgical procedures for PD performed today +utilize deep brain stimulation (DBS). +DBS simulates +the effects of a lesion without necessitating a brain +lesion. +In cases with intolerable +side effects, stimulation can be stopped and the sys- +tem removed. +DBS for PD primarily targets the STN or the GPi. +Generally, drugs should be started in low doses and titrated to optimal dose. +Abbreviations: COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase type B. +SECTION III +Diseases of the Nervous System +344 paresthesias, depression, and rarely suicide). +While not all PD patients are candidates, the procedure +is profoundly beneficial for many. +Several open-label studies reported +positive results. +Anxiety can be treated with short-acting benzo- +diazepines. +Psychosis can be a major problem in PD. +Psychosis in +PD often responds to low doses of atypical neurolep- +tics. +Hallucinations in PD patients are +often a harbinger of a developing dementia. +Dementia in PD (PDD) is common, affecting as many +as 80% of patients. +29). +These +patients are particularly prone to have hallucinations +and diurnal fluctuations. +It is likely that DLB and PDD represent a PD spec- +trum rather than separate disease entities. +Memantine, +an antiglutamatergic agent, may also provide benefit for +some PDD patients. +Autonomic disturbances are common and frequently +require attention. +Orthostatic hypotension can be +problematic and contribute to falling. +Low doses of fludrocortisol (Florinef) or midodrine +control most cases. +If orthostatic hypotension is promi- +nent in early disease, MSA should be considered. +Sexual +dysfunction can be helped with sildenafil or tadalafil. +Anticholinergic agents, such as Ditropan, may +be helpful. +Constipation can be a very important prob- +lem for PD patients. +Agents that +promote GI motility can also be helpful. +Restless leg syndrome, sleep apnea, +and other sleep disorders should be treated as appropri- +ate. +REM behavior disorder (RBD) may precede the onset +of motor features. +Low doses of clonazepam +are usually effective in controlling this problem. +Canes and walkers may become +necessary. +The +needs of the caregiver should not be neglected. +Support groups for patients and +caregivers may be useful. +However, no therapy has yet been proved +to be disease-modifying. +The next important issue to address is when to ini- +tiate symptomatic therapy. +30-7. +Decision +points include: + a. +b. +c. +d. +e. +Source: Adapted from CW Olanow et al: Neurology 72:S1, +2009. +Tremor is also +assessed based on distribution, frequency, and related +neurologic dysfunction. +It can present in childhood, but dramatically +increases in prevalence over the age of 70 years. +The tremor is most often manifest as a postural +or kinetic tremor. +It is typically bilateral and symmet- +ric, but may begin on one side and remain asymmetric. +Patients with severe ET can have an intention tremor +with overshoot and slowness of movement. +The tremor is characteristically improved by +alcohol and worsened by stress. +Subtle impairment of +coordination or tandem walking may be present. +The major differential is +a dystonic tremor (see later) or PD. +These typically begin after a +latency of a few seconds (emergent tremor). +ETIOLOGY AND PATHOPHYSIOLOGY +The etiology and pathophysiology of ET are not +known. +Candidate genes +include the dopamine D3 receptor and proteins that +map to the cerebellum. +However, the precise +pathologic correlate of ET remains to be defined. +TREATMENT +Many cases are mild and require no treatment other +than reassurance. +β Blockers or primidone are the standard drug +therapies for ET and help in about 50% of cases. +The drug is contra- +indicated in patients with bradycardia or asthma. +Hand +tremor tends to be most improved, while head tremor +is often refractory. +Benefits have +been reported with gabapentin and topiramate. +PRIMARY DYSTONIAS +Several gene mutations are associated with dystonia. +The majority of patients have an age of onset younger +than 26 years (mean 14 years). +In severe cases, patients can suf- +fer disabling postural deformities that compromise +mobility. +Why some gene carriers +express dystonia and others do not is not known. +The +precise pathology responsible for dystonia is not known. +DRD is typified by an excellent and sustained response +to small doses of levodopa. +FOCAL DYSTONIAS +These are the most common forms of dystonia. +They +typically present in the fourth to sixth decades and +affect women more than men. +Most cases affect the adductor muscles +and cause speech to have a choking or strained quality. +Less commonly, the abductors are affected, leading to +speech with a breathy or whispering quality. +Muscle contractions can be painful, and associated +with a secondary cervical radiculopathy. +Their cause is not +known, but genetic factors, autoimmunity, and trauma +have been suggested. +Focal dystonias are often associ- +ated with a high-frequency tremor that resembles ET. +SECONDARY DYSTONIAS +These develop as a consequence of drugs or other neu- +rologic disorders. +In these +cases, dystonia often assumes a segmental distribution. +PATHOPHYSIOLOGY OF DYSTONIA +The pathophysiologic basis of dystonia is not known. +Further, ablation or stimulation of the globus pallidus +can both induce and ameliorate dystonia. +Wilson’s disease +should be ruled out in young patients with dystonia. +Levodopa should be tried in all cases of childhood- +onset dystonia to rule out DRD. +Clonazepam and diazepam are rarely effective. +Two serotypes of +botulinum toxin are available (A and B). +Some patients fail to respond after having +experienced an initial benefit. +DBS of the pal- +lidum can provide dramatic benefits for patients with +primary DYT1 dystonia. +Better results are typically obtained in younger +patients. +Patients may experience +rhabdomyolysis with renal failure. +Patients should be +managed in an ICU with protection of airway if required. +Spasms may be difficult to control, and anesthesia with +muscle paralysis may be required. +60 years. +HD is characterized by rapid, nonpatterned, +semipurposeful, involuntary choreiform movements. +Dysarthria, gait disturbance, and oculomotor +abnormalities are common features. +Functional decline is often predicted by +progressive weight loss despite adequate calorie intake. +The disease +predominantly strikes the striatum. +30-8). +More diffuse cortical atrophy is seen in the +middle and late stages of the disease. +Supportive stud- +ies include reduced metabolic activity in the caudate +nucleus and putamen. +The larger the number of repeats, the ear- +lier the disease is manifest. +There is no adequate treatment for the cognitive or +motor decline. +Most patients are of +African descent. +FIGURE 30-8 +Huntington’s disease. +A. +Coronal FLAIR MRI shows +enlargement of the lateral ventricles reflecting typical atrophy +(arrows). +B. +Axial FLAIR image demonstrates abnormal high +signal in the caudate and putamen (arrows). +Dopamine-block- +ing agents may control the chorea. +Syden- +ham’s chorea (originally called St. +Vitus’ dance) is more +common in females and is typically seen in childhood +(5–15 years). +Mutations in the VPS13A gene on chromosome +9q21 encoding chorein have been described. +It is important to ensure that patients +with these types of choreas do not have HD. +Prognosis is usually +good, with spontaneous remission in later life. +Low-dose +anticonvulsant therapy (e.g., carbamazepine) is usually +effective if required. +Treatment is not +indicated if the condition is mild and self-limited. +Proximal limb muscles tend to be pre- +dominantly affected. +Dopamine-blocking drugs can be helpful but +can themselves lead to movement disorders. +In extreme +cases, pallidotomy can be very effective. +TS is characterized by multi- +ple motor tics often accompanied by vocalizations (phonic +tics). +A tic is a brief, rapid, recurrent, and seemingly pur- +poseless stereotyped motor contraction. +The risk of a family with +one affected child having a second is about 25%. +Drug treatment is indicated when the tics are disabling +and interfere with quality of life. +If these agents are +not effective, antipsychotics can be employed. +Myoclonic jerks can be disabling when they interfere with +normal movement. +Recent studies suggest that +levetiracetam may be particularly effective. +ACUTE +Dystonia is the most common acute hyperkinetic drug +reaction. +SUBACUTE +Akathisia is the commonest reaction in this category. +It +consists of motor restlessness with a need to move that +is alleviated by movement. +Therapy consists of remov- +ing the offending agent. +In severe cases, the trunk, limbs, and respira- +tory muscles may also be affected. +In contrast, abnormal +movements may develop after stopping the offend- +ing agent. +Treatment primarily consists of stopping the offend- +ing agent. +Abrupt +cessation of a neuroleptic should be avoided as acute +withdrawal can induce worsening. +TD can persist after +withdrawal of antipsychotics and can be difficult to +treat. +Benefits may be achieved with valproic acid, anti- +cholinergics, or botulinum toxin injections. +In refrac- +tory cases, catecholamine depleters such as tetrabenazine +may be helpful. +Tetrabenazine can be associated with +dose-dependent sedation and orthostatic hypotension. +Valproic acid, anticholin- +ergics, and botulinum toxin may occasionally be ben- +eficial. +Neuroleptic medications can also be associated with +a neuroleptic malignant syndrome (NMS). +Symptoms typically evolve within +days or weeks after initiating the drug. +Myoclonus is often a prominent fea- +ture, in contrast to NMS, which it resembles. +Symptoms most commonly begin in the legs, but +can spread to or even begin in the upper limbs. +The +unpleasant sensation is often described as a creepy- +crawly feeling, paresthesia, or burning. +RLS is a heterogeneous condition. +The mean age of onset in +genetic forms is 27 years, although pediatric cases are +recognized. +The severity of symptoms is variable. +The neurologic examination is normal. +Most RLS sufferers have mild symptoms that do not +require specific treatment. +General measures to improve +sleep hygiene and quality should be attempted first. +Other drugs that +can be effective include anticonvulsants, analgesics, and +even opiates. +Iron infusion +may also be helpful for severe primary RLS but requires +expert supervision. +It is caused by mutations in the gene +encoding a P-type ATPase. +About half of WD patients +(especially younger patients) manifest with liver abnor- +malities. +The tremor is usually +in the upper limbs, bilateral, and asymmetric. +KF rings represent the deposition of cop- +per in Descemet’s membrane around the cornea. +WD should always be considered in the differential +diagnosis of a movement disorder in a child. +MRI shows symmet- +ric hyperintensity on T2-weighted images in the puta- +men, caudate, and pallidum. +However, correlation of +imaging changes with clinical features is not good. +It is +very rare for WD patients with neurologic features not +to have KF rings. +Side effects are common and can to some degree be +attenuated by coadministration of pyridoxine. +Trien- +tine and zinc are useful drugs for maintenance therapy. +KF rings tend +to decrease after 3–6 months and disappear by 2 years. +Adherence to maintenance therapy is a major chal- +lenge in long-term care. +Tremor affecting the +upper limbs is the most common psychogenic move- +ment disorder. +13). +Patients with hypochondriasis, factitious dis- +orders, and malingering have a poor prognosis. +Roger N. +11 ). +Rarely, weakness of +proximal leg muscles mimics cerebellar disease. +39 ). +Hyponatremia has also been associated with +ataxia. +44 ). +43 ). +CT or MRI studies will +reveal clinically significant processes of this type. +Acute surgical decompression may be required +(Chap. +28). +Chronic etiologies of progressive ataxia include +multiple sclerosis (Chap. +39) and congenital lesions such +as a Chiari malformation (Chap. +35) or a congenital cyst +of the posterior fossa (Dandy-Walker syndrome). +Rarely, dementia is present as well. +The +clinical phenotypes of these SCAs overlap. +The geno- +type has become the gold standard for diagnosis and clas- +sification. +The most common disorders are discussed +later. +Dysarthria, dysphagia, and oculo- +motor and facial palsies may also occur. +Extrapyramidal +symptoms include rigidity, an immobile face, and par- +kinsonian tremor. +Dementia may be noted but is +usually mild. +Impairment of sphincter function is com- +mon, with urinary and sometimes fecal incontinence. +Cerebellar and brainstem atrophy are evident on MRI +(Fig. +31-1). +A few patients with +38–40 CAG repeats have been described. +Transgenic mice carry- +ing SCA1 developed ataxia and Purkinje cell pathology. +Normal alleles con- +tain 15–32 repeats; mutant alleles have 35–77 repeats. +In most populations, it is the most common +autosomal dominant ataxia. +Symptoms and signs +MJD has been classified into three clinical types. +Patellar and ankle +clonus are common, as are extensor plantar responses. +There is no truncal titubation. +Pharyngeal weakness and spasticity cause difficulty with +speech and swallowing. +MRI, magnetic resonance imaging; SCA1, +spinocerebellar ataxia type 1. +Type +II is the most common form of MJD. +Type II MJD can be distinguished +from the clinically similar disorders SCA1 and SCA2. +The mean age of onset of symptoms in MJD is +25 years. +Usually, +patients retain full intellectual function. +Purkinje cell loss and granule cell loss occur in +the cerebellar cortex. +Cell loss also occurs in the den- +tate nucleus and in the cranial nerve motor nuclei. +Spar- +ing of the inferior olives distinguishes MJD from other +dominantly inherited ataxias. +GENETIC CONSIDERATIONS +The gene for MJD maps to 14q24.3-q32. +An earlier age of onset +is associated with longer repeats. +MJD-ataxin codes for a ubiquitin protease, which +is inactive due to expanded polyglutamines. +Missense mutations in this gene result in +familial hemiplegic migraine. +The genetic defect is an expanded CAG +repeat in the SCA7 gene at 3p14-p21.1. +The expanded +repeat size in SCA7 is highly variable. +Marked anticipation has been recorded, especially with +paternal transmission. +The mutation is not fully penetrant. +Other features include nystagmus, leg spas- +ticity, and reduced vibratory sensation. +Severely affected +individuals are nonambulatory by the fourth to sixth +decades. +MRI shows cerebellar atrophy. +Larger expansions are found in patients with ear- +lier onset. +The number of repeats is 49 in patients with +DRPLA and f26 in normal individuals. +Startle, +sudden change in posture, and exercise can induce epi- +sodes. +Acetazolamide or anticonvulsants may be thera- +peutic. +Patients with EA-2 have episodes of ataxia with +nystagmus that can last for hours or days. +Stress, exer- +cise, or excessive fatigue may be precipitants. +The lower extremities are more severely +involved than the upper ones. +Loss of vibratory and proprioceptive sen- +sation occurs. +The median age of death is 35 years. +Women have a significantly better prognosis than men. +Cardiac involvement occurs in 90% of patients. +Car- +diomegaly, symmetric hypertrophy, murmurs, and con- +duction defects are reported. +Musculo- +skeletal deformities are common and include pes cavus, +pes equinovarus, and scoliosis. +MRI of the spinal cord +shows atrophy (Fig. +31-2). +Slight atrophy of the cerebellum and cerebral gyri may +occur. +The cerebral cortex is histologically normal +except for loss of Betz cells in the precentral gyri. +The +peripheral nerves are extensively involved, with a loss +of large myelinated fibers. +There is homozygosity for expanded +GAA repeats in >95% of patients. +Normal persons have +7–22 GAA repeats, and patients have 200–900 GAA +repeats. +Frataxin is a mitochondrial protein involved +in iron homeostasis. +Defects +in MTP result in impairment of formation and secre- +tion of VLDL in liver. +AVED is due to mutations in the gene for α-tocopherol +transfer protein (α-TTP). +The inferior olives of the medulla may also have +neuronal loss. +A poorly developed or absent thymus gland is the most +consistent defect of the lymphoid system. +Defective DNA repair in AT +fibroblasts exposed to ultraviolet light has been demon- +strated. +48). +Mass lesions must be recognized promptly and treated +appropriately. +44). +Malabsorption syndromes leading to +vitamin E deficiency may lead to ataxia. +Vitamin E +therapy is indicated for these rare patients. +Hypothyroidism is easily treated. +There is no proven therapy for any of the autosomal +dominant ataxias (SCA1 to SCA28). +Acetazolamide can reduce the dura- +tion of symptoms of episodic ataxia. +Robert H. +Brown, Jr. +12 ). +In ALS, the motor neu- +ron cytoskeleton is typically affected early in the illness. +This is the basis for the term +amyotrophy . +32-1 ) and brainstem to the lateral +and anterior white matter columns of the spinal cord. +A remarkable feature of the disease is the selec- +tivity of neuronal cell death. +Within the motor system, there +is some selectivity of involvement. +In the hands, a preponder- +ance of extensor over flexor weakness is common. +The latter +leads to involuntary excess in weeping or laughing (pseu- +dobulbar affect). +Dementia is not a component of sporadic ALS. +A committee of the World Federation of Neurology +has established diagnostic guidelines for ALS. +There are very rare reports of stabilization +or even regression of ALS. +In most societies there is an +incidence of 1–3 per 100,000 and a prevalence of 3–5 +per 100,000. +FAMILIAL ALS +Several forms of selective motor neuron disease are +inheritable (Table 32-3). +Familial ALS (FALS) involves +both corticospinal and lower motor neurons. +Rare mutations in other genes are also clearly impli- +cated in ALS-like diseases. +Mutations in senataxin, a heli- +case, cause an early adult-onset, slowly evolving ALS +variant. +Kennedy’s syndrome is an X-linked, adult- +onset disorder that may mimic ALS, as described later. +These are readily identi- +fied by appropriate laboratory tests. +Rarely, ALS develops concurrently with features +indicative of more widespread neurodegeneration. +Sandhoff +disease +5q Hexosamini- +dase B +AR Childhood Ganglioside +recycling +2. +AB variant 5q GM2-activator +protein +AR Childhood Ganglioside +recycling +3. +29). +In +other cases, ALS develops simultaneously with a strik- +ing frontotemporal dementia. +PATHOGENESIS +The cause of sporadic ALS is not well defined. +The mutant protein is conformation- +ally unstable and prone to aberrant catalytic reactions. +It has recently been observed that mutations in the +TDP43 and FUS/TLS genes also cause ALS. +In +one trial, the survival rate at 18 months with riluzole was +similar to placebo at 15 months. +Finger extension splints +can potentiate grip. +Respiratory support may be life- +sustaining. +This is highly effective in clearing airways and prevent- +ing aspiration pneumonia. +These facilitate oral com- +munication and may be effective for telephone use. +For this reason, a careful search for +causes of secondary motor neuron disease is warranted. +DNA test- +ing is available. +In rare +cases, spasticity may also be present, although it is gen- +erally absent. +Several clinical forms exist. +Though alert, afflicted infants are weak and +floppy (hypotonic) and lack muscle stretch reflexes. +Death generally ensues within the first year of life. +MMCB is not typically associated with corticospi- +nal signs. +There are +rare X-linked and autosomal dominant forms of appar- +ent SMA. +31). +The periph- +eral motor neurons and other neuronal systems are +spared. +39). +35). +The clini- +cal course and laboratory testing will distinguish these +possibilities. +FSP typically has a +long survival, presumably because respiratory function is +spared. +Some family members may have spas- +ticity without clinical symptoms. +More than 20 FSP genes have now been identified. +Another recessive variant is +caused by defects in the paraplegin gene. +Louis (www.neuro.wustl.edu/neuromuscular). +Phillip A. +Low ■ John W. +It regu- +lates blood pressure (BP), heart rate, sleep, and bladder +and bowel function. +Hypo- +thalamic disorders that cause disturbances in homeostasis +are discussed in Chap. +38. +33-1 ) . +These are +thinly myelinated. +Lesions of the +efferent limb cause the most consistent and severe OH. +Some syndromes do not +fi t easily into any classifi cation scheme. +Symptoms may be +widespread or regional in distribution. +It is also important to +recognize the modulating effects of age. +Specific symptoms of orthostatic intolerance are +diverse (Table 33-3). +Early symptoms may be overlooked. +Cold feet may indicate periph- +eral vasomotor constriction. +Gastrointestinal autonomic dysfunction typically pres- +ents as severe constipation. +Autonomic disorders with brain involvement + A. +Associated with multisystem degeneration + 1. +Multisystem degeneration: autonomic failure +clinically prominent + a. +Multiple system atrophy (MSA) + b. +Parkinson’s disease with autonomic failure + c. +Diffuse Lewy body disease (some cases) + 2. +Multisystem degeneration: autonomic failure +clinically not usually prominent + a. +Parkinson’s disease + b. +Unassociated with multisystem degeneration +(focal CNS disorders) + 1. +Disorders mainly due to cerebral cortex +involvement + a. +Frontal cortex lesions causing urinary/bowel +incontinence + b. +Partial complex seizures (temporal lobe or +anterior cingulate) +c. +Cerebral infarction of the insula + 2. +Disorders of the limbic and paralimbic circuits + a. +Shapiro’s syndrome (agenesis of corpus +callosum, hyperhidrosis, hypothermia) + b. +Autonomic seizures + c. +Limbic encephalitis + 3. +Disorders of the hypothalamus + a. +Wernicke-Korsakoff syndrome + b. +Diencephalic syndrome + c. +Neuroleptic malignant syndrome + d. +Serotonin syndrome + e. +Fatal familial insomnia + f. +Antidiuretic hormone syndromes (diabetes + insipidus, inappropriate ADH secretion) + g. +Disturbances of temperature regulation +(hyperthermia, hypothermia) + h. +Disturbances of sexual function + i. +Disturbances of appetite + j. +Disturbances of BP/HR and gastric function + k. +Horner’s syndrome + 4. +Disorders of the brainstem and cerebellum + a. +Posterior fossa tumors + b. +Syringobulbia and Arnold-Chiari malformation + c. +Disorders of BP control (hypertension, +hypotension) + d. +Cardiac arrhythmias + e. +Central sleep apnea + f. +Baroreflex failure + g. +Horner’s syndrome + h. +Vertebrobasilar and Wallenberg syndromes + i. +Brainstem encephalitis +II. +Autonomic disorders with spinal cord involvement +A. +Traumatic quadriplegia +B. +Syringomyelia +C. +Subacute combined degeneration +D. +Multiple sclerosis and Devic’s disease +E. +Amyotrophic lateral sclerosis +F. +Tetanus +G. +Stiff-man syndrome +H. +Spinal cord tumors +III. +Autonomic neuropathies +A. +Acute/subacute autonomic neuropathies +1. +Subacute autoimmune autonomic +ganglionopathy (AAG) +a. +Subacute paraneoplastic autonomic +neuropathy +b. +Guillain-Barré syndrome +c. +Botulism +d. +Porphyria +e. +Toxic autonomic neuropathies +g. +Subacute cholinergic neuropathy +B. +Chronic peripheral autonomic neuropathies +1. +Distal small fiber neuropathy +2. +Combined sympathetic and parasympathetic +failure +a. +Amyloid +b. +Diabetic autonomic neuropathy +c. +Autoimmune autonomic ganglionopathy +(paraneoplastic and idiopathic) +d. +Sensory neuronopathy with autonomic failure +e. +Familial dysautonomia (Riley-Day syndrome) +f. +Diabetic, uremic, or nutritional deficiency +g. +Dysautonomia of old age +3. +Syncope results when the drop in BP impairs +cerebral perfusion. +Neurocardiogenic and +cardiac causes of syncope are considered in Chap. +10. +Standing time to first symptom and presyncope +should be followed for management. +Physical examination includes measurement of supine +and standing pulse and BP. +The Valsalva response is tested in the supine +position. +There are four phases +of BP and heart rate response to the Valsalva maneuver. +Increased +total peripheral resistance arrests the BP drop ∼5–8 s +after the onset of the maneuver. +Late phase II begins with +a progressive rise in BP toward or above baseline. +Venous +return and cardiac output return to normal in phase IV. +Sudomotor Function Sweating is induced by +release of ACh from sympathetic postganglionic fibers. +CHAPTER 33 +Disorders of the Autonomic Nervous System +385 +ACh-induced sweating. +A reduced or absent response +indicates a lesion of the postganglionic sudomotor +axon. +The pattern of color +changes is a measure of regional sweat secretion. +A +postganglionic lesion is present if both QSART and TST +show absent sweating. +In a preganglionic lesion, QSART +is normal but TST shows anhidrosis. +A positive nitroglyc- +erin-stimulated test predicts recurrence of syncope. +SPECIFIC SYNDROMES OF ANS +DYSFUNCTION +MULTIPLE SYSTEM ATROPHY (CHAP. +SECTION III +Diseases of the Nervous System +386 +syndrome (MSA-c). +Although autonomic abnormalities are com- +mon in advanced Parkinson’s disease (Chap. +33-2). +MSA generally progresses relentlessly to death 7–10 +years after onset. +GI management includes frequent small meals, +soft diet, stool softeners, and bulk agents. +Domperidone has been used in +other countries but is not available in the United States. +Autonomic dysfunction is also a common feature in +dementia with Lewy bodies (Chap. +29); the severity is +usually less than that found in MSA or Parkinson’s dis- +ease. +In multiple sclerosis (MS; Chap. +Quadriparetic patients exhibit both supine +hypertension and OH after upward tilting. +Associated symptoms can include flushing, headache, or +piloerection. +In patients +with supine hypertension, BP can be lowered by tilt- +ing the head upward. +Vasodilator drugs may be used to +treat acute elevations in BP. +PERIPHERAL NERVE AND +NEUROMUSCULAR JUNCTION DISORDERS +Peripheral neuropathies (Chap. +45) are the most com- +mon cause of chronic autonomic insufficiency. +47). +FIGURE 33-2 +Multiple system atrophy, cerebellar type (MSA-c). +Treatment of familial cases with +liver transplantation can be successful. +The response of +primary amyloidosis to melphalan and stem cell trans- +plantation has been mixed. +Death is usually due to car- +diac or renal involvement. +Pathologic examination +reveals a loss of unmyelinated and myelinated nerve +fibers. +OH is usually due to +brainstem involvement. +28). +56). +Other prominent symptoms include anxiety, abdomi- +nal pain, nausea, and vomiting. +Abnormal autonomic +function can occur both during acute attacks and during +remissions. +Guillain-Barré syndrome (Chap. +46) +BP fluctuations and arrhythmias can be severe. +In general, the antibody +titer correlates with the severity of autonomic failure. +Symptoms of cholinergic failure are also associated with +a high antibody titer. +Onset of the neuropathy follows +a viral infection in approximately half of cases. +Symptomatic management of OH, gastro- +paresis, and sicca symptoms is essential. +AAN can have a paraneoplastic basis (Chap. +44). +The neoplasm may be truly +occult and possibly suppressed by the autoantibody. +The disorder begins in the middle decades +and occurs in women more often than men. +The +symptoms can be disabling, but the disease does not +shorten life span. +Some studies have questioned +the specificity of PAF as a distinct clinical entity. +Some +cases are ganglionic antibody–positive and thus rep- +resent a type of AAN. +Between 10 and 15% of cases +evolve into MSA. +Approximately half of +affected patients report an antecedent viral infection. +Recurrent unexplained episodes of dysautonomia and +fatigue also occur. +Some cases are due to an underlying limited autonomic +neuropathy. +Reconditioning and a sustained +exercise program are very important. +INHERITED DISORDERS +There are five known hereditary sensory and auto- +nomic neuropathies (HSAN I–V). +The most impor- +tant ones are HSAN I and HSAN III (Riley-Day syn- +drome; familial dysautonomia). +The responsible gene, +on chromosome 9q, is designated SPTLC1. +SPTLC +is an important enzyme in the regulation of ceramide. +Episodic abdominal crises and fever are +common. +Pathologic examination of nerves reveals a +loss of small myelinated and unmyelinated nerve fibers. +The defective gene, named IKBKAP, is also located on +the long arm of chromosome 9. +Onset of symptoms is +usually in adolescence; the condition tends to improve +with age. +Topical antiperspirants are occasionally help- +ful. +More useful are potent anticholinergic drugs such +as glycopyrrolate (1–2 mg PO tid). +T2 ganglionectomy +or sympathectomy is successful in >90% of patients +with palmar hyperhidrosis. +The surge +can cause seizures, neurogenic pulmonary edema, and +myocardial injury. +Phenylpropanol- +amine, now off the market, was in the past a potent +cause of this syndrome. +Cocaine, including “crack,” +can cause a hypertensive state with CNS hyperstimula- +tion. +The hyperadrenergic state with Guillain-Barré syn- +drome can produce a moderate autonomic storm. +Sepsis and +encephalitis need to be excluded with appropriate stud- +ies. +The patient should be managed +in an intensive care unit. +Treatment +may need to be maintained for several weeks. +For +chronic and milder autonomic storm, propranolol and/ +or clonidine can be effective. +38). +CRPS type I is a regional pain syndrome that usu- +ally develops after tissue trauma. +Pain is the primary clinical feature of CRPS. +The pain is diffuse, spontane- +ous, and either burning, throbbing, or aching in qual- +ity. +The involved extremity is warm and edematous, +and the joints are tender. +Increased sweating and hair +SECTION III +Diseases of the Nervous System +390 growth develop. +In phase II (3–6 months after onset), +thin, shiny, cool skin appears. +The natural history of typical CRPS may be more +benign than reflected in the literature. +PATIENT EDUCATION Only a minority of patients +with OH require drug treatment. +Other helpful measures may +include keeping a BP log and dietary education (salt/ +fluids). +SYMPTOMATIC TREATMENT Nonpharmaco- +logic approaches are summarized in Table 33-9. +Prolonged recumbency +should be avoided when possible. +The +hematocrit increases after 2–6 weeks. +A weekly mainte- +nance dose is usually necessary. +If these measures are not sufficient, drug treat- +ment may be necessary. +It has a duration of action of 2–4 h. +Midodrine +should not be taken after 6 P.M. +Fludrocortisone will reduce +OH, but it aggravates supine hypertension. +Potassium supplements are often +necessary with chronic administration of fludrocortisone. +Sustained elevations of supine BP >180/110 mmHg +should be avoided. +Postprandial OH may respond to several measures. +The subcutaneous dose ranges from 25 μg bid +to 200 μg tid. +The patient should be taught to self-treat transient +worsening of OH. +A daily glass of wine, if requested +by the patient, can be taken shortly before bedtime. +M. +Flint Beal ■ Stephen L. +Hauser +392 + Symptoms and signs of cranial nerve pathology are com- +mon in internal medicine. +Disorders of ocular movement are discussed in + Chap. +21 , disorders of hearing in Chap. +24 , and vertigo +and disorders of vestibular function in Chap. +11 . +34-1 ) . +Its motor part innervates the masseter and +pterygoid masticatory muscles. +Middle-aged and elderly persons are affected primarily, +and ∼60% of cases occur in women. +Remissions may be long-lasting, +but in most patients the disorder ultimately recurs. +8) and from pain +arising from diseases of the jaw, teeth, or sinuses. +Laboratory evaluation +An ESR is indicated if temporal arteritis is suspected. +Most patients require a maintenance dose of +200 mg qid. +Doses >1200 mg daily provide no additional +benefit. +If treatment is effective, it is usually con- +tinued for 1 month and then tapered as tolerated. +Baclofen may also +be administered, either alone or in combination with an +anticonvulsant. +The initial dose is 5–10 mg tid, gradually +increasing as needed to 20 mg qid. +If drug treatment fails, surgical therapy should be +offered. +This procedure requires a +suboccipital craniotomy. +It is used less often now than in the past. +Most present with sensory loss on the +face or with weakness of the jaw muscles. +Among infectious +causes, herpes zoster and leprosy should be considered. +Rarely, an idiopathic form of trigeminal neuropathy is +observed. +Gradual recovery is the rule. +34-2) The seventh cranial nerve supplies all the +muscles concerned with facial expression. +The motor +nucleus of the seventh nerve lies anterior and lateral to +the abducens nucleus. +It then passes +through the parotid gland and subdivides to supply the +facial muscles. +The lower lid sags and falls away from the +conjunctiva, permitting tears to spill over the cheek. +Food collects between the teeth and lips, and saliva may +dribble from the corner of the mouth. +If the nerve to the stapedius is interrupted, there is +hyperacusis (sensitivity to loud sounds). +The palpebral fissure becomes narrowed, and +the nasolabial fold deepens. +Facial spasms, ini- +tiated by movements of the face, may develop (hemifacial +spasm). +Anomalous regeneration of seventh nerve fibers +may result in other troublesome phenomena. +BELL’S PALSY +The most common form of facial paralysis is Bell’s palsy. +Pain +behind the ear may precede the paralysis for a day or +two. +Taste sensation may be lost unilaterally, and hyper- +acusis may be present. +In some cases there is mild cere- +brospinal fluid lymphocytosis. +Approximately +80% of patients recover within a few weeks or months. +The presence of incom- +plete paralysis in the first week is the most favorable +prognostic sign. +A +variety of other viruses have also been implicated less +commonly. +Motor nucleus +VI n. +V n. +1 +2 +3 +B +C +A +FIGURE 34-2 +The facial nerve. +(Adapted +from MB Carpenter: Core Text of Neuroanatomy, 2nd ed. +Facial palsy that +is often bilateral occurs in sarcoidosis and in Guillain- +Barré syndrome (Chap. +46). +Its cause is unknown. +Acoustic neuromas +frequently involve the facial nerve by local compression. +MRI often shows swelling and enhancement +of the facial nerve in idiopathic Bell’s palsy (Fig. +34-3). +Most cases +appear related to vascular compression of the exit- +ing facial nerve in the pons. +Mild cases can be treated +with carbamazepine, gabapentin, or, if these drugs fail, +with baclofen. +46). +It usually begins in adolescence or early adult years and +is slowly progressive. +The facial hair may turn white and fall +out, and the sebaceous glands become atrophic. +Bilat- +eral involvement may occur. +A limited form of systemic +sclerosis (scleroderma) may be the cause of some cases. +Treatment is cosmetic, consisting of transplantation of +skin and subcutaneous fat. +It resembles trigeminal neu- +ralgia in many respects but is much less common. +Spasms of pain may be initiated by +swallowing or coughing. +Cardiac symptoms—brady- +cardia or asystole, hypotension, and fainting—have +been reported. +Very rarely, herpes zoster involves the glossopharyn- +geal nerve. +Loss of sensation at +the external auditory meatus and the posterior pinna +may also be present. +This nerve +may be involved by infection with varicella zoster virus. +Dysphagia is also a symptom in some +patients with myotonic dystrophy. +However, a substan- +tial number of cases of recurrent laryngeal palsy remain +idiopathic. +Most +but not all patients recover. +Iso- +lated lesions of unknown cause can occur. +Atrophy and +fasciculation of the tongue develop weeks to months +after interruption of the nerve. +The opposite is true of primary lesions +within the brainstem. +A purely motor disorder +without atrophy always raises the question of myasthenia +gravis (Chap. +47). +As noted earlier, Guillain-Barré syn- +drome commonly affects the facial nerves bilaterally. +46). +28). +The cavernous sinus syndrome (Fig. +34-4) is a dis- +tinctive and frequently life-threatening disorder. +Anticoagulant therapy may benefit cases of primary +thrombosis. +Repair or occlusion of the carotid artery may +be required for treatment of fistulas or aneurysms. +The +Tolosa-Hunt syndrome generally responds to glucocorti- +coids. +The syndrome is frequently responsive to +glucocorticoids. +Ant. +cerebral a. +Int. +carotid a. +Ant. +clinoid process +Subarachnoid +space +Oculomotor (III) n. +Trochlear (IV) n. +Ophthalmic (VI) n. +Abducens (VI) n. +Maxillary (V2) n. +Hauser ■ Allan H. +Ropper +400 + Diseases of the spinal cord are frequently devastating. +DISEASES OF THE SPINAL CORD + CHAPTER 35 +dorsal sensory roots. +CHAPTER 35 +Diseases of the Spinal Cord +401 mately the first lumbar vertebral body. +The lower spinal +nerves take an increasingly downward course to exit +via intervertebral foramens. +15-2 and 15-3). +With +severe and acute transverse lesions, the limbs initially +may be flaccid rather than spastic. +The main features of transverse damage at each level +of the spinal cord are summarized next. +Cervical Cord Upper cervical cord lesions produce +quadriplegia and weakness of the diaphragm. +Useful +markers for localization are the nipples (T4) and umbi- +licus (T10). +Leg weakness and disturbances of bladder +and bowel function accompany the paralysis. +The bulbocaverno- +sus (S2-S4) and anal (S4-S5) reflexes are absent (Chap. +1). +Muscle strength is largely preserved. +Cauda equina syndromes are also discussed in +Chap. +9. +35-1. +Partial forms are more common than the +fully developed syndrome. +Spinal trauma, syringo- +myelia, and intrinsic cord tumors are the main causes. +C, cervical; D, distal; E, extensors; F, +flexors; L, lumbar; P, proximal; S, sacral; T, thoracic. +The result is extensive bilateral +tissue destruction that spares the posterior columns. +There is typically suboccipital pain spreading +to the neck and shoulders. +The differentiating features are only +relative and serve as clinical guides. +Consequently, a long duration +of symptoms favors an intradural origin. +There may be only mild sensory symptoms +or a devastating functional transection of the cord. +Paresthesias or numbness typically begins in the +feet and ascends symmetrically or asymmetrically. +Rarely, pain is mild or absent. +MRI provides +excellent anatomic resolution of the extent of spinal +tumors (Fig. +If spinal cord compression is suspected, imaging +should be obtained promptly. +Up to 40% of +FIGURE 35-2 +Epidural spinal cord compression due to breast carci- +noma. +The low-intensity bone marrow signal in A signifies +replacement by tumor. +Radiotherapy appears +to be effective even for most classically radioresistant +metastases. +Meningiomas (Fig. +Ther- +apy is by surgical resection. +Primary intramedullary tumors of the spinal cord +are uncommon. +In adults, these +lesions are ependymomas, hemangioblastomas, or low- +grade astrocytomas (Fig. +35-4). +FIGURE 35-4 +MRI of an intramedullary astrocytoma. +Irregular peripheral enhancement occurs within the +mass (arrows). +especially in patients with advanced metastatic disease +(Chap. +37), although these are not nearly as frequent as +brain metastases. +Prompt recognition of this distinctive process will +in most cases prevent permanent sequelae. +Aching pain +is almost always present, either over the spine or in a +radicular pattern. +As the abscess expands, further +spinal cord damage results from venous congestion and +thrombosis. +Once weakness and other signs of myelopa- +thy appear, progression may be rapid. +35-5). +MRI scans localize the abscess and exclude other +causes of myelopathy. +A high cervical tap is +sometimes the safest approach. +Blood +cultures are positive in <25% of cases. +Therapeutic anti- +coagulation, trauma, tumor, or blood dyscrasias are predis- +posing conditions. +Rare cases complicate lumbar puncture +or epidural anesthesia. +MRI and CT confirm the clinical +suspicion and can delineate the extent of the bleeding. +FIGURE 35-5 +MRI of a spinal epidural abscess due to tuberculosis. +A. +Sagittal T2-weighted free spin-echo MR sequence. +B. +Hematomyelia pres- +ents as an acute painful transverse myelopathy. +28). +Diagnosis is by MRI +or CT. +Therapy is supportive, and surgical intervention is +generally not useful. +MRI of spinal cord with and without contrast (exclude +compressive causes). +2. +3. +melitensis. +Also consider nasal/pharyngeal/anal cul- +tures for enteroviruses; stool O&P for Schistosoma ova. +4. +5. +6. +7. +Vascular causes: CT myelogram; spinal angiogram. +39); and infectious (primarily +viral) causes. +Sharp midline or radiating back +pain localized to the area of ischemia is frequent. +The antiphospholipid antibody syndrome is +treated with anticoagulation. +Some will later mani- +fest additional symptoms of an immune-mediated disease. +Multiple sclerosis +MS (Chap. +39) may present with acute myelitis, par- +ticularly in individuals of Asian or African ancestry. +There are no adequate trials of therapy for MS- +associated transverse myelitis. +A +course of plasma exchange is indicated for severe cases +if glucocorticoids are ineffective. +NMO is discussed in Chap. +39. +The usefulness of spinal +fluid ACE is uncertain. +As +in the related disorder acute disseminated encephalo- +myelitis (Chap. +Nonetheless, the two processes are often difficult to +distinguish. +Chronic viral myelitic infections, such as that due to +HIV, are discussed later. +Schistosomiasis is an important cause of parasitic myeli- +tis in endemic areas. +mansoni. +In some cases, coughing or straining pro- +duces leg weakness or radiating arm or shoulder pain. +A tendon reflex in the arms is +often diminished at some level, most often at the biceps +(C5-C6). +In individual cases, radicular, myelopathic, or +combined signs may predominate. +Cervical spondylo- +sis and related degenerative diseases of the spine are dis- +cussed in Chap. +9. +Most +common are fistulas located posteriorly along the surface +of the cord or within the dura. +Most patients have incomplete sensory, +motor, and bladder disturbances. +Pain over the dorsal spine, +dysesthesias, or radicular pain may be present. +Less commonly, AVM disorders are intramed- +ullary rather than dural. +Spinal bruits are infrequent but should be sought at +rest and after exercise in suspected cases. +High-resolution MRI with contrast administration +detects many but not all AVMs (Fig. +35-6). +Endovascular embolization +FIGURE 35-6 +Arteriovenous malformation. +Numerous punctate +flow voids indent the dorsal and ventral spinal cord (arrow). +These represent the abnormally dilated venous plexus +supplied by a dural arteriovenous fistula. +This patient was a 54-year-old man with a 4-year +history of progressive paraparesis. +Approxi- +mately half of patients have mild back or leg pain. +This presentation may resemble pri- +mary progressive MS or a thoracic AVM. +A progressive myelopathy may also result from HIV +infection (Chap. +42). +Many +young patients acquire a cervical-thoracic scoliosis. +35-7). +FIGURE 35-7 +MRI of syringomyelia associated with a Chiari malforma- +tion. +TREATMENT Syringomyelia +Treatment of syringomyelia is generally unsatisfactory. +Obstruction of fourth +ventricular outflow is reestablished by this procedure. +Surgery may stabilize the +neurologic deficit, and some patients improve. +Cases due to intramedullary spinal cord +tumor are generally managed by resection of the tumor. +Diagnosis is facili- +tated by identification of earlier attacks such as optic +neuritis. +MRI, CSF, and evoked-response testing are +confirmatory. +The value of +anti-B cell therapy in primary progressive MS is under +investigation. +MS is discussed in Chap. +39. +Low levels of serum copper are +found and often there is also a low level of serum ceru- +loplasmin. +Many cases +are idiopathic. +The pathophysiology and pathology of +the idiopathic form are not known. +Ataxia of +the legs and gait due to loss of position sense occurs in +half of patients. +Diabetic polyradiculopathy +may simulate tabes. +32). +Sensory symptoms and signs are +absent or mild, but sphincter disturbances may be pres- +ent. +The onset may be as early as the first year of life or +as late as middle adulthood. +Only symptomatic therapies +for the spasticity are currently available. +ADRENOMYELONEUROPATHY +This X-linked disorder is a variant of adrenoleukodys- +trophy. +OTHER CHRONIC MYELOPATHIES +Primary lateral sclerosis (Chap. +Sensory function is spared. +Treatment is with surgical release. +37) +and rare paraneoplastic myelopathies. +The latter are most +often associated with lung or breast cancer and anti-Hu +antibodies (Chap. +44); NMO can also be paraneoplastic +in origin (Chap. +39). +Metastases to the cord are probably +more common than either of these in patients with can- +cer. +Often, a cause of intrinsic myelopathy can be identi- +fied only through periodic reassessment. +Even a com- +plete high cervical cord lesion may be compatible with +a productive life. +Bladder areflexia due to acute spinal shock or +conus lesions is best treated by catheterization. +Patients with acute cord injury are at risk for venous +thrombosis and pulmonary embolism. +In cases of +persistent paralysis, anticoagulation should probably be +continued for 3 months. +Randomized controlled +studies indicate that gabapentin or pregabalin is useful in +this setting. +Management of chronic pain is discussed in +Chap. +7. +Allan H. +17 ). +The mechanism of amnesia is not +known. +Amnesia is discussed in Chap. +18 . +Trauma sufficient +to cause prolonged unconsciousness usually produces +some degree of contusion. +A hemiparesis or gaze preference is fairly typical of +moderately sized contusions. +Con- +tusions in the temporal lobe may cause delirium or an +aggressive, combative syndrome. +36-1) and +some subarachnoid bleeding. +Blood in the cerebrospinal +fluid (CSF) due to trauma may provoke a mild inflam- +matory reaction. +17), but small ischemic-hemorrhagic lesions in +the midbrain and thalamus are as often the cause. +FIGURE 36-1 +Traumatic cerebral contusion. +Noncontrast CT scan dem- +onstrating a hyperdense hemorrhagic region in the anterior +temporal lobe. +Consequently, +fractures are primarily markers of the site and severity of +injury. +Severe +orthostatic headache results from lowered pressure in +the spinal fluid compartment. +Most fractures are linear and extend from the point +of impact toward the base of the skull. +The location of an intermittent leak is rarely delineated, +and many resolve spontaneously. +Fractures of the dorsum sella cause sixth or seventh +nerve palsies or optic nerve damage. +Delayed palsy, the mechanism of which is +unknown, has a good prognosis. +Dizziness, +tinnitus, and high-tone hearing loss occur from cochlear +concussion. +26). +The severity of injury +roughly determines the risk of future seizures. +Penetrating inju- +ries have a much higher rate of subsequent epilepsy. +Acute subdural hematoma (Fig. +Stupor or coma, hemiparesis, and unilateral pupillary +enlargement are signs of larger hematomas. +36-3). +Epidural hematoma (Fig. +36-4) +These evolve more rapidly than subdural hematomas +and are correspondingly more treacherous. +Most patients are unconscious +when first seen. +Compare to Fig. +36-4. +FIGURE 36-4 +Acute epidural hematoma. +CHAPTER 36 +Concussion and Other Head Injuries +419 sequence. +Chronic subdural hematoma (Fig. +Headache is common but +not invariable. +The headache fluctuates in severity, some- +times with changes in head position. +CT without contrast initially shows a low-density +mass over the convexity of the hemisphere (Fig. +36-5). +MRI +reliably identifies subacute and chronic hematomas. +Small hematomas are resorbed, leaving only +the organizing membranes. +Vasovagal syncope that follows +injury may cause undue concern. +Generalized or frontal +headache is common in the following days. +It may be +migrainous (throbbing and hemicranial) in nature or +aching and bilateral. +SECTION III +Diseases of the Nervous System +420 that can be anticipated after discharge. +A cerebral contu- +sion or hematoma is usually found. +Grade 3: Any LOC, either brief (seconds) or prolonged (minutes). +On-Site Evaluation +1. +Mental status testing + a. +Orientation—time, place, person, circumstances of injury + b. +Concentration—digits backward, months of year in reverse order + c. +Finger-to-nose with eyes open and closed +3. +Pupillary symmetry and reaction +4. +Romberg and tandem gait +5. +Examine immediately and at 5-min intervals. +May return to contest if exam clears within 15 min. +Grade 2: Remove from contest, cannot return for at least 1 week. +Examine at frequent intervals on sideline. +Formal neurologic +exam the next day. +If headache or other symptoms persist for 1 week or longer, CT or MRI scan is indicated. +If imaging +shows abnormality, player is removed from play for the season. +Neurologic exam and, when indicated, CT or MRI scan will guide subsequent management. +The American Academy of Neurology, St. +Paul, MN, 1997. +After surgical removal of hematomas, most patients +in this category improve over weeks. +Persistent cognitive problems are +discussed later. +Management of raised ICP, a frequent +feature of severe head injury, is discussed in Chap. +28. +Over 85% of patients with aggregate +scores of <5 die within 24 h. +The syndrome +simulates asthenia and anxious depression. +Intermediate +scores correlate with proportional chances of recovery. +Care is taken to avoid prolonged use of drugs that +produce dependence. +Headache may initially be treated +with acetaminophen and small doses of amitryptiline. +Vestibular exercises (Chap. +Previ- +ously energetic and resilient individuals usually have the +best recoveries. +Lisa M. +DeAngelis ■ Patrick Y. +At least +one-half of these tumors are malignant and associated +with a high mortality rate. +Headache may be accompanied by nau- +sea or vomiting when intracranial pressure is elevated. +Focal or lateral- +izing fi ndings include hemiparesis, aphasia, or visual +fi eld defect. +Lateralizing symptoms such as hemipare- +sis are typically subacute and progressive. +Language diffi culties may be mistaken for con- +fusion. +CT scan should be reserved for +those patients unable to undergo MRI (e.g., pacemaker). +Dural metastases or a dural lymphoma +can have a similar appearance. +In such patients a brain biopsy may be helpful +in determining a definitive diagnosis. +Neuroimaging is the only test necessary to diagnose a +brain tumor. +However, +symptomatic treatments apply to brain tumors of any +type. +Patients with brain tumors who present with seizures, +require anticonvulsant drug therapy. +The agents +of choice are those drugs that do not induce the hepatic +microsomal enzyme system. +These include levetirace- +tam, topiramate, lamotrigine, valproic acid, or lacos- +amide (Chap. +26). +A small minority of patients have a family history of +brain tumors. +Some of these familial cases are associated +with genetic syndromes (Table 37-2). +37-1). +The majority are primary glioblastomas. +The molecular subtypes of +medulloblastomas are also being elucidated. +Grades I and II are con- +sidered low-grade, and grades III and IV high-grade, +astrocytomas. +Low-grade astrocytoma +These tumors occur predominantly in children and +young adults. +Grade I astrocytomas +Pilocytic astrocytomas (WHO grade I) are the most +common tumor of childhood. +A slash indicates one or the other or both. +Fre- +quently they appear as cystic lesions with an enhanc- +ing mural nodule. +They are potentially curable if they +can be completely resected. +They appear as nonenhancing +tumors with increased T2/FLAIR signal (Fig. +37-2). +They generally present in the fourth +and fifth decades of life as variably enhancing tumors. +This lesion did not enhance. +The +tumors appear as ring-enhancing masses with central +necrosis and surrounding edema (Fig. +37-3). +Note +the decreased enhancement and mass effect. +Despite optimal therapy, glioblastomas invariably +recur. +Reirradiation is rarely +helpful. +37-4). +Whenever feasible, patients with recur- +rent disease should be enrolled in clinical trials. +Treatment involves radiotherapy +and temozolomide chemotherapy. +Oligodendroglioma +Oligodendrogliomas account for approximately 15–20% +of gliomas. +Some tumors have both an oligodendroglial as +well as an astrocytic component. +These tumors present +similarly to grade II astrocytomas in young adults. +The +tumors are nonenhancing and often partially calcified. +They should be treated with surgery and, if necessary, +radiotherapy and chemotherapy. +Patients with oligoden- +drogliomas have a median survival in excess of 10 years. +They +are more responsive to therapy than grade III astrocytomas. +Median survival of patients with AO or AOA is approxi- +mately 3–6 years. +Ependymomas +Ependymomas are tumors derived from ependymal +cells that line the ventricular surface. +Ependy- +momas that can be completely resected are potentially +curable. +Partially resected ependymomas will recur and +require irradiation. +Other less common gliomas +Gangliogliomas and pleomorphic xanthoastrocytomas occur +in young adults. +They behave as more indolent forms of +grade II gliomas and are treated in the same way. +Brainstem +gliomas usually occur in children or young adults. +For unclear reasons, +its incidence is increasing, particularly in immunocom- +petent individuals. +PCNSL in immunocompetent patients usually con- +sists of diffuse large B-cell lymphomas. +The +periventricular location and diffuse enhancement pattern are +characteristic of lymphoma. +immunocompromised with CD4 counts of less than +50/mL. +On contrast-enhanced MRI, PCNSL usually appears +as a densely enhancing tumor (Fig. +37-5). +Immuno- +competent patients have solitary lesions more often +than immunosuppressed patients. +Frequently there is +involvement of the basal ganglia, corpus callosum, or +periventricular region. +Stereotactic biopsy is necessary +to obtain a histologic diagnosis. +Bone +marrow biopsy and testicular ultrasound are occasion- +ally performed. +Durable complete responses and long-term +survival are possible with these treatments. +As a result +radiotherapy is frequently omitted in older patients with +PCNSL. +At least 50% of patients will eventually develop +recurrent disease. +In organ +transplant recipients, reduction of immunosuppression +may improve outcome. +They present with headache, +ataxia, and signs of brainstem involvement. +Seeding of the CSF is common. +A major +goal of current research is to improve survival while +minimizing long-term complications. +PINEAL REGION TUMORS +A large number of tumors can arise in the region of the +pineal gland. +These typically present with headache, +visual symptoms, and hydrocephalus. +Patients may +have Parinaud’s syndrome characterized by impaired +upgaze and accommodation. +They are now the most common pri- +mary brain tumor, accounting for approximately 32% +of the total. +Their incidence increases with age. +They +tend to be more common in women and in patients +with neurofibromatosis type 2. +They also occur more +commonly in patients with a past history of cranial +irradiation. +Many meningiomas are found incidentally follow- +ing neuroimaging for unrelated reasons. +They can also +present with headaches, seizures, or focal neurologic +deficits. +37-6). +The main differential diagnosis +of meningioma is a dural metastasis. +Larger, symptomatic lesions +should be resected surgically. +If complete resection is +achieved, the patient is cured. +These treat- +ments may also be helpful in patients whose tumor has +recurred after surgery. +Hormonal therapy and chemo- +therapy are currently unproven. +Rarer tumors that resemble meningiomas include +hemangiopericytomas and solitary fibrous tumors. +are treated with surgery and radiotherapy but have a +higher propensity to recur. +37-7). +The differential diagnosis includes menin- +gioma. +Very small, asymptomatic lesions can be +observed with serial MRIs. +Larger lesions should be +treated with surgery or stereotactic radiosurgery. +The tumor can be seen to involve the internal auditory canal. +SECTION III +Diseases of the Nervous System +432 symptoms, and the patient’s preference. +PITUITARY TUMORS (CHAP. +38) +These account for approximately 9% of primary brain +tumors. +They can be divided into functioning and +nonfunctioning tumors. +Treatment involves surgery, radiother- +apy, or the combination of the two. +They typically occur in children and +young adults with a long-standing history of seizures. +If +the seizures are refractory, surgical resection is curative. +Epidermoid cysts +These consist of squamous epithelium surrounding a +keratin-filled cyst. +They may present with headaches, cra- +nial nerve abnormalities, seizures, or hydrocephalus. +Treatment involves surgical resection. +Unlike epidermoid cysts, these tumors usually +have a midline location. +Symptomatic dermoid cysts +can be treated with surgery. +Most of these disorders have an autosomal dominance +inheritance with variable penetrance. +It is an autosomal dominant dis- +order with full penetrance. +As with NF1, approxi- +mately half the cases arise from new mutations. +These patients +may also have posterior subcapsular lens opacities and +retinal hamartomas. +Patients frequently require anticonvulsants +for seizures. +SEGAs often do not need treatment but +occasionally require surgical resection. +There is emerg- +ing evidence that mTOR inhibitors may have activity +in SEGAs. +Other tumor types such as ovarian and esophageal car- +cinoma rarely metastasize to the brain. +37-8). +Enhancement may be in a ring pat- +tern or diffuse. +Note the diffuse +enhancement pattern and absence of central necrosis. +Brain metastases are single in +approximately one-half of patients and multiple in the +other half. +However, it is not curative. +Median survival is only 4–6 months. +Surgical resection can afford rapid symptomatic +improvement and prolonged survival. +CHEMOTHERAPY Chemotherapy is rarely use- +ful for brain metastases. +of patients with brain metastases because they have a +known systemic cancer. +37-9). +Demonstration of tumor cells in the CSF is defini- +tive and often considered the gold standard. +CSF cytologic exami- +nation is most useful in hematologic malignancies. +Nodules along the dorsal +surface of the spinal cord (A) and cauda equina (B) are seen. +but is useful when present. +Systemic chemotherapy with agents that +can penetrate the blood-CSF barrier may be helpful. +In addition, impaired CSF flow +dynamics can compromise intrathecal drug delivery. +However, it +compromises delivery of chemotherapy into the CSF. +The thoracic spine is affected +most commonly, followed by the lumbar and then cer- +vical spine. +Leg weakness is +seen in about 50% of patients as is sensory dysfunction. +Sphincter problems are present in about 25% of patients +at diagnosis. +37-10). +Con- +trast is not needed to identify spinal or epidural lesions. +Any patient with cancer who has severe back pain +should undergo an MRI. +TREATMENT Epidural Metastasis +Epidural metastasis requires immediate treatment. +Patients generally fare well if +treated before there is severe neurologic deficit. +Acute toxicity +Acute cerebral toxicity usually occurs during RT to the +brain. +There is no acute RT toxicity that affects the +spinal cord. +Pseudoprogression can resolve on +its own or, if very symptomatic, may require resection. +Leukoencephalopathy is seen most commonly after +WBRT as opposed to focal RT. +Increased age is a +risk factor for leukoencephalopathy but not for radia- +tion necrosis. +Necrosis appears to depend on an as yet +unidentified predisposition. +The peripheral nervous system is relatively resistant +to RT toxicities. +Peripheral nerves are rarely affected +by RT, but the plexus is more vulnerable. +Radiation plexopathy is also more commonly associated +with lymphedema of the affected limb. +Sensory loss and +weakness are seen in both. +The taxanes also cause a predom- +inately sensory neuropathy. +Agents such as bortezomib +and thalidomide also cause neuropathy. +Encephalopathy and seizures are common toxici- +ties from chemotherapeutic drugs. +Fludarabine also causes a +severe global encephalopathy that may be permanent. +Bevacizumab and other anti-VEGF agents can cause +posterior reversible encephalopathy syndrome. +Cispla- +tin can cause hearing loss and less frequently vestibular +dysfunction. +Shlomo Melmed ■ J. +Abbreviations: M, male; F, female. +For other abbreviations, see text. +Totowa, NJ, Humana, +2005. +440 +SECTION III +Diseases of the Nervous System +an array of specific hypothalamic releasing factors. +Each +of these pituitary hormones elicits specific responses in +peripheral target tissues. +38-1). +Pituitary tumors cause +characteristic hormone-excess syndromes. +Hormone +deficiency may be inherited or acquired. +Peripheral hormones feed back to regu- +late hypothalamic and pituitary hormones. +For abbreviations, +see text. +38-2). +Posterior pituitary hormones are +derived from direct neural extensions. +38-3). +The posterior pituitary is supplied by the inferior +hypophyseal arteries. +Autosomal dominant or +recessive Pit-1 mutations cause combined GH, PRL, +and TSH deficiencies. +These patients usually present +with growth failure and varying degrees of hypothy- +roidism. +The pituitary may appear hypoplastic on MRI. +Prop-1 is expressed early in pituitary development +and appears to be required for Pit-1 function. +Because of +gonadotropin deficiency, these individuals do not enter +puberty spontaneously. +In some cases, the pituitary +gland is enlarged. +TPIT mutations result in ACTH defi- +ciency associated with hypocortisolism. +Genetic +abnormalities, in addition to KAL mutations, also can +cause isolated GnRH deficiency. +GnRH deficiency prevents +progression through puberty. +Females present with primary amenor- +rhea and failure of secondary sexual development. +Central diabetes insipidus may or may not be associ- +ated. +GnRH deficiency occurs in 75% of males and +half of affected females. +Retinal degeneration begins in +early childhood, and most patients are blind by age 30. +Multiple somatic +defects also involve the skull, eyes, ears, hands, and feet. +Diminished hypothalamic oxytocin- and vasopressin- +producing nuclei have been reported. +Consequently, diabetes insipidus occurs +in half of patients with these disorders. +Growth retar- +dation is seen if attenuated GH secretion occurs before +pubertal epiphyseal closure. +Hypogonadotropic hypo- +gonadism and hyperprolactinemia are also common. +Most +patients manifest symptoms of progressive mass effects +with headache and visual disturbance. +The erythro- +cyte sedimentation rate often is elevated. +Therefore, severe +ophthalmoplegia or visual deficits are indications for +early surgery. +Hypopituitarism is very common after +apoplexy. +Empty sella +A partial or apparently totally empty sella is often an +incidental MRI finding. +Hypopi- +tuitarism, however, may develop insidiously. +TSH and ACTH deficiency usually develop later in +the course of pituitary failure. +PRL deficiency causes failure +of lactation. +Provocative tests may be required to assess pituitary +reserve (Table 38-3). +Effective dosage schedules are out- +lined in Table 38-4. +Note: For abbreviations, see text. +Note: For abbreviations, see text. +Note: For abbreviations, see text. +responsiveness to physiologic inhibitory pathways. +Hor- +mone production does not always correlate with tumor +size. +True pituitary carcinomas with documented +extracranial metastases are exceedingly rare. +Several etiologic genetic events have been implicated +in the development of pituitary tumors. +Compelling evidence also favors growth factor pro- +motion of pituitary tumor proliferation. +Acromeg- +aly occurs in about 20% of these patients. +A subset of +patients have mutations in the R1α regulatory subunit +of protein kinase A (PRKAR1A). +The Gsα mutations occur postzygotically, leading +to a mosaic pattern of mutant expression. +The disorder is associated with LOH at a chromosome +11q13 locus distinct from that of MENIN. +Craniopharyngiomas are often large, cystic, and +locally invasive. +About half of affected children present with +growth retardation. +Most patients require lifelong pituitary hormone +replacement. +Rarely, hydrocephalus develops. +Cyst contents range from CSF-like fluid to +mucoid material. +Arachnoid cysts are rare and generate an +MRI image that is isointense with cerebrospinal fluid. +Mucinous material may be obtained by fine-needle +aspiration. +Meningiomas typically enhance on MRI and may +show evidence of calcification or bony erosion. +Menin- +giomas may cause compressive symptoms. +Histiocytosis X includes a variety of syndromes asso- +ciated with foci of eosinophilic granulomas. +Rarely, the pituitary +stalk may be involved. +Pituitary metastases occur in ∼3% of cancer patients. +Bloodborne metastatic deposits are found almost exclu- +sively in the posterior pituitary. +Rarely, pituitary stalk involvement results +in anterior pituitary insufficiency. +Primary or metastatic lymphoma, leukemias, and plas- +macytomas also occur within the sella. +These tumors may +overexpress hypothalamic neuropeptides, including +GnRH, GHRH, and CRH. +Adults +have more aggressive tumors; about a third are associ- +ated with neurofibromatosis. +Brain germ cell tumors may arise within the sellar +region. +They rarely metastasize. +Many +patients are GH-deficient with short stature. +Acute hyperthermia usually +is due to a hemorrhagic insult, but poikilothermia may +also occur. +Central disorders of thermoregulation result +from posterior hypothalamic damage. +These patients are predisposed to cardiac arrhythmias, +hypertension, and gastric erosions. +Bony inva- +sion may occur as well. +Bony erosion is +rare, as is direct brain compression. +Microadenomas may present +with headache. +34). +The stalk should be midline and vertical. +CT scan is reserved to define the extent of bony erosion +or the presence of calcification. +38-4). +images. +If hormone +hypersecretion is evident, specific therapies are indi- +cated. +21). +Homonymous cuts reflect post- +chiasmal lesions, and monocular field cuts prechiasmal +lesions. +Loss of red perception is an early sign of optic +tract pressure. +Early diagnosis reduces the risk of blind- +ness, scotomas, or other visual disturbances. +Additional +hormonal evaluation may be indicated based on the +results of these tests. +Occasionally, ultrastructural +assessment by electron microscopy is required for diagnosis. +Most pituitary tumors +are benign and slow-growing. +Thus, lifelong +management and follow-up are necessary for these +patients. +Ideally, adenoma recurrence should be pre- +vented. +38-5). +and +fasting plasma +cortisol mea- +sured at 8 A.M. +Operative mor- +tality rate is about 1%. +Transient diabetes insipidus and +hypopituitarism occur in up to 20% of patients. +CSF leaks occur in 4% of +patients. +Permanent side effects are rare after surgery +for microadenomas. +A total of <50 Gy +(5000 rad) is given as 180-cGy (180-rad) fractions divided +over about 6 weeks. +In contrast, PRL- and GH-secreting tumor tissues +are amenable to medical therapy. +Side Effects In the short term, radiation may cause +transient nausea and weakness. +Alopecia and loss of +taste and smell may be more long-lasting. +The use of stereotactic radiother- +apy may reduce damage to adjacent structures. +For prolacti- +nomas, dopamine agonists are the treatment of choice. +For acromegaly, somatostatin analogues and GH recep- +tor antagonists are indicated. +PRL is synthesized in lactotropes, +which constitute about 20% of anterior pituitary cells. +These transient functional changes +in the lactotrope population are induced by estrogen. +SECRETION +Normal adult serum PRL levels are about 10–25 μg/L +in women and 10–20 μg/L in men. +Peak serum PRL +levels (up to 30 μg/L) occur between 4:00 and 6:00 A.M. +The circulating half-life of PRL is about 50 min. +Pituitary dopamine type +2 (D2) receptors mediate inhibition of PRL synthesis +and secretion. +Breast suckling activates neu- +ral afferent pathways in the hypothalamus that induce +PRL release. +With time, suckling-induced responses +diminish and interfeeding PRL levels return to normal. +In men, attenuated LH +secretion leads to low testosterone levels and decreased +spermatogenesis. +These hormonal changes decrease libido +and reduce fertility in patients with hyperprolactinemia. +Pregnancy and lactation are the important physi- +ologic causes of hyperprolactinemia. +Sleep-associated +hyperprolactinemia reverts to normal within an hour of +awakening. +Nipple stimulation and sexual orgasm also +may increase PRL. +Chronic renal failure elevates PRL by decreasing +peripheral clearance. +Plurihormonal adenomas (including GH +and ACTH tumors) may hypersecrete PRL directly. +Hormonal agents that induce PRL +include estrogens and TRH. +If hyperprolac- +tinemia develops before menarche, primary amenorrhea +results. +Galac- +torrhea is present in up to 80% of hyperprolactinemic +women. +Although usually bilateral and spontaneous, it +may be unilateral or expressed only manually. +Patients +also may complain of decreased libido, weight gain, and +mild hirsutism. +Physiologic hypersecretion +Pregnancy +Lactation +Chest wall stimulation +Sleep +Stress +II. +Pituitary hypersecretion +Prolactinoma +Acromegaly +IV. +455 + +CHAPTER 38 +Neurologic Disorders of the Pituitary and Hypothalamus +and oligospermia. +True galactorrhea is uncommon in +men with hyperprolactinemia. +Some +of these patients may harbor small microadenomas +below visible MRI sensitivity (∼2 mm). +Galactorrhea may occur +spontaneously, or it may be elicited by nipple pressure. +Acromegaly is associated with galactorrhea in about +one-third of patients. +Both false- +positive and false-negative results may be encountered. +Hypothyroidism should be excluded by measuring TSH +and T4 levels. +Granulomatous infiltrates occasionally +respond to glucocorticoid administration. +In patients +with irreversible hypothalamic damage, no treatment +may be warranted. +Microadenomas are classified as <1 cm in diam- +eter and usually do not invade the parasellar region. +PRL lev- +els remain stable in most patients, reflecting the slow +growth of these tumors. +About 5% of microadenomas +progress in the long term to macroadenomas. +Presentation and diagnosis +Women usually present with amenorrhea, infertility, +and galactorrhea. +For this reason, +an MRI should be performed in all patients with hyper- +prolactinemia. +MRI, magnetic resonance imaging; PRL, prolactin. +enlargement; these patients should be monitored by +regular serial PRL and MRI measurements. +38-6). +A nor- +malized PRL level does not ensure reduced tumor size. +However, tumor shrinkage usually is not seen in those +who do not respond with lowered PRL levels. +Dopamine agonists +suppress PRL secretion and synthesis as well as lacto- +trope cell proliferation. +These patients should be moni- +tored carefully for evidence of prolactinoma recurrence. +D2 receptor gene mutations in the pituitary +have not been reported. +Cabergoline normalizes PRL and +shrinks ∼70% of macroprolactinomas. +Cabergoline also may be effective in patients resistant to +bromocriptine. +Adverse effects and drug intolerance are +encountered less commonly than with bromocriptine. +Because it is short-acting, +the drug is preferred when pregnancy is desired. +Most +patients are controlled with a daily dose of ≤7.5 mg +(2.5 mg tid). +These symptoms may persist in some +patients. +In general, fewer side effects are reported with +cabergoline. +Nonetheless, most +authorities recommend strategies to minimize fetal +exposure to the drug. +Surgical decompression may be indicated +if vision is threatened. +Five distinct +genes encode GH and related proteins. +SECRETION +GH secretion is controlled by complex hypothalamic +and peripheral factors. +GHRH is a 44-amino-acid +hypothalamic peptide that stimulates GH synthesis and +release. +Surface receptors on the somatotrope regulate GH +synthesis and secretion. +Inactivating mutations of the GHRH receptor cause +profound dwarfism (discussed later). +These changes are paralleled by an +age-related decline in lean muscle mass. +Integrated 24-h GH secretion is higher in women and +is also enhanced by estrogen replacement. +GH secretion is profoundly influenced by nutritional +factors. +β-Adrenergic blockage +induces basal GH and enhances GHRH- and insulin- +evoked GH release. +ACTION +The pattern of GH secretion may affect tissue responses. +The +liver and cartilage contain the greatest number of GH +receptors. +A GH receptor antagonist (pegvisomant) is approved for +treatment of acromegaly. +GH stimulates epiphyseal +prechondrocyte differentiation. +The liver is the major source of circulating IGF-I. +GH deficiency and malnutrition usually are asso- +ciated with low IGFBP3 levels. +Serum IGF-I concentrations are profoundly affected +by physiologic factors. +IGF-I concentrations are +higher in women than in men. +IGF-I physiology +IGF-I has been approved for use in patients with GH- +resistance syndromes. +Longer-term subcutaneous IGF-I injections +enhance protein synthesis and are anabolic. +Although +bone formation markers are induced, bone turnover also +may be stimulated by IGF-I. +Avascular +femoral head necrosis has been reported. +Chronic excess +IGF-I administration presumably would result in features +of acromegaly. +Malnutrition +impairs chondrocyte activity and reduces circulating +IGF-I and IGFBP3 levels. +Linear bone growth rates are very high in infancy and +are pituitary-dependent. +Peak +growth rates occur during midpuberty when bone age is +12 (girls) or 13 (boys). +Growth hormone insensitivity +This is caused by defects of GH receptor structure or +signaling. +Very rarely, defective IGF-I, IGF-I receptor, or IGF-I +signaling defects are also encountered. +Circulating GH receptor anti- +bodies may rarely cause peripheral GH insensitivity. +A nurturing environment restores growth rates. +Random GH +measurements do not distinguish normal children from +those with true GH deficiency. +Adequate adrenal and +thyroid hormone replacement should be assured before +testing. +Pituitary MRI +may reveal pituitary mass lesions or structural defects. +The sequential order of hormone loss is usually +GH → FSH/LH → TSH → ACTH. +Bone mineral content is reduced, +with resultant increased fracture rates. +For other abbrevia- +tions, see text. +testing should be selected carefully on the basis of well- +defined criteria. +A significant proportion (∼25%) of truly GH-defi- +cient adults have low-normal IGF-I levels. +38-7). +Women +require higher doses than men, and elderly patients +require less GH. +Lumbar spine bone mineral +density increases, but this response is gradual (>1 year). +Patients with type 2 +diabetes mellitus initially develop further insulin resis- +tance. +Headache, increased intracranial pres- +sure, hypertension, and tinnitus occur rarely. +To date, development of these potential side +effects does not appear significant. +IGF, insulin-like growth factor. +Abbreviations: GH, growth hormone; PRL, prolactin. +The most common cause of GHRH- +mediated acromegaly is a chest or abdominal carcinoid +tumor. +Excessive GHRH also may be elabo- +rated by hypothalamic tumors, usually choristomas or +neuromas. +38-8). +The most significant clinical impact of GH excess +occurs with respect to the cardiovascular system. +Laboratory investigation +Age- and sex-matched serum IGF-I levels are elevated +in acromegaly. +Their clinical features began to +diverge at the age of approximately 13 years. +When newer ultrasensitive GH assays are used, +normal nadir GH levels are even lower (<0.05 μg/L). +About 20% of patients exhibit a paradoxical GH rise +after glucose. +PRL should be measured, as it is elevated +in ∼25% of patients with acromegaly. +Surgical resection of GH-secreting adenomas is the +initial treatment for most patients (Fig. +38-9). +Irradiation is also relatively ineffective in +normalizing IGF-I levels. +Somatostatin analogues +may be required while awaiting the full benefits of +radiotherapy. +Mandibular surgical +repair may be indicated. +Soft tissue swelling +improves immediately after tumor resection. +GH levels +return to normal within an hour, and IGF-I levels are +normalized within 3–4 days. +Octreotide acetate is +an eight-amino-acid synthetic somatostatin analogue. +In +contrast to native somatostatin, the analogue is relatively +resistant to plasma degradation. +Fewer +than 10% of patients do not respond to the analogue. +Side Effects Somatostatin analogues are well toler- +ated in most patients. +GH lev- +els, however, remain elevated as the drug does not have +antitumor actions. +Side effects include reversible liver +enzyme elevation, lipodystrophy, and injection site pain. +Tumor size should be monitored by MRI. +An advantage of radiation is +that patient compliance with long-term treatment is +not required. +Tumor mass is reduced, and GH levels are +attenuated over time. +In summary, surgery is the preferred primary treat- +ment for GH-secreting microadenomas (Fig. +38-9). +GH, growth hormone; CNS, +central nervous system; IGF, insulin-like growth factor. +and reaching a +nadir about midnight. +Adrenal glucocorticoid secre- +tion, which is driven by ACTH, follows a parallel +diurnal pattern. +The +resulting cortisol elevation restrains the inflammatory +response and enables host protection. +Rarely, TPIT or POMC mutations result in +primary ACTH deficiency. +Some authorities +advocate lower maintenance doses in an effort to avoid +cushingoid side effects. +Doses should be increased sever- +alfold during periods of acute illness or stress. +ACTH-producing adenomas account for about +10–15% of all pituitary tumors. +However, macroadenomas +also are seen while some ACTH-expressing adenomas +are clinically silent. +Cushing’s disease is 5–10 times +more common in women than in men. +These pitu- +itary adenomas exhibit unrestrained ACTH secretion, +with resultant hypercortisolemia. +Hematopoietic features of hypercortisolism +include leukocytosis, lymphopenia, and eosinopenia. +Immune suppression includes delayed hypersensitivity. +In children and in +young females, early osteoporosis may be particularly +prominent. +Measurement of 24-h urine free cortisol (UFC) is a +precise and cost-effective screening test. +Totowa, NJ, Humana, 1997. +The sensitivity of this test is >95%, with very +rare false-positive results. +False-negative results may be +encountered in patients with aberrant venous drain- +age. +Iatrogenic Cushing’s syndrome is excluded by history. +38-10). +The remission +rate for this procedure is ∼80% for microadenomas but +<50% for macroadenomas. +ACTH, adrenocorti- +cotropin hormone; MRI, magnetic resonance imaging. +*Not +usually required. +tion with pituitary irradiation to block adrenal effects of +persistently high ACTH levels. +Side effects include nausea and vomiting, rash, +and exacerbation of acne or hirsutism. +It also may lead to hypoaldosteronism. +Glucocorticoid insuf- +ficiency is a potential side effect of agents used to block +steroidogenesis. +The use of steroidogenic inhibitors has decreased +the need for bilateral adrenalectomy. +Like TSH and hCG, LH and FSH are glycopro- +tein hormones that consist of α and β subunits. +Gonadotropin synthesis and release are dynami- +cally regulated. +38-3). +Estrogens act at +both the hypothalamus and the pituitary to modulate +gonadotropin secretion. +Progesterone slows GnRH pulse frequency but +enhances gonadotropin responses to GnRH. +Inhibin selectively suppresses FSH, whereas activin stimu- +lates FSH synthesis. +In women, FSH regulates ovar- +ian follicle development and stimulates ovarian estrogen +production. +LH mediates ovulation and maintenance +of the corpus luteum. +Osteoporosis occurs in both untreated +hypogonadal women and men. +Men have reduced sperm counts. +Normal +responses vary according to menstrual cycle stage, age, +and sex of the patient. +Generally, LH levels increase +about threefold, whereas FSH responses are less pro- +nounced. +Testosterone gels are also avail- +able. +Gonadotropin +therapy is used for ovulation induction. +Some adenomas +express α subunits without FSH or LH. +PRL levels are usually slightly increased, also because +of stalk compression. +Free α subunit levels may be elevated +in 10–15% of patients with nonfunctioning tumors. +GnRH testing, how- +ever, is not helpful for making the diagnosis. +38-11). +Within 5–6 years +after successful surgical resection, ∼15% of nonfunctioning +tumors recur. +Radiotherapy may be +deferred if no postoperative residual mass is evident. +TSH is structurally +related to LH and FSH. +It shares a common α subunit +with these hormones but contains a specific TSH β sub- +unit. +Consequently, single deter- +minations of TSH suffice to assess its circulating levels. +Moreover, free thyroid hormone levels are normal in +these disorders, most of which are familial. +Total resection is not often achieved as +most of these adenomas are large and locally invasive. +Stephen L. +Hauser ■ Douglas S. +MS affects ∼350,000 individuals in +the United States and 2.5 million individuals world- +wide. +39-1 ). +Conduction block +occurs when the nerve impulse is unable to traverse +the demyelinated segment. +Immunoreg- +ulatory effects of vitamin D could explain this apparent +relationship. +A second factor seems to occur during adolescence. +Moreover, the fact that +concentrated at the nodes) redistribute along the +naked axon (Fig. +39-1). +Conduction +block may be incomplete, affecting high- but not low- +frequency volleys of impulses. +Epidemiology +MS is approximately threefold more common in women +than men. +A. +B. +Two +different populations of proinflammatory T cells are +likely to mediate autoimmunity in MS. +High circu- +lating levels of IL-17 may also be a marker of a more +severe course of MS. +At this time, however, +a causal role for EBV is not definitively established. +Despite this, the influence of genetics on MS pathogen- +esis is substantial. +CLINICAL MANIFESTATIONS +The onset of MS may be abrupt or insidious. +Examination often reveals evidence of +neurologic dysfunction, often in asymptomatic locations. +For example, a patient may present with symptoms in +one leg but signs in both. +Exercise-induced weakness is a characteristic symp- +tom of MS. +The weakness is of the upper motor neu- +ron type (Chap. +12-2). +lesions to occur, both in experimental models and in +human MS. +Thus, early in MS +most disease activity is clinically silent. +Constipation occurs in >30% of patients. +Fecal urgency +or bowel incontinence is less common (15%) but can be +socially debilitating. +Cognitive dysfunction sufficient to impair activ- +ities of daily living is rare. +Facial weakness due to a lesion in the pons may resem- +ble idiopathic Bell’s palsy (Chap. +34). +11). +Hearing loss may also occur in MS but is uncommon. +12) is commonly associated with +spontaneous and movement-induced muscle spasms. +More than 30% of MS patients have moderate to severe +spasticity, especially in the legs. +This is often accom- +panied by painful spasms interfering with ambulation, +work, or self-care. +These symptoms can +be mild or may progress to severe visual loss. +Rarely, +there is complete loss of light perception. +Visual symp- +toms are generally monocular but may be bilateral. +Periorbital pain (aggravated by eye movement) often +precedes or accompanies the visual loss. +An afferent +pupillary defect (Chap. +21) is usually present. +Fundu- +scopic examination may be normal or reveal optic disc +swelling (papillitis). +Pallor of the optic disc (optic atro- +phy) commonly follows ON. +21). +Prominent +nystagmus is often observed in the abducting eye, along +with a small skew deviation. +A bilateral INO is partic- +ularly suggestive of MS. +It +is often accompanied by a bandlike sensation of tightness +around the torso. +Pain is a common symptom of MS, +experienced by >50% of patients. +Pain can occur any- +where on the body and can change locations over time. +Ataxia usually manifests as cerebellar tremors (Chap. +31). +CHAPTER 39 +Multiple Sclerosis and Other Demyelinating Diseases +479 +1. +Secondary progressive MS (SPMS) always begins as +RRMS (Fig. +39-2B). +SPMS produces a greater +amount of fixed neurologic disability than RRMS. +SPMS appears to represent a late stage of the same +underlying illness as RRMS. +1. +Primary progressive MS (PPMS) accounts for ∼15% of +cases. +39-2C). +Despite these differences, PPMS appears +to represent the same underlying illness as RRMS. +2. +Progressive/relapsing MS (PRMS) overlaps PPMS and +SPMS and accounts for ∼5% of MS patients. +39-2D). +(see “Acute Attacks or Initial Demyelinating Episodes,” +later). +Such heat-related symptoms probably result from +transient conduction block (discussed earlier). +Rarely, +it radiates into the arms. +It is generally self-limited but +may persist for years. +They may be precipitated by +hyperventilation or movement. +Trigeminal neuralgia, hemifacial spasm, and glossopharyn- +geal neuralgia (Chap. +It results +from lesions of the corticobulbar tracts or brainstem +course of the facial nerve. +DISEASE COURSE +Four clinical types of MS have been described (Fig. +39-2): +1. +There is often complete recov- +ery over the ensuing weeks to months (Fig. +39-2A). +Between attacks, patients are neurologically stable. +A. +Relapsing/ +remitting MS. +B. +Secondary progressive MS. +C. +Primary pro- +gressive MS. +D. +Progressive/relapsing MS. +SECTION III +Diseases of the Nervous System +480 neurologic examination. +DIAGNOSIS +There is no definitive diagnostic test for MS. +Symptoms must last for >24 h and occur as distinct +episodes that are separated by a month or more. +Lesions are multifocal within the brain, +brainstem, and spinal cord. +Such leakage occurs +AB +CD +FIGURE 39- 3 +MRI findings in MS. +A. +B. +Lesions in the anterior corpus callosum +are frequent in MS and rare in vascular disease. +C. +D. +OCBs +are detected by agarose gel electrophoresis. +Two or more +OCBs are found in 75–90% of patients with MS. +DIFFERENTIAL DIAGNOSIS +No single clinical sign or test is diagnostic of MS. +Different criteria for the +use of MRI in the diagnosis of MS have been proposed +(Table 39-3). +These tests provide +the most information when the pathways studied are +clinically uninvolved. +Abnormalities on one or +more EP modalities occur in 80–90% of MS patients. +The total CSF protein is usually normal or +slightly elevated. +CHAPTER 39 +Multiple Sclerosis and Other Demyelinating Diseases +483 20 years is ∼80%. +Conversely, with a normal brain MRI, +the likelihood of developing MS is <20%. +Death can occur dur- +ing an acute MS attack, although this is distinctly rare. +More commonly, death occurs as a complication of MS +(e.g., pneumonia in a debilitated individual). +Death can +also result from suicide. +Glucocorticoids are +used to manage either first attacks or acute exacerbations. +The likelihood of having benign MS is +thought to be <20%. +Relative efficacy can only be +determined from a non-biased head-to-head clinical +trial. +Interferon-a IFN-β is a class I interferon originally +identified by its antiviral properties. +IFN-β should be considered in patients with either +RRMS or SPMS with superimposed relapses. +In patients +with SPMS but without relapses, efficacy has not been +established. +IFN-β-1a +(Avonex), 30 μg, is administered by intramuscular injec- +tion once every week. +IFN-β-1a (Rebif), 44 μg, is admin- +istered by subcutaneous injection three times per week. +IFN-β-1b (Betaseron), 250 μg, is administered by subcu- +taneous injection every other day. +Rarely, more +severe hepatotoxicity may occur. +In +any event, side effects to IFN-β therapy usually subside +with time. +Whether treatment provides any long-term benefit +on the course of the illness is less clear. +Therefore, mild +attacks are often not treated. +Physical and occupational +therapy can help with mobility and manual dexterity. +Outpatient treatment is almost +always possible. +However, the cost is high, and conclu- +sive evidence of efficacy is lacking. +An eighth, cladrib- +ine (Leustatin), is currently awaiting an FDA decision +on its approval. +Glatiramer acetate, 20 mg, is administered by +subcutaneous injection every day. +Injection-site reactions +also occur with glatiramer acetate. +This systemic +reaction is unpredictable, brief (duration <1 h), and tends +not to recur. +outcomes of disability and relapse rate. +The reason for +this clinical-radiologic dissociation is unresolved. +For- +tunately, however, there are few situations where mea- +surement of antibodies is necessary. +Glatiramer acetate reduces the attack rate (whether +measured clinically or by MRI) in RRMS. +Therefore, glatiramer acetate should be considered +in RRMS patients. +Its usefulness in progressive disease is +entirely unknown. +dNew lesions seen on T2-weighted MRI. +ep = .001. +fp = .01. +gp = .05. +hNot FDA-approved at time of publication. +Possible side effects include hepatic toxicity, nau- +sea, and hair thinning. +Mitoxantrone received (from the FDA) +the broadest indication of any current treatment for MS. +As a result, a cumula- +tive dose >140 mg/m2 is not recommended. +Fur- +thermore, >40% of women will experience amenorrhea, +which may be permanent. +Its usefulness in the treat- +ment of progressive disease has not been studied. +Natalizumab, 300 μg, is administered by IV infusion +each month. +Treatment with natalizumab is, in general, well +tolerated. +The major concern with long-term treatment is the +risk of PML. +It +is well tolerated, and the oral dosing schedule makes it +very convenient for patients. +However, as with any new therapy, long-term safety +remains to be established. +Fingolimod, 0.5 +mg, is administered orally each day. +Treatment with fin- +golimod is also, in general, well tolerated. +IFN-β is probably ineffective in patients +with SPMS who are not having acute attacks. +39-4). +The value of +combination therapy is unknown. +IFN-β1a, or +2. +IFN-β1b, or +3. +Glatiramer acetate or +4. +IFN-β1a, or +2. +IFN-β1b +Intolerant or +poor response +1. +Mitoxantrone +2. +Azathioprine +3. +Methotrexate +4. +Pulse cyclophosphamide +5. +IVIg +6. +Ataxia/tremor is often intractable. +Wrist weights occasionally reduce tremor in the arm or +hand. +Thalamotomy or deep-brain stimulation has been +tried with mixed success. +Spasticity and spasms may improve with physical ther- +apy, regular exercise, and stretching. +Avoidance of triggers +(e.g., infections, fecal impactions, bed sores) is extremely +important. +Therefore, +no evidence-based recommendation can be made with +regard to its use in this setting. +PPMS No therapies have been convincingly shown +to modify the course of PPMS. +A phase III clinical trial +of glatiramer acetate in PPMS was stopped because of +lack of efficacy. +A trial of mitoxantrone in +PPMS is ongoing. +Patients should +avoid costly or potentially hazardous unproven treat- +ments. +Many such treatments lack biologic plausibility. +PROMISING EXPERIMENTAL THERAPIES +Numerous clinical trials are currently underway. +If these approaches fail, patients should be referred to a +comprehensive pain management program. +Bladder dysfunction management is best guided by +urodynamic testing. +Evening fluid restriction or fre- +quent voluntary voiding may help detrusor hyperreflexia. +Coadministration of pseu- +doephedrine (30–60 mg) is sometimes beneficial. +Loss of reflex bladder wall contraction may +respond to bethanechol (30–150 mg/d). +However, both +conditions often require catheterization. +Urinary tract infections should be treated promptly. +Patients with large postvoid residual urine volumes are +predisposed to infections. +Prevention by urine acidifi- +cation (with cranberry juice or vitamin C) inhibits some +bacteria. +Intermittent catheterization may +help to prevent recurrent infections. +Treatment of constipation includes high-fiber diets +and fluids. +Natural or other laxatives may help. +Fecal +incontinence may respond to a reduction in dietary fiber. +Depression should be treated. +Patients with frequent nocturia may benefit from anti- +cholinergic medication at bedtime. +Cognitive problems may respond to the cholinester- +ase inhibitor donepezil hydrochloride (10 mg/d). +Heat sensitivity may respond to heat avoidance, air- +conditioning, or cooling garments. +Sexual dysfunction may be helped by lubricants to aid +in genital stimulation and sexual arousal. +In contrast to MS, progressive +symptoms do not occur in NMO. +ADEM is more common in children than adults. +Infec- +tion with measles virus is the most common antecedent +(1 in 1000 cases). +Modern vaccines that do +not require viral culture in CNS tissue have reduced the +ADEM risk. +Attempts to demonstrate +direct viral invasion of the CNS have been unsuccessful. +or mixed connective tissue disease. +Rare cases +appear to be paraneoplastic and associated with breast, +lung, or other cancers. +NMO is often idiopathic, how- +ever. +Seropositive patients have a very high +risk for future relapses. +Typically, there are no remissions. +When acute MS presents as a solitary, usually cavitary, +lesion, a brain tumor is often suspected. +In such cases, a +brain biopsy is usually required to establish the diagnosis. +An antibody-mediated process appears to be responsible +for most cases. +Fever reappears, and +headache, meningismus, and lethargy progressing to coma +may develop. +Seizures are common. +In ADEM due to chickenpox, cerebellar +involvement is often conspicuous. +CSF protein is mod- +estly elevated (0.5–1.5 g/L [50–150 mg/dL]). +Lympho- +cytic pleocytosis, generally 200 cells/μL, occurs in 80% +of patients. +Transient CSF oligoclonal +banding has been reported. +The simultaneous onset of dis- +seminated symptoms and signs is common in ADEM and +rare in MS. +Similarly, meningismus, drowsiness, coma, or +seizures suggest ADEM rather than MS. +By +contrast, oligoclonal bands in the CSF are more common +in MS. +The prognosis reflects +the severity of the underlying acute illness. +Children who recover may have persistent sei- +zures and behavioral and learning disorders. +Karen L. +Roos ■ Kenneth L. +APPROACH TO THE +PATIENT +Meningitis, Encephalitis, Brain Abscess, + and Empyema + ( Fig. +Kernig’s and Brudzinski’s +signs are also classic signs of meningeal irritation. +Immunocompromised? +History of recent head trauma, known + cancer, sinusitis? +Haemophilus +influenzae type b accounts for <10% of cases of bacterial +meningitis in most series. +N. +meningitidis is the causative +organism of recurring epidemics of meningitis every +8 to 12 years. +ETIOLOGY +S. +The mortality rate remains +∼20% despite antibiotic therapy. +The incidence of meningitis due to N. +In some patients the disease +is fulminant, progressing to death within hours of symp- +tom onset. +Gram-negative meningitis +can also complicate neurosurgical procedures, particu- +larly craniotomy. +aureus, Haemophilus sp., +and Enterobacteriaceae. +Meningitis complicating endo- +carditis may be due to viridans streptococci, S. +aureus, S. +Group B streptococcus, or S. +L. +Infection is acquired by +ingesting foods contaminated by Listeria. +The frequency of H. +More frequently, H. +influenzae causes meningitis +in unvaccinated children and older adults, and non-b +H. +influenzae is an emerging pathogen. +PATHOPHYSIOLOGY +The most common bacteria that cause meningitis, +S. +pneumoniae and N. +meningitidis, initially colonize the +nasopharynx by attaching to nasopharyngeal epithelial +cells. +Some bacteria, such as +S. +40-2). +40-2). +CSF, cerebrospinal fluid; SAS, subarachnoid +space. +28). +The +combination of interstitial, vasogenic, and cytotoxic +edema leads to raised ICP and coma. +A decreased level of consciousness occurs in +>75% of patients and can vary from lethargy to coma. +Nausea, vomiting, and photo- +phobia are also common complaints. +The most disastrous complication +of increased ICP is cerebral herniation. +The diagnosis of bacte- +rial meningitis is made by examination of the CSF +(Table 40-2). +The need to obtain neuroimaging stud- +ies (CT or MRI) prior to LP requires clinical judg- +ment. +The CSF glucose concentration is low when the +CSF/serum glucose ratio is <0.6. +pneumoniae, +N. +meningitidis, H. +influenzae type +b, E. +pneumoniae, N. +meningitidis, Escherichia +coli, L. +monocytogenes, H. +influenzae, and S. +agalactiae can +be obtained based on the clinical suspicion of the men- +ingeal pathogen. +The latex agglutination (LA) test for +the detection of bacterial antigens of S. +pneumoniae, N. +meningitidis, H. +influenzae type b, group B streptococ- +cus, and E. +The CSF LA +test has a specificity of 95–100% for S. +pneumoniae and +N. +How- +ever, the sensitivity of the CSF LA test is only 70–100% +for detection of S. +pneumoniae and 33–70% for detec- +tion of N. +meningitidis antigens, so a negative test does +not exclude infection by these organisms. +The test has a specificity of 85–100% and a +sensitivity approaching 100%. +Petechial skin lesions, if present, should be biopsied. +Some patients with HSV +encephalitis have a distinctive periodic pattern on EEG +(discussed later). +Rickettsial disease can resemble bacterial meningi- +tis. +Most patients develop a characteristic rash +within 96 h of the onset of symptoms. +The color of the lesions changes from bright +red to very dark red, then yellowish-green to black. +Diag- +nosis is made by immunofluorescent staining of skin +biopsy specimens. +Ehrlichioses are also transmitted by +a tick bite. +These are small gram-negative coccobacilli +of which two species cause human disease. +The clinical and laboratory man- +ifestations of the infections are similar. +Patients present +with fever, headache, nausea, and vomiting. +Twenty +percent of patients have a maculopapular or petechial +rash. +A number of noninfectious CNS disorders can mimic +bacterial meningitis. +Subarachnoid hemorrhage (SAH; +Chap. +28) is generally the major consideration. +On occasion, subacutely evolving meningitis (Chap. +41) +may be considered in the differential diagnosis of acute +meningitis. +S. +pneumoniae and +N. +meningitidis are the most common etiologic organ- +isms of community-acquired bacterial meningitis. +Due to +the emergence of penicillin- and cephalosporin-resistant +S. +Ceftriaxone or cefotaxime provide good coverage for +susceptible S. +pneumoniae, group B streptococci, and +H. +influenzae and adequate coverage for N. +meningiti- +dis. +pneumoniae and N. +meningitidis and greater activity against Enterobacter spe- +cies and Pseudomonas aeruginosa. +aeruginosa. +Ampicillin +should be added to the empirical regimen for coverage +of L. +aeruginosa are the most common +etiologic organisms. +aeruginosa. +Meropenem is a carbapenem antibiotic that is highly +active in vitro against L. +monocytogenes, has been dem- +onstrated to be effective in cases of meningitis caused +by P. +aeruginosa, and shows good activity against pen- +icillin-resistant pneumococci. +Isolates of N. +CSF isolates of +N. +Rifampin is not recommended in +pregnant women. +All CSF isolates of S. +pneumoniae should +be tested for sensitivity to penicillin and the cephalo- +sporins. +For S. +pneumoniae meningitis, an isolate +of S. +Metronidazole +aDoses are as indicated in Table 40-1. +Isolates of S. +For MIC >1 μg/mL, vancomycin is the +antibiotic of choice. +A 2-week course of intravenous antimicrobial therapy +is recommended for pneumococcal meningitis. +Patients with S. +Patients with penicillin- and ceph- +alosporin-resistant strains of S. +Listeria Meningitis Meningitis due to L. +mono- +cytogenes is treated with ampicillin for at least 3 weeks +(Table 40-3). +Staphylococcal Meningitis Meningitis due to +susceptible strains of S. +aureus or coagulase-negative +staphylococci is treated with nafcillin (Table 40-3). +In +these patients, the CSF should be monitored during +therapy. +aeruginosa, +which should be treated with ceftazidime, cefepime, or +meropenem (Table 40-3). +Dexamethasone does not alter TNF-α +production once it has been induced. +influenzae +and S. +25%, p = .03) including death (7 vs. +15%, p = .04). +The benefits were most striking in patients +with pneumococcal meningitis. +pneumoniae meningitis. +Alternatively, +vancomycin can be administered by the intraventricular +route. +This has not been the case in clinical series. +Treatment of increased intracranial pressure is discussed +in detail in Chap. +28. +PROGNOSIS +Mortality rate is 3–7% for meningitis caused by H. +influenzae, N. +meningitidis, or group B streptococci; +15% for that due to L. +monocytogenes; and 20% for +S. +pneumoniae. +Louis encephalitis virus Mumps +aImmunocompromised host. +Organisms are not seen on +Gram’s stain of CSF. +CSF PCR +tests are available for WNV but are not as sensitive as +detection of WNV-specific CSF IgM. +During enteroviral infections, viral shedding +in stool may persist for several weeks. +CSF oligoclonal gamma globulin bands occur in +association with a number of viral infections. +The asso- +ciated antibodies are often directed against viral proteins. +Cases may either be +sporadic or occur in clusters. +Coxsackievirus strains A9, B3, and B4 are more +commonly associated with individual cases. +Meningitis outside the neonatal period +is usually benign. +In +rare cases, PMNs may predominate during the first 48 h +of illness. +Treatment is supportive, and patients usually +recover without sequelae. +Arbovirus infections occur predominantly in the sum- +mer and early fall. +Louis encephalitis virus, +and the California encephalitis group of viruses. +In +WNV epidemics, avian deaths may serve as sentinel +infections for subsequent human disease. +Of these patients, 20% go on to have recurrent attacks +of meningitis. +VZV meningitis should be suspected in the presence +of concurrent chickenpox or shingles. +EBV is +almost never cultured from CSF. +Diagnosis can be +confirmed by detection of HIV genome in blood or +CSF. +For further discussion of HIV infection, see +Chap. +42. +Patients with meningitis have a CSF pleocy- +tosis that can exceed 1000 cells/μL in 25%. +Lympho- +cytes predominate in 75%, although CSF neutrophilia +occurs in 25%. +Hypoglycorrhachia occurs in 10–30% of +patients and may be a clue to the diagnosis when present. +CSF PCR is available in some diagnostic and research +laboratories. +Some cases present with a marked CSF pleo- +cytosis (>1000 cells/μL) and hypoglycorrhachia (<30%). +Diagnosis is based on serology and/or culture of virus +from CSF. +Fluid and electrolyte status +should be monitored. +Data concerning treatment of HSV, EBV, and VZV menin- +gitis are extremely limited. +Patients who are less +ill can be treated with oral drugs alone. +Patients with HIV +meningitis should receive highly active antiretroviral ther- +apy (Chap. +42). +A live attenuated VZV vaccine (Varivax) is +available in the United States. +An +inactivated varicella vaccine is available for transplant +recipients. +PROGNOSIS +In adults, the prognosis for full recovery from viral +meningitis is excellent. +Focal or generalized seizures occur in many patients +with encephalitis. +Louis encephalitis virus and the California encephalitis +virus serogroup. +In rare +cases, a pleocytosis may be absent on the initial LP but +present on subsequent LPs. +CSF cell counts exceed +500/μL in only about 10% of patients with encephali- +tis. +The +sensitivity and specificity of CSF PCRs varies with the +virus being tested. +In both +situations a positive test makes the diagnosis almost cer- +tain (98–99%). +PCR results are generally not affected by ≤1 week +of antiviral therapy. +Enteroviral CSF PCR appears to +have a sensitivity and specificity of >95%. +The specificity +of EBV CSF PCR has not been established. +and glycoprotein antigens have been detected in the +CSF. +The lesions are typically hyperintense on T2-weighted +images. +CT is +less sensitive than MRI and is normal in up to 20–35% +of patients. +DIFFERENTIAL DIAGNOSIS +Infection by a variety of other organisms can mimic +viral encephalitis. +Motile +trophozoites can be seen in a wet mount of warm, fresh +CSF. +No effective treat- +ment has been identified, and mortality approaches +100%. +Encephalitis can be caused by the raccoon pinworm +Baylisascaris procyonis. +Most patients are children, and many have an associated +eosinophilia. +The diagnostic +procedure of choice in these patients is CSF PCR analysis +for HSV. +The anatomic distribution of lesions may provide +an additional clue to diagnosis. +Louis +encephalitis virus, Japanese encephalitis virus), HSV, +rabies, or L. +monocytogenes. +This +percentage likely increases to >90% when FLAIR and DWI +MR sequences are also utilized. +The CSF HSV PCR test may be negative in the first 72 h +of symptoms of HSV encephalitis. +Negative CSF viral cultures are of no value in excluding the +diagnosis of HSV or EBV encephalitis. +VZV CSF IgM antibodies may be present in patients with a +negative VZV CSF PCR. +Both tests should be performed +in patients with suspected VZV CNS disease. +The specificity of EBV CSF PCR for diagnosis of CNS +infection is unknown. +Positive tests may occur in patients +with a CSF pleocytosis due to other causes. +SECTION III +Diseases of the Nervous System +512 parkinsonian features. +PCR amplification +of viral nucleic acid from CSF and saliva or tears may +also enable diagnosis. +Geo- +logical Survey (USGS) websites (http://www.cdc.gov and +http://diseasemaps.usgs.gov). +44); acute disseminated encephalo- +myelitis and related fulminant demyelinating disorders +(Chap. +39); and lymphoma. +Finally, Creutzfeldt-Jakob +disease (Chap. +43) can rarely present in an explosive +fashion mimicking viral encephalitis. +TREATMENT Viral Encephalitis +Specific antiviral therapy should be initiated when +appropriate. +Host cell +enzymes then phosphorylate this compound to form a +triphosphate derivative. +Prior to intravenous administration, acyclovir should +be diluted to a concentration ≤7 mg/mL. +Care should +be taken to avoid extravasation or intramuscular or sub- +cutaneous administration. +The alkaline pH of acyclovir +can cause local inflammation and phlebitis (9%). +Dose +adjustment is required in patients with impaired renal +glomerular filtration. +Penetration into CSF is excellent, +with average drug levels ∼50% of serum levels. +Ganciclovir is a synthetic nucleoside analogue of +2′-deoxyguanosine. +The drug is preferentially phos- +phorylated by virus-induced cellular kinases. +Doses should be +adjusted in patients with renal insufficiency. +Induction therapy +for 14–21 days is followed by maintenance therapy +(60–120 mg/kg per day). +Many patients +experience fatigue and nausea. +Nephrotoxicity is +common; the dose should be reduced if renal function +deteriorates. +However, clinical trials are +lacking. +Hemolysis, with resulting anemia, has been the +major side effect limiting therapy. +In the case of EEE virus infection, nearly 80% of +survivors have severe neurologic sequelae. +Of 32 acyclovir-treated patients, +26 survived (81%). +Cranial nerve abnormalities and night +sweats may be present. +This syndrome overlaps that of +chronic meningitis, discussed in detail in Chap. +41. +ETIOLOGY +Common causative organisms include M. +tuberculosis, +C. +neoformans, H. +capsulatum, C. +immitis, and T. +pallidum. +Initial infection with M. +tuberculosis is acquired by +inhalation of aerosolized droplet nuclei. +These tubercles enlarge and are usually caseating. +Fungal infections are typically acquired by the +inhalation of airborne fungal spores. +The pulmonary infection is often self-limited. +The most common +pathogen causing fungal meningitis is C. +neoformans. +This fungus is found worldwide in soil and bird excreta. +H. +C. +T. +pallidum invades the CNS early in the +course of syphilis. +Cranial nerves VII and VIII are most +frequently involved. +Cultures of CSF take 4–8 weeks to +identify the organism and are positive in ∼50% of adults. +Culture remains the gold standard to make the diagnosis +of tuberculous meningitis. +PCR for the detection of +M. +There may be eosinophils in the CSF in +C. +immitis meningitis. +A reactive CSF cryptococcal antigen test establishes +the diagnosis. +capsulatum. +It may be falsely positive in coccidioidal +meningitis. +A reactive CSF FTA-ABS is not definitive evi- +dence of neurosyphilis. +The CSF FTA-ABS can be falsely +positive from blood contamination. +A negative CSF VDRL +does not rule out neurosyphilis. +A negative CSF FTA- +ABS or MHA-TP rules out neurosyphilis. +When the antimicrobial +sensitivity of the M. +tuberculosis isolate is known, eth- +ambutol can be discontinued. +Dexametha- +sone therapy is recommended for HIV-negative patients +with tuberculous meningitis. +The dose is 12–16 mg per +day for 3 weeks, then tapered over 3 weeks. +Meningitis due to C. +Therapy should be extended +for a total of 6 weeks in the patient with neurologic +complications. +Follow CSF yeast cultures +for sterilization rather than the cryptococcal antigen +titer. +HIV-infected patients may +require indefinite maintenance therapy with fluconazole +200 mg/d. +Meningitis due to H. +capsulatum is treated +with AmB (0.7–1.0 mg/kg per day) for 4–12 weeks. +A +total dose of 30 mg/kg is recommended. +Therapy with +AmB is not discontinued until fungal cultures are sterile. +C. +Intrathecal AmB +(0.25–0.75 mg/d three times weekly) may be required +to eradicate the infection. +Lifelong therapy with fluco- +nazole (200–400 mg daily) is recommended to prevent +relapse. +The most common complication of fungal +meningitis is hydrocephalus. +Patients who develop +hydrocephalus should receive a CSF diversion device. +The standard criterion for treatment success +is reexamination of the CSF. +The CSF should be reexam- +ined at 6-month intervals for 2 years. +Seizures occur in ∼20% of +patients, predominantly in those with lesions abutting the +cortex. +Almost all patients have an underlying immunosup- +pressive disorder. +It has been esti- +mated that up to 5% of AIDS patients will develop +PML. +Diagnostic studies +The diagnosis of PML is frequently suggested by MRI. +PML +lesions are not typically associated with edema or mass +effect. +The CSF is typically normal, although mild elevation +in protein and/or IgG may be found. +PCR amplification of JCV +DNA from CSF has become an important diagnostic +tool. +Patients with negative CSF PCR studies may require +brain biopsy for definitive diagnosis. +Serologic studies are of no utility in diagnosis due to +high basal seroprevalence level (>80%). +TREATMENT Progressive Multifocal +Leukoencephalopathy +No effective therapy for PML is available. +Neither of these agents has been tested in random- +ized controlled clinical trials. +The frequency +has been estimated at 1 in 100,000–500,000 measles +cases. +An average of five cases per year are reported in +the United States. +The incidence has declined dramati- +cally since the introduction of a measles vaccine. +Initial manifestations +include poor school performance and mood and person- +ality changes. +Typical signs of a CNS viral infection, +including fever and headache, do not occur. +Measles virus can be cultured from brain tissue using +special cocultivation techniques. +TREATMENT Subacute Sclerosing Panencephalitis +No definitive therapy for SSPE is available. +After a latent period of 8–19 years, patients develop +progressive neurologic deterioration. +The manifesta- +tions are similar to those seen in SSPE. +No therapy is +available. +The term cerebritis is often employed to describe +a nonencapsulated brain abscess. +In immunocompetent individuals +the most important pathogens are Streptococcus spp. +(anaerobic, aerobic, and viridans [40%]), Enterobacteria- +ceae (Proteus spp., E. +coli sp., Klebsiella spp. +[25%]), +anaerobes (e.g., Bacteroides spp., Fusobacterium spp. +[30%]), +and staphylococci (10%). +neoformans. +Otogenic abscesses occur pre- +dominantly in the temporal lobe (55–75%) and cerebellum +(20–30%). +In some series, up to 90% of cerebellar abscesses +are otogenic. +milleri), Haemophilus spp., Bacteroides spp., Pseudomonas +spp., and S. +aureus. +Hematogenous abscesses account for ∼25% of brain +abscesses. +The microbiology +of hematogenous abscesses is dependent on the primary +source of infection. +aureus. +aureus (MRSA), S. +epidermidis, +Enterobacteriaceae, Pseudomonas spp., and Clostridium +spp. +Enterobacteriaceae and P. +aeruginosa are impor- +tant causes of abscesses associated with urinary sepsis. +Similar phenomena can +occur with pulmonary arteriovenous malformations. +Streptococci are the most +common pathogens in this setting. +The +intact brain parenchyma is relatively resistant to infec- +tion. +Marked edema +surrounds the lesion at this stage. +This stage correlates with the appearance of +a ring-enhancing capsule on neuroimaging studies. +This gliotic process may contribute to the +development of seizures as a sequelae of brain abscess. +Hemiparesis is the +most common localizing sign of a frontal lobe abscess. +Nystagmus and ataxia are signs of a cerebellar +abscess. +DIAGNOSIS +Diagnosis is made by neuroimaging studies. +MRI +(Fig. +Aerobic and anaerobic bacterial cultures and +mycobacterial and fungal cultures should be obtained. +Up +to 10% of patients will also have positive blood cultures. +FIGURE 40-4 +Pneumococcal brain abscess. +and vancomycin for coverage of +staphylococci. +Meropenem plus vancomycin also provides +good coverage in this setting. +All patients should receive a minimum of +6–8 weeks of parenteral antibiotic therapy. +If the EEG is abnormal, anticonvulsant therapy +should be continued. +Glucocorticoids should not be given routinely to +patients with brain abscesses. +In modern series, +the mortality rate is typically <15%. +solium. +Toxoplasmosis is a parasitic disease +caused by T. +gondii and acquired from the ingestion of +undercooked meat and from handling cat feces. +Cysticerci may develop in the brain +parenchyma and cause seizures or focal neurologic defi- +cits. +Spinal cysticerci can mimic the +presentation of intraspinal tumors. +Primary Toxoplasma infection is often asymptomatic. +However, during this phase parasites may spread to the +CNS, where they become latent. +During this phase patients present with headache, fever, +seizures, and focal neurologic deficits. +DIAGNOSIS +The lesions of neurocysticercosis are readily visual- +ized by MRI or CT scans. +The scolex can often be visualized +on MRI. +Lesions may appear as contrast-enhancing lesions +surrounded by edema. +In the presence of the characteristic +neuroimaging abnormalities of T. +gondii infection, +serum IgG antibody to T. +gondii should be obtained +and, when positive, the patient should be treated. +Albendazole and prazi- +quantel are used in the treatment of neurocysticercosis. +The dose +of albendazole is 15 mg/kg per day in two doses for +8 days. +Antiepileptic therapy can be stopped once the follow-up +CT scan shows resolution of the lesion. +Folinic acid is added to +the regimen to prevent megaloblastic anemia. +40-5). +EPIDEMIOLOGY +SDE is a rare disorder that accounts for 15–25% of focal +suppurative CNS infections. +SDE may also develop as a +complication of head trauma or neurosurgery. +Subdural +empyema +Thrombosed +veins +Arachnoid +Dura mater +FIGURE 40-5 +Subdural empyema. +Patients with underlying sinusitis frequently have +symptoms related to this infection. +Seizures begin +as partial motor seizures that then become secondarily +generalized. +DIAGNOSIS +MRI (Fig. +40-6) is superior to CT in identifying SDE +and any associated intracranial infections. +FIGURE 40-6 +Subdural empyema. +TREATMENT Subdural Empyema +SDE is a medical emergency. +Patients with hospital- +acquired SDE may have infections due to Pseudomonas +spp. +or MRSA and should receive coverage with a carba- +penem (e.g., meropenem) and vancomycin. +Metronidazole +is not necessary for anti-anaerobic therapy when merope- +nem is being used. +Parenteral antibiotic therapy should be +continued for a minimum of 3–4 weeks after SDE drainage. +Patients with associated cranial osteomyelitis may require +longer therapy. +40-7). +As a result, epi- +dural abscesses are often smaller than SDEs. +The bacteriology of a cranial epidural +abscess is similar to that of SDE (discussed earlier). +TREATMENT Epidural Abscess +Immediate neurosurgical drainage is indicated. +Metronidazole is not necessary for anti-anaerobic +coverage in patients receiving meropenem. +When the +organism has been identified, antimicrobial therapy can +be modified accordingly. +Antibiotics should be contin- +ued for 3–6 weeks after surgical drainage. +Patients with +associated osteomyelitis may require additional therapy. +The superior sagittal sinus is the largest of +the venous sinuses (Fig. +40-8). +Infection can also spread to the +superior sagittal sinus from nearby SDE or epidural +abscess. +The superior sagittal sinus drains into the transverse +sinuses (Fig. +40-8). +The transverse sinus becomes the +sigmoid sinus before draining into the internal jugular +vein. +The cavernous sinuses are inferior to +the superior sagittal sinus at the base of the skull. +Bacteria in +the facial veins enter the cavernous sinus via these veins. +There may be a rapid +development of stupor and coma. +34-4). +There +may be evidence of dilated, tortuous retinal veins and +papilledema. +Headache and earache are the most frequent symptoms +of transverse sinus thrombosis. +Sigmoid sinus and internal jugular vein thrombosis may +present with neck pain. +527 + Walter J. +Koroshetz ■ Morton N. +The causes +are varied, and appropriate treatment depends on identi- +fi cation of the etiology. +These can +occur alone or in combination. +34). +Meningeal inflam- +mation can encircle the cord, resulting in myelopathy. +Two clinical forms of chronic meningitis exist. +Balamuthia mandrillaris causing chronic meningoencephalitis in immunocompetent hosts. +Aphthous oral lesions, genital ulcers, and hypopyon sug- +gest Behçet’s syndrome. +Hepatosplenomegaly suggests +lymphoma, sarcoid, tuberculosis, or brucellosis. +Herpetic +lesions in the genital area or on the thighs suggest HSV-2 +infection. +Obstructive hydrocephalus +usually requires direct ventricular drainage of CSF. +41-1). +Imaging studies are also useful to localize +areas of meningeal disease prior to meningeal biopsy. +performed. +cantonensis, G. +spinigerum, +B. +procyonis, or Toxocara canis infection, cysticercosis, +schistosomiasis, echinococcal disease, T. +The diagnosis of fungal menin- +gitis may require large volumes of CSF for culture of +sediment. +Occa- +sionally, empirical therapy must be initiated when all +attempts at diagnosis fail. +THE IMMUNOSUPPRESSED PATIENT +Chronic meningitis is not uncommon in the course of +HIV infection. +41-1). +Anthony S. +Fauci ■ H. +Source: MMWR 42(No. +RR-17), December 18, 1992. +Con- +ditions listed in categories B and C must not have occurred. +Source: MMWR 42(No. +RR-17), December 18, 1992. +MORPHOLOGY OF HIV +Electron microscopy shows that the HIV virion is an +icosahedral structure (Fig. +The structure of HIV-1 is +schematically diagrammed in Fig. +42-1B. +42-2). +It is also expressed on the surface of monocytes/ +macrophages and dendritic/Langerhans cells. +The two major co-receptors for HIV-1 +are CCR5 and CXCR4. +Electron micrograph of HIV. +B. +(Copyright by +George V. +Kelvin. +HIV has evolved +a powerful strategy to protect itself from APOBEC. +The viral protein Vif targets APOBEC for proteasomal +degradation. +See text for description. +HIV-infected individuals may manifest white mat- +ter lesions as well as neuronal loss. +Astrocytes may play diverse roles in HIV neu- +ropathogenesis. +In addition, astrocyte-derived +IL-6 can induce HIV expression in infected cells in +vitro. +cruzi, or Acanthamoeba. +Over- +all, secondary diseases of the CNS occur in approximately +one-third of patients with AIDS. +Most HIV-infected patients have some +neurologic problem during the course of their disease. +Increased tone and deep +tendon reflexes may be found in patients with spinal +cord involvement. +Late stages may be complicated by +bowel and/or bladder incontinence. +Some +patients develop a state of agitation or mild mania. +These changes usually occur without significant changes +in level of alertness. +As +immunologic function declines, the risk and severity of +HIV encephalopathy increase. +Less commonly, diffuse or focal spongiform changes +occur in the white matter. +Areas of the brain involved +in motor, language, and judgment are most severely +affected. +The +diagnosis of dementia depends upon demonstrating +a decline in cognitive function. +However, changes in MMSE scores +may be absent in patients with mild HIV-associated +dementia. +42-3). +MRI may also reveal small areas of +increased density on T2-weighted images. +Mild signs (snout response, slowed ocular or extremity movements) may +be present. +Gait and strength are normal. +Can walk without assistance. +Ambulatory, but may require a single prop. +4 (End-stage) Nearly vegetative. +Intellectual and social comprehension and output are at a rudimentary level. +Nearly or absolutely mute. +Paraparetic or paraplegic with urinary and fecal incontinence. +Source: Adapted from JJ Sidtis, RW Price: Neurology 40:197, 1990. +FIGURE 42-3 +AIDS dementia complex. +The lateral and third ventricles +and the cerebral sulci are abnormally prominent. +CHAPTER 42 +HIV Neurology +543 making a diagnosis of opportunistic infections. +Combination antiretroviral therapy is of benefit in +patients with HIV-associated dementia. +Rarely, an acute +encephalopathy due to encephalitis may occur. +CSF find- +ings include a lymphocytic pleocytosis, elevated protein +level, and normal glucose level. +This syndrome, which +cannot be clinically differentiated from other viral men- +ingitides (Chap. +Three main +types of spinal cord disease are seen in patients with +AIDS. +The first of these is a vacuolar myelopathy. +The clinical course is rapidly progressive over a +period of weeks. +HIV neuropathy +Peripheral neuropathies are common in patients with +HIV infection. +They occur at all stages of illness and +take a variety of forms. +46). +Patients commonly +present with progressive weakness, areflexia, and mini- +mal sensory changes. +Plasma exchange or IVIg has +been tried with variable success. +It is more common in taller +individuals, older individuals, and those with lower +CD4 counts. +Presenting symp- +toms are usually painful burning sensations in the feet +and lower extremities. +Motor +changes are mild and are usually limited to weakness +of the intrinsic foot muscles. +Treatment-naive patients may respond +to cART. +The clinical significance of this +as an isolated laboratory finding is unclear. +Profound muscle wasting, +often with muscle pain, may be seen after prolonged +zidovudine therapy. +It +is reversible following discontinuation of the drug. +Red +ragged fibers are a histologic hallmark of zidovudine- +induced myopathy. +This is a 120- +fold increase in incidence compared to the general +population. +As HIV disease progresses, the +risk of lymphoma increases. +Virtually any site in the body +may be involved. +Approximately 60% of +these cases are primary CNS lymphoma. +In one study, +the incidence of Epstein-Barr positivity was 100%. +This +malignancy does not have a predilection for any par- +ticular age group. +The median CD4+ T cell count at +the time of diagnosis is ~50/μL. +Thus, CNS lymphoma +generally presents at a later stage of HIV infection +than systemic lymphoma. +This fact may at least in part +explain the poorer prognosis for this subset of patients. +MRI or CT gener- +ally reveals a limited number (one to three) of 3- to +5-cm lesions (Fig. +42-4). +The lesions often show +ring enhancement on contrast administration and may +occur in any location. +Locations that are most com- +monly involved with CNS lymphoma are deep in the +white matter. +Contrast enhancement is usually less pro- +nounced than that seen with toxoplasmosis. +Systemic lymphoma is generally treated by +the oncologist with combination chemotherapy. +Treatment of primary CNS lymphoma +remains a significant challenge. +Palliative measures such as radia- +tion therapy provide some relief. +The prognosis remains +poor in this group, with a 2-year survival of 29%. +The +risk of many such infections correlates well with the +CD4+ T cell count (Fig. +42-5). +Cryptococcosis +C. +neoformans is the leading infectious cause of men- +ingitis in patients with AIDS. +The incidence of +seizures and focal neurologic deficits is low. +In addition to meningitis, patients may develop crypto- +coccomas and cranial nerve involvement. +Approximately +one-third of patients also have pulmonary disease. +Uncommon manifestations of cryptococcal infection +FIGURE 42-4 +Central nervous system lymphoma. +Multiple enhancing lesions, some +ring-enhancing, are present. +The prostate +gland may serve as a reservoir for smoldering cryptococ- +cal infection. +A biopsy may be needed to make a diag- +nosis of CNS cryptococcoma. +Repeated lumbar puncture may be required to +manage increased intracranial pressure. +Symptoms may +recur with initiation of cART as an immune reconstitu- +tion syndrome. +Other fungi that may cause meningitis in +patients with HIV infection are C. +immitis and H. +capsu- +latum. +Meningoencephalitis has also been reported due +to Acanthamoeba or Naegleria. +It is +most common in patients from the Caribbean and from +France, where the seroprevalence of T. +gondii is around +50%. +Cerebral toxoplasmo- +sis is thought to represent a reactivation of latent tissue +cysts. +Patients diagnosed with HIV infection should be +screened for IgG antibodies to T. +gondii during the time +of their initial workup. +There +is usually evidence of surrounding edema. +The definitive diag- +nostic procedure is brain biopsy. +If the patient is seronegative for T. +gondii, the likelihood that a mass lesion is due to toxo- +plasmosis is <10%. +In that setting, one may choose to +be more aggressive and perform a brain biopsy sooner. +Fortu- +nately, the same daily regimen of a single double-strength +tablet of TMP/SMX used for P. +jiroveci prophylaxis pro- +vides adequate primary protection against toxoplasmosis. +PML is the only known +clinical manifestation of JC virus infection. +It is a late +manifestation of AIDS and is seen in ~4% of patients +with AIDS. +The cerebral hemispheres, cerebellum, and +brainstem may all be involved. +Approxi- +mately 20% of patients experience seizures. +Ataxia, +hemiparesis, visual field defects, aphasia, and sensory +defects may occur. +Stud- +ies with other antiviral agents such as cidofovir have +failed to show clear benefit. +Baseline HIV-1 viral load does not have +independent predictive value of survival. +The presence of +antibodies to Trypanosoma cruzi supports the diagnosis. +SECTION III +Diseases of the Nervous System +548 the initial AIDS-defining condition. +The majority of +cases occur in patients with CD4+ T cell counts <200 +cells/μL. +T. +cruzi amasti- +gotes, or trypanosomes, can be identified from biopsy +specimens or CSF. +Other CSF findings include ele- +vated protein and a mild (<100 cells/μL) lymphocytic +pleocytosis. +Organisms can also be identified by direct +examination of the blood. +Specific neurologic presentations +Stroke +Stroke may occur in patients with HIV infection. +It also appears that HIV infection itself can +lead to an increase in carotid artery stiffness. +Seizures may be the +presenting clinical symptom of HIV disease. +Of these 32 cases, 28 were due to toxoplasmosis and 4 +to lymphoma. +HIV-associated dementia accounted for +an additional 24 new-onset seizures. +Stanley B. +Prusiner ■ Bruce L. +43-1 ). +A. +NMR structure of Syrian ham- +ster recombinant (rec) PrP(90–231). +Presumably, the structure +of the α-helical form of recPrP(90–231) resembles that of PrP C . +recPrP(90–231) is viewed from the interface where PrP Sc is +thought to bind to PrP C . +Shown are: α-helices A (residues 144– +157), B (172–193), and C (200–227). +Flat ribbons depict β-strands +S1 (129–131) and S2 (161–163). +( A , from SB Prusiner: N Engl J +Med 344:1516, 2001; with permission.) B. +Structural model of +PrP Sc . +(Image prepared by C. +Prions are composed entirely +of PrP Sc molecules. +PrP Sc Disease-causing isoform of the prion +protein. +This protein is the only identifi able +macromolecule in purifi ed preparations of +scrapie prions. +Pr PC Cellular isoform of the prion protein. +PrP C is +the precursor of PrP Sc . +PrP 27-30 +retains prion infectivity and polymerizes +into amyloid. +PRNP PrP gene located on human chromosome 20. +Prion rod An aggregate of prions composed +largely of PrP 27-30 molecules. +Created +by detergent extraction and limited +proteolysis of PrP Sc . +Morphologically and +histochemically indistinguishable from +many amyloids. +SPECTRUM OF PRION DISEASES +The sporadic form of CJD is the most common prion dis- +order in humans. +Six diseases of animals are caused by prions (Table +43-2). +Scrapie of sheep and goats is the prototypic prion +disease. +In contrast +to other prion diseases, CWD is highly communicable. +EPIDEMIOLOGY +CJD is found throughout the world. +sFI Humans Somatic mutation or spontaneous conversion of PrPC into PrPSc? +In humans, the PrP gene is desig- +nated PRNP and is located on the short arm of chro- +mosome 20. +43-2). +In the pres- +ence of detergent, PrP 27-30 polymerizes into amyloid. +This analysis was extended when patients with spo- +radic fatal insomnia (sFI) were identified. +Bar diagram of Syrian hamster PrP, +which consists of 254 amino acids. +After processing of the +NH2 and COOH termini, both PrPC and PrPSc consist of 209 +residues. +PrPSc acts as a template +for the conversion of PrPC into nascent PrPSc. +fCJD, familial Creutzfeldt-Jakob disease; FFI, fatal familial insomnia. +CHAPTER 43 +Prion Diseases +553 to be sufficiently low as to be not detected by routine +bioassay. +The normal human PrP +sequence contains five repeats of an eight-amino-acid +sequence. +One case of CJD occurred +after repair of an eardrum perforation with a pericar- +dium graft. +These patients received +injections of hGH every 2–4 days for 4–12 years. +Four cases of CJD have occurred in women receiving +human pituitary gonadotropin. +More than 190 cases of vCJD have +occurred, with >90% of these in Britain. +Patients +who survive for several years have variable degrees of +cerebral atrophy. +Astrocytic gliosis is a constant but +nonspecific feature of prion diseases. +Astro- +cytic processes filled with glial filaments form extensive +networks. +Amyloid plaques have been found in ∼10% of CJD +cases. +These plaques stain with antibodies raised +against PrP. +They +are often located adjacent to blood vessels. +Congophilic +angiopathy has been noted in some cases of GSS disease. +Most patients with CJD +present with deficits in higher cortical function. +Frequently the cerebellar deficits +are rapidly followed by progressive dementia. +Unlike +other involuntary movements, myoclonus persists dur- +ing sleep. +Dementia +with myoclonus can also be due to Alzheimer’s disease +(AD) (Chap. +29), dementia with Lewy bodies (Chap. +29), corticobasal degeneration (Chap. +26). +In other +cases, incubation periods of up to 40 years have been +suggested. +Clinical abnormalities in CJD +are confined to the CNS. +Variations in the typical course appear in inherited +and transmitted forms of the disease. +fCJD has an earlier +mean age of onset than sCJD. +Rare sporadic +cases have been identified. +DIFFERENTIAL DIAGNOSIS +Many conditions may mimic CJD superficially. +Demen- +tia with Lewy bodies (Chap. +29) is the most common +disorder to be mistaken for CJD. +It can present in a sub- +acute fashion with delirium, myoclonus, and extrapyra- +midal features. +Other neurodegenerative disorders (Chap. +26). +Unlike CJD, fluctuations in severity typically occur in +Hashimoto’s encephalopathy. +Myoclonus is +exceptional with cerebral vasculitis, but focal seizures +may confuse the picture. +Other diseases that can simulate CJD include neurosyphi- +lis, AIDS dementia complex (Chap. +42), progressive multi- +focal leukoencephalopathy (Chap. +40), diffuse intracranial tumor +(gliomatosis cerebri; Chap. +In humans, the +diagnosis of CJD can be established by brain biopsy if +PrPSc is detected. +CT may be normal or show cortical atrophy. +MRI is +valuable for distinguishing sCJD from most other condi- +tions. +43-3). +CSF is nearly always normal but may show pro- +tein elevation and, rarely, mild pleocytosis. +During the early phase of CJD, the EEG is +usually normal or shows only scattered theta activity. +As CJD progresses, normal background +rhythms become fragmentary and slower. +Whether such an approach can +be used to treat CJD remains to be established. +Like the acridines, anti-PrP antibodies have been +shown to eliminate PrPSc from cultured cells. +Unfortunately, the antibodies were ineffective in mice +inoculated intracerebrally with prions. +Josep Dalmau ■ Myrna R. +In 60% of patients the neurologic symp- +toms precede the cancer diagnosis. +T cell–mediated +cytotoxicity may contribute directly to cell death in these +PNDs. +Thus both humoral and cellular immune mecha- +nisms participate in the pathogenesis of many PNDs. +44-1 ) . +Other PNDs are likely immune-mediated, although +their antigens are unknown. +These include several syn- +dromes of infl ammatory neuropathies and myopathies. +In addition, many patients with typical PND syndromes +are antibody-negative. +For still other PNDs, the cause remains quite +obscure. +Abbreviations: CRMP, collapsing response-mediator protein; SCLC, small cell lung cancer. +there is evidence that prompt tumor control improves the +neurologic outcome. +bAnti-VGKC-related proteins are pathogenic for some types of neuromyotonia. +cAnti-VGCC antibodies are pathogenic for LEMS. +dThese antibodies are strongly suspected to be pathogenic. +AB +(e.g.,  metastasis, infection), neuropathologic findings are +not specific for PND. +In +most PNDs the MRI findings are nonspecific. +44-2). +Note +the abnormal hyperintensity involving the medial aspect of +the temporal lobes. +CHAPTER 44 +Paraneoplastic Neurologic Syndromes +561 after the neurologic diagnosis. +Combined CT and +PET scans often uncover tumors undetected by other +tests. +It is often associated with dorsal root ganglia and +autonomic dysfunction. +Patients with SCLC +and these syndromes usually have anti-Hu antibodies in +serum and CSF. +44-3); some patients develop hypersomnia, cata- +plexy, and severe hypokinesia. +The oncologic asso- +ciations of these antibodies are shown in Table 44-2. +AB C +FIGURE 44-3 +MRI and tumor of a patient with anti-Ma2-associated +encephalitis. +The positive (brown) cells correspond to an intra- +tubular germ-cell neoplasm. +Less commonly, +patients develop neuromyotonia or a mixed clinical picture +(Morvan’s syndrome). +Encephalitis with N -methyl-D-aspartate (NMDA) recep- +tor antibodies (Fig. +In male patients the +detection of a tumor is rare. +The neurologic disorder responds to treatment +of the tumor and immunotherapy. +Neurologic symp- +toms often respond to immunotherapy and treatment +of the tumor if found. +The examination usually shows +downbeating nystagmus and, rarely, opsoclonus. +Opsoclonus-myoclonus may be cancer- +related or idiopathic. +Most patients +do not have detectable antineuronal antibodies. +At least 50% of children with opsoclonus-myoclonus +have an underlying neuroblastoma. +Hypotonia, ataxia, +behavioral changes, and irritability are frequent accom- +panying symptoms. +Many patients are left with psycho- +motor retardation and behavioral and sleep problems. +Some patients with +encephalomyelitis and rigidity have glycine receptor +antibodies. +Symptoms improve with sleep and general +anesthetics. +Electrophysiologic studies demonstrate con- +tinuous motor unit activity. +All +modalities of sensation and any part of the body includ- +ing face and trunk can be involved. +Specialized sensa- +tions such as taste and hearing can also be affected. +Glucocorticoids occasionally produce clinical +stabilization or improvement. +The benefit of IVIg and +plasma exchange is not proved. +If demyelinating features predomi- +nate (Chap. +45), IVIg, plasma exchange, or glucocorti- +coids may improve symptoms. +The paraneoplastic variety has several +distinctive features. +Treatment of the plasmacytoma or scle- +rotic lesions usually improves the neuropathy. +46). +SCLC and lymphoma are the pri- +mary tumors involved. +Glucocorticoids and cyclophos- +phamide often result in neurologic improvement. +CNS dysfunction, including mood changes, sleep disor- +der, or hallucinations, may occur. +Approximately +20% of patients have serum antibodies to Caspr2-related +proteins. +Phenytoin, carbamazepine, +and plasma exchange improve symptoms. +Glucocorticoids and treatment of the underlying +tumor rarely control the disorder. +The most commonly associated +tumor is SCLC. +Melanoma-associated retinopathy +affects patients with metastatic cutaneous melanoma. +The ERG shows reduced b waves +with normal dark adapted a waves. +Some patients +with paraneoplastic uveitis harbor anti-CV2/CRMP5 +antibodies. +33). +LAMBERT-EATON MYASTHENIC +SYNDROME +LEMS is discussed in Chap. +47. +MYASTHENIA GRAVIS +Myasthenia gravis is discussed in Chap. +47. +POLYMYOSITIS-DERMATOMYOSITIS +Polymyositis and dermatomyositis are discussed in detail +in Chap. +49. +Amato ■ Richard J. +Barohn +566 + Peripheral nerves are composed of sensory, motor, and +autonomic elements. +Most peripheral nerves +are mixed and contain sensory and motor as well as +autonomic fi bers. +Motor axons are usually large +myelinated fi bers that conduct rapidly (approximately +50 m/s). +Sensory fi bers may be any of the three types. +Autonomic nerves are +also small in diameter. +The infl ammatory neuropathies are dis- +cussed in Chap. +46 . +45-1 ) . +INFORMATION FROM THE HISTORY AND +PHYSICAL EXAMINATION: SEVEN KEY +QUESTIONS ( TABLE 45-1 ) + 1. +What systems are involved? +33 ). +The majority of neuropathies are pre- +dominantly sensory in nature. +2. +What is the distribution of weakness? +and (2) Is the weakness focal and asymmet- +ric or is it symmetric? +Findings of an asymmetric or multifocal pattern of +weakness narrows the differential diagnosis. +Some neu- +ropathic disorders may present with unilateral extremity +weakness. +32). +3. +What is the nature of the sensory +involvement? +15). +Severe proprioceptive loss also narrows the differ- +ential diagnosis. +CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; +GBS, Guillain-Barré syndrome. +Patient Complaint: ? +Neuropathy +History and examination compatible with neuropathy? +Is entrapment or + compression present? +Is a contributing systemic + disorder present? +4. +Is there evidence of upper motor neuron +involvement? +5. +What is the temporal evolution? +It is important to determine the onset, duration, and evo- +lution of symptoms and signs. +Is the course monophasic, progres- +sive, or relapsing? +Most neuropathies are insidious and +slowly progressive in nature. +A +relapsing course can be present in CIDP and porphyria. +6. +Is there evidence for a hereditary +neuropathy? +7. +Does the patient have any other medical +conditions? +Each +pattern has a limited differential diagnosis. +What systems are involved? +– Motor, sensory, autonomic, or combinations +2. +What is the distribution of weakness? +– Only distal versus proximal and distal +– Focal/asymmetric versus symmetric +3. +What is the nature of the sensory involvement? +Is there evidence of upper motor neuron involvement? +– Without sensory loss +– With sensory loss +5. +What is the temporal evolution? +– Acute (days to 4 weeks) +– Subacute (4 to 8 weeks) +– Chronic (>8 weeks) +6. +Is there evidence for a hereditary neuropathy? +– Family history of neuropathy +– Lack of sensory symptoms despite sensory signs +7. +Are there any associated medical conditions? +SECTION III +Diseases of the Nervous System +570 be valuable. +33). +In idiopathic cases of GBS +and CIDP, there should not be pleocytosis in the CSF. +Some patients with GBS +and CIDP have abnormal liver function tests. +Neu- +ropathy can be the initial manifestation of Sjögren’s syn- +drome. +Further, some patients can manifest sicca complex with- +out full-blown Sjögren’s syndrome. +44). +NERVE BIOPSIES +Nerve biopsies are now rarely indicated for evaluation of +neuropathies. +The primary indication for nerve biopsy +is suspicion for amyloid neuropathy or vasculitis. +Nerve biopsies should +only be done if the NCS studies are abnormal. +SKIN BIOPSIES +Skin biopsies are sometimes used to diagnose a small- +fiber neuropathy. +However, it adds little to what one already knows +from the clinical examination and EDx. +Both are associated +with autosomal dominant inheritance, with a few excep- +tions. +Muscle stretch reflexes are unobtainable or reduced +throughout. +(Frabin) +CMT2H AD 8q21.3 ? +Source: Modified from AA Amato, J Russell: Neuromuscular Disease. +New York, McGraw-Hill, 2008. +This results in patients having three cop- +ies of the PMP-22 gene rather than two. +CMT2 +CMT2 tends to present later in life compared to CMT1. +Clinically, CMT2 is for the most part indistinguish- +able from CMT1. +The other genes associated with CMT2 are +much less common. +Affected children +are severely weak. +Motor NCVs are markedly slowed, +typically 5–10 m/s or less. +Electrophysiologic and histologic evaluations can show +demyelinating or axonal features. +CMT4 is genetically +heterogenic (Table 45-4). +CMT1X accounts for approximately 10–15% of CMT +overall. +Obligate women carri- +ers are frequently asymptomatic, but can develop signs and +symptoms. +In men, motor NCVs in the arms and legs +are moderately slowed (in the low to mid 30-m/s range). +CMT1X is caused by mutations in the con- +nexin 32 gene. +Connexins are gap junction structural +proteins that are important in cell-to-cell communication. +These +pressure-related mononeuropathies may take weeks or +months to resolve. +These attacks are similar to those +seen with idiopathic brachial plexitis (discussed later). +Attacks may occur in the postpartum period, follow- +ing surgery, or at other times of stress. +Most patients +recover over several weeks or months. +EDx demon- +strate an axonal process. +HNA is caused by mutations in +septin 9 (SEPT9). +Nevertheless, +affected individuals can develop motor weakness and there +can be overlap with CMT. +Of the HSANs, only HSAN1 typically presents in +adults. +The HSAN1 is the most common of the HSANs +and is inherited in an autosomal dominant fashion. +Affected +individuals with HSAN1 usually manifest in the second +through fourth decade of life. +HSAN1A is caused by +mutations in the serine palmitoyltransferase long-chain base +1 (SPTLC1) gene. +Some patients also +manifest primarily with a dilated cardiomyopathy. +A +decrease in α-galactosidase activity is evident in leuko- +cytes and cultured fibroblasts. +Patients with ALD manifest with +CNS abnormalities. +35). +EDx is suggestive of a primary axonopathy with sec- +ondary demyelination. +Very +long chain fatty acid (VLCFA) levels (C24, C25, and +C26) are increased in the urine. +Laboratory evidence of +adrenal insufficiency is evident in approximately two- +thirds of patients. +The diagnosis can be confirmed by +genetic testing. +Subsequently, +the proximal leg and arm muscles may become weak. +Serum phytanic acid levels are elevated. +Refsum disease is genetically heterogeneous but +autosomal recessive in nature. +Less commonly, mutations in +the gene encoding peroxin 7 receptor protein (PRX 7) +are responsible. +35]). +Nerve biopsies reveal axonal degenera- +tion with demyelination and remyelination. +There is no +specific treatment. +PORPHYRIA +Porphyria is a group of inherited disorders caused by +defects in heme biosynthesis. +An acute attack of porphyria may begin with sharp +abdominal pain. +Subsequently, patients may develop +agitation, hallucinations, or seizures. +Several days later, +back and extremity pain followed by weakness ensues, +mimicking GBS. +Constipation, urinary retention, and +incontinence can also be seen. +The CSF protein is typically normal or mildly elevated. +Liver function tests and hematologic parameters are usu- +ally normal. +Some patients are hyponatremic due to inap- +propriate secretion of antidiuretic hormone. +Specific enzyme activities can also be measured in erythro- +cytes and leukocytes. +The porphyrias are inherited in an autosomal domi- +nant fashion. +The pathogenesis of +the neuropathy is not completely understood. +Treat- +ment with glucose and hematin may reduce the accu- +mulation of heme precursors. +Intravenous glucose is +started at a rate of 10–20 g/h. +The majority of patients with FAP have +mutations in the TTR gene. +Amyloid deposition may +be evident in abdominal fat pad, rectal, or nerve biop- +sies. +Carpal tunnel syndrome (CTS) is common. +Amyloid +deposition also occurs in the heart, kidneys, liver, and +the corneas. +Gradually, the symptoms progress, leading to proximal +and distal weakness and atrophy. +Over time, a mild generalized +sensorimotor polyneuropathy develops. +Autonomic dys- +function does not occur. +ACQUIRED NEUROPATHIES +PRIMARY OR AL AMYLOIDOSIS +Besides FAP, amyloidosis can also be acquired. +However, the trunk can be involved and some manifest +with a mononeuropathy multiplex pattern. +CTS occurs in +25% of patients and may be the initial manifestation. +Patients generally +die from their systemic illness (renal failure, cardiac disease). +The monoclonal protein may be composed of IgG, +IgA, IgM, or only free light chain. +Lambda (λ) is more +common than κ light chain (>2:1) in AL amyloidosis. +46). +Tingling, +burning, deep aching pains may also be apparent. +NCS +usually show reduced amplitudes and mild to moder- +ate slowing of conduction velocities (CVs). +Diabetic autonomic neuropathy +Autonomic neuropathy is typically seen in combina- +tion with DSPN. +300–1200 mg TID Cognitive changes, sedation, peripheral +edema +Pregabalin p.o. +50–100 mg TID Cognitive changes, sedation, peripheral +edema +Duloxetine p.o. +200–400 mg q 6–8 h Cognitive changes, dizziness, leukopenia, +liver dysfunction +Phenytoin p.o. +50 mg qid Cognitive changes, GI upset +Third-Line +Mexiletine p.o. +Local erythema +Capsaicin 0.025%–0.075% +cream +Apply cutaneously q.i.d. +Painful burning skin +Source: Modified from AA Amato, J Russell: Neuromuscular Disease. +New York, McGraw-Hill, 2008. +Sensory and motor NCS +generally demonstrate features described earlier with +DSPN. +Typically, patients present with severe pain in the low +back, hip, and thigh in one leg. +Rarely, the diabetic poly- +radiculoneuropathy begins in both legs at the same time. +The neuropathy is often accompanied or heralded +by severe weight loss. +CSF protein is usually elevated, while the +cell count is normal. +ESR is often increased. +Nerve biopsies may demonstrate axonal degeneration +along with perivascular inflammation. +Diabetic third nerve +palsies are characteristically pupil-sparing (Chap. +21). +Treatment is correction of the +hypothyroidism. +Sjögren’s syndrome is also associated +with sensory neuronopathy/ganglionopathy. +The onset can be acute or +insidious. +NCS +demonstrate reduced amplitudes of sensory studies in the +affected limbs. +Nerve biopsy demonstrates axonal degen- +eration. +There is no specific treatment for neuropathies related to +Sjögren’s syndrome. +When vasculitis is suspected, immu- +nosuppressive agents may be beneficial. +The neuropathy often is responsive +to immunomodulating therapies. +Less +common are multiple mononeuropathies presumably +secondary to necrotizing vasculitis. +Immunosuppressive therapy +is beneficial in SLE patients with neuropathy due to +vasculitis. +Patients with a GBS or CIDP-like neuropathy should +be treated accordingly (Chap. +46). +Multiple mononeuropathies also occur. +The most com- +mon cranial nerve involved is the seventh nerve, which +can be affected bilaterally. +Some patients develop radic- +ulopathy or polyradiculopathy. +With a generalized root +involvement, the clinical presentation can mimic GBS +or CIDP. +Some have features +of a pure small-fiber neuropathy. +EDx reveals an axonal +neuropathy. +Neurosarcoidosis may respond to treatment with gluco- +corticoids or other immunosuppressive agents. +A generalized peripheral +neuropathy or a mononeuropathy multiplex occurs in +6–14% of patients. +Nerve biopsy may reveal a loss of large myelinated +fibers. +The neuropathy may be secondary to malabsorp- +tion of vitamins B12 and E. +However, some patients have +no appreciable vitamin deficiencies. +The neuropathy does not appear +to respond to a gluten-free diet. +Mononeuropathies can also occur, the most +common of which is carpal tunnel syndrome. +EDx studies are +consistent with a sensory greater than motor axonopa- +thy. +Sural nerve biopsy reveals both segmental demy- +elination and axonal loss. +47). +From +a clinical and EDx standpoint, it can be quite difficult to +distinguish these disorders. +Most specialists suggest that +CIM is more common. +Both CIM and CIP develop as +a complication of sepsis and multiple organ failure. +They +usually present as an inability to wean a patient from a +ventilator. +A coexisting encephalopathy may limit the +neurologic exam, in particular the sensory examination. +Muscle stretch reflexes are absent or reduced. +The pathogenic basis of CIP is not +known. +Neu- +ropathies are most common in patients with borderline +leprosy. +Superficial cutaneous nerves of the ears and dis- +tal limbs are commonly affected. +Sen- +sory NCS are usually absent in the lower limb and are +reduced in amplitude in the arms. +Leprosy is +usually diagnosed by skin lesion biopsy. +Nerve biopsy can +also be diagnostic, particularly when there are no appar- +ent skin lesions. +The tuberculoid form is characterized +by granulomas, and bacilli are not seen. +Patients are generally treated with multiple drugs: dap- +sone, rifampin, and clofazimine. +Patients +are generally treated for 2 years. +Erythema nodosum leprosum (ENL) is also treated with +glucocorticoids or thalidomide. +Neurologic complications may develop +during the second and third stages of infection. +Involvement of nerves is frequently asymmetric. +Some +patients present with a polyradiculoneuropathy or mul- +tiple mononeuropathies. +EDx is suggestive of a primary +axonopathy. +Nerve biopsies can reveal axonal degenera- +tion with perivascular inflammation. +Treatment is with +antibiotics. +DIPHTHERITIC NEUROPATHY +Diphtheria is caused by the bacteria Corynebacterium diph- +theriae. +CSF protein can be elevated with or without +lymphocytic pleocytosis. +EDx suggests a diffuse axonal +sensorimotor polyneuropathy. +Antitoxin and antibiotics +should be given within 48 h of symptom onset. +The neuropathy usually resolves +after several months. +It is characterized by numbness and +painful paresthesias involving the distal extremities. +EDx studies reveal features of active axonal degen- +eration. +The polyradiculoneuropathy may improve with +antiviral therapy. +Weakness, numbness, paresthesias, and pain occur in the +distribution of affected nerves. +Glucocorticoid treatment is indi- +cated for vasculitis directly due to HIV infection. +Patients develop sensory ataxia similar to +idiopathic sensory neuronopathy/ganglionopathy. +NCS +reveal reduced amplitudes or absence of SNAPs. +Treatment of postherpetic neuralgia is symptomatic +(Table 45-6). +44). +The onset can be acute or insidiously progres- +sive. +Prominent loss of proprioception leads to sensory +ataxia. +CSF may be nor- +mal or may demonstrate mild lymphocytic pleocytosis +and elevated protein. +Treatment of +the underlying cancer generally does not affect the course +of PEM/SN. +However, occasional patients may improve +following treatment of the tumor. +Peripheral neuropathy in BMT is often associ- +ated with graft-versus-host disease (GVHD). +EDx can be compatible +with either an axonal or demyelinating process. +CSF +may reveal lymphocytic pleocytosis and an elevated +protein. +A monoclonal population of cells +favors lymphomatous invasion. +The neuropathy may +respond to treatment of the underlying lymphoma or +immunomodulating therapies. +Clinical and EDx features of neu- +ropathy occur in as many as 40% of patients. +The most +common pattern is that of a distal, axonal, sensory, or +sensorimotor polyneuropathy. +Less frequently, a chronic +demyelinating polyradiculoneuropathy may develop (see +POEMS, Chap. +46). +Expanding plasmacytomas can compress cranial nerves +and spinal roots as well. +A superimposed +median neuropathy at the wrist is common. +Abdominal +fat pad, rectal, or sural nerve biopsy can be performed to +look for amyloid deposition. +NEUROPATHIES ASSOCIATED WITH +MONOCLONAL GAMMOPATHY OF +UNCERTAIN SIGNIFICANCE (SEE CHAP. +The more common neuropathies +associated with these agents are discussed here. +Serum CK levels are usually elevated due +to the superimposed myopathy. +Neurogenic MUAPs and +reduced recruitment are found in more distal muscles. +Nerve biopsy demonstrates autophagic vacuoles within +Schwann cells. +Vacuoles may also be evident in muscle +biopsies. +Source: From AA Amato, J Russell: Neuromuscular Disease. +New York, McGraw-Hill, 2008. +Source: From AA Amato, J Russell: Neuromuscular Disease. +New York, McGraw-Hill, 2008. +AMIODARONE +Amiodarone can cause a neuromyopathy similar to +chloroquine and hydroxychloroquine. +The neuromy- +opathy typically appears after patients have taken the +medication for 2–3 years. +Nerve biopsy demonstrates +a combination of segmental demyelination and axo- +nal loss. +COLCHICINE +Colchicine can also cause a neuromyopathy. +EDx reveals +features of an axonal polyneuropathy. +Muscle biopsy +reveals a vacuolar myopathy, while sensory nerves dem- +onstrate axonal degeneration. +Colchicine inhibits the +polymerization of tubulin into microtubules. +Motor NCS are usually normal. +Nerve +biopsy reveals a loss of large-diameter myelinated fibers +and axonal degeneration. +Degeneration of dorsal root +ganglion cells has been reported at autopsy. +NCS reveal absent or markedly reduced SNAP ampli- +tudes with relatively preserved CMAPs. +Nerve biopsy +reveals axonal loss of fiber at all diameters. +ISONIAZID +One of the most common side effects of isonia- +zid (INH) is peripheral neuropathy. +INH +inhibits pyridoxal phosphokinase, resulting in pyridox- +ine deficiency and the neuropathy. +Prophylactic admin- +istration of pyridoxine 100 mg/d can prevent the neu- +ropathy from developing. +NCS reveal decreased amplitudes of the SNAPs with +normal motor studies. +NCS demonstrate decreased ampli- +tudes of the SNAPs and CMAPs with slightly slow +CVs. +Sensation is generally preserved; however, the +autonomic nervous system can be affected. +A 24-h urine collection demonstrates +elevated levels of lead excretion. +The NCS may reveal +reduced CMAP amplitudes, while the SNAPs are typ- +ically normal. +The pathogenic basis may be related to +abnormal porphyrin metabolism. +The most important +principle of management is to remove the source of the +exposure. +Motor weakness can also develop. +CNS symp- +toms often overshadow the neuropathy. +EDx shows +features of a primarily axonal sensorimotor polyneu- +ropathy. +The primary site of neuromuscular pathology +appears to be the dorsal root ganglia. +The mainstay of +treatment is removing the source of exposure. +Increased thirst, +sleep disturbances, and psychotic behavior may be +noted. +With severe intoxica- +tion, proximal weakness and involvement of the cranial +nerves can occur. +Some patients require mechani- +cal ventilation due to respiratory muscle involvement. +The lethal dose of thallium is variable, ranging from 8 +to 15 mg/kg body weight. +Death can result in less than +48 h following a particularly large dose. +NCS demon- +strate features of a primarily axonal sensorimotor poly- +neuropathy. +However, there may be +no benefit once thallium has been absorbed. +Unfortu- +nately, chelating agents are not very efficacious. +ARSENIC +Arsenic is another heavy metal that can cause a toxic +sensorimotor polyneuropathy. +An underappreciated cause of +cobalamin deficiency is food-cobalamin malabsorption. +Complaints of numb hands typically appear before +lower extremity paresthesias are noted. +The full clinical picture of +subacute combined degeneration is uncommon. +EDx shows an axonal sensorimotor neuropathy. +CNS involvement produces abnormal somatosensory +and visual evoked potential latencies. +The diagnosis is +confirmed by finding reduced serum cobalamin levels. +In up to 40% of patients, anemia and macrocytosis are +lacking. +Cobalamin deficiency can be treated with various +regimens of cobalamin. +An oral +cobalamin dose of 1000 μg per day should be sufficient. +Thiamine is water-soluble. +Dry beriberi refers to neuro- +pathic symptoms. +The term wet beriberi is used when car- +diac manifestations predominate (in reference to edema). +Symptoms of neuropathy follow prolonged defi- +ciency. +Pain may be the predomi- +nant symptom. +Blood and urine assays for thiamine are not reli- +able for diagnosis of deficiency. +EDx shows +nonspecific findings of an axonal sensorimotor poly- +neuropathy. +Thiamine is +usually given intravenously or intramuscularly at a dose +of 100 mg/d. +Patients with cys- +tic fibrosis may also have vitamin E deficiency secondary +to steatorrhea. +There are genetic forms of isolated vita- +min E deficiency not associated with lipid malabsorption. +Clinical features may not appear until many years after +the onset of deficiency. +The onset of symptoms tends to +be insidious, and progression is slow. +Vitamin E deficiency +may present as an isolated polyneuropathy, but this is +very rare. +Diagnosis is made by measuring α-tocopherol levels +in the serum. +EDx shows features of an axonal neuropa- +thy. +Treatment is replacement with oral vitamin E, but +high doses are not needed. +Vita- +min B6 toxicity was discussed earlier. +Vitamin B6 defi- +ciency is most commonly seen in patients treated with +isoniazid or hydralazine. +Vitamin B6 deficiency can +be detected by direct assay. +This same dose is appro- +priate for replacement in cases of nutritional deficiency. +PELLAGRA (NIACIN DEFICIENCY) +Pellagra is produced by deficiency of niacin. +When peripheral nerves are involved, the neuropathy is +usually mild and resembles beriberi. +Treatment is with +niacin 40–250 mg/d. +Most +patients present with lower limb paresthesias, weakness, +spasticity, and gait difficulties. +Large-fiber sensory func- +tion is impaired, reflexes are brisk, and plantar responses +are extensor. +Excess zinc is an established cause of cop- +per deficiency. +Replacement +consists of oral copper sulfate or gluconate 2 mg one +to three times a day. +Thereafter, oral daily copper therapy can +be resumed. +Neuropathy +following weight loss surgery usually occurs in the first +several months after surgery. +The initial manifestations are usually +numbness and paresthesias in the feet. +In many cases, no +specific nutritional deficiency factor is identified. +Management consists of parenteral vitamin supple- +mentation, especially including thiamine. +CSPN should +be considered a distinct diagnostic subset of periph- +eral neuropathy. +The onset of CSPN is predominantly +in the sixth and seventh decades. +However, +tandem gait may be abnormal in a minority of cases. +Neither subjective nor objective evidence of weakness +is a prominent feature. +Most patients have evidence of +both large- and small-fiber loss on neurologic exam and +EDx. +Approximately 10% of patients have only evi- +dence of small-fiber involvement. +Therapy primarily involves the control of +neuropathic pain (Table 45-6) if present. +These drugs +should not be used if the patient has only numbness and +tingling but no pain. +The disorder does not lead to sig- +nificant motor disability over time. +The relatively benign +course of this disorder should be explained to patients. +CTS is common and often misdiagnosed +as thoracic outlet syndrome. +These often occur as a par- +tial form of brachial plexitis. +Triceps +and brachioradialis strength is often normal, and triceps +reflex is often intact. +The +neuropathy affecting this nerve is also known as meral- +gia paresthetica. +Symptoms and signs consist of paresthe- +sias, numbness, and occasionally pain in the lateral thigh. +Symptoms are increased by standing or walking and are +relieved by sitting. +There is normal strength and knee +reflexes are intact. +The diagnosis is clinical, and further +tests usually are not performed. +EDx is only needed to +rule out lumbar plexopathy, radiculopathy, or femoral +neuropathy. +If the symptoms and signs are classic, elec- +tromyography is not necessary. +Treatment con- +sists of weight loss and avoiding tight belts. +Rarely, locally injecting the nerve +with an anesthetic can be tried. +There is no role for +surgery. +Patients with femoral +neuropathy have difficulty extending their knee and +flexing the hip. +The quadriceps (patellar) +reflex is diminished. +In addition, many sci- +atic neuropathies are idiopathic. +Sensory loss occurs in the +entire foot and the distal lateral leg. +There is usually +no pain. +Onset may be on awakening in the morning. +Peroneal neuropathy needs to be distinguished from +L5 radiculopathy. +EDx can help localize the lesion. +Peroneal motor conduction velocity shows slowing +and amplitude drop across the fibular head. +Manage- +ment consists of rapid weight loss and avoiding leg +crossing. +Footdrop is treated with an ankle brace. +A +knee pad can be worn over the lateral knee to avoid +further compression. +Most cases spontaneously resolve +over weeks or months. +9. +45-2). +There are several disorders commonly associated +with brachial plexopathy. +IBPN usually presents with an acute onset of severe +pain in the shoulder region. +The intense pain usually +lasts several days to a few weeks, but a dull ache can +persist. +However, as the pain dissipates, +weakness and often sensory loss are appreciated. +Attacks +can occasionally recur. +Additionally, the phrenic +and anterior interosseous nerves may be concomitantly +affected. +Any of these nerves may also be affected in iso- +lation. +EDx is useful to confirm and localize the site(s) +of involvement. +Empirical treatment of severe pain with +glucocorticoids is often used in the acute period. +Sec- +ondary tumors affecting the brachial plexus are more +common and are always malignant. +These may arise +from local tumors, expanding into the plexus. +Chest CT scans or MRI can demon- +strate extension of the tumor into the plexus. +45-3). +The +obturator nerve arises from the ventral branches of the +same lumbar rami. +45-4). +T12 +Lateral femoral +cutaneous n. +Femoral n. +T12 +Iliohypogastric n. +Ilioinguinal n. +Genitofemoral n. +Obturator n. +Lumbosacral trunk +L1 +L2 +L3 +L4 +L5 +FIGURE 45-3 +Lumbar plexus. +Posterior divisions are in orange, anterior +divisions are in yellow. +(From J Goodgold: Anatomical Cor- +relates of Clinical Electromyography. +Baltimore, Williams and +Wilkins, 1974, p. +126, with permission.) +FIGURE 45-2 +Brachial plexus anatomy. +L, lateral; M, medial; P, poste- +rior. +(From J Goodgold: Anatomical Correlates of Clinical +Electromyography. +Baltimore, Williams and Wilkins, 1974, p. +The causes of lumbosacral plexopathies are listed in +Table 45-10. +Diabetic radiculopathy (discussed ear- +lier) is a fairly common cause of painful leg weakness. +Lumbosacral plexopathies are a well-recognized compli- +cation of retroperitoneal hemorrhage. +Radiation-induced plexopathy can develop months +or years following therapy and is dose dependent. +Posterior divisions are in orange, +anterior divisions are in yellow. +(From J Goodgold: Anatomi- +cal Correlates of Clinical Electromyography. +Baltimore, Wil- +liams and Wilkins, 1974, p. +Stephen L. +Hauser ■ Anthony A. +The usual +pattern is an ascending paralysis that may be fi rst noticed +as rubbery legs. +Deep tendon refl exes attenuate or +disappear within the fi rst few days of onset. +Bladder dys- +function may occur in severe cases but is usually tran- +sient. +Autonomic involvement is common and may occur +even in patients whose GBS is otherwise mild. +These features require +close monitoring and management and can be fatal. +These +pains are self-limited and often respond to standard +analgesics ( Chap. +7 ). +The most common +variant is acute infl ammatory demyelinating polyneurop- +athy (AIDP). +In addition, a range +of limited or regional GBS syndromes are also encoun- +tered. +33). +C. +It is likely that both cellular and humoral immune +mechanisms contribute to tissue damage in AIDP. +46-1). +The neural targets are likely +to be glycoconjugates, specifically gangliosides (Table +46-2; Fig. +46-2). +jejuni +infection. +Furthermore, isolates of C. +Sialic +acid residues from pathogenic C. +Anti-GQ1b IgG antibodies are found in >90% of +patients with MFS (Table 46-2; Fig. +jejuni infection. +B cells recognize glycoconjugates +on C. +Some B cells, activated via a T cell–indepen- +dent mechanism, secrete primarily IgM (not shown). +SECTION III +Diseases of the Nervous System +602 +of IgG are highest early in the course. +In addition, a monoclonal anti- +GQ1b antibody raised against C. +jejuni isolated from a +patient with MFS blocked neuromuscular transmission +experimentally. +Source: Modified from HJ Willison, N Yuki: Brain 125:2591, 2002. +Hence, recovery can take place rapidly as remyelination +occurs. +Diagnosis +GBS is a descriptive entity. +Laboratory tests are +helpful primarily to exclude mimics of GBS. +Tau +increases in CSF may reflect axonal damage and pre- +dict a residual deficit. +A combination of the two therapies is not signifi- +cantly better than either alone. +IVIg is administered as five +daily infusions for a total dose of 2 g/kg body weight. +Brief retreatment with +the original therapy is usually effective in such cases. +Glucocorticoids have not been found to be effective in +GBS. +Required for Diagnosis +1. +Progressive weakness of variable degree from mild +paresis to complete paralysis +2. +Generalized hypo- or areflexia + II. +Supportive of Diagnosis +1. +Clinical Features +a. +Symptom progression: Motor weakness rapidly +progresses initially but ceases by 4 weeks. +Nadir +attained by 2 weeks in 50%, 3 weeks 80%, and +90% by 4 weeks. +b. +Demonstration of relative limb symmetry regard- +ing paresis. +c. +Mild to moderate sensory signs. +d. +e. +Recovery typically begins 2–4 weeks following +plateau phase. +f. +g. +2. +Cerebrospinal Fluid Features Supporting Diagnosis +a. +Elevated or serial elevation of CSF protein. +b. +CSF cell counts are <10 mononuclear cell/mm3. +3. +Electrodiagnostic Medicine Findings Supportive of +Diagnosis +a. +b. +Patchy reduction in NCV attaining values less +than 60% of normal. +c. +Distal motor latency increase may reach 3 times +normal values. +d. +F-waves indicate proximal NCV slowing. +e. +About 15–20% of patients have normal NCV +findings. +f. +No abnormalities on nerve conduction studies +may be seen for several weeks. +III. +Findings Reducing Possibility of Diagnosis +1. +Asymmetric weakness +2. +Failure of bowel/bladder symptoms to resolve +3. +Severe bowel/bladder dysfunction at initiation of +disease +4. +Greater than 50 mononuclear cells/mm3 in CSF +5. +Well-demarcated sensory level + IV. +Exclusionary Criteria +1. +2. +Source: AA Amato, D Dumitru, in D Dumitru et al (eds): Electrodiag- +nostic Medicine, 2nd ed. +Philadelphia, Hanley & Belfus, 2002. +The out- +look is worst in patients with severe proximal motor +and sensory axonal damage. +Most cases occur in +adults, and males are affected slightly more often than +females. +Symptoms are +both motor and sensory in most cases. +There is considerable variability from case +to case. +A small +proportion have cranial nerve findings, including exter- +nal ophthalmoplegia. +Death from CIDP is uncommon. +Diagnosis +The diagnosis rests on characteristic clinical, CSF, and +electrophysiologic findings. +The CSF is usually acellular +with an elevated protein level, sometimes several times +normal. +Evidence of axonal loss, presum- +ably secondary to demyelination, is present in >50% of +patients. +Other associated conditions include +inflammatory bowel disease and lymphoma. +46-1). +If the dis- +order is mild, management can be expectant, awaiting +spontaneous remission. +Early +experience with anti-CD20 (rituximab) has also shown +promise. +Use of these therapies requires periodic reas- +sessment of their risks and benefits. +Sensory fibers +are relatively spared. +The arms are affected more fre- +quently than the legs, and >75% of all patients are +male. +32). +Pathology reveals demyelination and +mild inflammatory changes at the sites of conduction +block. +Some refractory patients have +responded to rituximab or cyclophosphamide. +Gluco- +corticoids and PE are not effective. +In most cases, Edx +and pathologic features are consistent with a process of +axonal degeneration. +Most patients are male and older than age 50 years. +46-1). +Demyelination and remyelination are the hallmarks +of the lesions. +Symptoms +of neuropathy are a common presenting complaint in +patients with PAN. +The Edx findings are those of an +axonal process. +Consti- +tutional symptoms are absent, and the course is more +indolent than that of PAN. +Neurologic +symptoms usually precede, by ≤6 months, the identi- +fication of SCLC. +Daniel B. +Treatment now available for MG is highly +effective, although a specifi c cure has remained elusive. +PATHOPHYSIOLOGY + At the neuromuscular junction ( Fig. +AChE, acetylcholinesterase. +See text for +description of normal neuromuscular transmission. +Failure of transmission at many neuromuscular junctions +results in weakness of muscle contraction. +The pathogenic antibodies are IgG, and are T cell- +dependent. +An additional +10% of patients have thymic tumors (thymomas). +CLINICAL FEATURES +MG is not rare, having a prevalence of 2–7 in 10,000. +Overall, women +are affected more frequently than men, in a ratio of +∼3:2. +The cardinal features are weakness and fatigability +of muscles. +The course of MG is often variable. +Remis- +sions are rarely complete or permanent. +The distribution of muscle weakness often has a +characteristic pattern. +Facial weakness produces a +“snarling” expression when the patient attempts to +smile. +Weakness in chewing is most noticeable after +prolonged effort, as in chewing meat. +Bul- +bar weakness is especially prominent in MuSK anti- +body–positive MG. +In ∼85% of patients, the weakness +becomes generalized, affecting the limb muscles as well. +The limb weakness in MG is often proximal and may +be asymmetric. +Despite the muscle weakness, deep ten- +don reflexes are preserved. +Anti-AChE medication is +stopped 6–24 h before testing. +It is best to test weak +muscles or proximal muscle groups. +An initial IV dose +of 2 mg of edrophonium is given. +If definite improve- +ment occurs, the test is considered positive and is ter- +minated. +If there is no change, the patient is given an +additional 8 mg IV. +False-negative or equivocal tests may also +occur. +∼40% +of AChR antibody–negative patients with generalized +MG have anti-MuSK antibodies. +Source: From RT Johnson, JW Griffin (eds): Current Therapy in +Neurologic Disease, 4th ed. +St. +Louis, Mosby Year Book, 1994; with +permission. +Features of four of the most com- +mon forms of CMS are summarized in Table 47-2. +These autoantibod- +ies result in impaired release of ACh from nerve ter- +minals. +Treatment of LEMS involves plasmapher- +esis and immunosuppression, as for MG. +3,4-Diami- +nopyridine (3,4-DAP) and pyridostigmine may also +be symptomatically helpful. +Pyridostigmine prolongs the +action of ACh, allowing repeated interactions with +AChRs. +Most commonly, botulism is caused +by ingestion of improperly prepared food containing +toxin. +Rarely, the nearly ubiquitous spores of C. +botu- +linum may germinate in wounds. +In infants the spores +may germinate in the GI tract, and release toxin, caus- +ing muscle weakness. +Weakness +may generalize to the limbs and may result in respira- +tory failure. +Reflexes are present early, but they may be +diminished as the disease progresses. +Mentation is nor- +mal. +Antitoxin +should be given as early as possible to be effective. +A +preventive vaccine is available for laboratory workers +or other highly exposed individuals. +Neurasthenia is the historic term for a myasthenia-like +fatigue syndrome without an organic basis. +Abnormali- +ties of thyroid function (hyper- or hypothyroidism) may +increase myasthenic weakness. +48). +Thymic abnor- +malities occur in ∼75% of patients, as noted earlier. +Hyperthy- +roidism occurs in 3–8% of patients and may aggravate +the myasthenic weakness. +Thyroid function tests should +be obtained in all patients with suspected MG. +Source: From RT Johnson, JW Griffin (eds): Current Therapy in +Neurologic Disease, 4th ed. +St. +Louis, Mosby Year Book, 1993, p +379; with permission. +Chronic infection +of any kind can exacerbate MG and should be sought +carefully. +Nearly all myasthenic patients +can be returned to full productive lives with proper +therapy. +47-2). +Pyridostigmine +is the most widely used anticholinesterase drug. +Treatment is begun with a moderate dose, e.g., +30–60 mg three to four times daily. +The maximum useful dose of pyridostig- +mine rarely exceeds 120 mg every 4–6 h during day- +time. +Overdosage with anticholinesterase medication +may cause increased weakness and other side effects. +Atropine/ +diphenoxylate or loperamide is useful for the treatment +of gastrointestinal symptoms. +However, the +improvement is typically delayed for months to years. +FVC, forced vital capacity. +We recommend +maintenance immunotherapy after rebooting, to sus- +tain the beneficial effect. +Few patients are able to do +without immunosuppressive agents entirely. +A dose of +1–1.5 g bid is recommended. +Its mechanism of action +involves inhibition of purine synthesis by the de novo +pathway. +An initial dose of 50 mg/d should be used +for several days to test for these side effects. +The beneficial effect of azathioprine +takes 3–6 months to begin and even longer to peak. +In +patients taking azathioprine, allopurinol should never +be used to treat hyperuricemia. +Their beneficial effect appears more rapidly +than that of azathioprine. +“Trough” blood levels are measured 12 h after the +evening dose. +This treatment +has the advantages of not requiring special equipment +or large-bore venous access. +The usual dose is 2 g/kg, +which is typically administered over 5 days (400 mg/kg +per d). +If tolerated, the total dose of IVIg can be given +over a 3- to 4-day period. +Crisis rarely occurs in properly +managed patients. +The most common cause of crisis is intercurrent +infection. +As discussed earlier, plasmapheresis or IVIg is frequently +helpful in hastening recovery. +Conversely, not all +“safe” drugs can be used with impunity in patients with +MG. +47-3. +Azathioprine +Avoid allopurinol—combination may result in myelosup- +pression. +Anthony A. +Amato ■ Robert H. +Brown, Jr. +Myasthenia gravis and related disorders are discussed +in Chap. +47 ; dermatomyositis, polymyositis, and inclu- +sion body myositis are discussed in Chap. +49 . +However, asymmetric and predomi- +nantly distal weakness can be seen in some myopathies. +Muscle weakness + Symptoms of muscle weakness can be either intermit- +tent or persistent. +Disorders causing intermittent weakness + ( Fig. +Most muscle disorders cause persistent weakness ( Fig. +48-2 ) . +The dif- +ferential diagnosis is more restricted for other patterns +of weakness. +Facial weakness (diffi culty with eye closure +and impaired smile) and scapular winging ( Fig. +48-3 ) +are characteristic of facioscapulohumeral dystrophy +(FSHD). +The Gowers’ sign ( Fig. +48-4 ) is particularly +useful. +Examina- +tion reveals one of seven patterns of weakness. +The pattern +of weakness in combination with the laboratory evaluation +leads to a diagnosis. +48-5). +A waddling gait is caused by the inabil- +ity of weak hip muscles to prevent hip drop or hip dip. +Associated +symptoms may help differentiate asthenia and pathologic +fatigability. +There may be feelings of +overwhelming stress and depression. +Thus, asthenia is not +a myopathy. +Pathologic fatigability is accompanied by abnormal clinical +or laboratory findings. +Fatigue without those supportive +features almost never indicates a primary muscle disease. +Certain drugs cause +true myalgia (Table 48-3). +Fibromyalgia is a common, yet poorly +understood, type of myofascial pain syndrome. +The ESR is elevated, while +serum CK, EMG, and muscle biopsy are normal. +Vision is threatened by ischemic optic +neuritis. +Glucocorticoids can relieve the myalgias and +protect against visual loss. +Localized muscle pain is most often traumatic. +The biceps brachii and Achilles tendons are +particularly vulnerable to rupture. +Infection or neoplas- +tic infiltration of the muscle is a rare cause of localized +muscle pain. +Cramps are abrupt in onset, +short in duration, and may cause abnormal posturing +of the joint. +The EMG shows firing of motor units, +reflecting an origin from spontaneous neural discharge. +Muscle cramps often occur in neurogenic disorders, +especially motor neuron disease (Chap. +32), radicu- +lopathies, and polyneuropathies (Chap. +45), but are not +a feature of most primary muscle diseases. +Muscle cramps are +also common during pregnancy. +A muscle contracture is different from a muscle cramp. +The muscle is unable to relax after an active muscle con- +traction. +The EMG shows electrical silence. +Muscle stiffness can refer to different phenomena. +Some patients with inflammation of joints and periar- +ticular surfaces feel stiff. +The gait becomes stiff and labored, with hyper- +lordosis of the lumbar spine. +The muscles +relax during sleep. +Myotonia is a condition of prolonged muscle con- +traction followed by slow muscle relaxation. +Myotonia +typically causes difficulty in releasing objects after a firm +grasp. +Another sodium channelopa- +thy, paramyotonia congenita, also is associated with muscle +stiffness. +The calf muscles remain very strong even late +in the course of these disorders. +In contrast, muscle atrophy is char- +acteristic of other myopathies. +Atrophy of the humeral muscles is characteristic +of facioscapulohumeral dystrophy (FSHD). +LABORATORY EVALUATION +A limited battery of tests can be used to evaluate a sus- +pected myopathy. +Serum enzymes +CK is the preferred muscle enzyme to measure in the +evaluation of myopathies. +Electrodiagnostic studies +EMG, repetitive nerve stimulation, and nerve conduc- +tion studies (Chap. +5) are essential methods for evalu- +ation of the patient with suspected muscle disease. +Nevertheless, there are +a number of limitations in currently available molecu- +lar diagnostics. +Many variations of the fore- +arm exercise test exist. +The test is performed by placing a small indwell- +ing catheter into an antecubital vein. +A baseline blood +sample is obtained for lactic acid and ammonia. +A three- to four- +fold rise of lactic acid is typical. +If there is lack of +effort, neither lactic acid nor ammonia will rise. +Patients +with selective failure to increase ammonia may have +myoadenylate deaminase deficiency. +Not all +techniques are needed for every case. +A specific diag- +nosis can be established in many disorders. +Biopsied muscle tissue can be sent +for metabolic enzyme or mitochondrial DNA analyses. +The boys fall frequently and have difficulty +keeping up with friends when playing. +Running, +jumping, and hopping are invariably abnormal. +By age +5 years, muscle weakness is obvious by muscle test- +ing. +48-4]). +By age 12 years, most patients are wheelchair +dependent. +By age 16–18 years, patients are predisposed +to serious, sometimes fatal pulmonary infections. +Other +causes of death include aspiration of food and acute gas- +tric dilation. +Congestive heart failure seldom occurs except with +severe stress such as pneumonia. +Cardiac arrhyth- +mias are rare. +Laboratory features +Serum CK levels are invariably elevated to between 20 +and 100 times normal. +EMG demonstrates features typical +of myopathy. +Connective tissue and fat replace +lost muscle fibers. +The dystrophin gene is >2000 kb in size +and thus is one of the largest identified human genes. +Many features overlap (see text). +Xp21. +The most common gene mutation is a deletion. +The size varies but does not correlate with disease +severity. +Less often, Duch- +enne’s dystrophy is caused by a gene duplication or +point mutation. +48-6). +Dystrophin binds +to F-actin at its amino terminus and to β-dystroglycan +at the carboxyl terminus. +The laminin heavy +chain of skeletal muscle is designated laminin α2. +Colla- +gen proteins IV and VI are also found in the ECM. +These +include caveolin-3, α7 integrin, and collagen VI. +Dystrophin localizes to the cytoplasmic face of +the muscle cell membrane. +It complexes with two +transmembrane protein complexes, the dystroglycans +and the sarcoglycans. +Deficiency of one member of +the complex may cause abnormalities in other compo- +nents. +This sequence +of events occurs repeatedly during the life of a patient +with muscular dystrophy. +Proximal muscles, especially of the lower extremities, +are prominently involved. +As the disease progresses, +weakness becomes more generalized. +Significant facial +muscle weakness is not a feature. +Hypertrophy of mus- +cles, particularly in the calves, is an early and prominent +finding. +Mental retardation may occur in Becker’s dystro- +phy, but it is not as common as in Duchenne’s. +LIMB-GIRDLE MUSCULAR DYSTROPHY +The syndrome of LGMD represents more than one +disorder. +The LGMDs typically manifest with progres- +sive weakness of pelvic and shoulder girdle musculature. +Respiratory insufficiency from weakness of the dia- +phragm may occur, as may cardiomyopathy. +Disorders receive letters in the order +in which they are found to have chromosomal linkage. +This results in an ever-expanding list of conditions. +The cardiomyopathy is potentially +life threatening and may result in sudden death. +Some patients have a dilated cardiomyopathy. +Laboratory features +Serum CK may be elevated two- to tenfold. +EMG is +myopathic. +ECGs demonstrate atrial and atrioventricular +rhythm disturbances. +X-linked EDMD usually arises from defects in the +emerin gene encoding a nuclear envelope protein. +48-7). +Stretching of contractures is difficult. +The position of +the dystrophin-dystroglycan complex is also illustrated. +Calf muscle hypertrophy is +seen in some patients. +Most patients have +joint contractures of varying degrees at elbows, hips, +knees, and ankles. +Contractures present at birth are +referred to as arthrogryposis. +Respiratory failure may be +seen in some cases. +The CNS is affected in some forms of CMD. +Three forms of congenital muscular dystrophy have +severe brain impairment. +Patients are severely disabled in all three of +these conditions. +In MEB disease and WWS, but not +in FCMD, ocular abnormalities impair vision. +WWS is +the most severe congenital muscular dystrophy, causing +death by 1 year of age. +Laboratory features +Serum CK is markedly elevated in all of these con- +ditions. +The EMG is myopathic and muscle biopsies +show nonspecific dystrophic features. +Skin biopsies can also demonstrate defects in laminin +α2 chain. +All forms of CMD are inherited as autosomal reces- +sive disorders. +Chromosomal linkage and specific gene +defects are presented in Table 48-8. +TREATMENT Congenital Muscular Dystrophy +There is no specific treatment for CMD. +Proper wheel- +chair seating is important. +Management of epilepsy and +cardiac manifestations is necessary for some patients. +MYOTONIC DYSTROPHY +Myotonic dystrophy is also known as dystrophia myo- +tonica (DM). +Frontal baldness is also characteristic of +the disease. +Weakness of wrist extensors, finger extensors, and +intrinsic hand muscles impairs function. +Ankle dorsi- +flexor weakness may cause footdrop. +Myotonia causes +a slow relaxation of hand grip after a forced voluntary +closure. +Advanced muscle wasting makes myotonia +more difficult to detect. +Cardiac disturbances occur commonly in patients +with DM1. +Complete heart block and sudden death can +occur. +Mitral valve prolapse also occurs commonly. +DM2, or PROMM, has a distinct pattern of muscle +weakness affecting mainly proximal muscles. +A very +striking difference is the failure to clearly identify a con- +genital form of DM2. +Serum CK lev- +els may be normal or mildly elevated. +bThere is phenotypic overlap between disorders related to defective glycosylation. +Clinically, Walker-Warburg syndrome is more severe, with death by 1 year. +DM1 and DM2 are both autosomal dominant +disorders. +New mutations do not appear to contribute +to the pool of affected individuals. +A similar type of mutation +has been identified in fragile X syndrome. +The unsta- +ble triplet repeat in myotonic dystrophy can be used +for prenatal diagnosis. +Molded ankle- +foot orthoses help stabilize gait in patients with foot +drop. +Excessive daytime somnolence with or without +sleep apnea is not uncommon. +There are two forms of FSHD that have +similar pathogenesis, as will be discussed. +Most patients +have FSHD type 1 (95%), while approximately 5% have +FSHD2. +FSHD1 and FSHD2 are clinically and his- +topathologically identical. +FSHD is not to be confused +with the genetically distinct scapuloperoneal dystrophies. +Clinical features +The condition typically has an onset in childhood or +young adulthood. +Loss of scapular stabi- +lizer muscles makes arm elevation difficult. +Scapular +winging (Fig. +48-3) becomes apparent with attempts at +abduction and forward movement of the arms. +Laboratory features +The serum CK level may be normal or mildly elevated. +EMG usually indicates a myopathic pattern. +The mus- +cle biopsy shows nonspecific features of a myopathy. +The cause or significance of this finding is +unknown. +FSHD1 is associated with +deletions of tandem 3.3-kb repeats at 4q35. +The dele- +tion reduces the number of repeats to a fragment of +<35 kb in most patients. +Within these repeats lies the +DUX4 gene, which usually is not expressed. +Scapular stabilization proce- +dures improve scapular winging but may not improve +function. +The extraocular muscle impairment +is less prominent in the early phase but may be severe +later. +Mild weakness of the neck and extremities +also occurs. +Laboratory features +The serum CK level may be two to three times normal. +Myopathic EMG findings are typical. +Oculopharyngeal dystrophy has an autosomal domi- +nant inheritance pattern with complete penetrance. +Large kindreds of Italian and of eastern European Jew- +ish descent have been reported. +Cricopha- +ryngeal myotomy may improve swallowing, although +it does not prevent aspiration. +The major distal myopa- +thies are summarized in Table 48-9. +In the +other conditions, serum CK is only slightly increased. +EMGs are myopathic. +In the MFMs, myotonic or pseu- +domyotonic discharges are common. +The affected genes and their gene products are listed +in Table 48-9. +The gene for Welander’s disease awaits +identification. +Laing’s-type distal myopathy can also be associated with +a cardiomyopathy. +Sarcotubular myopathy +is caused by mutations in TRIM-32 and is identical to +LGMD2H. +Hypotonia +and delay in motor milestones, particularly in walk- +ing, are common. +On examination, there is mild facial, +neck-flexor, and proximal-extremity muscle weakness. +Legs are more affected than arms. +Most cases are nonpro- +gressive, but exceptions are well documented. +The serum CK level is usually normal. +Needle EMG +demonstrates a myopathic pattern. +Autosomal dominant inheritance is characteristic; +sporadic cases also occur. +Nemaline myopathy is clinically het- +erogeneous. +Nemaline myopathy usually presents +in infancy or childhood with delayed motor milestones. +The course is nonprogressive or slowly progressive. +Facial and gen- +eralized muscle weakness, including respiratory muscle +weakness, is common. +An adult-onset disorder with +progressive proximal weakness may be seen. +Myocar- +dial involvement is occasionally present in both the +childhood and adult-onset forms. +The serum CK level +is usually normal or slightly elevated. +The EMG dem- +onstrates a myopathic pattern. +Occasionally, the rods are also +apparent in myonuclei. +The muscle often shows type 1 +muscle fiber predominance. +Rods originate from the Z +disk material of the muscle fiber. +Six genes have been associated with nemaline myop- +athy. +No specific treatment is available. +CENTRONUCLEAR (MYOTUBULAR) +MYOPATHY +Three distinct variants of centronuclear myopathy +occur. +The late infancy–early childhood form presents +with delayed motor milestones. +Later, difficulty with +running and stair climbing becomes apparent. +A mar- +fanoid, slender body habitus, long narrow face, and +high-arched palate are typical. +Scoliosis and clubbed feet +may be present. +Most patients exhibit progressive weak- +ness, some requiring wheelchairs. +A third +variant, the late childhood–adult form, has an onset in +the second or third decade. +Patients have full extraocu- +lar muscle movements and rarely exhibit ptosis. +45]). +Normal or slightly elevated CK levels occur in each +of the forms. +In transverse sections, central nuclei +are found in 25–80% of muscle fibers. +Carrier +identification and prenatal diagnosis are possible. +No specific medical treatments are available +at this time. +The infantile form is the most common, with onset of +symptoms in the first 3 months of life. +Infants develop +severe muscle weakness, cardiomegaly, hepatomegaly, +and respiratory insufficiency. +Death usually occurs +by 1 year of age. +In the childhood form, the picture +resembles muscular dystrophy. +The heart may +be involved, but the liver and brain are unaffected. +The heart and liver are not +involved. +EMG discharges are very promi- +nent in the paraspinal muscles. +Electron +microscopy reveals membrane-bound and free tis- +sue glycogen. +Enzyme analysis of dried blood spots is +a sensitive technique to screen for Pompe’s disease. +Rarely, myoglobinuria may be seen. +Clinical muscle manifestations in these conditions +usually begin in adolescence. +Acute renal failure accompanies significant pigmenturia. +Certain features help distinguish some enzyme defects. +CK levels >100 times normal are +expected, accompanying myoglobinuria. +An +impaired rise in venous lactate is highly indicative of a +glycolytic defect. +Phospho- +glycerate kinase deficiency is X-linked recessive. +Training may enhance exercise tolerance, perhaps +by increasing perfusion to muscle. +Oxidation of fatty acids occurs in the +mitochondria. +CPT I is present +on the inner side of the outer mitochondrial membrane. +Onset is usually in the teenage +years or early twenties. +Strength is +normal between attacks. +Episodes of rhabdomyolysis may produce severe +weakness. +Serum CK levels and EMG findings are both usually +normal between episodes. +Muscle biopsy does not show lipid accumu- +lation and is usually normal between attacks. +The diag- +nosis requires direct measurement of muscle CPT or +genetic testing. +A mutation in the gene +for CPT II (chromosome 1p36) causes the disease in +some individuals. +Most individuals +with myoadenylate deaminase deficiency have no symp- +toms. +Mitochondria play a key role in energy production. +A novel feature of mitochondria is their genetic com- +position. +Each mitochondrion possesses a DNA genome +that is distinct from that of the nuclear DNA. +The +genetics of mitochondrial diseases differ from the genet- +ics of chromosomal disorders. +Some patients with CPEO and ragged +red fibers may not fulfill all of the criteria for KSS. +Death attributed to heart block occurs in +∼20% of the patients. +Both mental retardation and dementia are +common accompaniments to this disorder. +Serum CK +levels are normal or slightly elevated. +Serum lactate and +pyruvate levels may be elevated. +EMG is myopathic. +Nerve conduction studies may be abnormal related to +an associated neuropathy. +KSS is a sporadic disorder. +Monitoring for +cardiac conduction defects is critical. +Prophylactic pace- +maker implantation is indicated when ECGs demon- +strate a bifascicular block. +Onset is usually +after puberty. +Fatigue, exercise intolerance, and com- +plaints of muscle weakness are typical. +Some patients +notice swallowing problems. +A sensorineural hearing +loss may be encountered. +Mild facial, neck flexor, and +proximal weakness are typical. +Rarely, respiratory mus- +cles may be progressively affected and may be the direct +cause of death. +Serum CK is normal or mildly elevated. +The resting lactate level is normal or slightly elevated +but may rise excessively after exercise. +CSF protein is +normal. +The EMG is myopathic, and nerve conduction +studies are usually normal. +Ragged red fibers are prom- +inently displayed in the muscle biopsy. +In the chromosome 10q– +related disorder, mutations of the gene C10orf2 are +found. +Autosomal recessive PEO has also been described with +mutations in the POLG gene. +Exercise may improve function but will depend on +the patient’s ability to participate. +The seizure disorder +is an integral part of the disease and may be the initial +symptom. +Cerebellar ataxia precedes or accompanies +epilepsy. +It is slowly progressive and generalized. +Serum CK levels are normal or slightly increased. +The +serum lactate may be elevated. +EMG is myopathic, and in +some patients nerve conduction studies show a neuropa - +thy. +The electroencephalogram is abnormal, corroborat- +ing clinical findings of epilepsy. +Typical ragged red fibers +are seen on muscle biopsy. +MERRF is caused by mater- +nally inherited point mutations of mitochondrial tRNA +genes. +Other tRNAlys +mutations include base-pair substitutions T8356C and +G8363A. +Only supportive treatment is possible, with spe- +cial attention to epilepsy. +The onset in the majority of patients is before +age 20. +In its full expression, MELAS leads to +dementia, a bedridden state, and a fatal outcome. +Serum +lactic acid is typically elevated. +The CSF protein is also +increased but is usually f1 g/L (100 mg/dL). +Muscle +biopsies show ragged red fibers. +Neuroimaging dem- +onstrates basal ganglia calcification in a high percentage +of cases. +Focal lesions that mimic infarction are present +predominantly in the occipital and parietal lobes. +MELAS is caused by maternally inherited point +mutations of mitochondrial tRNA genes. +The +A3243G point mutation in tRNALeu(UUR) is the most +common, occurring in ∼80% of MELAS cases. +Mutations have also been reported in mtDNA +polypeptide-coding genes. +Two mutations were found in +the ND5 subunit of complex I of the respiratory chain. +No specific treatment is available. +Supportive treat- +ment is essential for the strokelike episodes, seizures, and +endocrinopathies. +The clinical phenotypes associated with MDS +vary. +The heart may +also be involved, resulting in life-threatening complica- +tions (Table 48-10). +Men are more often +affected because of decreased penetrance in women. +Weakness usually affects proximal limb muscles more +than distal. +Ocular and bulbar muscles are less likely to be +affected. +Respiratory muscles are usually spared but when +they are involved, the condition may prove fatal. +Weak- +ness may take as long as 24 h to resolve. +Life-threatening +cardiac arrhythmias related to hypokalemia may occur +during attacks. +Attacks of thyrotoxic periodic paralysis resemble +those of primary HypoKPP. +Attacks abate with treatment of the underlying +thyroid condition. +HypoKPP is caused by mutations in either of two +genes. +48-8). +The chloride channel is envisioned to have 10 +membrane-spanning domains. +Muscle strength and ECG should be moni- +tored. +bMay be paradoxical in paramyotonia congenita. +Abbreviations: AD, autosomal dominant; PP, periodic paralysis. +SECTION III +Diseases of the Nervous System +642 +30 min. +Only rarely is IV therapy necessary (e.g., when +swallowing problems or vomiting is present). +Mannitol is the preferred vehicle for admin- +istration of IV potassium. +The long-term goal of therapy +is to avoid attacks. +This may reduce late-onset, fixed +weakness. +If attacks per- +sist on acetazolamide, oral KCl should be added. +The association of the four domains +is thought to form a pore through which ions pass. +Sodium +channel mutations are shown along with the phenotype that +they confer. +See text for details. +patients require treatment with triamterine (25–100 +mg/d) or spironolactone (25–100 mg/d). +The fact that attacks +are precipitated by potassium administration best defines +the disease. +The onset is in the first decade; males and +females are affected equally. +Attacks are brief and mild, +usually lasting 30 min to 4 h. +Weakness affects proximal +muscles, sparing bulbar muscles. +Attacks are precipitated +by rest following exercise and fasting. +The symp- +toms are aggravated by cold, and myotonia makes the +muscles stiff and painful. +Potassium may be slightly elevated but may also be +normal during an attack. +In between attacks of weakness, +the conduction studies are normal. +The EMG will often +demonstrate myotonic discharges during and between +attacks. +HyperKPP and potassium-aggravated myotonia +are inherited as autosomal dominant disorders. +Muta- +tions of the voltage-gated sodium channel SCN4A +gene (Fig. +48-8) cause these conditions. +For patients +with frequent attacks, acetazolamide (125–1000 mg/d) +is helpful. +We have found mexiletine to be helpful in +patients with significant myotonia. +Myotonia is a prominent feature but worsens +with muscle activity (paradoxical myotonia). +This is in +contrast to classic myotonia in which exercise alleviates +the condition. +Attacks of weakness are seldom severe +enough to require emergency room treatment. +PC is usually associ- +ated with normokalemia or hyperkalemia. +Serum CK is usually mildly elevated. +Routine sen- +sory and motor nerve conduction studies are normal. +EMG reveals diffuse myotonic potentials in PC. +PC is inherited as an autosomal dominant condition; +voltage-gated sodium channel mutations (Fig. +Patients with +PC seldom seek treatment during attacks. +Oral adminis- +tration of glucose or other carbohydrates hastens recovery. +Patients should be advised to increase carbo- +hydrates in their diet. +The cardiac arrhythmias are potentially seri- +ous and life threatening. +In addition, the +potassium levels differ among kindreds but are consis- +tent within a family. +Inheritance is autosomal dominant, +with incomplete penetrance and variable expressivity. +The episodes of weakness may dif- +fer between patients because of potassium variability. +Acetazolamide may decrease the attack frequency and +severity. +Symptoms are +noted in infancy and early childhood. +The severity less- +ens in the third to fourth decade. +Myotonia is worsened +by cold and improved by activity. +The gait may appear +slow and labored at first but improves with walking. +Muscle hypertrophy is usually +present. +Myotonic discharges are prominently displayed +by EMG recordings. +Serum CK is normal or mildly elevated. +The muscle +biopsy shows hypertrophied fibers. +48-8) that increase +muscle cell excitability. +Many patients will not require +treatment and learn that the symptoms improve with +activity. +Medications that can be used to decrease myo- +tonia include quinine, phenytoin, and mexiletine. +ENDOCRINE AND METABOLIC +MYOPATHIES +Many endocrine disorders cause weakness. +Muscle +fatigue is more common than true weakness. +The cause +of weakness in these disorders is not well defined. +Nearly all endocrine myopathies respond to treatment. +THYROID DISORDERS +Abnormalities of thyroid function can cause a wide +array of muscle disorders. +Muscle cramps, pain, and +stiffness are common. +Some patients have enlarged +muscles. +EMG is typically normal. +Activ- +ity of deep tendon reflexes may be enhanced. +Some +patients develop neck extensor weakness (part of the +dropped head syndrome). +Serum CK levels are usually +normal or slightly elevated. +Serum parathyroid hor- +mone levels are elevated. +Muscle biopsies show +only varying degrees of atrophy without muscle fiber +degeneration. +Hypoparathyroidism +An overt myopathy due to hypocalcemia rarely occurs. +Neuromuscular symptoms are usually related to local- +ized or generalized tetany. +Serum CK levels may be +increased secondary to muscle damage from sustained +tetany. +Muscle wasting may be +striking. +A cushingoid appearance usually accompanies +clinical signs of myopathy. +Adrenal insufficiency commonly causes muscle +fatigue. +The degree of weakness may be difficult to +assess but is typically mild. +The clinical picture is one +of persistent muscle weakness. +Long-standing hyperal- +dosteronism may lead to proximal limb weakness and +wasting. +These changes relate to hypokalemia and +are not a direct effect of aldosterone on skeletal muscle. +Muscles often +appear enlarged but exhibit decreased force gen- +eration. +The area of muscle infarction is hard and indurated. +CT +or MRI can demonstrate focal abnormalities in the +affected muscle. +Pain reflects the underlying bone dis- +ease (osteomalacia). +Vitamin E deficiency may result from +malabsorption. +Progressive external oph- +thalmoplegia is a distinctive finding. +It has not been +established that deficiency of other vitamins causes a +myopathy. +Fatigue +is usually a more significant problem than weakness, +which is typically mild. +There is +proximal limb weakness with bone pain. +Gangrenous calcification represents a separate, rare, +and sometimes fatal complication of CRF. +In this con- +dition, widespread arterial calcification occurs and +results in ischemia. +Extensive skin necrosis may occur, +along with painful myopathy and even myoglobinuria. +Others impact practice to a lesser degree but are impor- +tant to consider in specific situations. +Glucocorticoids Acute, high-dose glucocorticoid +treatment can cause acute +quadriplegic myopathy. +Chronic steroid +administration produces pre- +dominantly proximal weakness. +Zidovudine Mitochondrial myopathy with +ragged red fibers. +Local injections cause muscle +necrosis, skin induration, and +limb contractures. +Muscle biopsy shows +autophagic vacuoles. +SECTION III +Diseases of the Nervous System +646 statins), niacin (nicotinic acid), and ezetimibe. +Myalgia, +malaise, and muscle tenderness are the most common +manifestations. +Muscle pain may be related to exer- +cise. +Patients may exhibit proximal weakness. +Elevated serum CK is an important indi- +cation of toxicity. +Patients usually improve with drug cessation, +although this may take several weeks. +Rare cases con- +tinue to progress after the offending agent is discontin- +ued. +In chronic steroid myopathy, +the serum CK is usually normal. +Serum potassium may +be low. +Calpain stains show diffusely reac- +tive atrophic fibers. +Withdrawal of glucocorticoids will +improve the chronic myopathy. +In acute quadriplegic +myopathy, recovery is slow. +Patients require supportive +care and rehabilitation. +Myopathy is a well- +established complication of this agent. +The complication occurs in +about 17% of patients treated with doses of 1200 mg/d +for 6 months. +Serum CK is elevated and EMG is myopathic. +Ethanol is one of the most +commonly abused substances with potential to dam- +age muscle. +Other potential toxins include cocaine, +heroin, and amphetamines. +The effects of alcohol are more +controversial. +Alcoholics are also prone to +neuropathy (Chap. +56). +Elevated +serum CK and myopathic EMG are characteristic of these +reactions. +In all of these condi- +tions, counseling is essential to limit drug abuse. +This drug chelates copper and is used in the treatment +of Wilson’s disease. +The incidence of this inflammatory +muscle disease is about 1%. +Myasthenia gravis is also +induced by D-penicillamine, with a higher incidence +estimated at 7%. +In most cases, a cause-and-effect +relationship is uncertain. +A complication of interest +was related to L-tryptophan. +The product was withdrawn, and +incidence of EMS diminished abruptly following this +action. +OTHER DRUG-INDUCED MYOPATHIES +Certain drugs produce painless, largely proximal, muscle +weakness. +Marinos C. +CLINICAL FEATURES + The prevalence of the infl ammatory myopathies is esti- +mated at 1 in 100,000. +PM as a stand-alone entity is a +rare disease. +DM affects both children and adults and +women more often than men. +In advanced +and rarely in acute cases, respiratory muscles may also be +affected. +Severe weakness, if untreated, is almost always +associated with muscle wasting. +Sensation remains +normal. +48 ) or slowly progressive motor neu- +ron disorder ( Chap. +32 ). +This is in contrast to +DM, in which the rash facilitates early recognition (dis- +cussed later). +PM mimics many other myopathies and is +a diagnosis of exclusion. +In some patients, the rash is +pruritic, especially on the scalp, chest, and back. +Dilated +capillary loops at the base of the fingernails are also +characteristic. +The weakness can be mild, moderate, or severe enough +to lead to quadriparesis. +At times, the muscle strength +appears normal, hence the term dermatomyositis sine myo- +sitis. +DM usually occurs alone but may overlap with +scleroderma and mixed connective tissue disease. +Some patients present with falls because their knees col- +lapse due to early quadriceps weakness. +Dysphagia is common, occurring in up to 60% +of IBM patients, and may lead to episodes of choking. +cHIV (human immunodeficiency virus) and HTLV-I (human T cell lymphotropic virus type I). +Other myotoxic drugs may cause myopathy but not an inflammatory myopathy (see text for details). +eParasites (protozoa, cestodes, nematodes), tropical and bacterial myositis (pyomyositis). +SECTION III +Diseases of the Nervous System +650 that presumably is age-related. +A subset of h-IBM that spares the quadriceps muscles +has emerged as a distinct entity. +2. +Joint contractures, mostly in DM and especially in chil- +dren. +3. +4. +5. +6. +7. +If malignancy is clinically suspected, screening +with whole-body PET scan should be considered. +49-1). +The remaining capillaries often have dilated lumens in +response to the ischemic process. +Larger intramuscular +blood vessels may also be affected in the same pattern. +Increased expression of type I interferon- +inducible proteins is also noted in these regions. +By contrast, in PM and IBM a mechanism of T +cell–mediated cytotoxicity is likely. +Viruses have not been identified +within the muscle fibers. +Key molecules involved in +T cell–mediated cytotoxicity are depicted in Fig. +49-2. +VCAM-1 +TCR +CD28 CTLA-4 LFA-1 +Chemokines +(MCP-1, Mig, IP-10) +Infection? +Muscle fiber +necrosis occurs via perforin granules released by the autoag- +gressive T cells. +Death of the muscle fiber +is mediated by necrosis. +The best evidence of a viral connection in PM +and IBM is with the retroviruses. +Histologic findings +are identical to retroviral-negative PM or IBM. +AZT inhib- +its γ-DNA polymerase, an enzyme found solely in the +mitochondrial matrix. +32). +The muscular dystrophies (Chap. +Identification of the MHC/CD8 lesion by muscle +biopsy is helpful to identify cases of PM. +44). +47). +Repetitive +nerve stimulation and single-fiber EMG studies aid in +diagnosis. +46), transverse myeli- +tis (Chap. +35), a neurotoxin (Chap. +48), or a neuro- +tropic viral infection such as poliomyelitis or West +Nile virus (Chap. +40). +48). +Pyomyositis, previously rare in the West, is now occa- +sionally seen in AIDS patients. +Most patients respond to glucocorticoid therapy, and +the overall prognosis seems favorable. +The weakness can be severe. +Coexist- +ing interstitial lung disease and cardiomyopathy may be +present. +The disorder may develop after a viral infec- +tion or in association with cancer. +Some patients have +antibodies against signal recognition particle (SRP). +Muscle MHC-I expression is only slightly and focally +upregulated. +Some patients respond to immu- +notherapy, but others are resistant. +It may be caused by group +A β-hemolytic streptococcus, methicillin-sensitive S. +Systemic varicella is a predisposing factor in +children. +As noted earlier, AZT causes a +mitochondrial myopathy. +The muscle biopsy is either normal or discloses type II +muscle fiber atrophy. +The muscle +biopsy is usually normal or nonspecific. +52). +These patients do +not have muscle weakness, and the muscle biopsy is +normal. +The most sensitive enzyme is CK, which in active +disease can be elevated as much as fiftyfold. +The CK is always elevated in patients with active PM. +MRI is not routinely used for the diagnosis of PM, +DM, or IBM. +49-3, +49-4, and 49-5). +49-3). +49-4). +The pres- +ence of perifascicular atrophy is diagnostic of DM, even +in the absence of inflammation. +In IBM (Fig. +Careful muscle testing may reveal mild muscle weakness. +cSee text for details. +dAn adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases. +Electron microscopy dem- +onstrates filamentous inclusions in the vicinity of the +rimmed vacuoles. +SECTION III +Diseases of the Nervous System +658 dysphagia, dyspnea, fever). +When strength improves, +the serum CK falls concurrently; however, the reverse is +not always true. +Agents used in the treat- +ment of PM and DM include the following: +1. +Glucocorticoids. +High-dose prednisone, +at least 1 mg/kg per day, is initiated as early in the +disease as possible. +2. +Other immunosuppressive drugs. +Approximately 75% of +patients ultimately require additional treatment. +The dose is up to 3 mg/kg daily. +(2) +Methotrexate has a faster onset of action than aza- +thioprine. +(3) Mycophenolate mofetil also has a faster +onset of action than azathioprine. +At doses up to 2.5 +or 3 g/d in two divided doses, it is well tolerated for +long-term use. +(5) Cyclo- +sporine has inconsistent and mild benefit. +(7) Tacro- +limus (formerly known as Fk506) has been effective in +some difficult cases of PM. +3. +Immunomodulation. +A dose of 2 g/kg divided over +2–5 days per course is recommended. +Uncontrolled +observations suggest that IVIg may also be beneficial +for patients with PM. +Neither plasmapheresis nor leu- +kapheresis appears to be effective in PM and DM. +IBM is generally resistant to immunosuppressive +therapies. +Another trial of IVIg com- +bined with prednisone was ineffective. +Older patients, and those with associated cancer also +have a worse prognosis. +DM responds more favorably +to therapy than PM and thus has a better prognosis. +Up to 30% may be left with some +residual muscle weakness. +Relapses may occur at any +time. +IBM has the least favorable prognosis of the inflam- +matory myopathies. +In general, the older +the age of onset in IBM, the more rapidly progressive is +the course. +S. +Andrew Josephson ■ Martin A. +Common reasons +for neurologic consultation include stroke ( Chap. +27 ), +seizures ( Chap. +26 ), altered mental status ( Chap. +16 ), +headache ( Chap. +8 ), and management of coma and +other neurocritical care conditions (Chaps. +17 and 28). +The diagnosis in all of these conditions is clinical. +50-1). +However, this +term has fallen out of favor because none of its ele- +ments are completely accurate. +Therefore, normal +serum levels of these medications do not exclude them +as inciting agents. +SECTION III +Diseases of the Nervous System +662 capability. +Seizures must be iden- +tified and controlled, often necessitating continuous EEG +monitoring. +50-2). +This shower of microemboli results in a number of +clinical syndromes. +More commonly, the +emboli released are multiple and smaller. +Treatment primarily involves lowering the drug dosage +or discontinuing the drug. +Hypernatremia leads to the loss of intracellular water, +leading to cell shrinkage. +HYPONATREMIA +Hyponatremia is commonly defined as a serum sodium +<135 mmol/L (<135 meq/L). +28-6), but now has been described +elsewhere in the CNS. +Treatment of hyponatremia is dependent on the +cause. +Hypertonic hyponatremia treatment focuses on +the underlying condition, such as hyperglycemia. +Seizures can occur but are more common in +states of low calcium. +Hypocalcemia in adults often follows surgical treatment +of the thyroid or parathyroid. +Hypomag- +nesemia presents neurologically with seizures, tremor, and +myoclonus. +High levels of magnesium, in con- +trast, lead to CNS depression. +45). +Imag- +ing with MR neurography may allow these causes to +be distinguished definitively. +50-3A). +Sparing of the triceps is the rule when the +nerve is injured in this location. +50-3B). +Sensory loss involves the lat- +eral aspect of the leg as well as the dorsum of the foot +(Fig. +50-3C). +50-3D). +Rarely, attempts at femoral vein +or arterial puncture can be complicated by injury to this +nerve. +A. +Radial nerve. +B. +Ulnar nerve. +C. +Peroneal nerve. +D. +Femoral nerve. +E. +Lateral femoral cutaneous nerve. +50-3E). +There is no +motor component to the nerve, and therefore weakness +is not a part of this syndrome. +Symptoms often are wors- +ened by standing or walking. +The +differential diagnosis of these symptoms includes hip +problems such as trochanteric bursitis. +Andre Furtado ■ William P. +Dillon +668 + FIGURE 51-1 + Limbic encephalitis ( Chap. +There was +no enhancement on postgadolinium images (not shown). +Axial (C, D) T1-weighted images postgadolinium. +Of note, there was no evidence of restricted diffusion +(not shown). +ADC map (D, E) demonstrates restricted diffusion of water +molecules in the lesions (arrowheads). +Some of the lesions also show vasogenic +edema. +B. +T1-weighted image pregadolinium demonstrates low sig- +nal in left anterior clinoid process (arrow). +C. +T1-weighted image postgadolinium demonstrates enhance- +ment of lesion (arrow). +FIGURE 51-16 +Middle cerebral artery stenosis (Chap. +SECTION III +Diseases of the Nervous System +684 +FIGURE 51-17 +Lacunar infarction (Chap. +There is no evidence of restricted diffusion in the old infarct +(arrow). +In some of these areas, there are small areas +of tissue loss (encephalomalacia) (arrowheads). +SECTION III +Diseases of the Nervous System +686 +FIGURE 51-19 +CNS vasculitis (Chap. +These +abnormalities are suggestive of vasculitis. +CHAPTER 51 +Atlas of Neuroimaging +687 +FIGURE 51-20 +Superior sagittal sinus thrombosis (Chap. +These findings are suggestive of vasogenic +edema with subarachnoid hemorrhage (arrowheads). +SECTION III +Diseases of the Nervous System +690 +FIGURE 51-22 +Huntington’s disease (Chap. +There is also +diffuse prominence of the sulci indicating generalized cortical +atrophy. +Coronal T1-weighted image (D) demonstrates enlarged fron- +tal horns with abnormal configuration. +CHAPTER 51 +Atlas of Neuroimaging +691 +FIGURE 51-23 +Bell’s palsy (Chap. +Note that there is no evidence of a mass +lesion. +SECTION III +Diseases of the Nervous System +692 +FIGURE 51-24 +Spinal cord infarction (Chap. +T1-weighted MR image of the lumbar spine postgadolinium +(B) demonstrates mild enhancement (arrow). +FIGURE 51-25 +Acute transverse myelitis (Chap. +Some of the lesions +reveal concentric layers, typical of Baló’s concentric sclero- +sis (arrows). +There is also a small area of abnormal high signal in the +precentral gyrus. +CHAPTER 51 +Atlas of Neuroimaging +697 +FIGURE 51-29 +Brachial plexopathy (Chap. +These +findings are compatible with radiation-induced brachial +plexopathy. +FIGURE 51-31 +CT facet fracture +Axial CT demonstrates fracture line along the C2 facet (arrow). +This is sug- +gestive of interspinous ligament injury. +Note the pad under +the patient’s neck to maintain neck alignment during the +scanning time. +Also noted is mass effect on the spinal +cord (arrowheads). +CT is the imaging procedure of choice to +detect acute hematoma. +There is also a large retropharyngeal hema- +toma (*). +Jefferson fracture is usually caused by axial +impact to the head such as diving in shallow water. +1: Anterior vertebral body line; 2: Posterior ver- +tebral body line; 3: Spinolaminar line. +Note that the epidural fat is compressed but not involved (arrow). +Sagittal T2-weighted MRI (B) dis- +plays cord injury (arrow). +Criteria for the diagnosis of CFS have +been developed by the U.S. +Centers for Disease Control +and Prevention ( Table 52-1 ) . +EPIDEMIOLOGY + CFS is seen worldwide, with adult prevalence rates +varying between 0.2 and 0.4%. +Approximately 75% of all CFS patients are women. +The mean age of onset is between 29 and 35 years. +It is +probable that many patients go undiagnosed and/or do +not seek help. +Psychiatric +illness and physical hyperactivity in adulthood raise the +risk of CFS in later life. +Precipitating factors + Physical or psychological stress may elicit the onset of +CFS. +Relatively high percentages of CFS follow +Q fever and Lyme disease. +A third +of all patients cannot recall a trigger. +Perpetuating factors +Once CFS has developed, numerous factors may impede +recovery. +A patient’s focus on illness and avoidance of activities +may perpetuate symptoms. +A lack of social +support is another known perpetuating factor. +PATHOPHYSIOLOGY +The pathophysiology of CFS is unclear. +Neurophysiologic studies have +shown altered CNS activation patterns during muscle +contraction. +Evidence for immunologic dysfunction is inconsis- +tent. +The heart rate of CFS patients is often slightly +above normal. +Serology for viral or bacterial infections is usually not +helpful. +No specific abnormalities have been identified +on MRI or CT scans. +Also, CFS is excluded if the +chronic fatigue developed immediately after a depres- +sive episode. +Depression developing in the course of the +fatigue, however, does not preclude CFS. +Next, +potential fatigue-precipitating factors are sought. +52-1). +Countless anecdotes circulate +regarding other traditional and nontraditional thera- +pies. +How have you felt during the last two weeks? +Please rate all four statements and per statement check the box that reflects your situation best. +1. +I tire easily No, + that is not true +3. +I feel fit No, + that is not true +4. +Walking +or cycling is systematically increased, with set target +heart rates. +Evidence that deconditioning is the basis +for symptoms in CFS is lacking, however. +Not all patients benefit from CBT or GET. +Predictors of +poor outcome are somatic comorbidity, current disability +claims, and severe pain. +Messing ■ John H. +Rubenstein ■ Eric J. +54 . +Further discussion of alcoholism can +be found in Chap. +56 , opiate addiction in Chap. +57 , and +cocaine and other drugs of abuse in Chap. +58 . +In the 1950s–1960s, psychological factors were held to +underlie autism. +Finally, there is reduced cell size and increased +cell density in the limbic areas of the brain. +For unknown reasons, ASDs affect four +times as many boys as girls. +ASDs are also geneti- +cally heterogeneous. +Many of the genes linked to ASDs can also cause +other illnesses. +They may be detrimental by +altering the balance of excitatory vs. +Advanced paternal age, birth order, and season of birth +have also been implicated. +This is accompanied by a reduc- +tion in cortical thickness. +Moreover, the responsible genes within the +DiGeorge region have not yet been identified. +As for ASDs, the same allele may be a risk +factor for multiple disorders. +However, it is unknown +whether this is a primary or compensatory feature of the +disorder. +54) to ameliorate the positive +symptoms of schizophrenia. +MOOD DISORDERS +Mood disorders are divided into depressive and bipolar +disorders. +Between 40–50% of the risk for depression appears to +be genetic. +Depres- +sion and obesity/metabolic syndrome are important +risk factors for each other. +53-1). +Depressed individu- +als show a small reduction in hippocampal size. +Furthermore, stress +leads to a decrease in the birth of new neurons in the +adult hippocampus. +Only a subset of the known interconnections among +these brain regions is shown. +Also shown is the innervation +of several of these brain regions by monoaminergic neurons. +In addition, there are strong connections between the +hypothalamus and the VTA-NAc pathway. +SECTION V +Psychiatric Disorders +716 postmortem brains of depressed patients. +Thus the role +of BDNF in regulating mood is highly brain-region +specific. +The nature of these thera- +peutic drug-induced adaptations has not been identified +with certainty. +53-1) provide the anatomic basis of their therapeu- +tic actions. +HDAC inhibitors +have shown some antidepressant effects in animal mod- +els of depression. +However, there is no +established pathology associated with addiction risk. +Patients who abuse alcohol or psychostimulants show +reduced gray matter in the prefrontal cortex. +53-1). +Three major +pathologic adaptations have been described. +corticotrophin releasing factor), and intracellular signal- +ing cascades. +Repeated administration of +these drugs (Fig. +These +changes contribute to the altered phenotype of the drug- +addicted state. +720 + MENTAL DISORDERS + CHAPTER 54 + Victor I. +The biology of psychiatric and addictive dis- +orders is discussed in Chap. +53 . +Par- +esthesias, gastrointestinal distress, and feelings of unreal- +ity are also common. +The lifetime prevalence of +panic disorder is 1–3%. +Palpitations, pounding heart, or accelerated heart rate + 2. +Sweating + 3. +Trembling or shaking + 4. +Sensations of shortness of breath or smothering + 5. +Feeling of choking + 6. +Chest pain or discomfort + 7. +Nausea or abdominal distress + 8. +Feeling dizzy, unsteady, lightheaded, or faint + 9. +Derealization (feelings of unreality) or depersonaliza- +tion (being detached from oneself) +10. +Fear of losing control or going crazy +11. +Fear of dying +12. +Paresthesias (numbness or tingling sensations) +13. +Copyright +© 2000 American Psychiatric Association. +TABLE 54-2 +DIAGNOSTIC CRITERIA FOR AGORAPHOBIA +1. +2. +3. +Copyright +© 2000 American Psychiatric Association. +will fail to recognize the syndrome if direct questioning is +not pursued. +Agents that block serotonin +reuptake can prevent attacks. +The cornerstone of drug therapy is antidepressant med- +ication (Tables 54-3 through 54-5). +Food and Drug Administration +(FDA) for this indication. +Homework assign- +ments and monitored compliance are important +components of successful treatment. +Interestingly, family studies indicate that +GAD and panic disorder segregate independently. +B. +The person finds it difficult to control the worry. +C. +D. +E. +F. +Copyright © +2000 American Psychiatric Association. +Withdrawal must be closely monitored as +relapses can occur. +Adverse effects of benzodiazepines generally parallel +their relative half-lives. +It is usually more difficult to taper patients +off shorter-acting benzodiazepines. +Buspirone is a nonbenzodiazepine anxiolytic agent. +However, it requires several weeks to take effect and +requires thrice-daily dosing. +Benzodiazepines +are contraindicated during pregnancy and breast-feeding. +Anticonvulsants with GABAergic properties may also +be effective against anxiety. +Panic +attacks may be triggered by the phobic stimulus or may +occur spontaneously. +Common phobias +include fear of closed spaces (claustrophobia), fear of +blood, and fear of flying. +Examples include having to converse at a party, use +public restrooms, and meet strangers. +The +specific content of a phobia may vary across gender, +ethnic, and cultural boundaries. +Phobic disorders are common, affecting ∼10% of the +population. +2. +The person’s response involved intense fear, +helplessness, or horror. +B. +The traumatic event is persistently reexperienced in +one (or more) of the following ways: + 1 . +2. +Recurrent distressing dreams of the event. +3. +4. +5. +C. +Efforts to avoid thoughts, feelings, or conversations +associated with the trauma + 2. +Efforts to avoid activities, places, or people that +arouse recollections of the trauma + 3. +Inability to recall an important aspect of the trauma + 4. +Markedly diminished interest or participation in +significant activities + 5. +Feeling of detachment or estrangement from others + 6. +Restricted range of affect (e.g., unable to have loving +feelings) + 7. +Difficulty falling or staying asleep + 2. +Irritability or outbursts of anger + 3. +Difficulty concentrating + 4. +Hypervigilance + 5. +Exaggerated startle response +E. +Duration of the disturbance (symptoms in criteria B, C, +and D) is more than 1 month +F. +Copyright +© 2000 American Psychiatric Association. +These changes theoretically facilitate the encoding +of fear-based memories. +OCD has a lifetime prevalence of 2–3% +worldwide. +Onset is usually gradual, beginning in early +adulthood, but childhood onset is not rare. +Etiology and pathophysiology +A genetic contribution to OCD is suggested by twin +studies. +Only 50–60% of +patients with OCD show adequate improvement with +pharmacotherapy alone. +When a therapeutic +response is achieved, long-duration maintenance ther- +apy is usually indicated. +56 through +58). +Virtually every class of medication includes some agent +that can induce depression. +Hyperthyroid states may also present +in a similar fashion, usually in geriatric populations. +The lifetime prevalence of depression in HIV-positive +individuals has been estimated at 22–45%. +Some chronic disorders of uncertain etiology, such +as chronic fatigue syndrome (Chap. +Depression is often +undiagnosed, and, even more frequently, it is treated +inadequately. +The presence of anxiety, panic, or agitation significantly +increases near-term suicidal risk. +Dysthymic disorder exists in ∼5% of pri- +mary care patients. +1. +Insomnia or hypersomnia nearly every day + 5. +Fatigue or loss of energy nearly every day + 7 . +The symptoms do not meet criteria for a mixed episode +C. +Copyright +© 2000 American Psychiatric Association. +Some +patients experience multiple episodes that become +more severe and frequent over time. +The duration of +an untreated episode varies greatly, ranging from a few +months to ≤1 year. +The pattern of recurrence and clinical +progression in a developing episode are also variable. +Antidepressant treatment leads +to normalization of these abnormalities. +The pathogenesis of depression is discussed in detail +in Chap. +53. +54-1). +It is judicious to prescribe only a 10-day +supply when suicide is a risk. +Geriatric +patients may require a low starting dose and slow esca- +lation. +Second-generation antidepressants include amoxap- +ine, maprotiline, trazodone, and bupropion. +Long-term use +of this drug carries a risk of tardive dyskinesia. +An extended-release preparation is available. +Serotoner- +gic agonists taken in combination should be monitored +closely for this reason. +Sexual dysfunction fre- +quently results in noncompliance and should be asked +about specifically. +SSRI, selective serotonin reuptake +inhibitor; TCA, tricyclic antidepressant. +Unlike the SSRIs, venlafaxine has a +relatively linear dose-response curve. +Mirtazapine is a TCA that has a +unique spectrum of activity. +It is also strongly antihista- +minic and, as such, may produce sedation. +Transdermal selegiline may avert this risk at low dose. +Regardless of the treatment undertaken, the response +should be evaluated after ∼2 months. +If this +approach is unsuccessful, referral to a mental health spe- +cialist is advised. +Occasional empathic silence may be as +helpful for the treatment alliance as verbal reassurance. +It may be difficult to distinguish +mixed mania from agitated depression. +This pattern occurs +in 15% of all patients, almost all of whom are women. +Bipolar disorder is common, affecting ∼1.5% of +the population in the United States. +A detailed discussion of the pathogenesis of bipolar disor- +der is presented in Chap. +53. +Some 95% of a +given dose is excreted unchanged through the kidneys +within 24 h. +TABLE 54-10 +CRITERIA FOR A MANIC EPISODE +A. +Inflated self-esteem or grandiosity + 2. +Decreased need for sleep (e.g., feels rested after +only 3 h of sleep) + 3. +More talkative than usual or pressure to keep talking + 4. +Flight of ideas or subjective experience that +thoughts are racing + 5. +The symptoms do not meet criteria for a mixed episode. +D. +E. +Copyright © 2000 American Psychiatric Association. +effect by interfering with the synthesis and release of +thyroid hormones. +The recurrent nature of bipolar mood disorder +necessitates maintenance treatment. +Loss of efficacy over time may +be observed with any of the mood-stabilizing agents. +In such situations, an alternative agent or combina- +tion therapy is usually helpful. +Source: From GS Sachs et al: Postgrad Med April, 2000. +Onset is usually before age 30 years, +and the disorder is persistent. +B. +Either of the following: + 1. +The symptoms are not intentionally produced or +feigned (as in factitious disorder or malingering). +Copyright +© 2000 American Psychiatric Association. +In true factitious illness, the sick role itself is gratifying. +Such an approach +is doomed to failure and does not address the core issue. +Personality disorders have been grouped into three +overlapping clusters. +Cluster A includes paranoid, schiz- +oid, and schizotypal personality disorders. +Individuals have +a restricted emotional range and remain socially isolated. +Improvement +may be subtle and observable only over time. +There are no patho- +gnomonic features. +However, marked +variability in the course and individual character of +symptoms is typical. +The four main subtypes of schizophrenia are catatonic, +paranoid, disorganized, and residual. +Many individu- +als have symptoms of more than one type. +Prognosis depends not on symptom sever- +ity but on the response to antipsychotic medication. +A +permanent remission without recurrence does occasion- +ally occur. +About 10% of schizophrenic patients commit +suicide. +Schizophrenia is present in 0.85% of individuals +worldwide, with a lifetime prevalence of ∼1–1.5%. +Drug causes +should be ruled out in any case of newly emergent psy- +chosis. +Genetic factors are involved in at least a subset of individu- +als who develop schizophrenia. +Schizophrenia is observed +in ∼6.6% of all first-degree relatives of an affected proband. +If both parents are affected, the risk for offspring is 40%. +The concordance rate for monozygotic twins is 50%, +compared to 10% for dizygotic twins. +The pathogenesis of schizo- +phrenia is discussed in detail in Chap. +53. +cortices. +Conventional neuroleptics differ in their potency +and side-effect profile. +Its principal disadvantage is a risk of blood +dyscrasias. +Unlike other antipsychotics, clozapine +does not cause a rise in prolactin level. +Que- +tiapine is distinct in having a weak D2 effect but potent +α1 and histamine blockade. +Antipsychotic agents are effective in 70% of patients +presenting with a first episode. +Improvement may be +observed within hours or days, but full remission usually +requires 6–8 weeks. +If medications are completely discontinued, +however, the relapse rate is 60% within 6 months. +Akathisia may respond to +beta blockers. +Weekly white blood cell counts are required, particularly +during the first 3 months of treatment. +Close monitoring of plasma glucose and +lipid levels are indicated with the use of these agents. +The +prevalence increases with age, total dose, and dura- +tion of drug administration. +The risk associated with +second-generation agents appears to be much lower. +The cause may involve formation of free radicals and +perhaps mitochondrial energy failure. +Vitamin E may +reduce abnormal involuntary movements if given +early in the syndrome. +Drug treatment of schizophrenia is by itself insuffi- +cient. +Physicians are frequently +the first point of contact for both victim and abuser. +Approximately 2 million older Americans and 1.5 mil- +lion U.S. +children are thought to experience some +form of physical maltreatment each year. +Spousal abuse +is thought to be even more prevalent. +Charles W. +Hoge +742 + Neuropsychiatric sequelae are common in combat vet- +erans. +Certain events such as loss of a close friend in +combat, leave indelible scars. +52). +PTSD +PTSD is the most common mental disorder docu- +mented following war-zone service. +54). +Misuse of alcohol or substances is most preva- +lent, often reflecting self-medication. +These +responses only become symptoms when they impair +functioning after warriors return home. +CONCUSSION/mTBI +TBI (Chap. +GCSs are usually normal (15 out of 15). +Nevertheless, mass +population screening for concussion/mTBI was man- +dated for all U.S. +However, they need to be addressed within the +context of all other war-related health concerns. +Were constantly on guard, watchful, or easily startled? +Felt numb or detached from others, activities, or your surroundings? +Prim Care Psychiatr 9:9, 2004. +PHQ-2 Depression Screen +2. +Over the last 2 weeks, how often have you been +bothered by any of the following problems? +Feeling down, depressed, or hopeless. +Med Care 41:1284, 2003. +AUDIT-C Alcohol Screen +3a. +How often do you have a drink containing alcohol? +How many drinks containing alcohol do you have on a typical day when you are drinking? +1 or 2 (0) 3 or 4 (1) 5 or 6 (2) 7 or 9 (3) 10 or more (4) +3c. +How often do you have six or more drinks on one occasion? +Arch Intern +Med 158:1789, 1998. +It is important to know that combat is not the only +important trauma in a war-zone environment. +Rape, +assault, and accidents also occur. +Mirtazapine use can cause drowsiness and +weight gain. +All antidepressants have potential drug-drug +interactions that must be considered. +Benzodiazepines, in particular, should be avoided +in combat veterans. +8). +DISCLOSURE +This material has been reviewed by the Walter Reed Army +Institute of Research. +There is no objection to its presentation +and/or publication. +This page intentionally left blank +SECTION VI +ALCOHOLISM +AND DRUG +DEPENDENCY + Marc A. +Unfortunately, most clinicians +have had only limited education regarding these con- +ditions. +Con- +geners include methanol, butanol, acetaldehyde, hista- +mine, tannins, iron, and lead. +56-1 ) . +MEOS, microsomal ethanol- +oxidizing system. +Beverage alcohol is probably responsible for +more overdose deaths than any other drug. +This alteration disappears almost +as rapidly as it develops. +Subsequent decreases in +blood levels contribute to symptoms of withdrawal. +Patients may also experi- +ence prominent and sometimes disturbing dreams. +In the United States, ∼40% of +drinkers have at some time driven while intoxicated. +Approximately +1% of alcoholics develop cerebellar degeneration or atrophy. +54). +Another common comorbid- +ity occurs with dependence on illicit substances. +Recovery is likely within several days to +4 weeks of abstinence. +This contrib- +utes to an increase in fat accumulation in liver cells. +CANCER +As few as 1.5 drinks per day increases a woman’s risk +of breast cancer 1.4-fold. +Exercise-induced increases in cardiac +oxygen consumption are higher after alcohol intake. +Thus, heavy drinking is an important factor in mild to +moderate hypertension. +Hormone irregularities should be reevaluated as they +may disappear after a month of abstinence. +These +differences reflect both cultural and genetic influences, +as described later. +The lifetime risk for alcoholism among +physicians is similar to that of the general population. +How often do you have a drink +containing alcohol? +Never (0) to 4+ per +week (4) + 2. +How many drinks containing +alcohol do you have on a typical +day? +1 or 2 (0) to 10+ (4) + 3. +How often do you have six or +more drinks on one occasion? +Never (0) to daily or +almost daily (4) + 4. +Never (0) to daily or +almost daily (4) + 5. +Never (0) to daily or +almost daily (4) + 6. +Never (0) to daily or +almost daily (4) + 7. +How often during the last year +have you had a feeling of guilt or +remorse after drinking? +Never (0) to daily or +almost daily (4) + 8. +Never (0) to daily or +almost daily (4) + 9. +Have you or someone else been +injured as a result of your drink- +ing? +No (0) to yes, during +the last year (4) +10. +No (0) to yes, during +the last year (4) +aThe AUDIT is scored by summing the 10 values. +A score >8 may +indicate harmful alcohol use. +New York, Springer 2006. +While most CNS depressants are effective, benzo- +diazepines (Chap. +The rare patient with status epilepticus must be treated +aggressively (Chap. +26). +Sleep +medications have the danger of being misused and of +rebound insomnia when stopped. +Thomas R. +Two +of the most important adverse effects of all these agents +are overdose and dependence. +SECTION VI +Alcoholism and Drug Dependency +762 primarily associated with the mu receptor. +Thus, +opiates acutely inhibit neuronal activity. +How- +ever, the “high” only occurs when the rate of change in +dopamine is fast. +Opiate dependence and withdrawal are chronic +effects related to the cyclic AMP system. +Epigenetic methyla- +tion changes also occur on the DNA of the mu receptor +gene of opiate addicts. +DNA methylation inhibits gene +transcription. +They then are conjugated +to glucuronic acid and excreted in small amounts in feces. +The role of endogenous opioid peptides in opioid +dependence is uncertain. +Symptoms of opioid withdrawal +begin 8–10 h after the last dose. +Many of these symp- +toms reflect increased activity of the autonomic nervous +system. +Lacrimation, rhinorrhea, yawning, and sweat- +ing appear first. +The acute course of withdrawal may last 7–10 days. +An +increase in prolactin also contributes to the reduced +sex drive in males. +Two other hormones affected are +decreased thyrotropin and increased growth hormone. +In overdoses, aspiration +pneumonia is a common complication due to loss of +the choking reflex. +Opi- +ates may prolong QT intervals and lead to sudden death +in some patients. +Alpha-2-ad- +renergic agonists are primarily used for detoxification. +methadone). +Clonidine, a centrally +acting sympatholytic agent, has also been used for +detoxification. +Clonidine has no narcotic action and is not +addictive. +Lofexidine, a clonidine analogue with less +hypotensive effect, is being developed for use. +methadone have been +comparable. +Buprenorphine is combined with nal- +oxone at a 4:1 ratio in order to reduce its abuse liability. +A +subcutaneous buprenorphine implant has also been tested, +but results are not yet available. +Retention in office-based +buprenorphine treatment has been greater than 70% at +6-month follow-ups. +PREVENTION +Preventing opiate abuse represents a critically impor- +tant challenge for physicians. +The major sources of these drugs are family +members, not drug dealers or the Internet. +Finally, phy- +sicians should never prescribe opiates for themselves. +Nancy K. +Mello ■ Jack H. +COCAINE + Cocaine is a stimulant and a local anesthetic with potent +vasoconstrictor properties. +The leaves of the coca plant +( Erythroxylon coca ) contain ∼0.5–1% cocaine. +The drug + COCAINE AND OTHER COMMONLY +ABUSED DRUGS + CHAPTER 58 +a Deceased. +Intravenous cocaine is often used concurrently +with IV heroin. +The effects rarely last more +than 1 h. +Cocaine has a short plasma half-life +of approximately 45–60 min. +It is metabolized by plasma +esterases, and cocaine metabolites are excreted in urine. +Hepatic necrosis may occur following chronic crack/ +cocaine use. +Hashish is prepared from concentrated resin of +C. +sativa and contains a THC concentration of between +8 and 12% by weight. +Smoking is the most common +mode of marijuana or hashish use. +During pyrolysis, +>150 compounds in addition to THC are released in +the smoke. +THC is quickly absorbed from the lungs into blood, +and then rapidly sequestered in tissues. +Tolerance for marijuana-induced tachycardia +develops rapidly among regular users. +Department of Justice in 2009. +Methamphetamine can be used by smoking, snorting, +IV injection, or oral administration. +Methamphetamine +abusers report that drug use induces feelings of euphoria +and decreased fatigue. +Therapy of acute methamphetamine overdose is +largely symptomatic. +Ammonium chloride may be use- +ful to acidify the urine and enhance clearance of the +drug. +Hypertension may respond to sodium nitroprus- +side or α-adrenergic antagonists. +Sedatives may reduce +agitation and other signs of central nervous system +hyperactivity. +MDMA (3,4-methylenedioxymethamphetamine), or +ecstasy, is a derivative of methamphetamine. +Ecstasy is usu- +ally taken orally but may be injected or inhaled; its effects +last for 3–6 h. +The long-term consequences of +recreational use of MDMA by young persons are poorly +understood. +These effects of LSD may persist for +12–18 h, even though the half-life of the drug is only +3 h. +Treat- +ment of these disorders is best carried out in specialized +psychiatric facilities. +Abrupt abstinence +following continued use does not produce withdrawal +signs or symptoms. +There have been no clinical reports +of death caused by the direct effects of LSD. +PCP is easily synthesized; +its abusers are primarily young people and polydrug users. +It is used orally, by smoking, by snorting, or by IV injec- +tion. +It is also used as an adulterant in THC, LSD, amphet- +amine, or cocaine. +Confirmation of PCP use is possible by deter- +mination of PCP levels in serum or urine. +PCP assays +are available at most toxicologic centers. +PCP remains in +urine for 1–5 days following high-dose intake. +There is no specific +antidote or antagonist for PCP. +PCP excretion from the +body can be enhanced by gastric lavage and acidifica- +tion of urine. +PCP, +like LSD and mescaline, produces vasospasm of cerebral +arteries at relatively low doses. +Flunitrazepam is typically +used orally but can be snorted or injected. +Overdose can +produce life-threatening respiratory depression and coma. +GHB is usu- +ally taken orally and has no distinctive color or odor. +In veterinary +medicine, it is used for brief immobilization. +In clini- +cal medicine, it is used for sedation, analgesia, and to +supplement anesthesia. +Like PCP, it binds to NMDA receptors and acts +as an uncompetitive NMDA antagonist. +The extent to which +chronic recreational use leads to memory impairment +remains controversial. +There are +relatively few controlled studies of multiple drug inter- +actions. +One determinant of +polydrug use patterns is the relative availability and cost +of the drugs. +This page intentionally left blank + Alexander Kratz ■ Michael A. +Pesce ■ Robert C. +Basner + ■ Andrew J. +A variety of factors can infl uence reference values. +Values supplied in +this Appendix refl ect typical reference ranges in adults. +Pediatric reference ranges may vary signifi cantly from +adult values. +Therefore, both +systems are provided in the Appendix. +In all other instances in the text the +SI unit is followed by the traditional unit in parentheses. +8 P.M.–8 A.M. +JAMA 2001; 285:2486–97. +bIgG index = CSF IgG (mg/dL) × serum albumin (g/dL)/serum IgG +(g/dL) × CSF albumin (mg/dL). +Abbreviation: M:E, myeloid to erythroid ratio. +Source: BJ Bain: Br J Haematol 94:206, 1996. +Philadelphia, Lippincott +Williams & Wilkins, 2004. +Phil- +adelphia, Mosby, 2003. +Philadelphia, W.B. +Saunders Co., 2001. +Source: Values adapted from: American Society of Echocardiography, Guidelines and Standards. +http://www.asecho.org/i4a/pages/index.cfm?pageid=3317. +Accessed Feb 23, 2010. +A Manual of Uniform Laboratory Procedures, 2nd ed. +Salt Lake City, +Utah, Intermountain Thoracic Society, 1984. +Daniel J. +Fink, Patrick M. +Sluss, +James L. +Januzzi, and Kent B. +We also express our gratitude to +Drs. +Amudha Palanisamy and Scott Fink for careful review of +tables and helpful suggestions. +801 801 +QUESTIONS +REVIEW AND +SELF-ASSESSMENTa +Charles Wiener ■ Cynthia D. +Brown ■ Anna R. +Hemnes +DIRECTIONS: Choose the one best response to +each question. +4. +You are concerned about the possibility of +subarachnoid hemorrhage. +What is the most ap- +propriate initial test for diagnosis? +A. +Cerebral angiography +B. +CT of the head with IV contrast +C. +CT of the head without IV contrast +D. +Lumbar puncture +E. +Transcranial Doppler ultrasound +5. +A 74-year-old woman has a recent diagnosis of +small cell lung cancer. +She is now complaining of +headaches, and her family has noticed confusion as +well. +Metastatic disease to the brain is suspected. +A +mass lesion on magnetic resonance imaging (MRI) +is demonstrated in the right parietal lobe. +Which +MRI technique would best identify the extent of +the edema surrounding the lesion? +A. +MR angiography +B. +FLAIR +C. +T1-weighted +D. +T2-weighted +E. +B and D +6. +A. +Acute renal failure +B. +Hyperthyroidism +C. +Hypocalcemia +D. +Lactic acidosis +E. +Nephrogenic systemic sclerosis +7. +A. +Brain abscess +B. +Herpes simplex encephalitis +C. +Locked-in syndrome +D. +Metabolic encephalopathy +E. +Nonconvulsive status epilepticus +1. +What is the name of this test? +A. +Babinski sign +B. +Dysdiadochokinesis +C. +Lhermitte symptom +D. +Pronator drift +E. +Romberg sign +2. +A positive test is a sign of: +A. +Abnormal sensation +B. +Early dementia +C. +Localized brainstem disease +D. +Potential weakness +E. +Underlying cerebellar dysfunction +3. +The symptoms involve both arms and +legs. +She also has developed urinary incontinence +over the past 24 hours. +Anal sphincter tone is +decreased. +Babinski sign is positive. +Sensation is +decreased in the extremities, but not in the face. +Cranial nerves are symmetric and intact, and men- +tal status is normal. +A. +Brainstem +B. +Cerebrum +C. +Cervical spinal cord +D. +Lumbar spinal cord +E. +New York: +McGraw-Hill, 2012. +Review and Self-Assessment 802 +8. +She +has no medical history and takes no medications. +She experiences a brief loss of consciousness for +about 20 seconds. +She has no seizure-like activity +and immediately returns to her usual level of func- +tioning. +She is diagnosed with vasovagal syncope, +and no follow-up testing is recommended. +Which +of the following statements regarding neurally me- +diated syncope is TRUE? +A. +Neurally mediated syncope occurs when there are +abnormalities of the autonomic nervous system. +B. +C. +D. +E. +The usual finding with cardiovascular monitoring is +hypotension and tachycardia. +9. +She has +a history of hypertension, diabetes mellitus, and +chronic kidney disease (stage III). +She does recall +at least two prior episodes of syncope similar to +this one. +By the time she arrived in the emergency +department, she reports feeling back to her usual +self. +Witnesses report some jerking of her +upper extremities. +She regained full consciousness +in less than 2 minutes. +She is +afebrile. +Her physical examination is unremarkable +and includes a normal neurologic examination. +A. +CT scan of the head +B. +Electrocardiogram +C. +Fingerstick glucose measurement +D. +Orthostatic blood pressure measurement +E. +Tilt table testing +10. +A 48-year-old man presents to the emergency de- +partment complaining of dizziness. +He describes it +as a sensation that the room is spinning. +All of the +following would be consistent with a central cause +of vertigo EXCEPT: +A. +Absence of tinnitus +B. +Gaze-evoked nystagmus +C. +Hiccups +D. +Inhibition of nystagmus by visual fixation +E. +Purely vertical nystagmus +11. +A 62-year-old woman presents complaining of se- +vere dizziness. +She notes it especially when she turns +over in bed and immediately upon standing. +Her ini- +tial physical examination findings are normal. +Upon +further testing, you ask the patient to sit with her +head turned 45 degrees to the right. +You lower the +patient to the supine position and extend the head +backward 20 degrees. +This maneuver immediately +reproduces the patient’s symptoms, and you note +torsional nystagmus. +What is the most appropriate +next step in evaluation and treatment of this patient? +A. +MRI of the brainstem +B. +Methylprednisolone taper beginning at 100 mg daily +C. +Repositioning (Epley) maneuvers +D. +Rizatriptan 10 mg orally once +E. +Valacyclovir 1000 mg three times daily for 7 days +12. +A 42-year-old man presents complaining of pro- +gressive weakness over a period of several months. +A disorder affecting lower motor neurons +is suspected. +Decreased muscle tone +B. +Distal greater than proximal weakness +C. +Fasciculations +D. +Hyperactive tendon reflexes +E. +Severe muscle atrophy +13. +A 78-year-old man is seen in clinic because of re- +cent falls. +He reports gait difficulties with a sensa- +tion of being off balance at times. +One recent fall +caused a shoulder injury requiring surgery to repair +a torn rotation cuff. +In epidemiologic case series, +what is the most common cause of gait disorders? +A. +Cerebellar degeneration +B. +Cerebrovascular disease with multiple infarcts +C. +Cervical myelopathy +D. +Parkinson’s disease +E. +Sensory deficits +Review and Self-Assessment 803 +14. +A 65-year-old man presents complaining of fre- +quent falls and gait abnormalities. +He first noticed +the difficulty about 6 months ago. +He has a history +of hypertension and hypothyroidism and hyper- +lipidemia. +On neurologic exami- +nation, you observe his gait to be wide based with +short, shuffling steps. +He has difficulty rising from +his chair and initiating his gait. +Upon turning, he +takes multiple steps and appears unsteady. +How- +ever, cerebellar testing results are normal, including +heel-to-shin and Romberg testing. +He shows no evidence of muscle spasticity +on passive movement. +His neurologic examination +is consistent with which of the following causes? +A. +Alcoholic cerebellar degeneration +B. +Communicating hydrocephalus +C. +Neurosyphilis +D. +Multiple system atrophy +E. +Lumbar myelopathy +15. +Her initial blood pressure was +70/40 mmHg with a heart rate of 130 beats/min. +She is volume resuscitated but requires dopamine +to maintain an adequate blood pressure. +Her men- +tal status improved initially, but now she is agitated +and pulling at her IV catheters. +She is screaming +that she is trapped, and she is not oriented to place +or year. +All of the following statements regarding +the patient’s condition are true EXCEPT: +A. +An episode of delirium is associated with an in- +hospital mortality rate of 25% to 33%. +B. +C. +D. +Delirium is typically short-lived and does not persist +longer than several days. +E. +Individuals who experience delirium have longer +lengths of stay in the hospital. +16. +He was admitted 36 hours previously for treat- +ment of community-acquired pneumonia. +He re- +ceived treatment with levofloxacin 500 mg daily + 16. +( Continued) + and required oxygen 2 L/min. +He has a medical +history of tobacco abuse, diabetes mellitus, and hy- +pertension. +He reports alcohol intake of 2–4 beers +daily. +Currently, the patient is agitated and pac- +ing his room. +He is reporting that he needs to leave +the “meeting” immediately and go home. +He states +that if he does not do this, someone is going to take +his house and car away. +He has removed his IV and +oxygen tubing from his nose. +He is noted to be somewhat tremulous +and diaphoretic. +All of the following should be +considered as part of the patient’s diagnostic work- +up EXCEPT: +A. +Arterial blood gas testing +B. +Brain imaging with MRI or head CT +C. +Fingerstick glucose testing +D. +More thorough review of the patient’s alcohol in- +take with his wife +E. +Review of the recent medications received by the +patient +17. +Which of the +following patients is at the highest risk for develop- +ing delirium? +A. +A 36-year-old man admitted to the medical ward +with a deep venous thrombosis +B. +A 55-year-old man postoperative day 2 from a total +colectomy +C. +A 68-year-old woman admitted to the intensive care +unit (ICU) with esophageal rupture +D. +A 74-year-old woman in the preoperative clinic +before hip surgery +E. +An 84-year-old man living in an assisted living +facility +18. +A 28-year-old woman has severe head trauma after +a motor vehicle accident. +She does not speak or follow any commands. +She breathes independently but is fed through a +gastrostomy tube. +She can move all extremities +Review and Self-Assessment 804 + 18. +( Continued) + spontaneously but without purposeful movement. +What term best describes this patient’s condition? +A. +Coma +B. +Locked-in +C. +Minimally conscious state +D. +Persistent vegetative state +E. +Vegetative state +19. +There is concern that the patient +has brain death. +What test is most commonly used +to diagnose brain death in this situation? +A. +Apnea testing +B. +Cerebral angiography +C. +Demonstration of absent cranial nerve reflexes +D. +Demonstration of fixed and dilated pupils +E. +Performance of transcranial Doppler ultrasonography +20. +A. +Third-nerve compression and ipsilateral papillary +dilation +B. +Catatonia +C. +“Locked-in” state +D. +Miotic pupils +E. +Respiratory arrest +21. +Which of the following is the most common find- +ing in aphasic patients? +A. +Alexia +B. +Anomia +C. +Comprehension +D. +Fluency +E. +Repetition +22. +After the stroke, an +assessment reveals the findings shown in Figure 22. +What diagnosis does this figure suggest? +A. +Construction apraxia +B. +Hemianopia +C. +Hemineglect +D. +Object agnosia +E. +Simultanagnosia +23. +He works at a glass factory that requires him to +work rotating shifts. +He notes the problem to be most severe when he +is on the night shift. +Twice he has fallen asleep +on the job. +( Continued) + falls asleep again. +However, he feels fully +functional at work on day and evening shifts. +He is up +by about 3 pm when his children arrive home +from school. +He drinks about 2 cups of coffee +daily but tries to avoid drinking more than this. +He does not snore and has a body mass index of +21.3 kg/m2. +All of the following are reasonable +approaches to treatment in this man EXCEPT: +A. +Avoidance of bright light in the morning after his +shifts +B. +Exercise in the early evening before going to work +C. +Melatonin 3 mg taken at bedtime on the morning +after a night shift +D. +Modafinil 200 mg taken 30–60 minutes before +starting a shift +E. +Strategic napping of no more than 20 minutes dur- +ing breaks at work +24. +She first notices the symptoms +around 8 pm when she is sitting quietly watch- +ing television. +They inter- +fere with her ability to fall asleep about four times +weekly. +She also some- +times takes a very hot bath to alleviate the symp- +toms. +During sleep, her husband complains that she +kicks him throughout the night. +She has no history +of neurologic or renal disease. +The physical examination findings, +including thorough neurologic examination, are +normal. +Her hemoglobin is 9.8 g/dL and hema- +tocrit is 30.1%. +The mean corpuscular volume is +68 fL. +Serum ferritin is 12 ng/mL. +Which is the +most appropriate initial therapy for this patient? +A. +Carbidopa/levodopa +B. +Hormone replacement therapy +C. +Iron supplementation +D. +Oxycodone +E. +Pramipexole +25. +A 20-year-old man presents for evaluation of ex- +cessive daytime somnolence. +He is finding it in- +creasingly difficult to stay awake during his classes. +Recently, his grades have fallen because whenever +he tries to read, he finds himself drifting off. +He +finds that his alertness is best after exercising or +brief naps of 10–30 minutes. +Because of this, he +states that he takes 5 or 10 “catnaps” daily. +The +sleepiness persists despite averaging 9 hours of sleep +nightly. +He describes these occurrences as +a voice calling his name as he drifts off. +Once he had to lean against +a wall to keep from falling down. +He undergoes +an overnight sleep study and multiple sleep latency +test. +There is no sleep apnea. +His mean sleep laten- +cy on five naps is 2.3 minutes. +In three of the five +naps, rapid eye movement sleep is present. +Which +of the following findings of this patient is most spe- +cific for the diagnosis of narcolepsy? +A. +Cataplexy +B. +Excessive daytime somnolence +C. +Hypnagogic hallucinations +D. +Rapid eye movement sleep in more than two naps +on a multiple sleep latency test +E. +Sleep paralysis +26. +Which of the following is the most common sleep +disorder in the U.S. +population? +A. +Delayed sleep phase syndrome +B. +Insomnia +C. +Obstructive sleep apnea +D. +Narcolepsy +E. +Restless legs syndrome +27. +In which stage of sleep are the parasomnias som- +nambulism and night terrors most likely to occur? +A. +Stage 1 +B. +Stage 2 +C. +Slow-wave sleep +D. +Rapid eye movement sleep +28. +A 44-year-old man is seen in the emergency de- +partment after a motor vehicle accident. +Which of +Review and Self-Assessment 806 + 28. +( Continued) + the following is most likely to be found on further +evaluation? +A. +Retinal detachment +B. +Occipital lobe glioma +C. +Optic nerve injury +D. +Parietal lobe infarction +E. +Pituitary adenoma +29. +A 42-year-old construction worker complains of +waking up with a red, painful left eye. +She often +works without goggles at her construction site. +Her only current medication is lisinopril. +On examination, the left eye is diffusely red and +sensitive to light. +The eyelids are normal. +In dim +light, visual acuity is normal in both eyes. +All of +the following diagnoses will explain her findings +EXCEPT: +A. +Acute angle-closure glaucoma +B. +Anterior uveitis +C. +Corneal abrasion +D. +Posterior uveitis +E. +Transient ischemic attack +30. +A 75-year-old triathlete complains of gradually +worsening vision over the past year. +It seems to +be involving near and far vision. +He takes no regular medications. +Physical examination is normal except for bilateral +visual acuity of 20/100. +There are no focal visual +field defects and no redness of the eyes or eyelids. +Which of the following is the most likely diagnosis? +A. +Age-related macular degeneration +B. +Blepharitis +C. +Diabetic retinopathy +D. +Episcleritis +E. +Retinal detachment +31. +All of the following statements regarding olfaction +are true EXCEPT: +A. +Decrements in olfaction may lead to nutritional +deficiency. +B. +More than 40% of patients with traumatic anosmia +will regain normal function over time. +C. +D. +E. +Women identify odorants better than men at all ages. +32. +A 64-year-old man is evaluated for hearing loss that +he thinks is worse in his left ear. +His wife and chil- +dren have told him for years that he does not listen to +them. +In ad- +dition, he reports a continuous buzzing that is louder +in his left ear. +He denies any sensation of vertigo, +headaches, or balance difficulties. +He has no family history of deafness, al- +though his father had hearing loss as he aged. +He has a +medical history of hypertension, hyperlipidemia, and +coronary artery disease. +Which of the following +findings would you expect on physical examination? +A. +A deep tympanic retraction pocket seen above the +pars flaccida on the tympanic membrane. +B. +Cerumen impaction in the external auditory canal. +C. +Hearing loss that is greater at lower frequencies on +pure tone audiometry. +D. +E. +33. +Epilepsy +B. +Lambert-Eaton syndrome +C. +Migraine +D. +Parkinson’s disease +E. +Spinocerebellar ataxia +34. +Lambert-Eaton syndrome: acetylcholine +B. +Myasthenia gravis: acetylcholine +C. +Orthostatic tachycardia syndrome: serotonin +D. +Parkinson’s disease: dopamine +E. +Stiff-person syndrome: GABA +35. +These episodes +had occurred every few months during high school +and he never told anyone. +( Continued) + when sleep deprived. +The episodes last +about 3–5 minutes and stop spontaneously. +He has +never lost consciousness. +During the episodes, he can +communicate with friends. +Which of the following is +the most accurate classification of his seizure disorder? +A. +Focal seizures with dyscognitive features +B. +Focal seizures without dyscognitive features +C. +Generalized seizure +D. +Myoclonic seizures +E. +Typical absence seizure +36. +The patient has a history +of intractable focal seizures that rarely generalize. +Which of these additional historic fac- +tors is also likely to be present in this patient? +A. +History of febrile seizures +B. +Hypothyroidism +C. +Neurofibromas +D. +Recurring genital ulcers +E. +Type 2 diabetes mellitus +37. +He did not lose consciousness. +He was +brought in 2 hours after symptom onset and is cur- +rently awake, alert, and oriented. +He has not had any +further seizures but has been unable to move his left +hand since his seizure. +His electrolytes and complete +blood count are within normal limits. +A noncontrast +CT scan of his head is unremarkable. +What is the best course of action at this time? +A. +Cerebral angiogram +B. +Lumbar puncture +C. +Magnetic resonance angiogram +D. +Psychiatric evaluation +E. +Reassess in a few hours +38. +He does +not have a known seizure disorder. +There is no his- +tory of head trauma, stroke, or tumor. +The patient +is unemployed, married, and takes no medication. +The +patient is postictal. +His neck is difficult to maneu- +ver due to stiffness. +His white blood cell count is +19,000/μL, hematocrit 36%, and platelets 200,000/ +μL. +Urine toxicology screen is positive +for cocaine metabolites. +Which next step is most ap- +propriate in this patient’s management? +A. +Electroencephalogram (EEG) +B. +IV loading with antiepileptic medication +C. +Lumbar puncture +D. +Magnetic resonance imaging +E. +Substance abuse counseling +39. +All of the following statements regarding epilepsy +are true EXCEPT: +A. +The incidence of suicide is higher in epileptic pa- +tients than it is in the general population. +B. +Mortality is no different in patients with epilepsy +than it is in age-matched controls. +C. +D. +E. +Tricyclic antidepressants lower the seizure threshold +and may precipitate seizures. +40. +She has no identifying information, +and her past medical history is unknown. +What is +the most likely cause of her seizure? +A. +Amyloid angiopathy +B. +Fever +C. +Genetic disorder +D. +Illicit drug use +E. +Uremia +41. +A 36-year-old man is brought to the emergency +department because of a seizure. +He had a brief seizure at home that stopped within +Review and Self-Assessment 808 + 41. +( Continued) + a few minutes. +On physical examination he +is afebrile, hypertensive, and actively seizing. +All of +the following are potential therapies for his condition +EXCEPT: +A. +Carbamazepine +B. +Fosphenytoin +C. +Lorazepam +D. +Phenobarbital +E. +Valproate +42. +The most common cause of a cerebral embolism is: +A. +Atrial fibrillation +B. +Cardiac prosthetic valves +C. +Dilated cardiomyopathy +D. +Endocarditis +E. +Rheumatic heart disease +43. +A 54-year-old male is referred to your clinic for +evaluation of atrial fibrillation. +He first noted the ir- +regular heartbeat 2 weeks ago and presented to his pri- +mary care physician. +He denies chest pain, shortness +of breath, nausea, or gastrointestinal symptoms. +Past +medical history is unremarkable. +There is no history +of hypertension, diabetes, or tobacco use. +His medica- +tions include metoprolol. +The examination is notable +for a blood pressure of 126/74 mmHg and a pulse of +64 beats/min. +The jugular venous pressure is not ele- +vated. +His heart is irregularly irregular, with normal S1 +and S2. +The lungs are clear, and there is no peripheral +edema. +An echocardiogram shows a left atrial size of +3.6 cm. +Left ventricular ejection fraction is 60%. +There +are no valvular or structural abnormalities. +Which of +the following statements regarding his atrial fibrillation +and stroke risk is true? +A. +He requires no antiplatelet therapy or anticoagula- +tion because the risk of embolism is low. +B. +C. +D. +His risk of an embolic stroke is less than 1%, and he +should take a daily aspirin. +E. +He should be started on SC low-molecular-weight +heparin and transitioned to warfarin. +44. +Aspirin +B. +Blood pressure control + 44. +( Continued) +C. +Clopidogrel +D. +Statin therapy +E. +Warfarin +45. +He has a past his- +tory of hypertension and hypercholesterolemia. +His medications include atorvastatin and enala- +pril. +He is alert but aphasic with upper and lower left +extremity hemiparesis. +He is able to move his right +side normally. +Anticoagulation +B. +Blood pressure lowering +C. +Hypothermia protocol +D. +Intracerebral stent placement +E. +IV thrombolysis +46. +The history and examination are most consis- +tent with which of the following? +A. +Alzheimer’s disease +B. +Binswanger’s disease +C. +Creutzfeldt-Jakob disease +D. +Multi-infarct dementia +E. +Vitamin B12 deficiency +47. +Her symptoms +originally began approximately 3 years ago. +She also has had several more episodes of syn- +cope. +She has never had an injury from syncope. +A final recent symptom has been periodic flushing +Review and Self-Assessment 809 + 47. +( Continued) + and sweating. +Her only other medical history is re- +cent recurrent urinary tract infections. +Her medi- +cations are ropinirole 24 mg daily and nitrofuran- +toin 100 mg daily. +She reports no history of drug +use. +Upon standing, her blood pres- +sure drops to 90/50 mmHg with a heart rate of +110 beats/min. +Her ocular movements are full and +intact. +She has recurrent motor movements of the +right side of her face. +Deep tendon reflex- +es are brisk and 3+ in upper and lower extremities. +Three beats of myoclonus are present at the ankles +bilaterally. +She walks with a spastic gait. +Strength is +normal. +What is the most likely diagnosis? +A. +Corticobasal degeneration +B. +Diffuse Lewy body dementia +C. +Drug-induced Parkinson’s disease +D. +Multiple system atrophy with parkinsonian features +E. +Parkinson’s disease with inadequate treatment +48. +He states that he first noticed a slowing of +his gait approximately 6 months ago. +He has diffi- +culty rising to a standing position and states that he +shuffles when he walks. +In addition, he states that +his right hand shakes more so than his left, and he +is right handed. +His past medical history is significant for hyperten- +sion and hypercholesterolemia. +He drinks a glass +of wine with dinner daily and is a lifelong non- +smoker. +On physical examination, he has masked +facies. +His gait shows decreased arm swing with +slow shuffling steps. +He turns en bloc. +A pill-rolling +tremor is present on the right side. +There is cog- +wheel rigidity bilaterally. +Eye movements are full +and intact. +There is no orthostatic hypotension. +A + 48. +You diagnose the patient with Parkinson’s disease. +The patient asks about his prognosis and likelihood +of disability. +A. +B. +C. +D. +Levodopa should be started immediately to prevent +the development of disabling rigidity. +E. +MAO inhibitors are contraindicated once the diag- +nosis of Parkinson’s disease is established. +49. +All of the following statements regarding restless +legs syndrome (RLS) are true EXCEPT: +A. +Dopamine antagonists are effective therapy. +B. +Most patients develop symptoms before the age of +30 years old. +C. +RLS may cause sleep disorder and daytime hyper- +somnolence. +D. +RLS is more common in Asians than in the general +U.S. +population. +E. +Symptoms may involve the upper extremity. +50. +Which of the following statements regarding +Alzheimer’s disease is true? +A. +Delusions are uncommon. +B. +It accounts for over half of the cases of significant +memory loss in patients over 70 years of age. +C. +It typically presents with rapid (<6 months) signifi- +cant memory loss. +D. +Less than 5% of patients present with nonmemory +complaints. +E. +Pathologically, the most notable abnormalities are in +the cerebellar regions. +51. +He denies back pain. +His only medication +is atorvastatin. +His left leg strength is notably +Review and Self-Assessment 810 + 51. +( Continued) + diminished in the hip flexors, hip adductors, quad- +riceps, and calf muscles. +There is atrophy of the +quadriceps and calf. +His ankle and knee reflexes are +increased on the left. +He has subtle weakness on +the right quadriceps. +There are no sensory abnor- +malities in light touch, pinprick, temperature, or +proprioception. +There are occasional fasciculations +of the abdominal muscles. +Cervical spondylosis +B. +Foramen magnum tumor +C. +Lead poisoning +D. +Multifocal motor neuropathy with conduction block +E. +Vitamin C deficiency +52. +She has taken her pulse and it feels fast to her. +Sitting or lying down improves the +symptoms. +She +reports lightheadedness during the episode. +An +ECG while symptomatic shows sinus tachycardia +without any conduction abnormalities. +Which of +the following is the most likely diagnosis? +A. +Addison’s disease +B. +Autoimmune autonomic neuropathy +C. +Diabetic neuropathy +D. +Multisystem atrophy +E. +Postural orthostatic tachycardia syndrome +53. +A 45-year-old male complains of severe right arm +pain. +There was +some arm swelling and warmth. +He was evaluated +in an urgent care setting. +There were no radio- +graphic abnormalities and he was not treated. +Since +the injury, the pain and swelling have persisted. +53. +There is no +specific weakness or sensory change. +The patient’s +pain most likely is due to: +A. +Acromioclavicular separation +B. +Brachial plexus injury +C. +Cervical radiculopathy +D. +Complex regional pain syndrome +E. +Subclavian vein thrombosis +54. +Which of the following criteria suggests the diag- +nosis of trigeminal neuralgia? +A. +Deep-seated, steady facial pain +B. +Elevated erythrocyte sedimentation rate (ESR) +C. +Objective signs of sensory loss on physical examina- +tion +D. +Response to gabapentin therapy +E. +None of the above +55. +On physical examination, she appears +well with normal vital signs. +Detailed cranial nerve +examination reveals no sensory or motor abnormali- +ties. +The remainder of her neurologic examination +is normal. +What is the next step in her management? +A. +Brain MRI +B. +Brain MRI plus carbamazepine therapy +C. +Carbamazepine therapy +D. +Glucocorticoid therapy +E. +Referral to Otolaryngology for surgical cure +56. +Touching the lips or moving +the tongue can initiate these intense spasms of pain. +The results of a physical examination are normal. +MRI of the head is also normal. +The most likely +cause of this patient’s pain is: +A. +Acoustic neuroma +B. +Amyotrophic lateral sclerosis +C. +Meningioma +D. +Trigeminal neuralgia +E. +Facial nerve palsy +57. +The pain is not relieved by lying down or by wear- +ing a soft neck collar. +( Continued) + from sleep. +The pain is severe and is impeding her +daily activities. +She denies any arm pain or weak- +ness. +There is no history of prior back or neck pain, +trauma, or arthritis. +She works as a postal delivery +agent and her only physical activity is walking. +She +is monogamous with her husband and has no illicit +activities. +Her family history is notable for an aunt +and mother with breast cancer. +Her MRI is shown +in Figure 57. +Which is the most likely diagnosis? +A. +Cervical spondylosis +B. +Hematomyelia +C. +Metastatic breast cancer +D. +Spinal epidural abscess +E. +Spinal epidural hematoma +58. +A 34-year-old female complains of lower extrem- +ity weakness for the last 3 days. +She had had some low-grade fevers for the last +week. +She denies recent travel. +Past medical history is +unremarkable. +Physical examination is notable for a +sensory level at the level of the umbilicus. +The lower +extremities show +3/5 strength bilaterally proximally +and distally. +Reflexes, cerebellar examination, and +mental status are normal. +All of the following are ap- +propriate steps in evaluating this patient EXCEPT: +A. +Antinuclear antibodies +B. +Electromyography +C. +Lumbar puncture +D. +MRI of the spine +E. +Viral serologies +59. +Which of the following statements about syringo- +myelia is true? +A. +More than half the cases are associated with Chiari +malformations. +59. +( Continued) +B. +Symptoms typically begin in middle age. +C. +Vibration and position sensation are usually diminished. +D. +Syrinx cavities are always congenital. +E. +Neurosurgical decompression is usually effective in +relieving the symptoms. +60. +Head imaging was normal. +The patient’s physical examination is entirely +normal except for a somewhat flattened affect. +Which +of the following statements regarding his condition is +true? +A. +He has an excellent prognosis. +B. +He meets the criteria for postconcussive syndrome +and should improve over 1–2 months. +C. +He should avoid contact sports for 2 weeks. +D. +He is most likely malingering. +E. +Low-dose narcotics should be started for headache. +61. +A 68-year-old man is brought to the clinic by his +wife for evaluation. +His only complaint is a mild +but persistent, diffuse headache. +His head CT is +shown in Figure 61. +What is the most likely diagnosis? +FIGURE 57 +FIGURE 61 +Review and Self-Assessment 812 + 61. +( Continued) +A. +Acute epidural hematoma +B. +Acute subarachnoid hemorrhage +C. +Alzheimer’s disease +D. +Chronic subdural hematomas +E. +Normal-pressure hydrocephalus +62. +The fall was not witnessed; however, she was +suspected to have hit her head. +She is not respon- +sive to verbal or light tactile stimuli. +At baseline she is +able to converse but is frequently disoriented to place +and time. +Immediately after triage she is taken for a +CT scan of the head. +Which of the following is true +regarding head injury and hematomas? +A. +B. +Epidural hematomas generally arise from venous +sources. +C. +Epidural hematomas are common among the elderly +with minor head trauma. +D. +Most patients presenting with epidural hematomas +are unconscious. +E. +63. +A 49-year-old man is admitted to the hospital +with a seizure. +He does not have a history of sei- +zures and he currently takes no medications. +He +has AIDS and is not under any care at this time. +His physical examination is most notable for small, +shoddy lymphadenopathy in the cervical region. +A head CT shows a ring-enhancing lesion in the +right temporal lobe, with edema but no mass effect. +A lumbar puncture shows no white or red blood +cells, and the Gram stain is negative. +His serum +Toxoplasma IgG is positive. +He is treated with pyri- +methamine, sulfadiazine, and levetiracetam. +What +is the best course of action for this patient at this +time? +A. +Continue treatment for CNS toxoplasmosis. +B. +Dexamethasone. +C. +IV acyclovir. +D. +Stereotactic brain biopsy. +E. +Whole-brain radiation therapy. +64. +A laboratory workup reveals a decreased +morning cortisol level of 1.9 μg/dL. +A. +Growth hormone +B. +Follicle-stimulating hormone +C. +Prolactin +D. +Thyroid-stimulating hormone +65. +The seizure lasted a short time and termi- +nated spontaneously. +Her initial +CT scan showed no acute hemorrhage but was +abnormal. +An MRI is obtained and is shown in +Figure 65. +What is the most likely diagnosis in +this patient? +A. +Brain abscess +B. +Glioblastoma +C. +Low-grade astrocytoma +D. +Meningioma +E. +Oligodendroglioma +FIGURE 65 +Review and Self-Assessment 813 +66. +All of the following hormones are produced by the +anterior pituitary EXCEPT: +A. +Adrenocorticotropic hormone +B. +Growth hormone +C. +Oxytocin +D. +Prolactin +E. +Thyroid-stimulating hormone +67. +One day postpartum she complains of +visual changes and severe headache. +Two hours +after these complaints, she is found unresponsive +and profoundly hypotensive. +She is intubated and +placed on mechanical ventilation. +Physical exam is unremarkable. +Which +of the following is most likely to reverse her hypo- +tension? +A. +Activated drotrecogin alfa +B. +Hydrocortisone +C. +Piperacillin/tazobactam +D. +T4 +E. +Transfusion of packed red blood cells +68. +In addition, he reports +low libido and decreased energy. +Physical examina- +tion shows frontal bossing and enlarged hands. +An +MRI confirms that he has a pituitary mass. +Which +of the following screening tests should be ordered +to diagnose the cause of the mass? +A. +24-hour urinary free cortisol +B. +ACTH assay +C. +Growth hormone level +D. +Serum IGF-1 level +E. +Serum prolactin level +69. +All of the following are potential causes of hyper- +prolactinemia EXCEPT: +A. +Cirrhosis +B. +Hirsutism +C. +Nipple stimulation +D. +Opiate abuse +E. +Rathke’s cyst +70. +A 28-year-old woman presents to her primary +care physician’s office with 1 year of amenorrhea. +She reports mild galactorrhea and headaches. +Al- +though she is sexually active, a urine pregnancy test + 70. +( Continued) + is negative. +Which of the following represents the primary +goal of bromocriptine therapy for her condition? +A. +Control of hyperprolactinemia +B. +Reduction in tumor size +C. +Resolution of galactorrhea +D. +Restoration of menses and fertility +E. +All of the above +71. +A 58-year-old man undergoes severe head trauma +and develops pituitary insufficiency. +After recov- +ery, he is placed on thyroid hormone, testosterone, +glucocorticoids, and vasopressin. +All of +the following are potential signs or symptoms of +growth hormone deficiency EXCEPT: +A. +Abnormal lipid profile +B. +Atherosclerosis +C. +Increased bone mineral density +D. +Increased waist:hip ratio +E. +Left ventricular dysfunction +72. +His laboratory evaluation shows +a hypokalemic metabolic alkalosis. +Cushing’s syn- +drome is suspected. +Which of the following state- +ments regarding this syndrome is true? +A. +Basal ACTH level is likely to be low. +B. +Circulating corticotropin-releasing hormone is likely +to be elevated. +C. +Pituitary MRI will visualize all ACTH-secreting +tumors. +D. +Referral for urgent performance of inferior petrosal +venous sampling is indicated. +E. +Serum potassium level below 3.3 mmol/L is sugges- +tive of ectopic ACTH production. +73. +She reports moderate compli- +ance with her medications but feels generally well. +A TSH is checked and is below the limits of de- +tection of the assay. +Which of the following is the +next most appropriate action? +A. +Decrease levothyroxine dose to half of current dose. +B. +Do nothing. +C. +Order free T4 level. +D. +Order MRI of her brain. +E. +Order thyroid uptake scan. +Review and Self-Assessment 814 +74. +She +has been amenorrheic for several months. +Cush- +ing’s syndrome is suspected. +Which of the follow- +ing tests should be used to make the diagnosis? +A. +24-hour urine free cortisol +B. +Basal adrenocorticotropic hormone (ACTH) +C. +Corticotropin-releasing hormone (CRH) level at 8 am +D. +Inferior petrosal venous sampling +E. +Overnight 1-mg dexamethasone suppression test +75. +A patient visited a local emergency room 1 week +ago with a headache. +What should +be the next step in her management? +A. +Diagnose her with subclinical panhypopituitarism, +and initiate low-dose hormone replacement. +B. +Reassure her and follow laboratory results closely. +C. +Reassure her and repeat MRI in 6 months. +D. +E. +76. +All of the following are frequent initial symptoms +of multiple sclerosis EXCEPT: +A. +Optic neuritis +B. +Paresthesias +C. +Sensory loss +D. +Visual loss +E. +Weakness +77. +Which of the following is the most common clini- +cal classification of multiple sclerosis? +A. +Autoimmune autonomic neuropathy +B. +Primary progressive +C. +Progressive relapsing +D. +Relapsing/remitting +E. +Secondary progressive +78. +Depressed consciousness +B. +Focal neurologic abnormality +C. +Known central nervous system (CNS) mass lesion +D. +Positive Kernig’s sign +E. +Recent head trauma +79. +A 78-year-old man with diabetes mellitus presents with +fever, headache, and altered sensorium. +His neck is stiff and he has photophobia. +CSF Gram stain is negative. +A. +Acyclovir +B. +Dexamethasone after antibiotics +C. +Dexamethasone prior to antibiotics +D. +IV γ globulin +E. +Valacyclovir +80. +A. +Immunocompromised patients +B. +Elderly patients +C. +Infants +D. +All of the above +81. +A. +Acetaminophen +B. +Acyclovir +C. +β-lactam antibiotics +D. +Ibuprofen +E. +Phenobarbital +82. +Variant Creutzfeldt-Jakob disease (vCJD) has been +diagnosed in which of the following populations? +A. +New Guinea natives practicing cannibalism +C. +Patients accidentally inoculated with infected mate- +rial during surgical procedures +D. +Worldwide, in sporadic cases, mostly during the +fifth and sixth decades of life +E. +A. +A 55-year-old woman presents with progressive +incoordination. +She also has an unsteady +gait. +MRI reveals atrophy of both lobes of the cer- +ebellum. +Serologic evaluation reveals the presence +of anti-Yo antibody. +Which of the following is the +most likely cause of this clinical syndrome? +A. +Non–small cell cancer of the lung +B. +Small cell cancer of the lung +C. +Breast cancer +D. +Non-Hodgkin’s lymphoma +E. +Colon cancer +85. +A 24-year-old man presents for evaluation of foot- +drop. +His right leg is more +affected than his left leg. +He has not noted any sen- +sory changes. +He has several family members with +similar complaints. +Knee and ankle jerk re- +flexes are unobtainable. +Calves are reduced in size +bilaterally. +Upper extremity examination is normal. +Which of the following is the most likely diagnosis? +A. +Charcot-Marie-Tooth syndrome +B. +Fabry disease +C. +Guillain-Barré syndrome +D. +Hereditary neuralgic amyotrophy +E. +Hereditary sensory and autonomic neuropathy +86. +( Continued) + past several weeks. +He also reports some difficulty +walking. +His medications include niacin, aspirin, and iso- +niazid. +Which of the following is likely to reverse +his symptoms? +A. +Cobalamin +B. +Levothyroxine +C. +Neurontin +D. +Pregabalin +E. +Pyridoxine +87. +She +also reports tingling and burning in the same loca- +tion, but no weakness. +Her symptoms have been +intermittently present for the last several months. +Which of the following statements regarding +this condition is true? +A. +Autonomic neuropathy is rarely seen in combina- +tion with sensory neuropathy. +B. +C. +This is the most common cause of peripheral neu- +ropathy in developed countries. +D. +Tight glucose control from now on will reverse her +neuropathy. +E. +None of the above is true. +88. +All the following cause primarily a sensory neu- +ropathy EXCEPT: +A. +Acromegaly +B. +Critical illness +C. +HIV infection +D. +Hypothyroidism +E. +Vitamin B12 deficiency +89. +A 50-year-old male complains of weakness and +numbness in the hands for the last month. +He de- +scribes paresthesias in the thumb and the index and +middle fingers. +The symptoms are worse at night. +He also describes decreased grip strength bilaterally. +He works as a mechanical engineer. +The patient de- +nies fevers, chills, or weight loss. +You consider the diagnosis of carpal +Review and Self-Assessment 816 + 89. +( Continued) + tunnel syndrome. +All the following are causes of +carpal tunnel syndrome EXCEPT: +A. +Amyloidosis +B. +Chronic lymphocytic leukemia +C. +Diabetes mellitus +D. +Hypothyroidism +E. +Rheumatoid arthritis +90. +Which of the following bacteria have been im- +plicated in cases of Guillain-Barré syndrome? +A. +Bartonella henselae +B. +Campylobacter jejuni +C. +Escherichia coli +D. +Proteus mirabilis +E. +Tropheryma whippelii +91. +A 34-year-old female complains of weakness and +double vision for the last 3 weeks. +The patient denies pain. +The +symptoms are worse at the end of the day and with +repeated muscle use. +You suspect myasthenia gravis. +All the following are useful in the diagnosis of myas- +thenia gravis EXCEPT: +A. +Acetylcholine receptor (AChR) antibodies +B. +Edrophonium +C. +Electrodiagnostic testing +D. +Muscle-specific kinase (MuSK) antibodies +E. +Voltage-gated calcium channel antibodies +92. +You intend to initiate therapy with anticho- +linesterase medications and glucocorticoids. +All of +the following tests are necessary before instituting +this therapy EXCEPT: +A. +MRI of mediastinum +B. +Purified protein derivative skin test +C. +Lumbar puncture +D. +Pulmonary function tests +E. +Thyroid-stimulating hormone +93. +All of the following lipid-lowering agents are as- +sociated with muscle toxicity EXCEPT: +A. +Atorvastatin. +B. +Ezetimibe. +C. +Gemfibrozil. +D. +Niacin. +E. +All of the above are associated with muscle toxicity. +94. +All of the following endocrine conditions are as- +sociated with myopathy EXCEPT: +A. +Hypothyroidism. +B. +Hyperparathyroidism. +C. +Hyperthyroidism. +D. +Acromegaly. +E. +All of the above are associated with myopathy. +95. +A 34-year-old woman seeks evaluation for weak- +ness. +She has noted tripping when walking, par- +ticularly in her left foot, for the past 2 years. +She has not seen a physician in +many years and has no past medical history. +Her +only medications are a multivitamin and calcium +with vitamin D. +Her speech is mildly dysarthric, and the +palate is high and arched. +Strength is 4/5 in the +intrinsic muscles of the hand, wrist extensors, and +ankle dorsiflexors. +What is the most likely diag- +nosis? +A. +Acid maltase deficiency (Pompe’s disease) +B. +Becker muscular dystrophy +C. +Duchenne muscular dystrophy +D. +Myotonic dystrophy +E. +Nemaline myopathy +96. +An elevation in which of the following serum en- +zymes is the most sensitive indicator of myositis? +A. +Aldolase +B. +Creatinine kinase +C. +Glutamic-oxaloacetic transaminase +D. +Glutamate pyruvate transaminase +E. +Lactate dehydrogenase +97. +A 64-year-old woman is evaluated for weakness. +For several weeks she has had difficulty brushing +her teeth and combing her hair. +She has also noted +a rash on her face. +Examination is notable for a +heliotrope rash and proximal muscle weakness. +Serum creatine kinase (CK) is elevated and she is +Review and Self-Assessment 817 + 97. +( Continued) + diagnosed with dermatomyositis. +After evaluation +by a rheumatologist, she is found to have anti-Jo-1 +antibodies. +She is also likely to have which of the +following findings? +A. +Ankylosing spondylitis +B. +Inflammatory bowel disease +C. +Interstitial lung disease +D. +Primary biliary cirrhosis +E. +Psoriasis +98. +A 63-year-old woman is evaluated for a rash on her +eyes and fatigue for 1 month. +She reports difficulty +with arm and leg strength and constant fatigue, but +no fevers or sweats. +She also notes that she has a red +discoloration around her eyes. +She has hypothy- +roidism but is otherwise well. +On examination she +has a heliotrope rash and proximal muscle weak- +ness. +Which of the following +studies should be performed as well to look for as- +sociated conditions? +A. +Mammogram +B. +Serum antinuclear antibody measurement +C. +Stool examination for ova and parasites +D. +Thyroid-stimulating immunoglobulins +E. +Titers of antibodies to varicella zoster +99. +You are seeing your patient with polymyositis for +follow-up. +He began a steroid taper 2 weeks +ago. +He no longer needs a cane and his +voice has returned to normal. +Laboratory data +show a creatine kinase (CK) of 1300 U/L, which +is unchanged from 2 months ago. +What is the most +appropriate next step in this patient’s management? +A. +Continue current management. +B. +Continue high-dose steroids with no taper. +C. +Switch mycophenolate to methotrexate. +D. +Repeat muscle biopsy. +100. +For the last day +she has complained about headache and confu- +sion. +Her medications include diltiazem, cyclospo- +rine, prednisone, and mycophenolate mofetil. +She +is now awake but somnolent. +Her vital signs are +normal except a blood pressure of 150/90 mmHg. +100. +Hearing is +intact. +There is no nuchal rigidity. +Her cyclospo- +rine level is therapeutic. +The FLAIR image of her +MRI is shown in Figure 100. +Which of the fol- +lowing is the most likely diagnosis? +A. +Acoustic neuroma +B. +Calcineurin-inhibitor toxicity +C. +Panhypopituitarism +D. +Streptococcal meningitis +E. +Tuberculous meningitis +101. +However, his wife re- +ports that he seems depressed and is often confused. +His short-term memory is poor and he exhibits no +enthusiasm for teaching. +He has no fever or night +sweats. +Current medications include lovastatin and +lisinopril. +Which of +the following is the most likely diagnosis? +A. +Multiple sclerosis +B. +Post–cardiac bypass brain injury +C. +Streptococcal meningitis +D. +Variant Creutzfeldt-Jacob disease +E. +West Nile virus encephalitis +FIGURE 100 +Review and Self-Assessment 818 +102. +A 24-year-old man is recovering from ARDS due +to severe influenza A infection. +Passive splints were placed on his upper and +lower extremities. +He is now extubated and awake, +requiring only nasal oxygen. +The rest +of the neurologic examination of the right leg and +foot appears normal. +Which of the following is the +most likely etiology of his defects? +A. +Cauda equina syndrome +B. +Femoral nerve injury +C. +L4 radiculopathy +D. +L5 radiculopathy +E. +Peroneal nerve injury +103. +Delusional disorder +B. +Impaired memory or concentration +C. +Muscle pain +D. +Sore throat +E. +Tender cervical or axillary lymph nodes +104. +Which of the following is a beneficial therapy for +chronic fatigue syndrome? +A. +Bupropion +B. +Cognitive behavioral therapy +C. +Doxycycline +D. +Fluoxetine +E. +Olanzapine +105. +She +feels lightheaded and dizzy. +She denies any immediate +precipitating cause, although she has been under +105. +She does not take +any medications and has no medical history. +She de- +nies tobacco, alcohol, or drug use. +On initial examina- +tion, she appears somewhat anxious and diaphoretic. +She is afebrile. +Her examination +is normal. +Her arterial blood gas shows a pH of 7.52, +PaCO2 of 28 mmHg, and PaO2 of 116 mmHg. +The +ECG is normal as is a chest radiograph. +What is the +next best step in the management of this patient? +A. +Initiate therapy with alprazolam 0.5 mg four times daily. +B. +Initiate therapy with fluoxetine 20 mg daily. +C. +Perform a CT pulmonary angiogram. +D. +E. +Refer for cognitive behavioral therapy. +106. +Duloxetine—Selective serotonin reuptake inhibitor +B. +Fluoxetine—Selective serotonin reuptake inhibitor +C. +Nortriptyline—Tricyclic antidepressant +D. +Phenelzine—Monoamine oxidase inhibitor +E. +Venlafaxine—Mixed norepinephrine/serotonin +reuptake inhibitor and receptor blocker +107. +She is +irritable with her husband and children and cries fre- +quently. +You con- +cur that post-traumatic stress disorder is likely. +What +treatment do you recommend for this patient? +A. +Avoidance of alcohol +B. +Cognitive behavioral therapy +C. +Paroxetine 20 mg daily +D. +Trazodone 50 mg nightly +E. +All of the above +Review and Self-Assessment 819 +108. +A 36-year-old man is being treated with venlafax- +ine 150 mg twice daily for major depression. +He +has currently been on the medication for 4 months. +He has had +one prior episode of major depression when he +was 25. +He asks when he +can safely discontinue his medication. +What is your +advice to the patient? +A. +He should continue on the medication indefinitely +as his depression is likely to recur. +B. +C. +D. +The medication can be discontinued safely now as +his symptoms are well controlled. +E. +109. +A. +Coadministration with a carbonated beverage +B. +Concentration of alcohol of more than 20% by +volume +C. +Concurrent intake of a high-carbohydrate meal +D. +Concurrent intake of a high-fat meal +E. +Concurrent intake of a high-protein meal +110. +Which of the following best reflects the effect of +alcohol on neurotransmitters in the brain? +A. +Decreases dopamine activity +B. +Decreases serotonin activity +C. +Increases γ-aminobutyric acid activity +D. +Stimulates muscarinic acetylcholine receptors +E. +Stimulates N-methyl-D-aspartate excitatory gluta- +mate receptors +111. +A. +0.02 +B. +0.08 +C. +0.28 +D. +0.40 +E. +0.60 +112. +B. +Approximately 60% of the risk for alcohol abuse +disorders is attributed to genetics. +C. +Children of alcoholics have a 10-fold higher risk of +alcohol abuse and dependence. +D. +E. +113. +A 42-year-old man with alcohol dependence is admit- +ted to the hospital for acute pancreatitis. +He typically drinks 24 12-ounce beers daily. +He is agitated, diaphoretic, and pacing his room. +He is +oriented to person only. +His neurologic examination +appears nonfocal, although he does not cooperate. +He +is tremulous. +What is the next step in the manage- +ment of this patient? +A. +Administer a bolus of 1 L of normal saline and thia- +mine 100 mg IV. +B. +C. +Perform an emergent head CT. +D. +Perform two peripheral blood cultures and begin +treatment with imipenem 1 g IV every 8 hours. +E. +Place the patient in four-point restraints and treat +with haloperidol 5 mg IV. +114. +She has a medical history of stroke oc- +curring during a hypertensive crisis. +Which of the +following medications could be considered? +A. +Acamprosate +B. +Disulfiram +Review and Self-Assessment 820 +114. +( Continued) +C. +Naltrexone +D. +A and C +E. +All of the above +115. +What is the most common initial illicit drug of +abuse among U.S. +adolescents? +A. +Benzodiazepines +B. +Heroin +C. +Marijuana +D. +Methamphetamines +E. +Prescription narcotics +116. +She uses IV heroin on a +daily basis, often spending $100 or more per day +on drugs. +The +abscess is drained and packed, and the patient is +initiated on therapy with IV clindamycin. +You are suspecting narcotic withdrawal. +All +of the following symptoms are consistent with this +diagnosis EXCEPT: +A. +Hyperthermia +B. +Hypotension +C. +Piloerection +D. +Sweating +E. +Vomiting +117. +Upon arrival at the scene, +117. +The patient was +intubated in the field and naloxone 2 mg IM was +administered. +His blood pressure is 82/50 +mmHg and heart rate is 70 beats/min. +A. +Activated charcoal +B. +Naloxone continuous infusion at a rate of 0.4 mg/h +D. +Urine drug screen, acetaminophen levels, and blood +alcohol content +E. +All of the above +118. +Which of the following statements is TRUE with +regard to the chronic effects of marijuana use? +A. +Chronic use of marijuana is associated with low +testosterone levels. +B. +Chronic use of marijuana is the primary cause of +amotivational syndrome. +C. +D. +Physical and psychological tolerance does not de- +velop in chronic users of marijuana. +E. +There is no withdrawal syndrome associated with +cessation of marijuana use. +ANSWERS +1 and 2. +The answers are D and D, respectively. +(Chap. +The motor examination is further characterized by +appearance, tone, strength, and reflexes. +Pronator drift is a +useful tool for determining if upper extremity weakness is +present. +Other tests of motor strength include tests of +maximal effort in a specific muscle or muscle group. +It has many causes +including cervical spondylosis and multiple sclerosis. +Romberg sign is performed with an individual standing +with feet together and arms at the side. +The individual is +then asked to close his or her eyes. +3. +The answer is C. +(Chap. +1) This patient likely has metastatic disease to the +cervical spinal cord. +4. +The answer is C. +(Chap. +The procedure of choice +for initial diagnosis is a CT of the head without IV con- +trast. +5. +The answer is E. +(Chap. +The two relaxation rates that +influence the signal intensity of the image are T1 and T2. +T2 images are also more sensitive for detecting +demyelination, infarction, or chronic hemorrhage. +6. +The answer is E. +(Chap. +However, +gadolinium was recently linked to a rare disorder called +nephrogenic systemic fibrosis. +The +risk of this can be minimized if the patient is adequately +hydrated. +Typically +a patient is asked to hold metformin for 48 hours before +and after a CT scan. +In very rare instances, administration of iodinated contrast +can unmask hyperthyroidism. +7. +The answer is D. +(Chap. +The EEG generally slows in metabolic encephalopathies, +and triphasic waves may be present. +8. +The answer is D. +(Chap. +10) Syncope is a common medical complaint that +occurs when there is global cerebral hypoperfusion. +Syn- +cope accounts for 3% of all emergency department vis- +its and 1% of all hospitalizations. +The most common +cause of syncope in young adults is neurally mediated +syncope. +The incidence of neurally mediated syncope is +higher in females and has a familial predisposition. +This results in hypotension with accom- +panying bradycardia. +Syncope occurs when blood flow to +the brain drops abruptly. +Triggers of the reflex pathway +are varied. +Individuals who +faint at the sight of blood experience vasovagal syncope. +Reassurance and avoidance +of triggers are the primary treatments. +Liberal intake of +fluids and salt expand plasma volume and are protective +against syncopal events. +9. +The answer is A. +(Chap. +Likewise, older individuals are at greater risk +of cardiac syncope. +Hypoglycemia +can present with syncope as well and needs to be consid- +ered in this case. +Neurologic causes of syncope include +seizures and vertebrobasilar insufficiency. +10. +The answer is D. +(Chap. +Most dizziness is benign, self-limited, and +must be distinguished from vertigo. +However, central lesions of the brainstem +and cerebellum can also lead to vertigo. +By history, deafness or tinnitus is typically absent with +central lesions. +Visual fixation +does not, however, inhibit nystagmus in central lesions. +These include hiccups, diplopia, +cranial neuropathies, and dysarthria. +11. +The answer is C. +(Chap. +By +far, the most commonly affected canal is the posterior one. +Less commonly, +the horizontal canal is affected, leading to horizontal nys- +tagmus. +The Epley maneuver is the most common +repositioning procedure. +Thus, the use of rizatriptan would not be helpful. +12. +The answer is D. +(Chap. +Over time, +Review and Self-Assessment 824 +severe muscle atrophy can occur. +A Babinski sign should +not be present. +13. +The answer is E. +(Chap. +13) Approximately 15% of individuals older +than 65 years have an identifiable gait disorder. +By age +80 years, 25% of individuals require a mechanical aid to +assist ambulation. +In most +case series, the most common cause of gait disorders is a +sensory deficit. +Other common causes of gait disorders +include myelopathy and multiple cerebrovascular in- +farcts. +14. +The answer is B. +(Chap. +In this case, the patient presents with signs +of a frontal gait disorder or parkinsonism. +The patient may have difficulty rising from a +chair and has a slow, hesitating start. +Likewise, there is +great difficult with turning with multiple steps required to +complete a turn. +The patient has very significant postural +instability. +However, cerebellar signs are typically absent. +Communicating hydrocephalus also +presents with a gait disorder of this type. +Character- +istics of cerebellar ataxia include a wide-based gait with +variable velocity. +Gait initiation is normal, but the pa- +tient is hesitant during turns. +The stride is lurching and +irregular. +Falls are a late event. +The heel-to-shin test is +abnormal, and the Romberg test is variably positive. +Neurosyphilis and lumbar myelopathy are examples of +sensory ataxia. +Sensory ataxia presents with frequent falls. +The gait with sensory ataxia, however, is narrow based. +Often the patient is noted to be looking down while +walking. +The patient tends to walk slowly but have path +deviation. +Gait is initiated normal, but the patient may +have some difficulty with turning. +The Romberg test is +typically unsteady and may result in falls. +15. +The answer is D. +(Chap. +For elderly +patients in intensive care, the incidence rises to between +70 and 87%. +However, it has been estimated the diagnosis +is missed in one-third of individuals with delirium. +Delirium also has sig- +nificant associated morbidity and mortality. +However, the increased mortality is not simply limited +to the hospital stay. +16. +The answer is B. +(Chap. +Although commonly ordered, brain +imaging is most often not helpful in the evaluation of +delirium. +17. +The answer is C. +(Chap. +Delirium is used to describe an acute confusional +state. +There is often +dramatic fluctuation between states. +Patients in the intensive care +unit have especially high rates of delirium, ranging from +70–87%. +The clinic setting represents the lowest risk. +18. +The answer is D. +(Chap. +A patient in a +vegetative state can open the eyes spontaneously and of- +ten track objects. +At this point, the likelihood of meaningful +recovery of mental faculties is almost zero. +A minimally +conscious state is a less severe manifestation of bilateral +cerebral injury. +19. +The answer is A. +(Chap. +If an individual is +determined to have brain death, life-sustaining therapies +are withdrawn. +Most hospitals have developed +specific protocols to diagnose a patient with brain death. +Three essential elements should be demonstrated for the +diagnosis of brain death. +Finally, there should be no evidence of medullary +activity manifested by apnea. +This test is important for document- +ing the absence of medullary function. +At +this point, ventilator support is stopped. +20. +The answer is E. +(Chap. +Coma may occur because of compression of +the midbrain. +21. +The answer is B. +(Chap. +Indeed, anomia is present in all types of aphasia +except pure word deafness or pure alexia. +Fluency is assessed by listening to +spontaneous speech. +Alexia refers to the inability +to read aloud or comprehend written language. +22. +The answer is C. +(Chap. +18) The parietofrontal area of the brain is respon- +sible for spatial orientation. +In addition, subcorti- +cal areas in the striatum and thalamus are also important. +This is an example of a target detection task. +A +third finding in Balint’s syndrome is simultanagnosia. +23. +The answer is C. +(Chap. +The results of this lead to decreased alertness and increased +errors during night shifts. +Night shift workers should be +encouraged to wear dark sunglasses in the morning on the +way home. +Sleep during the day is frequently disrupted +in night shift workers. +Melatonin is not one of the recommended therapies +for shift work sleep disorder. +24. +The answer is C. +(Chap. +20) This patient complains of symptoms that are +consistent with restless legs syndrome (RLS). +Renal disease, neuropathy, and iron defi- +ciency are known secondary causes of RLS symptoms. +Pramipexole +or ropinirole is recommended as first-line treatment. +Other options for treating RLS include +narcotics, benzodiazepines, and gabapentin. +Hormone re- +placement therapy has no role in the treatment of RLS. +25. +The answer is A. +(Chap. +This neurotransmitter is released from +a small number of neurons in the hypothalamus. +Of these symptoms, cataplexy is the +most specific for the diagnosis of narcolepsy. +Cataplexy +refers to the sudden loss of muscle tone in response to +strong emotions. +It most commonly occurs with laugh- +ter or surprise but may be associated with anger as well. +During this +time, individuals are aware of their surroundings and are +not unconscious. +26. +The answer is B. +(Chap. +htm, accessed May 12, 2011) Insomnia is the most com- +mon sleep disorder in the population. +These symptoms occur despite +adequate time and opportunity for sleep. +Insomnia can +be further characterized as primary or secondary. +It is +directly related to obesity and has an increased incidence +in men and in older populations. +Narcolepsy affects 1 in +4000 people and is caused by deficit of hypocretin (orex- +in) in the brain. +The symptoms have an onset with quiescence, +especially at night, and are relieved with movement. +This disorder is most common in adolescence and +young adulthood. +27. +The answer is C. +(Chap. +20) Parasomnias are abnormal behaviors or expe- +riences that arise from slow-wave sleep. +Typical treatment is a +benzodiazepine. +There are no typical parasomnias that arise +from stage I or stage II sleep. +REM parasomnias include +nightmare disorder and REM-behavior disorder. +28. +The answer is E. +(Chap. +Crossed fibers +are more damaged by compression than uncrossed fibers. +These lesions +are often insidious and may be unnoticed by the patient. +They will escape detection by the physician unless each +eye is tested separately. +Review and Self-Assessment 829 +29. +The answer is E. +(Chap. +Uveitis requires slit-lamp exami- +nation for diagnosis. +The risk is re- +mote and rarely causes permanent vision loss. +The value +of a complete funduscopic examination outweighs the risk +of this rare event. +TIA is usually associated with atheroscle- +rosis. +If flow is restored quickly vision returns to normal. +30. +The answer is A. +(Chap. +It +occurs as nonexudative (dry) or exudative (wet) forms. +The mechanism link for that association is un- +known. +The nonexudative form is associated with retinal +drusen that leads to retinal atrophy. +Treatment with vita- +min C, vitamin E, beta-carotene, and zinc may retard the +visual loss. +Acute visual loss may occur +because of bleeding. +Retinal detachment is usually unilateral and causes visual +loss and an afferent pupillary defect. +31. +The answer is B. +(Chap. +Fewer than 10% of patients with +posttraumatic anosmia regain normal function. +Signifi- +cant decrements in smell are present in more than 50% of +people older than 65 years old. +32. +The answer is E. +(Chap. +24) Hearing loss is a common complaint, partic- +ularly in older individuals. +In this age group, 33% have +hearing loss to a degree that requires hearing aids. +The primary site of dam- +age is the hair cells of the inner ear. +Examination of the external auditory ca- +nal can identify cerumen or foreign body impaction. +In the Rinne’s test, air +conduction is compared with bony conduction of sound. +A tuning fork is placed over the mastoid process and then +in front of the external ear. +In the Weber test, the tuning fork is placed in +the midline of the head. +Thus, the sound is expected to +be greatest in the right ear on the Weber test. +Pure tone audiometry establishes the severity, type, and +laterality of hearing loss. +33. +The answer is D. +(Chap. +Parkinson’s disease is +the classic example of neurotransmitter system–mediated +disease. +34. +The answer is C. +(Chap. +25) Synaptic neurotransmission is the predomi- +nant mechanism for neuronal communication. +Neurotransmitters bind to spe- +cific receptors that are either ionotropic or metabotropic. +Parkinson’s +syndrome is related to selective cell death in the nigros- +triatal dopamine pathway. +Orthostatic tachycardia +syndrome is related to mutations in the norepinephrine +transporter. +35. +The answer is B. +(Chap. +Seizures are classified as focal or generalized. +They are fre- +quently associated with a structural lesion. +The terms “simple partial sei- +zure” and “complex partial seizure” have been eliminated. +36. +The answer is A. +(Chap. +An aura is common before the seizures. +There is postictal +memory loss or disorientation. +Patients often have a his- +tory of febrile seizures or a family history of seizures. +MRI +will show hippocampal sclerosis, a small temporal lobe, or +enlarged temporal horn. +37. +The answer is E. +(Chap. +Overt deficits +in strength are not compatible with a primary psychiat- +ric disorder. +38. +The answer is C. +(Chap. +In addition, acute cocaine in- +toxication is a plausible reason for this new-onset seizure. +Figure 26-2 illustrates the evaluation of the adult patient +with a seizure. +MRI would be indicated if the patient had +a negative metabolic and toxicologic screening. +39. +The answer is B. +(Chap. +The goal is to prevent seizures and minimize the side +effects of therapy. +The minimal effective dose is deter- +mined by trial and error. +In choosing medical therapies, +drug interactions are a key consideration. +In patients with +epilepsy other considerations are critical. +Psychosocial se- +quelae such as depression, anxiety, and behavior problems +may occur. +40. +The answer is D. +(Chap. +Fever rarely causes seizure in pa- +tients older than 12 years. +Amyloid angiopathy and uremia +are more common in older adults. +41. +The answer is A. +(Chap. +GCSE +is obvious when the patient is having overt convulsions. +However, after 30–45 minutes of uninterrupted seizures, +the signs may become increasingly subtle. +Patients may +have mild clonic movements of only the fingers or fine, +rapid movements of the eyes. +There may be paroxysmal +episodes of tachycardia, hypertension, and pupillary dila- +tion. +In such cases, the EEG may be the only method of +establishing the diagnosis. +Carbam- +azepine is a first-line therapy for focal seizures. +Review and Self-Assessment 832 +42. +The answer is A. +(Chap. +27) Cardioembolism accounts for up to 20% of all +ischemic strokes. +If the thrombus lyses quickly, +only a transient ischemic attack may develop. +If the arte- +rial occlusion lasts longer, brain tissue may die and a stroke +will occur. +Atrial fibrillation +is the most common cause of cerebral embolism overall. +This may be detected +by bubble-contrast echocardiography. +43. +The answer is D. +(Chap. +27) Nonrheumatic atrial fibrillation is the most +common cause of cerebral embolism overall. +The average annual +risk of stroke is around 5%. +The risk of stroke can be estimated by calculating +the CHADS2 score (see Table 27-3). +Therefore, it is +recommended that these patients only take aspirin daily +for stroke prevention. +44. +The answer is E. +(Chap. +27) Numerous studies have identified key risk fac- +tors for ischemic stroke. +Hyperten- +sion is the most significant among these risk factors. +All +cases of hypertension must be controlled in the setting of +stroke prevention. +Antiplatelet therapy has been shown to +reduce the risk of vascular atherothrombotic events. +A recent Euro- +pean study confirmed this finding. +45. +The answer is C. +(Chap. +There are +no clinical findings that definitively distinguish ischemia +from hemorrhage. +Subsequent +studies using different dosing and timing ranges have not +been as positive. +46. +The answer is D. +(Chap. +29) All the choices given in the question are causes +of or may be associated with dementia. +Vitamin B12 deficiency may also lead to a +subcortical type of dementia. +Brain imaging demonstrates multiple areas of stroke. +47. +The answer is D. +(Chap. +Orthostasis and autonomic +symptoms are typically prominent. +On pathologic examination, α-synuclein–positive inclu- +sions would be seen in the affected areas. +Median sur- +vival after diagnosis is 6–9 years. +Corticobasal +degeneration is a sporadic tauopathy that presents in the +sixth to seventh decades. +Its +progressive nature leads to spastic paraplegia. +Diffuse Lewy +body disease has prominent dementia with parkinsonian +features. +48. +The answer is C. +(Chap. +Choice of initial drug therapy is usually with +dopamine agonists, levodopa, or MAO inhibitors. +Over this period, escalating doses are frequently +required, and side effects may be limiting. +By 5 years, +over half of individuals will require levodopa to control +motor symptoms. +In this setting, deep-brain +stimulation can alleviate disabling symptoms. +49. +The answer is D. +(Chap. +It is rare in +Asians. +Symptoms most commonly begin in the legs, +but can spread to or even begin in the upper limbs. +The mean age of onset in genetic forms is 27 years, +although pediatric cases are recognized. +The severity of +symptoms is variable. +The neurologic examination is normal. +Most RLS sufferers +have mild symptoms that do not require specific treat- +ment. +Other +drugs that can be effective include anticonvulsants, anal- +gesics, and even opiates. +Management of secondary RLS +should be directed to correcting the underlying disorder. +50. +The answer is B. +(Chap. +So- +cial graces, routine behavior, and superficial conversation +may be surprisingly intact. +Language becomes impaired— +first naming, then comprehension, and finally fluency. +In +some patients, aphasia is an early and prominent feature. +Simple +calculations and clock reading become difficult in parallel. +Loss of judgment and reasoning is inevitable. +In end-stage AD, +patients become rigid, mute, incontinent, and bedridden. +Generalized seizures may also occur. +The typical duration of AD is 8–10 years, but +the course can range from 1 to 25 years. +51. +The answer is E. +(Chap. +32) The combination of upper and lower mo- +tor neuron findings is highly suggestive of ALS. +MMCB is not typically associated with corticospinal signs. +52. +The answer is E. +(Chap. +There is no orthostat- +ic hypotension. +Approximately half +of affected patients report an antecedent viral infection. +Recurrent, unex- +plained episodes of dysautonomia and fatigue also occur. +Expansion of fluid volume and +postural training are initial approaches to treatment. +Reconditioning and a sustained ex- +ercise program are very important. +All of the other listed +choices are associated with orthostatic hypotension. +53. +The answer is D. +(Chap. +CRPS type I is a regional pain syndrome that +usually develops after tissue trauma. +Allodynia, hyperpathia, and +spontaneous pain occur. +Pain is the primary clinical feature +of CRPS. +The pain +is diffuse, spontaneous, and either burning, throbbing, or +aching in quality. +The involved extremity is warm and +edematous, and the joints are tender. +Increased sweating +and hair growth develop. +In phase II (3–6 months after +onset), thin, shiny, cool skin appears. +54. +The answer is A. +(Chap. +34) Trigeminal neuralgia is a clinical diagnosis +based entirely on patient history. +Symptoms are often, but +not always, elicited by tactile stimuli on the face, tongue, +or lips. +An elevated ESR is not part of the clinical syn- +drome. +First-line therapy is with +carbamazepine, not gabapentin. +If treatment is ef- +fective, it is continued for 1 month then tapered. +55. +The answer is C. +(Chap. +Carbamazepine is first-line therapy. +Oxcarbazepine +likely has equivalent efficacy to carbamazepine with less +toxicity. +Lamotrigine, orphenytoin, and baclofen are other +potential therapeutic options. +Steroids have no +therapeutic role, as trigeminal neuralgia is not an inflam- +matory condition. +56. +The answer is D. +(Chap. +57. +The answer is C. +(Chap. +The low-intensity bone marrow +signal in panel A of Figure 57 signifies replacement by +tumor. +MRI is the optimal diagnostic modality to im- +age the spinal cord. +Therapeutic anticoagulation, +trauma, tumor, or blood dyscrasias are predisposing condi- +tions. +Hematomyelia presents as an acute, pain- +ful transverse myelopathy. +58. +The answer is B. +(Chap. +35) This patient has a history and examination +consistent with a myelopathy. +59. +The answer is A. +(Chap. +Symptoms typically +begin in adolescence or early adulthood. +They may un- +dergo spontaneous arrest after several years. +More than +half are associated with Chiari malformations. +Acquired +cavitations of the spinal cord are referred to as syrinx cavi- +ties. +They may result from trauma, myelitis, infection, or +tumor. +Vibration and +position sensation are typically preserved. +MRI scans are the diagnostic modal- +ity of choice. +Surgical therapy is generally unsatisfactory. +Direct decompression of the cavity is of debatable benefit. +Although relief may occur, recurrence is common. +60. +The answer is A. +(Chap. +Transient loss of consciousness is com- +mon, as are confusion and amnesia. +Many patients do not +lose consciousness but feel dazed, stunned, or confused. +Head imaging is typically normal. +The patient described fits this +diagnosis; strict diagnostic criteria do not exist. +Typically +patients will improve over a 6- to 12-month period. +Treatment is +aimed at reassurance and relieving prominent symptoms. +Dizziness can be treated with Phenergan, which acts as a +vestibular suppressant. +He should avoid contact sports at +least until his symptoms resolve. +61. +The answer is D. +(Chap. +36) The head CT (Figure 61) shows chronic bilat- +eral subdural hematomas of varying age. +Some areas of re- +solving blood are contained in the more recently formed +collection on the left. +During the isodense phase +(2–6 weeks after injury), they may be difficult to discern. +Headache +is common. +Underlying cortical damage may serve +as a seizure focus. +62. +The answer is D. +(Chap. +They can be life- +threatening, and prompt evaluation and management are +imperative. +Several clinical features allow these conditions +to be distinguished from one another. +Subdural bleeding is +typically slower than epidural bleeding due to their differ- +ent sources. +Small subdural bleeds are asymptomatic and +often do not require evacuation. +A lacerated middle meningeal artery +from an overlying skull fracture often causes these. +63. +The answer is D. +(Chap. +If the imaging +shows clear improvement, continue antibiotics. +64. +The answer is A. +(Chap. +ACTH, prolactin, and gonadotropins have an +intermediate sensitivity. +Early delayed radiation injury occurs +within the first 4 months after therapy. +It is associated with +increased white matter signal on MRI and is steroid re- +sponsive. +Late delayed radiation injury occurs more than +4 months after therapy, typically 8–24 months. +65. +The answer is D. +(Chap. +37) The postgadolinium MRI shows multiple me- +ningiomas along the falx and left parietal cortex. +Menin- +giomas derive from the cells that give rise to the arachnoid +granulations. +They are usually benign (WHO classification grade 1) +and attached to the dura. +They rarely invade the brain. +Many meningiomas are found inci- +dentally following neuroimaging for unrelated reasons. +They can also present with headaches, seizures, or focal +neurologic deficits. +The main differential diagnosis of meningioma is a +dural metastasis. +Total surgical resection of a meningioma +is curative. +They have +a more benign course and are more responsive than other +gliomas to cytotoxic therapy. +For low-grade oligodendro- +mas, the median survival is 7–8 years. +66. +The answer is C. +(Chap. +The +posterior pituitary produces vasopressin and oxytocin. +67. +The answer is B. +(Chap. +38) The patient has evidence of Sheehan’s syn- +drome postpartum. +This leads to bilateral visual changes, +headache, and meningeal signs. +Ophthalmoplegia may +be observed. +In severe cases, cardiovascular collapse and +altered levels of consciousness may be observed. +Labo- +ratory evaluation commonly shows hypoglycemia. +Pitu- +itary CT or MRI may show signs of sellar hemorrhage +if present. +68. +The answer is D. +(Chap. +IGF-1 is +made by the liver in response to growth hormone stimu- +lation. +69. +The answer is B. +(Chap. +Nipple stimulation, sleep, and stress may +all increase prolactin levels. +Hypothalamic-pituitary stalk damage may +also cause hyperprolactinemia. +70. +The answer is E. +(Chap. +The most +common presentations are amenorrhea, infertility, and/or +galactorrhea. +Microadenomas rarely progress to become +macroadenomas. +71. +The answer is C. +(Chap. +38) Adult growth hormone deficiency is usually +caused by hypothalamic or pituitary damage. +Thus, deficiency of +growth hormone causes the opposite effects. +72. +The answer is E. +(Chap. +38) The patient has a clinical presentation con- +sistent with Cushing’s syndrome. +ACTH levels will be high, as this +is the underlying cause of both types of Cushing’s syn- +drome. +Corticotropin-releasing hormone is rarely the +cause of Cushing’s syndrome. +73. +The answer is C. +(Chap. +This, coupled with her symptoms, will aid in the +determination of proper levothyroxine dosing. +There is +no evidence of recurrent disease clinically; thus MRI is +not useful. +74. +The answer is A. +(Chap. +38) The diagnosis of Cushing’s syndrome relies on +documentation of endogenous hypercortisolism. +Rarely, pa- +tients have Cushing’s syndrome and elevated ACTH due +to a CRH-releasing tumor. +In this case, CRH levels are +elevated. +75. +The answer is B. +(Chap. +38) The identification of an empty sella is often +the result of an incidental MRI finding. +Typically these +patients will have normal pituitary function and should +be reassured. +It is likely that the surrounding rim of pitu- +itary tissue is functioning normally. +Unless her clinical +situation changes, repeat MRI is not indicated. +Endocrine +malignancy is unlikely, and surgery is not part of the man- +agement of an empty sella. +76. +The answer is D. +(Chap. +39) The onset of multiple sclerosis (MS) may be +abrupt or insidious. +Examination often reveals evidence of +neurologic dysfunction, often in asymptomatic locations. +For example, a patient may present with symptoms in one +leg but signs in both. +77. +The answer is D. +(Chap. +There +is often complete recovery over the ensuing weeks to +months. +Between attacks, patients are neurologically stable. +Sec- +ondary progressive MS (SPMS) always begins as RRMS. +SPMS produces a +greater amount of fixed neurologic disability than RRMS. +SPMS +appears to represent a late stage of the same underlying +illness as RRMS. +Primary progressive MS (PPMS) ac- +counts for approximately 15% of cases. +These patients do +not experience attacks but only a steady functional decline +from disease onset. +Despite these differences, PPMS appears to represent the +same underlying illness as RRMS. +Progressive/relapsing +MS (PRMS) overlaps PPMS and SPMS and accounts for +about 5% of MS patients. +Autoimmune autonomic neu- +ropathy is a distinct clinical syndrome not related to MS. +78. +The answer is D. +(Chap. +Kernig’s sign is elicited in a supine +patient by flexing the thigh and knee. +79. +The answer is B. +(Chap. +Glucocorticoids can blunt this response by inhibiting tu- +mor necrosis factor and interleukin-1. +They work best if +administered before antibiotics. +The dexamethasone was continued for +4 days. +The benefits were most striking in pneumococ- +cal meningitis. +However, in this case the LP is highly suggestive +of acute bacterial infection. +80. +The answer is D. +(Chap. +Ampicillin is the agent +most often added to the initial empirical regimen to cover +L. +monocytogenes. +81. +The answer is D. +(Chap. +Most causes of chronic (not recurrent) +meningitis cause a predominance of mononuclear cells. +The differential for chronic meningitis is broad and a di- +agnosis is often difficult to make. +82. +The answer is E. +(Chap. +43) Prions are infectious particles that cause cen- +tral nervous system degeneration. +There has been a steady decline of cases of vCJD in Europe +over the past decade. +Fa- +milial CJD (fCJD) is due to germ-line mutations that follow +an autosomal dominant inheritance. +Kuru is due to infec- +tion through ritualistic cannibalism. +Sporadic cases of fatal +insomnia (sFI) have been described. +83. +The answer is B. +(Chap. +Clinical abnormalities in CJD are confined to the CNS. +Both EEG and MRI can help differentiate +CJD from these disorders. +These proteins cannot be +measured from cerebrospinal fluid (CSF). +CSF in CJD is +usually normal except for a minimally elevated protein. +Many patients with CJD have elevated CSF stress protein +14-3-3. +84. +The answer is C. +(Chap. +Radiologic +imaging reveals cerebellar atrophy. +Cerebellar ataxia may also be seen in Hodgkin’s +lymphoma in association with anti-Tr antibodies. +85. +The answer is A. +(Chap. +45) Charcot-Marie-Tooth (CMT) syndrome is +the most common type of hereditary neuropathy. +CMT1 +is the most common and is an inherited demyelinating +sensorimotor neuropathy. +This would not fit the clinical pat- +tern described here. +Fabry disease is an X-linked +disorder in which men are more commonly affected than +women. +Burning pain in the hands and +feet often is found in late childhood or early adult life. +86. +The answer is E. +(Chap. +45) One of the most common side effects of iso- +niazid treatment is peripheral neuropathy. +Prophylactic administration +of pyridoxine can prevent the neuropathy from devel- +oping. +Symptoms are generally dysesthesias and sensory +ataxia. +Impaired large-fiber sensory modalities are found +on examination. +Cobalamin (B12) is not reduced in this +condition and is unaffected by isoniazid. +Neurontin and +pregabalin may alleviate symptoms but will not reverse +the neuropathy. +There is no indication that hypothyroid- +ism is present. +87. +The answer is C. +(Chap. +Symptoms also may include +tingling, burning, and deep, aching pains. +88. +The answer is B. +(Chap. +45) Peripheral neuropathy is a general term indi- +cating peripheral nerve disorders of any cause. +Mononeuropathy typically results +from local compression, trauma, or entrapment of a nerve. +Polyneuropathy often results from a more systemic pro- +cess. +HIV infection causes a common, distal, symmetric, mainly +sensory polyneuropathy. +Critical illness polyneuropathy is pre- +dominantly motor in presentation. +Patients typically pres- +ent with weakness that can be profound. +These patients +may recover over the course of weeks to months. +89. +The answer is B. +(Chap. +45) Carpal tunnel syndrome is caused by the en- +trapment of the median nerve at the wrist. +Symptoms +begin with paresthesias in the median nerve distribution. +With worsening, atrophy and weakness may develop. +Most cases are idiopathic other than those related +to occupational or environmental associations. +This may be suspected when bilateral disease is apparent. +Acute or chronic leukemia is not typically associated with +carpal tunnel syndrome. +90. +The answer is B. +(Chap. +Other implicated infec- +tions include Epstein-Barr virus, CMV, and Mycoplasma +pneumoniae. +T. +whippelii is the etiologic agent of Whipple’s +disease and B. +henselae is implicated in cat-scratch fever. +91. +The answer is E. +(Chap. +MG is +not rare, affecting at least 1 in 7500 individuals. +Women +are affected more frequently than men. +The key features of +MG are weakness and fatigability. +Diplopia and ptosis are common +initial complaints. +Weakness in chewing is noticeable af- +ter prolonged effort. +Speech may be affected secondary +to weakness of the palate or tongue. +Swallowing may re- +sult from weakness of the palate, tongue, or pharynx. +In +the majority of patients the weakness becomes general- +ized. +The diagnosis is suspected after the appearance of +the characteristic symptoms and signs. +False-positive tests may occur in patients with other neu- +rologic diseases. +Testing for +the specific antibodies to AChR are diagnostic. +Review and Self-Assessment 844 +92. +The answer is C. +(Chap. +47) Except for lumbar puncture, all of the options +listed are indicated at this time. +Thymic abnormalities are +present in 75% of patients with myasthenia gravis. +Hyperthyroidism occurs in 3–8% of pa- +tients with myasthenia gravis and may aggravate weakness. +93. +The answer is E. +(Chap. +Proximal weakness may be found on examina- +tion. +In severe cases, rhabdomyolysis and myoglobinuria +may occur, though most cases are mild. +After cessation, improve- +ment generally occurs after several weeks. +94. +The answer is E. +(Chap. +48) A number of endocrinologic conditions are as- +sociated with myopathy. +Both hypo- and hyperthyroidism +are associated with proximal muscle weakness. +Hyperparathyroidism is as- +sociated with muscle weakness that is generally proximal. +Muscle wasting and brisk reflexes are also generally pres- +ent. +Serum CK levels may be normal or slightly elevated. +Serum calcium and phosphate levels show no correlation +with clinical weakness. +Hypoparathyroid patients also of- +ten have myopathy due to hypocalcemia. +Patients with +acromegaly usually have mild proximal weakness with- +out atrophy. +95. +The answer is D. +(Chap. +Myotonic dystro- +phy 1 (DM1) is the most common form and the most +likely disorder in this patient. +The failure of relaxation +after a forced hand-grip is characteristic of myotonia. +Percussion of the thenar eminence can also elicit myo- +tonia. +Cardiac conduction +abnormalities and heart failure are also common in myo- +tonic dystrophy. +An electromyogram would +confirm myotonia. +Genetic testing for DM1 would show +a characteristic trinucleotide repeat on chromosome 19. +Other features +of the disease overlap with DM1. +Otherwise, their fea- +tures are similar. +This disease is inherited in an autosomal dominant +fashion. +96. +The answer is B. +(Chap. +CK is +always elevated in active polymyositis and thus is consid- +ered most sensitive. +97. +The answer is B. +(Chap. +98. +The answer is A. +(Chap. +Exhaustive +cancer searches are not recommended, however. +99. +The answer is A. +(Chap. +The goal of therapy is to improve strength. +If that goal is +being achieved, no augmentation of therapy is necessary. +100. +The answer is B. +(Chap. +The diagnosis is clinical and radiographic. +CSF findings +are nonspecific. +Acoustic neuroma would present +on MRI with a discrete mass. +The radiologic and clinical +appearance is not consistent with pituitary apoplexy. +101. +The answer is B. +(Chap. +vCJD is associated with ingestion of prion-contaminated +product. +102. +The answer is E. +(Chap. +50) The peroneal nerve winds around the head +of the fibula below the lateral aspect of the knee. +This +superficial location makes it vulnerable to trauma. +Patients may present with footdrop (dorsiflexion defect) +with weakness of foot eversion. +Cauda equina syndrome is +usually a medical emergency to avoid permanent func- +tional loss. +The femoral nerve branches into anterior +and posterior portions in the leg. +103. +The answer is A. +(Chap. +Criteria for +the diagnosis of CFS have been developed by the U.S. +Centers for Disease Control and Prevention (see Table +52-1). +CFS is seen worldwide, with adult prevalence rates + varying between 0.2% and 0.4%. +Approximately 75% of all CFS patients are women. +The +mean age of onset is between 29 and 35 years. +It is prob- +able that many patients go undiagnosed and/or do not +seek help. +104. +The answer is B. +(Chap. +Walking +or cycling is systematically increased, with set target heart +rates. +Evidence that deconditioning is the basis for symp- +toms in CFS is lacking, however. +Not all patients ben- +efit from CBT or GET. +Predictors of poor outcome are +somatic comorbidity, current disability claims, and severe +pain. +105. +The answer is D. +(Chap. +In this situation, no specific treatment +is required. +The symptoms usually subside spontaneously over +the course of an hour. +If +a patient subsequently develops panic disorder, a variety +of treatment options can be pursued. +The dose of medication +for panic disorder is typically lower than the antidepres- +sant dose. +For fluoxetine, this would be 5–10 mg daily. +106. +The answer is A. +(Chap. +54) There are increasing numbers of antidepres- +sant medications available in a variety of classes. +Selec- +tive serotonin reuptake inhibitors (SSRIs) are the most +commonly used antidepressant drugs. +Tricyclic +antidepressants were commonly used in past decades for +the treatment of depression. +Medica- +tions in this class include venlafaxine, desvenlafaxine, du- +loxetine, and mirtazapine. +There is a +wide range of drug and food interactions that can lead to +hypertensive crises. +Examples of medication in this class +include phenelzine, tranylcypromine, and isocarboxazid. +107. +The answer is E. +(Chap. +54) Post-traumatic stress disorder (PTSD) was +only added as a discrete disorder in 1980. +Treatment +with antidepressant medications can decrease anxiety +and avoidance behaviors. +Trazodone is often given +at night for its sedating properties. +108. +The answer is B. +(Chap. +Treatment +can be any of a number of medications across a variety of +classes. +In this patient, a dosage increase yielded control +of depressive symptoms at 4 months. +109. +The answer is A. +(Chap. +Several factors can increase the rate +of absorption. +110. +The answer is C. +(Chap. +56) Alcohol has effects on many neurotransmit- +ters in the brain. +The effects on dopamine are thought to +be important in alcohol craving and relapse. +111. +The answer is D. +(Chap. +At this level, decreases in cognitive and mo- +tor abilities are seen. +However, in in- +dividuals who drink heavily, tolerance begins to develop +to alcohol. +112. +The answer is C. +(Chap. +How- +ever, this is to be differentiated from alcohol dependence. +However, there may be higher rates +in Ireland, France, and Scandinavian countries. +This has been seen +in Native Americans, Maoris, and the aboriginal tribes +of Australia. +About 60% of the risk for alcohol use disorders is attrib- +uted to genetic influences. +113. +The answer is B. +(Chap. +Thus, the use of IV lorazepam or diazepam is preferred +in this patient. +In some instances a continuous infusion may be +required, although bolus dosing is preferred. +The other options listed are not appropriate for ini- +tial management of this patient. +Intravenous fluids and +thiamine had been administered since hospital admis- +sion. +114. +The answer is D. +(Chap. +The two medications with the best +risk-benefit ratio are acamprosate and naltrexone. +Acam- +prosate inhibits NMDA receptors, decreasing symptoms +of prolonged alcohol withdrawal. +Naltrexone is an opi- +oid antagonist than can be administered orally or as a +monthly injection. +115. +The answer is E. +(Chap. +The annual prevalence of heroin abuse +is approximately 0.14% of the population. +In contrast, +this prevalence is only one-third the rate of prescription +opiate abuse. +Among prescription narcotics, oxycodone +is the single most commonly abused drug. +Other com- +mon prescription narcotics that are abused include mor- +phine and hydrocodone. +Among health care profession- +als, meperidine and fentanyl are more frequently abused. +116. +The answer is B. +(Chap. +57) Tolerance and withdrawal begin within 6–8 +weeks of chronic daily opioid use. +This manifests +as increased lacrimation, rhinorrhea, and sweating. +Hyper- +tension, hyperthermia, and tachypnea can occur as well. +Hypotension is not a symptom of opioid withdrawal. +117. +The answer is E. +(Chap. +In the emergency +room, however, the patient remained hypotensive and +unresponsive. +One could also consider +sending for levels of aspirin or tricyclic antidepressants. +118. +The answer is C. +(Chap. +whitehousedrugpolicy.gov/publications/pdf/nsduh. +pdf, accessed July 25, 2011). +In addition, impaired judgment, cognition, +and psychomotor performance are seen. +Occasionally, +acute intoxication can lead to negative emotional re- +sponses as well. +A consensus about the chronic effects +of marijuana usage is not clearly defined. +The physical effects of chronic marijuana use are also +not clearly known. +Acutely, marijuana causes increased +heart rate, but tolerance for this effect occurs rapidly. +Acute ingestion can also precipitate angina. +Most studies have not found an associa- +tion with emphysema. +The psychological tolerance that +develops is more prominent and predictable. +See Brain abscess +epidural. +See Alzheimer’s disease (AD) +ADAMTS13, 775t +A-delta (Aδ) fibers, 40, 41 +ADEM. +See also Alcohol use +absorption of, 752–753, 819, 847–848 +abuse of. +See Infective endocarditis +Bacterial meningitis. +See Craniopharyngioma +meningioma. +See Meningioma +pituitary tumors. +See Brain abscess +cranial epidural abscess, 524, 524f +dementia due to, 328–329 +empyema. +See Subdural empyema +encephalitis. +See Encephalitis +meningitis. +See Anterior cerebral artery +middle. +See Middle cerebral artery +posterior. +See Charcot-Marie-Tooth (CMT) disease +CMV. +See Cytomegalovirus (CMV) infections +CNS. +infections. +moderate/severe head injury, 745t. +See Cerebrospinal fluid (CSF) +CSTB gene, 235t +CT. +substance abuse, 716. +See Electroencephalography (EEG) +Ehrlichia chaffeensis, 500 +Elderly. +See +Electroencephalography (EEG) +electrophysiologic studies. +See Electrophysiologic +studies +evoked potentials. +See Follicle-stimulating hormone (FSH) +FTD. +See Tension-type headache +Head drop, 648 +Head impulse test, 99 +Head injury, 415. +See Epidural hematoma +spinal, 406 +subdural. +See Hereditary sensory and autonomic +neuropathy (HSAN) +HSV infections. +See Limb-girdle muscular dystrophy +(LGMD) +LH. +See Monoamine oxidase type B +(MAO-B) inhibitors +MAOIs. +influenzae, 495, 496 +incidence of, 495–496 +increased ICP in, 503 +L. +monocytogenes, 495, 496, 501t, 502, 841 +M. +See also specific disorders +bipolar disorder. +See Huntington’s disease +hyperkinetic, 346, 347t. +See also specific disorders +PD. +See Parkinson’s disease (PD) +psychogenic, 356 +tics, 347t, 352–353 +Tourette’s syndrome. +See Tourette’s syndrome +Moyamoya disease, 268, 290 +MPTP, 336–337 +MRA. +See Magnetic resonance angiography (MRA) +MRF (myelin gene regulatory factor), 224 +MRI. +See Magnetic resonance imaging (MRI) +MS. +See Multiple sclerosis (MS) +MSA. +See Myopathy(ies) +muscular dystrophy. +See Duchenne’s muscular dystrophy +Emery-Dreifuss. +infections, 514–515, 529t. +See also Muscular dystrophy +HIV-related, 544 +Index 869 +Myopathy(ies) (Cont.): +inflammatory. +See also specific disorders +atlas of, 668–701f +CT. +See Magnetic resonance angiography +(MRA) +MRI. +See Magnetic resonance imaging (MRI) +myelography, 23–24 +PET. +See also specific diseases +angiography in, 25 +apoptosis in, 226–227 +approach to the patient. +See Optic neuropathy +paraneoplastic syndromes, 564–565 +peripheral. +See Neurofibromatosis type 1 (NF1) +NF1 gene, 425t, 432 +NF2. +See Anti-NMDA receptor +antibodies +Nocardia spp. +See Insomnia +narcolepsy. +See Meningitis +Streptomycin, 185 +Stress disorders, 727, 727t +Stroke, 257. +See Intracranial +hemorrhage +ischemic. +See Orthostatic +hypotension +pathophysiology of, 90 +in psychiatric disorders, 96, 97 +vs. +See also Seizure(s) +characteristics of, 233–234 +vs. +infections +chronic meningitis in, 530t. +See Thiamine +Vitamin B2. +See Riboflavin +Vitamin B6. +See Pyridoxine +Vitamin B12. +See Venous thromboembolism (VTE) +VZV infections. +breathtaking level of complexity far beyond the linear +sequence of the genome. +Noncoding DNA +The human genome contains some 3.2 billion DNA +base pairs. +Many of these proteins are recognizable homologs of +molecules expressed in humans. +What then separates humans +from worms? +There are five major classes of functional non–protein- +coding sequences in the human genome (Fig. +1.1): +• Promoter and enhancer regions that provide binding sites +for transcription factors. +• Binding sites for factors that organize and maintain higher +order chromatin structures. +• Noncoding regulatory RNAs. +• Mobile genetic elements (e.g., transposons) make up more +than a third of the human genome. +Chromosomes (as shown) can be visualized only during mitosis. +• SNPs occur across the genome—within exons, introns, +intergenic regions, and coding regions. +In +other words, the SNP and the causative genetic factor +are in linkage disequilibrium. +CNVs can be biallelic and simply duplicated or, alterna- +tively, deleted in some individuals. +1.2): +• Histones and histone-modifying factors. +The resulting DNA-histone +complex resembles a series of beads joined by short DNA +linkers. +The naked DNA of a single human cell is about +1.8 m long. +In most cases, this +structured DNA, termed chromatin, is not wound uni- +formly. +1.1). +In +general, only the regions that are “unwound” are available +for transcription. +In contrast, inactive genes have +histone marks that enable DNA compaction into hetero- +chromatin. +• Histone methylation. +• Histone acetylation. +• Histone phosphorylation. +• DNA methylation. +• Chromatin organizing factors. +Histones sit on 20- to 80-nucleotide stretches of linker DNA between nucleosomes. +Histone subunits are positively +charged, thus allowing compaction of negatively charged DNA. +DNA can also be methylated, leading to transcriptional inactivation. +that many other diseases are associated with inherited or +acquired epigenetic alterations. +1.3). +In +this way the target mRNA is posttranscriptionally silenced. +These +genomic sequences are transcribed but not translated. +lncRNAs +modulate gene expression by several mechanisms (Fig. +1.4). +Promote chromatin modification +Methylation, +acetylation +Ribosome +GENE SILENCING +D. +Multi-subunit complex +Figure 1.4 Roles of long noncoding RNAs (lncRNAs). +(A) lncRNAs can +facilitate transcription factor binding and thus promote gene activation. +(B) Conversely, lncRNAs can preemptively bind transcription factors to +inhibit transcription. +Conversely, many +enhancers are actually sites of lncRNA synthesis. +1.4). +1.5). +Cas9 +then induces double-stranded DNA breaks at the site of +gRNA binding. +Predictably the technology has inspired +a vigorous debate regarding the ethics of its use. +1.6). +HDR is less efficient than NHEJ but has the capacity to introduce +precise changes in DNA sequence. +The figure shows geographic relationships but is not intended to be accurate to scale. +ER, Endoplasmic reticulum. +I. +Morphometric model, stereologic methods, and +normal morphometric data for rat liver. +The contents and location of cellular organelles are also +highly regulated. +1.7). +Proper localization of these molecules is important for cell +health. +(A) The plasma membrane is a bilayer of phospholipids, cholesterol, and associated proteins. +In +platelets, phosphatidylserine is also a cofactor in blood +• clotting. +The means by which +these proteins associate with membranes frequently reflects +function. +In general, proteins associate with the lipid bilayer by one +of four mechanisms. +• Peripheral membrane proteins may noncovalently associ- +ate with true transmembrane proteins. +The latter strategy is used to maintain cell +polarity (e.g., top/apical/free vs. +bottom/basolateral/ +bound to extracellular matrix [ECM]) in epithelial cells. +This glycocalyx can form a chemical and +mechanical barrier. +Several mechanisms contribute to this transport. +Passive Diffusion. +Lipid bilay- +ers are also impermeant to ions due to their charge and +hydration. +Carriers and Channels (Fig. +1.8). +Ions +and small molecules can be transported by channel proteins +and carrier proteins. +Similar pores and channels also mediate +transport across organellar membranes. +For example, some transporters accommodate +glucose but reject galactose. +Receptor-mediated and fluid-phase uptake of material involves membrane bound vesicles. +They can subsequently fuse with +endosomes or recycle to the membrane. +Endocytosis of receptor-ligand pairs often involves clathrin-coated pits and vesicles. +After internalization the +clathrin disassembles and individual components can be re-used. +Other transporters are +ATPases. +Water movement into or out of cells is passive and +directed by solute concentrations. +Similar transport mechanisms also regulate +concentrations of other ions (e.g., Ca2+ and H+). +This is critical +to many processes. +Uptake of fluids or macromolecules by the cell is called +endocytosis. +Receptor-Mediated and Fluid-Phase Uptake (see Fig. +In both cases, activity +of the “pinchase” dynamin is required for vesicle release. +Macromolecules can also be exported from cells by +exocytosis. +Common examples include +peptide hormones (e.g., insulin) and cytokines. +We now return to the specifics of endocytosis (see Fig. +1.8). +• Caveolae-mediated endocytosis. +• Receptor-mediated endocytosis. +Trapped within these vesicles is also a gulp of +the extracellular milieu (fluid-phase pinocytosis). +Without recycling, +the plasma membrane would be rapidly depleted. +1.9). +In eukaryotic cells, there are three major classes of +cytoskeletal proteins. +1.9). +Examples +include: +• Vimentin, in mesenchymal cells (fibroblasts, +endothelium). +• Desmin in muscle cells forms the scaffold on which +actin and myosin contract. +• Neurofilaments are critical for neuronal axon structure +and confer both strength and rigidity. +• Glial fibrillary acidic protein is expressed in glial cells. +• Cytokeratins are expressed in epithelial cells. +gastrointestinal epithelium). +These fibrils are extremely dynamic +and polarized, with “ +” and “ −” ends. +• Mediate sister chromatid segregation during mitosis. +Similar complexes +also mediate interaction with the ECM. +Cell-cell junctions +are organized into three basic types (see Fig. +Adherens junctions are often closely +associated with and beneath tight junctions. +Desmosomes +are more basal and form several types of junctions. +Focal adhesion complexes are +composed of >100 proteins and localize at hemides- +mosomes. +Gap +junctions play a critical role in cell-cell communication. +It is also the initial site +of synthesis for secreted proteins. +1.6). +If a protein fails to appropriately fold +or oligomerize, it is retained and degraded within the +ER. +A good example of this is the most common mutation +of the CFTR protein in cystic fibrosis. +1.10B). +(A) Lysosomal degradation. +1.8). +(B) Proteosomal degradation. +If this is inadequate to cope with +the levels of misfolded proteins it can lead to apoptosis. +1.10). +These include proteosomes and peroxisomes. +The latter are responsible for catabolism of long-chained +fatty acids. +1.10). +Autophagy +is discussed in more detail in Chapter 2. +The material +is engulfed to form a phagosome that subsequently fuses +with lysosomes. +• Proteasomes play an important role in degrading cytosolic +proteins (see Fig. +1.11). +Details of mitochondrial functions follow: +• Energy generation. +Notably, the electron transport chain need not neces- +sarily be coupled to ATP generation. +TCA, Tricarboxylic acid. +lead to oxidative stress, characterized by increases in +intracellular reactive oxygen species. +• Intermediate metabolism. +• Cell death. +The role of mitochondria in cell death is +detailed in Chapter 2 and briefly mentioned here. +In turn, +these proteins activate intracellular programmed +cell death pathways. +CELLULAR ACTIVATION +Intercellular communication is essential to multicellular +organisms. +Receptors may be present on the cell +surface or within the cell (Fig. +1.12). +Depending on the receptor, ligand binding can: +1. +Open ion channels, typically at the synapse between +electrically excitable cells. +2. +Activate an associated GTP-binding regulatory protein +(G protein). +3. +Activate an endogenous or associated enzyme (often +a tyrosine kinase). +4. +1.12). +1.12). +Multiple signals at once, +in a certain ratio, may trigger yet another totally unique +response. +The signals that most cells respond to can be classified +into several groups. +• Danger and pathogens. +The involved +receptors are discussed in Chapters 3 and 6. +• Cell-cell contacts, mediated through adhesion molecules +and/or gap junctions. +• Cell-ECM contacts, mediated through integrins. +• Secreted molecules. +• Paracrine signaling. +Only cells in the immediate vicinity +are affected. +• Autocrine signaling occurs when molecules secreted by a +cell affect that same cell. +• Synaptic signaling. +• Endocrine signaling. +The released β-catenin can then +migrate to the nucleus and act as a transcription factor. +(B) Signaling from a +tyrosine kinase–based growth factor receptor. +Activated RAS interacts with and activates RAF (also known as MAP kinase +kinase kinase). +• Receptors associated with kinase activity. +Downstream +phosphorylation is a common pathway of signal transduc- +tion. +• Nuclear receptors. +• Other classes of receptors. +Normally, +β-catenin is continuously targeted for ubiquitin- +directed proteasomal degradation. +This is particularly true of signaling +pathways that rely on enzymatic activity. +• Nuclear (or cytoplasmic) localization of transcription +factors (see later). +• Transcription factor activation (or inactivation). +• Actin polymerization (or depolymerization). +• Protein degradation (or stabilization). +• Activation of feedback inhibitory (or stimulatory) loops. +Adaptor proteins play a key role in organizing intracel- +lular signaling pathways. +• DNA-binding domains permit specific binding to short +DNA sequences. +• Relieve blocks on cell cycle progression (thus promoting +replication). +• Prevent apoptosis. +1.12. +Epidermal Growth Factor (EGF) and Transforming +Growth Factor- α (TGF- α). +The ERB-B2 receptor (also known as HER-2) is +overexpressed in a subset of breast cancers. +Hepatocyte Growth Factor (HGF). +The receptor for HGF +is MET, which has intrinsic tyrosine kinase activity. +Consequently, +MET inhibitors are being evaluated for cancer therapy. +Platelet-derived Growth Factor (PDGF). +PDGF proteins are stored in cytoplasmic granules +and released by activated platelets. +Vascular Endothelial Growth Factor (VEGF). +Other VEGF inducers—produced at sites of inflammation +or wound healing—include PDGF and TGF- α. +Fibroblast Growth Factor (FGF). +FGF refers to a family +of growth factors with more than 20 members. +Transforming Growth Factor β (TGF-β). +It does +this by inhibiting lymphocyte proliferation and activity +of other leukocytes. +Animals lacking TGF-β have wide- +spread and persistent inflammation. +The ECM occurs in two basic forms: interstitial matrix +and basement membrane (Fig. +1.14). +• Interstitial matrix. +normal tissue architecture (Fig. +1.13). +• Scaffolding for tissue renewal. +Thus ECM disruption prevents +effective tissue regeneration and repair. +• Foundation for establishment of tissue microenvironments. +1.17C). +Both epithelial and +mesenchymal cells (e.g., fibroblasts) interact with ECM via integrins. +• Basement membrane. +The major constituents +are nonfibrillar type IV collagen and laminin. +Components of the Extracellular Matrix (Fig. +1.16). +Elastin. +1.15A). +Proteoglycans and Hyaluronan (see Fig. +1.15B). +bFGF regulation by association with +A. +Fibrillar collagen and elastin B. +Proteoglycan +the extracellular matrix +Figure 1.15 Extracellular matrix (ECM) components. +(A) Fibrillar collagen and elastic tissue structures. +(B) Proteoglycan structure. +Heparan sulfate binds bFGF secreted in the ECM. +FGF, Fibroblast growth factor. +1.15C). +Adhesive Glycoproteins and Adhesion Receptors. +1.17). +1.17A). +• Laminin is the most abundant glycoprotein in basement +membranes. +1.17B). +The N-terminus propeptide is variably processed depending on +the collagen chain. +mRNA, Messenger RNA. +inflammation (Chapter 3); they also play a critical role +in platelet aggregation (Chapter 4). +1.17C). +cells that are not actively cycling are in the G0 (gap 0) state +(Fig. +1.18). +Cells can enter G1 either from the G0 quiescent +cell pool or after completing a round of mitosis. +The cell cycle is regulated by activators and inhibitors. +1.19). +(C) Integrins and integrin-mediated signaling events at focal adhesion complexes. +Cyclin A-CDK2 and cyclin A-CDK1 are active in the S phase. +Cyclin B-CDK1 is essential +for the G2-to-M transition. +Two families of CDK inhibitors can block activity of CDKs and progression through the cell cycle. +The other family of three inhibitors, p21, p27, and p57, can +inhibit all CDKs. +There are several different CDKIs. +1.20). +• Symmetric division occurs when both daughter cells +retain self-renewal capacity. +• Embryonic stem (ES) cells are the most undifferentiated. +1.21). +They are normally protected within specialized +tissue microenvironments called stem cell niches. +1.22). +Another issue arises from the immunologic reactivity +of most stem cells. +Skin B. +Intestine C. +Liver +Figure 1.22 Stem cell niches in various tissues. +[A brief primer on the pathways that regulate +chromatin structure and accessibility]. +[Overview of +endocytosis with specific emphasis on its role in modulating intracellular +signaling]. +Choi AM, Ryter SW, Levine B: Autophagy in human health and disease, +N Engl J Med 368:651, 2013. +[Superb review concerning the physiologic +and pathophysiologic aspects of autophagy]. +[Topical discussion about cellular +interactions and the mechanical basis of tissue maintenance]. +[Mechanisms underlying +endoplasmic reticulum editing and cellular homeostasis]. +[Excellent review of the +mechanisms and consequences of cellular autophagy]. +[A well-written overview +of the intracellular architecture that directs and maintains polarity]. +[Nice review of the general principles +of membrane architecture emphasizing domain organization]. +[Solid review of the interplay between +cell metabolism, cell proliferation, and cell death]. +Burke PJ: Mitochondria, bioenergetics and apoptosis in cancer, Trends +Cancer 3:857, 2017. +Friedman JR, Nunnari J: Mitochondrial form and function, Nature +505:335, 2014. +[Good overview of mitochondrial replication and response +to cellular injury]. +[Review of the role of mitochondria in cell death pathways]. +[Excellent overall review of cell +signaling and proliferation]. +Morrison DK: MAP kinase pathways, Cold Spring Harb Perspect Biol +4:1, 2012. +[Review of mitogen-activated kinase signaling pathways]. +1.23). +Concluding Remarks. +[Good review regarding +long noncoding RNA biology]. +[An excellent review of the roles +played by noncoding RNAs]. +[Overview of signaling pathways with an +emphasis on how these become dysregulated in malignancy]. +[Very good review of +the fundamental concepts in stem cell biology]. +Blau HM, Daley GQ: Stem cells in the treatment of disease, N Engl J +Med 380:1748, 2019. +[Excellent review on stem cell biology and its thera- +peutic potential]. +De Los Angeles A, Ferrari F, Xi R et al: Hallmarks of pluripotency, +Nature 525:469, 2015. +Fuchs E, Chen T: A matter of life and death: self-renewal in stem cells, +EMBO Rep 14:39, 2013. +[A +focused review of applications of induced stem cell–derived endothelial +cells]. +Martello G, Smith A: The nature of embryonic stem cells, Annu Rev +Cell Dev Biol 30:647, 2014. +[Good comprehensive overview of cell plasticity +and stemness]. +Scadden DT: Nice neighborhood: emerging concepts of the stem cell +niche, Cell 157:41, 2014. +[Well-written paper describing the role of niche +in stem cell biology]. +Traditionally, the study of pathology is divided into +general pathology and systemic pathology. +General +pathology is concerned with the common reactions of cells +and tissues to injurious stimuli. +In Chapter 1 we examined +the cellular and molecular properties of healthy cells. +• Clinical manifestations. +Hence, clini- +copathologic correlations are very important in the study +of disease. +Virtually all diseases start with molecular or structural +alterations in cells. +Virchow +emphasized the idea that individuals are sick because their +cells are sick. +• Etiology is the initiating cause of a disease. +The study of pathogenesis +is a central focus of pathology. +This, of course, is the goal of +precision medicine. +2.1). +2.1). +Unless the blood supply is +quickly restored, the cells suffer irreversible injury and die +(Fig. +2.2). +It results from diverse causes, includ- +ing ischemia (reduced blood flow), infection, and toxins. +There are two principal pathways of cell death, necrosis +and apoptosis. +Calcium may be deposited at sites of cell death, resulting +in pathologic calcification. +This adaptation leads to thickening of +the left ventricular wall (compare with the normal heart). +Most injurious stimuli can be +grouped into the following broad categories. +Hypoxia is an +extremely important and common cause of cell injury and +cell death. +Depending on the severity +of the hypoxic state, cells may adapt, undergo injury, or +die. +Chemical Agents and Drugs +The list of chemicals that may produce cell injury defies +compilation. +Even +oxygen at high concentrations is toxic. +These are discussed +further in Chapter 9. +In between are rickettsiae, +bacteria, fungi, and higher forms of parasites. +The ways +by which these biologic agents cause injury are diverse +(Chapter 8). +Nutritional Imbalances +Nutritional imbalances continue to be major causes of +cell injury. +Deficiencies of specific vitamins are found throughout +the world (Chapter 9). +Ironically, nutritional excess also +is an important cause of cell injury. +2.3). +The sequential structural changes in cell injury progressing +to cell death are illustrated in Fig. +The ultrastructural changes of reversible cell injury, visible by +electron microscopy (Fig. +2.6B), include the following: +1. +Plasma membrane alterations, such as blebbing, blunting, and +loss of microvilli +2. +Mitochondrial changes, including swelling and the appearance +of small amorphous densities +3. +Dilation of the ER, with detachment of polysomes +5. +Different injurious +stimuli induce death mainly by necrosis and/or apoptosis +(see Fig. +2.4 and Table 2.1). +Two features are consistently seen in reversibly injured cells. +Swelling of cells results from influx of water. +• Fatty change occurs in organs that are actively involved +in lipid metabolism (e.g., liver). +This +is discussed in Chapter 18. +• Other alterations are described in the following +sections. +A B C +Figure 2.5 Morphologic changes in reversible cell injury and necrosis. +(A) Normal kidney tubules with viable epithelial cells. +The ultrastructural features of these stages of cell injury are shown in Fig. +2.6. +(Courtesy Drs. +(A) Electron micrograph of a normal epithelial +cell of the proximal kidney tubule. +Note abundant microvilli (mv) lining the luminal surface (L). +(C) Proximal tubular cell showing late injury, expected to be irreversible. +(A, Courtesy Dr. +Brigitte Kaisslin, Institute of Anatomy, University of Zurich, Switzerland. +B, C, +Courtesy Dr. +Necrosis +Necrosis is a pathologic process that is the consequence +of severe injury. +All of these initiating triggers lead to irreparable damage +of numerous cellular components. +When damage to membranes is +severe, lysosomal enzymes enter the cytoplasm and digest +the cell. +2.6C). +Here the +chromatin condenses into a dense, shrunken basophilic mass. +2.7).The affected tissue has a firm texture. +A +localized area of coagulative necrosis is called an infarct. +(A) A wedge-shaped kidney infarct (yellow). +Figure 2.8 Liquefactive necrosis. +An infarct in the brain, showing +dissolution of the tissue. +This occurs +in the calamitous abdominal emergency known as acute pancreatitis +(Chapter 19). +2.10). +2.11). +2.8). +2.9). +Figure 2.11 Fibrinoid necrosis in an artery. +Figure 2.9 Caseous necrosis. +This phenomenon, called dystrophic calcification, is considered +later in the chapter. +It is estimated that humans turn +over almost 1 million cells per second! +Central to this process +is death of cells by apoptosis and their removal by phago- +cytes. +Cell death is critical for +involution of primordial structures and remodeling of +maturing tissues. +• Accumulation of misfolded proteins. +2.4 +and Table 2.1). +During this process, there can be significant +tissue damage. +relatively normal, are more tightly packed. +This contrasts with +necrosis, in which an early feature is cell swelling, not shrinkage. +Chromatin condensation. +2.12B). +The nucleus itself may break up into two +or more fragments. +Formation of cytoplasmic blebs and apoptotic bodies. +2.12C). +Phagocytosis of apoptotic cells or cell bodies, usually +by macrophages. +2.12A). +2.12; see Fig. +2.4). +Cell shrinkage. +Cell size is reduced, the cytoplasm is dense +and eosinophilic (see Fig. +2.12A), and the organelles, although +A B +C +Figure 2.12 Morphologic features of apoptosis. +(A) Apoptosis of an epidermal cell in an immune reaction. +The cell is reduced in size and contains brightly +eosinophilic cytoplasm and a condensed nucleus. +(B, From Kerr JFR, Harmon BV: Definition and incidence of apoptosis: a historical perspective. +In Tomei LD, Cope FO, editors: Apoptosis: The Molecular +Basis of Cell Death. +Cold Spring Harbor, NY, 1991, Cold Spring Harbor Laboratory Press, pp 5–29; C, Courtesy Dr. +The presence of active caspases is therefore a marker +for cells undergoing apoptosis (see Fig. +2.12C). +2.13). +2.14). +• Anti-apoptotic. +2.14A). +VIABLE CELL B. +APOPTOSIS +thus protecting cells from apoptosis. +BH3-only proteins may also bind to and +block the function of BCL2 and BCL-XL. +2.14). +Thus, IAP inhibition permits initiation of the +caspase cascade. +This death domain is essential for delivering +apoptotic signals. +2.15). +The ligand +for Fas is called Fas ligand (FasL). +• Pro-apoptotic. +The precise mechanism +by which BAX-BAK oligomers permeabilize membranes +is not settled. +According to one model illustrated in Fig. +• Regulated apoptosis initiators. +Other +steps in apoptosis are less well-defined. +For instance, we +do not know how membrane blebs and apoptotic bodies +are formed. +tion of active caspase-8. +The combined activation of both pathways delivers +a fatal blow to the cells. +FADD, +Fas-associated death domain; FasL, Fas ligand. +• Necroptosis. +2.16). +As indicated in Fig. +This explains the morphologic similarity of necroptosis +with necrosis initiated by other injuries. +See text for details. +Caspase-1 and the closely related caspases-4 and -5 +also induce death of the cells. +• Ferroptosis. +The newly formed autophagosome +fuses with lysosomes to form an autophagolysosome. +It is therefore prominent in atrophic cells exposed +to severe nutrient deprivation. +• Necroptosis is triggered by ligation ofTNFR1 and by proteins +found in RNA and DNA viruses. +• Necroptosis is caspase-independent and depends on the RIPK1 +and RIPK3 complex. +• Release of cellular contents evokes an inflammatory reaction +as in necrosis. +Caspase-1 along with other +closely related caspases also cause death of the infected cell. +• Ferroptosis is an iron-dependent pathway of cell death induced +by lipid peroxidation. +It involves the delivery of +cytoplasmic materials to the lysosome for degradation. +It proceeds through several steps (Fig. +In the final stage, the digested materials are +released for recycling of metabolites. +See text for details. +LC3, Light chain 3. +This pathway of cell death is distinct from +necrosis and apoptosis, but the mechanism is unknown. +Nevertheless, autophagic vacuolization often precedes or +accompanies cell death. +This is an area of active +investigation, as discussed in Chapter 7. +In Huntington disease, mutant huntingtin impairs +autophagy. +Macrophage-specific deletion of Atg5 increases susceptibil- +ity to tuberculosis. +How these polymor- +phisms promote intestinal inflammation is not known. +• The consequences of cell injury depend on the type, +state, and adaptability of the injured cell. +How vulnerable +is a cell, for example, to loss of blood supply and hypoxia? +2.18). +The consequences of injury of each of these cellular com- +ponents are distinct but overlapping. +Thus, +in many ways, they are the arbiters of life and death of +cells. +In addition, mutations +in mitochondrial genes are the cause of some inherited +diseases (Chapter 5). +There are three major consequences of mitochondrial +damage. +• ATP depletion. +2.19). +ATP is produced in two ways. +Autophagy plays a role in host defense +against certain microbes. +ATP, Adenosine triphosphate; ROS, reactive oxygen species. +2.19). +• Cellular energy metabolism is altered. +As a consequence, glycogen +stores are rapidly depleted. +This reduces the intracellular pH, resulting in +decreased activity of many cytosolic enzymes. +Membrane damage may affect the integrity and functions +of all cellular membranes. +Several biochemical mechanisms may +contribute to membrane damage (Fig. +2.20): +• ROS. +Oxygen free radicals cause injury to cell membranes +by lipid peroxidation, discussed later. +• Decreased phospholipid synthesis. +• Increased phospholipid breakdown. +• Cytoskeletal abnormalities. +Damage to different cellular membranes has diverse +effects on cells. +• Mitochondrial membrane damage. +• Plasma membrane damage. +Two of these general pathways are +discussed next. +Free radicals are chemical species that have a +single unpaired electron in an outer orbit. +ROS are a type of oxygen-derived free radical whose +role in cell injury is well established. +The +properties of some of the most important free radicals are +summarized in Table 2.2. +Generation of Free Radicals +Free radicals may be generated within cells in several ways +(Fig. +2.21): • +The reduction-oxidation reactions that occur during normal +metabolic processes. +• Absorption of radiant energy (e.g., ultraviolet light, x-rays). +For example, ionizing radiation can hydrolyze water into +˙OH and hydrogen (H) free radicals. +• Rapid bursts of ROS are produced in activated leukocytes +during inflammation. +In addition, some intracellular oxidases (e.g., +xanthine oxidase) generate O2•. +Defects in leukocytic +superoxide production lead to chronic granulomatous +disease (Chapter 6). +The production of ROS is increased by many injurious +stimuli. +These free radicals are removed by spontaneous decay and by specialized enzymatic systems. +thus sources of iron and O2• may cooperate in oxidative +cell damage. +Removal of Free Radicals +Free radicals are inherently unstable and generally decay +spontaneously. +2.21). +• As we have seen, free iron and copper can catalyze the +formation of ROS. +• Several enzymes act as free radical–scavenging systems +and break down H2 O2 and O2•. +Catalase, present in peroxisomes, decomposes H2 O2 +(2H2 O2 → O2 + 2H2 O). +2. +3. +2.21): +• Lipid peroxidation in membranes. +• Oxidative modification of proteins. +• Lesions in DNA. +However, +it is now clear that free radicals can also trigger apoptosis. +2.23). +This process is called ER stress. +Diseases caused by +misfolded proteins are listed in Table 2.3. +2.22). +For this +reason, ischemia causes more rapid and severe cell and tissue +injury than hypoxia. +2.24 and shown earlier in Figs. +2.5 and +2.6. +The con- +sequences of ATP depletion were described earlier in the +Mitochondrial Damage section. +It +can also occur due to reduced venous drainage. +How does reperfusion injury occur? +Several mechanisms have been proposed: +• Oxidative stress. +• Intracellular calcium overload. +This, in turn, causes further cell injury. +• Inflammation. +The inflammation causes additional +tissue injury (Chapter 3). +• Activation of the complement system may contribute to +ischemia-reperfusion injury. +For unknown reasons, some +IgM antibodies have a propensity to deposit in ischemic +tissues. +The +morphologic changes shown here are indicative of reversible cell injury. +Further depletion of ATP results in cell death, typically by necrosis. +ER, +Endoplasmic reticulum. +Mammalian cells have developed protective responses +to deal with hypoxic stress. +Several promising investigational compounds that promote +HIF-1 signaling are being developed. +All of these may contribute to decreased cell and +tissue injury. +Because +many drugs are metabolized in the liver, this organ is a +major target of drug toxicity. +Here the major pathways of chemically induced +injury with selected examples are described. +Chemicals induce cell injury by one of two general +mechanisms: +• Direct toxicity. +Some chemicals injure cells directly by +combining with critical molecular components. +Cyanide +poisons mitochondrial cytochrome oxidase and thus +inhibits oxidative phosphorylation. +• Conversion to toxic metabolites. +These and other examples of chemical injury are described +in Chapter 9. +hypertrophied organ has no new cells, just larger cells. +• Pathologic hypertrophy. +The most common +stimulus for hypertrophy of skeletal and cardiac muscle is +increased workload. +2.2). +• Physiologic hypertrophy. +2.25). +Mechanisms of Hypertrophy +Hypertrophy is a result of increased cellular protein produc- +tion. +Much of our understanding of hypertrophy is based +on studies of the heart. +Hypertrophy +results from the action of growth factors and direct effects +on cellular proteins (Fig. +2.26): +• Mechanical sensors in the cell detect the increased load. +• Some of the signaling pathways stimulate increased +production of growth factors (e.g. +Death by necrosis and +apoptosis due to release of cytochrome c from mitochondria. +Complement may be +activated locally by IgM antibodies deposited in ischemic tissues. +• Chemicals may cause injury directly or by conversion into toxic +metabolites. +Such adaptations +may take several distinct forms. +The major known signaling pathways and their functional effects are shown. +In extreme cases, myocyte death can occur. +It can be physiologic or pathologic. +• Physiologic hyperplasia. +The classic +illustration of compensatory hyperplasia comes from the +study of liver regeneration. +The regulation of hematopoiesis +is discussed further in Chapter 13. +• Pathologic hyperplasia. +Endometrial hyperplasia is an example of abnormal +hormone-induced hyperplasia. +This form of +pathologic hyperplasia is a common cause of abnormal +uterine bleeding. +Atrophy can be +physiologic or pathologic. +Physiologic atrophy is common +during normal development. +Pathologic atrophy has several causes, and it can be local +or generalized. +Common causes of atrophy include the +following: +• Decreased workload (disuse atrophy). +The initial decrease in cell size is reversible +once activity is resumed. +• Loss of innervation (denervation atrophy). +Damage to the nerves leads to +atrophy of the muscle fibers supplied by those nerves +(Chapter 27). +• Diminished blood supply. +2.27). +This is called +senile atrophy. +• Inadequate nutrition. +This results +in marked muscle wasting (cachexia; Chapter 9). +Cachexia +is also seen in patients with chronic inflammatory diseases +and cancer. +• Loss of endocrine stimulation. +• Pressure. +Tissue compression for any length of time can +cause atrophy. +An enlarging benign tumor can cause +atrophy in the surrounding uninvolved tissues. +The fundamental cellular changes associated with atrophy +are similar in all of these settings. +The degradation of cellular proteins occurs mainly by the +ubiquitin-proteasome pathway. +An example +of residual bodies is lipofuscin granules, discussed later in the +chapter. +Autophagy +is associated with various types of cell injury, as discussed +earlier. +Figure 2.27 Atrophy. +(A) Normal brain of a young adult. +Note that loss of brain substance narrows the gyri and widens the sulci. +The most common epithelial metaplasia is columnar to squamous +(Fig. +2.28), as occurs in the respiratory tract in response to +chronic irritation. +However, the change to metaplastic +squamous cells comes with a price. +Thus, epithelial metaplasia, +in most circumstances, represents an undesirable change. +Unlike epithelial +metaplasia, this type of metaplasia is not associated with +increased cancer risk. +(A) +Schematic diagram. +There are four main mechanisms leading to abnormal +intracellular accumulations (Fig. +The resulting +disorders are called lysosomal storage diseases (Chapter 5). +Accumulation of carbon or +silica particles is an example of this type of alteration +(Chapter 15). +In many cases, if the overload can be controlled or +stopped, the accumulation is reversible. +Phospholipids are components of the myelin figures found +in necrotic cells. +Triglyceride and cholesterol accumula- +tions are discussed here. +2.30), but it also +occurs in the heart, muscle, and kidney. +Fatty liver is discussed in more detail in Chapter 18. +Cholesterol-laden macrophages (foam cells, +arrow) in a focus of gallbladder cholesterolosis. +(Courtesy Dr. +High-power detail of fatty change of the liver. +(Courtesy Dr. +By electron microscopy, they can be +amorphous, fibrillar, or crystalline in appearance. +2.32). +• Atherosclerosis. +• Xanthomas. +• Cholesterolosis. +2.31). +The mechanism of accumulation +is unknown. +• Niemann-Pick disease, type C. +(Courtesy Dr. +• Defective intracellular transport and secretion of critical +proteins. +• Accumulation of cytoskeletal proteins. +• Aggregation of abnormal proteins. +Abnormal or misfolded +proteins may deposit in tissues and interfere with normal +functions. +Certain forms of +amyloidosis (Chapter 6) fall in this category of diseases. +These disorders are sometimes called proteinopathies or +protein-aggregation diseases. +It is widely used as a descriptive his- +tologic term rather than a specific marker for cell injury. +Extracellular hyaline has been more difficult +to analyze. +Glycogen is a readily available source of glucose +stored in the cytoplasm of healthy cells. +Diabetes mellitus is the prime example of a disorder of +glucose metabolism. +Tattooing is a +form of localized, exogenous pigmentation of the skin. +The pigments do not usually evoke any +inflammatory response. +Lipofuscin is not injurious to the cell or its +functions. +Its importance lies in its being a telltale sign +of free radical injury and lipid peroxidation. +derived from the Latin (fuscus, brown), referring to brown +lipid. +2.33). +It is discussed +further in Chapter 25. +For practical purposes, melanin is +the only endogenous brown-black pigment. +Iron metabolism and +hemosiderin are considered in detail in Chapters 14 and +18. +Iron is normally carried by a specific transport protein +called transferrin. +In cells, it is stored in association with +a protein, apoferritin, to form ferritin micelles. +Ferritin is +a constituent of most cell types. +Hemosiderin +pigment represents aggregates of ferritin micelles. +Local or systemic excesses of iron cause hemosiderin to +accumulate within cells. +Local excesses result from hemor- +rhages in tissues. +The best example of localized hemosiderosis +is the common bruise. +In parallel, the iron released from heme is incorporated +into ferritin and eventually hemosiderin. +There are two forms +of pathologic calcification. +Calcification +is almost always present in the atheromas of advanced +atherosclerosis. +It also commonly develops in aging or +damaged heart valves, further hampering their function +(Fig. +2.34). +Massive deposits in the kidney (nephrocalcinosis) may in +time cause renal damage (Chapter 20). +It is markedly narrowed (stenosis). +They can be intracellular, extracellular, or in both locations. +In +the course of time, heterotopic bone may form in the focus +of calcification. +Some types of papillary cancers +(e.g., thyroid) are apt to develop psammoma bodies. +Serum calcium is +normal in dystrophic calcification. +Hypercalcemia also +accentuates dystrophic calcification. +Sadly, Toth and Hermes are nowhere to be found, henceCellular aging 67 +the elixir remains a secret. +Individuals age because their cells age. +2.35). +Such findings suggest that aging +is associated with definable mechanistic alterations. +DNA Damage. +Several +lines of evidence point to the importance of DNA repair in +the aging process. +Cellular Senescence. +Aging is associated with progressive +replicative senescence of cells. +Two mechanisms are believed to +underlie cellular senescence: +• Telomere attrition. +Telomere length is maintained +by nucleotide addition mediated by an enzyme called +telomerase. +Similar data +exist for the role of autophagy and proteasomal degradation +of proteins. +Rapamycin has +multiple effects, including promotion of autophagy. +Abnor- +mal protein homeostasis can have many effects on cell +survival, replication, and functions. +In addition, it may lead +to accumulation of misfolded proteins, which can trigger +apoptosis. +Dysregulated Nutrient Sensing. +Paradoxical though it +may seem, eating less increases longevity. +• Insulin and insulin-like growth factor 1 (IGF-1) signaling +pathway. +• Sirtuins. +Sirtuins are a family of NAD-dependent protein +deacetylases. +Sirtuins are thought to promote the expression of several +genes whose products increase longevity. +This effect can be mim- +icked by rapamycin. +Telomere length is plotted against the number of cell +divisions. +In cancer cells, telomerase is often +reactivated. +This is +discussed more fully in Chapter 7. +• Activation of tumor suppressor genes. +This is +discussed further in Chapter 7. +Defective Protein Homeostasis. +Nagata S: Apoptosis and clearance of apoptotic cells, Annu Rev Immunol +36:489–517, 2018. +[An excellent review of the mechanisms by which apoptotic +cells and their fragments are cleared]. +Necroptosis and Pyroptosis +Galluzzi L, Kepp O, Chan FK, et al: Necroptosis. +Mechanisms and +relevance to disease, Annu Rev Pathol 12:103–130, 2017. +[A current +review of necroptosis and its pathophysiologic significance]. +[A review of +the mechanisms and consequences of pyroptosis]. +[A review of newly discovered +pathways of cell death and possible therapeutic interventions]. +[A description of the pathology of +various pathways of cell death]. +[An excellent overview of the biochemistry and significance of necroptosis]. +[An excellent discussion of the mechanisms +and significance of autophagy]. +Doherty J, Baehrecke EH: Life, death and autophagy, Nat Cell Biol +20:1110–1117, 2018. +[A review of the link between autophagy and cell +death]. +[An excellent review of the cell biology +and genetics of autophagy]. +[A review of the control of +protein turnover and its role in atrophy of muscle]. +[A review +of the mechanisms of hypertrophy, with an emphasis on the heart]. +[A landmark review that suggests nine hallmarks +of aging and directions for future research]. +• Nutrient sensing system:Caloric restriction increases longevity. +Mediators may be reduced IGF-1 signaling and increased +sirtuins. +[The role of mitochondria in cellular response to stress]. +[The +molecular basis of reperfusion injury and possible therapeutic targets]. +Hotchkiss RS, Strasser A, McDunn JE, et al: Cell death, N Engl J Med +361:1570–1583, 2009. +The mediators of defense include phagocytic +leukocytes, antibodies, and complement proteins. +The typical inflammatory reaction develops through a +series of sequential steps (Fig. +• Repair consists of a series of events that heal damaged +tissue. +• Components of the inflammatory response. +3.1). +• Harmful consequences of inflammation. +• Recognition of the noxious agent that is the initiat- +ing stimulus for inflammation. +These receptors are described in +more detail later. +• Recruitment of leukocytes and plasma proteins into the +tissues. +If the offending stimulus is +eliminated, the reaction subsides, and residual injury is +repaired. +Chronic inflammation may follow acute inflamma- +tion or arise de novo. +These signs are hallmarks of +acute inflammation. +These diseases and their pathogenesis are discussed in relevant +chapters. +This serious disorder is +discussed in Chapter 4. +• Mediators of inflammation. +• Acute and chronic inflammation. +IL-1 recruits leukocytes +and thus induces inflammation (see later). +These disorders are discussed later +in this and other chapters. +• Other cellular receptors involved in inflammation. +• Circulating proteins. +Other proteins called collectins also +bind to and combat microbes. +• Tissue necrosis elicits inflammation regardless of the cause +of cell death. +Inflammation is a major cause of +tissue injury in these diseases (Chapter 6). +• Cellular receptors for microbes. +• Sensors of cell damage. +It is one +of the earliest manifestations of acute inflammation. +3.1). +3.2). +Its presence +Hydrostatic +Colloid osmotic +pressure +pressure +A. +Plasma proteins +NORMAL +Fluid and protein leakage +B. +TRANSUDATE +(low protein content, few cells) +Figure 3.2 Formation of exudates and transudates. +Therefore the net flow of fluid across the vascular bed is almost nil. +The system of lymphatics and lymph +nodes filters and polices the extravascular fluids. +The +presence of red streaks near a skin wound is a telltale sign +of bacterial infection. +as vascular congestion and localized redness of the +involved tissue. +3.3). +It is elicited by histamine, bradykinin, +leukotrienes, and other chemical mediators. +Sunburn is a classic example of damage that results in +late-appearing vascular leakage. +Often the immediate and +delayed responses occur along a continuum. +A. +NORMAL +Vessel lumen +Leukocytes +Plasma proteins +Endothelium +Tissues +B. +Fluid leak from blood vessels results +in edema. +C. +These leukocytes perform the key function of eliminating +the offending agents. +Macrophages also +produce growth factors that aid in repair. +This process can be divided into sequential +phases (Fig. +3.4). +1. +In the lumen: margination, rolling, and adhesion to endothe- +lium. +Vascular endothelium in its normal state does not +bind circulating cells or allow their passage. +2. +Migration across the endothelium and vessel wall. +3. +Migration in the tissues toward a chemotactic stimulus. +This process of leukocyte redistribution is called +margination. +They are expressed on leukocytes and endothelial cells. +• Selectins. +The ligands for selectins are sialylated oligosac- +charides bound to mucin-like glycoproteins. +• Integrins. +Leukocytes normally express integrins in a +low-affinity state. +These chemokines bind to and activate +the rolling leukocytes. +Transmigration of +leukocytes occurs mainly in postcapillary venules. +After leukocytes pass through, the basement +membranes become continuous again. +These leu- +kocyte adhesion deficiencies are described in Chapter 6. +Both exogenous and endogenous substances +act as chemoattractants. +3.5). +3.6). +(Courtesy Dr. +Morris J. +Karnovsky, Harvard Medical School, Boston, Mass.) +of cellular infiltration. +(A) Early (neutrophilic) infiltrates and congested blood vessels. +(B) Later (mononuclear) cellular infiltrates. +(C) The +approximate kinetics of edema and cellular infiltration. +Phagocytosis +Phagocytosis involves sequential steps (Fig. +Phagocytic Receptors. +Therefore the +mannose receptor recognizes microbes and not host cells. +Macrophage scavenger +receptors bind a variety of microbes in addition to modified +LDL particles. +Macrophage integrins, notably MAC-1 +(CD11b/CD18), may also bind microbes for phagocytosis. +Engulfment. +3.7). +This table lists the major differences between neutrophils and macrophages. +The reactions summarized above are described in the text. +into the phagolysosome (see Fig. +3.8). +During this process +the phagocyte may also release lysosome contents into the +extracellular space. +Different classes of cell surface receptors of leukocytes recognize different stimuli. +The receptors initiate responses that +mediate the functions of the leukocytes. +Only some receptors are depicted (see text for details). +Lipopolysaccharide (LPS) first binds to a circulating +LPS-binding protein (not shown). +IFN-γ, Interferon-γ.82 CHAPTER 3 Inflammation and Repair +1. +ENGULFMENT +Phagocyte membrane +zips up around +microbe 3. +During phagocytosis, granule contents may be +released into extracellular tissues (not shown). +iNOS, Inducible nitric oxide synthase; MPO, myeloperoxidase; ROS, reactive oxygen species. +oxide (NO), and these as well as lysosomal enzymes destroy +phagocytosed materials (see Fig. +3.8). +This is the final step +in the elimination of infectious agents and necrotic cells. +Reactive Oxygen Species. +Phagocyte oxidase is an +enzyme complex consisting of at least seven proteins. +O2• is converted into hydrogen peroxide (H2 O2), +mostly by spontaneous dismutation. +H2 O2 is not able to +efficiently kill microbes by itself. +The H2 O2-MPO- +halide system is the most potent bactericidal system of +neutrophils. +H2 O2 is also converted to hydroxyl radical +(˙OH), another powerful destructive agent. +These ROS are implicated in tissue damage +accompanying inflammation. +Nitric Oxide. +There are three different types of NOS: +endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). +Lysosomal Enzymes and Other Lysosomal Proteins. +Neutrophils have two main types +of granules. +Different granule enzymes serve different functions. +Foremost among +these is α1-antitrypsin, which is the major inhibitor of +neutrophil elastase. +α2-Macroglobulin is another antiprotease found +in serum and various secretions. +3.9). +In this process, the nuclei of the neutrophils +are lost, leading to death of the cells. +NETs have also been +detected in the blood during sepsis. +(A) Healthy neutrophils with nuclei stained red and cytoplasm stained green. +(C) Electron micrograph of bacteria (staphylococci) trapped in +NETs. +This fact becomes +evident in the discussion of specific disorders throughout +this book. +Controlled secretion of granule contents is a normal +response of activated leukocytes. +These functions of macrophages are discussed +later in the chapter. +IL-17 induces the +secretion of chemokines that recruit other leukocytes. +Many mediators have +been identified and targeted therapeutically to limit inflam- +mation. +However, there is also some overlap (redundancy) in +the actions of the mediators. +• Mediators are either secreted by cells or generated from +plasma proteins. +• Enzymes and ROS may be released into the extracellular +environment. +• Antiinflammatory mediators terminate the acute inflammatory +reaction when it is no longer needed. +Histamine also causes contrac- +tion of some smooth muscles. +It is also a vasoconstrictor, but the +importance of this action in inflammation is unclear. +Active AAs +are derived from an esterified precursor found in membrane +phospholipids. +3.10). +They are generated by the actions of two +cyclooxygenases, called COX-1 and COX-2. +• Active mediators are produced only in response to offend- +ing stimuli. +These stimuli include microbial products and +substances released from necrotic cells. +• Most mediators are short-lived. +They quickly decay, or +are inactivated by enzymes, or they are otherwise scav- +enged or inhibited. +There is thus a system of checks and +balances that regulates mediator actions. +These built-in +control mechanisms are discussed with each class of +mediator. +• One mediator can stimulate the release of other mediators. +It is also found in basophils and platelets. +Neuropeptides (e.g., substance P) and cytokines (IL-1, IL-8) +may also trigger release of histamine. +Histamine causes dilation of arterioles and increases +the permeability of venules. +and a subscript numeral (e.g., 1, 2) that indicates the number +of double bonds in the compound. +Some of these enzymes have restricted tissue +distributions. +PGD2 also is +a chemoattractant for neutrophils. +• Lipoxygenase inhibitors. +Pharmacologic agents that inhibit +leukotriene production are useful in the treatment of +asthma. +These drugs +are useful in the treatment of asthma. +The general properties and functions of +cytokines are discussed in Chapter 6. +The cytokines involved +in acute inflammation are reviewed here (Table 3.7). +The production of TNF is induced by signals through TLRs +and other microbial sensors. +The actions of TNF and IL-1 contribute to the local and +systemic reactions of inflammation (Fig. +3.11). +The most +important roles of these cytokines in inflammation are the +following. +• Endothelial activation. +There are three different lipoxygenases, 5-lipoxygenase +being the predominant one in neutrophils. +These antiinflam- +matory drugs include the following. +Selective +COX-2 inhibitors are 200- to 300-fold more potent in +blocking COX-2 than COX-1. +The most important cytokines involved in inflammatory reactions are listed. +Many other cytokines may play lesser roles in inflammation. +• Activation of leukocytes and other cells. +IL-1 also stimulates Th17 responses, which in +turn induce acute inflammation. +• Systemic acute-phase response. +They have two main +functions. +• In acute inflammation. +Inflammatory chemokines are the +ones whose production is induced by microbes and other +stimuli. +• Maintenance of tissue architecture. +Cytokines also +play key roles in chronic inflammation; these are described +later. +The system consists +of more than 20 proteins, some of which are numbered C1 +through C9. +The activation and functions of complement +are outlined in Fig. +3.12. +About 40 different chemokines and 20 different +receptors for chemokines have been identified. +A +subset of these chemokines acts primarily on neutro- +phils. +IL-8 (now called CXCL8) is typical of this group. +Its most important inducers +are microbial products and other cytokines, mainly IL-1 +and TNF. +• C-C chemokines have the first two conserved cysteine +residues adjacent. +• C chemokines lack the first and third of the four conserved +cysteines. +The C chemokines (e.g., lymphotactin, XCL1) +are relatively specific for lymphocytes. +• CX3 C chemokines contain three amino acids between the +two cysteines. +The only known member of this class is +called fractalkine (CX3CL1). +Chemokines mediate their activities by binding to seven- +transmembrane G protein–coupled receptors. +Activation of complement by different pathways leads to cleavage of C3. +The complement system has three main functions (see +Fig. +3.12). +• Inflammation. +C5a is also a chemotactic agent for neutrophils, +monocytes, eosinophils, and basophils. +• Opsonization and phagocytosis. +• Cell lysis. +Inherited +deficiency of this inhibitor is the cause of hereditary +angioedema. +The complement system contributes to disease in several +ways. +These effects are similar to those of histamine. +Nerve fibers containing +substance P are prominent in the lung and gastrointestinal +tract. +Now, we are +wallowing in them! +• Kinins: Produced by proteolytic cleavage of precursors;mediate +vascular reaction, pain. +Figure 3.13 Serous inflammation. +3.13). +3.14A), and pleura. +3.14B). +Fibrinous exudates +may be dissolved by fibrinolysis and cleared by macrophages. +(A) Deposits of fibrin on the pericardium. +(A) Multiple bacterial abscesses (arrows) in the lung in a case of bronchopneumonia. +scarring. +A common example of +an acute suppurative inflammation is acute appendicitis. +They are produced by seeding of pyogenic bacteria into a +tissue (Fig. +3.15). +Abscesses have a central liquefied region +composed of necrotic leukocytes and tissue cells. +In time the abscess may +become walled off and ultimately replaced by connective +tissue. +3.16). +A B +Figure 3.16 The morphology of an ulcer. +(A) A chronic duodenal ulcer. +3.17). +• Complete resolution. +• Healing by connective tissue replacement (scarring, or fibrosis). +• Progression of the response to chronic inflammation +(discussed later). +If the injurious agent cannot be quickly eliminated, +the result may be chronic inflammation. +Fibrosis may dominate the +late stages. +• Prolonged exposure to potentially toxic agents, either +exogenous or endogenous. +Loss of function (functio laesa) results from pain and injury +to the tissues. +Causes of Chronic Inflammation +Chronic inflammation arises in the following settings. +These organisms often evoke an +immune reaction called delayed-type hypersensitivity +(Chapter 6). +Acute and chronic +inflammation may coexist, as in a peptic ulcer. +• Hypersensitivity diseases. +3.18). +• Tissue destruction, induced by the persistent offending +agent or by the inflammatory cells. +Macrophages +are professional phagocytes that eliminate microbes and +damaged tissues. +They also serve important roles in the +repair of injured tissues. +Here we review the development +and functions of macrophages. +3.19). +Circulating cells of this lineage +are known as monocytes. +Macrophages are normally dif- +fusely scattered in most connective tissues. +(A) In postnatal life, macrophages arise mainly from bone marrow progenitors and blood monocytes. +(B) The morphology of a monocyte and activated macrophage. +Different stimuli activate monocytes/macrophages to develop into functionally distinct +populations. +They phagocytose and +destroy microbes and dead tissues and can potentiate inflammatory reactions. +These processes +are discussed later in the chapter. +Thus, macrophages contribute to the initiation +and propagation of inflammatory reactions. +3.20). +Prolonged reactions involving T cells and macrophages may result in granuloma formation. +of long-lived memory cells. +• Th1 cells produce the cytokine IFN-γ, which activates +macrophages by the classical pathway. +Th2 cells are important in defense against helminthic +parasites and in allergic inflammation. +These T-cell subsets +and their functions are described in more detail in Chapter 6. +3.21). +The result is +a cycle of cellular reactions that fuel and sustain chronic +inflammation. +However, +the contribution of antibodies to most chronic inflammatory +disorders is unclear. +• Eosinophils are abundant in immune reactions mediated +by IgE and in parasitic infections (Fig. +3.22). +Epithelioid cells +and giant cells are apposed to the surface of the foreign +body. +3.21). +Figure 3.22 Focus of inflammation containing numerous eosinophils. +also may injure host epithelial cells. +Mast cells express on their surface the receptor +(FcεRI) that binds the Fc portion of IgE antibody. +This +pattern of inflammation has been called acute on chronic. +Some +activated macrophages may fuse, forming multinucleate +giant cells. +3.23). +The aggregates of +epithelioid macrophages are surrounded by a collar of lymphocytes. +Older granulomas may have a rim of fibroblasts and connective +tissue. +Grossly, this has a granular, cheesy +appearance and is therefore called caseous necrosis. +Healing of granulomas is accompanied +by fibrosis that may be extensive in involved organs. +In this disease the granuloma is referred +to as a tubercle. +Granulomas may also develop in some +immune-mediated inflammatory diseases. +• It is characterized by coexisting inflammation, tissue injury, and +attempted repair by scarring. +• The cellular infiltrate consists of macrophages, lymphocytes, +plasma cells, and other leukocytes. +The acute-phase response consists of several clinical and +pathologic changes. +NSAIDs, including aspirin, reduce +fever by inhibiting prostaglandin synthesis. +They also +bind chromatin, possibly aiding in clearing necrotic cell +nuclei. +Both processes involve the proliferation of +cells and close interactions between cells and the ECM. +Based on these criteria, the +tissues of the body are divided into three groups. +• Labile (continuously dividing) tissues. +These tissues +can readily regenerate after injury as long as the pool of +stem cells is preserved. +• Stable tissues. +3.24). +• Regeneration. +However, these +cells are capable of dividing in response to injury or loss +of tissue mass. +Stable cells constitute the parenchyma of +most solid tissues, such as liver, kidney, and pancreas. +With the exception of liver, +stable tissues have a limited capacity to regenerate after +• injury. +Permanent tissues. +The majority of neurons and cardiac muscle +cells belong to this category. +In permanent tissues, repair is typically +dominated by scar formation. +Cell proliferation is driven by signals provided by +growth factors and from the ECM. +Growth factors are typically produced by cells near the +site of damage. +Several growth factors are displayed at +high concentrations bound to ECM proteins. +The reality, although less dramatic, is still quite +impressive. +Following +partial hepatectomy, the liver regenerates by proliferation of surviving cells. +The process occurs in stages, including priming, followed by growth +factor–induced proliferation. +The main signals involved in these steps are +shown. +Once the mass of the liver is restored, the proliferation is +terminated (not shown). +repopulation from progenitor cells. +Which mechanism plays +the dominant role depends on the nature of the injury. +• Proliferation of hepatocytes following partial hepatectomy. +The process occurs in distinct +stages (Fig. +3.25). +Almost +all hepatocytes replicate during liver regeneration after +partial hepatectomy. +In the final, termination, phase, hepa- +tocytes return to quiescence. +• Liver regeneration from progenitor cells. +formation. +The subsequent steps are sum- +marized here (Fig. +3.26): +• Inflammation. +As the injurious agents and necrotic cells are +cleared, the inflammation resolves. +• Cell proliferation. +Each cell +type serves unique functions. +• Formation of granulation tissue. +• Regeneration of the liver is a classic example of repair by +regeneration. +(A) Inflammation. +3.27A). +• Deposition of connective tissue. +Granulation tissue is progres- +sively replaced by deposition of collagen. +3.27B). +The macrophages that are involved +in repair are mostly of the alternatively activated (M2) type. +We next describe the steps in the formation of granulation +tissue and the scar. +Angiogenesis +Angiogenesis is the process of new blood vessel develop- +ment from existing vessels. +• Migration of endothelial cells toward the area of tissue injury. +• Proliferation of endothelial cells just behind the leading front +(“tip”) of migrating cells. +• Remodeling into capillary tubes. +• Suppression of endothelial proliferation and migration and +deposition of the basement membrane. +Mechanisms of Angiogenesis. +Fibroblast growth factors +(FGFs), mainly FGF-2, stimulate the proliferation of endo- +thelial cells. +Collagen is stained blue by the trichrome stain; minimal mature collagen can be seen at this point. +It does this by +inhibiting lymphocyte proliferation and the activity of other +leukocytes. +Collagen +deposition is critical for the development of strength in a +healing wound site. +These cells contribute to the contrac- +tion of the scar over time. +After +its deposition, the connective tissue in the scar continues +to be modified and remodeled. +In tissue repair, angiogenesis occurs mainly by +sprouting of new vessels. +The steps in the process and the major signals +involved are illustrated. +The newly formed vessel joins up with other +vessels (not shown) to form the new vascular bed. +role in angiogenesis and the structural maturation of new +vessels. +Complete restoration can occur only in tissues +composed of stable and labile cells. +• The location of the injury is also important. +This is +called organization. +The activity of +the MMPs is tightly controlled. +• Multiple growth factors stimulate the proliferation of the cell +types involved in repair. +3.29). +• Within 24 hours, neutrophils are seen at the incision +margin, migrating toward the fibrin clot. +In some instances, however, +these effects of glucocorticoids are desirable. +In the latter, note the large amount of granulation tissue and +wound contraction. +the edge of the incision begin to show increased mitotic +activity. +• By day 5, neovascularization reaches its peak as granula- +tion tissue fills the incisional space. +Thus, new granulation tissue +is often edematous. +• During the second week, there is continued collagen +accumulation and fibroblast proliferation. +The leukocyte +infiltrate, edema, and increased vascularity are substan- +tially diminished. +The following are some common +examples. +• Venous leg ulcers (Fig. +These ulcers +fail to heal because of poor delivery of oxygen to the site +of the ulcer. +• Arterial ulcers (Fig. +The ischemia results in atrophy and then +necrosis of the skin and underlying tissues. +These lesions +can be quite painful. +• Diabetic ulcers (Fig. +3.30C) affect the lower extremities, +particularly the feet. +Histologically, these lesions are +characterized by epithelial ulceration (Fig. +3.30E) and +extensive granulation tissue in the underlying dermis +(Fig. +3.30F). +• Pressure sores (Fig. +The lesions are caused by mechanical pressure +and local ischemia. +When a surgical incision reopens internally or externally +it is called wound dehiscence. +In abdominal wounds it can be precipitated +by vomiting and coughing. +3.31A). +3.31B, +C). +Con- +sequently, large defects have a greater potential for +secondary, inflammation-mediated injury. +A greater volume of granulation tissue generally results +in a greater mass of scar tissue. +Ultimately the original granulation +tissue scaffold is converted into a pale, avascular scar. +The dermal appendages that have been destroyed in the +line of the incision are permanently lost. +Hence it is an important feature +in healing by secondary union. +As already +mentioned, the terms scar and fibrosis are used interchange- +ably. +Fibrosis +may be responsible for substantial organ dysfunction and +even organ failure. +These conditions are +discussed in the appropriate chapters throughout the book. +(A–D) External appearance of skin ulcers. +(E, F) Histologic appearance of a diabetic ulcer. +(E) Ulcer crater; (F) chronic +inflammation and granulation tissue. +Contraction in the size of a wound is an important part +of the normal healing process. +Contractures are commonly +seen after serious burns and can compromise the movement +of joints. +• Excessive production of ECM can cause keloids in the skin. +[A discussion +of the role of neutrophil extracellular traps in tissue injury and +resolution]. +[A discussion of the diverse functions of +integrins]. +[An excellent review of +neutrophil biology]. +[An overview +of the roles of selectins in leukocyte recruitment]. +Muller WA: Mechanisms of leukocyte transendothelial migration, Annu +Rev Pathol 6:323, 2011. +[A thoughtful review of the mechanisms by which +leukocytes traverse the endothelium]. +[A review +of the mechanisms of leukocyte recruitment and leukocyte adhesion +deficiencies]. +[A review of the mechanisms of neutrophil extracellular trap formation]. +Dennis EA, Norris PC: Eicosanoid storm in infection and inflammation, +Nat Rev Immunol 15:511, 2015. +[A review of the proinflammatory and +antiinflammatory activities of eicosanoids]. +[An overview of the functions of chemokines in host +defense and inflammation]. +(A) Hypertrophic scar. +(B) Keloid. +(C) Microscopic appearance +of a keloid. +Note the thick connective tissue deposition in the dermis. +[A comprehensive +review of diseases caused by mutations in inflammasome-related +pathways]. +Zlotnik A, Yoshie O: The chemokine superfamily revisited, Immunity +36:705–716, 2012. +Nathan C, Ding A: Nonresolving inflammation, Cell 140:871–882, 2010. +[A discussion of the abnormalities that lead to chronic inflammation]. +[A modern review of host responses that contribute to tissue repair]. +[A modern discussion of the biochemical +mechanisms of liver regeneration]. +Novak ML, Koh TJ: Macrophage phenotypes during tissue repair, J +Leukoc Biol 93:875–881, 2013. +Depending on its severity and location, +edema may have minimal or profound effects. +The structural integrity of blood vessels is frequently +compromised by trauma. +4.1). +If the net rate of fluid movement exceeds +the rate of lymphatic drainage, fluid accumulates. +Edema fluids and effusions may be inflammatory or non- +inflammatory (Table 4.1). +Inflammation-related edema and +effusions are discussed in detail in Chapter 3. +In contrast, +noninflammatory edema and effusions are protein-poor fluids +called transudates. +4.2). +We will +now discuss the various causes of edema. +Either condition can injure the medullary +of lymphatic channels and lymph nodes. +This may result centers and cause death (Chapter 28). +Edema is most commonly seen in subcutaneous +tissues, the lungs, and the brain. +Subcutaneous edema can be +diffuse or more conspicuous in regions with high hydrostatic +pressures. +Affected tissues turn red (erythema) +because of increased delivery of oxygenated blood. +Conges- +tion is a passive process resulting from reduced venous +outflow of blood from a tissue. +It can be systemic, as in +cardiac failure, or localized, as in isolated venous obstruction. +As a result of increased hydrostatic pressures, +congestion commonly leads to edema. +within intact blood vessels or within the chambers of the +heart. +The general sequence of events leading to +hemostasis at a site of vascular injury is shown in Fig. +4.4. +4.4A). +• Primary hemostasis: the formation of the platelet plug. +4.4B). +• Secondary hemostasis: deposition of fibrin. +Vascular injury +exposes tissue factor at the site of injury. +In acute hepatic congestion, the +central vein and sinusoids are distended. +4.3A). +4.3B). +(B) Centrilobular +necrosis with degenerating hepatocytes and hemorrhage. +(Courtesy Dr. +(A) After vascular injury, neurohumoral +factors induce transient vasoconstriction. +A. +4.4C). +• Clot stabilization and resorption. +4.4D) and eventually lead to clot resorption and +tissue repair. +4.10). +4.4. +α-Granules have the +adhesion molecule P-selectin on their membranes (Chapter 3) +B. +4.4B). +4.5). +Platelets also adhere to exposed collagen via the platelet +collagen receptor Gp1a/IIa. +ADP acts by binding two G-protein–coupled +receptors. +P2Y1 and P2Y12. +All of these antiplatelet drugs are used in the +treatment of coronary artery disease. +• Platelet aggregation follows their activation. +Platelet contraction is +dependent on the cytoskeleton and consolidates the +aggregated platelets. +Aggregation is accomplished by +fibrinogen bridging GpIIb-IIIa receptors on different platelets. +ADP, Adenosine diphosphate. +Factors marked with an asterisk (*) are +vitamin K dependent as are protein C and S (not depicted). +blood vessels in vivo (Fig. +4.6). +However, clotting in vitro +and in vivo both follow the same general principles, as follows. +4.7). +4.6B). +Calcium ions hold the assembled components together and are essential for the reaction. +4.6A). +4.6B). +• Platelet activation. +4.6B). +Thrombin also +directly activates leukocytes. +ECM, Extracellular matrix; PDGF, platelet- +derived growth factor. +See Fig. +4.10 for additional anticoagulant activities +mediated by thrombin. +PARs also are expressed on +inflammatory cells, endothelium, and other cell types +(Fig. +• Anticoagulant effects. +4.9). +4.10). +• Platelet inhibitory effects. +NO is the product of endothelial nitric oxide +synthase eNOS. +• Anticoagulant effects. +Activated protein C/protein S +complex is a potent inhibitor of coagulation cofactors Va +and VIIIa. +• Fibrinolytic effects. +The presentation of abnormal +bleeding varies widely. +(B) Fatal intracerebral bleed. +following are general principles related to abnormal bleeding +and its consequences. +These bleeds typically take the +form of petechiae, minute 1- to 2-mm hemorrhages (Fig. +4.11A), or purpura, which are slightly larger (≥3 mm) than +petechiae. +• Generalized defects involving small vessels often present with +“palpable purpura” and ecchymoses. +Ecchymoses (some- +times simply called bruises) are hemorrhages of 1 to 2 cm +in size. +4.12). +Endothelial integrity is the +most important factor. +Injury to endothelial cells can alter local blood flow +and affect coagulability. +Abnormal blood flow (stasis or turbulence), in turn, +can cause endothelial injury. +Obviously, severe endothelial injury may trigger +thrombosis by exposing vWF and tissue factor. +Here it suffices to mention several of the major +prothrombotic alterations: +• Procoagulant changes. +• Antifibrinolytic effects. +These are listed below: +• Factor V Leiden. +This mutation renders factor +V resistant to cleavage and inactivation by protein C. +As +a result, an important antithrombotic counterregulatory +pathway is lost (see Fig. +4.10). +The inheritance pattern +for factor V Leiden is autosomal dominant. +• Prothrombin gene mutation. +• Other inherited causes. +• Homocysteinemia. +Elevated levels of homocysteine may +be inherited or acquired. +Acquired causes include +deficiency of vitamin B6, B12, and folic acid. +In +some cases (e.g., cardiac failure or trauma), stasis or vascular +injury may be most important. +In disseminated cancers, release of various procoagulants +from tumors predisposes to thrombosis. +The hypercoagulabil- +ity seen with advancing age may be due to reduced +endothelial PGI2 production. +Smoking and obesity promote +hypercoagulability by unknown mechanisms. +PF4-IgG immune complex (Fig. +It occurs in approximately 50% of cases and +affects both veins and arteries. +Diagnosis requires the demonstration of +anti–PF4-heparin antibodies. +APS may be primary or secondary. +Our focus here is on the primary form. +Diagnosis of APS is based +on clinical features and demonstration of aPL antibodies +in the serum. +Therapy of APS involves various forms of +anticoagulation. +Thrombi occurring in heart chambers or in the aortic lumen +are designated mural thrombi. +4.14B). +vegetations, and thrombocytopenia. +The pathogenesis of antiphospholipid syndrome is +complex and not fully understood. +Proteins that are recognized +by these antibodies include cardiolipin and β2-glycoprotein I. +(A) Thrombus in the left and right ventricular apices (arrows), overlying a white fibrous scar. +(B) Laminated thrombus in a +dilated abdominal aortic aneurysm (asterisks). +• Organization and recanalization. +4.15). +Postmortem clots can sometimes be mistaken for ante- +mortem venous thrombi. +Thrombi on heart valves are called vegetations, which may +be infected or sterile. +Thrombi accumulate additional platelets and +fibrin (discussed earlier). +• Embolization. +Thrombi dislodge and travel to other sites +in the vasculature (discussed later). +• Dissolution. +If unchecked, this may result in a mycotic aneurysm +(Chapter 11). +The clinical presenta- +tion depends on the involved site. +Venous Thrombosis (Phlebothrombosis). +Most venous +thrombi occur in the superficial or deep veins of the leg. +Superficial venous thrombi typically occur in the saphenous +veins in the setting of varicosities. +Such thrombi can cause +local congestion, swelling, pain, and tenderness, but rarely +embolize. +Regardless of the +specific clinical setting, advanced age also increases the risk +of DVT. +Arterial and Cardiac Thrombosis. +4.14B). +Both cardiac and +aortic mural thrombi are prone to embolization. +• Thrombosis causes tissue injury by local vascular occlusion or +by distal embolization. +DIC is discussed in greater detail along with other +bleeding diatheses in Chapter 14. +The vast majority of emboli are +dislodged thrombi, hence the term thromboembolism. +It is +somewhat more common in males than in females. +PE causes +about 100,000 deaths per year in the United States. +An +estimated 20% of individuals with PE die before or shortly +after a diagnosis is made. +In more than 95% of cases, PE +originates from leg DVT. +Hence the risk factors for PE are +the same as for DVT (see Table 4.2). +4.16). +• Most pulmonary emboli (60% to 80%) are clinically silent +because they are small. +• Multiple emboli over time may cause pulmonary hypertension +and right ventricular failure. +It +is fairly common, occurring in some 90% of individuals +with severe skeletal injuries (Fig. +4.17). +Fat embolism +syndrome is the term applied to the minority of patients +who become symptomatic. +Scuba and deep sea +divers, and underwater construction workers are all at risk. +Amniotic fluid embolism is an ominous complication +of labor and the immediate postpartum period. +4.18). +Figure 4.17 Bone marrow embolus in the pulmonary circulation. +The relatively uniform red +area on the right of the embolus is an early organizing thrombus. +Introduction of 300 to 500 mL of air at 100 mL/sec +may be fatal. +Entry of air in the pulmonary vasculature +does not merely block perfusion of downstream region. +Bubbles in the central nervous +system can cause mental impairment and even sudden onset +of coma. +• Red infarcts (Fig. +• White infarcts (see Fig. +4.19B). +In comparison, +in the lung hemorrhagic infarcts are the rule (see Fig. +4.19A). +(Courtesy +Dr. +Tissue infarction is a common and extremely important +cause of clinical illness. +Arterial thrombosis or arterial embolism underlies the +vast majority of infarctions. +(A) Hemorrhagic, roughly wedge- +shaped pulmonary red infarct. +• Tissue vulnerability to hypoxia. +Neurons undergo irreversible +damage when deprived of their blood supply for only +3 to 4 minutes. +• Hypoxemia. +Figure 4.20 Remote kidney infarct replaced by a large fibrotic scar. +The dominant histologic characteristic of infarction is ischemic +coagulative necrosis (Chapter 2). +Eventually a reparative response begins in the preserved +margins (Chapter 3). +However, most infarcts +are ultimately replaced by scar (Fig. +Factors That Influence Development of an Infarct. +• Rate of occlusion. +In both +of these forms of shock, acute vasodilation leads to +hypotension and tissue hypoperfusion. +Of these, 50% require treatment in +intensive care units. +Despite improvements in care, the mortality rate remains +around 50%. +4.21). +Markers of acute inflammation such +as C-reactive protein and procalcitonin are also elevated. +Additional details +are given in the text. +Current evidence suggests that both are triggered +simultaneously. +• Endothelial activation and injury. +Another +feature of sepsis is microvascular dysfunction. +These changes cause a mismatch in +oxygen needs and oxygen delivery. +• Induction of a procoagulant state. +Sepsis alters the expression of many factors so as to favor +coagulation. +4.10). +They also dampen fibrinolysis by increasing PAI-1 expres- +sion (see Fig. +4.10). +• Metabolic abnormalities. +Septic patients exhibit insulin +resistance and hyperglycemia. +• Organ dysfunction. +Mitochondrial damage resulting from oxidative stress +impairs oxygen use. +Thus, blood is shunted away from the skin to the +vital organs such as the heart and the brain. +With widespread tissue +hypoxia, vital organs are affected and begin to fail. +Myocardial +contractile function worsens, in part because of increased +NO synthesis. +• Shock of any form can lead to hypoxic tissue injury if not +corrected. +[An older but still useful +review of heart failure and fluid overload]. +[An updated discussion of fibrinolysis and +its role in the regulation of coagulation]. +[Advances in understanding the role +of tissue factor in coagulation]. +[An excellent +review of the multiple functions of protein C]. +Versteeg HH, Heemskerk JWM, Levi M et al: New fundamentals in +hemostasis, Physiol Rev 93:327, 2013. +[An update of several issues in +hemostasis]. +Clin Appl Thromb Hemost +23:922, 2017. +[A short review on the central role of tissue factor in +coagulation]. +[An exhaustive review of this common clinical +condition]. +[An excellent clinical +and molecular discussion of genetic thrombophilic states]. +Montagnana M, Lippi G, Danese: An overview of thrombophilia and +associated laboratory testing. +[A laboratory-oriented review of genetic and +acquired factors underlying thrombosis]. +Prince M, Wenham T: Heparin-induced thrombocytopenia, Postgrad +Med J 94:453, 2018. +[A concise and up-to-date review of this serious clinical +disorder]. +Nisio MD, van Es N, Buller H: Deep Vein thrombosis and pulmonary +embolism, Lancet 388, 2016. +[An excellent review of this important clinical +condition]. +Clinical Features +The clinical manifestations of shock depend on the precipitat- +ing insult. +However, the cardiac, cerebral, +and pulmonary changes rapidly aggravate the situation. +Prognosis varies with the origin of shock and its duration. +[An excellent discussion of the pathogenesis +and clinical features of APS]. +[An exhaustive review of an uncommon +but serious disorder]. +Fukumoto LE, Fukomoto KD: Fat embolism syndrome, Nurs Clin North +Am 335, 2018. +[An excellent discussion of the pathophysiology and clinical +features of this disorder]. +[A discussion of an uncommon syndrome with high +mortality]. +Septic Shock +Cecconi M, Evans L, Levy M et al: Sepsis and septic shock, Lancet +392:75, 2018. +[A lucid and comprehensive review of septic shock]. +Levi M, Poll TVD: Coagulation and sepsis, Thromb Res 149:38, 2017. +[A discussion of coagulopathy in sepsis]. +Moskovitz JB, Levy ZD, Todd LS: Cardiogenic shock, Emerg Med Clin +North Am 645, 2015. +[A discussion of the pathophysiology of cardiogenic +shock]. +[The emerging role of NETs in septic shock]. +Pool R, Gomez H, Kellum JA: Mechanism of organ dysfunction in +sepsis, Crit Care Clin 34:63, 2018. +[An in-depth discussion of the multiple +mechanisms that contribute to organ dysfunction in sepsis]. +Russell JA, Rush B, Boyd J: Pathophysiology of septic shock, Crit Care +Clin 34:43, 2017. +How many +more mutations remain hidden? +• Disorders related to mutations in single genes with large effects. +Here we build on that knowledge to discuss +the genetic basis of human diseases. +Genetic disorders are far more common than is widely +appreciated. +The lifetime frequency of genetic diseases is +estimated to be 670 per 1000. +A few important exceptions to this rule +are noted later. +• Chromosomal disorders. +These arise from structural or +numerical alteration in the autosomes and sex chromo- +somes. +Like monogenic disease, they are uncommon but +associated with high penetrance. +• Complex multigenic disorders. +These are far more common +than diseases in the previous two categories. +They are +caused by interactions between multiple variant forms +of genes and environmental factors. +Such variations in +genes are common within the population and are also +called polymorphisms. +Even normal +traits such as height and weight are governed by poly- +morphisms in several genes. +meaning of the sequence of the encoded protein, they +are often termed missense mutations. +5.1). +• Mutations within noncoding sequences. +Deleterious effects +may also result from mutations that do not involve the +exons. +Such is the case in certain forms of +hereditary anemias called thalassemias (Chapter 14). +Therefore translation cannot take place, and the gene +product is not synthesized. +• Deletions and insertions. +General principles relating to the effects of gene mutations +follow. +• Point mutations within coding sequences. +A point mutation +is a change in which a single base is substituted with a +different base. +Partial mRNA sequence of the β-globin chain of hemoglobin showing +codons for amino acids 38 to 40. +. +. +T ATC +Val +. +. +. +CTC GTG GTG ACC CCT T . +. +. +Val Thr Pro . +. +. +. +. +. +Leu +ABO A allele +Normal DNA GTT—. +. +. +F508 +–– T—GGT +ATC +GTT +. +. +. +T —AT– +CF DNA . +. +. +— +lle———— +Gly— +Val +lle +— +. +. +. +CTC GTG GT– ACC CCT T . +. +. +Because the deletion is a multiple of three, this is not a frameshift +mutation. +. +. +Leu Val Val Pro Leu . +. +. +5.2). +5.3 and 5.4). +• Alterations in protein-coding genes other than mutations. +As with +mutations, structural changes may occur in the germline +or be acquired in somatic tissues. +• Alterations in noncoding RNAs. +• Trinucleotide-repeat mutations. +Trinucleotide-repeat muta- +tions belong to a special category of genetic anomaly. +These mutations are characterized by amplification of +a sequence of three nucleotides. +In normal +populations the number of repeats is small, averaging +29. +To summarize, mutations can interfere with gene expres- +sion at various levels. +Transcription may be suppressed by +gene deletions and point mutations involving promoter +sequences. +Abnormal mRNA processing may result from +mutations affecting introns or splice junctions or both. +. +. +. +. +.– Arg +CGT +Normal HEXA allele +. +. +. +GAC . +. +. +ATA +TCT +ATC +CTA +TGC +– Arg – +Ile – +Ser – +Leu – +Ile – +Cys +CCC +Pro +TGA +Stop +C . +. +. +. +. +CGT +. +Tay-Sachs allele +. +. +. +This mutation is the major cause of Tay-Sachs disease in +Ashkenazi Jews. +These are discussed later in this +chapter. +It is beyond the scope of this book to review normal +human genetics. +Some fundamentals of DNA structure and +regulation of gene expressions were described in Chapter +1. +It is important here to clarify several commonly used +terms—hereditary, familial, and congenital. +Only some comments of medical relevance +are made. +About +80% to 85% of these mutations are familial. +The remainder +represent new mutations acquired de novo by an affected +individual. +Sickle cell anemia is caused by substitution of +normal hemoglobin (HbA) by hemoglobin S (HbS). +Histocompatibility and blood group antigens +are good examples of codominant inheritance. +Sickle +cell anemia is an example of pleiotropism. +Single-gene disorders +with nonclassic patterns of inheritance are described later. +Their siblings +are neither affected nor at increased risk for disease +development. +Many +new mutations seem to occur in germ cells of relatively +older fathers. +• Clinical features can be modified by variations in penetrance and +expressivity. +Some individuals inherit the mutant gene but +are phenotypically normal. +This is referred to as incomplete +penetrance. +Penetrance is expressed in mathematical terms. +Thus 50% penetrance indicates that 50% of those who +carry the gene express the trait. +2. +Table 5.1 lists common autosomal dominant disorders. +Many are discussed more logically in other chapters. +They occur when both alleles at +a given gene locus are mutated. +• Complete penetrance is common. +• Onset is frequently early in life. +• Many of the mutated genes encode enzymes. +In hetero- +zygotes, equal amounts of normal and defective enzyme +are synthesized. +Many others are discussed elsewhere in the text. +An illustrative condition +is glucose-6-phosphate dehydrogenase (G6PD) deficiency. +Such red cells are at the same risk +for undergoing hemolysis as the red cells in hemizygous +males. +Most of the +X-linked conditions listed in Table 5.3 are covered +elsewhere in the text. +There are only a few X-linked dominant conditions. +They +are caused by dominant disease-associated alleles on the X +chromosome. +Vitamin D– +resistant rickets and Alport syndrome are examples of this +type of inheritance. +ensures that cells with half the usual complement of the +enzyme function normally. +Autosomal recessive disorders include almost all inborn +errors of metabolism. +The various consequences of enzyme +deficiencies are discussed later. +The more common of these +conditions are listed in Table 5.2. +Most are presented elsewhere; +a few prototypes are discussed later in this chapter. +X-Linked Disorders +All sex-linked disorders are X-linked, and almost all are +recessive. +X-linked recessive inheritance accounts for a small number +of well-defined clinical conditions. +Sons of heterozygous +women have, of course, one chance in two of receiving +the mutant gene. +Males and females are affected equally. +Female carriers usually +are protected because of random inactivation of one X +chromosome. +In either case, the consequence is a metabolic block. +Fig. +In this model the final product exerts feedback control +on enzyme 1. +M1, M2, +Products of a minor pathway. +of M1 and M2 also exists. +This special area of genetics, called pharma- +cogenetics, is of considerable clinical importance. +In some cases these genetic factors have a major impact +on drug sensitivity and adverse reactions. +Many are discussed +elsewhere in the text. +thus lead to an excess of M1 and M2. +If the end product +is a feedback inhibitor of the enzymes involved in the +early reactions (in Fig. +In some cases, transport is achieved by receptor-mediated +endocytosis. +Its prevalence is estimated to +be 1 in 5000. +Approximately 70% to 85% of cases are familial +and transmitted by autosomal dominant inheritance. +The +remainder are sporadic and arise from new mutations. +Each of these is discussed below. +• Fibrillin is the major component of microfibrils found in the +extracellular matrix (Chapter 1). +These fibrils provide a +scaffold on which tropoelastin is deposited to form elastic +fibers. +Most of these +are missense mutations that give rise to abnormal +fibrillin-1. +These can inhibit polymerization of fibrillin +fibers (dominant negative effect). +• TGF- β bioavailability. +It is +now established that fibrillin-1 controls the bioavailability +of TGF-β. +This schema is supported by two +sets of observations. +Similar +changes may affect the tricuspid and, rarely, the aortic valves. +This +genetic heterogeneity also poses formidable challenges in +the diagnosis of Marfan syndrome. +MORPHOLOGY +Skeletal abnormalities are the most striking feature of +Marfan syndrome. +Ocular changes take many forms. +Cardiovascular lesions are the most life-threatening features +of this disorder. +Unlike many other EDS subtypes, the skin +is not usually hyperextensible. +This is accom- +plished by N-terminal–specific and C-terminal–specific +peptidases. +Hence the mode of inheritance of EDSs encompasses +all three Mendelian patterns. +On the basis of clinical and +molecular characteristics, six variants of EDS have been +recognized. +These are listed in Table 5.5. +Although individu- +ally rare, the collective frequency of EDSs is 1 in 5000 births. +It is believed that most contortionists have one of the EDSs. +A predisposition to joint dislocation, however, is one of the +prices paid for this virtuosity. +The skin is extraordinarily +stretchable, extremely fragile, and easily bruised. +The basic defect in connective tissue +may lead to serious internal complications. +Affected patients have markedly reduced +levels of this enzyme. +To summarize, the common thread in EDSs is some +abnormality of collagen. +These disorders, however, are +extremely heterogeneous. +FH caused by LDL receptor mutations is one of the most +frequently occurring Mendelian disorders. +Myocardial +infarction may occur before age 20 years. +The chylomicron +remnants, rich in cholesterol, are then delivered to the liver. +The endogenous synthesis +of cholesterol and LDL begins in the liver (Fig. +5.6). +• The major tissues affected are the skeleton, eyes, and cardio- +vascular system. +Wound healing is poor. +Mutations in the LDL receptor gene (LDLR) +account for 80% to 85% of cases of FH. +The func- +tions of these genes in cholesterol metabolism are discussed +below. +ApoB-100, Apolipoprotein B-100 (ApoB); +HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A. +lipoprotein (VLDL) from the liver into the blood. +VLDL +particles are rich in triglycerides, but they contain lesser +amounts of cholesteryl esters. +In addition, they carry +apolipoproteins ApoB, ApoC, and ApoE on their surface. +ApoC +is lost, but ApoB and ApoE are retained. +After release from +the capillary endothelium, the IDL particles have one of two +fates. +In the liver cells, IDL is recycled to generate VLDL. +5.7). +Here the LDL +dissociates from the receptor, which is recycled to the surface. +The impact of mutations in these +genes is as follows: +• Mutations in LDLR gene. +5.6). +• Mutations in gene encoding ApoB. +This compromise in the binding of LDL particles +to its receptors increases serum LDL cholesterol. +• Activating mutation in the PCSK9 gene. +The molecular genetics of FH is extremely complex. +Each class is heterogeneous at the DNA level. +© 1990 by Annual Reviews.) +These can be classified into six groups (Fig. +5.8). +5.8). +Cholesterol also deposits along tendon +sheaths to produce xanthomas. +They contain a battery of hydrolytic enzymes, which +have two special properties. +First, they function in the acidic +milieu of the lysosomes. +the Golgi (Fig. +5.9). +The +cellular and molecular mechanisms of this linkage will be +discussed below. +The lysosomal enzymes catalyze the breakdown of a +variety of complex macromolecules. +5.10). +There are three general approaches to the treatment of +lysosomal storage diseases. +The most obvious is enzyme +replacement therapy, currently in use for several of these +diseases. +A more recent strategy is based on the +understanding of the molecular basis of enzyme deficiency. +Such molecular chaperone therapy is under active +investigation. +Such interconnectedness stems from +the multifunctionality of the lysosome. +Approximately 70 lysosomal storage diseases have been +identified. +Within each group are several entities, +each resulting from the deficiency of a specific enzyme. +• There is a tight linkage between autophagy, mitochondrial +functions, and lysosomes. +In particular, autophagy +is essential for turnover of mitochondria by a process +termed mitophagy. +This serves as a quality control system +whereby dysfunctional mitochondria are degraded. +Only a few of the more common conditions are +considered here. +The underlying enzyme defect, however, +is different for each. +Sufficient functional enzyme can then be rescued to ame- +liorate the effects of the inborn error. +Antenatal diagnosis +and carrier detection are possible by enzyme assays and +DNA-based analysis. +Patients usually survive into +adulthood. +As with Tay-Sachs disease, Niemann-Pick disease +types A and B are common in Ashkenazi Jews. +5.11A). +5.11B). +A B +Figure 5.11 Ganglion cells in Tay-Sachs disease. +(A) Under the light microscope, a large neuron has obvious lipid vacuolation. +Part of the nucleus is shown above. +(A, Courtesy Dr. +Individuals affected with types A and B as well as +carriers can be detected by DNA analysis. +NPC1 is membrane bound, whereas NPC2 is soluble. +Both +are involved in the transport of free cholesterol from the +lysosomes to the cytoplasm. +Niemann-Pick disease type C +is clinically heterogeneous. +It is the most common lysosomal storage +disorder. +Splenic and skeletal involvements dominate this +pattern of the disease. +It is found principally in Jews of +European stock. +Individuals with this disorder have +reduced but detectable levels of glucocerebrosidase +activity. +Longevity is shortened, but not markedly. +• Type II, or acute neuronopathic Gaucher disease, is the +infantile acute cerebral pattern. +This form has no predilec- +tion for Jews. +In these patients there is virtually no +detectable glucocerebrosidase activity in the tissues. +• A third pattern, type III, is intermediate between types +I and II. +5.12). +The neuronal involvement is diffuse, affecting all parts of the +nervous system. +Infants typically have a protuberant abdomen +because of hepatosplenomegaly. +Death +occurs usually within the first or second year of life. +Figure 5.12 Niemann-Pick disease in liver. +The hepatocytes and Kupffer +cells have a foamy, vacuolated appearance due to deposition of lipids. +(Courtesy Dr. +In type I disease, the spleen is enlarged, sometimes up +to 10 kg. +The lymphadenopathy is mild to moderate and is +body-wide. +Bone destruction occurs due to the secretion of cytokines by +activated macrophages. +Similar cells may be found +in both the alveolar septa and the air spaces in the lung. +5.13). +Periodic acid–Schiff staining is +usually intensely positive. +DNA testing is also available in select +populations. +Clinical Features +The course of Gaucher disease depends on the clinical +subtype. +Most commonly there is pancytopenia or thrombocytopenia +secondary to hypersplenism. +Pathologic fractures and bone +pain occur if there has been extensive expansion of the +marrow space. +Although the disease is progressive in adults, +it is compatible with long life. +In principle, heterozygotes can be identified by detec- +tion of mutations. +(A) Wright stain; (B) hematoxylin and eosin. +(Courtesy Dr. +However, such therapy is extremely expensive. +Substrate reduction therapy with +inhibitors of glucosylceramide synthetase is also being +evaluated. +They are abundant in +extracellular matrix, joint fluid, and connective tissue. +coronary arteries, and lesions in the brain are common +threads that run through all the MPSs. +Thus myocardial infarction and cardiac +decompensation are important causes of death. +Hurler syndrome, also +called MPS I-H, results from a deficiency of α-L-iduronidase. +It is one of the most severe forms of MPS. +Affected children +appear normal at birth but develop hepatosplenomegaly +by age 6 to 24 months. +Death occurs by age 6 to 10 years and +is often due to cardiovascular complications. +• Niemann-Pick disease types A and B are caused by a deficiency +of sphingomyelinase. +In type B, neuronal damage is not present. +Types II and III are +characterized by variable neuronal involvement. +Gaucher disease +has a strong association with Parkinson disease. +Hunter syndrome is associated with a milder clinical course. +5.14). +Glycogen is a storage form of glucose. +This +can be further degraded only by the debranching enzyme. +Asterisks mark the enzyme deficiencies associated with glycogen storage diseases. +Types V and VI result from deficiencies of muscle and liver +phosphorylases, respectively. +(Modified from Hers H, et al: Glycogen storage diseases. +On the +basis of pathophysiology glycogenoses can be divided into +three major subgroups (Table 5.7). +• Hepatic forms. +The liver is a key player in glycogen metabo- +lism. +5.15). +5.15). +• Myopathic forms. +5.16). +They are associated with glycogen storage in many +organs and death early in life. +5.16). +The liver is enlarged, and patients have hypoglycemia. +This subject is discussed +in Chapter 7. +Specific forms of familial tumors are described +in various chapters. +(B) Effects of an inherited deficiency of hepatic enzymes involved +in glycogen metabolism. +A B +Figure 5.16 Pompe disease (glycogen storage disease type II). +(A) Normal myocardium with abundant eosinophilic cytoplasm. +(Courtesy Dr. +This +is best illustrated in autoimmune diseases (Chapter 6). +For example, +type 2 diabetes has many of the features of a multifactorial +disorder. +It is well recognized that individuals often first +manifest this disease after weight gain. +Thus, obesity as +well as other environmental influences unmask the dia- +betic genetic trait. +Nutritional influences may cause even +monozygous twins to achieve different heights. +A culturally +deprived child cannot achieve his or her full intellectual +capacity. +Assigning a disease to this mode of inheritance must be +done with caution. +The study of chromosomes—karyotyping—is the basic tool +of the cytogeneticist. +The one most commonly used involves a Giemsa +stain and is hence called G banding. +A normal male karyotype +with G banding is illustrated in Fig. +5.17. +With standard G +banding, approximately 400 to 800 bands per haploid set +can be detected. +The resolution obtained by banding can be +markedly improved by obtaining the cells in prophase. +(Courtesy Dr. +For example, a male with +trisomy 21 is designated 47,XY, +21. +The regions are numbered (e.g., 1, 2, 3) +from the centromere outward. +5.17). +The normal chromosome complement is expressed as 46,XX +for females and 46,XY for males. +Any exact multiple of the +haploid number of chromosomes (23) is called euploid. +The usual causes for +aneuploidy are nondisjunction and anaphase lag. +The result is one +normal cell and one cell with monosomy. +Mosaicism affecting the sex chromosomes is relatively +common. +Autosomal mosaicism seems to be much less common +than that involving the sex chromosomes. +Deletion refers to loss of a portion of a chromosome (Fig. +5.18). +Most deletions are interstitial, but rarely terminal +deletions may occur. +One can specify in which regions and +at what bands the breaks have occurred. +The deleted end of the retained chromosome is +protected by acquiring telomeric sequences. +A ring chromosome is a special form of deletion. +5.18). +If significant +genetic material is lost, phenotypic abnormalities result. +This might be expressed as 46,XY,r(14). +5.18). +An +inversion involving only one arm of the chromosome is +known as paracentric. +If the breaks are on opposite sides of +the centromere, it is known as pericentric. +Inversions are +often fully compatible with normal development. +5.18). +An isochromosome +has morphologically identical genetic information in both +arms. +with monosomy for genes on the short arm of X and with +trisomy for genes on the long arm of X. +In a translocation, a segment of one chromosome is +transferred to another (see Fig. +5.18). +A balanced +translocation carrier, however, is at increased risk for produc- +ing abnormal gametes. +Typically the breaks occur close to the +centromeres of each chromosome. +Transfer of the segments +then leads to one very large chromosome and one extremely +small one. +Usually the small product is lost (see Fig. +Even in live-born infants the +frequency is approximately 0.5% to 1.0%. +Hence we focus attention on +those few that are most common. +In the United States the incidence in newborns is about 1 +in 700. +Approximately 95% of affected individuals have +trisomy 21, so their chromosome count is 47. +FISH with +chromosome 21–specific probes reveals the extra copy of +chromosome 21 in such cases (Fig. +5.19). +The parents +of such children have a normal karyotype and are normal +in all respects. +Maternal age has a strong influence on the incidence +of trisomy 21. +5.20)—are usually readily evident, even at birth. +Down syndrome is a leading cause of severe intellectual +disability. +• Approximately 40% of the patients have congenital heart disease. +Cardiac +problems are responsible for the majority of the deaths +in infancy and early childhood. +The latter, most commonly, +is acute megakaryoblastic leukemia. +Currently the median age at death is 47 years (up from 25 +years in 1983). +A +sampling of some of the observations follows. +• Gene dosage. +The majority of the protein coding genes +mapped to chromosome 21 are overexpressed. +Included +among these is the gene for amyloid-beta precursor +protein (APP). +• Mitochondrial dysfunction. +• Noncoding RNAs. +(Courtesy Dr. +Stuart Schwartz, Department of Pathology, University of +Chicago, Chicago, IL.) +older than age 45. +Symptoms in such cases are variable and milder, depending +on the proportion of abnormal cells. +Clearly, in cases of +translocation or mosaic Down syndrome, maternal age is +of no importance. +Much progress is being made in the molecular diagnosis +of Down syndrome prenatally. +Most laboratories require +confirmation of a positive screening test with conventional +karyotyping. +As noted in Fig. +5.20, +they share several karyotypic and clinical features with +trisomy 21. +As in Down syndrome, an association with increased +maternal age is also noted. +In contrast to trisomy 21, however, +the malformations are much more severe and wide ranging. +As a result, only rarely do infants survive beyond the first +year of life. +Most succumb within a few weeks to months. +In a very small number of cases +there is a deletion of 10p13-14. +Less frequently, these patients also have +immunodeficiency. +In addition, attention-deficit/ +hyperactivity disorder is seen in 30% to 35% of affected +children. +5.21). +The molecular basis of this syndrome is not fully under- +stood. +The deleted region is large (approximately 1.5 Mb) +and includes 30 to 40 genes. +Approximately 30 candidate genes have been mapped +to the deleted region. +The 22q11.2 probe is in red, and the control probe, +localized to 22q, is in green. +(Courtesy Dr. +Thus, it seems that both X chromosomes +are required for normal growth as well as oogenesis. +For this reason +they are called pseudoautosomal regions. +These genes also +escape X inactivation. +For quite some time this was considered to be +the only gene of significance on the Y chromosome. +All of these are +believed to be testis-specific and are involved in spermato- +genesis. +In keeping with this, all Y chromosome deletions +are associated with azoospermia. +By comparison, the X +chromosome has 840 coding genes. +The following features +are common to all sex chromosome disorders. +The incidence of this condition is +reported to be approximately 1 in 660 live male births. +These features +are discussed briefly in relation to sex chromosomal +disorders. +In 1961, Mary Lyon outlined the idea of X-inactivation, +now commonly known as the Lyon hypothesis. +The XIST allele is switched off in the +active X chromosome. +Gynecomastia may be present. +Patients with Klinefelter syndrome develop +several comorbid conditions. +In addition there is a +higher prevalence of atrial and ventricular septal defects. +There is also an increased incidence of osteoporosis and +fractures due to sex hormonal imbalance. +Klinefelter syndrome is an important genetic cause of +reduced spermatogenesis and male infertility. +In others, +apparently normal tubules are interspersed with atrophic +tubules. +Mean plasma estradiol levels are elevated by an as yet +unknown mechanism. +The ratio of estrogens and testosterone +determines the degree of feminization in individual cases. +Classic Klinefelter syndrome is associated with a 47,XXY +karyotype (90% of cases). +Maternal and paternal +nondisjunction at the first meiotic division is roughly equally +involved. +Advanced maternal +age (>40 years) is a risk factor. +Why +then, do the patients with this disorder have hypogonadism +and associated features? +• One pathogenic mechanism is related to uneven dosage +compensation during X inactivation. +It is now known that +about 35% of the X-linked genes escape inactivation. +A similar mechanism +may also dictate some somatic features. +This implies +that the supernumerary X chromosome can regulate gene +expression on autosomes. +• Approximately 57% are missing an entire X chromosome, +resulting in a 45,X karyotype. +The latter may +have an almost normal appearance and may present only +with primary amenorrhea. +A very small number of +patients are able to conceive. +These patients are at a higher risk for development of a +gonadal tumor (gonadoblastoma). +Congenital heart disease is +also common, affecting 25% to 50% of patients. +Approximately 5% of young women initially +diagnosed with coarctation of aorta have Turner syndrome. +The principal clinical features in adolescents and adults are +illustrated in Fig. +5.22. +At puberty there is failure to develop +normal secondary sex characteristics. +The genitalia remain +infantile, breast development is inadequate, and there is little +pubic hair. +Some have +full-fledged metabolic syndrome. +During normal fetal +development, ovaries contain as many as 7 million oocytes. +Among the genes involved in the Turner +phenotype is the SHOX gene at Xp22.33. +Thus +both normal males and normal females have two copies of +this gene. +Haploinsufficiency of SHOX in Turner syndrome +is believed to give rise to short stature. +It is also expressed in the first +and second pharyngeal arches. +Clearly several other genes located on the +short arm of X chromosome are involved. +Growth hormone +and estradiol are used to treat Turner syndrome with a +reasonable degree of success. +Genetic sex is +determined by the presence or absence of a Y chromosome. +Gonadal sex is based on the histologic +characteristics of the gonads. +Ductal sex depends on the +presence of derivatives of the müllerian or wolffian ducts. +Phenotypic, or genital, sex is based on the appearance of the +external genitalia. +The term true hermaphrodite implies the presence of +both ovarian and testicular tissue. +It is the +most common cause of male sterility. +This group of disorders can be classified +into four categories. +All the disorders discovered so far are associated +with neurodegenerative changes. +Some general principles +apply to these diseases. +• The proclivity to expand depends strongly on the sex of +the transmitting parent. +5.23). +Much more needs to be learned before therapeutic +strategies can be developed. +UTR, Untranslated region. +FXS has a frequency of 1 in 1550 for affected males and +1 in 8000 for affected females. +5.24). +Males with FXS have marked intellectual disability. +The latter two affect 50% to 75% of males with +FXS. +As with other X-linked diseases, FXS affects males pre- +dominantly. +5.25). +• Risk of phenotypic effects: Risk depends on the position of +the individual in the pedigree. +In +the normal population, the number of CGG repeats is small, +ranging from 6 to 55 (average, 29). +The presence and severity +of clinical symptoms is related to the amplification of the +CGG repeats. +Thus, normal transmitting males and carrier +females carry 55 to 200 CGG repeats. +Expansions of this +size are called premutations. +In contrast, patients with FXS +Figure 5.24 Fragile X seen as discontinuity of staining. +(Courtesy Dr. +Note that in the first generation all sons are normal and all females are carriers. +However, only 50% of +females who inherit the full mutation are affected and only mildly. +(Courtesy Dr. +How this process takes place is quite +peculiar. +Carrier males transmit the repeats to their progeny +with small changes in repeat number. +Why only 50% of the females with the full mutation are +clinically affected is not clear. +The resulting absence +of FMRP is believed to cause the phenotypic changes. +5.26). +FRMP is a translation regulator. +Thus a reduction +in FMRP in FXS results in increased translation of the +bound mRNAs at synapses. +The pathogenesis of fragile X–associated primary +ovarian insufficiency is less well understood. +Aggregates +containing FMR1 mRNA have been detected in granulosa +cells and ovarian stromal cells. +Perhaps these aggregates +cause premature death of ovarian follicles. +Most such mutations produce neurodegenerative +disorders. +• In the normal population, there are about 29 to 55 CGG +repeats in the FMR1 gene. +When full mutations are transmitted to progeny, FXS occurs. +Synaptic +plasticity is essential for learning and memory. +This condition +is called fragile X–associated primary ovarian failure. +Affected +women have menstrual irregularities and decreased fertility. +They develop menopause approximately 5 years earlier than +controls. +How do premutations cause disease? +Several mitochondrial genes exist, however, that +are inherited in quite a different manner. +A feature unique +to mtDNA is maternal inheritance. +Hence the mtDNA complement of the zygote is derived +entirely from the ovum. +5.27). +Several other features apply to mitochondrial inheritance. +The remaining 13 genes encode subunits of the respiratory +chain enzymes. +tissue before oxidative dysfunction gives rise to disease. +Therefore the expres- +sion of disorders resulting from mutations in mtDNA is +quite variable. +Leber hereditary optic neuropathy is a +prototype of this type of disorder. +It is a neurodegenerative +disease that manifests as progressive bilateral loss of central +vision. +Visual impairment is first noted between ages 15 +and 35, leading eventually to blindness. +These differences result from an epigenetic process +called imprinting. +In most cases, imprinting selectively +inactivates either the maternal or the paternal allele. +Other mecha- +nisms include histone H4 deacetylation and methylation +(Chapter 1). +The exact number of imprinted genes +is not known; estimates range from 200 to 600. +They are described next. +In most cases the breakpoints are the same, causing +a 5-Mb deletion. +It is striking that in all cases the deletion affects +the paternally derived chromosome 15. +The molecular basis of these two syndromes lies in the +process of genomic imprinting (Fig. +5.28). +Three mechanisms +are involved. +• Deletions. +When these are lost as a +result of a deletion, the person develops Prader-Willi +syndrome. +Only the maternally derived allele +of this gene is normally active. +gene on chromosome 15 gives rise to the Angelman +syndrome. +Deletions account for about 70% cases. +• Uniparental disomy. +Inheritance of +both chromosomes of a pair from one parent is called +uniparental disomy. +This is +the second most common mechanism, responsible for +20% to 25% cases. +• Defective imprinting. +In a small minority of patients (1% +to 4%), there is an imprinting defect. +The genetic basis of these two imprinting disorders is +now being unraveled. +Absence of UBE3A inhibits synapse formation +and synaptic plasticity. +The imprinting is tissue-specific +in that UBE3A is expressed from both alleles in most +tissues. +• In contrast to Angelman syndrome, no single gene has +been implicated in Prader-Willi syndrome. +These include the SNORP family of genes that +encode small nucleolar RNAs. +The importance of imprinting is not restricted to rare chro- +mosomal disorders. +For +such genes, only one functional copy exists in the individual. +These +patients have intellectual disability, ataxia, seizures, and inap- +propriate laughter. +comprehensive NGS-based approaches. +Proper +test design requires careful consideration of these factors. +This is not always the case, +however. +This clearly violates the laws +of Mendelian inheritance. +Studies indicate that gonadal +mosaicism may be responsible for such unusual pedigrees. +Prenatal testing should be offered for all fetuses at risk for +a cytogenetic abnormality. +It is most +commonly performed on peripheral blood DNA and is +targeted based on clinical suspicion. +The technical approaches are the same +as those used for germline Mendelian disorders. +Many options exist for subsequent +analysis, each with different strengths and weaknesses. +A +few of the more common options are described below: +• Sanger sequencing. +• Next-generation sequencing (NGS). +• Single-base primer extension. +The relative +amounts of normal/variant fluorescence are then detected +(Fig. +5.29). +• Restriction fragment length analysis. +As discussed +earlier, large expansions are not uncommon in FXS. +• Real-time PCR. +Such genomic-scale altera- +tions can be studied using a variety of hybridization-based +techniques. +• Amplicon length analysis. +Fig. +5.30 reveals how PCR analysis can be used +to detect this mutation. +It is used to detect numeric abnor- +malities of chromosomes (aneuploidy) (see Fig. +5.19), subtle +microdeletions (see Fig. +• Array-based comparative genomic hybridization. +• Single nucleotide polymorphism genotyping arrays. +5.31). +Genomic DNA is labeled and hybridized to +an array containing potentially millions of probe spots. +Copy number is determined by overall intensity, and genotype is determined by allelic ratio. +The +example shown is the p arm of chromosome 12 in a patient with pediatric leukemia. +Notably, unlike CGH arrays, SNP +arrays can identify loss of heterozygosity. +Microsatellites are usually less than +1 kb and are characterized by a repeat size of 2 to 6 bp. +Fig. +Special techniques are needed to detect DNA methylation. +Methylated +cytosines are protected from modification and remain +unchanged. +Nonetheless, +RNA analysis is critical in several areas of molecular diag- +nostics. +5.33). +• Spatial separation. +The specifics of this process are +platform-dependent. +• Local amplification. +Parallel sequencing. +Sequence reads +from NGS instruments are generally short, less than +500 bp. +However, it is worth describing the basic steps +necessary to process this type of data. +• Alignment. +• Variant calling. +• Variant annotation and interpretation. +Once completed by the clinical laboratory, +the annotated data are ready for reporting. +Most current clinical laboratory NGS +tests fall in this category. +In cancer testing, gene panels are widely used to perform +detailed tumor profiling. +• Whole-exome sequencing (WES). +WES is also used +in oncology to perform a very broad analysis, mostly in +the research setting. +• Whole-genome sequencing (WGS). +WGS is the most com- +prehensive type of DNA analysis that can be performed +on an individual. +Continuing technologic +advances may even extend the applications further. +[A nice review +of Marfan syndrome by a pioneer in the field]. +Salik I, Rawla P: Marfan syndrome. +[Updated 2019 Feb 28]. +In StatPearls +[internet], Treasure Island, FL, 2019, StatPearls Publishing. +Available +from: https://www.ncbi.nlm.nih.gov/books/NBK537339/?report= +classic. +[An up-to-date and well-written article on the clinical and molecular +features of Marfan syndrome]. +Tinkle B, Castori M, Berglund B et al: Hypermobile Ehlers-Danlos +syndrome (a.k.a. +[Clinically +oriented review of the most common form of Ehlers-Danlos syndrome]. +[A good accounting of low-density +lipoprotein metabolism in familial hypercholesterolemia]. +[The various less +well-known genetic causes of familial hypercholesterolemia are discussed]. +[A good and easy-to- +follow overview of familial hypercholesterolemia]. +Sabatine MS: PCSK9 inhibitors: clinical evidence and implementation, +Nat Rev Cardiol 16:155, 2019. +[A discussion of lysosomal storage disorders +and neurodegenerative diseases]. +[A review of ganglioside +metabolism and pathogenesis of Tay-Sachs disease]. +Ferreiraa CR, Gahlc WA: Lysosomal storage diseases, Transl Sci Rare +Dis 2(1):2017. +[An exhaustive description of all the lysosomal storage +disorders]. +[A detailed discussion of these disorders in +the pediatric population]. +[This article discusses details of Pompe +disease]. +[Current approaches for the treatment +of lysosomal storage disorders]. +Schuchman EH, Desnick RJ: Types A and B Niemann-Pick disease, +Mol Genet Metab 120(1–2):27, 2017. +[This article discusses details of types +A and B Niemann-Pick disease]. +[This article discusses details of Gaucher disease]. +[An excellent discussion of treatment of genetic +disorders based on molecular pathogenesis]. +[A discussion of the causes of +Down syndrome due to imbalance in gene expression]. +[Utility of prenatal noninvasive testing of trisomies]. +Zamponi Z, Helguera PR: The shape of mitochondrial dysfunction in +Down syndrome. +Dev Neurobiol Epub 2019. +[A discussion of emerging +evidence for the role of mitochondrial dysfunction in Down syndrome]. +[An exhaustive and updated review +of pathogenesis of Klinefelter syndrome]. +Skuse D, Printzlau F, Wolstencroft J: Sex chromosomal aneuploidies. +In Geschwind DH, Paulson HL, Klein C, editors: Handbook of clinical +neurology, 2018, p 147. +(3rd series) Neurogenetics, Part 1 355, [An +excellent overview of sex chromosomal disorders]. +[A discussion of +the loss of synaptic plasticity in the pathogenesis of fragile X syndrome]. +[A well- +balanced discussion of the genetic basis of fragile X syndrome and related +disorders]. +[A +succinct update on the molecular basis of fragile X syndrome and related +conditions]. +[An excellent up-to-date review]. +[A well-written review of Prader-Willi syndrome]. +But the immune +system is itself capable of causing tissue injury and disease. +This chapter is devoted to diseases caused by too little or +too much immunologic reactivity. +If microbes breach epithelial boundaries, other +defense mechanisms come into play. +They capture +protein antigens and display peptides for recognition by +T lymphocytes. +The mechanisms of immunity fall into two broad +categories (Fig. +6.1). +It develops more +slowly than innate immunity, but is even more powerful +in combating infections. +By convention, the term immune +response usually refers to adaptive immunity. +The receptors and components of innate +immunity have evolved to serve these purposes. +They are +thought to be sources of inflammatory cytokines during +early phases of immune reactions. +• Other cell types. +Several other cell types can sense and +react to microbes. +• Plasma proteins. +In addition to these cells, several soluble +proteins play important roles in innate immunity. +These microbial structures are +called pathogen-associated molecular patterns. +6.2). +Several +classes of these receptors have been identified. +Toll-like receptors. +A family of related proteins was +later shown to be essential for host defense against microbes. +Mammals have 10 TLRs, each recognizing a different set of +microbial molecules. +The TLRs are present in the plasma +membrane and endosomal vesicles (see Fig. +6.2). +RIG, +retinoic acid-inducible gene. +stimulate the production of the antiviral cytokines, type I +interferons. +NOD-like receptors and the inflammasome. +NOD-like receptors +(NLRs) are cytosolic receptors named after the founding +member NOD-2. +6.3). +As +discussed later, IL-1 is a mediator of inflammation that +recruits leukocytes and induces fever. +NK cells make up approximately 5% +to 10% of peripheral blood lymphocytes. +This phenomenon +is known as antibody-dependent cellular cytotoxicity +(ADCC). +6.4). +Thus, these receptors +enable NK cells to recognize damaged or infected cells. +The inhibitory +receptors prevent NK cells from killing normal cells. +Reactions of Innate Immunity +The innate immune system provides host defense by two +main reactions. +• Inflammation. +The recruited +leukocytes destroy microbes and ingest and eliminate +damaged cells. +The innate immune response also triggers +the repair of damaged tissues. +These processes are +described in Chapter 3. +• Antiviral defense. +ATP, Adenosine triphosphate; IL, interleukin; TLR, Toll-like +receptor. +which result from T and B lymphocyte reactions against self +antigens). +The autoinflammatory syndromes respond very +well to treatment with IL-1 antagonists. +The inflammasome +pathway may also play a role in many common disorders. +Other cellular receptors for microbial products. +These receptors stimulate +the production of antiviral cytokines. +The major classes of lymphocytes and their functions in +adaptive immunity are illustrated in Fig. +6.5. +The process of lymphocyte differentia- +tion into effector and memory cells is summarized later. +We start with a consideration of the diversity of T and B +lymphocytes. +This +fundamental concept is called clonal selection. +The result +is that NK cells are activated and the infected cells are killed. +NK cells recognize virus-infected cells, as described +above. +The +nature of some of these signals is described later. +Innate immunity, unlike adaptive immunity, does not +have memory or fine antigen specificity. +B and T lymphocytes are the cells of adaptive immunity. +NK cells are discussed earlier. +encoded in the genome. +T Lymphocytes +There are three major populations of T cells, which serve +distinct functions. +Each T cell recognizes +a specific cell-bound antigen by means of an antigen-specific +TCR. +6.6), each having a variable (antigen- +binding) region and a constant region. +6.6). +The CD3 and ζ proteins are invariant (i.e., +identical) in all T cells. +Together with the TCR, these proteins +form the TCR complex. +However, the functions of γδ T cells are not established. +The functions of NK-T cells are also not +well defined. +These include CD4, CD8, CD28, and integrins. +CD4 and CD8 are expressed on two mutually exclusive +subsets of αβ T cells. +Normally, approximately 60% of mature +T cells are CD4+, and about 30% are CD8+. +Most +CD8+ cells function as CTLs that destroy host cells harboring +microbes. +CD4 and CD8 serve as coreceptors in T-cell activa- +tion. +Integrins are +adhesion molecules that promote the attachment of T-cells +to APCs. +B lymphocytes develop from precursors in the bone marrow. +B cells recognize antigen via the B-cell +antigen receptor complex. +6.7). +CD4 and CD28 are also +involved in T-cell activation. +Immature DCs within the +epidermis are called Langerhans cells. +Thus, macrophages function as antigen-presenting +cells in T-cell activation. +• Macrophages also participate in the effector phase of humoral +immunity. +Macrophages efficiently phagocytose and +destroy microbes that are opsonized (coated) by IgG +or C3b. +Primary Lymphoid Organs. +These organs are described +in Chapter 13. +Secondary Lymphoid Organs. +CD21 is a receptor for a +complement component that also promotes B-cell activation. +(Courtesy Dr. +B cells also express several other molecules that are essential +for their responses. +CR2 is also used by Epstein-Barr virus (EBV) as a +receptor to enter and infect B cells. +Several features of DCs +account for their key role in antigen presentation. +6.8). +Blood entering the spleen flows through a network of +sinusoids lined by macrophages and DCs. +They respond to +antigens that enter through breaches in the epithelium. +6.8). +The T lymphocytes are +concentrated in the paracortex, adjacent to the follicles. +(A) The histology of a lymph +node, with an outer cortex containing follicles and an inner medulla. +(Courtesy Drs. +The genes +encoding HLA molecules are clustered on a small segment +of chromosome 6 (Fig. +6.9). +This, as we see subsequently, constitutes +a formidable barrier in organ transplantation. +• Class I MHC molecules are expressed on all nucleated cells +and platelets. +6.9). +The extracellular region of the α chain is divided +into three domains: α1, α2, and α3. +The α1 and α2 domains +form a cleft, or groove, where peptides bind. +Peptide-loaded MHC +A. +(A) The location of genes in the HLA complex. +The relative +locations, sizes, and distances between genes are not to scale. +(B) Schematic diagrams and crystal structures of class I and +class II HLA molecules. +(Crystal structures are courtesy Dr. +P. +6.9). +The combination of HLA alleles in each individual is +called the HLA haplotype. +MHC molecules play several key roles in regulating T +cell–mediated immune responses. +Cytokines contribute to different types of immune +responses. +These cytokines include TNF, IL-1, IL-12, +type I IFNs, IFN-γ, and chemokines (Chapter 3). +Some cytokines serve mainly to limit and terminate +immune responses; these include TGF-β and IL-10. +They are produced by marrow stromal cells, +T lymphocytes, macrophages, and other cells. +Examples +include GM-CSF and other CSFs, and IL-3. +The knowledge gained about cytokines has numerous +practical therapeutic applications. +Microbes and their protein +antigens are captured by DCs that are resident in epithelia +and tissues. +These cells carry their antigenic cargo to draining +lymph nodes (Fig. +6.10). +6.6). +6.10). +6.11). +Cells of the Th1 +subset secrete the cytokine IFN-γ, which is a potent +macrophage activator. +Naïve T cells recognize MHC-associated +peptide antigens displayed on dendritic cells. +CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm. +APC, +Antigen-presenting cell. +pathway of macrophage activation, which is associated with +tissue repair and fibrosis (Chapter 3). +By +destroying the infected cells, CTLs eliminate the reservoirs +of infection. +6.12). +Antibody +responses to most protein antigens require T cell help and are +said to be T-dependent. +These populations may be capable of converting from one +to another. +Some activated T cells produce multiple cytokines and do not fall into a distinct subset. +Polysaccharides and lipids stimulate secretion mainly of +IgM antibody. +Helper T cells also +stimulate the production of antibodies with high affinities for +the antigen. +This process, called affinity maturation, improves +the quality of the humoral immune response. +The humoral immune response combats microbes in many +ways (see Fig. +6.12). +Antibodies bind to microbes and prevent +them from infecting cells, thus neutralizing the microbes. +Some antibodies serve special roles at particular +anatomic sites. +Most circulating IgG antibodies have half-lives of about +3 weeks. +Generation of memory cells underlies the effectiveness +of vaccination. +B cells are +activated to become plasma cells, which secrete antibodies. +Innate immune reactions +often manifest as inflammation. +Innate immunity, unlike adaptive +immunity, does not have fine antigen specificity or memory. +Immune +responses against self, or autologous, antigens, cause +autoimmune diseases. +We will return to this concept when +we consider autoimmunity. +This is followed by diseases caused by a defective immune +system, called immunodeficiency diseases. +Hypersensitivity implies an excessive or +harmful reaction to an antigen. +There are several important +general features of hypersensitivity disorders. +(A) Kinetics of the immediate and late-phase reactions. +(Courtesy Dr. +Antibodies may also interfere with cellular +functions and cause disease without tissue injury. +These reactions +are often called allergy, and the antigens that elicit them are +allergens. +Immediate hypersensitivity may occur as a sys- +temic disorder or as a local reaction. +Sometimes, within minutes +the patient goes into a state of shock, which may be fatal. +Local reactions are diverse and vary depending on the portal +of entry of the allergen. +Many local type I hypersensitivity reactions have two +well-defined phases (Fig. +6.13). +These Th2-mediated disorders show a +characteristic sequence of events (Fig. +6.14), described next. +IL-13 +enhances IgE production and acts on epithelial cells to +stimulate mucus secretion. +Over time, +the Th2 cells become the dominant contributors to the local +cytokine response. +Mast cells are bone marrow–derived cells +that are widely distributed in the tissues. +The granules +also contain acidic proteoglycans that bind basic dyes such +as toluidine blue. +Similar to other granulocytes, basophils can be recruited +to inflammatory sites. +In the first step of activation, +the antigen binds to the IgE antibodies on the mast cell +surface. +• Leukotrienes. +Leukotrienes C4 and D4 are the most potent +vasoactive and spasmogenic agents known. +Leukotriene B4 is highly che- +motactic for neutrophils, eosinophils, and monocytes. +• Prostaglandin D2. +This is the most abundant mediator +produced in mast cells by the cyclooxygenase pathway. +It causes intense bronchospasm and increases mucus +secretion. +• Platelet-activating factor (PAF). +Its role in imme- +diate hypersensitivity reactions is not well established. +Cytokines. +Eosinophils are +often an abundant leukocyte population in these reactions +(see Fig. +6.13C). +The Th2 cytokine IL-5 is the most potent eosinophil- +activating cytokine known. +PAF, Platelet-activating factor. +de novo synthesis and release of additional mediators +including lipid products and cytokines (Fig. +6.15). +Granule contents. +The most important mast cell–derived +amine is histamine (Chapter 3). +• Enzymes. +• Proteoglycans. +These include heparin, a well-known +anticoagulant, and chondroitin sulfate. +The proteoglycans +serve to package and store the amines in the granules. +Lipid mediators. +The major lipid mediators are arachidonic +acid–derived products (Chapter 3). +A propensity to develop immediate +hypersensitivity reactions is called atopy. +A positive +family history of allergy is found in 50% of atopic individuals. +How the disease- +associated polymorphisms influence the development of +allergies is not known. +Environmental factors are also important in the develop- +ment of allergic diseases. +Thus, paradoxically, +improved hygiene in early childhood may increase allergies +later in life. +This hypothesis, however, is difficult to prove, +and the underlying mechanisms are not defined. +These reactions can lead +to a wide spectrum of injury and clinical manifestations +(Table 6.2). +Laryngeal edema results +in hoarseness and further compromises breathing. +The risk of anaphylaxis must be borne in +mind when certain therapeutic agents are administered. +6.16A). +This mechanism is probably effective in destroying only +cells and microbes with thin cell walls. +The antibody-dependent +mechanisms that cause tissue injury and disease are illus- +trated in Fig. +6.16 and described next. +These reactions are +the cause of several important diseases (Table 6.3). +A. +(A) Opsonization of cells by antibodies and complement components and ingestion by phagocytes. +(C) Antireceptor antibodies disturb +the normal function of receptors. +cytotoxicity (ADCC). +The +contribution of ADCC to common hypersensitivity diseases +is uncertain. +6.16B). +The leukocytes are activated by engagement of their C3b +and Fc receptors. +6.16C). +The converse (i.e., antibody-mediated stimulation +of cell function) is the basis of Graves disease. +Examples of immune complex disorders and the antigens +involved are listed in Table 6.4. +The pathogenesis of systemic immune complex disease +can be divided into three phases (Fig. +6.17). +1. +Formation of immune complexes. +2. +Deposition of immune complexes. +In the next phase, the +circulating antigen-antibody complexes are deposited +in vessels. +Inflammation and tissue injury. +Once immune complexes are +deposited in the tissues, they initiate an acute inflamma- +tory reaction. +In fact, serum C3 levels can, in some cases, be used to +monitor disease activity. +2.15). +6.31 and 6.32). +(macrophages), which express receptors for the Fc tails of lgG +and for complement proteins. +The result is depletion of the +opsonized cells. +The inflammatory +reaction causes tissue injury. +6.18). +The inflammatory reactions stimulated by CD4+ T cells +can be divided into sequential stages. +A form of +chronic serum sickness results from repeated or prolonged +exposure to an antigen. +Included in this category are membranous +glomerulonephritis and several vasculitides. +(B) In some diseases, CD8+ cytotoxic T lymphocytes directly kill tissue cells. +APC, Antigen-presenting cell. +Inflammation mediated by Th17 (and +Citrullinated self proteins? +Th1?) cytokines; role of antibodies +and immune complexes? +CTLs, Cytotoxic T lymphocytes. +6.19). +6.20). +The granuloma in the center shows +several multinucleate giant cells. +(Courtesy Dr. +Contact dermatitis is a common example of tissue injury +resulting from DTH reactions. +Chemicals +may also modify HLA molecules, making them appear +foreign to T cells. +These often manifest as skin rashes. +They also play a role in +reactions against viruses. +A B +Figure 6.19 Delayed type hypersensitivity reaction in the skin. +(Courtesy Dr. +In the target cell cytoplasm, perforin +facilitates the release of the granzymes from the complex. +Subsequent exposure to the antigen results +in the secretion of cytokines. +The classical T cell–mediated inflam- +matory reaction is DTH. +CD8+ T cells also secrete +IFN-γ. +b An autoimmune basis of these disorders is suspected, but the supporting +evidence is not strong. +The clinical manifestations of autoimmune disorders are +extremely varied. +A growing +number of diseases have been attributed to autoimmunity +(Table 6.6). +How, then, does one define pathologic autoimmunity? +6.21). +Each of these is considered briefly. +The mechanisms +of central tolerance eliminate these potentially dangerous +lymphocytes. +This process is called negative selection or clonal deletion. +Central tolerance, however, is imperfect. +The principal mechanisms of central and peripheral self-tolerance in T and B cells are +illustrated. +These mechanisms include the following: +• Anergy. +Several mechanisms of T-cell anergy +have been demonstrated in various experimental systems. +Anergy also affects mature B cells in peripheral tissues. +• Suppression by regulatory T cells. +6.21), but they may also be induced in +peripheral lymphoid tissues. +Regulatory T cells may +suppress immune responses by multiple mechanisms. +• Deletion by apoptosis. +T cells that recognize self antigens +may receive signals that promote their death by +apoptosis. +Depletion of T cells occurs not only in the +thymus, discussed earlier, but also in the periphery. +Unopposed Bim +triggers apoptosis by the mitochondrial pathway (Chapter +2). +A second mechanism involves the Fas-Fas ligand +system. +The engagement of Fas by FasL induces apoptosis by +the death receptor pathway (Chapter 2). +Self-reactive B cells may also +be deleted by FasL on T cells engaging Fas on the B cells. +This is the postulated mechanism +for post-traumatic orchitis and uveitis. +Understanding why tolerance fails in these diseases +is an important goal of immunologists. +6.22). +• Abnormal display of self antigens. +• Inflammation or an initial innate immune response. +Role of Susceptibility Genes +Most autoimmune diseases are complex multigenic dis- +orders. +has a genetic component. +Many autoimmune diseases are associated with different class +II HLA alleles. +Three recently described genetic associa- +tions are especially interesting. +The net +result is excessive lymphocyte activation. +The data are from +European-derived populations. +b Anti-CCP Ab = antibodies directed against cyclic citrullinated peptides. +Data are +from patients who test positive for these antibodies in the serum. +Courtesy Dr. +Michelle Fernando, Imperial College London. +the vast majority of individuals who inherit this allele never +develop ankylosing spondylitis. +Modified from Zenewicz LA, Abraham C, Flavell RA, Cho JH: Unraveling the genetics of autoimmunity. +These genes include +AIRE, CTLA4, PD1, FAS, FASL, and IL2 and its receptor +CD25. +Two mechanisms have been postulated to explain the link +between infections and autoimmunity (Fig. +6.23). +First, +infections may upregulate the expression of costimulators +on APCs. +Second, some microbes may +express antigens that share amino acid sequences with self +antigens. +This phenomenon is called molecular mimicry. +More subtle +molecular mimicry may be involved in classic autoimmune +diseases as well. +Microbes may induce other abnormalities that promote +autoimmune reactions. +Infections may protect against some autoimmune +diseases. +With this background, we can proceed to a discussion +of specific autoimmune diseases. +Table 6.6 lists both systemic +and organ-specific autoimmune disorders. +ANAs. +The pattern of nuclear fluorescence +suggests the type of antibody present in the patient’s serum. +Four basic patterns are recognized (Fig. +It was updated in 2012 +by the Systemic Lupus International Collaborating Clinics. +Some details have been omitted from the table. +% positive refers to the approximate % of patients who test positive for each antibody. +The table was compiled with the help of Dr. +(D) Nucleolar pattern is typical of antibodies against nucleolar proteins. +• Speckled pattern refers to the presence of uniform or +variable-sized speckles. +This pattern is reported most often +in patients with systemic sclerosis. +• Centromeric pattern. +Nevertheless, the staining pattern +is considered of diagnostic value, and the test remains +in use. +In addition to ANAs, lupus patients have a host of other +autoantibodies. +Antiphospholipid +antibodies are present in 30% to 40% of lupus patients. +• TLR engagement by nuclear DNA and RNA contained +in immune complexes may activate B lymphocytes. +These +TLRs function normally to sense microbial products, +including nucleic acids. +• Type I interferons play a role in lymphocyte activation +in SLE. +It may be that nucleic +acids engage TLRs on DCs and stimulate the production +of interferons. +In other words, self nucleic acids mimic +their microbial counterparts. +Therefore, these antibodies are sometimes referred to as +lupus anticoagulant. +Genetic Factors. +SLE is a genetically complex disease with +contributions from MHC and multiple non-MHC genes. +Many lines of evidence support a genetic predisposition. +• Family members of patients have an increased risk of +developing SLE. +Immunologic Factors. +Environmental Factors. +• Exposure to ultraviolet (UV) light exacerbates the disease +in many individuals. +A Model for the Pathogenesis of SLE. +6.25). +UV irradiation and other +environmental insults lead to the apoptosis of cells. +Inad- +equate clearance of the nuclei of these cells results in a large +burden of nuclear antigens. +The nucleic acid components engage TLRs and stimulate +B cells to produce more autoantibodies. +If cell nuclei are exposed, however, the ANAs can bind to +them. +Related to this phenomenon is the LE cell, which is readily +seen when blood is agitated in vitro. +The demonstration of LE cells in vitro was used in the +past as a test for SLE. +Sometimes, LE cells are found in pericardial or +pleural effusions in patients. +These are examples of antibody-mediated (type II) +hypersensitivity. +• Antiphospholipid antibody syndrome. +Some patients develop these autoantibodies and the +clinical syndrome without associated SLE. +They are said +to have the primary antiphospholipid antibody syndrome +(Chapter 4). +which further enhance the immune response and cause more +apoptosis. +Mechanisms of Tissue Injury. +Different autoantibodies +are the cause of most of the lesions of SLE. +• Most of the systemic lesions are caused by immune +complexes (type III hypersensitivity). +DNA–anti-DNA +complexes can be detected in the glomeruli and small +blood vessels in animal models. +T-cell infiltrates are +also frequently seen in the kidneys and may be involved in +tissue damage. +IFN, Interferon; +TLRs, Toll-like receptors. +MORPHOLOGY +The morphologic changes in SLE are extremely variable. +The +frequency of individual organ involvement is shown in Table 6.11. +Blood Vessels. +The arteritis is characterized by fibrinoid necrosis of the vessel +walls. +In chronic stages, vessels undergo fibrous thickening with +luminal narrowing. +Kidney. +Table compiled with the assistance of Dr. +Meenakshi Jolly, Rush Medical Center, +Chicago, Ill. +it can be subclassified as Class IV segmental (IV-S) or Class +IV global (IV-G). +Involved glomeruli show proliferation of +endothelial, mesangial, and epithelial cells (Fig. +6.26B), with the +latter producing cellular crescents that fill Bowman’s space +(Chapter 20). +6.26C). +Immune +complexes can be readily detected by electron microscopy +(Fig. +6.26D) and immunofluorescence (Fig. +6.26E). +Lesions +may progress to scarring of glomeruli. +Hypertension and mild to severe renal +insufficiency are also common. +Changes in the interstitium and tubules are frequently present +in lupus nephritis. +Rarely, tubulointerstitial lesions may be +the dominant abnormality. +Skin. +Urticaria, bullae, maculopapular lesions, and ulcerations also +occur. +Exposure to sunlight incites or accentuates the erythema. +6.27A). +Joints. +CNS. +No clear morphologic abnormalities account for the +neuropsychiatric symptoms of SLE. +Pericarditis and Other Serosal Cavity. +Inflammation of the +serosal lining membranes may be acute, subacute, or chronic. +During the acute phases, the mesothelial surfaces are sometimes +covered with fibrinous exudate. +Pleural and +pericardial effusions may be present. +Cardiovascular System. +Involvement may manifest as damage +to any layer of the heart. +Symptomatic or asymptomatic pericardial +involvement is present in up to 50% of patients. +Suffice it to say that class I is the least +common and class IV is the most common pattern. +• Focal lupus nephritis (class III) is defined by involvement of +fewer than 50% of glomeruli. +6.26A). +The clinical presentation +ranges from mild hematuria and proteinuria to acute renal +insufficiency. +Red blood cell casts in the urine are common +when the disease is active. +Some patients progress to diffuse +glomerulonephritis. +• Diffuse lupus nephritis (class IV) is the most common and severe +form of lupus nephritis. +Extracapillary proliferation is not prominent in this case. +(B) Diffuse proliferative glomerulonephritis. +Note the marked increase in cellularity +throughout the glomerulus (H&E stain). +(D) Electron micrograph of a renal glomerular capillary loop from a patient with lupus nephritis. +Subendothelial dense deposits (arrowheads) correspond to “wire loops” seen by light microscopy. +B (with arrow) refers to the basement membrane. +(E) +Deposition of IgG antibody in a granular pattern, detected by immunofluorescence. +(A–C, Courtesy Dr. +Helmut Rennke, Department of Pathology, +Brigham and Women’s Hospital, Boston, Mass. +D, Courtesy Dr. +E, Courtesy Dr. +Splenomegaly, capsular thickening, and follicular +hyperplasia are common features. +Lungs. +None +of these changes is specific for SLE. +Other Organs and Tissues. +LE, or hematoxylin, bodies in the +bone marrow or other organs are strongly indicative of SLE. +It may be acute or insidious in its onset. +(A, Courtesy Dr. +Jag Bhawan, Boston +University School of Medicine, Boston, Mass. +B, Courtesy Dr. +6.28). +Figure 6.28 Libman-Sacks endocarditis of the mitral valve in lupus +erythematosus. +The vegetations attached to the margin of the thickened +valve leaflet are indicated by arrows. +(Courtesy Dr. +The course of the disease is variable and unpredictable. +Rarely, death ensues within weeks to months. +Disease flares are usually +treated with corticosteroids or other immunosuppressive +drugs. +The +most common causes of death are renal failure and intercur- +rent infections. +Coronary artery disease is also becoming +an important cause of death. +As mentioned earlier, involvement of skin along with +multisystem disease is fairly common in SLE. +Secondly, most +patients have mild systemic symptoms consistent with SLE. +There is a strong association with antibodies to the SS-A +antigen and with the HLA-DR3 genotype. +Although multiple organs +are affected, renal and CNS involvement is distinctly uncom- +mon. +There are serologic and genetic differences from classic +SLE, as well. +Abundant evidence supports the autoimmune nature +of the disease. +(A) Enlargement of the salivary gland. +(A) Courtesy Dr. +(B) +Courtesy Dr. +Eventually +the lymphocytic infiltrate becomes extensive (Fig. +6.29B), and +lymphoid follicles with germinal centers may appear. +The ductal +lining epithelial cells may show hyperplasia, thus obstructing the +ducts. +In some cases, the lymphoid infiltrate may be +so intense as to give the appearance of a lymphoma. +Indeed, these +patients are at high risk for development of B-cell lymphomas. +ANAs are detected in 50% to 80% of patients by immuno- +fluorescence assay. +A host of other organ-specific and +non–organ-specific antibodies have also been identified. +These antibodies are +thus considered serologic markers of the disease. +The significance of such associations in disease +causation or manifestations is not clear. +The result is inflammation, tissue damage, and, eventually, +fibrosis. +The nature of the autoantigens recognized by these lym- +phocytes is also mysterious. +Clinical Features +Sjögren syndrome occurs most commonly in women between +50 and 60 years of age. +As might be expected, symptoms +result from inflammatory destruction of the exocrine glands. +These are more common in patients with high +titers of antibodies specific for SS-A. +In contrast to SLE, +glomerular lesions are extremely rare in Sjögren syndrome. +The combination of lacrimal and salivary gland inflam- +mation was once called Mikulicz disease. +As mentioned earlier, the involved glands show intense +inflammatory infiltrates. +About 5% of Sjögren +patients develop lymphoma, an incidence that is 40-fold +greater than normal. +Visceral involvement occurs late; hence, the clinical course +is relatively benign. +6.30). +• Autoimmunity. +EXTERNAL STIMULI? +GENETIC SUSCEPTIBILITY EXTERNAL STIMULI? +Other cytokines recruit leuko- +cytes and propagate the chronic inflammation. +• Vascular damage. +Intimal proliferation is evident in +the digital arteries of patients with systemic sclerosis. +Capillary dilation with leaking, as well as destruction, is +also common. +Nailfold capillary loops are distorted early +in the course of disease, and later they disappear. +Eventually, widespread narrowing +of the microvasculature leads to ischemic injury and +• scarring. +Fibrosis. +with degeneration of collagen fibers, which become eosinophilic. +6.31B). +6.31C). +Sometimes the +tips of the fingers undergo autoamputation. +Alimentary Tract. +The alimentary tract is affected in approxi- +mately 90% of patients. +Loss of villi and microvilli in +the small bowel sometimes produces a malabsorption syndrome. +Musculoskeletal System. +In a small subset of patients (approximately +10%), inflammatory myositis may develop. +Kidneys. +Lungs. +Heart. +Clinical impairment by myocardial involvement, however, +is less common. +MORPHOLOGY +Virtually all organs may be involved in systemic sclerosis. +Skin. +(A) Normal skin. +(B) Skin biopsy from a patient with systemic sclerosis. +Loss of blood supply has led to cutaneous ulcerations. +(C, Courtesy Dr. +6.31C). +The disease tends to be more severe in people of +African descent, especially women. +Virtually all patients have ANAs that react with a variety +of nuclear antigens. +Two ANAs strongly associated with +systemic sclerosis have been described. +In general, these patients live longer than those +with diffuse visceral involvement at the outset. +vessels and showing strong evidence of an immunologic +pathogenic mechanism. +Noninfectious vasculitis is encountered in +many clinical settings. +6.32). +Many medical conditions +long viewed as confined to single organs are part of the +IgG4-RD spectrum. +The disease most often affects middle-age and older men. +Since most clinical trans- +plants are allografts, the discussion is focused on these. +These diseases are described +in Chapter 27. +The disease is +characterized serologically by high titers of antibodies to +U1 ribonucleoprotein. +The disease may, over time, evolve into classic SLE or +systemic sclerosis. +(A) Bile duct showing sclerosing cholangitis. +(B) Sclerotic area of the bile duct with storiform +fibrosis. +(C) Submandibular gland with infiltrates of lymphocytes and plasma cells and whorls of fibrosis. +These are called the direct and indirect pathways of +recognition of alloantigens. +For this reason, immune +responses to allografts are stronger than responses to +pathogens. +The activation of these B cells typically requires +T cell help. +Each type of rejection is mediated +by a particular kind of immune response. +(A) Deposition of antibody on endothelium and activation of complement causes thrombosis. +6.33A). +to vascular damage. +MORPHOLOGY +Acute cellular (T cell–mediated) rejection may produce two +different patterns of injury. +6.34B). +As +might be expected, the inflammatory infiltrates contain activated +CD4+ and CD8+ T lymphocytes. +• The vascular pattern shows inflammation of vessels (type II) +(Fig. +6.34C) and sometimes necrosis of vessel walls (type III). +6.33B). +Neutrophils rapidly accumulate within arterioles, glomeruli, and +peritubular capillaries. +Affected kidneys are nonfunctional and have to be +removed. +6.35A). +The +resultant inflammation and endothelial damage cause +graft failure. +6.34A). +6.35C). +Small vessels also may show focal thrombosis. +(A) Destruction of graft cells by T cells. +Collapsed tubules are outlined by wavy basement membranes. +(C) Rejection vasculitis in +a kidney graft. +(Courtesy Drs. +6.36A). +Alloantibodies also +contribute to chronic rejection. +The rejection of these grafts is described +in the relevant chapters. +6.36B). +6.36D). +(A) Graft damage caused by antibody deposition in vessels. +(C) Immunoperoxidase stain shows C4d deposition in peritubular capillaries +and a glomerulus. +(Courtesy Dr. +Thus, tacrolimus inhibits T cell responses. +Plasmapheresis is used in cases of severe antibody-mediated +rejection. +Although immunosuppression prolongs graft survival, +it carries its own risks. +The price paid in the form of increased +susceptibility to opportunistic infections is not small. +One +of the most frequent infectious complications is reactivation +of polyoma virus. +(A) Graft arteriosclerosis caused by T-cell cytokines and antibody deposition. +(B) Graft arteriosclerosis in a cardiac +transplant. +An artery showing prominent arteriosclerosis is shown (bottom +right). +(B, Courtesy of Dr. +Richard Mitchell, Department of Pathology, Brigham and Women’s Hospital, Boston, Mass. +C and D, Courtesy of Dr. +Several features +distinguish HSC transplants from solid-organ transplants. +• Acute GVHD occurs within days to weeks after allogeneic +HSC transplantation. +6.37A). +• Chronic GVHD may follow the acute syndrome or may +occur insidiously. +6.37B). +The changes may resemble +systemic sclerosis (discussed earlier). +Chronic liver disease +manifested by cholestatic jaundice is also frequent. +Damage to the gastrointestinal tract may cause esophageal +strictures. +Not surprisingly, patients experience +recurrent and life-threatening infections. +The epidermis is thinned, signifying atrophy. +The underlying dermis shows +thickening of collagen bundles, indicative of sclerosis. +(B, Courtesy Dr. +The latter graft-versus-leukemia effect can be +quite dramatic. +Immunodeficiency is a frequent complication of HSC +transplantation. +Affected individuals +are profoundly immunosuppressed and are easy prey to +infections. +This usually results from activation of latent +infection. +Cytomegalovirus-induced pneumonitis can be a +fatal complication. +• Chronic rejection. +Dominated by arteriosclerosis, this type +is caused by T-cell activation and antibodies. +• Types and mechanisms of rejection of solid organ grafts: +• Hyperacute rejection. +• Acute cellular rejection. +T cells destroy graft parenchyma +(and vessels) by cytotoxicity and inflammatory reactions. +We conclude with +immune defects associated with some systemic diseases. +Some of the defects whose molecular basis is +defined are summarized next. +Defects in Leukocyte Function +• Inherited defects in leukocyte adhesion. +• Inherited defects in phagolysosome function. +• Inherited defects in microbicidal activity. +• Defects in TLR signaling. +Rare defects have been described +in various TLRs and their signaling molecules. +• Deficiency of C2 is the most common complement protein +deficiency. +Modified in part from Gallin JI: Disorders of phagocytic cells. +It is associated with +recurrent pyogenic infections. +There is also an increased +incidence of immune complex–mediated glomerulonephri- +tis. +These individuals also show increased +susceptibility to infections. +• A deficiency of C1 inhibitor (C1 INH) gives rise to +hereditary angioedema. +This autosomal dominant disorder is +more common than complement deficiency states. +These immunodeficiencies result from +abnormalities in lymphocyte maturation or activation. +The +mutations responsible for many of these diseases have now +been identified (Fig. +6.38). +Without HSC transplantation, +death occurs within the first year of life. +X-linked SCID. +Autosomal Recessive SCID. +The remaining forms of SCID +are autosomal recessive disorders. +Hence +there may be a greater reduction in the number of T lym- +phocytes than of B lymphocytes. +This +blocks the development of T and B cells. +Mutations of JAK3 therefore have the +same effects as mutations in the γc chain. +The histologic findings in SCID depend on the underlying +defect. +The affected genes are indicated in parentheses for some of the disorders. +lymphoid cells. +Current trials are using +new vectors with safety features built in. +It is one of the more common +forms of primary immunodeficiency. +These organisms are normally opsonized by antibodies and +cleared by phagocytosis. +• Germinal centers of lymph nodes, Peyer patches, the +appendix, and tonsils are underdeveloped. +• Plasma cells are absent throughout the body. +• T cell–mediated reactions are normal. +The treatment of X-linked agammaglobu- +linemia is replacement therapy with immunoglobulins. +In +the past, most patients succumbed to infection in infancy +or early childhood. +Prophylactic IVIG therapy allows most +individuals to reach adulthood. +In +addition, the appearance of the mouth, ears, and facies may +be abnormal. +Ig levels may be normal or +reduced, depending on the severity of the T-cell deficiency. +In the remaining patients, the disease is +inherited in an autosomal recessive pattern. +The numbers of B and T cells in the blood are +normal. +Both sporadic and inherited forms of the disease occur. +In familial forms, there is no single pattern of inheritance. +These B +cells, however, are not able to differentiate into plasma cells. +However, the known mutations explain less +than 10% of cases. +Patients typically present with recurrent sinopulmonary +pyogenic infections. +In addition, about 20% of patients have +recurrent herpesvirus infections. +Serious enterovirus infec- +tions causing meningoencephalitis may also occur. +lamblia. +In the United States, it occurs +in about 1 in 600 individuals of European descent. +It is far +less common in people of African descent and Asians. +Affected individuals have extremely low levels of both serum +and secretory IgA. +Most individuals with IgA deficiency are asymptomatic. +Symp- +tomatic patients commonly present with recurrent sinopul- +monary infections and diarrhea. +The basis of the increased frequency +of autoimmune and allergic diseases is not known. +IgM levels in the serum are low, +but levels of IgG are usually normal. +Paradoxically the +levels of IgA and IgE are often elevated. +Patients are also +prone to developing B-cell lymphomas. +The only +treatment is HSC transplantation. +The immunologic defects +are of variable severity and may affect both B and T cells. +The T-cell defects, which are usually less pronounced, +are associated with thymic hypoplasia. +The most serious secondary immunodeficiency +is AIDS, which is described next. +The magnitude +of this modern plague is truly staggering. +Although initially +recognized in the United States, AIDS is a global problem. +Only about 80% of HIV-infected people +living worldwide know their status. +There is some good news. +Furthermore, improved antiviral therapies have +resulted in fewer people dying of the disease. +The +literature on HIV and AIDS is vast. +This includes about 5% who are +intravenous drug users as well. +Heterosexual transmission has +declined modestly since 2011 in the United States. +• HIV infection of the newborn. +In this regard, syphilis, chancroid, +and herpes are particularly important. +Of these three, +intravenous drug users constitute by far the largest group. +Currently, this risk is estimated to be 1 in more +than 2 million units of blood transfused. +• As alluded to earlier, mother-to-infant transmission is the +major cause of pediatric AIDS. +The reported transmission rates vary +from 7% to 49% in different parts of the world. +Spread by insect +bites is virtually impossible. +6.39). +The HIV-1 RNA genome contains the gag, pol, and env +genes, which are typical of retroviruses (Fig. +6.40). +The functions +of other accessory proteins are indicated in Fig. +6.40. +The central nervous +system (CNS) is also affected. +Profound immune deficiency, primarily affecting cell- +mediated immunity, is the hallmark of AIDS. +The functions of selected genes are shown. +Active viral replication is associated with more +infection of cells and progression to AIDS. +This is followed by a more detailed review of the +interaction between HIV and its cellular targets. +6.41). +The molecules and mechanisms of each of these +steps are understood in considerable detail. +Infection of Cells by HIV. +6.41). +Binding to CD4 is not sufficient for +infection, however. +HIV gp120 must also bind to other cell +surface molecules (coreceptors) for entry into the cell. +Chemokine receptors, particularly CCR5 and CXCR4, serve +this role. +(Modified with permission from Wain-Hobson S: +HIV. +One on one meets two, Nature 384:117, 1996. +Only rare +homozygotes for the mutation have been found in African +or East Asian populations. +Viral Replication. +6.41). +In quiescent T cells, HIV cDNA +may remain in the cytoplasm in a linear episomal form. +After integration, the +provirus may be silent for months or years, a form of latent +infection. +These mutations inhibit further DNA replica- +tion by mechanisms that are not fully defined. +Imagine now a +latently infected CD4+ cell that encounters an environmental +antigen. +These, in turn, stimulate +more HIV production, loss of additional CD4+ T cells, and +more infection. +The molecular mechanism +of this type of cell death is not known. +This form of cell death may play a role in spread of the +infection. +• Fusion of infected and uninfected cells with formation +of syncytia (giant cells) can occur. +Fused cells usually die within a few hours. +This +property of syncytia formation is generally confined to +the T-tropic X4 type of HIV-1. +Low-level chronic or latent infection of T cells is an +important feature of HIV infection. +FDCs in the germinal centers of lymph nodes are potential +reservoirs of HIV. +Infected T follicular helper +cells in the germinal centers are also reservoirs of HIV. +Impaired humoral immunity renders these patients +lymph nodes are latently infected. +CD4+ T cells play a pivotal role in regulating both cel- +lular and humoral immune responses. +In certain tissues, +such as the lungs and brain, as many as 10% to 50% of +macrophages are infected. +This property of HIV-1 is dependent on the +viral vpr gene. +pneumoniae and H. +influenzae, both of +which require antibodies for effective opsonization and +clearance. +The clinical +syndrome of CNS abnormalities is called HIV-associated +neurocognitive disorder (HAND). +It is believed +that HIV is carried into the brain by infected T cells or +monocytes. +The mechanism of HIV-induced damage of the +brain remains obscure. +Included among the soluble +factors are the usual culprits, such as IL-1, TNF, and IL-6. +In addition, nitric oxide induced in neuronal cells by gp41 +has been implicated. +Direct damage of neurons by soluble +HIV gp120 has also been postulated. +Natural History of HIV Infection +The virus typically enters through mucosal epithelia. +6.42 and 6.43). +Few infected cells are detectable in the blood +and other tissues. +DCs in epithelia at sites of virus entry capture the virus +and then migrate into the lymph nodes. +Once in lymphoid +tissues, DCs may pass HIV on to CD4+ T cells through +direct cell-to-cell contact. +Within days after the first exposure +to HIV, viral replication can be detected in the lymph nodes. +This corresponds to the early +acute phase of HIV infection. +(B) Immune response to HIV +infection. +The humoral +immune response to HIV peaks at about 12 weeks. +This typically +occurs 3 to 6 weeks after infection, and resolves spontaneously +in 2 to 4 weeks. +6.42). +Therefore, this phase of HIV disease is called the +clinical latency period. +Not unexpectedly, HIV RNA levels increase as the host +begins to lose the battle with the virus. +Asymptomatic, acute (primary) HIV, or persistent generalized lymphadenopathy A1 A2 A3 +B. +Symptomatic, not A or C conditions B1 B2 B3 +C. +immune control is not entirely clear, but several mechanisms +have been proposed. +Autoimmune thrombocytopenia may also be noted +(Chapter 14). +Exceptions to this typical course are +rapid progressors and long-term nonprogressors. +A brief summary of selected opportunistic infec- +tions is provided here. +States. +In contrast to infection with atypical mycobacteria, M. +tuberculosis infection manifests early in the course of AIDS. +• A variety of opportunistic infections target the CNS. +Cryptococcosis occurs in about 10% of AIDS patients. +It causes progressive multifocal +leukoencephalopathy (Chapter 28). +• Other infections preferentially involve the gastrointestinal +tract and genitalia. +These patients have +chronic, profuse, watery diarrhea with massive fluid +loss. +avium-intracellulare. +Kaposi Sarcoma. +Coincident +with the AIDS epidemic, the incidence of tuberculosis has +risen dramatically. +In addition, KS +lesions display chronic inflammatory cell infiltrates. +Many +of the features of KS suggest that it is not a malignant tumor +(despite its ominous name). +Exactly how HHV8 infection leads to KS is still unclear. +These include a viral homologue of cyclin D and +several inhibitors of p53. +HIV-mediated immune +suppression may aid in widespread dissemination of HHV8 +in the host. +HHV8 infection is not restricted to endothelial cells. +Clinically, AIDS-associated KS is quite different from +the sporadic form (Chapter 11). +These tumors also tend to be more aggressive than +classic KS. +Lymphomas. +6.44). +By adulthood, most normal individuals are infected +with EBV. +These +patients are also chronically infected with pathogens that +may lead to B-cell stimulation. +HIV infection results in several changes that may cooperate to produce +B-cell lymphomas. +• Germinal center B-cell hyperplasia in the setting of early +HIV infection. +What then explains +the increased risk of lymphoma? +Several other EBV-related proliferations also merit +mention. +Other Tumors. +These drugs are given in combination to reduce the emergence +of drug-resistant mutants. +Many AIDS- +associated disorders, such as P. +jirovecii infection and KS, +are very uncommon now. +ART also has reduced the transmis- +sion of the virus, especially from infected mothers to newborns. +This occurs +despite increasing CD4+ T-cell counts and decreasing viral +load. +MORPHOLOGY +The anatomic changes in the tissues are neither specific nor +diagnostic. +Common pathologic features of AIDS include oppor- +tunistic infections, KS, and B-cell lymphomas. +Lesions in the CNS are described +in Chapter 28. +The lymph nodes are depleted of lymphocytes, and the organized +network of FDCs is disrupted. +For example, myco- +bacteria may not evoke granuloma formation because CD4+ cells +are deficient. +With progres- +sive accumulation, it encroaches on and produces pressure +atrophy of adjacent cells. +In fact, +more than 20 different proteins can aggregate to form +amyloid. +Physical Nature of Amyloid. +6.45). +Chemical Nature of Amyloid. +This form of amyloid is +discussed in Chapter 28. +The proteins that form +amyloid fall into two general categories (Fig. +(C) Electron micrograph of +7.5- to 10-nm amyloid fibrils. +be localized to a single organ, such as the heart. +Among these, the most frequently +associated condition is rheumatoid arthritis. +However, +increased production of SAA by itself is not sufficient for +the deposition of amyloid. +There are two possible explana- +tions for this. +Heredofamilial Amyloidosis +A variety of familial forms of amyloidosis have been +described. +Most of them are rare and occur in limited +geographic areas. +It is sometimes associated with +widespread amyloidosis. +These familial amyloidotic polyneuropa- +thies have been described in different parts of the world. +As mentioned earlier, in all of these genetic disorders, the +fibrils are made up of mutant TTR. +With new dialysis +filters, the incidence of this complication has decreased +substantially. +In medullary carcinoma +of the thyroid, the presence of amyloid is a helpful diagnostic +feature. +Amyloid of Aging +Several well-documented forms of amyloid deposition occur +with aging. +Those who are symptomatic +present with a restrictive cardiomyopathy and arrhythmias +(Chapter 12). +The amyloid in this form is derived from +normal TTR. +The localization of amyloid deposits in the +hereditary syndromes is varied. +6.47A). +As the amyloid accumulates, it encroaches on the cells, in time +surrounding and destroying them. +The pattern of organ involvement in different clinical forms +of amyloidosis is variable. +Kidney. +Nonetheless, a few generalizations can be made. +(B) Note the yellow-green birefringence of the deposits when observed by polarizing microscope. +(C) Amyloidosis of the kidney. +The glomerular +architecture is almost totally obliterated by the massive accumulation of amyloid. +(A, B, Courtesy Dr. +Renal failure is +a common cause of death. +Cardiac amyloidosis may present as +an insidious congestive heart failure. +Gastrointestinal amyloidosis may be entirely asymptomatic, +or it may present in a variety of ways. +The test is +quite specific, but its sensitivity is low. +The prognosis for individuals with generalized amyloi- +dosis is poor. +6.47C). +Spleen. +For completely mysterious reasons, one of two patterns of +deposition is seen. +Liver. +The deposits may be inapparent grossly or may cause +moderate to marked hepatomegaly. +6.47). +Vascular involvement is frequent. +Even with extensive involvement, +liver function is usually preserved. +Heart. +Amyloidosis of the heart (Chapter 12) may occur in +any form of systemic amyloidosis. +Other Organs. +It may be present in so-called +plaques as well as blood vessels (Chapter 28). +The +symptoms depend on the magnitude of the deposits and +on the sites or organs affected. +Lambrecht BN, Hammad H: The immunology of asthma, Nat Immunol +16:45–56, 2015. +[A summary +of the mechanisms of immune complex–mediated tissue injury]. +[A review of +complement deficiencies and the role of the complement system in autoimmune +diseases]. +[An excellent review of thymic +selection as a mechanism for self-tolerance]. +[A review discussing the +abnormalities in regulatory T cells that may contribute to autoimmunity]. +Mueller DL: Mechanisms maintaining peripheral tolerance, Nat Immunol +11:21–27, 2010. +[A discussion of the mechanisms of peripheral tolerance, +with an emphasis on T cells]. +Schwartz RH: Historical overview of immunological tolerance, Cold +Spring Harb Perspect Biol 4:2012. +a006908. +[An update on +the contribution of microbes to the development of autoimmunity]. +Cheng MH, Anderson MS: Monogenic autoimmunity, Annu Rev Immunol +30:393–427, 2012. +[An excellent review of how HLA +polymorphisms may contribute to autoimmune diseases]. +Goodnow CC: Multistep pathogenesis of autoimmune disease, Cell +130:25, 2007. +[An excellent discussion of the checkpoints that prevent +autoimmunity and why these might fail]. +[A review of genetic associations with auto- +immune diseases and how these may be analyzed]. +[An excellent review of +genetic causes of autoimmunity]. +[An excellent discus- +sion of the biochemistry of inflammasome activation]. +[An excellent review of the structure and biology of innate immune +receptors]. +Goubau D, Deddouche S, Reis E et al: Cytosolic sensing of viruses, +Immunity 38:855–869, 2013. +[An excellent review on the numerous +mechanisms used by cells to recognize viral DNA and RNA]. +Cold Spring Harb Persp Biol +7:a016246, 2014. +[An excellent review of the receptors used by the innate +immune system to sense microbes]. +[An overview of helper T cell subsets and the functions of their +cytokines]. +[An excellent discussion of the major control points in the process +of antibody production]. +[An excellent review of the roles of IgE antibody and +mast cells in chronic allergic diseases]. +[A review of genes associated with +autoimmunity]. +[A summary of immu- +nologic aberrations that may cause autoimmunity]. +Kaul A, Gordon C, Crow MK et al: Systemic lupus erythematosus, Nat +Rev Dis Primers 2:16039, 2016. +[An excellent review of the clinical features +and pathogenesis of lupus]. +[An +excellent review of the pathogenesis of systemic sclerosis, and the many +unanswered questions]. +[A review of the pathogenesis +and clinical features of Sjogren’s syndrome]. +[A discussion of current concepts +of the pathogenesis of systemic sclerosis]. +[A review of the mecha- +nisms that lead to vascular disease in chronic graft rejection]. +Nagy ZA: Alloreactivity: an old puzzle revisited, Scand J Immunol +75:463–470, 2012. +Nankivell BJ, Alexander SI: Rejection of the kidney allograft, N Engl J +Med 363:1451, 2010. +[A review of the role of antibodies in the +rejection of transplants]. +Wood KJ, Goto R: Mechanisms of rejection: current perspectives, +Transplantation 93:1–10, 2012. +Durandy A, Kracker S, Fischer A: Primary antibody deficiencies, Nat +Rev Immunol 13:519–533, 2013. +[A summary of primary immunodeficiencies +affecting B cells]. +[A review of the pathogenesis and clinical features of severe combined +immunodeficiency]. +[An excellent review of newly described primary +immunodeficiency syndromes]. +[A balanced +discussion of the pathogenesis of AIDS, and the unresolved issues]. +Cohen MS, Shaw GM, McMichael AJ et al: 1 infection, N Engl J Med +364:1943–1954, 2011. +[An excellent summary of the early phase of HIV +infection and host responses to the virus]. +[A discussion of the mecha- +nisms by which HIV causes immunodeficiency]. +[A +review of the pathogenesis and clinical features of the AL form of +amyloidosis]. +[An excellent review of the pathogenesis and clinical features of a major +form of amyloidosis]. +Dogan A: Amyloidosis: insights from proteomics, Annu Rev Pathol +Mech Dis 12:277–304, 2017. +The only hope +for controlling cancer lies in learning more about its causes +and pathogenesis. +If the polyp has glandular tissue, it is called an adeno- +matous polyp (Fig. +7.1). +Tumor originally described swelling caused by +inflammation, but is now equated with neoplasm. +Oncology +(Greek oncos = tumor) is the study of tumors or neoplasms. +In some +tumors, connective tissue is scant, and the neoplasm is soft +and fleshy. +Predictably, +the patient generally survives. +Exceptions arise, however, +A B +Figure 7.1 Colonic polyp. +Nevertheless, the designation “malignant” always raises a +red flag. +Malignant neoplasms of epithelial cell origin +are called carcinomas. +Carcinomas may be further qualified. +7.2). +Figure 7.2 Mixed tumor of the parotid gland. +7.3). +The nomenclature of the more common types of tumors +is presented in Table 7.1. +Included in this list are some +inappropriate but deeply entrenched names. +Alternatively, ominous-sounding terms are +applied to some trivial lesions. +Hamartomas are disorganized +masses composed of cells indigenous to the involved tissue. +Note the presence of hair, sebaceous material, and a tooth. +Choristoma is the term applied to a heterotopic +(misplaced) rest of cells. +In general, benign +tumors are well differentiated (Figs. +7.4 and 7.5). +Note the normal- +looking (well-differentiated), colloid-filled thyroid follicles. +(Courtesy Dr. +One may get so close to the tree +that one loses sight of the forest. +In well-differentiated benign +tumors, mitoses are usually rare and are of normal +configuration. +In well-differentiated tumors, these features +may be quite subtle. +7.6). +7.7), a morphologic appearance that is +highly predictive of malignant behavior. +7.8). +Pleomorphism refers to variation in cell +size and shape. +7.9). +• Abnormal nuclear morphology. +This tumor is considered +moderately well differentiated because gland formation is seen. +The +malignant glands have invaded the muscular layer of the colon. +(Courtesy +Dr. +• +Metaplasia is defined as the replacement of one type of cell +with another type (Chapter 2). +Metaplasia is nearly always +found in association with tissue damage, repair, and +regeneration. +Often the replacing cell type is better suited +to some alteration in the local environment. +Unfortunately, the +metaplastic epithelium is prone to malignant transforma- +tion. +• Carcinoma in situ. +7.10). +Carcinoma in situ is often +seen in the skin, breast, bladder, and uterine cervix. +With +removal of inciting causes, even moderately severe dysplasias +may be completely reversible. +Even carcinoma in situ may +persist for years before it becomes invasive. +Note the marked cellular and nuclear pleomorphism, +hyperchromatic nuclei, and tumor giant cells. +(Courtesy Dr. +Abnormally large nucleoli are also commonly +seen. +• Mitoses. +The presence of mitoses, however, does +not equate with malignancy. +7.8). +• Loss of polarity. +Sheets or large masses of +tumor cells grow in a disorganized fashion. +• Other changes. +Low-power view shows that the epithelium is entirely replaced by atypical dysplastic cells. +There is no orderly +differentiation of squamous cells. +The basement membrane is intact, and there is no tumor in the subepithelial stroma. +accumulation of all the mutations that are needed to induce +a fully malignant phenotype. +7.11). +There are a few +exceptions to this rule, however. +7.12). +Most malignant tumors do not recognize normal +anatomic boundaries. +(A) The tan-colored, +encapsulated small tumor is sharply demarcated from the whiter breast +tissue. +(B, Courtesy Dr. +(A, Courtesy Dr. +Trace Worrell, University of Texas Southwestern Medical School, Dallas, Tex.; B, Courtesy Dr. +All malignant tumors can metas- +tasize, but some do so very infrequently. +It is evident then that the properties of invasiveness +and metastasis are separable. +Blood cancers (leukemias and +lymphomas) are a special case. +There are innumerable exceptions, +however. +Seeding of Body Cavities and Surfaces. +Most often involved is the peritoneal cavity (Fig. +7.13), but any body cavity—pleural, pericardial, subarach- +noid, and joint spaces—may be affected. +Sometimes, mucus-secreting +Figure 7.13 Involvement of omentum by metastatic ovarian carcinoma. +(Courtesy Dr. +Hematogenous Spread. +Hematogenous spread is typical +of sarcomas but is also seen with carcinomas. +Several factors influence the patterns of vascular metas- +tasis. +Understandably, the liver and the lungs (Fig. +(Courtesy Dr. +Lymphatic Spread. +7.14). +Sarcomas also sometimes use this +route. +The pattern of spread follows the natural +routes of lymphatic drainage. +(A) Liver studded with metastatic cancer. +(B) Microscopic view of lung metastasis. +A colonic adenocarcinoma has formed a +metastatic nodule in the lung. +(B, Courtesy Dr. +Unfortunately, most cancers +have not read pathology textbooks! +The basis of tissue-specific +patterns of metastasis is discussed later. +Certain cancers have a curious propensity for growth +within large veins. +Remarkably, such intravenous growth may not be +accompanied by widespread metastasis. +The distinguishing features of benign and malignant +tumors are summarized in Table 7.2 and Fig. +7.16. +7.17. +The most common +tumors in men arise in the prostate, lung, and colon/rectum. +In women, cancers of the breast, lung, and colon/rectum +are the most frequent. +• Benign tumors are slow growing,while malignant tumors generally +grow faster. +Carcinomas tend to spread +via lymphatics,whereas sarcomas prefer the hematogenous route. +2019 ESTIMATED CANCER INCIDENCE BY SITE AND SEX +B. +Excludes basal cell and squamous cell skin cancers and in situ carcinomas except +urinary bladder. +• Diet. +• Obesity. +The most overweight individuals in the U.S. +• Reproductive history. +• Environmental carcinogens. +Race is not a discrete biologic variable, but it can define +groups at risk for certain cancers. +7.18). +Among the best-established environmental factors affect- +ing cancer risk are the following. +• Infectious agents. +Specific +infectious agents and their associated cancers are discussed +later in this chapter. +• Smoking. +Age +Age has an important influence on the risk of cancer. +Most +carcinomas occur in adults older than 55 years of age. +A decline +in immune competence in older individuals may also be a +factor. +(A) Most common cancers in men by country. +(B) Variation in breast cancer incidence in women by +country. +These are +discussed in Chapter 10 and elsewhere in the text. +lesions, and immunodeficiency states. +Immunodeficiency states predispose to +virus-induced cancers. +Each of these acquired predisposing +conditions is described next. +• Chronic inflammation. +• Precursor lesions. +These changes may take the form of hyperplasia, meta- +plasia, or dysplasia. +Precursor lesions consisting of +hyperplasias often stem from chronic exposure to trophic +factors. +Other “at +risk” lesions consist of benign neoplasms. +• Immunodeficiency and cancer. +The geographic variation is thought to +mainly stem from different environmental exposures. +• Nonlethal genetic damage lies at the heart of carcinogenesis. +these individuals have a higher than normal incidence +of chronic infection with viruses. +The relationship +between infections, immunity, and cancer is discussed +later in this chapter. +See text for details. +Thus, in +genetic parlance, oncogenes are dominant over their +normal counterparts. +As a result, mutated tumor +suppressor genes usually behave in a recessive fashion. +Such a finding indicates that two “doses” +of the gene are essential for normal function. +7.19). +7.19). +7.20). +Evolution of a renal cell carcinoma (left panel) and Darwin’s finches (right panel). +Thus, +there is great interest in treating cancers with drugs that +correct epigenetic abnormalities. +Traditionally, the +functional consequences of these alterations were described +one gene at a time. +These changes are illustrated in Fig. +7.21 and consist of the +following: +• Self-sufficiency in growth signals. +• Insensitivity to growth-inhibitory signals. +• Altered cellular metabolism. +• Evasion of apoptosis. +Tumors are resistant to programmed +cell death. +• Limitless replicative potential (immortality). +• Sustained angiogenesis. +(Modified from Hanahan D, Weinberg +RA. +Hence, +tumors must induce angiogenesis. +• Ability to invade and metastasize. +• Ability to evade the host immune response. +Cancer cells exhibit +a number of alterations that allow them to evade the +host immune response. +Cells expressing oncoproteins are thus freed +from normal checkpoints and proliferate excessively. +This view has merit, and we will follow it in our initial +description of their activities. +Growth Factors. +Growth Factor Receptors. +GDP, Guanosine +diphosphate; GTP, guanosine triphosphate. +cytoplasmic tyrosine kinase domain (Chapter 1). +• ERBB2 encodes a different member of the receptor tyrosine +kinase family, HER2. +Unfortunately, these targeted therapies are usually not +curative in advanced cancers. +Downstream Components of the Receptor Tyrosine Kinase +Signaling Pathway. +Thus, GAPs prevent uncontrolled RAS activity. +• Mutations in kinases of the PI3K family are also very common +in certain cancers. +For example, about 30% of breast +carcinomas have PI3K gain-of-function mutations. +Here, +like BRAF, it activates a cascade of serine/threonine +kinases, including AKT. +AKT phosphorylates more than +150 proteins and constitutes a major signaling node. +Nonreceptor Tyrosine Kinases. +An important +example of this oncogenic mechanism involves the ABL tyro- +sine kinase. +Unfortunately, treatment of this “addiction” to +BCR-ABL does not lead to cure. +An example of this type of mutation is +found in the nonreceptor tyrosine kinase JAK2. +JAK/STAT activation alters the expression of +target genes that bind STAT transcription factors. +Transcription Factors. +MYC. +• MYC activates the expression of many genes that are involved +in cell growth. +• Some MYC target genes, like D cyclins, are directly +involved in cell cycle progression. +7.23), are those with the highest levels of MYC. +• In some contexts, MYC upregulates expression of telomerase. +Sometimes deregula- +tion involves genetic alterations of MYC itself. +The +functionally identical NMYC and LMYC genes are also +amplified in neuroblastomas (Fig. +7.24) and small cell cancers +of the lung, respectively. +The +integration involves other autosomes such as 4, 9, or 13. +Thus, there is seemingly no end +to the ways in which MYC may be deregulated in cancer +cells. +Cyclins and Cyclin-Dependent Kinases. +Amplification of the CDK4 gene also +occurs in melanomas, sarcomas, and glioblastomas. +• Loss-of-function mutations in genes that inhibit G1/S progres- +sion. +In molecular +terms, Knudson’s hypothesis can be stated as follows +(Fig. +7.25): • +Two mutations (hits), involving both alleles of RB are +required to produce retinoblastoma. +• Activation of RAS by point mutations (many cancers). +• Activation of PI3K and BRAF serine/threonine kinases by +point mutations (many cancers). +Tumor suppressor proteins +control a series of checkpoints that prevent uncontrolled +growth. +Ultimately, the growth inhibitory pathways may prod the +cells into apoptosis. +In +the sporadic form, both RB mutations in the tumor-founding retinal cell are acquired. +functions are listed in Table 7.7. +RB: Governor of Proliferation. +Its function may be com- +promised in two different ways. +• Loss-of-function mutations involving both RB alleles. +7.26). +The latter then activates +transcription of S-phase genes. +And, conversely, why are acquired mutations of +RB not found in all kinds of cancer? +TP53: Guardian of the Genome. +Less commonly, individuals inherit one +mutated TP53 allele. +TP53 encodes +the protein p53, which is tightly regulated at several levels. +Like RB, the transforming proteins +of several DNA viruses bind p53 and promote its degrada- +tion. +As a result, p53 is +virtually undetectable in normal cells. +• DNA damage and hypoxia. +The types of +damage sensed by ATM and ATR are different, but the +downstream effects are similar. +Once triggered, both ATM +and ATR stimulate the phosphorylation of p53 and +MDM2. +• “Oncogenic” stress. +p14/ +ARF binds MDM2 and displaces p53, again allowing p53 +levels to rise in the cell. +7.27). +• Transient p53-induced cell cycle arrest. +Rapid onset, +p53-mediated cell cycle arrest may be considered a +primordial response to DNA damage. +This pause in cell cycling +is welcome, as it gives the cells “breathing time” to repair +DNA damage. +The cells may then revert to a normal state. +• p53-induced senescence. +How cells become fixed in +the senescence state is unclear. +Senescent cells, while not normal, +cannot divide and therefore cannot develop into tumors. +• p53-induced apoptosis. +Thus the DNA repair pathway is stimulated first as +p53 begins to accumulate. +Thus +there is still much to be learned about the nuances of p53 +function. +Moreover, once a cancer is +established, its p53 status has important therapeutic implica- +tions. +As with other +tumor suppressor genes, both copies of APC must be lost +for an adenoma to arise. +7.28). +WNT molecules signal by binding to cell surface recep- +tors of the frizzled (FRZ) family. +This stimulates several +pathways, the central one involving APC and β-catenin. +A major function of the APC protein is to hold β-catenin +activity in check. +Thus +β-catenin, the target of APC, is itself a proto-oncoprotein. +E-Cadherin. +This pause allows cells to repair DNA damage. +• The majority of human cancers demonstrate biallelic loss-of- +function mutations in TP53. +• Like RB, p53 is inactivated by viral oncoproteins, such as the +E6 protein of HPV. +Other Tumor Suppressor Genes. +The full panoply of tumor +suppressor genes is still being defined. +Tumor suppressor genes all appear to impact one or more +of the hallmarks of cancer. +APC: Gatekeeper of Colonic Neoplasia. +APC and β-catenin are components of the +WNT signaling pathway. +This complex leads to the destruction of β-catenin, and intracellular levels of β-catenin are low. +those that arise in the esophagus, colon, breast, ovary, and +prostate. +CDKN2A. +p16 +also appears to be important in induction of cellular senes- +cence (described later). +TGF- β Pathway. +PTEN. +VHL. +Somatic mutations of VHL also +occur in a subset of sporadic renal cell carcinomas (Chapter +20). +Thus, VHL is part of the system +that regulates cellular responses to oxygen levels. +STK11. +development of thousands of colonic polyps and early-onset +colon carcinoma. +• Acquired somatic APC mutations are found in about 70% of +sporadic colon carcinomas. +• Germline loss-of-function mutations cause autosomal dominant +familial melanoma. +TGF-β pathway: potent inhibitor of cellular proliferation in normal +tissues. +PTEN: encodes a lipid phosphatase that is an important negative +regulator of PI3K/AKT signaling. +• Biallelic loss of function common in diverse cancers. +• Acquired biallelic loss-of-function mutations are common in +sporadic renal cell carcinoma. +7.29 +and include the following: +• Receptor tyrosine kinase/PI3K/AKT signaling. +• MYC. +Autophagy. +7.29 and +Chapter 2). +If this adaptation fails, the cells die of starvation. +tissues such as the bone marrow). +Most tumors are PET- +positive, and rapidly growing ones are markedly so. +It +follows that growing cells do rely on mitochondrial metabo- +lism. +So how is this reprogramming of metabolism triggered +in growing normal and malignant cells? +Oncometabolism. +7.30). +According to the model, loss of TET2 activity +leads to abnormal patterns of DNA methylation. +These drugs are now being used to treat leu- +kemias with IDH mutations. +• Stress may induce cells to consume their components in a +process called autophagy. +7.31). +7.31): +• Loss of TP53 function. +• Overexpression of anti-apoptotic members of the BCL2 family. +Overexpression of BCL2 is a common event leading to +the protection of tumor cells from apoptosis. +The resulting overabundance of BCL2 protects +the transformed lymphocytes from apoptosis. +How can it be that cancer cells +have seemingly discovered the proverbial fountain of eternal +youth? +• Evasion of senescence. +As discussed in Chapter 2, most +normal human cells have the capacity to divide 60 to 70 +times. +• Evasion of mitotic crisis. +7.32). +Replication of somatic cells, which do not express +telomerase, leads to shortened telomeres. +In the presence of competent checkpoints, cells undergo arrest and enter nonreplicative senescence. +If cells fail to +reexpress telomerase, they eventually undergo mitotic catastrophe and death. +likely to expire in this fashion. +However, cells in crisis +that reactivate telomerase can restore their telomeres and +survive. +Whatever the mechanism, telomere maintenance is seen +in virtually all types of cancers. +In 85% to 95% of tumors +it is due to expression of telomerase. +• Self-renewal. +7.33). +Angio- +genesis is thus an essential facet of malignancy. +How do growing tumors develop a blood supply? +Early in their development, most human tumors +do not induce angiogenesis. +• Driver mutations in certain tumor suppressors and oncogenes +favor angiogenesis. +Conversely, gain-of-function mutations in RAS +or MYC upregulate the production of VEGF. +These agents are now a part of the armamen- +tarium that oncologists use against cancers. +Why +is the metastatic process so inefficient? +The answer is +uncertain but undoubtedly relates to the complexity of the +process. +Sequential steps involved in the +hematogenous spread of a tumor. +7.34). +Throughout, we touch on some of the proposed molecular +mechanisms that underlie the process. +As shown in Fig. +7.34, tumor cells interact with the ECM +at several stages in the metastatic cascade. +This process is repeated in +reverse when tumor cells extravasate at a distant site. +Tumor cells detach from each other because of +reduced adhesiveness and attract inflammatory cells. +Proteases secreted +from tumor cells and inflammatory cells degrade the basement membrane. +Binding of tumor cells to proteolytically generated binding sites and tumor +cell migration follow. +ECM, Extracellular matrix. +inflammatory cells) to do so. +Also, what determines why metastases ultimately appear +where they do in the body? +While definitive answers to these questions are not known, +clues have emerged. +7.34), which are believed to +enhance tumor cell survival in the circulation. +However, many +exceptions to this “rule” exist. +Such migration is +accomplished by the binding of CD44 to hyaluronate on +high endothelial venules. +Solid tumors also often express +of cancers. +The third step in invasion involves changes in how +tumor cells attach to ECM proteins. +Additionally, the matrix itself is modified in ways that +promote invasion and metastasis. +• Some tissues may provide a favorable “soil” for the growth +of tumor seedlings. +Even when metastatic cells take root and survive within +distant tissues, they may fail to grow. +• The metastatic site of many tumors can be predicted by the +location of the primary tumor. +Many tumors arrest in the first +capillary bed they encounter (lung and liver, most commonly). +What host effector systems recognize tumor +cells? +How do tumors evade these host mechanisms? +And +how can immune reactions against tumors be exploited +therapeutically? +7.36). +• Cell-cell contacts are lost by the inactivation of E-cadherin +through a variety of pathways. +EBV, Epstein-Barr virus; MHC, major histocompatibility complex. +• Overexpressed or aberrantly expressed normal cellular proteins. +It may be surprising that the immune +system is able to respond to this normal self antigen. +Thus, for all practical purposes, +these antigens are tumor-specific. +Prototypic of this group +is the melanoma antigen gene (MAGE) family. +• Tumor antigens produced by oncogenic viruses. +The cellular effectors that mediate immunity +are described in Chapter 6. +Here we focus on the CTL +response to tumor antigens. +7.37), allowing the antigens to be +recognized by naïve CD8+ CTLs. +Activated macrophages also exhibit cytotoxicity against +tumor cells in vitro. +Several +mechanisms appear to be operative (Fig. +7.38). +• Selective outgrowth of antigen-negative variants. +7.39). +• Secretion of immunosuppressive factors. +Tumors may secrete +several products that inhibit the host immune response. +TGF-β is secreted in large quantities by many tumors +and is a potent immunosuppressant. +• Induction of regulatory T cells (Tregs). +• Engagement of pathways that inhibit T-cell activation. +PD-1, like CTLA-4, inhibits T-cell +activation. +MHC, Major histocompatibility complex. +• Combination of checkpoint inhibitors with other therapeutic +agents. +7.39). +Germline loss-of-function mutations in at least +four different genes can produce HNPCC syndrome. +Nucleotide Excision Repair Factors. +UV radiation causes +cross-linking of pyrimidine residues, preventing normal +DNA replication. +Such DNA damage is repaired by the +nucleotide excision repair system. +Several genes are involved +in nucleotide excision repair. +Several mechanisms contribute to genomic instability in +cancer cells. +DNA Mismatch Repair Factors. +With +“proofreading” function lost, errors accumulate throughout +the genome. +Some of these errors may by chance create +driver mutations, and with time a cancer may result. +One +of the hallmarks of mismatch-repair defects is microsatellite +instability. +Microsatellites are tandem repeats of one to six +nucleotides found throughout the genome. +In normal people +the length of these microsatellites remains constant. +Somatic driver muta- +tions in ATM also are common in certain types of lym- +phoid neoplasms. +Mutations in two genes, BRCA1 +and BRCA2, account for 25% of cases. +7.32). +DNA Polymerase. +Regulated Genomic Instability in Lymphoid Cells. +BRCA1 and +BRCA2, which are mutated in familial breast cancers, are involved +in DNA repair. +• T and B cells undergo regulated genomic instability during +somatic gene rearrangements. +Errors in this process are an +important cause of lymphoid neoplasms. +• Removal of growth suppressors. +The growth of epithelial +cells is normally suppressed by cell–cell and cell–ECM +interactions. +• Enhanced resistance to cell death. +• Inducing angiogenesis. +Inflammatory cells release numerous +factors, including VEGF, which stimulate angiogenesis. +• Activating invasion and metastasis. +• Evading immune destruction. +In addition, whole chromosomes may be gained +or lost. +7.32), it can be +an early event that initiates the transformation process. +Whatever technol- +ogy is used, the study of chromosomal changes in tumor +cells is important. +Chromosomal Translocations. +Notable examples of oncogenes activated by chro- +mosomal translocations are listed in Table 7.8. +Overexpression of a proto-oncogene caused by transloca- +tion is exemplified by Burkitt lymphoma. +7.23), placing it close to the immunoglobulin heavy chain +(IGH) gene. +The genetic notation for the translocation is +t(8;14)(q24;q32). +7.23). +BCR-ABL fusion genes encode +chimeric BCR-ABL proteins with constitutive tyrosine kinase +activity. +7.40). +How this fusion gene functions is now reasonably +well understood. +Normal RAR α binds to DNA +and activates transcription in the presence of retinoids. +There also is evidence that +ATRA-bound PML-RARA complexes are degraded more +rapidly. +Deletions. +Chromosomal deletions are another very common +structural abnormality in tumor cells. +Gene Amplification. +Such amplification may produce up to +several hundred copies of the oncogene in the tumor cell. +staining regions. +7.24). +ERBB2 amplification +occurs in about 20% of breast cancers. +Complex Chromosomal Rearrangements. +Gene amplification generally increases the expression +and function of oncogenes. +• Global changes in DNA methylation. +• Changes in histones. +Cancer cells often demonstrate changes in histones near +genes that influence cellular behavior. +Remarkably, in some cancers, driver mutations occur in +the histone genes themselves. +These altered +appearances stem from disturbances of chromatin organiza- +tion. +• The epigenome is a therapeutic target. +• Cancers likely exhibit considerable epigenetic heterogeneity. +One consequence of such +heterogeneity may be drug resistance. +The best characterized of these noncoding RNAs are +microRNAs. +What +is the evidence that this is so? +These are also described in subsequent chapters. +the Danish Chimney Sweeps Guild ruled that its members +must bathe daily. +No public health measure since that time +has achieved as much in controlling a form of cancer! +Subsequently, hundreds of chemicals have been shown to +be carcinogenic in animals. +Some of the major agents are +listed in Table 7.10. +Chemical Carcinogenesis +As discussed earlier, carcinogenesis is a multistep process. +It causes permanent DNA damage (mutations). +Application of promoters +leads to proliferation and clonal expansion of initiated +(mutated) cells. +With this brief overview, +initiation and promotion can be examined in more detail +(Fig. +7.41). +Their targets are DNA, RNA, and proteins, and in some +cases these interactions cause cell death. +The mutated cell then passes on +the DNA lesions to its daughter cells. +This is not to say that mutations induced by carcinogens +occur in an entirely random fashion. +The risk +of induced cancer is low, but its existence dictates judicious +use of such agents. +7.41). +Many other occupational carcinogens are listed in +Table 7.10. +Most indirect carcinogens are metabolized by cytochrome +P-450–dependent monooxygenases. +Approximately +10% of the white population carry a highly inducible form +of this gene. +Molecular Targets of Chemical Carcinogens. +There is no single or unique +alteration associated with cancer initiation. +Hence, polymorphisms of endogenous +enzymes such as cytochrome P-450 may influence +carcinogenesis. +The incidence peaked during 1988–1992 +and then declined. +Of these, UVB is believed to be +responsible for the induction of cutaneous cancers. +UVB light is carcinogenic because of its ability to cause +pyrimidine dimers to form in DNA. +The evidence is voluminous, and a few examples suffice. +Many individuals pioneering the use of x-rays developed +skin cancers. +Most telling is the follow-up of survivors +of the atomic bombs dropped on Hiroshima and Nagasaki. +Most frequent are myeloid leukemias (tumors of granulocytes +and their precursors; see Chapter 13). +Cancer of the thyroid +follows closely but only in young patients. +In the intermediate +category are cancers of the breast, lungs, and salivary glands. +• UV rays induce the formation of pyrimidine dimers within DNA, +leading to mutations. +Therefore UV rays can give rise to skin +cancers. +Despite intense +scrutiny, however, only a few viruses have been linked +with human cancer. +Our discussion focuses on human +oncogenic viruses as well as the role of the bacterium H. +pylori in gastric cancer. +HHV8 is discussed in Chapters 6 and 11. +Although not a DNA virus, HCV is also associated with +cancer and is discussed here briefly. +Human Papillomavirus. +At least 70 genetically distinct +types of HPV have been identified. +Some types (e.g., 1, 2, +4, and 7) cause benign squamous papillomas (warts) in +humans. +These +cancers are sexually transmitted diseases caused by chronic +HPV infection. +What explains the variation in cancer risk among HPV +strains? +7.42). +• Oncogenic activities of E6. +Oncogenic RNA Viruses +Human T-Cell Leukemia Virus Type 1. +Worldwide, it is estimated that 15 to 20 million people are +infected with HTLV-1. +In leukemic cells, however, +viral integration shows a clonal pattern. +7.26). +TERT, +Telomerase reverse transcriptase. +• Oncogenic activities of E7. +E7 also inactivates the CDK inhibitors p21 and p27. +Thus, +it is evident that HPV proteins promote many of the +hallmarks of cancer. +However, +infection with HPV itself is not sufficient for carcinogenesis. +Cotransfection +with a mutated RAS gene results in full malignant trans- +formation. +Epstein-Barr Virus. +This probably occurs in the tonsils +following exposure to the virus in saliva. +Concurrently, LMP-1 prevents apoptosis +by activating BCL2. +EBNA-2 +transactivates several host genes, including cyclin D and +the SRC family of proto-oncogenes. +A morphologically +identical lymphoma occurs sporadically throughout the +world. +• All affected patients have elevated antibody titers against +viral capsid antigens. +(2) The EBV genome is found in +only 15% to 20% of Burkitt lymphomas outside of endemic +regions. +Given these observations, how then does EBV contribute +to the genesis of endemic Burkitt lymphoma? +One possibility +is shown in Fig. +7.43. +These cells persist indefinitely, +even in the face of normal immunity. +Lymphoma cells may326 CHAPTER 7 Neoplasia +can evolve into monoclonal neoplasms. +Nasopharyngeal carcinoma also is strongly associated with +EBV. +This tumor is endemic in southern China, parts of +Africa, and the Inuit population of the Arctic. +Hepatitis B and C Viruses. +Worldwide, 70% to 85% of +hepatocellular carcinomas are associated with infection +with HBV or HCV. +CTLs, Cytotoxic T lymphocytes. +The role played by EBV is more direct in B-cell lym- +phomas arising in immunosuppressed patients. +Although not a DNA virus, HCV is also strongly linked +to the pathogenesis of liver cancer. +The molecular mecha- +nisms used by HCV are less well defined than are those of +HBV. +Helicobacter pylori +First incriminated as a cause of peptic ulcers, H. +Indeed, H. +The proposed scenario for the development of gastric +adenocarcinoma in the setting of H. +The H. +pylori genome also contains genes +directly implicated in oncogenesis. +Although H. +This sequence takes decades to +complete and occurs in only 3% of infected patients. +H. +Their molecular pathogenesis is incom- +pletely understood but seems to involve strain-specific H. +It is thought that H. +pylori infection leads +to the appearance of H. +pylori–reactive T cells, which in turn +stimulate a polyclonal B-cell proliferation. +At this stage, eradica- +tion of H. +pylori by antibiotic therapy “cures” the lymphoma +by removing the antigenic stimulus for T cells. +HPV: an important cause of benign warts, cervical cancer, and +oropharyngeal cancer. +• HPV cancers can be prevented by vaccination against high-risk +HPV types. +HBV and HCV: cause of 70% to 85% of hepatocellular carcinomas +worldwide. +H. +pylori: implicated in gastric adenocarcinoma and MALToma. +• Pathogenesis of H. +• H. +• Chronic H. +It is likely that additional mechanisms underlying +cancer cachexia await discovery. +These occur in +about 10% of persons with cancer. +• In affected patients they can cause significant clinical +problems and may even be lethal. +• They may mimic metastatic disease and therefore con- +found treatment. +A classification of paraneoplastic syndromes and their +presumed origins is presented in Table 7.11. +A few comments +on some of the more common and interesting syndromes +follow. +Endocrinopathies are frequently encountered paraneoplastic +syndromes. +Cushing syndrome +is the most common endocrinopathy. +Approximately 50% +of affected individuals have carcinoma of the lung, chiefly +the small-cell type. +The precursor of corticotropin is a +large molecule known as pro-opiomelanocortin. +The former +is not found in serum of patients with excess corticotropin +produced by the pituitary. +Neoplasms in the gut, both benign and malignant, +may cause obstruction as they enlarge. +Mortality is generally the consequence of atrophy of the +diaphragm and other respiratory muscles. +Only the second +mechanism is considered to be paraneoplastic. +As its name implies, PTHRP has +partial structural homology to parathyroid hormone (PTH). +association of squamous cell carcinomas with PTHRP- +induced hypercalcemia. +It occurs rarely as a genetically +determined disease in juveniles or adults (Chapter 25). +These skin changes may appear before the cancer is +discovered. +Hypertrophic osteoarthropathy is encountered in 1% to 10% +of patients with lung carcinoma. +Rarely, other forms of cancer +are involved. +The cause is unknown. +• Grading. +• Staging. +The major staging system currently in use is +the American Joint Committee on Cancer Staging. +TNM staging varies for +specific forms of cancer, but there are general principles. +The primary lesion is characterized as T1 to T4 based on +increasing size. +T0 is used to indicate an in situ lesion. +This method permits histologic evalu- +ation within minutes. +Better to wait a day or two, +despite the delay, than to perform inadequate or unnecessary +surgery. +Fine-needle aspiration of tumors is another approach that +is widely used. +While it may +be confounded by sampling errors, in experienced hands +it is rapid and quite reliable. +Cytologic smears provide yet another method for cancer +detection (Chapter 22). +7.44). +Histologic and Cytologic Methods. +The laboratory +diagnosis of cancer is, in most instances, not difficult. +Radiation changes in the skin or mucosa can be similar to +those associated with cancer. +Sections taken from a healing +fracture can mimic an osteosarcoma. +It must be adequate, representa- +tive, and properly preserved. +• Determination of site of origin of metastatic tumors. +Many +cancer patients present with metastases. +• Detection of molecules that have prognostic or therapeutic +significance. +In general, receptor-positive breast cancers have a +better prognosis than receptor-negative tumors. +so-called targeted therapies, drugs that are directed at +Flow Cytometry. +Flow cytometry rapidly and quantitatively +mutated oncoproteins. +Immunohistochemistry. +• Categorization of undifferentiated malignant tumors. +There are no malignant cells. +(Courtesy Dr. +P. +K. +(Courtesy Dr. +These include B-cell and T-cell lymphomas +and leukemias as well as myeloid neoplasms. +Circulating Tumor Cells. +Molecular Diagnostics and Cytogenetics. +• Diagnosis of malignant neoplasms. +• Prognosis of malignant neoplasms. +• Detection of minimal residual disease. +• Diagnosis of hereditary predisposition to cancer. +Such analysis usually requires detection +of a specific mutation or sequencing of the entire gene. +The latter is necessary when several different cancer- +associated mutations are known to exist. +• Guiding therapy with oncoprotein-directed drugs. +• Identifying mechanisms of drug resistance: liquid biopsies. +Thus, we are living in the age of “omics”! +7.46), which provide a snapshot of all of +the genetic alterations that exist in a particular tumor. +The main impact of cancer genome sequencing to date +has been in the area of research. +One goal of these analyses is to +identify therapeutically “actionable” genetic lesions. +Other clinically useful information is obtained, however. +Each of the 24 chromosomes in the cancer is +displayed in a circle. +c, Copy +number profiles, showing copy number losses (in red) and copy gains (in +blue). +d, Point mutations, represented as red dots. +additional tests of this type. +7.47). +7.48). +In principle, all of these diverse +“BRAFomas” are candidates for treatment with BRAF +inhibitors. +Thus, what lies ahead is not the replacement of one set of +techniques by another. +A host of tumor markers have been described, and new +candidates are identified every year. +Only a few have stood +the test of time and proved to have clinical usefulness. +Prostatic carcinoma can be suspected when elevated +levels of PSA are found in the blood. +However, PSA screening +highlights problems encountered with virtually every tumor +marker. +Furthermore, there is no PSA level that +ensures that a person does not have prostate cancer. +These +limitations are discussed in detail in Chapter 18. +(Courtesy +Dr. +An alternative approach is to +measure many cancer-associated markers simultaneously. +Get ready! +• Assays of circulating tumor cells and tumor DNA are under +development. +Their utility lies in their ability to follow +response to therapy. +Liang J, Shang Y: Estrogen and cancer, Annu Rev Physiol 75:225–240, +2013. +[Review of evidence +linking risk for various cancers to obesity]. +Greaves M, Maley CC: Clonal evolution in cancer, Nature 481:306–313, +2012. +[An updated compendium of driver mutations and cancer genes across a +broad range of cancer]. +[An update of a classic paper describing the key +features common to all cancers]. +Oncogenes +Cilloni D, Saglio G: Molecular pathways: BCR-ABL, Clin Cancer Res +18:930–937, 2012. +Stine ZE, Walton ZE, Altman BJ et al: MYC, metabolism, and cancer, +Cancer Discov 5:1024–1039, 2015. +[A review of the widespread oncogenic +role of the transcription factor MYC in cancer]. +Dyson NJ: RB1: a prototype tumour suppressor and an enigma, Genes +Dev 30:1492–1502, 2016. +[A discussion of what is known and unknown +about RB function]. +Worby CA, Dixon JE: PTEN, Annu Rev Biochem 83:641–669, 2014. +[A discussion of the +complex role of autophagy in cancer]. +Evasion of Apoptosis +Letai A: Apoptosis and cancer, Annu Rev Cancer Biol 1:275094, 2017. +[A review focusing on anti-apoptotic mechanisms in cancer cells and how +they can be targeted]. +Cancer Stem Cells +Batlle E, Clevers H: Cancer stem cells revisited, Nat Med 23:1124–1134, +2017. +[A critical appraisal of the cancer stem cell model, with an eye toward +therapeutic applications]. +[A review of the cellular and molecular +mechanisms that underlie solid tumor metastasis]. +Brabletz T, Kalluri R, Nieto MA et al: EMT in cancer, Nat Rev Cancer +18:128–134, 2018. +[A review describing mechanisms and consequences of chromothripsis in +cancer]. +eaa12380. +[A critical evaluation +of causal epigenetic aberrations in cancer]. +[A study +that describes and quantifies the mutational impact of sun exposure on +melanoma genomes]. +[A discussion +of the roles of hepatitis viruses in hepatocellular carcinoma]. +[A review focused +on the oncogenic activities of human papillomavirus E6 and E7 +proteins]. +[An overview of the clinical features and +possible mechanisms underlying cancer-related cachexia]. +[A broad discussion of paraneoplastic syndromes]. +[A discussion of the current and potential future uses of +NGS in oncology]. +Pao W, Iafrate AJ, Su Z: Genetically informed lung cancer medicine, +J Pathol 223:230–240, 2011. +Frank • Alexander J. +In these regions of the world, five of the ten leading +causes of death are infectious diseases. +Thus, their +presence is diagnostic of an infection. +Most skin infections are +initiated by mechanical injury of the epidermis. +The injury +may range from minor trauma to large wounds, burns, and +pressure-related ulcers. +The gastrointestinal +tract has several local defenses. +Uptake through M cells Poliovirus, Shigella spp., Salmonella spp. +Antimicrobial defensins are produced by gut +epithelial cells. +Peristalsis can clear organisms, preventing their local +overgrowth. +Many common gastrointestinal +pathogens are resistant to local defenses. +• Bacterial colonoization and toxin production. +Other bacteria +establish an infection and produce damaging toxins. +Examples include V. +These organisms +elaborate potent exotoxins that are responsible for +symptomatic disease. +• Adhesion and mucosal invasion. +Attachment induces the host cell to endo- +cytose the virus, leading to viral entry and replication. +Other organisms establish disease when local or systemic +defenses are impaired. +in patients with neutropenia. +Urogenital Tract +Urine contains small numbers of low-virulence bacteria. +The urinary tract is protected from infection by regular +emptying during micturition. +Urinary tract pathogens (e.g., +E. +Expulsion +of urine from the bladder eliminates microbes. +Antibiotics can kill the lactobacilli +and allow overgrowth of yeast, causing vaginal candidiasis. +Examples +include gonococcal and chlamydial conjunctivitis. +8.1). +Pathogens +can spread within the body in several ways. +Pathogens vary in hardiness in the environment. +Most pathogens are transmitted from person to person +by respiratory, fecal-oral, or sexual routes. +cholera, +Shigella spp., C. +jejuni, and S. +enterica. +There are several additional routes of transmission. +To enter the +body, microbes penetrate the epithelial or mucosal barriers. +Infection may +remain localized at the site of entry or spread to other sites in the body. +However, certain viruses and bacterial toxins may also travel through +nerves. +Microbes undergo continuous evolution to combat +host defenses. +8.2). +• Antigenic variation. +and trypanosomes). +• Resistance to antimicrobial peptides. +Pathogens, such as +Shigella spp., S. +• Resistance to killing by phagocytes. +The carbohydrate capsule +on the surface of many bacteria (S. +S. +• Evasion of apoptosis and manipulation of host cell metabolism. +• Resistance to cytokine-, chemokine- and complement-mediated +host defense. +• Evasion of recognition by CD8 + cytotoxic T lymphocytes (CTLs) +and CD4 + helper T cells. +Tumors +exploit the same mechanisms to suppress destructive +immune responses (Chapter 7). +Opportunistic +organisms (e.g., Aspergillus spp. +and Pseudomonas spp.) cause +significant disease in these patients. +tuberculosis). +Age-related decline in +immune function may increase infections in the elderly. +pneumoniae in people with sickle cell disease +due to loss of splenic macrophages, and P. +aeruginosa in +burns due to barrier disruption. +Finally, malnutrition can +impair immune defenses. +pneu- +moniae, H. +influenzae, and S. +aureus, as well as a few viruses +(rotavirus and enteroviruses). +aureus, some gram-negative bacteria, and fungi. +The granulomatous inflammatory +reaction to M. +pneumoniae), and +impaired TLR3 responses are associated with childhood +HSV encephalitis. +The predilection for viruses +to infect certain cells and not others is called tropism. +A major +determinant of tissue tropism is the presence of viral +receptors on host cells. +This is presumably one way in which viruses +evolve to infect, survive within cells, and spread. +Other tropisms are explained by cell-lineage–spe- +cific factors. +Physical barriers can contribute to tissue tropism. +8.3): +• Direct cytopathic effects. +unaffected. +• Antiviral immune responses. +• Transformation of infected cells. +Mechanisms of Bacterial Injury +Bacterial Virulence. +Pathogenic bacteria have virulence genes that encode proteins +responsible for these properties. +An example of the impor- +tance of such genes can be found in the various strains of +S. +enterica. +All S. +Differences in a rela- +tively small number of virulence genes determine whether +an isolate of S. +enterica causes life-threatening typhoid fever +or self-limited enteritis. +Virulence genes are frequently found +grouped together in clusters called pathogenicity islands. +aureus. +aureus), competence for genetic transformation (S. +pneu- +moniae), or generation of biofilms (P. +aeruginosa). +Bacterial Adherence to Host Cells. +Bacteria use various +surface structures to attach to host cells and tissues. +Adhesins +have a broad range of host cell specificity. +• Pili are filamentous structures on the surface of bacteria +that act as adhesins. +The precise tissue-tropism of E. +Pili can be +targets of the host antibody response and, in turn, some +bacteria such as N. +gonorrhoeae vary their pili to escape +from the host immune system. +Intracellular Bacteria. +Bacteria have evolved a variety of +mechanisms for entering host cells. +M. +Some gram- +negative bacteria use a type III secretion system to enter +epithelial cells. +Shigella spp. +and E. +coli inhibit host protein synthesis, replicate +rapidly, and lyse the host cell within hours. +M. +L. +In the cytoplasm, L. +An example of the latter is the +migration of infected macrophages carrying M. +tuberculosis +from the lung to draining lymph nodes and other more +distant sites. +Bacterial Toxins. +Any bacterial substance that contributes +to illness can be considered a toxin. +Exotoxins are secreted bacterial proteins that cause +cellular injury and disease. +They can be classified into broad +categories by their mechanism of action. +• Enzymes. +These enzymes +have roles in tissue destruction and abscess formation. +For example, exfoliative toxins produced by S. +• Toxins that alter intracellular signaling or regulatory pathways. +A-B toxins are made by many bacteria including +Bacillus anthracis, V. +cholerae, and some strains of E. +coli. +The +high levels of cytokines can lead to systemic inflammatory +response syndrome. +• Pathogens can induce immune responses that cause tissue +damage. +Similarly, in a patient +who is not immunocompromised, M. +There are five major histologic patterns of tissue reaction +in infections (Table 8.3). +3.15). +Masses of dying and dead neutrophils and liquefactive +necrosis of the tissue form pus. +How destructive the lesions are depends on their +location and the organism involved. +For example, S. +Bacterial pharyngitis +(S. +In addition, spirochetes and helminths provoke chronic +inflammatory responses. +For example, plasma +cells are abundant in the primary and secondary lesions of +syphilis (Fig. +8.4), whereas lymphocytes predominate in +HBV infection or viral infections of the brain. +• Infectious agents cause death or dysfunction by directly interact- +ing with the host cells. +Focal cell +damage in the skin may cause epithelial cells to become +detached, forming blisters (Fig. +8.5). +Finally, viruses can contribute to +the development of malignant neoplasms (Chapter 7). +At the other +extreme, macrophages may become filled with organisms, +as occurs in M. +tuberculosis, +Histoplasma capsulatum, schistosome eggs). +Figure 8.5 Herpesvirus blister in mucosa. +See Fig. +The parasite E. +8.6] or the constrictive fibrous pericarditis in tuberculosis). +Infections +that typically involve a specific organ are discussed in other +chapters. +In recent years, such outbreaks have occurred +several times each year in the United States. +There is only one serotype of +measles virus. +Three cell-surface receptors have been identified for measles +hemagglutinin protein. +Measles can replicate in a variety of cell types, including +epithelial cells and leukocytes. +Hence, the rash is less frequent in people with deficien- +cies in cell-mediated immunity. +Subacute sclerosing panencephalitis +Fi e 8.7 Measles giant cells in the lung. +immunocompromised individuals) are rare late complications +of measles. +Antibody-mediated immunity to measles virus protects +against reinfection. +8.7). +Like +measles virus, mumps virus is a member of the Paramyxo- +viridae family. +Mumps virus also can spread to other sites, including the +CNS, testis, ovary, and pancreas. +Poliovirus, like other enteroviruses, is transmitted by the +fecal-oral route. +The neurologic features and neuropathology of +poliovirus infection are described in Chapter 28. +West Nile virus is transmitted by +mosquitoes to birds and to mammals. +Infected birds develop +prolonged viremia and are the major reservoir for the virus. +Humans are incidental hosts. +A macu- +lopapular rash is seen in approximately one-half of cases. +Immunosuppressed persons +and older adults appear to be at the greatest risk for severe +disease. +Rare complications include hepatitis, myocarditis, +and pancreatitis. +The testicular damage can lead to scarring, +atrophy, and, if severe, sterility. +Poliovirus is a spherical, unencapsulated RNA virus +of the enterovirus genus. +Damage to blood vessels is often prominent. +A second outbreak +in the Democratic Republic of Congo occurred in 2019. +Ebola carries a very high mortality +rate, about 40% during the 2019 outbreak. +Two viral +proteins, VP24 and VP35, inhibit the action of type I IFN. +Large outbreaks occurred in the State of +Yap in 2007 and French Polynesia in 2013 to 2014. +Zika virus is transmitted by Aedes mosquitos, primarily +Aedes aegypti. +The rate of adverse +effects on newborns has been higher in Brazil than in other +nations. +There are +four serotypes of dengue virus. +The clinical manifestations ranged +from mild to severe respiratory illness. +The vast majority of +individuals who contract the virus recover after a flu-like +disease. +The genomic sequence shows COVID-19 is +related to bat coronaviruses and the SARS coronavirus. +Dissemination +of the infection and tissue injury stem from reactivation of +the latent virus. +The viruses that most frequently establish +latent infections in humans are herpesviruses. +8.8). +(A) Subcortical band of degenerating cells +with prominent calcifications. +(B) Cortex with degenerating neurons +(arrows). +No viral proteins appear to be +produced during latency. +HSV-1 is also the major +cause of fatal sporadic encephalitis in the United States. +8.9). +Due to cell fusion, HSV +also produces inclusion-bearing multinucleated syncytia. +Gingivostomatitis, which is usually encountered in children, +is caused primarily by HSV-1. +Genital herpes is more often caused by HSV-2 than by +HSV-1. +Two forms of corneal lesions are caused by HSV (Chapter +29). +Herpes epithelial keratitis shows typical virus-induced +cytolysis of the superficial epithelium. +Herpes simplex encephalitis is described in Chapter 28. +Herpes esophagitis is frequently compli- +cated by superinfection with bacteria or fungi. +Chickenpox is mild in children but more severe in +adults and in immunocompromised people. +Shingles is a +source of morbidity in older and immunosuppressed persons. +Also like HSV, VZV evades +immune responses and establishes a latent infection in +sensory ganglia. +Figure 8.10 Skin lesion of chickenpox (varicella-zoster virus) with +intraepithelial vesicle. +show intraepithelial vesicles (Fig. +8.10) with intranuclear inclusions +in epithelial cells at the base of the vesicles. +Similar to HSV, patients with mutations in TLR3 have an +increased risk of VZV encephalitis. +MORPHOLOGY +The chickenpox rash occurs approximately 2 weeks after +respiratory infection. +Lesions appear in multiple waves centrifugally +from the torso to the head and extremities. +Note the ganglion cell necrosis and associated inflammation. +(Courtesy Dr. +Transmission of CMV can occur by several routes, +depending on the age group affected. +CD4+ T cells, γδ T cells, +and NK cells are known to play a role in immune control of +the infection. +Thus, CMV both hides +from and actively suppresses immune responses. +Figure 8.12 Cytomegalovirus: distinct nuclear and ill-defined cytoplasmic +inclusions in the lung. +CMV causes focal necrosis with minimal inflammation in virtually +any organ. +Congenital Infections. +Infection acquired in utero may +take many forms. +In approximately 95% of cases, it is +asymptomatic. +Cytomegalic inclusion disease +resembles erythroblastosis fetalis. +Perinatal Infections. +Subtle effects on +hearing and intelligence later in life have been reported in +some studies. +CMV Mononucleosis. +In healthy young children and +adults, the disease is nearly always asymptomatic. +8.12). +Within the cytoplasm of infected cells, smaller basophilic +inclusions can also be seen. +The diagnosis is made by +serology. +CMV in Immunosuppressed Individuals. +In the past, CMV was the most common +opportunistic viral pathogen in AIDS. +The pneumonitis can progress to full-blown acute respiratory +distress syndrome. +HIV and HBV infection are described in +Chapters 6 and 18, respectively. +Oncogenic viruses can stimulate cell +growth and survival by a variety of mechanisms. +Only +infectious mononucleosis is discussed here. +Some people develop +hepatitis, meningoencephalitis, and pneumonitis. +EBV infects B cells and possibly epithelial +cells of the oropharynx. +Infection of B cells may take one of two forms. +These +so-called heterophile antibodies are detected in diagnostic tests +for mononucleosis. +The symptoms of infectious mononucleosis appear on +initiation of the host immune response. +The liver is usually involved to some degree, although hepa- +tomegaly is at most moderate. +This histologic picture is similar to that of other forms +of viral hepatitis. +One or more complications +occasionally supervene. +Splenic rupture +can occur even with minor trauma, leading to hemorrhage +that may be fatal. +This rare inherited immunodeficiency is char- +acterized by an ineffective immune response to EBV. +Patients +are usually normal until they are acutely infected with EBV, +often during adolescence. +In more than half the cases, EBV +causes an acute overwhelming infection that may be fatal. +tions related to hypogammaglobulinemia. +Similar changes commonly occur in the tonsils and lymphoid +tissue of the oropharynx. +The spleen is enlarged in most cases, weighing between 300 +and 500 g. +It is usually soft and fleshy, with a hyperemic cut surface. +Staphylococcal Infections +S. +8.14). +S. +aureus is a pyogenic +gram-positive coccus that forms clusters resembling bunches +of grapes. +The general characteristics of S. +aureus infection +are reviewed in the following sections. +Infections of specific +organs are described in other chapters. +Coagulase-negative +staphylococci, such as S. +S. +saprophyticus is a common cause of urinary tract infection +in young women. +Pathogenesis +S. +S. +S. +Selected examples of the most common +or clinically significant infections are discussed next. +S. +aureus Toxins. +S. +aureus produces multiple membrane- +damaging (hemolytic) toxins. +S. +aureus γ-toxin and leukocidin lyse +red cells and phagocytes, respectively. +The exfoliative A and B toxins produced by S. +Superantigens produced by S. +aureus cause food poisoning +and toxic shock syndrome (TSS). +aureus during +use. +It is now clear that TSS can be caused by growth of S. +aureus at many sites, most commonly the vagina and infected +surgical sites. +If not promptly treated, it +can be fatal. +TSS can also be caused by S. +pyogenes. +Superantigens +produced by S. +Antibiotic resistance is a growing problem in treatment +of S. +aureus infections. +Methicillin-resistant S. +aureus (MRSA) +are resistant to nearly all penicillin and cephalosporin +antibiotics. +As a result, empirical treatment of +S. +aureus infections with cephalosporin antibiotics is not +recommended. +face, axillae, groin, legs, and submammary folds. +Hidradenitis is chronic suppurative infection of apocrine glands, +most often in the axilla. +S. +aureus lung infections (Fig. +8.15) have a polymorphonuclear +infiltrate similar to that of S. +pneumoniae infections (see Fig. +3.18B), +but they cause much more tissue destruction. +aureus infection +of the nasopharynx or skin. +These bacteria are gram-positive cocci that grow in pairs or +chains. +aureus causes pyogenic inflammation that is +distinctive for its local destruction of host tissue. +A furuncle, or boil, is a focal +suppurative inflammation of the skin and subcutaneous tissue. +They may be solitary, or multiple, or recur in successive crops. +3.18B). +S. +S. +Streptococcus +mutans is the major cause of dental caries. +Pathogenesis +The different species of streptococci produce many virulence +factors and toxins. +S. +pyogenes, S. +agalactiae, and S. +pneumoniae +have capsules that resist phagocytosis. +S. +S. +pyogenes secretes +a phage-encoded pyrogenic exotoxin that causes fever and +rash in scarlet fever. +Virulent S. +Although the antiphagocytic +capsule is the most important virulence factor of S. +S. +Figure 8.16 Streptococcal erysipelas. +distribution on the face (Fig. +8.16). +Microabscesses may be formed, but tissue necrosis is usually minor. +Scarlet fever, associated with pharyngitis caused by S. +pyogenes, +is most common between 3 and 15 years of age. +S. +pneumoniae is an important cause of lobar pneumonia +(Chapter 15). +Respiratory diphtheria causes pharyngeal or, less often, +nasal or laryngeal infection. +Damage to the heart, nerves, +and other organs may be present. +C. +diphtheriae produces a phage- +encoded A-B toxin that blocks host cell protein synthesis. +This inhibits EF-2 function, which is required for +the translation of mRNA into protein. +Erysipelas is caused by exotoxins from superficial infec- +tion with S. +pyogenes. +monocytogenes infection. +In pregnant women, +L. +monocytogenes causes an amnionitis that may result in +abortion, stillbirth, or neonatal sepsis. +L. +monocytogenes is a facultative intracellular pathogen. +The bacteria bind to receptors on host epithelial cells and +macrophages and are phagocytosed. +This generates force to propel +the bacteria into adjacent, uninfected host cells. +Accordingly, +an effective host response to L. +MORPHOLOGY +Inhaled C. +The bacteria also form satellite +lesions in the esophagus or lower airways. +8.17). +Outbreaks of L. +In the United States, all clinical isolates of L. +monocytogenes have been typed for epidemiologic surveillance +MORPHOLOGY +In acute infections, L. +monocytogenes evokes an exudative pattern +of inflammation with numerous neutrophils. +The meningitis due +to L. +The finding of gram-positive bacilli in the +CSF is virtually diagnostic. +More varied lesions may be +encountered in neonates and immunosuppressed adults. +In infections of longer +duration, macrophages appear in large numbers, but granulomas +are rare. +Infants born with L. +A smear of the meconium will disclose +the gram-positive bacilli. +Livestock become infected by spores in their +environment or feed. +In 1979, accidental release of B. +anthracis spores +Figure 8.17 Membrane of diphtheria (arrow) lying within a transverse +bronchus. +(Courtesy Dr. +Robin A. +In 2001, 22 people in the United States were infected with +B. +anthracis, mostly through domestic bioterrorism with +spores delivered in the mail. +Bacteremia is rare. +• Inhalational anthrax occurs when airborne spores are +inhaled. +Frequently, +meningitis develops from bacteremia. +Inhalational anthrax +rapidly leads to shock and frequently death within 1 to +2 days. +• Gastrointestinal anthrax is usually contracted by eating +undercooked meat contaminated with B. +anthracis. +Mortality is approximately 40%. +Pathogenesis +B. +anthracis produces potent toxins and an antiphagocytic +polyglutamyl capsule. +The mechanisms of action of anthrax +toxins are well understood (Fig. +8.18). +There are two A +subunits and one B subunit. +PA is not toxic, but it serves to +deliver the toxic EF and LF into cells. +The bacterium releases +each subunit as a separate protein. +PA binds to a cell surface +receptor that is highly expressed on endothelial cells. +In the cytoplasm, EF binds to calcium and +calmodulin to form an adenylate cyclase. +LF has a different +mechanism of action. +LF is a protease that destroys mitogen- +activated protein kinase kinases (MAPKKs). +The +mechanism of cell death caused by dysregulation of MAPKs +is not understood. +Hemorrhagic lung lesions +associated with vasculitis are also present in about one-half of +cases. +B. +8.19). +are aerobic gram-positive bacteria found +in soil that cause opportunistic infections. +The organism +grows in distinctive branched chains. +In culture, Nocardia +form thin aerial filaments resembling hyphae. +Despite this +morphologic similarity to molds, Nocardia are true bacteria. +Nocardia spp. +Respiratory infection with +Nocardia spp. +In some cases, Nocardia spp. +infections +disseminate from the lungs to the CNS. +Infections of the +Ca2+ +Calmodulin +Lethal +factor +MAPKKs +Edema +factor +cAMP +? +EDEMA +CELL DEATH +Figure 8.18 Mechanism of action of anthrax toxins. +pneumoniae +and cephalosporin-resistant N. +gonorrhoeae. +Only a few +gram-negative bacteria are discussed in this section. +Anaerobic gram-negative organisms are +considered later in this chapter. +Gram-negative bacterial +infections are usually diagnosed by culture. +Neisserial Infections +Neisseria spp. +Pathogenic Neisseria +spp. +usually lack this ability. +The two clinically sig- +nificant Neisseria spp. +are N. +meningitidis and N. +gonorrhoeae. +N. +The organism is a common colonizer of the oropharynx +and is spread by the respiratory route. +There are several +capsular serotypes of N. +meningitidis, however five of them +cause most cases of meningitis. +N. +Highly +effective conjugate vaccines for N. +meningitidis (A, C, +W, and Y), and recombinant protein vaccines are available +for serogroup B. +Even in the absence of preexisting immunity, only a small +fraction of people infected with N. +meningitidis develop +meningitis. +The bacteria must invade respiratory epithelial +cells and enter the blood. +The importance of complement as +a first-line defense against N. +If N. +meningitidis escapes the host response, +the consequences can be severe. +Although antibiotic treatment +greatly reduces the mortality of N. +meningitidis infection, +about 10% of infected patients still die. +The pathology of +pyogenic meningitis is discussed in Chapter 28. +N. +It is second only to C. +tra- +chomatis among bacterial STIs. +Infection in men causes +urethritis. +In women, N. +(Courtesy Dr. +Lev +Grinberg, Department of Pathology, Hospital 40, Ekaterinburg, Russia, and +Dr. +N. +brasiliensis causes +skin infections following injuries contaminated with soil. +MORPHOLOGY +Nocardia spp. +appear in tissue as slender gram-positive organisms +arranged in branching filaments (Fig. +8.20). +Irregular staining gives +the filaments a beaded appearance. +Nocardia spp. +Nocardia spp. +elicit a +suppurative response with central liquefaction and surrounding +granulation and fibrosis. +Granulomas do not form. +Gram-Negative Bacterial Infections +There are a large number of gram-negative bacterial patho- +gens. +Note +the beaded, branched gram-positive organisms and leukocytes. +(Courtesy +Dr. +Infection is +diagnosed by culture and PCR tests. +Ceftriaxone-resistant N. +gonorrhoeae is +rare but has been detected in Canada and Japan. +Although N. +Like N. +meningitidis, N. +Neonatal +N. +gonorrhoeae infection causes conjunctivitis that may lead +to blindness and, rarely, sepsis. +Pathogenesis +Neisseria spp. +Adherence of N. +to epithelial cells and promote entry of bacteria +into cells. +Neisseria spp. +use antigenic variation as a strategy to +escape the immune response. +The existence of multiple +capsular serotypes of N. +In addition, Neisseria spp. +• Expression of different OPA proteins. +These changes +shift the reading frame of the gene so that it encodes +new sequences. +Thus, Neisseria spp. +can +express one, none, or multiple OPA proteins at any time. +Infants younger than 1 year +of age are at highest risk of death. +Children with pertussis +can have coughing spells for up to 10 weeks. +It is hypothesized that modifica- +tions of B. +pertussis may also be playing a role, but this +is unproven. +Pathogenesis +B. +pertussis colonizes the brush border of the bronchial +epithelium and also invades macrophages. +Virulence factors of B. +Pertussis toxin +is a typical A-B toxin that is composed of five subunits. +B. +MORPHOLOGY +Bordetella spp. +8.21). +Unless superinfected, the lung +alveoli remain open and intact. +MORPHOLOGY +Pseudomonas spp. +8.22). +aeruginosa infection. +Bronchial obstruction caused by mucus plugging and subsequent +P. +aeruginosa infection are frequent complications of cystic fibrosis. +Despite antibiotic treatment and the host immune response, +chronic P. +aeruginosa infection may result in bronchiectasis and +pulmonary fibrosis (Chapter 15). +In skin burns, P. +aeruginosa proliferates widely, penetrating deeply +into the veins and spreading hematogenously. +DIC is a frequent complication of +P. +aeruginosa bacteremia. +(Images courtesy Dr. +Many +people with cystic fibrosis die of pulmonary failure secondary +to chronic infection with P. +aeruginosa. +This bacterium can be +very resistant to antibiotics, making these infections difficult +to treat. +It often infects extensive skin burns, which can lead +to sepsis. +P. +Pathogenesis +P. +aeruginosa produces several toxins that contribute to local +tissue damage. +Wild rodents in the rural western United States are +infected with Y. +pestis and are the source of about 10 to 15 +human cases every year. +In 2017, an outbreak in Madagascar +resulted in over 2400 cases and more than 200 deaths. +Y. +enterocolitica and Y. +pseudotuberculosis are genetically similar +to Y. +The bacterial gene regulation shifts on sensing reloca- +tion from the insect gut to the human host. +Y. +Over several days, the surface +of the primary lesion erodes to produce an irregular, painful ulcer. +The base +of the ulcer is covered by shaggy, yellow-gray exudate. +MORPHOLOGY +Y. +Fulminant bacteremia also induces DIC with widespread +hemorrhages and thrombi. +As the lesion enlarges, its borders +become raised and indurated. +Silver stains (e.g., the Warthin- +Starry stain) may also demonstrate the organism. +Chancroid (Soft Chancre) +Chancroid is an acute, ulcerative STI caused by Haemophilus +ducreyi. +They are weakly gram-positive. +• Replication in macrophages. +M. +Coronin activates the phosphatase calcineurin, leading +to inhibition of phagosome-lysosome fusion. +Despite the +bacteremia, most people at this stage are asymptomatic +or have a mild flulike illness. +• Innate immunity. +Multiple pathogen associated molecular +patterns (Chapter 6) made by M. +tuberculosis are recog- +nized by innate immune receptors. +Mycobacterial lipo- +arabinomannan binds TLR2, and unmethylated CpG +nucleotides bind TLR9. +These interactions initiate and +enhance the innate and adaptive immune responses to +M. +tuberculosis, as described below. +• The Th1 response. +Stimulation of TLR2 by mycobacterial +ligands promotes production of IL-12 by dendritic cells. +• Th1-mediated macrophage activation and killing of bacteria. +Th1 cells, both in lymph nodes and in the lung, produce +IFN-γ. +IFN-γ is the critical mediator that activates mac- +rophages and enables them to contain the M. +tuberculosis +infection. +Second, +IFN-γ stimulates expression of inducible nitric oxide (NO) +synthase, which produces NO. +Third, IFN-γ +mobilizes antimicrobial peptides (defensins) against the +bacteria. +tuberculosis. +• Granulomatous inflammation and tissue damage. +tuberculosis, and the leading +infectious cause of death worldwide. +The mortality due to tuberculosis is +falling by 3% per year. +Tuberculosis flourishes wherever there is poverty, crowd- +ing, and chronic debilitating illness. +It is important that infection with M. +tuberculosis be +differentiated from active disease. +Viable organisms may remain dormant in such lesions for +decades. +Infection by M. +8.23). +Early in infection, M. +The steps in infection are +as follows: +• Entry into macrophages. +M. +(A) Events occurring during early infection, before activation of T-cell– +mediated immunity. +(B) The initiation and consequences of T-cell–mediated immunity. +IFN-γ, interferon-gamma; MHC, major histocompatibility complex; MTb, M. +tuberculosis; TNF, tumor necrosis factor. +• Host susceptibility to disease. +In summary, immunity to M. +tuberculosis is primarily +mediated by Th1 cells, which stimulate macrophages to +kill the bacteria. +tuberculosis (Fig. +8.24). +Clinically significant disease develops in about 5% +of newly infected people. +With primary tuberculosis, the +source of the organism is exogenous. +The diagnosis of progressive +primary tuberculosis in adults can be difficult. +(Modified from a sketch provided by Professor R. +K. +Secondary tuberculosis is the pattern of disease that +arises in a previously sensitized host. +On the other hand, +cavitation occurs readily in the secondary form. +Localized secondary tuberculosis may be asymptomatic. +When manifestations appear, they are usually insidious in +onset. +Some degree of hemoptysis is +present in about one-half of all cases of pulmonary tuber- +culosis. +Pleuritic pain may result from extension of the +infection to the pleural surfaces. +Extrapulmonary manifesta- +tions of tuberculosis are legion and depend on the organ +system involved. +There +are several tests available for detection of M. +tuberculosis in +patients with active disease. +Comprehensive antibiotic +susceptibility testing can only be performed by culture. +PCR +amplification of M. +tuberculosis DNA allows for even more +rapid diagnosis. +An FDA-approved PCR test is available +that identifies both the presence of M. +tuberculosis and, if +the organism is detected, whether it is resistant to rifampin. +tuberculosis +antigens. +tuberculosis. +tuberculosis, which induces a visible and palpable indura- +tion that peaks in 48 to 72 hours. +bovis that is +used as a vaccine in some countries. +False-positive results +are uncommon with IGRAs. +Tuberculosis is a leading cause of death in people with +AIDS. +All stages of HIV infection are associated with an +increased risk of tuberculosis. +tuberculosis in check. +MORPHOLOGY +Primary Tuberculosis. +In most cases, +the center of this focus undergoes caseous necrosis. +8.25). +In approximately 95% of cases, development +of cell-mediated immunity controls the infection. +8.26A to C). +This is the usual response in people who have developed cell-mediated immunity to the +organism. +granulomas coalesce that they become macroscopically visible. +The granulomas are usually enclosed within a fibroblastic rim +punctuated by lymphocytes. +Multinucleated giant cells are present +in the granulomas. +8.26D). +Secondary Tuberculosis. +8.27). +Histologically, the active lesions show characteristic coalescent +tubercles with central caseation. +Figure 8.27 Secondary pulmonary tuberculosis. +The apical lesion expands +into adjacent lung and eventually erodes into bronchi and vessels. +The cavities, now free of inflammation, +may persist or become fibrotic. +8.28). +In HIV-negative individuals, lymphadenitis tends +to be unifocal and localized. +Healing creates strictures. +tuberculosis and very fastidious M. +leprae. +The +prevalence of NTM disease has increased worldwide. +Of the +150 NTM species, the most frequent human pathogens are +Mycobacterium avium complex (MAC), M. +abscessus complex, +and M. +kansasii. +The prevalence of specific species of NTM +varies in different geographic regions of the world. +Treat- +ment differs for these pathogens, so identifying the specific +organism is important. +It has been difficult to distinguish +M. +avium and M. +Newer +molecular methods are better able to distinguish these two +species, as well as M. +chimaera in the same complex. +Patients are feverish, with +drenching night sweats and weight loss. +NTM biofilm +development on medical devices is a well-documented source +of a number of recent cases. +Figure 8.28 Miliary tuberculosis of the spleen. +In advanced cases of lepro- +matous leprosy, M. +leprae is present in sputum and blood. +People can also have intermediate forms of disease, called +borderline leprosy. +As with M. +Also, antibody production is low. +Occasionally, most often in the lepromatous +form, antibodies are produced against M. +leprae antigens. +Some leprosy patients have a mixed Th1/ +Th2 cytokine pattern. +This pattern is more +common in patients with acquired immunodeficiencies. +8.29). +Granulomas, lymphocytes, and +tissue destruction are rare. +Neuronal involvement dominates tuberculoid leprosy. +8.30). +Contractures, paralyses, and autoamputation of fingers or +toes may ensue. +The presence of granulomas +and absence of bacteria reflect strong T-cell immunity. +leprae. +8.31). +Because of the abundant +bacteria, lepromatous leprosy is referred to as multibacillary. +Most skin lesions are hypo- +esthetic or anesthetic. +Lesions in the nose may cause persistent +inflammation and bacilli-laden discharge. +leprae that mainly affects the skin and +peripheral nerves. +M. +It prolifer- +ates best at 32° to 34°C, the temperature of the human skin. +Like M. +tuberculosis, M. +tuberculosis that immunization +with BCG confers some protection against M. +leprae infection. +M. +leprae. +People with the less severe tuberculoid leprosy have +dry, scaly skin lesions that lack sensation. +They often have +asymmetric involvement of large peripheral nerves. +Other closely related treponemes cause yaws (T. +pallidum +subsp. +pertenue) and pinta (T. +pallidum subsp. +carateum). +The +causative spirochete, T. +pallidum subsp. +pallidum, hereafter +referred to simply as T. +8.32). +Transplacental +transmission of T. +pallidum occurs readily, and active disease +during pregnancy results in congenital syphilis. +T. +pallidum +cannot be easily grown in culture. +Loss of sensation and trophic changes +in the hands and feet follow the nerve lesions. +Treponema pallidum +subsp. +Figure 8.31 Lepromatous leprosy. +Acid-fast bacilli (“red snappers”) within +macrophages. +The chancre heals +with or without therapy. +Secondary Syphilis. +This stage is marked by painless, +superficial lesions of the skin and mucosal surfaces. +It occurs +2 to 10 weeks after the primary chancre in approximately +75% of untreated people. +Silvery-gray super- +ficial erosions may form on the oral, pharyngeal, and genital +mucous membranes. +Lymphadenopathy, mild fever, malaise, +and weight loss are also common in secondary syphilis. +Secondary syphilis lasts several weeks, and then +the person enters the latent stage of the disease. +Tertiary Syphilis. +These may occur alone +or in combination. +• Neurosyphilis may be symptomatic or asymptomatic. +Symptomatic neurosyphilis is discussed in Chapter 28. +Gummas are rare because +of the use of effective antibiotics. +Congenital Syphilis. +Much of the pathology of syphilis can +be ascribed to the ischemia produced by the vascular lesions. +The pathogenesis of endarteritis is unknown. +The immune response to T. +The infiltrating +CD4+ T cells are Th1 cells that may activate macrophages to +kill the bacteria. +In many patients, +the organism persists despite these host responses. +A protein +in the outer membrane of T. +Syphilis is divided into three stages, with distinct +clinical and pathologic manifestations (Fig. +8.33). +Primary Syphilis. +Hepatomegaly and skeletal abnormalities are common. +Late +manifestations develop in nearly one-half of untreated +children with neonatal syphilis. +Serologic Tests for Syphilis. +Serology remains the mainstay +of diagnosis of syphilis. +Serologic tests include nontrepo- +nemal antibody tests and antitreponemal antibody tests. +pallidum. +Treponemal antibody tests measure antibodies +that specifically react with T. +pallidum. +These include the +fluorescent treponemal antibody absorption test and the T. +pallidum enzyme immunoassay test. +There is only one FDA-approved point-of-care test in the +United States. +• Both types of test are very sensitive (>95%) for secondary +syphilis. +• Treponemal tests are very sensitive for tertiary and latent +syphilis. +• Treponemal tests, which are nonquantitative, remain +positive, even after successful therapy. +8.34). +8.4). +Red lesions in the mouth or vagina +contain the most organisms and are the most infectious. +Tertiary syphilis most frequently involves the aorta, +the CNS, and the liver, bones, and testes. +The aortitis is +caused by endarteritis of the vasa vasorum of the proximal aorta. +8.35 for the +histopathology of syphilis). +(Courtesy Dr. +Eighth-nerve deafness +and optic nerve atrophy develop secondary to meningovascular +syphilis. +afzelii and B. +garinii in Europe +and Asia. +These are each transmitted from rodents or, for +B. +garinii from birds, to people by Ixodes deer ticks. +Lyme +disease is endemic in the United States, Europe, and Asia. +Most cases occur +in the northeastern states and the upper Midwest. +In endemic +areas, B. +burgdorferi infects up to 50% of ticks, which may +also be infected with Ehrlichia spp. +and Babesia spp. +Serology +is the main method of diagnosis, but PCR can be done on +infected tissue. +Lyme disease involves multiple organ systems and is +divided into three stages (Fig. +8.36). +This lesion, +called erythema migrans, may be accompanied by fever +and lymphadenopathy. +The rash spontaneously disap- +pears in 4 to 12 weeks. +In Europe, B. +• The third stage, late disseminated disease, manifests many +months after the tick bite. +B. +burgdorferi usually causes a +chronic arthritis sometimes with severe damage to large +joints. +Less often, patients will have polyneuropathy and +encephalitis that vary from mild to debilitating. +Lyme +encephalopathy is less common in Europe than in the +United States. +Pathogenesis +B. +burgdorferi does not produce endotoxin or exotoxins that +damage the host. +The inflammatory lesions are likely triggered by T cells +and cytokines. +They occur in most organs +but particularly in skin, subcutaneous tissue, bone, and joints. +8.35). +The rash of congenital syphilis is more severe than that of +adult secondary syphilis. +It is a bullous eruption of the palms and +soles of the feet associated with epidermal sloughing. +The liver is often severely affected in congenital syphilis. +Gummas are occasionally found in the liver, +even in early cases. +The lungs may be affected by a diffuse +interstitial fibrosis. +(Figure modified from Dr. +Charles Chiu, +University of California, San Francisco, Calif. +burgdorferi escapes +the antibody response through antigenic variation. +B. +Environmental anaerobes also cause disease (tetanus, botu- +lism, and gas gangrene). +Abscesses are usually +caused by mixed anaerobic and facultative aerobic bacterial +infections. +The bacteria found in head and neck abscesses reflect +oral and pharyngeal microbiota. +Common anaerobes at +this site include the gram-negative bacilli Prevotella spp. +and Porphyromonas spp., often mixed with the facultative S. +aureus and S. +pyogenes. +and Clostridium spp., as well +as gram-negative Bacteroides fragilis and E. +coli. +coli or +S. +agalactiae. +MORPHOLOGY +Skin lesions caused by B. +burgdorferi are characterized by edema +and a lymphocytic-plasma cell infiltrate. +In late Lyme disease, +there may be extensive erosion of the cartilage in large joints. +difficile colitis with antibiotic treatment). +Otherwise, these lesions +pathologically resemble those of the common pyogenic infections. +If the respiratory +muscles are affected, botulism can lead to death. +C. +difficile. +There +has been significant success in treatment of C. +Clostridial Infections +Clostridium spp. +Four types of disease are caused by Clostridium +spp.: +• C. +perfringens, C. +Spontaneous gas gangrene due to +C. +septicum is highly associated with an underlying +malignancy. +• C. +• C. +• C. +The bacteria release toxin and cause pseudo- +membranous colitis (Chapter 17). +Pathogenesis +C. +C. +perfringens +secretes 14 toxins, the most important of which is α-toxin. +This toxin has multiple actions. +It also has a sphingomyelinase activity that +contributes to nerve sheath damage. +Ingestion of food contaminated with C. +perfringens causes +a brief diarrhea. +C. +The neurotoxins produced by C. +botulinum and C. +tetani +both inhibit release of neurotransmitters, resulting in +paralysis. +Botulism toxin, eaten in contaminated foods or +absorbed from wounds infected with C. +botulinum, binds +gangliosides on motor neurons and is transported into the +cell. +perfringens; these +are described next. +8.37). +Gas bubbles caused by bacterial +fermentation appear within the gangrenous tissues. +C. +trachomatis +causes lymphogranuloma venereum, a chronic, ulcerative +disease. +Rectal strictures are particularly +common in women. +dusk-colored, wedge-shaped infarcts in the small bowel, particularly +in neutropenic people. +Regardless of the site of entry, when C. +perfringens disseminates hematogenously, there is widespread +formation of gas bubbles. +Chlamydial Infections +C. +trachomatis is a small gram-negative bacterium that is an +obligate intracellular pathogen. +C. +trachomatis exists in two +forms during its unique life cycle. +The infectious form, called +the elementary body, is metabolically inactive. +The diseases caused by C. +The venereal infections caused by +C. +trachomatis are discussed here. +Genital infection by C. +trachomatis is the most common +bacterial STI in the world. +In 2016, approximately 1.6 million +cases of genital chlamydia were reported to the CDC. +Genital C. +gonorrhoeae. +Unlike N. +gonorrhoeae urethritis, C. +trachomatis +urethritis in men may be asymptomatic and so may go +untreated. +Both N. +gonorrhoeae and C. +trachomatis frequently +cause asymptomatic infections in women. +C. +MORPHOLOGY +The features of C. +Organisms are not visible in Gram-stained smears or +sections. +Regional lymphadenopathy +is common, usually occurring within 30 days of infection. +The latter, in turn, may cause +local lymphatic obstruction, lymphedema, and strictures. +It is associated +with wars and poverty, when individuals live in close +contact with poor hygiene. +• Scrub typhus (caused by Orientia tsutsugamushi) is transmit- +ted by chiggers (mites). +These +bacteria predominantly infect monocytes (E. +chaffeensis) +or neutrophils (A. +phagocytophilum). +Rash +occurs in approximately 40% of people with E. +chaffeensis +infections. +Subsequent CTL responses are critical for elimination of +rickettsial infections. +CTLs lyse infected cells, reducing +bacterial proliferation. +Figure 8.38 Typhus nodule in the brain. +in a minority of cases. +8.38). +Scrub typhus, or mite-borne infection, is usually a milder +version of typhus fever. +The rash is usually transitory or might +not appear. +Vascular necrosis or thrombosis is rare, but there +may be a prominent inflammatory lymphadenopathy. +Rocky Mountain Spotted Fever. +akari, R. +africae, and R. +8.39). +A noncar- +diogenic pulmonary edema causing adult respiratory distress +MORPHOLOGY +Typhus Fever. +Yeast Infections +Candidiasis +C. +albicans is the most prevalent fungal pathogen of +humans. +glabrata, C. +tropicalis, C. +parapsilosis, +and C. +krusei being more frequent. +This section will focus +on C. +albicans. +Most C. +Residing normally in the skin, mouth, gastrointestinal tract, +and vagina, Candida spp. +usually live as benign commensals +and seldom produce disease in healthy people. +These infec- +tions may be confined to the skin or mucous membranes or +may disseminate widely. +In otherwise healthy people, C. +albicans causes vaginitis and diaper rash. +albicans can spread to the bloodstream. +Pathogenesis +A single strain of C. +albicans can be successful as a commensal +or a pathogen. +There is no known environmental reservoir +for C. +albicans, unlike other Candida spp., and C. +C. +albicans can shift +between nine distinct cell shapes. +These variants can exhibit altered colony morphology, cell +shape, antigenicity, and virulence. +C. +C. +The ability of C. +C. +(Courtesy Dr. +Ehrlichiosis and anaplasmosis have similar presentations. +The rash is nonspecific and can be macular, maculopapular, or +petechial. +8.40). +Cell +walls give fungi their shape. +Yeasts are round to oval and +mainly reproduce by budding. +Some yeasts, such as C. +Molds consist of threadlike filaments (hyphae) +that grow and divide at their tips. +They can produce round +cells called conidia that easily become airborne, disseminating +the fungus. +• Neutrophils and macrophages phagocytose C. +albicans, +and oxidative killing by these phagocytes is a first line +of host defense. +The important role of neutrophils and +macrophages is illustrated by the increased risk of C. +albicans infection in individuals with neutropenia or +defects in NADPH oxidase or myeloperoxidase. +• C. +The Th17 responses elicited by C. +albicans +promote the recruitment of neutrophils and monocytes +(Chapter 6). +These responses are critical for protection +against C. +Deep under the surface, there is mucosal hyperemia and +inflammation. +C. +8.41). +C. +It is usually +associated with intense itching and a thick, curdlike discharge. +8.41). +A BC +Figure 8.41 The morphology of Candida infections. +(A) Severe candidiasis of the distal esophagus. +(B) Hematoxylin and eosin stain of esophageal +candidiasis reveals the dense mat of Candida spp. +(C) Characteristic pseudohyphae and budding yeast of Candida spp. +(C, Courtesy Dr. +It has subsequently been linked +to cryptococcal infections in other regions of the world. +Because most current tests used to diagnose cryptococcal +infections do not distinguish between C. +gatti and C. +neo- +formans, the true incidence of infections caused by these +two agents is currently uncertain. +Based on findings from +areas where C. +gattii is now specifically monitored, it appears +that C. +gattii is more likely than C. +C. +gattii is associated +with certain species of trees, is found in soil, and, like C. +neoformans, is acquired by inhalation. +Pathogenesis +Cryptococcus spp. +Cryptococcus +spp. +Cryptococcus spp. +Cryptococcus spp. +also produce small (micro) cells of 2 to 4 µm that may +be adapted for growth in macrophages. +• Melanin production. +• Enzymes. +Phospholipases degrade cell wall components +and may aid tissue invasion. +Urease helps neutralize the +reactive oxygen species and pH of the phagocytic cell. +• Differential cellular response to phagocytes. +A mechanism +has been hypothesized to explain the success of the C. +gattii strain in the Northwestern U.S. +Further investigation of these pathogenic pathways +is needed for complete understanding. +such as armpits or webs of the fingers and toes (intertrigo); and +penile skin (balanitis). +Candida spp. +In the +latter group, the tricuspid valve is involved. +Candida auris Infections +C. +auris is an emerging pathogen associated with multiple +nosocomial infections on five continents. +Increased colonization and infection +with non-albicans Candida spp. +are attributed in part to +increased use of prophylactic antifungal agents. +There is +an association of C. +Colonization +with C. +auris has been reported in nares, groin, axilla, and +rectum. +Mortality in patients with invasive C. +C. +Cryptococcosis +Two species of cryptococcus are known to cause disease in +humans, C. +neoformans and C. +gattii, both of which grow as +encapsulated yeasts. +It has long been recognized that +although C. +Many +of these patients receive high-dose corticosteroids, a major +risk factor for C. +neoformans infection. +C. +MORPHOLOGY +Cryptococcus spp. +have yeast forms, but not pseudohyphal or hyphal +forms, in human hosts. +8.42) and can be detected in blood or CSF with various +immunoassays. +C. +The +cysts have a characteristic cup-shaped appearance, or they are +oval with a central dot. +Clusters of organisms in bronchoal- +veolar lavage fluid may be 200 µm in diameter. +The nucleus +and mitochondria are visible by Wright-Giemsa stain. +8.43). +Fluorescein-conjugated +antibody stains are commonly used to diagnose these infec- +tions. +Many Pneumocystis spp. +exist, and each species is host- +specific. +No environmental source or external reservoir +outside of humans has been identified for P. +Most people +are infected transiently early in life, with subsequent effective +clearance. +Extrapulmonary findings with P. +Infection with P. +jirovecii induces both +a humoral and cellular immune response. +capsulatum, +and Coccidioides immitis. +This section discusses some impor- +tant hyaline (transparent) molds. +The major lesions caused by Cryptococcus spp. +are in +the CNS, involving the meninges, cortical gray matter, and +basal nuclei. +The host response to cryptococci is extremely +variable. +8.42). +In severely +immunosuppressed persons, C. +neoformans may disseminate +widely to the skin, liver, spleen, adrenals, and bones. +Suppuration also may occur, as +well as a rare granulomatous arteritis of the circle of +Willis. +Pneumocystis Infections +P. +The organism can cause a +AB +Figure 8.43 Pneumonia caused by Pneumocystis jirovecii. +(A) Alveoli of lung filled with foamy exudate (arrow) and interstitial inflammation. +(B) Silver stain of +alveoli, showing cysts of Pneumocystis jirovecii stained black (arrows). +Ann M. +Aspergillus fumigatus +is the most common pathogenic species of the fungus. +Pathogenesis +Aspergillus spp. +are transmitted as airborne conidia, and the +lung is the major portal of entry. +The small size of A. +fumigatus +spores, approximately 2 to 3 µm, enables them to reach +alveoli. +As conidia grow and form hyphae, these molecules +are exposed. +Both receptors activate +phagocytes to ingest and kill the conidia. +In immunosup- +pressed states, conidia can germinate into hyphae, which +then invade tissues. +Neutrophils +produce reactive oxygen intermediates that kill hyphae. +Invasive aspergillosis is highly associated with neutropenia +and impaired neutrophil defenses. +The antioxidant +defenses include melanin pigment, mannitol, catalases, and +superoxide dismutases. +Aflatoxin is made by Aspergillus spp. +Sensitization to Aspergillus spores +produces an allergic alveolitis (Chapter 15). +People with aspergillomas usually have +recurrent hemoptysis. +Invasive aspergillosis is an opportunistic infection that is +confined to immunosuppressed hosts. +8.44A). +8.44B). +by morphology alone. +A B +Figure 8.44 Aspergillus infection. +(A) Invasive aspergillosis of the lung in a bone marrow transplant patient. +Neutrophils +have a key role in killing hyphae after germination by directly +damaging hyphae walls. +PARASITIC INFECTIONS +Protozoal Infections +Protozoa are unicellular eukaryotic organisms. +Most protozoal infections are diagnosed by +microscopic examination of blood smears or lesions. +vivax, P. +ovale, P. +knowlesi, and P. +8.45). +Meningoencephalitis or +ophthalmitis +Bloodstream Plasmodium spp. +Malaria +Babesia spp. +Babesiosis +Trypanosoma spp. +Note +the irregular width and near right-angle branching of the hyphae. +Compare +with Aspergillus, Fig. +8.44.Parasitic infections 389 +after initial infection. +The infection of the liver and develop- +ment of merozoites is called the exoerythrocytic stage. +This +stage is asymptomatic. +Upon lysis of the red cell, the +new merozoites infect additional red cells. +Several features of P. +falciparum account for its greater +pathogenicity: +• P. +• P. +Adhesive +polypeptides, including P. +8.46). +• In P. +Host resistance to Plasmodium can be intrinsic or acquired. +The +mutations fall into four broad classes. +Pathogenesis +The life cycles of the Plasmodium spp. +are similar, although +P. +falciparum differs in ways that contribute to its greater +virulence. +P. +vivax, P. +ovale, P. +knowlesi, and P. +P. +The life cycle of Plasmodium spp. +8.46). +During P. +falciparum +infection, rupture usually occurs within 8 to 12 weeks. +In +contrast, P. +vivax and P. +Both exoerythrocytic and +erythrocytic stages are depicted. +ICAM-1, Intercellular adhesion molecule +1; RBC, red blood cell. +(Drawn by Dr. +vivax because they do +not have the Duffy antigen. +P. +Each haploid P. +falciparum +genome has multiple genes encoding variants of these +parasite proteins. +CTLs may also be important in resistance to P. +falciparum. +In some, the myocardium shows focal interstitial +infiltrates. +duncani +and B. +venatorum. +The white-footed mouse is the reservoir +for B. +microti, and in some areas, nearly all mice have a +persistent low-level parasitemia. +B. +Babesia spp. +parasitize +red cells and cause fever and hemolytic anemia. +Macrophages with +engulfed parasitized red cells are also numerous. +With progression of malaria, the liver becomes enlarged and +pigmented. +In cerebral malaria caused by P. +falciparum, brain vessels +are plugged with parasitized red cells (Fig. +8.47). +superficially resemble P. +8.48). +The level of B. +There are several forms +of disease that are caused by different Leishmania spp. +Old +World (L. +major, L. +tropica, L. +donovani, and L. +New World (L. +mexicana, L. +braziliensis, +and L. +chagasi) refers to the Western Hemisphere (parts of +Mexico, Central America, and South America). +A few cases +have been acquired in Texas and Oklahoma. +Leishmania spp. +manipulate innate host defenses to +facilitate their entry and survival in phagocytes. +Promas- +tigotes produce two abundant surface glycoconjugates that +contribute to their virulence. +Thus, the parasite becomes coated +with C3b but avoids destruction by the membrane attack +complex. +To escape killing by neutrophils, Leishmania spp. +Leishmania spp. +Amastigotes reproduce in macrophage phagolysosomes, +which normally have a pH of 4.5. +Leishmania spp. +In addition, macrophages +downregulate the transferrin receptor and remove iron from +the phagosome. +The primary mechanisms of resistance and susceptibility +to Leishmania spp. +are determined by Th1 and Th2 responses. +Parasite-specific CD4+ Th1 cells are needed to control +Leishmania spp. +in mice and humans. +Leishmania spp. +evade +host immunity by impairing the development of the Th1 +response. +By contrast, +mouse strains that are susceptible to leishmaniasis mount +a dominant Th2 response. +Leishmaniasis is endemic throughout the Middle +East, South Asia, Africa, and Latin America. +It may also +be epidemic, as is tragically the case in Sudan, India, Ban- +gladesh, and Brazil. +Culture, PCR, or histologic examination is used to +diagnose the infection. +Pathogenesis +The life cycle of Leishmania spp. +Mammals, including +rodents, dogs, and foxes, are reservoirs of Leishmania spp. +When sandflies bite infected humans or animals, macro- +phages harboring amastigotes are ingested. +How far the amastigotes spread throughout the body +depends on the specific Leishmania spp. +by +inhibiting the microbicidal activity of macrophages. +MORPHOLOGY +Leishmania spp. +In the late +stages, the liver becomes increasingly fibrotic. +Hemorrhages +related to thrombocytopenia may also be fatal. +Mucocutaneous leishmaniasis is found only in the New +World. +Microscopically, they contain +aggregates of foamy macrophages stuffed with Leishmania +organisms. +Figure 8.49 Giemsa stain of a tissue macrophage with Leishmania +donovani parasites. +fly (vector) populations. +A few hundred cases are reported +per year. +brucei rhodesiense) or from other +humans (T. +brucei gambiense). +Diagnosis is made by microscopic examination of +blood smears, lymph node, or chancre. +In this way, +African trypanosomes cause waves of fever before they +finally invade the CNS. +Trypanosomes have many VSG +genes, only one of which is expressed at a time. +The parasite +uses an elegant mechanism to turn VSG genes on and off. +To ensure +exposure to lysosomes, T. +T. +cruzii evades the complement +system activation by expressing complement regulatory +proteins. +• The presence of persistent T. +For +example, cross-reactive antibodies may induce electro- +physiologic dysfunction of the heart. +In addition, damage to the myenteric plexus causes dilation +of the colon (megacolon) and esophagus. +Figure 8.50 Slender bloodstream parasites of African trypanosomiasis. +8.50) concentrate in capillary +loops, such as the choroid plexus and glomeruli. +T. +cruzi parasites infect many animals, +including cats, dogs, and rodents. +At the site of skin entry, there may be +a transient, erythematous nodule. +Diagnosis can be made by a blood smear in the +acute case, but is made more commonly by serology. +MORPHOLOGY +In lethal acute myocarditis, the changes are diffusely distributed +throughout the heart. +Chronic Chagas cardiomyopathy +often has to be treated by cardiac transplantation. +Toxoplasmosis +Although millions of people carry the ubiquitous parasitic +protozoa T. +gondii without symptoms due to control by +their immune systems, T. +It is estimated that 11% of the US population +6 years of age and older has been infected. +In some regions +of the world, 95% of the population has been infected. +T. +Another route of infection +is vertical transmission during pregnancy. +Rarely, infec- +tion occurs via blood transfusion or organ transplantation. +Myocarditis and pneumonitis are two other +common manifestations in AIDS patients. +Pathogenesis +The cat is the only definitive host, and humans are a +dead-end host. +Unsporulated oocysts are shed in cat feces, +which sporulate in the environment. +The sporozoites +transform into tachyzoites that localize to tissues and develop +into bradyzoites. +Cats become infected after ingestion of +intermediate hosts. +T. +Bobbi S. +To avoid +clearance of the tachyzoites, T. +gondii also inhibits autophagy +of the parasite-containing vacuole. +Although +diagnosis is usually through serologic testing, cysts may be observed +in biopsies (Fig. +Tachyzoites may be observed with +periodic acid-Schiff, Giemsa, or hematoxylin and eosin stains. +Tissue +cysts can vary in size from 5 to 100 µm. +Intact cysts can remain +for the life of the host without causing inflammation. +The cyst +wall is thin and contains crescent-shaped bradyzoites of approxi- +mately 1.5 by 7 µm. +Metazoal Infections +Metazoa are multicellular, eukaryotic organisms with organ +systems. +It occurs sporadically in the United States, including in +Appalachia. +In immunocompetent hosts, S. +to +increase infective larvae production. +Figure 8.52 Strongyloides hyperinfection in a patient treated with +high-dose cortisone. +(Courtesy Dr. +These can grow to many +meters in length and produce mild abdominal symptoms. +The most serious manifestations result from encystment +in the brain (neurocysticercosis). +Convulsions, increased +intracranial pressure, and other neurologic disturbances +may occur. +Viable T. +When the cysticerci die +and degenerate, an inflammatory response develops. +In humans, these parasites live only in the gut +and do not form cysticerci. +For E. +granulosus the +definitive host is the dog, and the usual intermediate hosts +are sheep. +For E. +multilocularis the fox is the most important +definitive host, and rodents are intermediate hosts. +Eggs +hatch in the duodenum and larvae invade the liver, lungs, +or bones. +Hyperinfection with S. +There are many adult +worms, larvae, and eggs in the crypts of the duodenum and ileum +(Fig. +8.52). +Both diseases are caused by larvae that develop +after ingestion of tapeworm eggs. +T. +New proglottids +develop behind the scolex. +T. +spiralis, T. +nativa, or T. +britovi. +There are an estimated +10,000 cases in the world each year. +In the United States +the number of T. +Pathogenesis +The life cycle of T. +spiralis begins in the human intestine +but ends within muscle as humans are dead-end hosts. +In +the human gut, T. +In striated skeletal muscle, +T. +T. +In animal models of T. +Figure 8.53 Portion of a cysticercus cyst in the skin. +8.53). +E. +In time a dense +fibrous capsule forms. +Daughter cysts often develop within the +large mother cyst. +Larvae in the heart do not encyst and are difficult to +identify, because they die and disappear. +T. +8.54). +Coiled larvae are approximately 1 mm long and are +Trichinosis +Trichinella spp. +mansoni and S. +japonicum). +haematobium, +bladder walls, allowing the eggs to be shed in stool or urine, +respectively. +Infection of freshwater snails completes the +life cycle. +This immune response to S. +mansoni and S. +Figure 8.54 Multiple coiled Trichinella spiralis larvae within skeletal muscle +cells. +MORPHOLOGY +In early S. +mansoni or S. +japonicum infections, white, pinhead-sized +granulomas are scattered throughout the gut and liver. +8.55). +The affected organs and hence the site of major +disease vary with the species. +Shistosoma mansoni and S. +japonicum affect the liver and the gut predominantly. +Most +deaths are due to hepatic cirrhosis, which is caused by S. +mansoni in Latin America, Africa, and the Middle East and +by S. +japonicum and S. +mekongi in East Asia. +By contrast, S. +Severe hepatic fibrosis +is a serious manifestation of chronic schistosomiasis. +The life cycle of Schistosoma spp. +There is minimal skin +reaction. +Mosquitoes +that bite infected individuals take up the microfilariae and +can transmit the disease. +The genomes of W. +bancrofi and +B. +Wolbachia spp. +impair nematode survival and fertility. +Immune responses to the filarial worms produce damage +to the human host. +Figure 8.56 Pipe-stem fibrosis of the liver due to chronic Schistosoma +japonicum infection. +In late S. +mansoni or S. +japonicum infections, inflammatory +patches or pseudopolyps may form in the colon. +8.56). +In S. +The most frequent complication of S. +8.57). +Frequently +there is hydrocele and lymph node enlargement. +(B. +malayi [90%] or B. +timori [10%]), which +are responsible for 120 million infections worldwide. +Figure 8.57 Massive edema and elephantiasis caused by filariasis of the +leg. +(Courtesy Dr. +Willy Piessens, Harvard School of Public Health, Boston, +Mass.) +MORPHOLOGY +O. +Keratitis is sometimes +accentuated by treatment with antifilarial drugs (Mazzotti reaction). +deposits; the epidermis is thickened and hyperkeratotic. +Over time, the +dilated lymphatics develop polypoid infoldings. +It is transmitted by black flies and affects 17 million +people in Africa, South America, and Yemen. +infections in Africa and +South America. +Adult O. +The presence of an STI in a child, unless acquired +during birth, strongly suggests sexual abuse. +Some pathogens, such as Chlamydia trachomatis and N. +gonorrhoeae, are almost always spread by sexual intercourse, +whereas others, such as Shigella spp. +and E. +• Infection with one STI-associated organism increases the risk +for additional STIs. +This is mainly because the risk factors +are the same for all STIs. +In addition, the epithelial injury +caused by N. +gonorrhoeae or C. +Perinatally acquired C. +Syphilis frequently causes miscar- +riage. +Untreated HIV infection may be fatal to children +infected with the virus prenatally or perinatally. +Syphilis is discussed earlier in this chapter, and other +STIs are described in Chapters 21 and 22. +Table 8.8 lists the history of diseases that have emerged +over the past half century. +pylori gastritis, HBV and HCV, and Legionella +pneumophila. +Some infectious agents are new to humans, +such as HIV causing AIDS, and B. +burgdorferi causing Lyme +disease. +avium- +intracellulare, P. +jirovecii, and Cryptosporidium parvum). +Finally, +infectious diseases that are common in one area may be +introduced into a new area. +tuberculosis, N. +gonorrhoeae, S. +aureus, and K. +pneumoniae. +auris, and +some of the Babesia spp. +Agents of Bioterrorism. +Other category A agents +include B. +anthracis, Yersinia pestis, and Ebola virus. +Many +of these agents are food-borne or water-borne. +Examples +include Brucella spp. +and V. +cholerae. +Examples include Hantavirus and Nipah virus. +Changes in the environment occasionally +drive rates of infectious diseases. +[A concise presentation of a model of C. +[A +short discussion of Th1 and Th2 immune responses to M. +lesion rather than at its center, particularly if there is necrosis. +The presence of +specific IgM antibody shortly after the onset of symptoms +is diagnostic. +In the United States in 2018, there were nearly +3 million occupational injuries and illnesses. +Disease related +to malnutrition is even more pervasive. +In this chapter, we first consider the emerging problem +of the health effects of climate change. +During 2018, the global land temperature was +1.1°C warmer than the 20th century average. +9.1A), ozone (an +important air pollutant, discussed later), and methane. +9.1B). +(A, Courtesy Dr. +Richard +21st century. +Different computer models plot anticipated rises in global +located around the globe. +• Malnutrition, caused by changes in local climate that +disrupt crop production. +TOXICITY OF CHEMICAL AND +PHYSICAL AGENTS +Toxicology is defined as the science of poisons. +It studies +the distribution, effects, and mechanisms of action of toxic +agents. +We now consider some basic principles relevant to the +effects of toxic chemicals and drugs. +• The definition of a poison is not straightforward. +It is basi- +cally a quantitative concept that depends on dosage. +9.2). +• Chemicals may act at the site of entry or at other sites +following transport through the blood. +If repair is not effective, short-term +and long-term effects develop. +9.2 and 9.3) occur in two phases. +In phase I reactions, +chemicals undergo hydrolysis, oxidation, or reduction. +Water-soluble +compounds are readily excreted. +• The most important catalyst of phase I reactions is the +cytochrome P-450 enzyme system. +There is great variation in the activity of CYPs among +individuals. +Known CYP inducers include environmental +chemicals, drugs, smoking, alcohol, and hormones. +In +contrast, fasting or starvation can decrease CYP activity. +Air is +precious to life, but can also carry many potential causes +of disease. +Here we consider these hazards in outdoor and indoor air. +It may seem that +air pollution is a modern phenomenon, but this is hardly +the case. +Except for some comments on smoking, pollutant-caused +lung diseases are discussed in Chapter 15. +Major health effects +of outdoor pollutants are summarized in Table 9.1. +Ozone, +sulfur dioxide, particulates, and CO are discussed here. +This layer protects life on earth by +absorbing the most dangerous UV radiation emitted by the +sun. +These chemicals are released by industrial emissions +and motor vehicle exhaust. +Of greater concern is acute toxicity. +The mor- +phologic changes are not specific and stem from systemic hypoxia. +Only +a few comments about other agents are made here. +Radon is the number +one cause of lung cancer among nonsmokers, according +to EPA estimates. +Overall, radon is the second leading +cause of lung cancer. +Radon is responsible for about 21,000 +lung cancer deaths every year. +About 2,900 of these deaths +occur among people who have never smoked. +Formaldehyde is classified +as a carcinogen for humans and animals. +Lead exposure may +occur through contaminated air, food, and water. +A dramatic case of lead contamination +of drinking water occurred in Flint, Michigan, in 2014–2016. +As a result, 6000 to 12,000 resi- +dents developed very high lead levels in their blood. +A more permeable blood–brain barrier +in children creates a high susceptibility to brain damage. +The main clinical features of lead poisoning in children and +adults are shown in Figs. +9.4 and 9.5. +9.6). +Iron incorporation into heme is impaired, leading to micro- +cytosis (small red cells) and anemia. +The diagnosis +of lead poisoning requires constant vigilance. +Lead toxicity in a pregnant woman may impair brain +development in the fetus. +The gastrointestinal tract is also a major source of clinical +manifestations. +Lead colic is characterized by severe, poorly +localized abdominal pain. +Chronic renal damage leads eventually to interstitial fibrosis and +renal failure. +Decreases in uric acid excretion can lead to gout +(saturnine gout). +Alchemists +tried (without much success) to produce gold from mercury. +9.5). +Even more distinctive +is a punctate basophilic stippling of the red cells. +Brain damage is prone to occur in children. +(Courtesy Dr. +G. +W. +In some areas of the world, +mercury used in gold mining has contaminated rivers and +streams. +Almost 90% of ingested methyl mercury is absorbed in the +gastrointestinal tract. +Ingested mercury can +injure the gut and cause ulcerations and bloody diarrhea. +In the kidneys, mercury can cause acute tubular necrosis +and renal failure. +Chronic exposure can cause nephrotic +syndrome. +It may be released into the environment from mines and +smelting industries. +• Skin changes consisting of hyperpigmentation and hyper- +keratosis occur with chronic exposure. +Cadmium can contaminate the soil +and plants directly or through fertilizers and irrigation water. +Food is the most important source of cadmium exposure +for the general population. +Cadmium exposure +can also cause skeletal abnormalities associated with +calcium loss. +Industrial exposures to toxic +agents are as varied as the industries themselves. +Human +diseases associated with occupational exposures are listed +in Table 9.2. +Lower levels may cause liver and kidney toxic- +ity. +Occupational exposure to benzene and 1,3-butadiene +increases the risk of leukemia. +• Cadmium from nickel-cadmium batteries and chemical fertilizers +can contaminate soil. +Excess cadmium causes obstructive lung +disease and kidney damage. +Data from Leigh JP, et al: Occupational injury and illness in the United States. +DDT was banned in the United States in 1973. +Acute DDT poisoning in humans causes neurologic +toxicity. +• Nonpesticide organochlorines include PCBs and dioxin +(TCDD). +It can be accompanied by abnormali- +ties in the liver and CNS. +BPA has long +been known as a potential endocrine disruptor. +The extent of the human health risks +associated with BPA remains uncertain. +• Inhalation of mineral dusts causes chronic, nonneoplastic +lung diseases called pneumoconioses. +Expo- +sure to these agents nearly always occurs in the workplace. +Pneumoconioses and their pathogenesis are +discussed in Chapter 13. +Effects of Tobacco +Smoking is the most readily preventable cause of death +in humans. +Of these, almost 2.5 million died +as a result of inhalation of second-hand smoke. +Indeed, +tobacco is the leading exogenous cause of human cancers, +including 90% of lung cancers. +Of people alive today, an estimated 500 million +will die of tobacco-related illnesses. +The cumulative effects of +smoking over time are striking. +9.7). +Lung cancer mortality decreases by 21% within 5 +years, but the excess risk persists for 30 years. +The number of potentially noxious chemicals in tobacco +smoke is extraordinary. +Smoking and Lung Cancer. +9.8). +Moreover, smoking +increases the risk of other carcinogenic influences. +9.9). +Smoking and Other Diseases. +9.10). +• The toll taken by nonmalignant conditions associated with +smoking is even more terrible. +Measured +at age 75, the difference in survival between smokers and nonsmokers is +7.5 years. +Nicotine, an alkaloid present in tobacco leaves, is strongly +addictive. +Recent studies indicate that in addition +to being addictive, nicotine has other untoward effects. +Smoking exacerbates asthma and increases +the risk for pulmonary tuberculosis. +The Health Consequences of +Smoking—50 Years of Progress: A Report of the Surgeon General. +COPD, +Chronic obstructive pulmonary disease. +• Smoking also harms the developing fetus. +Birth weights of infants born to mothers +who stopped smoking before pregnancy are, however, +normal. +9.10). +It is clear +that the transient pleasure of smoking comes with a heavy +long-term price. +By the end of +2019 close to 2000 cases had been reported to the CDC, +with 42 fatalities. +The pathogenesis of this outbreak is +under intense investigations. +disease, and cerebrovascular disease. +It is estimated that alcohol consumption is +responsible for more than 80,000 deaths annually. +Worldwide, alcohol accounts for +approximately 3.3 million deaths per year (5.9% of all +deaths). +Less than +10% is excreted unchanged in the urine, sweat, and breath. +The rate of metabolism affects the +blood alcohol level. +Chronic alcoholics develop tolerance +to alcohol. +9.11). +Cessation +of smoking reduces the risk of lung cancer. +• Smokeless tobacco use is an important cause of oral cancers. +Oxidation of acetaldehyde by aldehyde dehydrogenase (ALDH) occurs in mitochondria. +ADH oxidation is the most important route; catalase is involved in only 5% of ethanol metabolism. +Oxidation through CYPs may also generate reactive +oxygen species (not shown). +(From Parkinson A: Biotransformation of xenobiotics. +Catalase +is of minor importance, being responsible for only about +5% of alcohol metabolism. +Several toxic effects result from ethanol metabolism. +Listed +here are only the most important of these. +Its deficiency is a main cause of the accumula- +tion of fat in the liver of alcoholics. +The increase in the +NADH/NAD ratio in alcoholics also causes lactic +acidosis. +• ROS generation. +The adverse effects of ethanol can be classified as acute +or chronic. +The gastric changes are acute gastritis +and ulceration. +Consequently, there is stimulation and disordered cortical, +motor, and intellectual behavior. +Respiratory arrest may follow. +• The liver is the main site of chronic injury. +• Neurologic effects. +• Cardiovascular effects. +Alcohol has diverse effects on the +cardiovascular system. +• Pancreatitis. +Excessive alcohol intake increases the risk +of acute and chronic pancreatitis (Chapter 19). +• Fetus. +• Carcinogenesis. +As mentioned earlier, +alcohol and cigarette smoke synergize in the causation +of various cancers. +• Malnutrition. +Ethanol is a substantial source of energy +(empty calories). +Not all is gloom and doom, however. +It seems that the old saying is true, +at least with respect to alcohol—all things in moderation! +Stupor and coma develop at higher +levels. +9.12). +Older adults (above 65 years) are much more likely to +suffer from adverse drug reactions. +B +Figure 9.12 Adverse drug reaction. +Skin pigmentation caused by +minocycline, a long-acting tetracycline derivative. +(A) Diffuse blue-gray +pigmentation of the forearm. +(B) Deposition of drug metabolite/iron/ +melanin pigment particles in the dermis. +(Courtesy Dr. +Warfarin is +an antagonist of vitamin K, and dabigatran is a direct inhibi- +tor of thrombin. +As a result, maintaining anticoagulation +in a relatively safe therapeutic range can be problematic. +They act by inhibiting ovulation or preventing +implantation. +Transdermal and implantable for- +mulations have also become available. +Nevertheless, there +is good evidence to support the following conclusions. +• Breast carcinoma. +The prevailing opinion is that OCs do +not increase breast cancer risk. +• Endometrial cancer and ovarian cancers. +• Cervical cancer. +OCs may increase risk of cervical carci- +nomas in women infected with human papillomavirus. +• Thromboembolism. +• Cardiovascular disease. +• Hepatic adenoma. +Acetaminophen +Acetaminophen is the most commonly used analgesic in +the United States. +It is present in more than 300 products, +alone or in combination with other agents. +However, subsequent randomized clinical trials have +produced decidedly mixed results. +But during the past few years +there has been a reappraisal of the risks and benefits of +MHT. +There +is no increase in the risk for ovarian cancer. +However, MHT should not be used for prevention of +cardiovascular disease or other chronic diseases. +• MHT increases the risk of stroke and VTE including deep +vein thrombosis and pulmonary embolism. +The risks of VTE and stroke appear to be lower with +transdermal than oral routes of estrogen. +The effect of +route of administration continues to be studied. +The +CNS changes may progress to convulsions and coma. +The +morphologic consequences of chronic salicylism are varied. +Approximately, 450,000 +people died in 2015 as a result of drug use. +Common drugs of abuse are listed +in Table 9.6. +Considered here are cocaine, opioids, amphet- +amines, and marijuana, among others. +Cocaine sold on the street is liberally diluted +with talcum powder, lactose, or other look-alikes. +It can be +snorted or dissolved in water and injected subcutaneously +or intravenously. +See text for details. +GSH, Glutathione; NAPQI, NAPQI, N-acetyl-p-benzoquinoneimine. +(Courtesy Dr. +Xavier Vaquero, Department of Pathology, University of +Washington, Seattle, Wash.) +(Fig. +9.13). +Some +patients also show evidence of concurrent renal damage. +From Hyman SE: A 28-year-old man addicted to cocaine, JAMA 286:2586, 2001. +sound it makes when heated to produce vapors that are +inhaled. +The pharmacologic actions of cocaine and crack +are identical, but crack is far more potent. +Experimental animals will press a lever more than 1000 times +and forgo food and drink to obtain it. +The acute and chronic effects of cocaine on various organ +systems are as follows. +• Cardiovascular effects. +9.14). +• CNS. +• Effects on pregnancy. +Neurologic development may be impaired in the fetus +of a pregnant woman who is a chronic drug user. +• Other effects. +Of +these deaths, 40% were from prescription opioids. +Heroin is a street drug derived from the poppy plant that +is closely related to morphine. +Use of heroin is even more +harmful than cocaine use. +The effects on the CNS are varied and include euphoria, +hallucinations, somnolence, and sedation. +• Infections. +Infectious complications are common. +• Skin. +Cutaneous lesions are probably the most frequent +telltale sign of heroin addiction. +Acute changes include +abscesses, cellulitis, and ulcerations due to subcutaneous +injections. +• Kidneys. +Kidney disease is a relatively common hazard. +Amphetamines and Related Drugs +Methamphetamine. +Some of the +most important adverse effects of heroin follow. +• Sudden death. +The yearly mortality +among heroin users in the United States is estimated to +be between 1% and 3%. +• Pulmonary injury. +Not much is known about the long-term deleterious +effects of any of these agents. +On the other hand, therapeutic uses for psychoactive +drugs are emerging. +About 5% to 10% of THC is +absorbed when it is smoked in a hand-rolled cigarette +(“joint”). +Marijuana use causes euphoria and a sense of +relaxation. +The functional and organic CNS consequences of +marijuana smoking have received the most scrutiny. +Marijuana cigarettes contain a large number of carcinogens +that are also present in tobacco. +Whether marijuana causes physical dependence and +addiction remains controversial. +These drugs include various stimulants, +depressants, analgesics, and hallucinogens (Table 9.6). +• Overdose of acetaminophen may cause centrilobular liver +necrosis, leading to liver failure. +Early treatment with agents +that restore GSH levels may limit toxicity. +Each type is considered separately. +Mechanical Trauma +Mechanical forces may inflict a variety of forms of damage. +Bone and head injuries +result in unique damage and are discussed elsewhere +(Chapters 26 and 28). +Details +about the practice of forensic pathology can be found in +specialized textbooks. +Thermal Injury +Both excessive heat and excessive cold are important causes +of injury. +• Superficial burns (formerly known as first-degree burns) +are confined to the epidermis. +• Partial-thickness burns (formerly known as second-degree +burns) involve injury to the dermis. +• Full-thickness burns (formerly known as third-degree burns) +extend to the subcutaneous tissue. +Shock, sepsis, and respiratory insufficiency are the +greatest threats to life in burn patients. +As a result, virtually all burns become colonized +with bacteria. +aureus, +and fungi, particularly Candida species, may also be involved. +Removal of the burn wound decreases +infection and reduces the need for reconstructive surgery. +• Heat cramps result from loss of electrolytes via sweating. +Cramping of voluntary muscles, usually in association +with vigorous exercise, is the hallmark. +Heat-dissipating +mechanisms are able to maintain normal core body +temperature. +• Heat exhaustion is probably the most common hyperthermic +syndrome. +• Heat stroke is associated with high ambient temperatures, +high humidity, and exertion. +Hyperkalemia, tachycardia, arrhythmias, +and other systemic effects are common. +RYR1 regulates the release of +calcium from the sarcoplasm. +• Malignant hyperthermia, despite the name, is not caused +by exposure to high temperatures. +Such changes are typical of trench foot. +Lightning is a classic cause of high-voltage electrical +injury. +Ionizing radiation is a double-edged sword. +Radiation Units. +This is an expression of the +amount of radiation emitted by a source. +The +cGy terminology has now replaced the Rad in medical +practice. +For the same absorbed +dose, various types of radiation produce different amounts +of damage. +The effective dose of x-rays in +radiographs and CT is commonly expressed in mil- +liSieverts (mSv). +For x-radiation, 1 mSv = 1 mGy. +Main Determinants of Biologic Effects of Ionizing Radia- +tion. +• Rate of delivery significantly modifies the biologic effect. +• Field size has a great influence on the consequences of +irradiation. +• Cell proliferation. +9.15). +• Oxygen effects and hypoxia. +• Vascular damage. +These changes +may appear months or years after exposure (Fig. +9.16). +Fig. +9.17 shows the overall consequences of radiation +exposure. +These consequences vary according to the dose +of radiation and type of exposure. +Several abnormal nuclear morphologies may be seen. +Early changes occur in hours to weeks; late changes occur +in months to years. +ARDS, Acute respiratory distress syndrome. +Acute Effects on Hematopoietic and Lymphoid +Systems. +After a brief rise in the circulating +neutrophil count, neutropenia appears within several days. +Neutrophil counts reach their nadir, often at counts near zero, +during the second week. +If the patient survives, recovery +of a normal granulocyte count may require 2 to 3 months. +when evaluating irradiated tissues for the possible persistence of +tumor cells. +Vascular changes and interstitial fibrosis are also prominent +in irradiated tissues (Fig. +9.18). +During the immediate postirradia- +tion period, vessels may show only dilation. +Affected vessels may rupture or thrombose. +Total-Body Irradiation. +Doses below 1 Sv produce minimal +symptoms, if any. +(A) Normal salivary gland. +(B) Fibrosis +caused by radiation. +(C) Fibrosis and vascular changes consisting of fibrointimal thickening and arteriolar sclerosis. +I, Thickened intima; V, vessel lumen. +(Courtesy Dr. +Anemia +appears after 2 to 3 weeks and may persist for months. +Fibrosis. +9.18). +9.19 and 9.20). +DNA Damage and Carcinogenesis. +The most serious damage to DNA +consists of DSBs. +Note the markedly thickened pericardium. +Cancer Risks From Exposures to Radiation. +Any cell +capable of division that has sustained a mutation has the +potential to become cancerous. +It is +believed that the risk of secondary cancers following irradia- +tion is greatest in children. +Radon gas is a ubiquitous +product of the spontaneous decay of uranium. +of these components are missing from the diet. +There are several conditions that may lead to primary +or secondary malnutrition. +• Poverty. +• Acute and chronic illnesses. +Failure to recognize these +nutritional needs may delay recovery. +• Chronic alcoholism. +• Ignorance and failure of diet supplementation. +Ignorance about the nutritional content of foods is also +a contributing factor. +• Self-imposed dietary restriction. +• Other causes. +Worldwide +about 50 million children are affected by SAM. +In addition to loss +of life, wars also exact a heavy toll on refugees who live in +abject poverty. +The sections that follow barely skim the surface of +nutritional disorders. +Other +nutrients and nutritional issues are discussed in the context +of specific diseases. +(A) Marasmus. +(B) Kwashiorkor. +The infant shows generalized edema, seen as ascites and puffiness of the face, hands, and legs. +At two ends of +SAM are marasmus and kwashiorkor. +These two compartments are regulated differently, +as detailed subsequently. +The diagnosis of SAM is obvious in its most severe forms. +Recent studies suggest a role for the gut +microbiome in the pathogenesis of SAM. +Marasmus. +Marasmus develops when the diet is severely +lacking in calories (Fig. +9.21A). +A child is considered to +have marasmus when weight falls to 60% of normal for sex, +height, and age. +In addition to muscle +proteins, subcutaneous fat is also mobilized and used as +fuel. +Kwashiorkor. +9.21B). +The prevalence of kwashiorkor +also is high in lower income countries of Southeast Asia. +9.21). +The weight of children with severe kwashiorkor typically +is 60% to 80% of normal. +However, the true loss of weight +is masked by the increased fluid retention (edema). +In further +contrast with marasmus, there is relative sparing of subcu- +taneous fat and muscle mass. +The modest loss of these +compartments may also be masked by edema. +Malnutrition in the Upper Income World. +well to full-strength, milk-based diets.With treatment, the mucosal +changes are reversible. +Depending on the predominant factor, the red cells +may be microcytic, normocytic, or macrocytic. +Cachexia. +Because of its common association with cancer, +cachexia is discussed in Chapter 7. +Anorexia +nervosa has the highest death rate of any psychiatric disorder. +The clinical findings in anorexia nervosa are generally +similar to those in SAM. +In addition, effects on the endocrine +system are prominent. +In addition, dehydration +and electrolyte abnormalities are frequently present. +The +skin becomes dry and scaly. +9.22). +9.23). +Retinol is then transported in chylomicrons to the liver for +esterification and storage. +Uptake in liver cells takes place +through the apolipoprotein E receptor. +Function. +In humans, the main functions of vitamin A are +the following: +• Maintenance of normal vision. +be present. +In bulimia, binge eating is the norm. +Large amounts of +food, principally carbohydrates, are ingested, followed by +induced vomiting. +The distinction between fat-soluble and water-soluble +vitamins is important. +• Metabolic effects of retinoids. +The association of RXR and +PPARγ thus explains the metabolic effects of retinoids +on adipogenesis. +• Enhancing immunity to infections. +Vitamin A Deficiency. +The +pathologic effects of vitamin A deficiency are summarized +in Fig. +9.24. +As already discussed, vitamin A is a component of +rhodopsin and other visual pigments. +Persistent deficiency gives rise to epithelial metaplasia and +keratinization. +The most devastating changes occur in the +eyes and are referred to as xerophthalmia (dry eye). +via neurons from the retina to the brain. +• Cell growth and differentiation. +Both RAR and RXR have three isoforms, α, β, and γ. +Not depicted are night blindness and immune deficiency. +Vitamin A Toxicity. +Both short-term and long-term excesses +of vitamin A may produce toxic manifestations. +Metabolism of Vitamin D. +This reaction results in the synthesis +of cholecalciferol, known as vitamin D3. +Herein, the term +vitamin D is used to refer to this compound. +The main steps of vitamin D metabolism are summarized +as follows: +1. +9.25). +Functions. +The receptors for +1,25-dihydroxyvitamin D are present in most cells of the +body. +Effects of Vitamin D on Calcium and Phosphorus +Homeostasis. +• Stimulation of calcium reabsorption in the kidney. +TRPV5 expression is also +regulated by PTH in response to hypocalcemia. +• Interaction with PTH in the regulation of blood calcium. +Vitamin D maintains calcium and phosphorus at +supersaturated levels in the plasma. +The parathyroid +glands have a key role in the regulation of extracellular +calcium concentrations. +• Mineralization of bone. +9.26A). +When hypocalcemia occurs due to vitamin D deficiency +(Fig. +Deficiency States. +In all of these situations, vitamin D deficiency can be +prevented by a diet high in fish oils. +(B) Detail of a rachitic costochondral junction in which the palisades of cartilage is lost. +Darker trabeculae are well-formed bone; paler +trabeculae consist of uncalcified osteoid. +(C) Rickets: note bowing of legs due to formation of poorly mineralized bones. +(B, Courtesy Dr. +Andrew E. +During the nonambulatory +stage of infancy, the head and chest sustain the greatest stresses. +An excess of osteoid produces +frontal bossing and a squared appearance to the head. +9.26C). +It was not +until 1932 that ascorbic acid was identified and synthesized. +All but the most restricted diets provide +adequate amounts of vitamin C. +Function. +Ascorbic acid has many functions affecting a +variety of processes: +• Collagen synthesis. +• Neurotransmitter synthesis. +Synthesis of norepinephrine +requires hydroxylation of dopamine, a step that requires +vitamin C. +• Antioxidant functions. +• Modulating the immune response. +Deficiency States. +Consequences of vitamin C deficiency +(scurvy) are illustrated in Fig. +9.28. +Nonskeletal Effects of Vitamin D. +Vitamin D Toxicity. +Vitamin C Excess. +Simi- +larly, there is no evidence that large doses of vitamin C +protect against cancer development. +It is +caused by diets low in protein but normal in calories. +It is caused by diets severely lacking in both protein +and nonprotein calories. +Bulimia is a condition in which food binges +alternate with induced vomiting. +Vitamin D is a key regulator of +calcium and phosphate homeostasis. +• Vitamin C and members of the vitamin B family are water-soluble. +Vitamin C is needed for collagen synthesis and collagen cross- +linking and tensile strength. +B vitamins have diverse roles in +cellular metabolism. +How does +one measure fat accumulation? +BMI is calculated as +(weight in kilograms)/(height in meters)2, or kg/m2. +In the +United States, obesity has reached epidemic proportions. +The etiology of obesity is complex and incompletely +understood. +Genetic, environmental, and psychologic factors +are involved. +However, simply put, obesity is a disorder of +energy homeostasis. +The hypothalamus is the master regula- +tor of energy homeostasis. +9.29 and 9.30). +• The peripheral or afferent system generates signals from +various sites. +The afferent systems +provide signals to the central processing system in the +brain. +Two sets of +neurons participate in central processing (see Fig. +9.30). +Here these signals inhibit anabolic circuits and +activate catabolic circuits. +This in turn reduces the energy stores, and energy sufficiency signals are blunted. +(AgRP). +These first-order neurons communicate with +second-order neurons. +See text for details. +NPY/AgRP neurons also directly inhibit +POMC/CART neurons, thus blunting their anorexigenic +effect. +The orderly functioning +of these two pedals maintains energy homeostasis. +Leptin. +Leptin is secreted by fat cells, and its output is +regulated by the adequacy of fat stores. +BMI and body fat +stores are directly related to leptin secretion. +In persons of stable weight, the activities of +these pathways are balanced. +The neurohumoral mediators +of leptin-induced energy expenditure are less well defined. +Both POMC/CART and NPY/AgRP neurons express insulin +receptors. +Adiponectin. +Its serum levels are lower in obese +than in lean individuals. +Adiponectin binds to two receptors, AdipoR1 and +AdipoR2. +Gut Hormones. +Gut peptides act as short-term meal initia- +tors and terminators. +They include ghrelin, PYY, and +GLP-1 (glucagon-like peptide-1), among others. +Its injection +in rodents elicits voracious feeding, even after repeated +administration. +Ghrelin acts centrally by activating orexigenic NPY/AgRP +neurons. +PYY and GLP-1 are secreted from endocrine cells in the +ileum and colon. +Plasma levels of PYY and GLP-1 are low +during fasting and increase shortly after food intake. +Adipose Tissue. +BAT has the +unique property of expending energy by nonshivering +thermogenesis. +BAT is abundant in newborns and is located +primarily in interscapular and supraclavicular areas. +Lesser +amounts are present around kidneys, aorta, heart, pancreas, +and trachea. +Until recently, it was thought that BAT is lost +in adults. +However, recent imaging studies have revealed +that some BAT is preserved in adolescents and adults. +Much +effort is now focused on how BAT can be preserved in +adulthood and activated to burn energy. +Role of the Gut Microbiome. +The relevance +of the mouse models to human obesity is tantalizing but +remains to be proven. +Differences between the gut micro- +biome of obese and lean humans have also been reported. +Whether this difference is causal or just an association is +unclear. +9.31). +(Modified from Renehan AG, et al: and cancer. +This in turn stimulates secretion of IL-1, which induces +systemic inflammation. +The following associations are worthy +of note. +Inflammation induced by IL-1 and other factors likely +contributes to insulin resistance. +• Nonalcoholic fatty liver disease is commonly associated with +obesity and type 2 diabetes. +It can progress to fibrosis +and cirrhosis (Chapter 18). +• Cholelithiasis (gallstones) is six times more common in obese +than in lean subjects. +Hypoventilation +syndrome is a constellation of respiratory abnormalities +in very obese persons. +The greater the body burdens of fat, +the greater the trauma to joints with the passage of time. +The +underlying mechanisms are unknown and are likely to be +multiple. +• Elevated insulin levels. +9.31). +For example, hyperinsulinemia causes a rise in levels of +free insulin-like growth factor 1 (IGF-1). +IGF-1 is a +mitogen, and its receptor, IGFR-1, is highly expressed +in many human cancers. +• As discussed earlier, adiponectin secretion from adipose +tissue is reduced in obese individuals. +Adiponectin sup- +presses cell proliferation and promotes apoptosis. +It does +so in part by promoting the actions of p53 and p21. +In +obese individuals these antineoplastic actions of adipo- +nectin may be compromised. +Bile acid +metabolites produced by these bacteria may function +as carcinogens. +KEY CONCEPTS +OBESITY +• Obesity is a disorder of energy regulation. +A few examples suffice here. +This is called primary prevention. +We know some, but not all, the answers. +Of these, the effect on kisses is the +best established! +[A large European study relating all-cause mortality and +particulate inhalation]. +Hon KL, Fung CK, Leung AKC: Childhood lead poisoning: an overview, +Hong Kong Med J 23:616, 2017. +[A discussion of lead poisoning in +childhood]. +[A comprehensive paper on heavy metal poisoning]. +[A discussion of alcohol usage +and cancer at different dose levels]. +https:// +www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung- +disease.html. +[CDC report on severe lung injury associated with use of +flavored e-cigarettes]. +[A discussion of +accumulating evidence for association of type 2 diabetes and tobacco smoking]. +[A summation of the evidence linking e-cigarette use +and disease]. +[A comprehensive report by the US Surgeon General on the health +effects of smoking]. +JAMA Internal Medicine published +online February 11, 2019. +E1 [A short article on the magnitude of the +US opioid crisis]. +National Institute on Drug Abuse (NIDA). +https://www.drugabuse.gov +updated in June 2019. +[An extensive discussion of the effects of marijuana +use and abuse including possible addiction]. +Million M, Diallo A, Raoult R: Review. +Gut microbiota and malnutrition, +Microb Pathog 106:127, 2017. +[An excellent discussion of the potential +role of microbiome in pathogenesis of malnutrition]. +Padayatty SJ, Levine M: Vitamin C: the known and unknown and +Goldilocks, Oral Dis 22:463, 2016. +[A detailed discussion of vitamin C +physiology and diseases associated with deficiency]. +[A broad overview of the role of dietary supplements including vitamins +in disease prevention]. +Sarri JC: Vitamin A metabolism in rod and cone visual cycles, Annu +Rev Nutr 32:125, 2012. +[A discussion of the biochemical mechanism of +vitamin A in vision]. +[An appraisal of the +possible role of vitamin C in sepsis management]. +[A review of several large studies linking obesity with +all-cause mortality]. +[A discussion of neurohumoral mechanisms and +obesity]. +[A balanced review of the role of +the microbiome in obesity]. +[A discussion of the +role of brown adipose tissue in energy homeostasis]. +[A discussion of the high risk +of cardiovascular disease with obesity in a South Asian population]. +Gonzalez-Muniesa P, Martinez-Gonzalez M-A, Hu FB et al: Obesity, +Nat Rev Dis Primers 3:1, 2017. +[A general review of obesity with focus +on visceral and truncal obesity]. +[A discus- +sion of the association of cancers with obesity]. +[An excellent discussion of energy homeostasis including neurohumoral +mechanisms]. +Zhao VW, Scherer PE: Adiponectin, the past two decades, J Mol Cell +Biol 8:93, 2016. +Husain • Selene C. +The chances for survival of infants improve with +each passing week. +Once the infant survives the first year +of life, the outlook brightens measurably. +Perhaps 20% of fertilized ova are so +anomalous that they are blighted at early stages. +Others +may be compatible with early fetal development, only to +a The prior contributions of Dr. +Anirban Maitra to this chapter are +gratefully acknowledged. +453454 CHAPTER 10 Diseases of Infancy and Childhood +Figure 10.1 Examples of malformations. +(A and C, Courtesy Dr. +Reade +Quinton; B, Courtesy Dr. +10.1). +Develop- +mental anomalies may present in several patterns. +10.2). +A variety +of environmental agents may cause disruptions (see +later). +Deformations are common +problems, affecting approximately 2% of newborn infants +to varying degrees. +The most common underlying factor responsible for +deformations is uterine constraint. +Thus, even the normal fetus is subjected to +some degree of uterine constraint. +Several factors increase +Figure 10.2 Disruption of morphogenesis by an amniotic band. +(Courtesy Dr. +For example, clubfeet can occur as a com- +ponent of Potter sequence, described later. +• A sequence is a cascade of anomalies triggered by one +initiating aberration. +A good example +is the oligohydramnios (or Potter) sequence (Fig. +10.3). +10.4). +The hips may be dislocated. +Nodules in the amnion +(amnion nodosum) are frequently present. +Note the flattened +facial features and deformed right foot (talipes equinovarus). +primordium. +Virtually all chromosomal syndromes are associated with +congenital malformations. +Examples include Down syndrome +and other trisomies, Turner syndrome, and Klinefelter +syndrome. +Most chromosomal disorders arise during +gametogenesis and hence are not familial. +disturbances. +These in combination are labeled the fetal +alcohol syndrome (also discussed in Chapter 9). +In light of these findings, it is best to avoid nicotine +exposure altogether during pregnancy. +1. +10.5). +During this period, organs are being crafted +out of the germ cell layers. +Instead, the fetus is susceptible to growth +restriction or injury to already formed organs. +2. +This is +illustrated by the following representative examples. +• Valproic acid is an antiepileptic and a recognized +teratogen during pregnancy. +Conversely, excessive exposure +to retinoic acid is also teratogenic. +Rupture +of membranes (ROM) before the onset of labor can be +spontaneous or induced. +In contrast, PROM refers to +spontaneous ROM occurring after 37 weeks of gestation. +• Intrauterine infection: This is a major cause of preterm +labor with and without intact membranes. +Maternal malnutrition (in +particular, prolonged hypoglycemia) may also affect fetal +growth. +Fetal infection should be considered in all infants with +FGR. +In some cases the +placenta (and the baby) may be small without any detectable +underlying cause. +Pathogenesis +The fundamental defect in RDS is pulmonary immaturity +and deficiency of surfactant. +At birth, +the first breath of life requires high inspiratory pressures +to expand the lungs. +The +hypoxemia itself further impairs surfactant synthesis, and +a vicious cycle ensues. +The role of glucocorticoids +is particularly important. +intrauterine stress and FGR that increase corticosteroid +release lower the risk of developing RDS. +This may explain, in part, why infants +of diabetic mothers have a higher risk of developing RDS. +Microscopically, alveoli are poorly +developed, and those that are present are collapsed (Fig. +10.7). +In uncomplicated cases, recovery begins +to occur within 3 or 4 days. +• Retinopathy of prematurity has a two-phase pathogenesis. +Treatment with mesenchymal stem cells has potential +but remains experimental. +It occurs in approximately +1 in 10 very-low-birth-weight infants (<1500 g). +Approxi- +mately 2500 cases occur annually in the United States. +The pathogenesis of NEC is uncertain but multifacto- +rial. +Perhaps alteration in the microbiome on enteral feeding +Figure 10.7 Hyaline membrane disease. +There are eosinophilic thick +hyaline membranes lining the dilated alveoli. +Fine rales can then be heard over both lung fields. +Critical to these +objectives is the ability to assess fetal lung maturity accu- +rately. +A large number of inflammatory mediators have +been associated with NEC. +Probiotic therapies are being evaluated for preven- +tion of NEC. +Such +infections may be acquired in utero or around the time of +birth. +As stated earlier, preterm birth is a common and +unfortunate consequence of infection. +10.8). +Figure 10.8 Necrotizing enterocolitis (NEC). +10.10). +The mother thus +becomes sensitized to the foreign antigen. +Thus, Rh +disease is uncommon with the first pregnancy. +chorionic villi. +10.9). +There is no effective protection against ABO reactions. +There are two consequences of excessive destruction of +red cells in the neonate (see Fig. +10.10). +• Anemia is a direct result of red cell loss. +Cardiac hypoxia may lead to cardiac decompensation +and failure. +• Jaundice develops because hemolysis produces unconju- +gated bilirubin (Chapter 18). +Bilirubin also passes through +the infant’s poorly developed blood-brain barrier. +10.13). +Fetal anemia, not +caused by Rh- or ABO-associated antibodies, can also result +in hydrops. +10.9). +In up to 20% of cases, the cause remains unknown. +Several +factors account for this. +First, most anti-A and anti-B antibod- +ies are of the IgM type and hence do not cross the placenta. +Second, neonatal red cells express blood group antigens A +and B poorly. +Therefore, the firstborn +may be affected. +(A) There is generalized accumulation of fluid in the fetus. +(Courtesy Dr. +The most serious threat in fetal hydrops is CNS damage, +known as kernicterus (Fig. +The biochemical abnormality in PKU is an inability to +convert phenylalanine into tyrosine. +The remainder is converted +to tyrosine by the phenylalanine hydroxylase system (Fig. +10.14). +coined the term in 1908, the number of recognized metabolic +diseases has increased exponentially. +Mitochondrial disorders (Chapter 5) form a distinct entity +by themselves. +About one-third of these children are never able to walk, +and two-thirds cannot talk. +Long-term toxicity in galactosemia has been variously +imputed to these metabolic intermediates. +The liver, +eyes, and brain bear the brunt of the damage. +Similar changes may occur in the cerebral +cortex and white matter. +These infants fail to thrive almost from birth. +Vomiting +and diarrhea appear within a few days of milk ingestion. +Even in untreated +infants, however, the disability is usually not as severe as +that seen in PKU. +Hemolysis and +coagulopathy in the newborn period can occur as well. +Newborn screening tests are widely utilized in the United +States. +They depend on fluorometric assay of GALT enzyme +activity on a dried blood spot. +A positive screening test +must be confirmed by assay of GALT levels in red cells. +Deficiency of +PAH or dihydropteridine reductase (DHPR) can give rise to +phenylketonuria. +excreted in large amounts in the urine and sweat. +These +impart a strong musty or mousy odor to affected infants. +It is believed that excess phenylalanine or its metabolites +contribute to the brain damage in PKU. +Concomitant lack +of tyrosine (see Fig. +10.14), a precursor of melanin, is +responsible for the light color of hair and skin. +At the molecular level, over 500 mutant alleles of the +PAH gene have been identified. +Mutations in both PAH +alleles are required to develop the disease. +Once a biochemical diagnosis is established, the +specific mutation causing PKU can be determined. +10.14). +It affects 1 in 60,000 live-born infants. +Galactose is then converted to glucose +in several steps catalyzed by distinct enzymes. +Two variants +of galactosemia have been identified. +The rare variant arises from a deficiency +of galactokinase. +10.15). +The two trans- +membrane domains form a channel through which chloride +passes. +Bottom, Normal cystic +fibrosis transmembrane conductance regulator (CFTR) structure and +activation. +This results in +opening of the chloride ion channel. +discussed later in the context of pulmonary and +gastrointestinal pathology in cystic fibrosis. +This is the basis +for the “salty” sweat that mothers can often detect in +their affected infants. +10.16). +CFTR, Cystic fibrosis transmembrane conductance regulator; ENaC, +epithelial sodium channel. +layer coating mucosal cells. +• CFTR regulates transport of bicarbonate ions. +The mutations can be grouped +into six classes based on their effect on the CFTR protein +(Fig. +10.17). +Class I mutations result in no protein production. +Class III mutations affect channel regulation, impairing +channel opening (e.g., Gly551Asp). +Class IV mutants show reduced conduction—i.e., decreased flow of ions (e.g., Arg117His). +Class V mutations cause +substantial reduction in mRNA or protein, or both. +Class VI mutations cause substantial plasma membrane instability. +• Class I: Defective protein synthesis (null mutations). +• Class II: Abnormal protein folding, processing, and trafficking +(processing mutations). +Worldwide, this mutation can be found in +approximately 70% of Caucasian cystic fibrosis patients. +• Class III: Defective regulation (gating mutations). +Thus, there is a normal amount +of CFTR on the apical surface, but it is nonfunctional. +• Class IV: Decreased conductance (conduction mutations). +There is a normal amount of CFTR at the apical +membrane, but with reduced chloride conduction. +• Class V: Reduced abundance (production mutations). +• Class VI: Decreased membrane CFTR stability (instability +mutations). +10.18). +Concurrent viral infections predispose +to such colonization. +Figure 10.19 End-stage pancreatic disease in cystic fibrosis. +The ducts are +markedly dilated, and exocrine glands are destroyed and replaced by +fibrous tissue. +proliferation and portal inflammation. +Hepatic steatosis is not +an uncommon finding in liver biopsies. +Such severe hepatic involvement is +encountered in less than 10% of patients. +The pulmonary changes are the most serious complications +of this disease (Fig. +10.20). +Superimposed infections give rise to severe chronic bronchitis +and bronchiectasis (Chapter 15). +In many instances, lung abscesses +develop. +As mentioned earlier, a mucoid +form of P. +aeruginosa (alginate-producing) is particularly frequent +and causes chronic inflammation. +cenocepacia are the +most common in cystic fibrosis patients. +MORPHOLOGY +The anatomic changes are highly variable in distribution and severity. +In all variants, the sweat glands are mor- +phologically unaffected. +Pancreatic abnormalities are present in approximately 85% +to 90% of patients with cystic fibrosis. +Sometimes +these cause small-bowel obstruction, known as meconium ileus. +Liver involvement follows the same basic pattern. +These patients have other features of classic cystic +fibrosis, such as pulmonary disease. +Chronic sinopulmonary disease manifested by +a. +Chronic cough and sputum production +c. +Airway obstruction manifested by wheezing and air trapping +e. +Nasal polyps; radiographic or computed tomographic +abnormalities of paranasal sinuses +f. +Digital clubbing +2. +Gastrointestinal and nutritional abnormalities, including +a. +Intestinal: meconium ileus, distal intestinal obstruction +syndrome, rectal prolapse +b. +Pancreatic: pancreatic insufficiency, recurrent acute pancreatitis, +chronic pancreatitis +c. +Salt-loss syndromes: acute salt depletion, chronic metabolic +alkalosis +4. +Figure 10.20 Lungs of a patient who died of cystic fibrosis. +There is +extensive mucus plugging and dilation of the tracheobronchial tree. +10.18). +Pancreatic insufficiency is +associated with protein and fat malabsorption and increased +fecal loss. +Hypoproteinemia may be severe enough to cause +generalized edema. +Persistent diarrhea may result in rectal +prolapse in up to 10% of children with this disease. +By 18 years of age, 80% of +patients with classic cystic fibrosis harbor P. +aeruginosa, and +3.5% harbor B. +cepacia. +Patients with mild pulmonary disease usually +have little or no pancreatic disease. +Adult-onset “idiopathic” +bronchiectasis has been linked to CFTR mutations in a subset +of cases. +However, asymptomatic hepa- +tomegaly may be present in up to one-third of individuals. +Sequencing the +CFTR gene is the gold standard for diagnosis of cystic +fibrosis. +New +treatment modalities for restoring mutant CFTR function +are being tested in clinical trials. +Based on the molecular +defect, three classes of agents are being developed: +• Potentiators. +These agents keep the “gate” of the CFTR +channel open. +Hence they are most useful in gating (class +III) and conduction (class IV) mutations. +• Correctors. +Hence they have the potential to help patients +with processing (class II) mutations. +These include patients +with ΔF508, the most common CFTR mutation. +• Amplifiers. +This number translates to about 1360 deaths due to SIDS +in the United States. +Most infants who +die of SIDS die at home, usually during the night after a +period of sleep. +The CNS demonstrates astrogliosis +of the brainstem and cerebellum. +Male sex is +associated with a slightly greater incidence of SIDS. +Benign tumors are even more +common than cancers. +(Courtesy Dr. +Hemangioma +Hemangiomas are the most common tumors of infancy +(Chapter 11). +Architecturally, they do not differ from those +occurring in adults. +10.21). +Teratomas +Teratomas illustrate the relationship of histologic maturity +to biologic behavior. +10.22). +They occur with a frequency of 1 in 20,000 to 40,000 live +Figure 10.22 Sacrococcygeal teratoma. +Histologically, many of the malignant nonhematopoietic +pediatric neoplasms are unique. +If the anatomic site of origin +is known, diagnosis is usually possible on histologic grounds +alone. +The +remaining tumors are discussed in their respective organ- +specific chapters. +Neuroblastoma is the most important member of this family. +The median age at diagnosis is 18 months; approxi- +mately 40% of cases are diagnosed in infancy. +On transection, they are composed +of soft, gray-tan tissue. +Larger tumors have areas of necrosis, +cystic softening, and hemorrhage. +Occasionally, foci of punctate +intratumoral calcification can be palpated. +Mitotic activity, nuclear breakdown +(“karyorrhexis”), and pleomorphism may be prominent. +10.23). +Some neoplasms show signs of maturation that can be +spontaneous or therapy-induced. +Spindle-shaped +Schwann cells are present in the background stroma. +10.24). +Metastases, when they develop, appear early and widely. +Staging. +The staging system is of paramount +importance in determining prognosis. +This tumor is composed of small +cells embedded in a finely fibrillar matrix (neuropil). +complaints. +The clinical course of neuroblastomas is extremely +variable. +The biologic basis of this welcome behavior is not +clear. +The age of 18 months has emerged as a critical +point of dichotomy in terms of prognosis. +• Tumor morphology. +The specific morphologic features that bear on prognosis +are listed in Table 10.7. +• MYCN amplification status. +MYCN is located on the distal short arm of chromosome +2 (2p23-p24). +10.25). +Whole-genome sequencing has uncovered alterations in +a variety of genes. +Some of these alterations have prognostic +implications. +The impact of these changes on prognosis is under +investigation. +(A, Courtesy Dr. +Their lifetime risk of developing +Wilms tumor is approximately 33%. +Individuals with +WAGR syndrome carry constitutional (germline) +deletions of 11p13. +The characteristic glomerular +lesion in these patients is diffuse mesangial sclerosis +(Chapter 20). +As in patients with WAGR, these patients +also demonstrate germline abnormalities in WT1. +The WT1 protein is +critical for normal renal and gonadal development. +BWS has served as a model +for tumorigenesis associated with genomic imprinting +(Chapter 5). +Some of them are +associated with specific histologic features described +later. +MORPHOLOGY +Grossly, Wilms tumor tends to present as a large, solitary, well- +circumscribed mass. +Approximately 10% are either bilateral or +multicentric at the time of diagnosis. +10.26). +10.27A). +Sheets of small blue cells with few distinctive features +characterize the blastemal component. +Epithelial differentiation +is usually in the form of abortive tubules or glomeruli. +10.27B). +Although +multiple mitotic figures are seen, none are atypical in this field. +As stated, most patients with Wilms tumor can expect +to be cured of their malignancy. +Anaplastic histology is +perhaps the most critical determinant of adverse prognosis. +Elborn JS: Cystic fibrosis, Lancet 388:2519–2531, 2016. +[An excellent +overview including clinical and molecular features of cystic fibrosis]. +http://ommbid.mhmedical.com/ +content.aspx?bookid=971§ionid=62673211. +(Accessed December +11, 2017). +[An in-depth online resource that reviews this prototypical +Mendelian disorder]. +[Updated consensus guidelines for the diagnosis of cystic fibrosis]. +[A concise review +of pathogenesis, diagnosis, and treatment of this condition]. +[A review of clinical, histologic, and molecular determinants +of prognosis for Wilms tumor]. +Matthay KK, Maris JM, Schleiermacher G et al: Neuroblastoma, Nat +Rev Dis Primers 2:16078, 2016. +[An excellent recent review of the clinical, +pathologic, and molecular features of neuroblastoma]. +PubMed PMID: 28814547. +Mitchell • Marc K. +veins at the same level of branching to accommodate pulsatile +flow and higher blood pressures. +11.1). +layer of ECM; the intima is demarcated from the media +by the internal elastic lamina. +• In muscular arteries, the media is composed predomi- +nantly of circumferentially oriented SMCs. +• Arterioles are the principal points of physiologic resistance +to blood flow. +The adventitia consists of loose +connective tissue and can also contain nerve fibers. +11.1). +Reverse flow (due to gravity) is prevented in the +extremities by venous valves. +Surgically generated arteriovenous fistulas +provide vascular access for chronic hemodialysis. +Like +berry aneurysms, arteriovenous fistulas can rupture. +The cause is +unknown. +In the renal +arteries, it can be a cause of renovascular hypertension +(Chapter 20). +ECs form a specialized simple squamous epithelium lining +for blood vessels. +capillaries, +arteries vs. +veins) have distinct gene expression profiles, +behaviors, and morphologic appearances. +ECs are versatile multifunctional cells with a wealth of +synthetic and metabolic properties. +11.2). +Viruses, +complement components, and hypoxia also activate ECs. +Normal EC function is characterized by a balance +of these responses. +VEGF, Vascular +endothelial growth factor.Hypertensive vascular disease 489 +1. +Recruitment of smooth muscle +cells or smooth muscle precursor +cells to the intima +3. +Elaboration of +2. +circulating precursors. +11.3). +The resulting neointima +is typically completely covered by ECs. +Thus intimal thickening +is the stereotypical response of the vessel wall to any insult. +Neointimal SMCs have a phenotype that is distinct from +that of medial SMCs. +Like height and weight, blood pressure is a continuously +distributed variable. +Table 11.2 lists the major causes of hypertension. +However, approximately 90% of hyperten- +sion is idiopathic—so-called essential hypertension. +anticoagulative, proinflammatory +vs. +antiinflammatory, and nonadhesive vs. +adhesive). +11.4). +• Cardiac output is a function of stroke volume and heart +rate. +Americans. +11.5). +The kidneys filter 170 liters of plasma containing 23 moles +of salt daily. +About 98% of the filtered +sodium is reabsorbed by several constitutively active +transporters. +The kidneys and heart contain cells that sense changes +in blood pressure or volume. +Mechanisms of Essential Hypertension. +They also induce systemic +vasodilation. +Blood volume in +turn is regulated mainly by renal sodium excretion or resorption. +11.5). +Infrequently, hypertension has an underly- +ing endocrine basis. +Mechanisms of Secondary Hypertension. +11.5). +It may +be idiopathic or less commonly caused by aldosterone- +secreting adrenal adenomas. +• Single-gene disorders cause severe but rare forms of +hypertension. +• Mutations affecting proteins that influence sodium reabsorp- +tion. +Three forms of small vessel +disease are hypertension-related (Fig. +11.6). +MORPHOLOGY +Hyaline arteriolosclerosis. +Arterioles show homogeneous, pink +hyaline thickening with associated luminal narrowing (Fig. +11.6A). +(A) Hyaline arteriolosclerosis. +Hyperplastic arteriolosclerosis. +11.6B). +These are described in greater detail in Chapter 15. +There are four general patterns, with different +clinical and pathologic consequences. +Adults older than +age 50 are most commonly affected. +The calcifications +do not encroach on the vessel lumen and are usually not +clinically significant. +• Fibromuscular intimal hyperplasia occurs in muscular arteries +larger than arterioles. +States. +11.7). +Epidemiology. +11.8). +Constitutional Risk Factors +• Genetics. +Family history is the most important independent +risk factor for atherosclerosis. +• Age is a dominant influence. +Thus between ages 40 and 60, the incidence of +myocardial infarction increases fivefold. +Death rates from +ischemic heart disease rise with each decade even into +advanced age. +• Gender. +Higher levels of HDL (“good +cholesterol”) correlate with reduced risk. +Interestingly, approaches that +exclusively raise HDL are not effective. +Smoking cessation reduces that risk substantially. +Clearly, other factors +are contributory. +Among those that are proven or suspected +are the following: +• Inflammation. +Relative +risk (y-axis) refers to the risk of a cardiovascular event (e.g., myocardial +infarction). +In +each risk group, C-reactive protein values further stratify the patients. +11.9). +Accordingly, CRP levels are now incorporated +into risk stratification algorithms. +• Hyperhomocysteinemia. +• Metabolic syndrome. +• Factors affecting hemostasis. +1, Normal. +2, Endothelial injury with monocyte and platelet +adhesion. +3, Monocyte and smooth muscle cell migration into the intima, +with macrophage activation. +4, Macrophage and smooth muscle cell uptake +of modified lipids, with further activation. +Endothelium +Intima +Media +Adventitia +1. +• Other factors. +11.10). +• Accumulation of lipoproteins (mainly LDL and its oxidized +forms) in the vessel wall. +• Platelet adhesion. +• SMC proliferation, ECM production, and recruitment of T +cells. +• Lipid accumulation both extracellularly and within cells +(macrophages and SMCs). +• Calcification of ECM and necrotic debris late in the +pathogenesis. +Endothelial Injury. +EC injury is the cornerstone of the +response-to-injury hypothesis. +Macrophage +activation, +smooth muscle recruitment +Smooth +muscle cell +Fatty streak +4. +Macrophages and +smooth muscle cells +engulf lipid +T lymphocyte +Fibrofatty atheroma +5. +• Modified LDL. +The early lesions containing lipid- +filled macrophages are called fatty streaks. +Inflammation. +Chronic inflammation contributes to the +initiation and progression of atherosclerotic lesions. +11.11). +Infection. +Smooth Muscle Proliferation and Matrix Synthe- +sis. +11.10). +Hemodynamic Disturbances. +Hypercholesterolemia. +All of these abnormalities are associated +with an increased risk of atherosclerosis. +Fig. +All four cell +types are capable of liberating mediators that can influence +atherogenesis. +MORPHOLOGY +Fatty streaks. +Fatty streaks are composed primarily of lipid-filled +foamy macrophages. +The lesions are not particularly raised and do not cause any +significant flow disturbance (Fig. +11.13). +Although fatty streaks +can evolve into plaques, not all are destined to become advanced +lesions. +Atherosclerotic plaque. +The key processes in atherosclerosis +are intimal thickening and lipid accumulation (see Figs. +11.7, 11.10, +and 11.12). +Plaques vary in size +but can coalesce to form larger masses (Fig. +11.14). +11.15A). +Hyperlipidemia, hyperglycemia, hypertension, and other influences cause endothelial +dysfunction. +IL-1, Interleukin-1; MCP-1, monocyte chemoattractant protein-1. +B +A +Figure 11.13 Fatty streak, a collection of foamy macrophages in the intima. +(A) Aorta with fatty streaks (arrows), associated largely with the ostia of +branch vessels. +(B, Courtesy Myron I. +(A) Mild atherosclerosis composed of fibrous plaques, one of which is denoted by the arrow. +of vascular hemodynamics. +Moreover, in any given vessel, lesions at +various stages often coexist. +The lumen (L) has been moderately compromised. +(A) Plaque rupture without superimposed thrombus +in a patient who died suddenly. +In both (A) and (B), an arrow +points to the site of plaque rupture. +11.15C). +11.15C). +Atherosclerotic plaques are susceptible to clinically important +pathologic changes. +11.16). +If the patient +survives, the thrombus may organize and become incorporated +into the growing plaque. +• Hemorrhage into a plaque. +• Atheroembolism. +Plaque rupture can discharge atherosclerotic +debris into the blood stream, producing microemboli. +• Aneurysm formation. +Atherosclerotic Stenosis. +11.17). +Acute Plaque Change. +11.16), resulting in acute tissue infarction +(e.g., myocardial or cerebral infarction) (see Fig. +11.17). +Compensatory enlargement initially prevents a reduction of blood flow through the vessel. +Thin cap plaques are the most prone to plaque +rupture, generally leading to sudden cardiac death. +This event can lead to sudden cardiac death. +syndromes are often asymptomatic before undergoing a +sudden, typically unpredictable change. +Thus a large number of asymptomatic adults may be at risk +for a catastrophic coronary event. +11.18). +Vulnerable plaques have +thin fibrous caps, large lipid cores, and increased inflammation. +Influences extrinsic to plaques also contribute to acute +plaque changes. +and 12 noon). +In +its most serious form, thrombus leads to total occlusion of +the affected vessel. +Mural thrombi in a coronary artery can also embolize. +• Atherosclerotic plaques develop and generally grow slowly over +decades. +11.19). +True aneurysm +A. +Normal vessel D. +False aneurysm E. +Dissection +(fusiform) +B. +True aneurysm +(saccular) +Figure 11.19 Aneurysms. +(A) Normal vessel. +(B) True aneurysm, saccular type. +The wall focally bulges outward and may be attenuated but is otherwise +intact. +(C) True aneurysm, fusiform type. +There is circumferential dilation of the vessel, without rupture. +(D) False aneurysm. +(E) Dissection. +Blood has entered (dissected) the wall of +the vessel and separated the layers. +Dissections are often, but not always, aneurysmal (see later). +Descriptively, aneurysms are classified by macroscopic +shape and size (see Fig. +11.19). +These types are +not specific for any disease or clinical manifestations. +• Abnormal transforming growth factor- β (TGF- β) signaling. +Both processes result in +a loss of elastic fibers necessary for recoil in diastole. +11.20). +Although adventitial lymphoplasmacytic +A +B +Figure 11.20 Cystic medial degeneration. +(B) Normal media for comparison showing the regular layered +pattern of elastic tissue. +AAAs occur more frequently in men and in smokers, +rarely developing before age 50. +be retroperitoneal fibrosis with bilateral hydronephrosis. +In such cases, +suppuration further destroys the media, potentiating rapid dilation +and rupture. +Most aneurysms expand at a rate of 0.2 to +0.3 cm/year, but 20% expand more rapidly. +11.21). +Not infrequently,AAAs +will be accompanied by smaller aneurysms of the iliac arteries. +There may +A B +Figure 11.21 Abdominal aortic aneurysm. +(B) Opened view, with the location of the rupture +tract indicated by a probe. +11.22). +Pathogenesis +Hypertension is the major risk factor for aortic dissection. +11.20); inflam- +mation is characteristically absent. +Thus the relationship +of the structural changes to the pathogenesis of dissection is +uncertain. +A B +Figure 11.22 Aortic dissection. +(B) Histologic view of dissection demonstrating an aortic intramural hematoma (asterisk). +11.22A). +11.22B). +Type A Type B +Figure 11.23 Classification of dissections. +Type B (distal or Debakey III) dissections arise +after the take-off of the great vessels. +Type A dissections typically have the +most serious complications and greatest mortality. +Accordingly, aortic dissec- +tions are generally classified into two types (Fig. +11.23): +• Type A dissections. +• Type B dissections. +Retrograde dissection into the aortic root can also +disrupt the aortic valve annulus. +Common clinical manifesta- +tions include cardiac tamponade and aortic insufficiency. +Com- +plications are related to rupture, thrombosis, and embolization. +Complications arise due to rupture or obstruction of vessels +branching off the aorta. +heart vs. +small bowel). +ANCA, Antineutrophil cytoplasmic antibody. +Nevertheless, several vasculitides +tend to affect only vessels of a particular size or location. +11.24). +As we will see, +there is considerable clinical and pathologic overlap among +many of them. +Often, +however, this type of vasculitis presents a number of +diagnostic challenges. +Only rarely is the specific antigen +responsible for immune complex formation identified. +Note that there is a +substantial overlap in distributions. +ANCA, Antineutrophil cytoplasmic antibody; SLE, systemic lupus erythematosus. +deposits are scarce. +• Vasculitis secondary to infections. +Although a number of +ANCAs have been described, two are most important. +• Anti-proteinase-3 (PR3-ANCA, previously c-ANCA). +PR3-ANCAs are associated with granulo- +matosis with polyangiitis (see later). +• Anti-myeloperoxidase (MPO-ANCA, previously p-ANCA). +MPO-ANCAs are associated with microscopic +polyangiitis and Churg-Strauss syndrome (see later). +A plausible mechanism for ANCA vasculitis is the +following. +Thus ANCA- +associated vasculitides are often described as pauci-immune. +It is +the most common form of vasculitis among elderly adults +in the United States and Europe. +Proinflammatory cytokines (especially TNF) and +anti-EC antibodies also contribute. +11.25), +granulomas and giant cells can be rare or absent. +Inflammatory +IT +A B C +Figure 11.25 Giant cell (temporal) arteritis. +(C, From Salvarani C, et al. +Clinical Features +Temporal arteritis is rare before age 50. +Diagnosis depends on biopsy and histologic +confirmation. +Corticosteroids or anti-TNF +therapies are typically effective. +11.26). +An +autoimmune etiology is likely. +Figure 11.26 Takayasu arteritis. +MORPHOLOGY +Takayasu arteritis classically involves the aortic arch. +11.26A and B). +Such narrowing explains the weakness of the peripheral pulses. +Granulomatous inflam- +mation, replete with giant cells and patchy medial necrosis, is also +seen. +The histology (Fig. +11.26C) is essentially indistinguishable +from giant cell (temporal) arteritis. +Occasion- +ally, aortic root involvement causes dilation and aortic valve +insufficiency. +The course of the disease is variable. +The cause remains unknown in the majority of cases. +Clinical +manifestations result from ischemia and infarction of affected +tissues and organs. +Renal involvement is often +a major cause of mortality. +Its clinical significance stems +from the involvement of coronary arteries. +Originally described in Japan, +the disease is now recognized in the United States and +elsewhere. +11.27). +Older lesions +show fibrous thickening of the vessel wall extending into the +adventitia. +MORPHOLOGY +Kawasaki disease vasculitis resembles that seen in PAN. +As with +other arteritides, healed lesions can also exhibit obstructive intimal +thickening. +Pathologic changes outside the cardiovascular system +are rarely significant. +Clinical Features +PAN is primarily a disease of young adults but can occur +in all age groups. +The course is frequently remitting and +episodic, with long symptom-free intervals. +It is also called hypersensitivity vasculitis or leukocy- +toclastic vasculitis. +There is segmental fibrinoid necrosis +and thrombotic occlusion of the lumen of this small artery. +Note that part +of the vessel wall at the upper right (arrow) is uninvolved. +Indeed, most cases are associ- +ated with MPO-ANCA. +11.28A). +11.28B). +(B and C) Granulomatosis with polyangiitis. +(A, Courtesy Michael A. +11.28C), and +alveolar hemorrhage may be prominent. +Lesions may ultimately +undergo progressive fibrosis and organization. +Clinical Features +Males are affected more often than females, at an average +age of about 40 years. +Rashes, myalgias, articular +involvement, neuritis, and fever can also occur. +Left +untreated, the disease is usually rapidly fatal with 80% +mortality within 1 year. +It occurs almost exclusively in heavy +cigarette smokers, usually before the age of 35. +Identifying the underlying pathology +has therapeutic significance. +11.30). +Raynaud phenomenon can be a primary +entity or secondary to other disorders. +It results from intrinsic hyperreactivity of +medial SMCs. +Ulceration and ischemic gan- +grene are rare. +Less commonly it is caused by infections. +11.24 and +Table 11.4). +A B +Figure 11.30 Raynaud phenomenon. +(A) Sharply demarcated pallor of the distal fingers resulting from the closure of digital arteries. +(B) Cyanosis of the +fingertips. +Of these, some 10% will +eventually manifest an underlying disorder. +Thrombi in the legs tend to produce few, if any, reliable +signs or symptoms. +In many cases the first +manifestation of thrombophlebitis is a pulmonary embolus. +Depending on the size and number of emboli, the outcome +can range from no symptoms to death. +Up to 20% of men and a third of women +develop lower extremity varicose veins. +A familial predilection to varicose veins +reflects defective venous wall development. +Varicosities in two other sites also deserve mention: +• Esophageal varices. +Pulmonary vessels can also +be compressed, inducing respiratory distress. +Eventually inadequate tissue perfusion can lead to skin +ulceration. +Primary tumors of large vessels (aorta, pulmonary +artery, and vena cava) are mostly sarcomas. +In general, benign and malignant +vascular neoplasms can be distinguished by the following +features. +Benign Tumors and Tumor-Like Conditions +Vascular Ectasias. +Most ultimately regress spontaneously. +• Spider telangiectasias are nonneoplastic vascular malforma- +tions grossly resembling a spider. +Hemangiomas. +Hemangiomas are very common tumors +composed of blood-filled vessels (Fig. +11.31); they constitute +7% of all benign tumors of infancy and childhood. +Nearly one-third of internal lesions +occur in the liver. +Malignant transformation is rare. +Several +histologic and clinical variants have been described. +(A) Hemangioma of the tongue. +(B) Histology of juvenile capillary hemangioma. +(C) Histology of cavernous hemangioma. +(D) Pyogenic granuloma of the lip. +(A and D, Courtesy John Sexton, MD, Beth Israel Hospital, Boston, Mass.; B, courtesy Christopher D. +M. +11.31A). +Histologically, +they are composed of thin-walled capillaries with scant +stroma (Fig. +11.31B). +• Cavernous hemangiomas are composed of large, dilated +vascular channels. +11.31C). +Intravascular thrombosis with associated dystrophic +calcification is common. +They bleed easily and are often +ulcerated (Fig. +11.31D). +Roughly a quarter of lesions develop +after trauma, reaching a size of 1 to 2 cm within a few +weeks. +Curettage and cautery is usually curative. +Lymphangiomas. +Lymphangiomas are the benign lymphatic +counterparts of hemangiomas. +The tumor margins are indistinct and +unencapsulated, making resection difficult. +Glomus Tumor (Glomangioma). +Although they may superficially resemble +hemangiomas, glomangiomas arise from SMCs rather than +ECs. +They are most commonly found in the distal portion +of the digits, especially under the fingernails. +Excision is +curative. +Bacillary Angiomatosis. +Lesions can +involve the skin, bone, brain, and other organs. +Two species +are implicated. +11.32). +The infections (and lesions) are cleared +by antibiotics. +Intermediate-Grade (Borderline) Tumors +Kaposi Sarcoma. +(A) Characteristic cutaneous lesion. +Inset, Modified silver (Warthin-Starry) stain demonstrates clusters of tangled bacilli (black). +Lesions can +regress as immunosuppression is reduced, but at the risk +of organ rejection. +Pathogenesis +Virtually all KS lesions are infected by HHV8. +Like Epstein- +Barr virus, HHV8 is a γ-herpesvirus. +HHV8 causes lytic and latent infections in ECs, both of +which contribute to KS pathogenesis. +Molecular +pathogenesis is discussed in more detail in Chapter 6 along +with HIV infections. +11.33A). +• With time, lesions become larger, violaceous, raised plaques +(see Fig. +11.33B), containing small vessels and slitlike spaces with +red cells. +Most primary HHV8 infections are +asymptomatic. +(A) Gross photograph illustrating coalescent red-purple macules and plaques of the skin. +(B, Courtesy Christopher D. +M. +Fletcher, MD, Brigham and +Women’s Hospital, Boston, Mass.) +including nodal involvement. +Hemangioendothelioma. +Malignant Tumors +Angiosarcoma. +Angiosarcomas are malignant endothelial +neoplasms (Fig. +All of these agents have long latencies between initial +exposure and eventual tumor development. +11.34A). +Necrosis and hemorrhage are common. +11.34B) +to wildly undifferentiated tumors with no discernible blood vessels. +11.34C). +• Benign tumors typically form obvious vascular channels lined +by normal-appearing ECs. +(A) Angiosarcoma involving the right ventricle. +11.35). +11.36). +Coronary stents are expandable tubes of metallic mesh. +[Overview of physiologic and developmental blood vessel +formation and remodeling]. +Bikfalvi A: The situation is more complex than anticipated. +In A Brief +History of Blood and Lymphatic Vessels, Cham, Switzerland, 2017, +Springer. +[Well-written scholarly +review of the etiology and outcomes of endothelial injury]. +Hansson GK, Libby P, Tabas I: Inflammation and plaque vulnerability, +J Intern Med 278:483, 2015. +[Nice review of the current concepts linking +inflammation and plaque vulnerability]. +[Epub ahead of print]. +[Solid review of the different macrophage activities +in the atherosclerotic plaque]. +(A) Angiogram demonstrating constriction (arrow). +(A, Courtesy Anthony D. +[Good overview +of the molecular and cellular basis for thoracic aneurysms]. +[Good discussion +of the molecular pathways underlying human abdominal aortic aneurysm +formation]. +Vasculitis +Jennette J, Falk R: Nosology of primary vasculitis, Curr Opin Rheumatol +19:10, 2007. +[Good clinical overview of +coronary spasm and its sequelae]. +[Solid and thorough +review]. +Goss JA, Greene AK: Congenital vascular tumors, Otolaryngol Clin +North Am 51:89, 2018. +[Good overview of vascular tumors and +malformations]. +Mitchell • Andrew J. +When the heart fails postnatally, the +results are equally catastrophic. +Thus, dilation of the aortic root can result in valvular +regurgitation. +Increasing evidence, +however, indicates that cardiomyocyte proliferation can be +augmented in mice. +Unfortunately, results thus far have been less than +exciting. +• Obstruction to flow. +• Regurgitant flow. +• Shunted flow. +• Disorders of cardiac conduction. +• Rupture of the heart or major vessel. +12.1). +The pattern of hypertrophy reflects the nature of the +stimulus. +Heart disease can lead to dramatic levels of cardiac +hypertrophy. +Important changes at the tissue and cell level occur with +cardiac hypertrophy. +VentricularHeart failure 531 +A B +C D +Figure 12.1 Left ventricular hypertrophy. +(A) Pressure hypertrophy due to left ventricular outflow obstruction. +The left ventricle is on the lower right in +this apical four-chamber view of the heart. +(B) Left ventricular hypertrophy with and without dilation, viewed in transverse heart sections. +(C) Normal myocardium. +(D) Hypertrophied myocardium (C and D are +photomicrographs at the same magnification). +12.2. +As illustrated, heart failure eventu- +ally supervenes. +In valvular heart +disease, the increased pressure or volume overloads the +myocardium globally. +Lungs. +The cardiovascular system is a closed circuit. +Early left-sided heart failure symptoms are related to +pulmonary congestion and edema. +Initially, cough and +dyspnea (breathlessness) may occur only with exertion. +Dyspnea at rest may follow. +• In diastolic failure, the left ventricle is abnormally stiff +and cannot relax during diastole. +MORPHOLOGY +Heart. +As in left-heart failure, the cardiac morphology varies +with cause. +Liver and Portal System. +Pleural, Pericardial, and Peritoneal Spaces. +Subcutaneous Tissues. +In chronically +bedridden patients, presacral edema may predominate. +Generalized +massive edema (anasarca) can also occur. +The kidney and the brain are also prominently affected +in right-sided heart failure. +Incidence +The incidence of CHD depends on what is counted as a +defect. +Twelve disorders account for about +85% of cases; their frequencies are listed in Table 12.2. +Percentages do not add up +to 100% because of rounding. +Does not include bicuspid aortic valves. +Many of these congenital +lesions also can occur sporadically, without specific genetic mutation. +This provides the rationale for early intervention +to close significant left-to-right shunts. +A complete obstruction is called +an atresia. +The altered hemodynamics of CHD usually cause cardiac +dilation or hypertrophy (or both). +be sufficient to derange cardiac development. +Even relatively +minor decrements in activity of particular genes can result +in significant defects. +Other single-gene mutations can alter structural proteins +or affect signaling pathway molecules. +12.3). +12.3A). +Ao +LA +PT +LA +RA +RV +LV +A +MORPHOLOGY +ASDs are classified according to their location. +Although +VSDs are more common, most close spontaneously. +The resulting pulmonary flow volumes may +be two to eight times normal. +Mortality is low, and postoperative survival is comparable +to that for an unaffected population. +However, in the remaining +20%, the unsealed flap can open if right-sided pressures +become elevated. +12.3B). +(A) Atrial septal defect (ASD). +(B) Ventricular +septal defect (VSD). +With VSD, the shunt is left-to-right, and the pressures +are the same in both ventricles. +(C) Patent ductus arteriosus (PDA). +failure to close a foramen (channel) that is part of normal +development. +PDAs account for about 7% +of cases of CHD (see Table 12.2 and Fig. +12.3C), and 90% +of these are isolated defects. +PDA produces a characteristic, continuous, harsh +“machinery-like” murmur. +Because the shunt is initially left-to-right, +there is no cyanosis. +Figure 12.4 A membranous type ventricular septal defect (arrow) just +proximal to the aortic valve. +(Courtesy William D. +About 90% occur in the region of the membranous interventricular +septum (membranous VSD; Fig. +12.4), and the majority are 2 to +3 cm in diameter. +The remaining 10% occur below the pulmonary +valve (infundibular VSD) or within the muscular septum. +Although most VSDs are single, those in the muscular septum may +be multiple. +Conversely, if a VSD +is first detected only in an adult, it is usually an isolated +defect. +Moreover, approximately 50% of small muscular +VSDs close spontaneously. +TOF, the most common in this group, +and TGA are illustrated schematically in Fig. +12.5. +Note that +the names of all of these conditions start with a T. +12.5A). +12.5B and Fig. +12.6). +Patients with d-TGA and a VSD (approximately +35%) often have a stable shunt. +(A) Tetralogy of Fallot. +(B) Dextro- +transposition of the great arteries with and without VSD. +by pulmonary valvular stenosis. +Most infants with TOF are cyanotic at birth +or soon thereafter. +The more severe the subpulmonic stenosis, +Fi e 12.6 Dextro-transposition of the great arteries. +(Courtesy William +the more hypoplastic are the pulmonary arteries (i.e., smaller gur +D. +Obstruction can also occur within +a chamber, as with subpulmonic stenosis in TOF. +12.8). +Without +surgery, most patients die within months. +12.7). +Tricuspid Atresia +Tricuspid atresia represents complete occlusion of the tri- +cuspid valve orifice. +Cyanosis is present virtually +from birth, and there is a high early mortality. +(B) Coarctation of the aorta, postductal type. +The coarctation is a segmental narrowing of the aorta (arrow). +Such +lesions typically manifest later in life than preductal coarctations. +The +dilated ascending aorta and major branch vessels are to the left of the +coarctation. +The lower extremities are perfused predominantly by way of +dilated, tortuous collateral channels. +(A, Courtesy William D. +Edwards, MD, Mayo +Clinic, Rochester, Minn. +isolated or part of a more complex anomaly—either TOF +or TGA. +Congenital aortic valve stenosis is an isolated +lesion in 80% of cases. +Subaortic stenosis is usually +associated with a prominent systolic murmur and sometimes +a thrill. +Most +children are asymptomatic, and the disease may go unrec- +ognized until well into adult life. +The long-standing pressure overload leads to +concentric left ventricular hypertrophy. +Lesions range from relatively asymptomatic to rapidly fatal. +• Right-to-left shunts are most commonly caused by TOF or +TGA. +year. +• Diagnostic and therapeutic advances, allowing earlier and +more effective treatments. +Even a +simple daily prophylactic aspirin can have therapeutic +benefit. +The individual elements and their interactions are dis- +cussed next. +Some conditions can +have multiple deleterious effects. +Thus, most atherosclerotic stenoses can be +accessed by coronary catheterization. +In some cases, microinfarcts can occur distal to +disrupted plaques due to thromboemboli. +This +can result from a fixed stenosis or acute plaque change. +Prinzmetal angina +generally responds promptly to vasodilators. +Myocardial Response. +The +anatomic region supplied by that artery is referred to as +the area at risk. +The outcome depends predominantly on +the severity and duration of flow deprivation (Fig. +12.9). +12.9A). +Such loss of function contributes to +decreased systolic function long before myocyte death occurs. +Pathogenesis +Coronary Arterial Occlusion. +• Activation of coagulation by tissue factor and other +mechanisms adds to the growing thrombus. +• Within minutes, the thrombus can evolve to completely +occlude the coronary artery lumen. +In approximately 10% of cases, MI occurs in the absence +of the typical coronary atherothrombosis. +(A) +Early changes include loss of adenosine triphosphate (ATP) and accumulation of lactate. +Thereafter, progressive loss of viability occurs that becomes complete by 6 to 12 hours. +(Originally modified with +permission from Antman E: Acute myocardial infarction. +Nevertheless, these early manifesta- +tions of ischemic injury are potentially reversible. +The temporal +progression of these events is summarized in Table 12.4. +The progression of ischemic necrosis in the myocardium +is summarized in Fig. +12.10. +Irreversible injury of ischemic +myocytes first occurs in the subendocardial zone. +The area that depends on the occluded vessel for perfusion is the “at risk” myocardium (shaded). +Thus, RCA occlusions can potentially +lead to left ventricular damage. +Patterns of Infarction. +12.11). +12.12). +Thereafter, the +infarct becomes progressively more sharply defined, yellow-tan, +and soft. +Over the succeeding weeks, the injured region evolves +to a fibrous scar. +The histopathologic changes also proceed in a fairly predictable +sequence (Fig. +12.13).The typical changes of coagulative necrosis +“ +become detectable in the first 6 to 12 hours. +The specimen is oriented with the posterior wall at the top. +A B C +D E +Figure 12.13 Microscopic features of myocardial infarction and its repair. +Widened spaces between the dead fibers contain edema fluid and scattered neutrophils. +(C) Removal of necrotic myocytes by phagocytosis +(approximately 7 to 10 days). +(D) Granulation tissue characterized by loose collagen and abundant capillaries. +The residual cardiac muscle cells show evidence of compensatory hypertrophy. +The effects of reperfusion on myocardial viability and +function are summarized in Fig. +12.14. +Further, leukocytes elaborate proteases and elastases that +cause cell death. +• Platelet and complement activation also contribute to +microvascular injury. +Infarct Modification by Reperfusion. +If perfusion is not restored (A), then nearly all myocardium in the affected region suffers death. +The earlier reperfusion occurs, the +greater the degree of salvage. +Gross (A) and microscopic (B) appearance of myocardium modified by +reperfusion. +12.12). +Specimen oriented with posterior wall at top. +The typical appearance of reperfused myocardium in +the setting of an acute MI is shown in Fig. +12.15. +Such infarcts +typically are hemorrhagic as a consequence of vascular injury +and leakiness. +In the absence of ATP, the sarcomeres +cannot relax and get stuck in an agonal tetanic state. +12.16). +Cardiac troponins begin to rise in 2 to 4 hours and +peak at 24 to 48 hours after an acute infarct. +Plasma membrane of necrotic +3. +Troponin leaks +out of cell into +myocytes becomes leaky +circulation +Days after onset of acute MI +1. +Onset of myocardial +infarction +4. +Troponin I or troponin T are now most routinely used as diagnostic biomarkers of +myocyte injury. +12.17): +• Contractile dysfunction. +In general, MIs affect left ventricular +pump function in proportion to the volume of damage. +• Papillary muscle dysfunction. +• Right ventricular infarction. +• Myocardial rupture. +Rupture complicates only 1% to 5% +of MIs, but is frequently fatal when it occurs. +12.17A). +Ventricular septal rupture +creates a VSD with left-to-right shunting (see Fig. +12.17B), +and papillary muscle rupture leads to severe mitral +regurgitation (see Fig. +12.17C). +• Arrhythmias. +MIs lead to myocardial irritability and +conduction disturbances that can cause sudden death. +(A) Anterior myocardial rupture in an acute infarct (arrow). +(B) Rupture of the ventricular septum +(arrow). +(C) Complete rupture of a necrotic papillary muscle. +E, Early expansion of anteroapical infarct with wall thinning (arrow) and mural thrombus. +F, Large apical left ventricular aneurysm (arrow). +The left +ventricle is on the right in this apical four-chamber view of the heart. +• Pericarditis. +12.17D). +• Chamber dilation. +• Mural thrombus. +12.17E), +potentially leading to left-sided thromboembolism. +• Ventricular aneurysm. +12.17F). +• Progressive heart failure. +This is discussed in the Chronic +Ischemic Heart Disease section later in this chapter. +With subendocardial infarcts, +only rarely do pericarditis, rupture, and aneurysm occur. +The +compensatory hypertrophy of noninfarcted myocardium is +initially hemodynamically beneficial. +The relationship of the causes, pathophysiology, and +consequences of MI are summarized in Fig. +12.18, including +the possible outcomes of chronic IHD and sudden death, +discussed later. +Patients with chronic IHD +account for almost 50% of cardiac transplant recipients. +Chest pain may occur, even at +rest or with minimal exertion. +Gross and histologic +changes of infarction require hours to days to develop. +Invariably there is some degree of stenotic +coronary atherosclerosis. +Discrete scars representing healed +infarcts are usually present. +Channelopathies are caused by +mutations in genes that are required for normal ion channel +function. +ARRHYTHMIAS +Abnormalities in myocardial conduction can be sustained +or sporadic (paroxysmal). +• Sick sinus syndrome. +• Atrial fibrillation. +• Heart block. +• SCD typically results from ventricular fibrillation and is most +frequently a consequence of CAD. +On that basis, almost one-half of individuals in the +general population (!!) are hypertensive. +The pathogenesis +of hypertension is discussed in Chapter 11. +(A) Systemic (left-sided) hypertensive heart disease. +There is marked concentric +thickening of the left ventricular wall causing reduction in lumen size. +A pacemaker is present in the right ventricle (arrow). +(B) Pulmonary (right-sided) hypertensive heart disease (cor pulmonale). +The +shape of the left ventricle (to the right) has been distorted by the enlarged right ventricle. +Isolated pulmonary HHD, or cor pulmonale, stems from +right ventricular pressure overload. +Acute cor pulmonale can follow massive pulmonary embo- +lism. +12.19B). +Valvular abnormalities can be congenital (discussed +earlier) or acquired. +The causes of acquired heart valve diseases are sum- +marized in Table 12.8. +Persistently elevated pressure overload can cause ventricular +failure with dilation. +• Stenosis is the failure of a valve to open completely, +obstructing forward flow. +Stenosis or insufficiency can occur alone or together in +the same valve. +The free edges of the cusps are usually +not involved (Fig. +12.20A). +Microscopically, the layered architecture +of the valve is largely preserved. +Inflammation is variable, and metaplastic bone can be seen. +In contrast with +rheumatic (and congenital) aortic stenosis (see Fig. +12.22E), +commissural fusion is not usually seen. +Fen-phen, Fenfluramine-phentermine. +Most notably, the abnormal +A B C D +Figure 12.20 Calcific valvular degeneration. +(A) Calcific aortic stenosis of a previously normal valve (viewed from aortic aspect). +Nodular masses of +calcium are heaped up within the sinuses of Valsalva (arrow). +12.22E). +(B) Calcific aortic stenosis of a congenitally bicuspid valve. +One cusp has a partial fusion at its center, called a raphe (arrow). +(C) Left atrial view. +The +raphe is frequently a major site of calcific deposits (see +Fig. +12.20B). +Other +bicuspid valve complications include aortic regurgitation +and infective endocarditis. +12.20C, D). +Mitral annular calcification +usually does not affect valvular function. +12.21A–C).The affected +leaflets are often enlarged, redundant, thick, and rubbery. +The tricuspid, aortic, +or pulmonary valves may also be affected. +12.21B); and (5) +focal calcifications at the base of the posterior mitral leaflet (Fig. +12.21C). +The diagnosis is confirmed +by echocardiography. +(C) Opened valve with pronounced hooding (double arrows) in a patient who died suddenly. +Note also mitral +annular calcification on the left side (arrowhead). +Normal heart valve (D) and myxomatous mitral valve (E). +(A, Courtesy William D. +In +keeping with an immunologic basis of RHD, streptococci +are completely absent from the lesions. +MORPHOLOGY +Key pathologic features of acute RF and chronic RHD are shown +in Fig. +12.22. +During acute RF, focal inflammatory lesions are found +in various tissues. +(A) Acute rheumatic mitral valvulitis superimposed on chronic rheumatic heart disease. +(B) Microscopic appearance of an Aschoff body in a patient with acute rheumatic carditis. +Note the neovascularization +of the anterior mitral leaflet (arrow, D). +(E, Reproduced from Schoen FJ, St. +12.24A). +One or many may be present (see Fig. +12.25). +Approximately 1% of affected +individuals die of fulminant RF involvement of the heart. +Damage to the valves is cumula- +tive. +Turbulence induced by ongoing valvular deformities +leads to additional fibrosis. +12.23). +The long-term prognosis is highly variable. +The aorta, aneurysms, other blood vessels, and prosthetic +devices can also become infected. +In contrast, more virulent S. +aureus is the major offender +in IE among intravenous drug abusers. +More rarely, +Gram-negative bacilli and fungi can be involved. +aureus and S. +aureus +(see later discussion of prosthetic valves). +(A) Endocarditis of mitral valve (subacute, caused by Streptococcus viridans). +The large, friable vegetations are +denoted by arrows. +“Possible” +infective endocarditis diagnosis requires either 1 major +1 minor, or 3 minor. +d Roth spots are oval retinal hemorrhages with pale centers. +In Mann D, et al., +editors: Braunwald’s Heart Disease. +a Textbook of Cardiovascular Medicine, ed 10, +Philadelphia, 2015, WB Saunders, p 1524. +12.24B). +Left untreated, IE +generally is fatal. +For infections involving low-virulence +organisms (e.g., S. +viridans), the cure rate is 98%, and for +enterococci and S. +12.23 and 12.25). +The thrombus is only loosely attached to the cusp (arrow). +12.23). +Similar lesions can occur +in the antiphospholipid antibody syndrome (Chapter 4). +12.26). +Underlying structures are intact. +With +right-sided involvement, typical findings are tricuspid insufficiency +and pulmonary stenosis. +• Tissue valves (bioprostheses). +(A) Characteristic endocardial fibrotic lesion involving the right ventricle and tricuspid valve. +(B) Microscopic +appearance of carcinoid heart disease with endocardial thickening. +The underlying myocardium is unaffected. +(called cryopreserved “homografts”) can also be used. +Tissue valves are flexible and function similarly to +natural semilunar valves. +Similarly, the freezing and thawing of human homografts +may also render them largely nonviable. +The complications that occur depend on which +type of valve has been implanted (Table 12.10 and Fig. +12.27). +• Thromboembolism is the major consideration with mechani- +cal valves (see Fig. +(A) Thrombosis of a +mechanical prosthetic valve. +Structural deterioration rarely causes failure of any of the +mechanical valves in current use. +12.27B). +• Infective endocarditis is a potentially serious complication +of any valve replacement. +In addition, vegetations may +directly involve the tissue of bioprosthetic valvular cusps. +Both types of valves have an +increased risk of developing endocarditis relative to native valves. +They may be genetic or acquired (e.g., viral myocarditis, +anthracycline cardiotoxic). +hemochromatosis, amyloidosis). +• Valve calcification is a degenerative process that typically results +in stenosis. +• Abnormal matrix synthesis and turnover result in myxomatous +degeneration and insufficiency. +• Inflammatory valve diseases lead to postinflammatory scarring. +Systemic embolization can produce +septic infarcts. +Pathogenesis +Several different pathways can lead to DCM (Fig. +12.29). +Note the changes in atrial and/or ventricular wall thickness. +12.30). +X-linked, autosomal recessive, and mitochondrial +inheritance of DCM are less common. +• Myocarditis. +Sequential endomyocardial biopsies have +documented progression from myocarditis to DCM. +• Alcohol and other toxins. +Alcohol or +its metabolites (especially acetaldehyde) have a direct +toxic effect on the myocardium. +The genetic causes of dilated cardiomyopathy involve mutations in any of a wide range of genes. +LV, left ventricle. +which can lead to beriberi heart disease (a form of DCM). +Cardiotoxic drugs used for +chemotherapy (discussed later) are also important causes +of DCM. +• Childbirth. +• Supraphysiologic stress can also result in DCM. +(A) Four-chamber dilatation and hypertrophy are evident. +The coronary arteries were patent. +12.31). +12.31B). +Clinical Features +The fundamental defect in DCM is ineffective contraction. +Death usually results from progres- +sive cardiac failure or arrhythmia, and it can occur suddenly. +HCM causes primarily diastolic +dysfunction; systolic function is usually preserved. +Occasion- +ally, valvular or congenital subvalvular aortic stenosis can +also mimic HCM. +The prognosis of HCM varies widely and +correlates strongly with specific mutations. +As mentioned earlier, HCM is a disease caused by muta- +tions in proteins of the sarcomere. +Left-sided involve- +ment with left-sided heart failure can also occur. +12.32). +A B +Figure 12.32 Arrhythmogenic cardiomyopathy. +In contrast, DCM is mostly associated +with abnormalities of cytoskeletal proteins (see Fig. +To +complicate matters, mutations in certain genes (highlighted +in Fig. +12.30) can give rise to either HCM or DCM, depending +on the site and nature of the mutation. +12.33B). +In about 10% of cases, the +hypertrophy is concentric and symmetrical. +12.33A). +A B +Figure 12.33 Hypertrophic cardiomyopathy with asymmetric septal hypertrophy. +These rearrangements produce fusion genes that +encode constitutively active PDGFR tyrosine kinases. +Diffuse involvement may be responsible for +rapid and progressive cardiac decompensation and death. +The natural history of HCM is highly variable. +Three other restrictive conditions merit brief mention. +12.34). +12.34B). +Pathogenesis +In the United States, viral infections are the most common +cause of myocarditis. +Coxsackie viruses A and B and other +enteroviruses probably account for most of the cases. +Other +less common etiologic agents include cytomegalovirus, HIV, +and influenza (Table 12.13). +There are also noninfectious causes of myocarditis. +(A) Lymphocytic myocarditis, associated with myocyte injury. +(D) The myocarditis of Chagas disease. +MORPHOLOGY +with lymphocytes, eosinophils, plasma cells, and macrophages. +Focal +to frequently extensive myocyte damage is present (see Fig. +12.35C). +12.35D). +Mural +thrombi may be present. +12.35A). +12.35B). +The clinical features of myocarditis can mimic those +of acute MI. +Discontinuing +the offending agent often leads to prompt resolution, without +apparent sequelae. +Occasionally, however, more extensive +damage produces myocyte death that can evolve to a DCM. +The major +causes of pericarditis are listed in Table 12.14. +• DCM results in systolic (contractile) dysfunction. +Causes include +myocarditis, toxic exposures (e.g., alcohol), and pregnancy. +• HCM results in diastolic (relaxation) dysfunction. +Viral +infections are the most common causes in the United States. +Clinically, myocarditis can be asymptomatic, give rise to acute +heart failure, or evolve into DCM. +Organization +into fibrous adhesions rarely occurs. +Common +causes include acute MI (see Fig. +A fibrinous reaction also follows routine cardiac +surgery. +A loud peri- +cardial friction rub is the most striking clinical finding. +The serosal surfaces are red- +dened, granular, and coated with the exudate (Fig. +12.36). +Complete resolution is infrequent, +and organization by scarring is the usual outcome. +Extensive purulent exudate is evident. +The clinical significance is similar to that of fibrinous +or suppurative pericarditis. +Two forms are worthy of some +discussion. +Systolic retraction of the rib cage +and diaphragm and pulsus paradoxus may be observed. +The increased workload occasionally causes significant +cardiac hypertrophy and dilation. +A prior history of pericarditis may +or may not be present. +MORPHOLOGY +The tumors are usually single, but can rarely be multiple. +The +region of the fossa ovalis in the atrial septum is the favored site +of origin. +12.37B). +Peculiar vessel-like +or glandlike structures are characteristic. +Hemorrhage and +mononuclear inflammation are usually present. +Myxomas are the most common primary tumor of the +adult heart (Fig. +12.37). +These are benign neoplasms arising +from primitive multipotent mesenchymal cells. +About 90% of myxomas arise in the atria, with +a left-to-right ratio of approximately 4:1. +Some- +times fragmentation and systemic embolization calls attention +to these lesions. +Echocardiography provides the opportunity to identify these +masses noninvasively. +12.38B and C). +12.38D), leading to ischemic injury. +Although +impressive, these various devices are not without (somewhat +predictable) risk. +12.38A). +ThereSuggested readings 581 +A B +C D +Figure 12.38 Complications of heart transplantation. +B and C,Antibody-mediated rejection. +(C, Courtesy Dr. +Fortunately, the manifest benefits significantly +outweigh the potential risks. +[A balanced +review of research in cardiovascular regeneration]. +[A review of cardiomyocyte regenerative biology with +a focus on basic science]. +Eschenhagen T et al: Cardiomyocyte regeneration: a consensus statement, +Circulation 136:680, 2017. +[A brief outline consensus overview of the current +evidence for cardiomyocyte regeneration]. +Lee RT, Walsh K: The future of cardiovascular regenerative medicine, +Circulation 133:2618, 2016. +[An overview of trends in cardiovascular +regenerative medicine]. +[An excellent review of the pathophysiology of heart +failure]. +[An overview of the relationships between cardiac development and congenital +heart disease]. +[A comprehensive review +of the genes and pathways underlying congenital heart disease]. +[An excellent +treatise on classification of congenital heart disease]. +[A review of trends in congenital +heart disease medical science and clinical management]. +[An +excellent, well-written review on plaque erosion and rupture in acute coronary +syndromes]. +Thygesen K et al: Fourth universal definition of myocardial infarction, +Circulation 138:e618, 2018. +[Good study +and discussion of sudden death in the young, an area of much recent +investigation]. +Bezzina CR, Lahrouchi N, Priori SG: Genetics of sudden cardiac death, +Circ Res 116:1919, 2015. +[A nice review of the cardiac consequences of systemic +hypertension]. +[An excellent review of right-sided +hypertension-associated pathology and pathobiology]. +Li C, Xu S, Gotlieb AI et al: The response to valve injury. +A paradigm to +understand the pathogenesis of heart valve disease, Cardiovasc Pathol +20:183, 2011. +[A nice overview of pathologic concepts in valvular disease]. +[A good overview of the mechanisms leading to degenerative calcifica- +tion on valves and vessels]. +[A nice review +of pathogenesis, clinical features, and clinical management]. +[An excellent review on mechanisms of valve disease +and therapeutic approaches]. +Cardiomyopathies +Arany Z, Elkayam U: Peripartum cardiomyopathy, Circulation 133:1397, +2016. +[A review of pathophysiology and clinical management]. +Braunwald E: Cardiomyopathies: an overview, Circ Res 121:711, 2017. +Buggey J, ElAmm CA: Myocarditis and cardiomyopathy, Curr Opin +Cardiol 33:341, 2018. +[A nice review of etiology, pathogenesis, and clinical +features]. +[A nice review of etiology, +pathogenesis, and clinical features]. +[An excellent review of the genetic defects underlying many of the +cardiomyopathies]. +[An interesting +report of a cardiovascular disease arising from a new therapy]. +[A review of cardiovascular +toxicity with current cancer therapies]. +[A good review of cardiac +amyloidosis]. +[The most recent consensus +classification scheme for tumors of the heart and pericardium]. +Sawyer DB: Anthracyclines and heart failure, N Engl J Med 38:1154, +2013. +[A succinct overview of chemotherapeutic cardiotoxicity]. +In +this chapter we discuss white cell diseases and disorders +affecting the spleen and thymus. +In Chapter 14 we consider +diseases of red cells and those affecting hemostasis. +By the fourth month +of development, HSCs shift in location yet again to the bone +marrow. +After puberty, hematopoiesis ceases +in distal bones and becomes restricted to the axial skeleton. +Thus in normal adults, only about half of the marrow space +is hematopoietically active. +13.1). +The origins of lymphoid cells are +revisited when tumors derived from these cells are discussed. +Some of these cells are referred to as colony-forming units +(see Fig. +Pluripotency refers to the +ability of a single HSC to generate all mature blood cells. +When an HSC divides, at least one daughter cell must self- +renew to avoid stem cell depletion. +13.1). +Many diseases alter the production of blood cells. +CFU, Colony forming unit; LIN−, negative for lineage-specific markers; NK, natural killer. +and cytokines. +The normal marrow is organized in subtle, but important, ways. +Marrow aspirate smears provide the best assessment of the +morphology of hematopoietic cells. +The most mature marrow +precursors can be identified based on their morphology alone. +Bone marrow biopsies are a +good means for estimating marrow activity. +In normal adults the +ratio of fat cells to hematopoietic elements is about 1:1. +Other +disorders (e.g., metastatic cancers and granulomatous diseases) +induce local marrow fibrosis. +In such cases the marrow usually +cannot be aspirated and the lesions are best seen in biopsies. +Proliferations of +white cells can be reactive or neoplastic. +Neoplastic disorders, +though less frequent, are much more important clinically. +LEUKOPENIA +The number of circulating white cells may be decreased in +a variety of disorders. +• Suppression of committed granulocytic precursors by exposure +to certain drugs (discussed later). +The most common cause of agranulocytosis is drug +toxicity. +It is a common reaction to a variety of +inflammatory states. +• The rate of release of cells from the storage pools into +the circulation. +• The proportion of cells that are adherent to blood vessel +walls at any time (the marginal pool). +• The rate of extravasation of cells from the blood into +tissues. +Some growth factors preferentially stimulate the produc- +tion of a single type of leukocyte. +Infections are a common consequence of agranulocytosis. +Sites +of infection often show a massive growth of organisms with little +leukocytic response. +With agranulocytosis, +infections are often overwhelming and may cause death +within hours to days. +Serious infections are most likely when the neutrophil +count falls below 500/mm3. +13.2). +6.8, Chapter 6). +The activation of resident immune cells leads to mor- +phologic changes in lymph nodes. +Paracortical +T-cell zones may also undergo hyperplasia. +Some that produce distinctive morphologic patterns are +described in other chapters. +Systemic viral infections (particularly in +Figure 13.2 Reactive changes in neutrophils. +MORPHOLOGY +The nodes are swollen, gray-red, and engorged. +Nodes involved by acute lymphadenitis are swollen and +painful. +When abscess formation is extensive the nodes +become fluctuant. +The overlying skin is red. +Healing of such lesions is associated with scarring. +Several different patterns of +morphologic change are seen, often within the same lymph +node. +MORPHOLOGY +Follicular hyperplasia is caused by stimuli that activate humoral +immune responses. +13.3). +This form of hyperplasia +is morphologically similar to follicular lymphoma (discussed later). +Figure 13.3 Follicular hyperplasia. +(A) Low-power view showing a +reactive follicle and surrounding mantle zone. +The right half of the follicle consists of the dark +zone. +These collections are sometimes called tertiary +lymphoid organs. +• Myeloid neoplasms arise from early hematopoietic progeni- +tors. +• The histiocytoses are uncommon proliferative lesions of +macrophages and dendritic cells. +Chromosomal Translocations and Other Acquired Muta- +tions. +For this reason, it is also sometimes referred to as macrophage +activation syndrome. +How these defects lead +to HLH is not known. +Coagulation studies may show evidence of +disseminated intravascular coagulation. +The resulting overexpression of the +involved proto-oncogene converts it to an oncogene. +Inherited Genetic Factors. +Viruses. +The possible mechanisms of transformation by viruses are +discussed in Chapter 7. +HTLV-1 is associated with adult +T-cell leukemia/lymphoma. +Chronic Inflammation. +Examples include the associations between H. +counterpart of the malignant cell. +Fig. +• Finally, mutations that inhibit apoptosis are prevalent +in certain hematologic malignancies. +These relationships are discussed in more detail in +Chapter 6. +Iatrogenic Factors. +Smoking. +Hodgkin lymphoma has distinc- +tive pathologic features and is treated in a unique fashion. +Another special group of tumors includes plasma cell neo- +plasms. +) +3. +Precursor B-Cell Neoplasms +B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) +II. +Precursor T-Cell Neoplasms +T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) +IV. +Peripheral T-cell and NK-cell neoplasms (neoplasms of +mature T cells and NK cells) +5. +of B- or T-cell differentiation (Fig. +13.5), a feature that is +used in their classification. +• Lymphoid neoplasms are often associated with immune +abnormalities. +• Neoplastic B and T cells tend to recapitulate the behavior of +their normal counterparts. +Stages of B- and T-cell differentiation from which specific lymphoid tumors emerge are shown. +About 85% +are B-ALLs, which typically manifest as childhood acute +leukemias. +The less common T-ALLs tend to present in +adolescent males as thymic lymphomas. +ALL is the most common cancer of children. +Hispanics have the highest incidence +of any ethnic group. +B-ALL +and T-ALL also occur less frequently in adults of all ages. +Similar themes are +relevant in the genesis of AML (discussed later). +b Most common tumors in adults. +Approximately 90% of ALLs have numerical or structural +chromosomal changes. +13.6A). +The nuclear membrane is often deeply subdivided, +imparting a convoluted appearance. +In keeping with the aggressive +clinical behavior, the mitotic rate is high. +13.15). +13.6B and C). +A +CD22 +CD19 +Intracellular TdT C CD10 +B +Figure 13.6 (A) Acute lymphoblastic leukemia/lymphoma (ALL). +Lymphoblasts with condensed nuclear chromatin, small nucleoli, and scant +agranular cytoplasm. +(B and C) Phenotype of ALL shown in (A) analyzed +by flow cytometry. +Thus this is a B-ALL. +(A, Courtesy Dr. +Robert W. +Louis Picker, Oregon Health Science Center, Portland, Ore.) +Immunophenotype. +13.6B). +In very +immature B-ALLs, CD10 is negative. +Similarly, T-ALLs +are arrested at various stages of pre–T-cell development. +In most cases the cells are positive for CD1, CD2, CD5, and +CD7. +Treatment of pediatric ALL is one of the great success +stories of oncology. +only 4% of NHLs. +CLL/SLL is much less common in Japan +and other Asian countries than in the West. +The most common +genetic anomalies are deletions of 13q14.3, 11q, and 17p +and trisomy 12q. +13.7). +When present, +proliferation centers are pathognomonic for CLL/SLL. +The blood contains variable numbers of small round lymphocytes +with scant cytoplasm (Fig. +13.8). +In almost all cases, the bone marrow, spleen, and +liver (Fig. +13.9) also are involved, albeit to widely varying degrees. +CLL is the most +common leukemia of adults in the Western world. +There +are about 15,000 new cases of CLL each year in the United +States. +The median age at diagnosis is 60 years, and there +is a 2:1 male predominance. +In contrast, SLL constitutes +Immunophenotype. +CLL/SLL has a distinctive immuno- +phenotype. +Low-power view of a typical periportal lymphocytic +infiltrate. +(Courtesy Dr. +A small monoclonal Ig “spike” is present in the blood of +some patients. +CLL/SLL disrupts normal immune function through +uncertain mechanisms. +The course and prognosis are extremely variable and +depend primarily on the clinical stage. +B +Figure 13.7 Small lymphocytic lymphoma/chronic lymphocytic leukemia +(lymph node). +(A) Low-power view shows diffuse effacement of nodal +architecture. +(B) At high power the majority of the tumor cells are small +round lymphocytes. +(A, Courtesy Dr. +A nucleated erythroid +cell is present in the lower left-hand corner of the field. +It affects 15,000 to 20,000 individuals per year. +It usually +presents in middle age and afflicts males and females equally. +It is less common in Europe and rare in Asian populations. +13.12). +A +B +Figure 13.10 Follicular lymphoma (lymph node). +(A) Nodular aggregates +of lymphoma cells are present throughout lymph node. +(A, Courtesy Dr. +Robert W. +13.10A). +13.10B). +In most +follicular lymphomas, centrocytes are in the majority. +13.11) and hepatic portal triads are also frequently +involved. +Figure 13.11 Follicular lymphoma (spleen). +Prominent nodules represent +white pulp follicles expanded by follicular lymphoma cells. +(Courtesy Dr. +AB +Figure 13.12 BCL2 expression in reactive and neoplastic follicles. +BCL2 +protein was detected by using an immunohistochemical technique that +produces a brown stain. +(Courtesy Dr. +Unlike CLL/SLL and mantle +cell lymphoma, CD5 is not expressed. +13.12). +Although incurable, it +usually follows an indolent waxing and waning course. +Histologic transformation occurs in 30% to 50% of fol- +licular lymphomas, most commonly to DLBCL. +The +median survival is less than 1 year after transformation. +Diffuse Large B-Cell Lymphoma +Diffuse large B-cell lymphoma (DLBCL) is the most +common form of NHL. +Each year in the United States there +are about 25,000 new cases. +There is a slight male predomi- +nance. +The median patient age is about 60 years, but DLBCL +also occurs in young adults and children. +13.13). +Other morphologic +features show substantial variation. +Most commonly, the tumor +Figure 13.13 Diffuse large B-cell lymphoma. +Tumor cells have large nuclei, +open chromatin, and prominent nucleoli. +(Courtesy Dr. +Robert W. +Bone marrow involvement is rela- +tively uncommon and usually occurs late in the course. +Rarely, a leukemic picture emerges. +DLBCLs are aggressive tumors that are rapidly fatal +without treatment. +The +cytoplasm is usually moderately abundant and may be pale or +basophilic. +Immunophenotype. +Most have +surface Ig. +Special Subtypes. +Several subtypes of DLBCL are suffi- +ciently distinctive to merit brief discussion. +The neoplastic B cells are usually infected with +EBV, which plays a critical pathogenic role. +Restoration +of T-cell immunity may lead to regression of these +proliferations. +In all cases the tumor cells are infected +with HHV-8, which appears to have a causal role. +It can arise virtually anywhere in +the body. +13.14). +Figure 13.14 Diffuse large B-cell lymphoma involving the spleen. +The +isolated large mass is typical. +In contrast, indolent B-cell lymphomas usually +produce multifocal expansion of white pulp (see Fig. +13.11). +(Courtesy +Dr. +macrophages. +These phagocytes have abundant clear cytoplasm, +creating a characteristic “starry sky” pattern. +Immunophenotype. +Most tumors manifest at extranodal sites. +Involvement of the bone marrow +and peripheral blood is uncommon, especially in endemic +cases. +Burkitt lymphoma is very aggressive but responds well +to intensive chemotherapy. +Most children and young adults +can be cured. +The outcome is more guarded in older adults. +It usually presents in the fifth +to sixth decades of life and shows a male predominance. +13.15). +Frequent sites of extranodal involvement include the bone marrow, +spleen, liver, and gut. +(B) At high power, tumor cells have multiple small nucleoli and +high mitotic index. +The lack of significant variation in nuclear shape and +size lends a monotonous appearance. +(B, Courtesy Dr. +• They remain localized for prolonged periods, spreading +systemically only late in their course. +• They may regress if the inciting agent (e.g., H. +pylori) is +eradicated. +The disease begins +as a polyclonal immune reaction. +At this stage, withdrawal of +the responsible antigen causes tumor involution. +pylori often leads to +tumor regression (Chapter 17). +With further clonal evolution, spread +to distant sites and transformation to DLBCL may occur. +to occasionally deeply clefted (cleaved) nuclear contours +(Fig. +13.16). +Immunophenotype. +This tumor is usually CD5+ and CD23−, which help +to distinguish it from CLL/SLL. +The IGH genes lack somatic +hypermutation, supporting an origin from a naive B cell. +Clinical Features +The most common presentation is painless lymphadenopathy. +Immunophenotype. +Splenomegaly, often massive, +is the most common and sometimes the only abnormal +physical finding. +Hepatomegaly is less common and not as +marked; lymphadenopathy is rare. +About +one-third of those affected present with infections. +Hairy cell leukemia follows an indolent course. +The overall prognosis +is excellent. +13.17). +Hepatic portal +triads are also involved frequently. +• Tumor of mature B cells that usually manifests with bone marrow +and lymph node involvement. +Follicular Lymphoma +• Most common indolent lymphoma of adults. +Diffuse Large B-Cell Lymphoma +• Most common lymphoma of adults. +Burkitt Lymphoma +• Very aggressive tumor of mature B cells that usually arises at +extranodal sites. +A +B +Figure 13.17 Hairy cell leukemia (peripheral blood smear). +(A) +Phase-contrast microscopy shows tumor cells with fine hairlike +cytoplasmic projections. +• Tumor cells often are latently infected by EBV. +Mantle Cell Lymphoma +• Tumor of naive B cells that pursues a moderately aggressive +course. +• Highly associated with translocations involving the cyclin D1 +gene. +• Often remain localized for long periods of time. +• Highly associated with mutations in the BRAF serine/threonine +kinase. +Figure 13.18 Peripheral T-cell lymphoma, unspecified (lymph node). +13.19A). +ALK is not expressed in normal +lymphocytes; thus the detection of ALK protein in tumor +cells (Fig. +13.19B) is a reliable indicator of an ALK gene +rearrangement. +The cure rate +with chemotherapy is 75% to 80%. +Both ALK+ and ALK− tumors +usually express CD30, a member of the TNF receptor family. +By contrast, for unknown reasons both T- and NK-cell +tumors occur more frequently in the Far East. +Only the most +common diagnoses and those of particular pathogenetic +interest will be discussed. +13.18). +Brisk neoangiogenesis may also be seen. +By definition, all peripheral T-cell lymphomas are derived +from mature T cells. +They usually express CD2, CD3, CD5, +and either αβ or γδ T-cell receptors. +However, many tumors have +phenotypes that do not resemble any known normal T cell. +Neverthe- +less, these are indolent tumors, with a median survival of +roughly 10 years. +Transformation to aggressive T-cell +lymphoma occurs occasionally as a terminal event. +Lymphadenopathy and hepatomegaly +are usually absent. +Infiltrates +also are usually present in the spleen and liver. +Neutropenia may be accompanied by a striking decrease +in late myeloid forms in the marrow. +Rarely, pure red cell +aplasia is seen. +There is also an increased incidence of +rheumatologic disorders. +A +B +Figure 13.19 Anaplastic large-cell lymphoma. +(B) Immunohistochemical stain demonstrating the +presence of ALK fusion protein. +(Courtesy Dr. +Extranodal NK/T-cell lymphoma is highly associated +with Epstein-Barr virus (EBV). +No consistent chromosome +aberration has been described. +Thus, the prognosis is gener- +ally poor in patients with advanced disease. +is multiple myeloma, of which there are about 15,000 new +cases per year in the United States. +A monoclonal Ig identified in the blood is referred to as +an M component, in reference to myeloma. +However, neoplastic plasma cells often synthesize excess +light chains along with complete Igs. +Occasionally only +light chains are produced, and rare tumors secrete only +heavy chains. +The common feature is the synthesis and +secretion of free heavy-chain fragments. +Its incidence is +higher in men and people of African descent. +It is chiefly +a disease of older adults, with a peak age of incidence of +65 to 70 years. +It is produced +by the tumor cells themselves and by resident marrow +stromal cells. +Figure 13.20 Multiple myeloma of the skull (radiograph, lateral view). +The +sharply punched-out bone lesions are most obvious in the calvaria. +13.20), and consist of soft, gelatinous, +red tumor masses. +and an eccentrically placed nucleus (Fig. +13.21). +Rarely, tumor cells flood the peripheral blood, +giving rise to plasma cell leukemia. +This important +complication is discussed in detail in Chapter 20. +GA M κλ ++ +Patient serum – +SP GA M κλ +Immunophenotype. +Bone resorption often leads to pathologic fractures and +chronic pain. +Decreased production of normal Igs sets the +stage for recurrent bacterial infections. +Cellular immunity +is relatively unaffected. +Of great significance is renal insuf- +ficiency, which trails only infections as a cause of death. +13.22). +Myelomas +expressing IgM, IgD, or IgE occur but are rare. +Both free light chains and a serum +M protein are observed together in 60% to 70% of patients. +(Courtesy Dr. +The prognosis is variable. +The median survival is 4 to 7 +years, and cures have yet to be achieved. +While still incurable, outcomes have improved over the +past decade with advances in therapy. +If these misfolded proteins are not degraded in proteasomes, +they trigger apoptosis. +Thalidomide +and related compounds such as lenalidomide also have +activity against myeloma. +HSC transplantation prolongs life but has not been +proven to be curative. +Smoldering Myeloma +This entity defines a middle ground between multiple +myeloma and MGUS. +About +75% of patients progress to multiple myeloma over a 15-year +period. +The bone lesions tend to occur +in the same locations as in multiple myeloma. +Extraosseous +lesions are often located in the lungs, oronasopharynx, or +nasal sinuses. +Modest elevations of M proteins in the blood +or urine may be found in some patients. +By +definition, patients are asymptomatic and the serum M +protein level is less than 3 g/dL. +13.23). +Immunophenotype. +Approximately +half the patients have lymphadenopathy, hepatomegaly, +and splenomegaly. +Anemia caused by marrow infiltration is +common. +Lymphoplasmacytic lymphoma is an indolent disorder. +Transformation to large-cell lymphoma occurs but is uncom- +mon. +The average age at diagnosis is 32 years. +It is one of the +most common cancers of young adults and adolescents, but +also occurs in the aged. +Classification. +The WHO classification recognizes five +subtypes of Hodgkin lymphoma: +1. +Nodular sclerosis +2. +Mixed cellularity +3. +Lymphocyte-rich +4. +Lymphocyte depletion +5. +These subtypes are often lumped together as classic +forms of Hodgkin lymphoma. +• May be associated withAL amyloidosis (as may other neoplasms +later). +• Smoldering myeloma: disseminated disease that pursues an +unusually indolent course. +Reed-Sternberg cells are aneuploid and possess diverse +clonal chromosomal aberrations. +Most notably among these factors are PD-L1 and PD-L2, +which antagonize cytotoxic T-cell responses. +13.28. +abundant. +Several Reed-Sternberg cell variants are also recognized. +Mononuclear variants contain a single nucleus with a large +inclusion-like nucleolus (Fig. +13.24B). +13.24C). +13.24D). +The clinical +manifestations common to all are presented later. +Nodular Sclerosis Type. +This is the most common form of Hodgkin +lymphoma, constituting 65% to 70% of cases. +13.25). +This subtype is uncommonly associated with EBV. +The nodular sclerosis type occurs with equal frequency in +males and females. +The prognosis is excellent. +Mixed-Cellularity Type. +This form of Hodgkin lymphoma consti- +tutes about 20% to 25% of cases. +13.26). +The immunophenotype is identical to +that observed in the nodular sclerosis type. +Mixed-cellularity Hodgkin lymphoma is more common in males. +Nonetheless, the overall prognosis is +very good. +(B) Reed-Sternberg cell, mononuclear variant. +(C) Reed-Sternberg cell, lacunar +variant. +(D) Reed-Sternberg cell, lymphohistiocytic variant. +(A, Courtesy Dr. +Robert W. +(Courtesy Dr. +Robert W. +(Courtesy Dr. +Robert W. +The Reed-Sternberg cells are infected with +EBV in over 90% of cases. +Nodular Lymphocyte Predominance Type. +This uncommon “nonclas- +sic” variant of Hodgkin lymphoma accounts for about 5% of cases. +13.27). +“Classic” Reed-Sternberg cells are usually difficult to find. +Eosinophils and plasma +cells are usually scant or absent. +In 3% to 5% of cases, this +type transforms into a tumor resembling diffuse large B-cell +lymphoma. +EBV is rarely associated with this subtype. +Mediastinal and bone marrow involvement is rare. +Figure 13.26 Hodgkin lymphoma, mixed-cellularity type. +(Courtesy Dr. +Robert W. +It is associated with EBV in about 40% of cases and has +a very good to excellent prognosis. +Lymphocyte Depletion Type. +This is the least common form of +Hodgkin lymphoma, amounting to less than 5% of cases. +more likely to have constitutional symptoms such as fever, +night sweats, and weight loss. +13.28). +The cure rate of patients with stages I +and IIA is close to 90%. +Even with advanced disease (stages +IVA and IVB), disease-free survival at 5 years is 60% to 70%. +See text for details. +Some of the best characterized pathogenic mecha- +nisms are summarized in Fig. +• Lymphocyte predominance type expresses B-cell markers and +is not associated with EBV. +13.1). +AML occurs at all ages, but the incidence rises +throughout life, peaking after 60 years of age. +There are +about 13,000 new cases each year in the United States. +Classification. +AML is quite heterogeneous, reflecting the +complexities of myeloid cell differentiation. +The current +WHO classification subdivides AML into four categories +(Table 13.10). +AMLs in these categories have +distinct genetic features and respond poorly to therapy. +A +fourth “wastebasket” category includes AMLs lacking any +of these features. +These are classified based on the degree +of differentiation and the lineage of the leukemic blasts. +IDH inhibitors are effective in treating IDH-mutated +forms of AML. +• Mutation of TP53 or genes that regulate p53. +The cytoplasm often contains fine, peroxidase-positive azurophilic +granules. +13.31A). +Monoblasts (Fig. +13.31B) have folded or lobulated nuclei, lack Auer +rods, and are nonspecific esterase-positive. +Rarely, the blasts of AML show erythroid differentiation. +The number of leukemic cells in the blood is highly variable. +Blasts may be more than 100,000/mm3, but are under 10,000/ +mm3 in about 50% of patients. +Occasionally, blasts are entirely +absent from the blood (aleukemic leukemia). +13.30A). +Immunophenotype. +(A, Courtesy Dr. +Robert W. +(A) Acute promyelocytic +leukemia with the t(15;17) (FAB M3 subtype). +(B) Acute myeloid leukemia with +monocytic differentiation (FAB M5b subtype). +Peripheral smear shows one +monoblast and five promonocytes with folded nuclear membranes. +(Courtesy Dr. +Robert W. +Cytogenetic analysis has a central role in the +classification of AML. +Particular chromosomal abnormalities correlate with +certain clinical features. +You will remember that these findings are very similar to +those produced by ALL. +Thrombocytopenia results in +abnormal bleeding, which often is prominent. +Central nervous system spread is +less common than in ALL. +Without systemic +treatment, such tumors inevitably progress to full-blown +AML over time. +However, the outcome varies +markedly among different molecular subtypes. +AMLs with t(8;21) or inv(16) also have a relatively +good prognosis with conventional chemotherapy. +t-MDS usually appears from 2 to 8 years after the genotoxic +exposure. +• RNA splicing factors. +A subset of tumors has mutations +involving components of the 3′ end of the RNA splicing +machinery. +Precisely how these mutations contribute to +the development of MDS has yet to be determined. +• Transcription factors. +Pseudo–Pelger-HüetDisorders of white cells 621 +A B +C D +Figure 13.32 Myelodysplasia. +Characteristic forms of dysplasia are shown. +(A) Nucleated red cell progenitors with multilobated or multiple nuclei. +(D) Megakaryocytes +with multiple nuclei instead of the normal single multilobated nucleus. +Treatment options are fairly limited. +Older +patients with MDS are treated supportively with antibiotics +and blood product transfusions. +Myeloid blasts may be increased but +make up less than 20% of the overall marrow cellularity. +Myeloid blasts usually make up less than 10% of the +leukocytes in the blood. +In up to half of the cases, +it is discovered incidentally on routine blood testing. +When +symptomatic, it presents with weakness, infections, and +hemorrhages, all due to pancytopenia. +Several prog- +nostic scoring systems have been developed. +The cell of origin is a pluripotent HSC. +13.33). +Megakaryocytes are also increased and usually include small, +dysplastic forms. +Peripheral blood smear shows +many mature neutrophils, some metamyelocytes, and a myelocyte. +(Courtesy Dr. +Robert W. +der, Derivative chromosome. +Figure 13.35 Chronic myeloid leukemia (spleen). +(Courtesy Dr. +In the other 50% of patients, blast +crises occur abruptly without an accelerated phase. +Blasts usually make up less than 10% of the circulating +cells. +Platelets are also usually increased, sometimes markedly. +The spleen is often greatly enlarged as a result of extensive +extramedullary hematopoiesis (Fig. +13.35), and often contains +infarcts of varying age. +Extramedullary hematopoiesis can also +produce mild hepatomegaly and lymphadenopathy. +Clinical Features +CML is primarily a disease of adults but also occurs in +children and adolescents. +The peak incidence is in the fifth +to sixth decades of life. +There are about 4500 new cases per +year in the United States. +The onset is insidious. +Understanding of the pathogenesis of CML has led to +the use of drugs that target BCR-ABL. +As a result, it is not clear if BCR-ABL +inhibitors are ever truly curative. +The elevated hematocrit leads to increased blood viscosity +and sludging. +13.33). +MORPHOLOGY +The marrow is hypercellular, but some residual fat is usually +present. +At diagnosis, a moderate +to marked increase in reticulin fibers is seen in about 10% of +marrows. +The peripheral blood often contains +increased numbers of basophils and abnormally large platelets. +13.36).Transformation to AML, with its typical +features, occurs in about 1% of patients. +Figure 13.36 Polycythemia vera, spent phase. +(Courtesy Dr. +It appears insidiously, usually in adults of late +middle age. +Most symptoms are related to the increased +red cell mass and hematocrit. +Usually, there is also an +increased total blood volume. +Headache, +dizziness, hypertension, and gastrointestinal symptoms are +common. +High cell turnover gives rise to hyperuricemia; +symptomatic gout is seen in 5% to 10% of cases. +Without treatment, death from bleeding or thrombosis +occurs within months of diagnosis. +The +mechanisms underlying the progression to the spent phase +are not known. +In about 2% of patients, PCV transforms to AML. +The JAK2 mutation is the same as that found in almost all +cases of PCV. +Why some patients with JAK2 mutations +present with PCV and others with ET is not understood. +As mentioned, most cases without JAK2 +or MPL mutations have calreticulin mutations instead. +Peripheral smears usually reveal abnormally large platelets +(Fig. +13.37), often accompanied by mild leukocytosis. +Uncommonly, a spent +phase of marrow fibrosis or transformation to AML supervenes. +Clinical Features +The incidence of ET is 1 to 3 per 100,000 per year. +It usually +occurs past the age of 60 but may also be seen in young +adults. +At this stage fibrosis is minimal, and the +blood may show leukocytosis and thrombocytosis. +With progres- +sion, the marrow becomes more hypocellular and diffusely +fibrotic. +Grossly, such spleens are firm and diffusely red to gray. +As in CML, subcapsular infarcts are common (see Fig. +13.41). +The liver may be enlarged +moderately by sinusoidal foci of extramedullary hematopoiesis. +Hematopoiesis may also appear within lymph nodes, but significant +lymphadenopathy is uncommon. +The marrow fibrosis is reflected in several characteristic blood +findings (Fig. +13.38). +Other common, albeit nonspecific, blood findings +include abnormally large platelets and basophilia. +Figure 13.37 Essential thrombocytosis. +Median survival times are 12 to 15 years. +Therapy +consists of “gentle” chemotherapeutic agents that suppress +thrombopoiesis. +As you +recall, platelet-derived growth factor and TGF-β are fibroblast +mitogens. +For +incompletely understood reasons, red cell production at +extramedullary sites is disordered. +This factor and the +concomitant suppression of marrow function result in +moderate to severe anemia. +Figure 13.38 Primary myelofibrosis (peripheral blood smear). +Two +nucleated erythroid precursors and several teardrop-shaped red cells +(dacryocytes) are evident. +Immature myeloid cells were present in other +fields. +Hyperuricemia and secondary gout due +to a high rate of cell turnover can complicate the picture. +These blood findings are not specific; bone marrow biopsy +is essential for diagnosis. +Primary myelofibrosis is a much more difficult disease +to treat than PCV or ET. +The course is variable, but the +median survival is in the range of 3 to 5 years. +MDS +• Myeloid tumors characterized by disordered and ineffective +hematopoiesis and dysmaturation. +• May occur de novo or following genotoxic exposures. +• Manifest with one or more cytopenias and often progress to +AML. +Less common mutations +have also been detected in TP53, RAS, and the receptor +tyrosine kinase MET. +13.39A).The presence +of Birbeck granules in the cytoplasm is characteristic. +13.39B), which +contain the protein langerin. +In addition, the tumor cells also +typically express HLA-DR, S-100, and CD1a. +The course of untreated disease +is rapidly fatal. +With intensive chemotherapy, 50% of +patients survive 5 years. +Eosinophils are usually, but not always, a prominent +component of the infiltrate. +Less commonly, unisystem lesions of +identical histology arise in the skin, lungs, or stomach. +Unifocal lesions most commonly affect the skeletal system +in older children or adults. +A +B +Figure 13.39 Langerhans cell histiocytosis. +(B, Courtesy Dr. +13.40). +As it traverses the red pulp, the blood takes two routesSpleen 629 +• Hematopoiesis. +• Sequestration of formed blood elements. +The spleen +also normally harbors approximately 30% to 40% of the +total platelet mass in the body. +Similarly, the enlarged spleen may trap white +cells and thereby induce leukopenia. +It is rarely the primary site of disease. +(Modified from Faller DV: +Diseases of the spleen. +• Antibody production. +Table 13.12 lists major disorders associated with spleno- +megaly. +Splenomegaly in virtually all the conditions +mentioned has been discussed elsewhere. +A few disorders +are left to consider. +Nonspecific Acute Splenitis +Enlargement of the spleen occurs in any blood-borne infec- +tion. +MORPHOLOGY +The spleen is enlarged (200 to 400 g) and soft. +Immunologic-Inflammatory Conditions +Rheumatoid arthritis +Systemic lupus erythematosus +V. +Storage Diseases +Gaucher disease +Niemann-Pick disease +Mucopolysaccharidoses +VI. +Cirrhosis of the liver is the main cause of massive +congestive splenomegaly. +Other forms of cirrhosis are less commonly +implicated. +MORPHOLOGY +Long-standing splenic congestion produces marked enlargement +(1000 to 5000 g). +The organ is firm, and the capsule is usually +thickened and fibrous. +In normal-sized spleens, infarcts are most +often caused by emboli that arise from the heart. +The infarcts +can be small or large, be single or multiple, or even involve +the entire organ. +encroach on and virtually efface the lymphoid follicles. +Rarely, abscess formation +occurs. +MORPHOLOGY +Bland infarcts are characteristically pale, wedge-shaped, and +subcapsular in location. +The overlying capsule is often covered +with fibrin (Fig. +13.41). +In septic infarcts this appearance is modified +by the development of suppurative necrosis. +In the course of +healing, large depressed scars often develop. +All of +these disorders ultimately lead to portal or splenic vein +hypertension. +Hypoplasia is a more common +finding. +They +can be found at any place within the abdominal cavity. +RUPTURE +Figure 13.41 Splenic infarcts. +Splenic rupture is usually precipitated by blunt trauma. +Much less often, it occurs in the apparent absence of a +physical blow. +(discussed earlier). +Benign fibromas, osteomas, chondro- +mas, lymphangiomas, and hemangiomas may arise in the +spleen. +Of these, lymphangiomas and hemangiomas are +most common and often cavernous in type. +Here, our interest +centers on the disorders of the gland itself. +At birth it weighs 10 to 35 g. +The fully developed thymus is composed of two fused, +well-encapsulated lobes. +During adulthood the +thymic production of T cells slowly declines as the organ +atrophies. +Pathologic changes within the thymus are limited and +will be described here. +The changes associated with myas- +thenia gravis are considered in Chapter 27. +The fluid +contents can be serous or mucinous and are often modified +by hemorrhage. +Such B-cell follicles are present in only small +numbers in the normal thymus. +In other instances, a morphologically normal thymus is +simply large for the age of the patient. +Such tumors typically also contain benign +immature T cells (thymocytes). +Males +and females are affected equally. +They +are uncommon in the posterior mediastinum. +The medullary-type epithelial cells +are elongated or spindle-shaped (Fig. +13.42A). +(A) Benign thymoma (medullary type). +Only a few small, +reactive lymphoid cells are interspersed. +(B) Malignant thymoma, type I. +Numerous small, reactive lymphoid +cells are interspersed. +Invasive thymoma refers to a tumor that is cytologically +benign but locally invasive. +These tumors are much more likely +to metastasize. +13.42B), and are usually mixed with numerous thy- +mocytes. +These tumors account for about 20% to 25% of all +thymomas. +By definition, invasive thymomas penetrate +through the capsule into surrounding structures. +Thymic carcinoma represents about 5% of thymomas. +Microscopically, most are squamous cell carcinomas. +[Discussion of +origins of hematopoietic stem cells]. +[Discussion of the +nature and biology of the marrow stem cell niche]. +[Up-to-date review of the pathogenesis and clinical +features of Langerhans cell histiocytosis]. +[Overview of the most recent version of +the classification system used for myeloid neoplasms]. +Hunger SP, Mullighan CG: Acute lymphoblastic leukemia in children, +N Engl J Med 373:2015, 1541. +Kumar SJ, Rajkuar V, Kyle RA et al: Multiple myeloma, Nat Rev Dis +Primers 3:17046, 2017. +[Review of the pathogenesis, clinical features, and +treatment of multiple myeloma]. +Ogawa S: Genetics of MDS, Blood 133:1049, 2019. +[Comprehensive review +of genetic drivers in myelodysplastic syndromes]. +[Recent review of emerging link between myelodysplastic syndromes and +inflammation]. +[Review of the molecular pathogenesis Burkitt lymphoma]. +[Overview of the most recent version of the classification +system used for lymphoid neoplasms]. +[Update on the pathogenesis of the major subtypes of myeloproliferative +neoplasms]. +Another 30% +to 45% are detected in the course of evaluating patients +with myasthenia gravis. +The rest are discovered incidentally +during imaging studies or cardiothoracic surgery. +Anemia reduces the +oxygen-carrying capacity of the blood, leading to tissue +hypoxia. +There are many classifications of anemia. +We will follow +one based on underlying mechanisms that is presented in +Table 14.1. +a Most often anemia stems from iron deficiency, not bleeding per se. +Adult reference ranges for red cell indices are shown in +Table 14.2. +Hypoxia can cause fatty change in the +liver, myocardium, and kidney. +Central nervous +system hypoxia can cause headache, dimness of vision, and +faintness. +Extravascular hemolysis is most commonly caused by +alterations that make red cells less deformable. +Extreme +changes in shape are required for red cells to navigate the +splenic sinusoids successfully. +Unlike in extravascular hemolysis, +splenomegaly is not seen. +In all types of uncomplicated hemolytic anemia, the excess +serum bilirubin is unconjugated. +the bleeding is external or internal. +This fluid shift produces hemodilution and +lowers the hematocrit. +13.1). +Initially, red cells appear normal in size and color (normo- +cytic, normochromic). +14.1). +Such iron accumulation is referred to as hemosiderosis. +Figure 14.1 Marrow aspirate smear from a patient with hemolytic +anemia. +There is an increased number of maturing erythroid progenitors +(normoblasts). +(Courtesy Dr. +The prevalence of HS is highest in northern Europe, where +rates of 1 in 5000 are reported. +An autosomal dominant +inheritance pattern is seen in about 75% of cases. +14.2), which lies +closely apposed to the internal surface of the plasma mem- +brane. +HS is caused by diverse mutations that lead to an +insufficiency of membrane skeletal components. +GP, Glycophorin.Anemias 639 +that the mutated allele fails to produce any protein. +The travails of spherocytic red cells are fairly +well defined. +In the life of the portly, inflexible spherocyte, +the spleen is the villain. +14.3). +After splenectomy the spherocytes persist, but the anemia +is corrected. +Figure 14.4 Hereditary spherocytosis (peripheral smear). +Note the +anisocytosis and several dark-appearing spherocytes with no central pallor. +(Courtesy Dr. +Robert W. +14.4). +Other features are common to +all hemolytic anemias. +These include reticulocytosis, marrow +erythroid hyperplasia, hemosiderosis, and mild jaundice. +Chole- +lithiasis (pigment stones) occurs in 40% to 50% of affected +adults. +Splenomegaly results from congestion of the +cords of Billroth and increased numbers of phagocytes. +The characteristic clinical features are anemia, spleno- +megaly, and jaundice. +The severity varies greatly. +Thus, older red cells are +much more prone to hemolysis than younger ones. +The other important initiators are drugs +and certain foods. +Some drugs cause +hemolysis only in individuals with the more severe Mediter- +ranean variant. +The most frequently cited food is the fava +bean, which generates oxidants when metabolized. +Oxidants cause both intravascular and extravascular +hemolysis in G6PD-deficient individuals. +These are seen as dark +inclusions within red cells stained with crystal violet +(Fig. +14.6). +Heinz bodies can damage the membrane suffi- +ciently to cause intravascular hemolysis. +Less severe +membrane damage results in decreased red cell deform- +ability. +14.6). +Other less severely damaged +cells become spherocytes due to loss of membrane surface +area. +Both bite cells and spherocytes are trapped in splenic +cords and removed by phagocytes. +The recovery phase is heralded by reticulocytosis. +The +synthesis of NADPH depends on the activity of G6PD. +GSSG, Oxidized +glutathione; NADP, nicotinamide adenine dinucleotide phosphate. +for even short periods leads to sudden worsening of the +anemia. +Transfusions may be necessary to support the patient +during the acute phase of the infection. +Gallstones, found in many +patients, may also produce symptoms. +14.5). +14.5). +In HbSC red cells, the percent- +age of HbS is 50%, as compared with only 40% in HbAS +cells. +• Mean cell hemoglobin concentration (MCHC). +Thus, intracellular dehydration, which +increases the MCHC, facilitates sickling. +(Courtesy Dr. +Robert W. +In affected individuals, almost all the +hemoglobin in the red cell is HbS (α2 βs2). +Although mechanistic details642 CHAPTER 14 Red Blood Cell and Bleeding Disorders +severity. +• Intracellular pH. +• Transit time of red cells through microvascular beds. +As a result, inflamed vascular beds are +prone to sickling and occlusion. +Sickling causes cumulative damage to red cells through +several mechanisms. +As a +result, with repeated sickling episodes, red cells become +dehydrated, dense, and rigid (Fig. +14.7). +Sickled red cells are also mechani- +cally fragile, leading to some intravascular hemolysis as well. +14.7). +Depletion of nitric oxide (NO) also +may play a part in the vascular occlusions. +HbA, Hemoglobin A; +HbS, hemoglobin S; RBC, red blood cell. +14.10). +(B) Higher magnification shows an +irreversibly sickled cell in the center. +(Courtesy Dr. +Robert W. +(B) Under +high power, splenic sinusoids are dilated and filled with sickled red cells. +(Courtesy Dr. +The most commonly involved sites are the +bones, lungs, liver, brain, spleen, and penis. +(Courtesy Drs. +A clinical trial +testing this approach is ongoing and has produced excellent +responses. +Sequestration crises occur in children +with intact spleens. +In addition to these dramatic crises, chronic tissue hypoxia +takes a subtle but important toll. +Increased susceptibility to infection with encapsulated +organisms is another threat. +Some +individuals suffer repeated vaso-occlusive crises, whereas +others have only mild symptoms. +About +90% of patients survive to 20 years of age, and close to 50% +survive beyond the fifth decade. +β-Thalassemia +β-thalassemia is caused by mutations that diminish the +synthesis of β-globin chains. +Its clinical severity varies +widely due to heterogeneity in the causative mutations. +These are the most common cause of +β+-thalassemia. +Others create an “ectopic” splice site within an intron. +• Promoter region mutations. +These mutations reduce +transcription by 75% to 80%. +These are the most common +cause of β0-thalassemia. +Both block translation +and prevent the synthesis of any functional β-globin. +Impaired β-globin synthesis results in anemia by two +mechanisms (Fig. +14.11). +Unpaired α chains precipitate +within red cell precursors, forming insoluble inclusions. +Many red cell precursors succumb to membrane +damage and undergo apoptosis. +In severe β-thalassemia, ineffective erythropoiesis creates +several additional problems. +Injury to parenchymal organs, particu- +larly the heart and liver, often follows (Chapter 18). +This condition is +referred to as β-thalassemia minor or β-thalassemia trait. +A +third genetically heterogeneous variant of moderate severity +is called β-thalassemia intermedia. +β-Thalassemia major is most +common in Mediterranean countries, parts of Africa, and +Southeast Asia. +In the United States, the incidence is highest +in immigrants from these areas. +The anemia manifests 6 to +9 months after birth as hemoglobin synthesis switches from +HbF to HbA. +In untransfused patients, hemoglobin levels +are 3 to 6 g/dL. +The major red cell hemoglobin is HbF, which +is markedly elevated. +HbA2 levels are sometimes high but +more often are normal or low. +β-Thalassemia Minor. +Most patients are heterozy- +gous carriers of a β+ or β0 allele. +These patients are usually +asymptomatic. +Anemia, if present, is mild. +Mild erythroid hyper- +plasia is seen in the bone marrow. +HbF levels +are generally normal or occasionally slightly increased. +Other major alterations involve the bone marrow and spleen. +In untransfused patients, there is a striking expansion of hemato- +poietically active marrow. +14.13). +The clinical course of β-thalassemia major is brief unless +blood transfusions are given. +Hepatosplenomegaly due to extramedullary hematopoiesis +is usually present. +Prenatal diagnosis is possible by molecular analysis +of DNA. +Figure 14.13 β-Thalassemia major. +(Courtesy Dr. +Hematopoietic stem cell +transplantation can be curative. +PNH has an incidence of 2 to 5 per million in the United +States. +Recall that proteins are anchored into the +lipid bilayer in two ways. +This manifests +as intravascular hemolysis, which is caused by the C5b-C9 +membrane attack complex. +The anemia is variable but usually +mild to moderate in severity. +Thrombosis is the leading cause of disease-related death +in individuals with PNH. +Each of the +four α-globin genes normally contributes 25% of the total +α-globin chains. +α-Thalassemia syndromes stem from +combinations of deletions that remove one to four α-globin +genes. +The different types of α-thalassemia and their salient +clinical features are listed in Table 14.3. +Silent Carrier State. +These +individuals are completely asymptomatic but have slight +microcytosis. +α-Thalassemia Trait. +The +former genotype is more common in Asian populations, +the latter in regions of Africa. +HbA2 levels are normal or low. +Hemoglobin H (HbH) Disease. +HbH disease is caused by +deletion of three α-globin genes. +It is most common in Asian +populations. +The result is a moderately severe anemia +resembling β-thalassemia intermedia. +Hydrops Fetalis. +Signs of fetal distress usually become evident by +the third trimester of pregnancy. +Quantitative immunologic tests to measure such antibodies +directly also are available. +Warm Antibody Type. +This form constitutes approximately +80% of cases of immunohemolytic anemia. +It is caused by +antibodies that bind stably to red cells at 37°C. +Most causative antibodies are of the IgG class; less +commonly, IgA antibodies are the culprits. +The red cell +hemolysis is mostly extravascular. +Moderate splenomegaly due to hyperplasia of splenic +phagocytes is usually seen. +As with other autoimmune disorders, the cause of primary +immunohemolytic anemia is unknown. +In drug-induced cases, two mechanisms have been described. +• Antigenic drugs. +• Tolerance-breaking drugs. +CD59 +CD59 +CD55 CD55 +B +A +Figure 14.14 Paroxysmal nocturnal hemoglobinuria (PNH). +(Courtesy Dr. +Scott Rodig, Department of Pathology, +Brigham and Women’s Hospital, Boston, Mass.) +cerebral veins. +14.14). +Immunosuppressive +drugs are sometimes beneficial for those with evidence of +marrow aplasia. +The only cure is hematopoietic stem cell +transplantation. +Cold Agglutinin Type. +It +accounts for 15% to 20% of cases. +IgM binding +agglutinates red cells and fixes complement rapidly. +The hemolysis +is of variable severity. +Chronic cold agglutinin +immunohemolytic anemia caused by IgM antibodies may +be difficult to treat. +The best approach, when possible, is +avoidance of cold temperatures. +Cold Hemolysin Type. +14.15). +• Ineffective erythropoesis increases iron absorption and can +lead to systemic iron overload. +(Courtesy Dr. +Robert W. +The causes of megaloblastic anemia +are given in Table 14.5. +Some of the metabolic roles of vitamin B12 and folate are +considered later. +Nucleated +red cell progenitors occasionally appear in the circulating blood +when anemia is severe. +14.16). +Megaloblastic +changes are detected at all stages of erythroid development. +Megakaryocytes +also may be abnormally large and have bizarre, multilobate nuclei. +Figure 14.16 Megaloblastic anemia. +A peripheral blood smear shows a +hypersegmented neutrophil with a six-lobed nucleus. +(Courtesy Dr. +Robert +W. +A to C, +Megaloblasts in various stages of differentiation. +(Courtesy Dr. +The anemia is further exacerbated by a +mild degree of red cell hemolysis of uncertain etiology. +Normal Vitamin B12 Metabolism. +The daily requirement is 2 to 3 µg. +14.18). +Biochemical Functions of Vitamin B12. +Only two reactions +in humans are known to require vitamin B12. +14.19). +In the same reaction, N5-methyl FH4 is converted to tetra- +hydrofolic acid (FH4). +14.20). +A deficiency of vitamin B12 thus leads to increased plasma +and urine levels of methylmalonic acid. +Pernicious Anemia +Incidence. +Three types of autoantibodies are +present in many, but not all, patients. +Type I antibodies are found in both +plasma and gastric juice. +Both type I and type II antibodies are found in +plasma and gastric juice. +In cobalamin (Cbl) deficiency, folate is sequestered +as N5-methyl FH4. +Serum +antibodies to intrinsic factor are highly specific for pernicious +anemia. +Vitamin B12 deficiency also may arise from causes other +than pernicious anemia. +With gastrectomy, intrinsic +factor is lost. +14.20). +Humans depend on dietary sources for folic +acid. +Most normal diets contain ample amounts. +The richest +sources are green vegetables such as lettuce, spinach, aspara- +gus, and broccoli. +The +folic acid in these foods is largely in the form of folylpoly- +glutamates. +The course is progressive unless halted by therapy.Anemias 655 +the transport form of folate. +A +normal diet contains folate in excess of the minimal daily +adult requirement. +Importantly, neurologic changes +do not occur. +Iron Metabolism. +The major sites of storage iron are the liver +and mononuclear phagocytes. +Iron in the body is recycled between the functional and +storage pools (Fig. +14.21). +Free iron is highly toxic (Chapter 18), and storage iron +must therefore be sequestered. +This is achieved by the +binding of storage iron to either ferritin or hemosiderin. +Here, it is metabolized to release Fe2+ iron, +which enters a common pool with nonheme Fe2+ iron. +Frequently, less than 5% of dietary +nonheme iron is absorbed. +14.21). +Conversely, with low body stores of iron, hepcidin levels +fall, facilitating iron absorption. +Alterations in hepcidin have a central role in diseases +involving disturbances of iron metabolism. +This is illus- +trated by the following examples. +Here iron is extracted from hemoglobin and recycled to plasma +transferrin. +In iron-overloaded +cells, most iron is stored in hemosiderin. +Iron balance is maintained by regulating the +absorption of dietary iron in the proximal duodenum. +By contrast, as body iron +stores increase, absorption decreases, and vice versa. +14.22) +and differ for nonheme and heme iron. +Duodenal epithelial cell uptake of heme and nonheme iron is described in the text. +DMT1, Divalent metal transporter 1. +Etiology. +To maintain a normal iron balance, about 1 mg +of iron must be absorbed from the diet every day. +The bioavailability of dietary +iron is as important as the overall content. +The absorption +of inorganic iron is influenced by other dietary contents. +Human breast milk provides only about +0.3 mg/L of iron. +Cow’s milk contains about twice as +much iron, but its bioavailability is poor. +Chronic blood loss is the most common cause of iron +deficiency in high income societies. +In this early stage, there is increased erythroid +activity in the bone marrow. +Figure 14.23 Iron deficiency (peripheral blood smear). +Note the +hypochromic microcytic red cells containing a narrow rim of peripheral +hemoglobin. +Scattered fully hemoglobinized cells, present due to recent +blood transfusion, stand in contrast. +(Courtesy Dr. +Robert W. +The diagnosis of iron deficiency anemia ultimately rests +on laboratory studies. +Reduced iron stores inhibit hepcidin synthesis, and its serum +levels fall. +In peripheral blood smears, the red cells are small (microcytic) +and pale (hypochromic). +14.23). +As a result, the erythroid precursors +are starved for iron in the midst of plenty. +What might be the reason for iron sequestration in the +setting of inflammation? +influenzae) that require +iron for pathogenicity. +The anemia is usually mild, and the dominant symptoms +are those of the underlying disease. +Etiology. +The most common circumstances associated with +aplastic anemia are listed in Table 14.7. +Most cases of +“known” etiology follow exposure to chemicals and drugs. +The impli- +cated drugs in these idiosyncratic reactions include chlor- +amphenicol and gold salts. +Why aplastic +anemia develops in certain individuals is not understood. +Whole-body irradiation can destroy hematopoietic stem +cells in a dose-dependent fashion. +• Inherited defects in telomerase are found in 5% to 10% of +adult-onset aplastic anemia. +Telomerase is required for +cellular immortality and limitless replication (Chapters +1 and 7). +Pathogenesis +The pathogenesis of aplastic anemia is not fully understood. +Indeed, it is unlikely that a single mechanism underlies all +cases. +If the damage is +extensive enough, aplastic anemia results. +14.25). +If the anemia necessitates multiple +transfusions, systemic hemosiderosis can appear. +IFNγ +TNF +T-cell response +Marrow +aplasia +Figure 14.24 Pathophysiology of aplastic anemia. +Either pathway could lead to marrow aplasia. +See text for +abbreviations. +14.24). +This scenario is supported by several +observations. +It is proposed that these therapies work +by suppressing or killing autoreactive T-cell clones. +The +antigens recognized by the autoreactive T cells are not +well defined. +Markedly +hypocellular marrow contains mainly fat cells. +(A) Low power. +(B) High +power. +(Courtesy Dr. +Clinical Features +Aplastic anemia can occur at any age and in either sex. +The +onset is usually insidious. +The red cells are usually slightly macrocytic and normo- +chromic. +Reticulocytopenia is the rule. +The diagnosis rests on examination of a bone marrow +biopsy. +The prognosis is variable. +Older patients +or those without suitable donors often respond well to +immunosuppressive therapy. +In severe cases, +red cell progenitors are completely absent from the marrow. +In patients without thymoma, immunosuppressive +therapy is often beneficial. +The following tests are used to evaluate different +aspects of hemostasis: +• Prothrombin time (PT). +This test assesses the extrinsic and +common coagulation pathways. +• Partial thromboplastin time (PTT). +This test assesses the +intrinsic and common clotting pathways. +The clotting +of plasma after addition of kaolin, cephalin, and Ca2+ +ions is measured in seconds. +• Platelet counts. +These are obtained on anticoagulated +blood using an electronic particle counter. +The reference +range is 150 × 103 to 350 × 103 platelets/ µL. +Affected individuals are usually +males who are hypertensive, obese, and anxious (“stressed”). +A pathophysiologic +classification of polycythemia divided along these lines is +given in Table 14.8. +Secondary +polycythemia stems from compensatory or pathologic +increases in erythropoietin secretion. +At present, no single test +provides an adequate assessment of the complex func- +tions of platelets. +It is +characterized by dilated, tortuous blood vessels with thin +walls that bleed readily. +• Perivascular amyloidosis can weaken blood vessel walls +and cause bleeding. +A count less +than 150,000 platelets/ µL is generally considered to constitute +thrombocytopenia. +When +thrombocytopenia is isolated, the PT and PTT are normal. +Spontaneous bleeding associated with +thrombocytopenia most often involves small vessels. +The causes of thrombocytopenia fall into four major +categories (Table 14.9). +• Decreased platelet production. +• Decreased platelet survival. +This important mechanism of +thrombocytopenia may have an immunologic or nonim- +munologic basis. +Autoimmune thrombocytopenia +is discussed in the following section. +In the overwhelming majority of cases, the +antiplatelet antibodies are of the IgG class. +The +marrow reveals a modestly increased number of mega- +karyocytes. +Some are apparently immature, with large, nonlobu- +lated, single nuclei. +made in the mother may cause clinically significant +thrombocytopenia in the fetus. +• Sequestration. +• Dilution. +Massive transfusions can produce dilutional +thrombocytopenia. +The diagnosis of primary +chronic ITP is made only after secondary causes are excluded. +The female-to-male ratio is 3 : 1. +It is +often insidious in onset and is characterized by bleeding +into the skin and mucosal surfaces. +Petechiae can become +confluent, giving rise to ecchymoses. +The +disease may manifest first with melena, hematuria, or +excessive menstrual flow. +Typical laboratory findings are reflective of isolated +thrombocytopenia. +The PT and PTT are normal. +Acute ITP is mainly a disease of childhood occurring with +equal frequency in both sexes. +Unlike chronic ITP, acute ITP is +self-limited, usually resolving spontaneously within 6 +months. +Glucocorticoids are given only if the thrombocy- +topenia is severe. +Much more rarely, drugs induce true autoantibodies through +unknown mechanisms. +It most likely results from a +direct platelet-aggregating effect of heparin. +• Type II HIT is less common but is often life threatening. +Both decreased platelet +production and increased platelet destruction contribute. +This group of disorders +includes TTP and HUS. +With time, experience, and increased mechanistic insight, +however, these distinctions have blurred. +ADAMTS13 deficiency may be inherited or acquired. +Less commonly, +patients inherit an inactivating mutation in ADAMTS13. +Children and older adults are at highest +risk. +Those affected present with bloody diarrhea, and a +few days later HUS makes its appearance. +Unlike TTP, the basis for the platelet activation in typical +and atypical HUS is unclear. +Immunosuppression +also may be beneficial to patients with inhibitory autoantibod- +ies. +Typical HUS is treated supportively. +The impact of HUS and TTP on the kidneys is discussed +further in Chapter 20. +Affected patients have +a variable, often severe, bleeding tendency. +• Glanzmann thrombasthenia exemplifies bleeding due to +defective platelet aggregation. +It is transmitted as an +autosomal recessive trait. +Among the acquired defects of platelet function, two are +clinically significant. +The first is caused by ingestion of aspirin +and other nonsteroidal anti-inflammatory drugs. +Hereditary deficiencies typically affect a single clotting +factor. +Vitamin K deficiency (Chapter +9) impairs the synthesis of factors II, VII, IX, X and protein +C. +By contrast, in DIC, multiple coagulation factors +are consumed, leading to their deficiency. +Acquired deficien- +cies of single factors occur, but are rare. +These are usually +caused by inhibitory autoantibodies. +Factor VIII is an essential cofactor of factor IX, which +converts factor X to factor Xa (Fig. +14.26; Chapter 4). +The two associate to form a complex in the circulation. +14.26). +Factor VIII and vWF protein levels are measured by +immunologic techniques. +It is inherited as an autosomal +dominant disorder. +The +plasma level of active vWF, measured as the ristocetin +cofactor activity, is reduced. +About 30% of patients have no family history; their disease +is caused by new mutations. +In such cases, factor VIII protein +levels may be normal by immunoassay. +Recurrent bleeding into the joints leads to +progressive deformities that can be crippling. +Petechiae are +characteristically absent. +Factor VIII–specific assays +are required for diagnosis. +Hemophilia A is treated with infusions of recombinant +factor VIII. +Efforts to develop somatic gene +therapy for hemophilia are ongoing. +A wide spectrum +of mutations involving the gene that encodes factor IX is +found in hemophilia B. +In about 15% of these patients, factor IX protein +is present but is nonfunctional. +As with hemophilia A, the +PTT is prolonged and the PT is normal. +The disease is treated with +infusions of recombinant factor IX. +It occurs as a secondary complication +of many disorders. +Sometimes the coagulopathy is local- +ized to a specific organ or tissue. +Clotting in vivo is initiated by exposure of tissue factor, +which activates factor VII. +Activation of factor X leads +to the generation of thrombin, the central player in clotting. +To prevent runaway clotting, +this process must be sharply limited to the site of tissue +injury. +Endothelial injury can initiate DIC in several ways. +However, even subtle endothelial injuries +can unleash procoagulant activity. +One mediator of endo- +thelial injury is TNF, which is implicated in DIC occurring +with sepsis. +The +triggers in these conditions are often multiple and inter- +related. +that secondarily activate platelets and granulocytes. +The possible consequences of DIC are twofold (Fig. +14.27). +• Widespread deposition of fibrin within the microcirculation. +cortical necrosis. +The only definitive treatment is +to remove or treat the inciting cause. +products (packed red blood cells, platelets, and fresh-frozen +plasma) are safer than ever before. +Nevertheless, complications still occur. +Most are minor +and transient. +These reactions are +thought to be caused by inflammatory mediators derived +from donor leukocytes. +Symptoms respond to antipyretics and are short-lived. +These are considerably +more common, occurring in 1% to 3% of transfusions, but +are generally mild. +Fever, shaking chills, and flank pain +appear rapidly. +The direct Coombs test is typically positive, +unless all of the donor red cells have lysed. +Deficiency of ADAMTS 13 results in +abnormally large vWF multimers that activate platelets. +• Hemophilia B:X-linked disorder caused by mutations in coagula- +tion factor IX. +It is clinically identical to hemophilia A. +Over +5 million red cell transfusions are given in US hospitals +each year. +potentially fatal reactions identical to those resulting from +ABO mismatches. +Though its pathogenesis is incompletely understood, current +models favor a “two-hit” hypothesis. +The first is neutrophil +sequestration and priming in the microvasculature of the +lung. +In other cases, donor antibodies to neutrophil-specific +antigens have been implicated as triggers. +Diffuse +bilateral pulmonary infiltrates that do not respond to diuretics +are seen on chest imaging. +Other associated findings include +fever, hypotension, and hypoxemia. +[A review of the molecular pathogenesis of thalassemia syndromes]. +Muckenthaler MU, Rivella S, Hentze MW: A red carpet for iron +metabolism, Cell 168:344, 2017. +[A review focused on normal iron +metabolism and disorders that perturb it]. +Narla J, Mohandas N: Red cell membrane disorders, Int J Lab Med +39(47):2017. +[An excellent overview of common hemolytic anemias caused +by inherited red cell membrane defects]. +[An updated discussion of how +sickle cell disease leads to tissue damage]. +Young NS: Aplastic anemia, N Engl J Med 379:2018, 1643. +[A discussion +of the pathophysiology, diagnosis, and treatment of aplastic anemia]. +[An overview of the pathophysiology +of disseminated intravascular coagulation]. +Leebeek FWG, Eikenboom JCJ: von Willebrand’s disease, N Engl J Med +375:2067, 2016. +Noris M, Remuzzi G: Atypical hemolytic uremic syndrome, N Engl J +Med 361:1676, 2009. +[A current review of basic and clinical aspects of +thrombotic thrombocytopenia purpura]. +Developmentally, the respiratory system is +an outgrowth from the ventral wall of the foregut. +The lobar bronchi +allow air to pass in and out of the lung. +The right mainstem bronchus is more +vertical and directly in line with the trachea. +15.35B). +of bronchioles leads to the terminal bronchioles, which are +less than 2 mm in diameter. +The microscopic structure of the alveolar walls (or alveolar +septa) consists of the following (Fig. +15.1): +• An intertwining network of anastomosing capillaries lined +with endothelial cells. +CONGENITAL ANOMALIES +Developmental anomalies of the lung are rare. +Severe hypoplasia is fatal in the early +neonatal period. +A bronchogenic cyst is rarely +connected to the tracheobronchial tree. +It may be associated with other congenital anomalies. +Intralobar sequestration occurs within the lung. +15.2). +Whatever the clinical setting, pulmonary +congestion and edema produce heavy, wet lungs. +Therapy +and outcome depend on the underlying etiology. +Alveolar microhemorrhages +and hemosiderin-laden macrophages (“heart failure” cells) may +be present. +These changes not only impair respiratory +function but also predispose to infection. +Dashed lines indicate +normal lung volume. +• Resorption atelectasis stems from obstruction of an airway. +Over time, air is resorbed from distal alveoli, which +collapse. +Since lung volume is diminished, the media- +stinum shifts toward the atelectatic lung. +With compression atelectasis, the mediastinum shifts +away from the affected lung. +Significant atelectasis reduces oxygenation and predis- +poses to infection. +Except in cases caused by fibrosis, atel- +ectasis is a reversible disorder. +Acute respiratory distress syndrome (ARDS) is a +manifestation of severe ALI. +The histologic manifestation of these diseases is diffuse +alveolar damage. +15.3). +• Endothelial activation is an important early event. +• Adhesion and extravasation of neutrophils. +• Accumulation of intra-alveolar fluid and formation of hyaline +membranes. +IL-1, Interleukin-1; ROS, reactive oxygen species; TNF, tumor necrosis factor. +In most cases the +granulation tissue resolves, leaving minimal functional impairment. +The alveolar walls become lined with waxy hyaline membranes +(Fig. +In the proliferative or +Figure 15.4 Diffuse alveolar damage (acute respiratory distress +syndrome). +Some of the alveoli are collapsed, while others are distended. +The majority of deaths are attributable to sepsis, multiorgan +failure, or severe lung injury. +diseases is based primarily on pulmonary function tests. +An FEV1/FVC ratio of less than 0.7 generally indicates +obstructive disease. +15.5). +Con- +versely, some patients with otherwise typical COPD have +a reversible component. +Clinicians commonly label such +patients as having COPD/asthma. +• Panacinar (panlobular) emphysema. +15.6C and +15.7B). +• Distal acinar (paraseptal) emphysema. +Figure 15.5 Schematic representation of overlap between chronic +obstructive lung diseases. +There is a strong association between +heavy cigarette smoking and COPD. +Women and African +Americans who smoke heavily are more susceptible than +other groups. +We will +finish our discussion by returning to the clinical features +of COPD. +Emphysema is classified according +to its anatomic distribution within the lobule. +Recall that +the lobule is a cluster of acini, the terminal respiratory units. +Of these, only the first two cause clinically significant airflow +obstruction (Fig. +15.6). +• Centriacinar (centrilobular) emphysema. +It occurs pre- +dominantly in heavy smokers with COPD. +15.6B and 15.7A). +(A) Structure of +the normal acinus. +(B) Centriacinar emphysema with dilation that initially +affects the respiratory bronchioles. +Central areas show marked emphysematous damage (E) surrounded by relatively spared alveolar spaces. +(B) Panacinar emphysema involving the entire pulmonary lobule. +• Airspace enlargement with fibrosis (irregular emphysema). +In most instances it occurs in small foci and is +clinically insignificant. +15.8): • +Toxic injury and inflammation. +• Protease-antiprotease imbalance. +• Oxidative stress. +The role of oxidants is supported by +studies of mice in which the NRF2 gene is inactivated. +• Infection. +About 1% of all patients with emphysema have +this defect. +It is encoded by the proteinase inhibitor (Pi) +locus on chromosome 14. +The Pi locus is polymorphic, and +approximately 0.012% of the U.S. +Several other genetic variants have also been linked to +risk of emphysema. +A number of factors contribute to airway obstruction in +emphysema. +Small airways are normally held open by the +elastic recoil of the lung parenchyma. +MORPHOLOGY +Advanced emphysema produces voluminous lungs, often overlapping +the heart anteriorly. +Large alveoli can easily be seen on the cut surface of +fixed lungs (see Fig. +15.7). +There is loss of +attachments between alveoli and the outer wall of small airways. +in the trachea and bronchi. +• Acquired cystic fibrosis transmembrane conductance regulator +(CFTR) dysfunction. +• Inflammation. +• Infection. +Cigarette smoke predisposes to chronic bronchitis in +several ways. +Sometimes, heavy casts of secretions +and pus fill the bronchi and bronchioles. +Several +factors contribute to its pathogenesis. +• Mucus hypersecretion. +• Underlying pulmonary pathology usually includes both chronic +bronchitis and emphysema. +Once COPD appears, symptoms often wax and wane +over time and are generally worse in the morning. +At one extreme end of the +spectrum lie “pink puffers,” patients in whom emphysema +dominates. +Weight loss is common and can +be so severe as to suggest an occult cancer. +Even with intervention, however, +COPD often progresses and frequently proves fatal. +• Compensatory hyperinflation. +• Obstructive overinflation. +In this condition the lung expands +because air is trapped within it. +A common cause is +subtotal obstruction of an airway by a tumor or foreign +object. +• Bullous emphysema. +15.9), often near the apex. +Rupture of the bullae may give rise to pneumothorax. +• Interstitial emphysema. +One biologically +meaningful and clinically useful way to classify asthma is +based on its triggers. +Atopic Asthma. +Non-Atopic Asthma. +A positive family history of +asthma is less common in these patients. +Drug-Induced Asthma. +Several pharmacologic agents +provoke asthma. +Occupational Asthma. +The +Figure 15.9 Bullous emphysema. +Note the large subpleural bullae +(upper left). +tissue produces interstitial emphysema. +Between +the attacks, patients may be virtually asymptomatic. +These +mediators might yet prove important in certain types of +chronic or non-allergic asthma. +It is thus clear that multiple mediators contribute to the +acute asthmatic response. +Genetic Susceptibility. +Genetic polymorphisms linked to asthma and +other allergic disorders were described in Chapter 6. +Th2 Responses, IgE, and Inflammation. +15.10). +Environmental Factors. +Asthma is a disease of industrial- +ized societies where the majority of people live in cities. +Two ideas, neither wholly satisfying, have been proposed +to explain this association. +Infections do not cause asthma by themselves, but may +be important co-factors. +Clinical Features +A classic acute asthmatic attack lasts up to several hours. +Therapy is based on the severity of the disease. +The Th2 +cytokines IL-4, IL-5, and IL-13 are important mediators. +widespread damage to airway walls. +Males with this +condition also tend to be infertile as a result of sperm +dysmotility. +It is a hyperimmune response +to the fungus Aspergillus fumigatus. +Pathogenesis +Obstruction and infection are the major conditions associated +with bronchiectasis. +Sometimes this defect stems from airway obstruction, leading +to distal pooling of secretions. +When tumor or aspiration of +foreign bodies leads to bronchiectasis, the involvement is localized. +The airways are dilated, sometimes up to four times +normal size. +15.12). +The histologic findings vary with the activity and chronicity +of the disease. +In some instances, necrosis destroys the bronchial or bronchiolar +walls and forms a lung abscess. +Diffuse restrictive diseases are +categorized based on histology and clinical features (Table +15.5). +In late stages the fungus may infiltrate the bronchial wall. +Obstructive respira- +tory insufficiency can lead to marked dyspnea and cyanosis. +IPF has +characteristic radiologic, pathologic, and clinical features. +15.13). +The implicated factors are as follows: +• Environmental factors. +Most important among these is +cigarette smoking, which increases the risk of IPF several- +fold. +• Genetic factors. +• Age. +IPF is a disease of older individuals, rarely appearing +before the age of 50 years. +Microscopically, the hallmark +is patchy interstitial fibrosis, which varies in intensity +(Fig. +15.14) and age. +The earliest lesions contain an exuberant +proliferation of fibroblasts (fibroblastic foci). +With time these +areas become more fibrotic and less cellular. +Quite typical is the690 CHAPTER 15 The Lung +survival is about 3.8 years after diagnosis. +Fibroblastic +foci, honeycombing, hyaline membranes, and granulomas are absent. +Figure 15.14 Usual interstitial pneumonia. +The fibrosis is more +pronounced in the subpleural region. +(Courtesy Dr. +In acute exacerbations, DAD may be +superimposed on these chronic changes. +Clinical Features +Patients present with dyspnea and cough of several months’ +duration. +They are more likely to be female nonsmokers in +their sixth decade of life. +15.16). +The connective +tissue is all of the same age, and the underlying lung +architecture is normal. +There is no interstitial fibrosis or +honeycomb lung. +The long-term prognosis is +dependent on the underlying disorder. +Most patients are 55 to 75 years +old at presentation. +Hypoxemia, cyanosis, and clubbing +occur late in the course. +The course in individual patients +is unpredictable. +The median +Figure 15.15 Usual interstitial pneumonia. +Fibroblastic focus with fibers +running parallel to surface and bluish myxoid extracellular matrix. +(A) Low power. +(B) High power. +dusts encountered in the workplace, now also includes +disease induced by chemical fumes and vapors. +A +simplified classification is presented in Table 15.6. +• Particle size. +• Particle solubility and cytotoxicity, which are influenced +by particle size. +These tend +to evoke fibrosing collagenous pneumoconioses, such as +is characteristic of silicosis. +This innate immune response amplifies the +intensity and the duration of the local reaction. +The ratio of FEV1 to FVC is normal. +• Ididopathic pulmonary fibrosis is prototypic of restrictive +lung diseases. +This histologic pattern is known as usual interstitial fibrosis. +Dust reduction measures in coal mines around the +globe have drastically reduced its incidence. +Contaminating silica in the coal dust favors the development +of progressive disease. +Coal +workers may also develop emphysema and chronic bronchitis +independent of smoking. +Of these, quartz +is most commonly implicated. +A large produce lesions. +amount of black pigment is associated with dense interstitial fibrosis. +As the disease progresses, these nodules coalesce into hard, +collagenous scars (Fig. +15.18). +Microscopically, the +lesions consist of dense collagen and pigment (Fig. +15.17).The center +of the lesion is often necrotic, most likely due to local ischemia. +Currently, silicosis is +the most prevalent chronic occupational disease in the world. +Both dose and race are important in developing silicosis +Figure 15.18 Advanced silicosis. +Scarring has contracted the upper lobe +into a small dark mass (arrow). +Note the dense pleural thickening. +(Courtesy +Dr. +Asbestos occurs in two distinct geometric forms, serpentine +and amphibole. +The serpentine chrysotile form accounts +for 90% of the asbestos used in industry. +Macrophages, both +Figure 15.19 Several coalescent collagenous silicotic nodules. +(Courtesy +Dr. +Fibrotic lesions may also occur in the hilar lymph nodes +and pleura. +15.19). +Examination of the nodules by polarized +microscopy reveals weakly birefringent silicate particles. +Chest radiographs typically show a fine nodularity in the +upper zones of the lung. +The disease may continue to +worsen even if the patient is no longer exposed. +It is slow +to kill, but impaired pulmonary function may severely limit +activity. +15.21). +Figure 15.21 Asbestos-related pleural plaques. +Large, discrete fibrocalcific +plaques are seen on the pleural surface of the diaphragm. +(Courtesy Dr. +Chest x-ray studies +reveal irregular linear densities, particularly in both lower +lobes. +With advancement of the pneumoconiosis, a honey- +comb pattern develops. +The disease may remain static or +progress to respiratory failure, cor pulmonale, and death. +Asbestosis +complicated by lung or pleural cancer is associated with a +particularly grim prognosis. +The lung +disease is progressive even after exposure stops. +Eye and skin +lesions are next in frequency. +Sarcoidosis usually occurs in adults younger than 40 years +of age but can affect any age group. +The prevalence is higher +in women but varies widely in different countries and +populations. +In contrast, the disease is rare among +the Chinese and Southeast Asians. +Patterns of organ involve- +ment also vary with race. +• Impaired dendritic cell function. +Additionally, there are systemic immunologic abnormali- +ties in individuals with sarcoidosis. +There is +twofold increased risk of lung cancer. +Complications of Therapies +Drug-Induced Lung Diseases. +Cough induced by +angiotensin-converting enzyme inhibitors is very common. +Illicit intravenous drug abuse most often causes lung +infections. +Radiation-Induced Lung Diseases. +It most often +involves the lung within the radiation field and occurs in acute +and chronic forms. +Involved tissues +contain well-formed non-necrotizing granulomas (Fig. +Central necrosis is unusual. +Conse- +quently, corneal opacities, glaucoma, and total loss of vision may +occur. +Muscle involvement is underdiagnosed, since it may be +asymptomatic. +Note subepithelial location of granulomas. +Sarcoidosis follows an unpredictable course. +Overall, +65% to 70% of affected patients recover with minimal or no +residual manifestations. +Twenty percent have permanent +loss of some lung function or some permanent visual impair- +ment. +The lung is a common site of involvement. +The bone marrow is involved in about 20% of cases. +Numerous syndromes are described, +depending on the occupation or exposure of the individual. +Humidifier +or air-conditioner lung is caused by thermophilic bacteria in +heated water reservoirs. +Pet birds and moldy basements +are easily missed unless asked about specifically. +• Most patients have specific antibodies against the causative +antigen in their serum. +Figure 15.23 Hypersensitivity pneumonitis. +Loosely formed interstitial +granulomas and chronic inflammation are characteristic. +hours after exposure and may last for 12 hours to several +days. +They recur with re-exposure. +This +is an acute illness of unknown cause. +It has a rapid onset +with fever, dyspnea, and hypoxemic respiratory failure. +Histology shows diffuse alveolar damage +and many eosinophils. +There is a prompt response to +corticosteroids. +Interstitial fibrosis and organizing pneumonia +are often present. +15.23). +Clinical Features +The clinical manifestations are varied. +It is a common histologic lesion in cigarette smokers. +In its mildest form, it is most often an incidental +finding in the lungs of smokers or ex-smokers. +discussed) and restrictive or interstitial diseases. +Mild peribronchiolar fibrosis is also seen, which expands contiguous +alveolar septa. +Centrilobular emphysema is common but not +severe. +Desquamative interstitial pneumonia is often found in +different parts of the same lung. +15.24). +Interstitial fibrosis, when present, is mild. +Emphysema +is often present. +Cessation of smoking usually +results in improvement. +Imaging of the chest shows characteristic cystic and +nodular abnormalities. +Langerhans cells are immature +dendritic cells with grooved, indented nuclei and abundant +cytoplasm. +They are positive for S100, CD1a, and CD207 +(langerin) and are negative for CD68. +Virtually all patients are +cigarette smokers. +Figure 15.24 Desquamative interstitial pneumonia. +Whole-lung lavage is the standard of care +and provides benefit regardless of the underlying defect. +PAP is characterized radiologically by bilateral patchy +asymmetric pulmonary opacifications. +• Autoimmune PAP is caused by autoantibodies that bind +and neutralize the function of GM-CSF. +This +form has an autosomal dominant mode of inheritance +and has a highly variable course. +This +form has an autosomal recessive mode of inheritance. +Death ensues +between 3 and 6 months of age unless lung transplantation +is performed. +15.25). +As a consequence there is a +marked increase in the size and weight of the lung. +15.26). +Sudden death often ensues, largely as a result of the blockage +of blood flow through the lungs. +Death may also be caused +by acute right-sided heart failure (acute cor pulmonale). +15.27). +15.28). +Often, +the apposed pleural surface is covered by a fibrinous exudate. +Such lesions are referred +to as septic infarcts, some of which turn into abscesses. +Figure 15.26 Pulmonary alveolar proteinosis associated with mutation of +the ABCA3 gene. +but also in a wide range of conditions that are associated +with hypercoagulability. +Blood clots that occlude the large +pulmonary arteries are almost always embolic in origin. +Pulmonary embolism causes +more than 50,000 deaths in the United States each year. +Patients +with hip fractures are at particularly high risk. +Rarely, pulmo- +nary embolism may consist of fat, air, or tumor. +Figure 15.28 Acute hemorrhagic pulmonary infarct. +Small emboli are silent or induce only transient chest +pain and cough. +Emboli that lead to +pulmonary infarction may additionally produce fever and +hemoptysis. +An overlying fibrinous pleuritis may produce +a pleural friction rub. +Rarely, other +diagnostic methods, such as ventilation-perfusion scanning, +are required. +Deep vein thrombosis can be diagnosed with +duplex ultrasonography. +Perhaps most important is that a small embolus +may presage a larger one. +Prevention of pulmonary embolism is a major clinical +challenge for which there is no easy solution. +• Antecedent congenital or acquired heart disease (group 2). +• Recurrent thromboemboli (group 4). +• Autoimmune diseases (group 1). +15.29). +See text for details. +Clinical signs +and symptoms in all types become evident only in advanced +disease. +Treatment choices depend on the underlying cause. +Lung transplantation provides definitive +treatment for selected patients. +15.30). +In addition, long-term follow-up shows +that some affected patients develop other immune disorders. +The majority of patients are active +smokers. +(A) +Atheroma-like changes, a finding usually limited to large vessels. +(B) +Marked medial hypertrophy. +(C) Plexiform lesion of small arteries that is +characteristic of advanced pulmonary hypertension. +(Fig. +Pneumonia can be +very broadly defined as any infection of the lung +parenchyma. +Pulmonary antimicrobial defense mechanisms are +described in Chapter 8. +• Accumulation of secretions in conditions such as cystic +fibrosis and bronchial obstruction. +• Pulmonary congestion and edema. +Several other points should be emphasized. +MORPHOLOGY +In the classic case, the lungs are heavy, with areas of red-brown +consolidation. +Often the alveoli +contain hemosiderin-laden macrophages (see Fig. +15.31). +Soon, manifestations of glomerulonephritis +appear, leading to rapidly progressive renal failure. +The +most common cause of death is uremia. +The once dismal +prognosis for this disease has been markedly improved by +intensive plasmapheresis. +Its features are discussed in Chapter 11. +Since the +amount of tissue is small, necrosis and granulomatous +vasculitis might not be present. +Often, a bacterial infection follows an upper respiratory +tract viral infection. +Examination of Gram-stained sputum is an important step +in the diagnosis of acute pneumonia. +Antibodies against the +capsule protect the host from H. +influenzae. +With routine use of H. +influenzae vaccines, the incidence of disease caused by the +b serotype has declined significantly. +By contrast, infections +with nonencapsulated forms, also called nontypeable forms, +are increasing. +H. +Before +a vaccine became widely available, H. +Mycoplasma pneumoniae +Chlamydia spp. +(C. +pneumoniae, C. +psittaci, C. +It may be bacterial or viral. +H. +Finally, +H. +influenzae is the most common bacterial cause of acute +exacerbations of COPD. +It is the second most +common bacterial cause of acute exacerbation of COPD. +Along with S. +pneumoniae and H. +influenzae, M. +catarrhalis +is one of the three most common causes of otitis media in +children. +It is also an +important cause of hospital-acquired pneumonia. +It commonly afflicts debilitated +and malnourished people, particularly chronic alcoholics. +Pseudomonas septicemia is a very +fulminant disease. +It also +causes Pontiac fever, a related self-limited upper respiratory +tract infection. +Organ transplant recipients are particularly susceptible. +Bronchopneumonia Lobar pneumonia +Figure 15.32 Comparison of bronchopneumonia and lobar pneumonia. +15.32). +Patchy consolidation of the lung is the dominant characteristic +of bronchopneumonia (Fig. +15.33). +15.35A). +The lower lobe is +uniformly consolidated. +A +pneumonia (Fig. +Moreover, the same organisms may produce either +pattern depending on patient susceptibility. +In the first stage of congestion, +the lung is heavy, boggy, and red. +15.35A). +15.35B), resulting in a color change +to grayish-brown. +15.35C). +More often it undergoes organization, leaving fibrous thickening +or permanent adhesions. +(A) Acute pneumonia. +Fibrin nets have not yet formed. +(C) Advanced organizing +pneumonia. +The viral genome is composed of eight single-stranded +RNAs, each encoding one or more proteins. +A single subtype of +influenza virus A predominates throughout the world at a +given time. +In this instance, essentially all individuals +are susceptible to the new influenza virus. +Of these, secondary +pneumonias caused by S. +aureus are particularly common +and often life-threatening. +Control of the infection relies on several host mechanisms. +When pleuritis is present it is accompanied by +pleuritic pain and pleural friction rub. +The clinical picture is markedly modified by the admin- +istration of effective antibiotics. +These viruses have tropisms that allow +them to attach to and enter respiratory lining cells. +Hemagglutinin has three major subtypes +(H1, H2, H3), while neuraminidase has two (N1, N2). +Both +proteins are embedded in a lipid bilayer, which constitutes +the influenza virus envelope. +Insight into future pandemics has come from studying +past pandemics. +What then might be the source of the next great pandemic? +One such strain, +type H5N1, has spread throughout the world in wild and +domestic birds. +Fortunately, the transmission of the current +H5N1 avian virus is inefficient. +Diagnostic methods include PCR tests for viral RNA. +Treat- +ment generally focuses on supportive measures. +Although +work is ongoing, a clinically effective and safe vaccine has +yet to be developed. +MORPHOLOGY +All viral infections produce similar morphologic changes. +Lung involvement may be quite patchy or may involve whole +lobes bilaterally or unilaterally. +The affected areas are red-blue +and congested. +Pleuritis or pleural effusions are infrequent. +The +histologic pattern depends on the severity of the disease. +Pre- +dominant is an interstitial inflammatory reaction involving +the walls of the alveoli. +15.4). +Eradication of the infection is followed by reconstitution +of the normal lung architecture. +Characteristic viral cytopathic changes are +described in Chapter 8. +Clinical Features +The clinical course of viral pneumonia is extremely varied. +Many cases masquerade as severe upper respiratory tract +infections or as chest colds. +Even individuals with well- +developed atypical pneumonia have few localizing symp- +toms. +Cough may be absent, and the major manifestations +may consist only of fever, headache, and myalgia. +Viral pneumonias are usually mild and resolve spontane- +ously without any lasting sequelae. +The most common organisms isolated are methicillin-resistant +S. +aureus and P. +aeruginosa. +These patients have a higher +mortality than those with community-acquired pneumonia. +Patients on mechanical ventilation are at particularly high +risk. +Gram-positive cocci (mainly S. +aureus, and +a host of gram-negative organisms. +• Antecedent primary lung infection. +Postpneumonic abscess +formations are usually associated with S. +aureus, K. +pneumoniae, and pneumococcus. +Posttransplant or oth- +erwise immunosuppressed individuals are at special risk. +• Septic embolism. +• Neoplasia. +• Miscellaneous. +These are referred to as primary cryptogenic +lung abscesses. +KEY CONCEPTS +ACUTE PNEUMONIA +• S. +• Other common causes of acute bacterial pneumonias in the +community include H. +influenzae and M. +catarrhalis (both associ- +ated with acute exacerbations of COPD), S. +aureus (usually +secondary to viral respiratory infections), K. +pneumoniae +(observed in patients who are chronic alcoholics), P. +aeruginosa +(seen in persons with cystic fibrosis and in those with neutro- +penia), and L. +These patients have abnormal gag and swallowing reflexes +that predispose to aspiration. +In patients who survive, lung +abscess is a common complication. +MORPHOLOGY +Abscesses vary in diameter from a few millimeters to large cavities +of 5 to 6 cm (Fig. +15.36). +They may affect any part of the lung +and may be single or multiple. +Abscesses that712 CHAPTER 15 The Lung +Histoplasmosis +H. +It is endemic along the Ohio and Mississippi +rivers and in the Caribbean. +Like M. +tuberculosis, H. +capsulatum is an intracellular pathogen that is found mainly +in phagocytes. +The pathogenesis of histoplasmosis is incompletely +understood. +The portal of entry is virtually always the lung. +Fever, chest pain, and weight loss are +common. +Clubbing of the fingers and toes may appear. +The course of abscesses is variable. +With antimicrobial +therapy, most resolve, leaving behind a scar. +Tuber- +culosis of the lung and other organs is described in Chapter +8. +Chronic pneumonias caused by fungi are discussed here. +Figure 15.36 Cut surface of lung showing two abscesses. +(Courtesy Dr. +M. +Septic emboli and pyemic +abscesses are multiple and may affect any region of the lungs. +Superimposed saprophytic infections are prone to develop within +the necrotic debris. +In chronic cases considerable fibroblastic +proliferation produces a fibrous wall. +15.37A). +15.37B). +The majority +of cases resolve spontaneously. +Progressive disease or disease +in immunocompromised patients is treated with antifungal +agents. +Blastomycosis +Blastomyces dermatitidis is a soil-inhabiting dimorphic fungus. +There are three clinical forms: pulmonaryPulmonary infections 713 +A B +Figure 15.37 Histoplasmosis. +(A) Laminated Histoplasma granuloma of the lung. +One reason for +the infectivity of C. +immitis infection, which frequently involves the skin and +meninges. +MORPHOLOGY +In the normal host, the lung lesions of blastomycosis are suppurative +granulomas. +Macrophages have a limited ability to ingest and kill +B. +dermatitidis, and the persistence of the yeast cells leads to the +recruitment of neutrophils. +In tissue, B. +dermatitidis is a round, +5- to 15-µm yeast cell that divides by broad-based budding. +It +has a thick, double-contoured cell wall, and visible nuclei (Fig. +15.38). +MORPHOLOGY +Within macrophages or giant cells, C. +15.39). +Rare progressive C. +immitis disease involves the lungs, meninges, +skin, bones, adrenals, lymph nodes, spleen, or liver. +At all these +sites, the inflammatory response may be purely granulomatous, +pyogenic, or mixed. +Indeed, more than 80% of people in endemic +A B +Figure 15.38 Blastomycosis. +(A) Rounded budding yeasts, larger than neutrophils, are present. +Note the characteristic thick wall and nuclei (not seen in +other fungi). +The implicated +organisms include S. +pneumoniae, S. +aureus, H. +influenzae, +and gram-negative rods. +• Not all pulmonary infiltrates in HIV-infected individuals are +infectious in etiology. +• The CD4 + T-cell count determines the risk of infection with +specific organisms. +Figure 15.39 Coccidioidomycosis. +Intact and ruptured spherules are seen. +Mortality from these opportunistic +infections is high. +The specific infections +are discussed in Chapter 8. +aeruginosa, Mycobacterium species, L. +jiroveci, Candida species, Aspergillus species, the Phycomycetes, +and Cryptococcus neoformans). +The transplanted lung is subject to two +major complications: infection and rejection. +In the early posttransplant period (the +first few weeks), bacterial infections are most common. +Most infections occur in the third +to twelfth month after transplantation. +P. +Patients present with fever, +dyspnea, cough, and radiologic infiltrates. +An adjacent pulmonary artery is +normal. +(Courtesy Dr. +Globally, in 2018 there were an estimated +2.1 million new cases and 1.8 million lung cancer deaths. +Each year, lung cancer kills more people than colon, breast, +and prostate cancer combined. +Only +2% of all cases occur before the age of 40. +However, the decrease in smoking among +women has lagged behind that of men. +In addition, there are +other genetic and environmental factors. +15.40). +Bronchiolitis obliterans is patchy and +therefore difficult to diagnose via transbronchial biopsy. +Bronchi- +ectasis and pulmonary fibrosis may also develop with long-standing +chronic rejection. +Its pro- +gress may be slowed or even halted for some time, but +it cannot be reversed. +Tobacco Smoking. +For unclear +reasons, it appears that women are more susceptible to +carcinogens in tobacco than men. +Pipe and cigar +smokers also incur an elevated risk, albeit only modestly. +What of heavy smokers who never develop cancer? +Industrial Hazards. +High-dose ionizing radiation is carcinogenic. +Asbestos +exposure also increases the risk for lung cancer development. +The latent period before the development of lung cancer is +10 to 30 years. +Air Pollution. +It may do so through several different mechanisms. +Acquired Mutations. +This subtype is also commonly +associated with amplification of genes of the MYC family. +Lung Cancer in Never-Smokers. +The WHO estimates that +25% of lung cancer worldwide occurs in never-smokers. +This percentage is probably closer to 10% to 15% in Western +countries. +Precursor (Preinvasive) Lesions. +The basis for this +change is unclear. +These have a far better +prognosis than invasive carcinomas of the same size. +Squamous cell carcinoma is more common in men and +is strongly associated with smoking. +Precursor lesions that give +rise to invasive squamous cell carcinoma are well characterized. +15.44). +15.45), but the lesion is asymptomatic and undetect- +able on radiographs. +Eventually, an invasive squamous cell carcinoma +appears. +The tumor may then follow a variety of paths. +15.46) into the adjacent carina or +mediastinum. +As in almost all types of lung +cancer, the neoplastic tissue is gray-white and firm to hard. +Sometimes these necrotic foci cavitate. +Mitotic activity +is higher in poorly differentiated tumors. +15.44). +The epithelium is +cuboidal, and there is mild interstitial fibrosis. +15.41). +It can be single +or multiple and can be in the lung adjacent to invasive tumor or +away from it. +15.42). +They vary histologically from +Figure 15.42 Adenocarcinoma in situ, mucinous subtype. +(B) Well-differentiated squamous cell carcinoma showing keratinization (arrow). +(C) Small cell carcinoma. +There are +islands of small, deeply basophilic cells and areas of necrosis. +(D) Large cell carcinoma. +The tumor cells are pleomorphic and show no evidence of +squamous or glandular differentiation. +chromatin (salt and pepper pattern), and absent or inconspicuous +nucleoli (see Fig. +15.43C). +The cells are round, oval, or spindle- +shaped, and nuclear molding is prominent. +Necrosis is +common and often extensive. +15.43D). +Combined Carcinoma. +Squamous dysplasia may progress through the stages of mild, moderate, and severe dysplasia. +(A–E, Courtesy Dr. +Adi Gazdar, Department of Pathology, University of Texas, Southwestern Medical School, Dallas, Tex. +Note the size of the +tumor cells compared with normal neutrophils (small arrow). +Figure 15.46 Lung carcinoma. +The gray-white tumor infiltrates the lung +parenchyma. +Distant spread of lung carcinoma occurs through both lymphatic +and hematogenous pathways. +Metastasis may be the first +manifestation of an underlying occult pulmonary lesion. +The liver (30% to +50%), brain (20%), and bone (20%) are other favored sites of +metastases. +Secondary Pathology. +Partial obstruction may cause +marked focal emphysema; total obstruction may lead to +atelectasis. +Pulmonary abscesses sometimes call attention +to an otherwise silent carcinoma. +Such tumors +are also referred to as Pancoast tumors. +Staging. +Overall, the outlook is +poor for most patients. +other tyrosine kinases with specific kinase inhibitors prolongs +survival. +Paraneoplastic Syndromes. +• Each of these is clinically and genetically distinct. +The other carcinomas may +be curable by surgery if limited to the lung. +Adenocarcinoma also is the most common +subtype in non-smokers. +• Lung cancers, particularly small cell lung carcinomas,often cause +paraneoplastic syndromes. +Carcinoid Tumors +Carcinoid tumors represent 1% to 5% of all lung tumors. +Approxi- +mately 20% to 40% of patients are nonsmokers. +Approximately, +10% of bronchial carcinoids give rise to this syndrome. +15.47A). +They rarely exceed 3 to 4 cm in diameter. +Most are confined to +the mainstem bronchi. +Peripheral tumors are solid and nodular. +15.47B).Typical carcinoids have fewer +A B +Figure 15.47 Bronchial carcinoid. +(A) Carcinoid growing as a spherical mass (arrow) protruding into the lumen of the bronchus. +(B) The tumor cells have +small, rounded, uniform nuclei and moderate amounts of cytoplasm. +(Courtesy Dr. +Most are solitary, less +than 3 to 4 cm in diameter, and well circumscribed. +Pul- +monary hamartoma consists of nodules of connective tissue +intersected by epithelial clefts. +Cartilage is the most common +connective tissue, but there may also be fibrous tissue and +fat. +The clefts are lined by ciliated or nonciliated epithelium +(Fig. +15.48). +The disease tends +to be slowly progressive over a period of several decades. +Only lung +transplantation is curative. +Presenting symptoms include fever, cough, chest pain, +and hemoptysis. +It may also be asymptomatic. +Imaging +studies usually show a round, well-defined, peripheral mass. +Calcification is present in about a quarter of cases. +Grossly, +the lesion is firm, 3 to 10 cm in diameter, and grayish white. +They often invade or compress the lungs. +Table 15.12 lists +the most common tumors in the various compartments of +the mediastinum. +Specific tumor types are discussed in +appropriate sections of this book. +Metastatic Tumors +The lung is the most common site of metastatic neoplasms. +Esophageal carcinoma and mediastinal +lymphoma may also invade the lung by direct extension. +MORPHOLOGY +The pattern of metastatic spread to the lungs is quite variable. +15.49). +Figure 15.48 Pulmonary hamartoma. +The sanguineous +exudate must be differentiated from hemothorax (discussed +later). +The fluid is clear and +straw colored. +Hydrothorax may be unilateral or bilateral, +depending on the underlying cause. +The escape of blood into the pleural cavity is known as +hemothorax. +Chylothorax is an accumulation of milky fluid, usually of +lymphatic origin, in the pleural cavity. +Chyle is milky white +because it contains finely emulsified fats. +(Courtesy Dr. +Secondary infections and +inflammations are particularly common findings at autopsy. +It may be spontaneous, traumatic, or +therapeutic. +Recurrent attacks are +common and can be quite disabling. +Pneumothorax may cause marked respiratory distress +due to collapse and atelectasis of the lung. +Pleural Tumors +The pleura may be involved by primary or secondary tumors. +Secondary metastatic involvement is far more common than +are primary tumors. +The most frequent metastatic malignan- +cies arise from primary neoplasms of the lung and breast. +For this reason, careful +cytologic examination of the sediment is of considerable +diagnostic value. +The tumor is often attached to the pleural +surface by a pedicle. +15.50). +Figure 15.50 Solitary fibrous tumor. +Cut surface is solid with a whorled +appearance. +(Courtesy Dr. +Justine A. +The solitary +fibrous tumor has no relationship to asbestos exposure. +Thoracic mesothelioma arises from +either the visceral or the parietal pleura. +Asbestos bodies (see Fig. +15.20) are found in increased +numbers in the lungs of patients with mesothelioma. +Another +marker of asbestos exposure, the asbestos plaque, has been +previously discussed (see Fig. +15.21). +15.51). +15.52A). +Immunohistochemi- +cal stains are very helpful in differentiating it from pulmonary +adenocarcinoma. +Most mesotheliomas show strong positivity for +keratin proteins, calretinin (Fig. +The biphasic type of mesothelioma contains +both epithelioid and sarcomatoid patterns (see Fig. +15.52B). +B +Figure 15.52 Histologic variants of malignant mesothelioma. +(A) +Epithelioid type. +(B) Mixed type, stained for calretinin (immunoperoxidase +method). +(Courtesy Dr. +Fifty +percent of patients die within 12 months of diagnosis, and +few survive longer than 2 years. +Figure 15.51 Malignant mesothelioma. +Global Initiative for Asthma. +Global strategy for asthma management and +prevention. +2019. +Available from: www.ginasthma.org. +Pocket guide also available]. +Israel E, Reddel HK: Severe and difficult-to-treat asthma in adults, N +Engl J Med 377:965, 2017. +Papi A et al: Asthma, Lancet 391:783, 2018. +Emerging therapies, controversies, +and uncertainties in asthma management are also discussed]. +Lederer DJ et al: Idiopathic pulmonary fibrosis, N Engl J Med 378:1811, +2018. +Obstructive Pulmonary Diseases +Global Initiative for Chronic Obstructive Lung Disease. +Global Strategy +for the Diagnosis, Management and Prevention of COPD. +2019. +Available +from: http://goldcopd.org. +A pocket guide is also available]. +Rabe KF et al: Chronic obstructive pulmonary disease, Lancet 389:1931, +2017. +[An excellent review of epidemiology, causes, pathophysiology, and +treatment of COPD]. +Boucherat O et al: Bridging lung development with chronic obstructive +pulmonary disease. +Jones RL et al: Airway remodelling in COPD: it’s not asthma!, Respirology +21:1347, 2016. +Perret JL et al: Coal mine dust lung disease in the modern era, Respirology +22:662, 2017. +Radiation Pneumonitis +Bledsoe TJ et al: Radiation pneumonitis, Clin Chest Med 38:201, 2017. +Sarcoidosis +Esteves T et al: Is there any association between sarcoidosis and infec- +tious agents? +A systematic review and meta-analysis, BMC Pulm +Med 16:165, 2016. +O’Regan A, Berman JS: Sarcoidosis, Ann Intern Med 156:ITC5-1, 2012. +Eosinophilic Lung Diseases +Cottin V: Eosinophilic lung diseases, Clin Chest Med 37:535, 2016. +[ePub ahead of +print]. +[Review of the pathogenesis, classification, and treatment of pulmonary +alveolar proteinosis]. +[Review of the most common inflammatory conditions involving +pulmonary vessels]. +[Excellent review of salient features +of various bacterial pneumonias]. +[Annual report +of registry data including numbers of transplants, indications, and outcomes]. +McIntyre A et al: Lung cancer—a global perspective, J Surg Oncol +115:550, 2017. +Thakrar R et al: Preinvasive disease of the airway, Cancer Treat Rev +58:77, 2017. +Lingen • Nicole A. +Caries is the principal cause of tooth +loss before age 35. +The former reflects improved oral hygiene and, in the United +States, drinking water fluoridation. +It may occur at any age but is most prevalent and +severe in adolescence. +If not removed, plaque can become mineralized to form +calculus (tartar). +This leads to loosen- +ing and eventual tooth loss. +Figure 16.1 Aphthous ulcer. +Single ulceration with an erythematous halo +surrounding a yellowish fibrinopurulent membrane. +color and frequently ulcerated (Fig. +16.3). +In some cases, rapid +growth can be alarming and elicit concerns of malignancy. +Complete +surgical excision is the definitive treatment for these lesions. +Peripheral ossifying fibromas +appear as red, ulcerated, nodular lesions of the gingiva. +The peak incidence is in young females. +It is generally covered by intact gingival mucosa, +but may be ulcerated. +Although not encapsulated, the lesions are usually well +delimited and easily excised. +16.1). +16.2). +It is +thought to be a reactive process induced by repetitive trauma. +Treatment is complete surgical excision. +This exophytic inflammatory lesion is red to purple in +Figure 16.2 Irritation fibroma. +Factors that +influence the likelihood of infection include the strain of +C. +albicans, oral microbiome composition, and the individual’s +immune status. +Oral candidiasis can be pseudomembranous, +erythematous, or hyperplastic. +Figure 16.3 Pyogenic granuloma. +Erythematous and hemorrhagic +exophytic mass arising from the gingival mucosa. +In children, primary infections are most +common between 2 and 4 years of age. +These lesions can +be accompanied by lymphadenopathy, fever, and anorexia. +In adults, acute herpes pharyngitis is common and may +recur. +Some of the more common disease associations +and their oral manifestations are cited in Table 16.1. +Only +hairy leukoplakia is considered in more detail here. +in immunocompromised patients. +Unlike +thrush, the lesion cannot be scraped off. +EBV RNA transcripts and proteins can be detected within +the lesional cells. +Superimposed candidal infection can add +to the “hairiness.” +chapters. +16.4). +Head and neck squamous +cell carcinoma (HNSCC) is the sixth most common neoplasm +in the world. +The pathogenesis of SCC is multifactorial. +• In India and Asia, the chewing of betel quid and paan +is a major regional predisposing influence. +HPV-associated SCC of the oropharynx has +increased more than twofold over the past two decades. +Unlike the oropharynx, HPV-associated +SCC of the oral cavity is relatively uncommon. +Prognosis is dependent on a number of factors including +the specific etiology of SCC. +Long-term survival is better in patients with HPV- +positive SCC. +Notably, second primary +A +B +Figure 16.4 Erythroplakia. +(A) Red discoloration of the maxillary gingiva. +(B) Red lesion of the mandibular alveolar ridge. +Biopsy of both lesions +revealed carcinoma in situ. +16.5A). +16.5B).736 CHAPTER 16 Head and Neck +A B +Figure 16.5 Leukoplakia. +(A) Clinical appearance of leukoplakia is highly variable. +In this example, the lesion is relatively smooth and thin with well- +demarcated borders. +tumors occur at 3% to 7% per year, the highest rate of +among all malignancies. +The second primary tumors are commonly +fatal. +Molecular Biology of Squamous Cell Carcinoma. +A number +of important findings have come from these studies. +Finally, the mutations identified +in HPV-positive and HPV-negative tumors were different. +For example, HPV-negative tumors harbored more somatic +mutations than HPV-positive tumors. +Either pattern may be superimposed on a background +of apparent leukoplakia or erythroplakia. +16.6A). +16.7B). +However, further testing, using PCR or in situ hybridization +(ISH) (Fig. +16.7C), may be required in certain cases. +In contrast to the rest of the skeleton, +epithelial-lined cysts are common in the jaws. +Complete surgical +excision is curative. +Treatment requires complete +excision because of locally aggressive behavior. +Recurrence +rates for inadequately removed lesions can be as high as +60%. +lack obvious surface mucosal lesions but are accompanied by +significant cervical lymphadenopathy. +16.6B). +Keratinizing SCCs range from well-differentiated to anaplastic, +and sometimes sarcomatoid, tumors. +SCC tends to infiltrate locally before metastasizing. +The +routes of extension depend on the primary site. +16.7A). +(A) Clinical appearance demonstrating ulceration and induration of the oral mucosa. +Some are true +neoplasms (both benign and malignant), and others are more +likely hamartomas. +The two most common and clinically significant +tumors are odontoma and ameloblastoma. +(A) Histologic +appearance demonstrating nests and cords of basaloid appearing cells. +(B) Immunohistochemistry demonstrating strong nuclear and cytoplasmic +tumor cell staining p16. +(C) In situ hybridization for high-risk human +papillomavirus E6 and E7 mRNA expression. +The radicular cyst is a common inflammatory lesion found +at the tooth apex. +It is +cystic, slow growing, and locally invasive with a typically +indolent course. +Treatment requires wide surgical resec- +tion to prevent recurrence. +is tooth destruction by acid end-products of bacterial sugar +fermentation. +• Gingivitis is a common, reversible inflammation of the mucosa +surrounding the teeth. +It is associated with poor oral hygiene and altered oral +microbiota. +• Aphthous ulcers are painful superficial ulcers of unknown +etiology. +• Fibromas and pyogenic granulomas are common reactive lesions +of the oral mucosa. +• The majority of oral cavity and oropharyngeal cancers are +SCCs. +Nasal Polyps. +16.8). +In +the absence of bacterial infection, the mucosal surface is +intact, but it may become ulcerated. +When multiple or large, +nasal polyps may encroach on the airway and impair sinus +drainage. +Chronic Rhinitis. +Superficial desquama- +tion or ulceration of the mucosal epithelium is common. +Inflammatory infiltrates include variable numbers of neu- +trophils, lymphocytes, and plasma cells. +Infections may +extend into the sinuses. +Sinusitis. +The resulting mucosal edema impairs sinus drainage and +may result in empyema of the sinus. +Outflow obstruction +occurs most often in the frontal and, less commonly, anterior +ethmoid sinuses. +This may occasionally lead to mucus +accumulation, producing a so-called mucocele. +Acute sinusitis may progress to chronic sinusitis, particu- +larly when drainage is disrupted. +These are most often viral in origin, but can be complicated +by superimposed bacterial infections. +Inflammatory Lesions +Infectious Rhinitis. +Infectious rhinitis, also known as the +common cold, is caused by one or more viruses. +These changes may extend, to produce pha- +ryngotonsillitis. +Fortunately, these +infections clear rapidly. +As the saying goes, “in a week if +treated, but in 7 days if ignored.” +Allergic Rhinitis. +It affects 20% of the US population. +The allergic reaction is740 CHAPTER 16 Head and Neck +A B +Figure 16.8 (A) Nasal polyps. +Low-power magnification showing edematous stroma lined by epithelium. +largely composed of normal oral microbiome components, +is present in most cases. +Fungi may cause severe chronic +sinusitis (e.g., in mucormycosis), especially in diabetic +patients. +Spread into the +cranial vault can cause septic thrombophlebitis within a +dural venous sinus. +Nasopharyngeal Angiofibroma. +NUT Midline Carcinoma. +Nasopharyngeal Carcinoma. +of choice. +16.9). +Sinonasal (Schneiderian) Papilloma. +Sinonasal papillomas are most +common in males between 30 and 60 years of age. +The +endophytic form may invaginate into the underlying stroma +(Fig. +16.10). +Malignant transformation occurs in approximately +10% of cases. +Most endophytic sinonasal papillomas have +EGFR gene mutations. +The remaining cases generally harbor +HPV DNA, often low-risk types 6 and 11. +Olfactory Neuroblastoma (Esthesioneuroblastoma). +The age distribution is bimodal, with +peaks at 15 and 50 years. +Patients typically present with nasal +obstruction and/or epistaxis. +16.11). +A fibrillary matrix, representing tangled neu- +ronal cell processes, is often present. +Consistent with their +Figure 16.10 Inverted papilloma. +The cells appear to swirl around a blood-filled vascular channel. +In the United States, nasopharyn- +geal carcinomas are rare in all age groups. +16.12B). +Abundant, +normal-appearing lymphocytes, predominantly T cells, infiltrate +the tumors. +16.12C) or immunohistochemistry, +respectively. +C +Figure 16.12 Nasopharyngeal carcinoma, nonkeratinizing undifferentiated +type. +(B) The syncytial clusters of malignant epithelium are infiltrated by +benign lymphocytes. +(C) In situ hybridization for EBER-1, a small nuclear +RNA encoded by Epstein-Barr virus. +standard treatment and results in an overall 5-year survival +of approximately 60%. +LARYNX +The most common disorders of the larynx are inflammatory. +The larynx may also be affected in +systemic infections, such as tuberculosis and diphtheria. +16.13). +Despite this, the risk of developing cancer in these lesions +is almost nonexistent. +By convention, vocal cord nodules +are bilateral and polyps are unilateral. +Adults are most often +affected. +The latter may be variably fibrotic, fibrinous, or highly +vascularized. +Nodules on opposing vocal cords may impinge +on each other and cause ulceration. +16.13). +The lesions are caused by HPV types +6 and 11 acquired via the maternal birth canal. +They fre- +quently recur but only rarely transform to SCC. +Hyperplasia-Dysplasia-Carcinoma Sequence. +16.13 and 16.14). +Nondysplastic hyperplasias have almost no potential for +malignant transformation. +Histologic evaluation is the only way +to grade dysplasia. +Laryngeal carcinoma is most often related to tobacco +smoke; risk is proportional to exposure. +Prior to malignant +transformation, epithelial changes frequently regress after +smoking cessation. +Alcohol synergizes with tobacco to +increase risk substantially. +MORPHOLOGY +About 95% of laryngeal carcinomas are typical SCCs. +16.14). +Laryngeal carcinoma presents most commonly in men +within the sixth decade of life. +The initial manifestation is +often persistent hoarseness, dysphagia, and dysphonia. +Prognosis is directly related to clinical stage. +Figure 16.14 Laryngeal carcinoma. +Note the large, ulcerated, fungating +lesion involving the right vocal cord and pyriform sinus. +• Laryngeal SCC is linked to smoking and alcohol use and is +most prevalent in older males. +Ears +Although they rarely shorten life, disorders of the ear often +impact its quality. +Paragangliomas are discussed later. +INFLAMMATORY LESIONS +Acute and chronic otitis media occur most often in infants and +children. +The origin is typically viral infection that induces +a serous exudate. +Superimposed bacterial infection, most +frequently by Streptococcus pneumoniae, nontypeable H. +influenzae, or Moraxella catarrhalis, can lead to suppurative +inflammation. +Repeated bouts of acute otitis media with failure of resolu- +tion lead to chronic disease. +The causative agents are usually +Pseudomonas aeruginosa, S. +aureus, fungus, or, in some cases, +a polymicrobial infection. +In individuals with diabetes, otitis media caused by P. +Cholesteatomas are non-neoplastic, cystic lesions asso- +ciated with chronic otitis media. +Cholesterol spicules may be +present. +Both ears are usually affected. +At first, there is fibrous ankylosis of the footplate. +This often +occurs in the early decades of life. +Over time, bony over- +growth anchors the footplate into the oval window. +The +severity of the hearing loss reflects the degree of immobiliza- +tion. +Over time the fibrosis is replaced +by dense new bone anchoring the footplate of the stapes. +These +tend to occur in elderly men and are associated with sun +exposure. +Despite local +invasion, basal cell carcinomas and SCCs involving the pinna +rarely spread. +KEY CONCEPTS +EARS +• Infections of the ear are common in children and typically viral +in etiology. +What remains to be considered here are a few uncommon +lesions unique to the neck. +The fibrous cyst +walls typically contain lymphoid tissue with prominent +germinal centers. +The cysts are readily excised. +Similar +lesions may appear in the parotid gland or oral cavity beneath +the tongue. +Branchial cysts do not undergo malignant +transformation. +Most cystic SCCs in the neck are metastases +from cancers of the upper airways or digestive tract. +Transitional epithelial differentiation patterns also +occur. +The fibrous cyst wall often includes lymphoid +aggregates or thyroid remnants. +Malignant transformation +of the lining epithelium is exceedingly rare. +Adrenal medullary pheochromo- +cytomas are the most common paraganglioma (Chapter 24). +Approximately 70% of extra-adrenal paragangliomas occur +in the head and neck. +Interestingly, the incidence of these +tumors is greater in people living at high altitudes. +These are innervated by +the parasympathetic nervous system and only rarely +produce catecholamines. +MORPHOLOGY +The carotid body tumor is a typical parasympathetic paragan- +glioma. +16.15). +There is little cellular pleomorphism, and mitoses are +scant. +A +B +Figure 16.15 Carotid body tumor. +(A) Low-power view showing tumor +clusters separated by septa (zellballen). +The septae are marked by +capillaries containing bright red blood cells. +(B) Immunohistochemistry +demonstrating positivity for chromogranin in the tumor cells. +dehydrogenase genes) typically involve the head and neck. +About 50% ultimately prove +fatal, largely because of infiltrative growth. +• Seventy percent of extra-adrenal paragangliomas occur in the +head and neck. +They commonly occur singly +and sporadically but also may be familial. +involves other glandular organs such as the pancreas and +testes (Chapter 8). +Mucocele. +Mucoceles are most often found on the lower +lip as the result of trauma (Fig. +16.16B). +Sialolithiasis and Nonspecific Sialadenitis. +aureus and Streptococcus +viridans following ductal obstruction by stones (sialoli- +thiasis). +In +Sjögren syndrome, inflammatory enlargement of the salivary +glands may also occur. +The most prevalent form +of sialadenitis is the mucocele. +(A) Fluctuant fluid-filled lesion on the lower lip subsequent to trauma. +Inflammation causes painful enlargement and, +sometimes, a purulent ductal discharge. +Disease is almost +always unilateral and involves a single gland. +These will be +the focus of the discussion that follows. +Salivary gland neoplasms represent less than 2% of all +tumors in humans. +There is a slight +female predominance overall, but this can vary with histol- +ogy. +Little is known about the origin of pleomorphic adenomas, +but radiation exposure increases risk. +Equally uncertain is +the histogenesis of the various components. +16.17). +These may lead to recurrences if the tumor is merely enucleated. +The dominant histologic feature is morphologic heterogeneity. +16.18). +In other instances, there may be strands or +sheets of myoepithelial cells. +Islands of well-differentiated squamous +epithelium may also be present. +The rate of recurrence following +parotidectomy is about 4%. +Recurrences occur months to +years after surgery. +Cancers are usually adenocarcinomas or undifferentiated +carcinomas. +(A) Slowly enlarging neoplasm in the parotid gland of many years’ duration. +It is unique in that it arises almost exclu- +sively in the parotid gland. +The risk is increased +eightfold in smokers. +Most Warthin tumors are unifocal, +but about 10% are multifocal and 10% bilateral. +(A) Low-power view showing epithelial and lymphoid elements. +Note the lymphoid follicular germinal center beneath the +epithelium (arrow). +the outer layer (Fig. +Secretory cells +dispersed in the inner layer account for secretions within the +dilated lumen. +Foci of squamous metaplasia may be present. +and frequently contain small, mucin-containing cysts. +Accordingly, mucoepidermoid carci- +nomas are subclassified as low, intermediate, or high grade. +A +MORPHOLOGY +B +Mucoepidermoid carcinomas can grow as large as 8 cm in diameter. +(A) Low-power view showing +sheets and microcysts containing cells of varying morphologies. +Low-grade tumors +may invade locally and recur in about 15% of cases, but +they rarely metastasize. +The 5-year survival rate is more +than 90%. +Up to 30% recur and 30% metastasize to distant +sites, yielding a 5-year survival of only 50%. +Adenoid cystic carcinomas. +Among major salivary +glands, parotid and submandibular glands are most com- +monly affected. +16.21A). +Less common histologic patterns are tubular and solid. +Figure 16.21 Adenoid cystic carcinoma. +(A) Three typical growth +patterns including cribriform (left), tubular (center), and solid (right). +(B) Perineural invasion by adenoid cystic carcinoma. +The neoplastic cells are +organized into sheets, microcysts, glands, follicles, or papillae. +16.21B). +Acinic cell carcinomas. +Most develop in the parotid glands, +with the remainder arising in the submandibular glands. +Like +Warthin tumors, acinic cell carcinomas can be bilateral or +multicentric. +The clinical course of acinic cell carcinomas reflects the +degree of cytologic pleomorphism. +Although recurrence is +uncommon after resection, 10% to 15% of tumors metastasize +to lymph nodes. +The survival rate is approximately 90% at +5 years and 60% at 20 years. +(B) High-power image of tumor cells with purple cytoplasmic granules and monotonous round nuclei. +Neville BW, Damm DD, Allen CM et al: Oral and maxillofacial pathology, +ed 4, 2016, Elsevier. +[A comprehensive +TCGA manuscript that defines the mutational landscape of head and neck +cancer]. +El-Naggar AK, Chan JKC, Grandis JR et al: Tumors of salivary glands, +Chapter 7. +In WHO classification of head and neck tumors, ed 4, 2017, +WHO, IARC, pp 159–201. +Most of the lesions are incompatible +with survival without prompt surgical repair. +17.1A). +17.1B). +In other cases a fistula can be present without +atresia (Fig. +17.1C). +This results in either partial or +complete obstruction. +Omphalocele is often associated with other birth defects +as well as chromosomal abnormalities. +Surgical repair of omphalocele and +gastroschisis is generally successful. +AB C +Figure 17.1 Esophageal atresia and tracheoesophageal fistula. +(A) Blind +upper and lower esophagus with thin cord of connective tissue linking the +two segments. +(B) Blind upper segment with fistula between lower segment +and trachea. +These are, technically, pseudodiverticula, but are +generally referred to simply as divericula. +They occur most +often in the sigmoid colon (discussed later). +PYLORIC STENOSIS +Pyloric stenosis may be either congenital or acquired. +The +most common congenital form is congenital hypertrophic +pyloric stenosis. +Turner syndrome and trisomy +18 also confer an increased risk. +Diagnosis is primarily by +ultrasonography. +Edema and inflammatory changes in the mucosa and +submucosa may aggravate the narrowing. +Surgical splitting +of the muscularis (myotomy) is curative. +ECTOPIA +Ectopic tissues (developmental rests) are common in the +GI tract. +Ectopic pancreatic tissue occurs less frequently +and is found in the esophagus or stomach. +These nodules +are most often asymptomatic but may produce local damage +and inflammation. +Because rests may be present within any layer +of the gastric wall, they can mimic invasive cancer. +This solitary diverticulum +extends from the antimesenteric side of the bowel (Fig. +17.2). +Hirschsprung disease occurs in approxi- +mately 1 in 5000 live births. +This produces a +Figure 17.2 Meckel diverticulum. +A B +Figure 17.3 Hirschsprung disease. +(Courtesy Dr. +Even after suc- +cessful surgery, it may take years to attain normal bowel +function and continence. +The rectum is always affected, but the length of the additional +involved segments varies widely. +The aganglionic region may have a grossly normal or contracted +appearance. +In contrast, the normally innervated proximal colon +undergoes progressive dilation (Fig. +• Atresia and fistulae are developmental anomalies that typically +present at birth. +• Stenosis may be developmental or acquired. +Both forms are +characterized by a thickened wall and partial or complete luminal +obstruction. +Acquired forms are often due to inflammatory +scarring. +Omphalocele and gas- +troschisis refer to ventral herniation of abdominal organs. +• Ectopia refers to normally formed tissues at an abnormal site. +Obstruc- +tion or constipation follows, often with visible but ineffective +peristalsis. +The major threatsEsophagus 757 +involution of the vitelline duct. +It is a frequent site of gastric +ectopia, which may result in peptic injury and occult bleeding. +The +defect, which always involves the rectum, extends proximally +for variable distances. +This can be impeded +by physical or functional obstruction. +The latter results from +disruption of coordinated peristalsis after swallowing. +Esophageal dysmotility falls into three principal patterns. +Manometry is, however, required for diagnosis. +Unlike nutcracker +esophagus, these contractions are of normal amplitude. +In contrast, +malignant strictures are often associated with weight loss. +Esophageal mucosal webs are uncommon ledge-like +mucosal protrusions. +Symptoms +include dysphagia, difficulty in belching, and chest pain. +The cause is unknown; +rare familial cases have been described. +Duodenal, colonic, and ureteric myenteric plexuses can also +be affected in Chagas disease. +transmural tearing and rupture of the distal esophagus. +This +catastrophic event produces severe mediastinitis and generally +requires surgical intervention. +Esophageal infections in otherwise healthy individuals +are most often due to herpes simplex virus. +Among fungi, +candidiasis is most common, although mucormycosis and +aspergillosis also occur. +These do not generally require +surgical intervention, and healing tends to be rapid and +complete. +Infection by fungi or bacteria can either cause injury or +complicate a preexisting ulcer. +The endoscopic appearance frequently indicates the cause of +viral esophagitis. +Herpesviruses typically cause punched-out ulcers +(Fig. +17.4A). +17.4B). +More significant gastric reflux is associated with +erosions (Fig. +17.5A) and influx of eosinophils into the squamous +mucosa (Fig. +17.6A). +Basal zone hyperplasia and elongation of +lamina propria papillae are also common. +B +A C +Figure 17.4 Viral esophagitis. +(A) Postmortem specimen with multiple, +overlapping herpetic ulcers in the distal esophagus. +(B) Multinucleate +squamous cells containing herpesvirus nuclear inclusions. +(C) +Cytomegalovirus-infected endothelial cells with nuclear and cytoplasmic +inclusions. +inclusions within capillary endothelium and stromal cells (Fig. +17.4C). +This relaxation is mediated +via vagal pathways and can be triggered by gastric distention. +Note the +tan islands of metaplastic epithelium within the white squamous mucosa. +(Courtesy Dr. +Linda S. +17.5B). +17.6B). +Esophageal Varices +Esophageal varices are dilated veins within the lower +esophagus. +Although most small varices never bleed, rupture +of large varices can result in exsanguination. +Worldwide, hepatic schistosomia- +sis is the second most common cause of varices. +A more +detailed consideration of portal hypertension is given in +Chapter 18. +A B +Figure 17.6 Esophagitis. +(A) Reflux esophagitis with scattered +intraepithelial eosinophils and mild basal zone expansion. +(B) Eosinophilic +esophagitis is characterized by numerous intraepithelial eosinophils. +Rarely, GERD- +associated chest pain may be mistaken for ischemic heart +disease. +Many patients have atopic dermatitis, allergic +rhinitis, asthma, or modest peripheral eosinophilia. +Con- +sistent with this, recent data suggest that mast cells may +also be important in pathogenesis. +In addition to +GERD-like symptoms, patients experience food impaction, +dysphagia, and vomiting. +Infants may also suffer from +feeding intolerance. +17.7). +DespiteEsophagus 761 +white males and typically presents between 40 and 60 years +of age. +The greatest clinical concern is that it confers an +increased risk of esophageal adenocarcinoma. +The vast majority of esophageal adenocarcinomas occur +in association with Barrett esophagus. +Nevertheless, most +individuals with Barrett esophagus do not develop esopha- +geal tumors. +17.5A) and interfaces +with light-brown columnar (gastric) mucosa distally (Fig. +17.8A, +B). +Barrett esophagus can be subclassified as long segment (≥3 cm), +or short segment (<3 cm). +C +Figure 17.7 Esophageal varices. +(C) Dilated varices beneath intact squamous mucosa. +Treatments include beta-blockers to reduce portal blood +flow and endoscopic variceal ligation. +Barrett esophagus is most common in +A B +C +Figure 17.8 Barrett esophagus. +(A) Normal gastroesophageal junction. +(B) Barrett esophagus. +Note the small islands of residual pale squamous +mucosa within the Barrett mucosa. +(C) Histologic appearance of the +gastroesophageal junction in Barrett esophagus. +A B +Figure 17.9 Dysplasia in Barrett esophagus. +(A) Abrupt transition from +metaplasia to low-grade dysplasia (arrow). +Note the nuclear stratification +and hyperchromasia. +Other major risk factors include tobacco use and exposure +to radiation. +Conversely, risk is reduced by diets rich in +fresh fruits and vegetables. +17.8C). +Dysplasia is classified as low grade or high grade. +17.9A). +Dysplastic glands display +budding, irregular shapes, and cellular crowding. +High-grade dysplasia +(Fig. +17.9B) exhibits more severe cytologic and architectural changes +than low-grade dysplasia. +Once diagnosed, the best course of management +is a matter of debate. +Intramucosal or invasive carcinoma requires therapeutic +intervention. +The regions +with highest incidence are Iran, central China, Hong Kong, +Brazil, and South Africa. +A B +Figure 17.10 Esophageal cancer. +(A) Adenocarcinoma usually occurs +distally and, as in this case, often involves the gastric cardia. +17.10A). +Microscopically, tumors typically produce mucin and form +glands (Fig. +Barrett esophagus is frequently present +adjacent to the tumor. +By the +time symptoms appear, the tumor has often spread to +submucosal lymphatic vessels. +As a result, overall 5-year +survival is less than 25%. +(A) Esophageal adenocarcinoma +organized into back-to-back glands. +17.10B). +Early lesions appear +as small, gray-white, plaque-like thickenings. +Most squamous cell carcinomas are moderately to well dif- +ferentiated (Fig. +17.11B). +Regardless of histology, +symptomatic tumors are generally large and invasive at diagnosis. +Clinical Features +The onset of esophageal squamous cell carcinoma is insidious. +Weight loss +and debilitation result from both impaired nutrition and +tumor cachexia. +Lymph node metas- +tases are associated with poor prognosis. +• Esophagitiscan result from chemicalorinfectiousmucosalinjury. +Infection is most common in immunocompromised individuals. +• The most prevalent cause of esophagitis is reflux of gastric +acid into the esophagus (GERD). +• Eosinophilic esophagitis is strongly associated with food allergy, +allergic rhinitis, or asthma. +It is a common cause of GERD-like +symptoms in children living in high income countries. +• Barrett esophagus is a risk factor for development of esophageal +adenocarcinoma. +The stomach is divided into four major anatomic regions: +cardia, fundus, body, and antrum. +The cardia and antrum +are lined mainly with mucin-secreting foveolar cells that +form small glands. +This harsh environment +contributes to digestion but also has the potential to cause +damage. +Multiple mechanisms have evolved to protect the +gastric mucosa (Fig. +17.12). +Gastropathy and gastritis occur when the damaging forces +overwhelm the protective factors (Fig. +17.12). +They also reduce acid secretion. +Although COX-1 plays +a larger role than COX-2, both isoenzymes contribute to +mucosal protection. +pylori. +causes hypersecretion of gastric acid. +Neutrophils may be +found among the epithelial cells or within mucosal gland lumina +in gastritis. +The lamina propria contains only a few lymphocytes +and plasma cells. +Hemorrhage may cause dark puncta +within hyperemic mucosa. +Concurrent erosion and hemorrhage +is termed acute erosive hemorrhagic gastritis. +Other complications, including perforation, can also occur. +NSAID use may enhance bleeding risk. +• Gastric antral vascular ectasia (GAVE) is responsible for 4% +of non-variceal upper GI bleeding. +The erythematous stripes are +created by ectatic mucosal vessels. +While most often +idiopathic, GAVE can be associated with cirrhosis and +systemic sclerosis. +Recurrent bleeding may produce a +positive test for fecal blood and lead to iron deficiency +anemia. +For example: +• Stress ulcers are most common in the setting of shock, +sepsis, or severe trauma. +They +have an elevated risk of perforation. +pylori infection. +Nausea and upper abdominal pain are typical, sometimes +with vomiting, but hematemesis is uncommon. +Helicobacter pylori Gastritis +H. +Acute H. +H. +pylori organisms are +present in the majority of individuals with chronic antral +gastritis. +Epidemiology. +In the United States, H. +Infection is typically +acquired in childhood and persists for life without treatment. +Improved sanitation explains the marked reduction in H. +pylori infection rates among younger people. +In well- +resourced countries, H. +It follows that environment +during childhood is a critical risk factor for H. +pylori +colonization. +Pathogenesis +H. +Alternatively, long-standing H. +pylori +gastritis may progress to involve the gastric body and fundus. +This may result in atrophic gastritis with reduced parietal +cell mass and intestinal metaplasia. +In contrast to autoimmune +gastritis (see later), atrophy induced by H. +pylori is not +associated with autoantibodies and is typically patchy. +Nevertheless, decreased acid secretion in H. +pylori +gastritis with atrophy reduces the risk of gastric and duodenal +ulcers. +H. +pylori organisms have adapted to the ecologic niche +provided by gastric mucus. +For example, the CagA gene is present +in 50% of H. +pylori isolates overall but in 90% of H. +pylori +isolates in populations with an increased prevalence of gastric +cancer. +pylori. +Host factors also play an important role in the outcome +of H. +pylori infection. +The course of H. +MORPHOLOGY +Gastric biopsy specimens generally demonstrate H. +pylori in infected +individuals. +Organisms are most +easily demonstrated with immunostains or histochemical stains +(Fig. +17.13A). +The antrum is the preferred biopsy site for evaluation of H. +pylori gastritis because it is most commonly infected. +H. +pylori–infected antral +mucosa is usually erythematous and has a coarse or even nodular +appearance. +Neutrophils infiltrate across the basement membrane +(Fig. +Lymphoid aggregates, some with +germinal centers, are frequently present (Fig. +Thus, chronic H. +B C +often associated with marked hyper gastrinemia (Table +17.2). +(A) Spiral-shaped H. +pylori are +highlighted in this Warthin-Starry silver stain. +Organisms are abundant +within surface mucus. +(B) Intraepithelial and lamina propria neutrophils are +prominent. +pylori gastritis. +Clinical Features +The changes seen in atrophic H. +pylori DNA. +Effective treatments for H. +pylori infection include com- +binations of antibiotics and proton pump inhibitors. +Individu- +als with H. +Autoimmune Atrophic Gastritis +Autoimmune atrophic gastritis, in contrast to H. +or nodules. +17.14B). +Endocrine +and enterochromaffin-like cell hyperplasia is commonly present. +The median +age at diagnosis is 60. +Uncommon Forms of Gastritis +Eosinophilic Gastritis. +pylori infection. +Lymphocytic Gastritis. +This disease preferentially affects +women and produces nonspecific abdominal symptoms. +Histologically there is a marked +increase in the number of intraepithelial T lymphocytes. +Granulomatous Gastritis. +The antrum and cardia are typically +spared. +In contrast to the superficial lamina propria +inflammation that is typical of H. +17.14A). +Loss of parietal and chief cells can +be extensive. +It encompasses a diverse group of diseases with +widely varying clinical and pathologic features. +Many cases +bacterial strains are involved. +are idiopathic. +pylori). +pylori infection, NSAIDs, or +cigarette smoking. +The most common form of PUD occurs +within the gastric antrum or duodenum as a result of chronic +H. +As mentioned earlier, H. +Epidemiology. +The incidence of PUD is falling along with +reduced prevalence of H. +pylori infection. +However, PUD +in patients older than 60 years has increased due to growing +NSAID use. +This can be amplified by H. +Other risk factors for PUD are listed in Table 17.3. +Thus, PUD generally develops on a background of +chronic gastritis. +However, as with H. +17.15A). +In +contrast, heaped-up margins are more characteristic of +cancers. +B +Figure 17.15 Acute gastric perforation in a patient presenting with free +air under the diaphragm. +(A) Mucosal defect with clean edges. +The risk of adeno- +carcinoma is greatest in autoimmune metaplastic atrophic +gastritis. +Intestinal metaplasia also occurs in +chronic H. +pylori gastritis but may regress after clearance +of the organism. +Preinvasive in situ lesions can be recognized +histologically as dysplasia. +As might be expected, the hypertrophic gastropathies are +linked to excessive growth factor release. +Some cases occur in association with viral or H. +pylori infec- +tion. +The base of peptic ulcers is smooth and clean as a result of +peptic digestion of exudate. +Larger vessels within the scarred +area are typically thickened and are occasionally thrombosed. +Bleeding from these vessels may cause life-threatening hemorrhage. +Others present with +iron deficiency anemia, hemorrhage, or perforation (Table +17.4). +and 2 +a.m.), and is relieved by alkali or food. +Nausea, vomiting, +bloating, belching, and significant weight loss are additional +manifestations. +Current therapies for PUD are aimed at H. +pylori eradica- +tion and neutralization of gastric acid, primarily with proton +pump inhibitors. +pylori. +Secondary +symptoms such as weight loss, diarrhea, and peripheral +edema are commonly present. +Risk +of gastric adenocarcinoma is increased in adults with +Ménétrier disease. +A +MORPHOLOGY +Ménétrier disease is characterized by irregular enlargement of +the gastric rugae. +Some areas may appear polypoid. +Enlarged rugae +are present in the body and fundus (Fig. +17.16A), but the antrum +is generally spared. +17.16B). +Inflammation is usually modest, although some cases +show marked intraepithelial lymphocytosis. +In cases associated with herpesvirus, CMV, or H. +pylori, +treatment of the infection may be helpful. +Antibodies that +block epidermal growth factor receptor activation are effec- +tive in many cases. +In severe cases gastrectomy remains a +therapeutic option. +B +Figure 17.16 Ménétrier disease. +(A) Marked hypertrophy of rugal folds. +(B) Foveolar hyperplasia with elongated and focally dilated glands. +(Courtesy Dr. +M. +These gastrinomas are almost +always found in the small intestine or pancreas. +Patients +often present with duodenal ulcers or chronic diarrhea. +Gastrin also induces hyperplasia of mucous +neck and endocrine cells within oxyntic mucosa. +Gastrinomas are sporadic, solitary lesions in 75% of +patients. +The remaining 25% of patients with gastrinomas +have multiple endocrine neoplasia type 1 (MEN1). +These +patients are younger and primarily have duodenal tumors +that commonly metastasize. +MEN1 gene mutations in +sporadic gastrinomas are also associated with aggressive +tumor behavior. +Somatostatin receptor scintigraphy or +endoscopic ultrasonography can help with identification. +Patients with metastatic disease may benefit from treatment +with somatostatin analogues. +Their incidence is correlated with the +regional prevalence of H. +pylori infection. +• The most common cause of chronic gastritis is H. +pylori infection. +Other injurious agents include NSAIDs and alcohol. +• H. +• H. +pylori gastritis induces MALT that can give rise to B-cell +lymphomas (MALTomas). +• After H. +pylori and NSAIDs, autoimmune atrophic gastritis is +the most frequent cause of chronic gastritis. +• Peptic ulcer disease is usually secondary to chronic H. +pylori– +induced gastritis and the resulting hyperchlorhydria. +pylori +eradication. +MORPHOLOGY +The majority of inflammatory or hyperplastic polyps are smaller +than 1 cm in diameter. +Polyps are frequently multiple, particularly +in individuals with atrophic gastritis. +Microscopically, polyps have +irregular, cystically dilated, and elongated foveolar glands +(Fig. +17.17B). +Fundic +gland polyps may be asymptomatic or associated with +nausea, vomiting, or epigastric pain. +They may be774 CHAPTER 17 The Gastrointestinal Tract +A B C D +Figure 17.17 Gastric polyps. +(A) Hyperplastic polyp containing corkscrew-shaped foveolar glands. +(B) Hyperplastic polyp with extensive ulceration. +(D) Gastric adenoma with epithelial nuclear +hyperchromasia and pseudostratification. +Epidemiology. +Gastric cancer incidence varies markedly +with geography. +Metastases are often +present at diagnosis. +Inflammation +is typically absent or minimal (Fig. +17.17C). +Dysplasia may occur +in FAP-associated fundic gland polyps, and rare cancers have been +reported. +They represent up to 10% of all gastric +polyps (see Table 17.5). +MORPHOLOGY +Gastric adenomas are usually solitary antral lesions. +All GI adeno- +mas exhibit dysplasia, which is classified as low- or high-grade +(Fig. +17.17D). +Decreased gastric cancer incidence is +largely attributed to reduced rates of H. +pylori infection and +primarily relates to intestinal-type cancers. +Thus, E-cadherin loss is a key step in the develop- +ment of diffuse gastric cancer. +pylori gastritis. +Thus, both host genetic background +and environmental factors affect risk. +Gastric tumors +with an intestinal morphology form bulky tumors (Fig. +17.18A) and are composed of glandular structures (Fig. +17.19A), +while cancers with a diffuse infiltrative growth pattern (Fig. +17.18B) are typically composed of signet-ring cells (Fig. +17.19B). +Release of extracellular +A +B +Figure 17.18 Gastric adenocarcinoma. +Compare to the peptic ulcer in Fig. +17.15A. +(B) Infiltrative type +(linitis plastica) gastric cancer. +Notably, the +remarkable decrease in gastric cancer incidence applies +only to the intestinal type. +Local invasion into the duo- +denum, pancreas, and retroperitoneum is common. +When possible, surgery +remains the preferred treatment approach. +In +contrast, the 5-year survival rate for advanced gastric cancer +remains less than 20%. +In the gut these tumors are often referred to +as lymphomas of MALT, or MALTomas. +These and other +lymphomas of the gut are discussed in Chapter 13. +H. +This creates a chimeric API2-MLT1 fusion +gene that encodes an API2-MALT1 fusion protein. +Note the absence of gland +formation. +17.18B). +The mean age of presentation is +55 years, and the male-to-female ratio is 2 : 1. +Thus, H. +Removal of this stimulus may explain why these tumors +tend to respond to H. +pylori eradication. +In contrast, tumors +bearing translocations involving MALT1 or BCL10 are +generally insensitive to H. +pylori clearance. +pylori eradication. +17.20A, inset). +17.20B) or infiltrate +the wall diffusely (Fig. +17.20C). +Like other tumors of mature B cells, MALTomas express the +B-cell markers CD19 and CD20. +A B +C +Figure 17.20 Lymphoma. +(A) Gastric mucosa-associated lymphoid tissue +lymphoma replacing much of the gastric epithelium. +(B) Disseminated lymphoma within the small +intestine with numerous small serosal nodules. +(C) Large B-cell lymphoma +infiltrating the small intestinal wall and producing diffuse thickening. +Clinical Features +The most common presenting symptoms are dyspepsia and +epigastric pain. +Hematemesis, melena, and constitutional +symptoms such as weight loss can also be present. +Because +gastric MALTomas and H. +Neuroendocrine Neoplasms +These tumors arise from the diffuse components of the +endocrine system. +Most are found in the GI tract, and more than 40% +occur in the small intestine. +The tracheobronchial tree and +lungs are the next most commonly involved sites. +17.21A). +17.21). +(A) Gross cross section of a submucosal tumor nodule. +(B) Microscopically the nodule is +composed of tumor cells embedded in dense fibrous tissue. +(C) In other areas the tumor has spread extensively within mucosal lymphatic channels. +(D) High magnification shows the characteristically bland cytology. +Despite their innocuous appearance, these tumors can be clinically aggressive. +(E) Electron microscopy reveals cytoplasmic dense +core neurosecretory granules. +Symptoms +reflect hormones released by the tumor cells. +For example, +those that produce gastrin cause Zollinger-Ellison syndrome. +Behavior is also affected by size and location, and staging is +region-specific. +This is particularly true for tumors that arise in +association with atrophic gastritis. +Gastric neuroendocrine +tumors without predisposing factors are often more +aggressive. +Those in the appendix occur at any age and are generally +located at the tip. +These tumors are rarely more than +2 cm in diameter and are almost always benign. +More +than half of these tumors occur in the stomach. +A wide variety of other +mesenchymal neoplasms may arise in the stomach. +These are all uncommon +in the gut and are discussed in Chapter 26. +Epidemiology. +Clinically silent, microscopic proliferations +that may represent precursors to GIST are common. +These +foci have low mitotic rates and extremely low risk of neo- +plastic transformation. +Constitutively active KIT and +PDGFRA trigger the same downstream signaling pathways. +Mutations of the correspondence genes are therefore mutually +exclusive. +Clinical Features +Symptoms of GISTs at presentation are typically related to +mass effects. +Complete +surgical resection is the primary treatment for localized +gastric GIST. +The overlying +mucosa is frequently ulcerated, and the cut tumor surface has a +whorled appearance. +GISTs composed of thin +elongated cells are classified as spindle cell type (Fig. +Nuclear pleomorphism is +uncommon. +These reactive lesions are associated with chronic +gastritis. +• Gastric adenocarcinoma incidence varies markedly with geography. +Individual tumors are classified according to location and gross and +histologic morphology. +Gastric adenocarcinomas are linked to chronic +gastritis. +pylori gastritis. +Finally, the colon is the most common +site of GI neoplasia in Western populations. +obstruction include abdominal pain and distention, vomiting, +and constipation. +Pressure at the neck of the pouch may impair +venous drainage of the entrapped viscus. +17.24). +17.23). +Figure 17.24 Intestinal obstruction. +Portion of bowel incarcerated within +an inguinal hernia. +Sequelae, including obstruction and strangulation, are similar +to external hernias. +Thus, volvulus presents with +features of both obstruction and infarction. +Because it is rare, volvulus can be over- +looked clinically, often with catastrophic results. +Once trapped, the invaginated +segment is propelled by peristalsis and pulls the mesentery +along. +In +idiopathic cases there is no underlying anatomic defect, +and the patient is otherwise healthy. +Surgical intervention is necessary when a mass is +present. +In a large majority of cases, acute obstruction +is caused by thrombosis or embolism. +Less +common causes of thrombosis include systemic vasculitides +(Chapter 11). +Obstructive emboli most commonly originate +from aortic atheromas or cardiac mural thrombi. +Pathogenesis +Intestinal responses to ischemia occur in two phases. +The lesions can be continuous but are +most often segmental and patchy (Fig. +17.25A). +The mucosa is +hemorrhagic and often ulcerated (Fig. +17.25B). +(A) Jejunal resection with dusky serosa of acute ischemia (mesenteric thrombosis). +(B) Mucosa is dark colored +because of hemorrhage. +(C) Characteristic attenuated villous epithelium in this case of acute mesenteric thrombosis. +(D) Chronic colonic ischemia with +atrophic surface epithelium and fibrotic lamina propria. +With appropriate management, mortality in the first 30 +days is approximately 10%. +Ischemic bowel injury can take a variety of +subacute or chronic forms. +Serositis, +with purulent exudates and fibrin deposition, may be prominent. +Propagation of the thrombus may lead +to secondary involvement of the splanchnic bed. +17.25C), often with hyperproliferative crypts. +Chronic ischemia is accompanied by fibrous +scarring of the lamina propria (Fig. +17.25D) and, uncommonly, +stricture formation. +Patients may progress to shock and vascular collapse within +hours in severe cases. +Presentation can range +from chronic, intermittent to acute, massive hemorrhage. +carbohydrates, electrolytes and minerals, and water. +Painful, bloody, small-volume +diarrhea is known as dysentery. +Only the malabsorption associated with cystic fibrosis is +considered here. +Some of these differences correlate with varia- +tion in wheat consumption. +17.26). +These lymphocytes express NKG2D, a natural +killer cell marker and receptor for MIC-A. +The right panel depicts a model for the pathogenesis of celiac disease. +While most people eat grain and are exposed to gluten +and gliadin, very few develop celiac disease. +Thus, host +factors determine whether disease develops. +However, the HLA locus accounts for less than half +of the genetic component of celiac disease. +Clinical Features +In adults, celiac disease presents most commonly between +the ages of 30 and 60. +These cases may +present with anemia due to chronic iron and vitamin +malabsorption. +Unfortunately, the only treatment currently available for +celiac disease is a gluten-free diet. +Noninvasive serologic tests are generally performed prior +to biopsy. +The most sensitive test is the measurement of +IgA antibodies against tissue transglutaminase. +IgA anti- +endomysial antibodies can also be present. +IgG anti–tissue +transglutaminase antibodies may be detected in patients with +IgA deficiency. +Individuals with celiac disease have an increased risk +of malignancy. +Small intestinal adenocarci- +noma is also more frequent in individuals with celiac disease. +17.27). +This loss of mucosal +and brush-border surface area contributes to malabsorption. +(A) Advanced cases of celiac disease show +complete loss of villi, or total villous atrophy. +Note the dense plasma cell +infiltrates in the lamina propria. +Affected individuals often suffer from malabsorption, +malnutrition, and stunted growth. +The underlying causes of environmental enteric dysfunc- +tion are unknown. +In +contrast to celiac disease, neutrophils are often seen infiltrat- +ing the intestinal mucosa. +In the absence of lactase, dietary lactose +cannot be broken into glucose and galactose. +Because +the defect is biochemical, histology is generally unremarkable. +Symptoms abate when exposure to milk +and milk products is terminated. +Flatulence also occurs due to +fermentation of the unabsorbed sugars by colonic +bacteria. +The factors responsible +for early or later presentation have not been defined. +Without MTP, lipids accumulate +intracellularly. +Abetalipoproteinemia presents in infancy with failure to +thrive, diarrhea, and steatorrhea. +and severe; the acquired form is common and usually presents +in adulthood. +This +global problem is responsible for over 1 million deaths each +year. +Bacterial +infections, such as enterotoxigenic E. +coli and Salmonella +spp., are frequently responsible for acute diarrheal illnesses. +Mycobacte- +rial infections of the GI tract are considered in detail in +Chapter 8. +This occurs because shell +fish and plankton can be reservoirs of Vibrio cholerae. +Over +half of cases required hospitalization, and 1% were fatal. +Pathogenesis +Severe diarrhea is caused by the toxin released by the +bacteria. +Vibrio organisms are noninvasive and remain within +the intestinal lumen. +Proteins involved in motility and +attachment are necessary for efficient colonization. +Cholera toxin is encoded by a virulence phage. +It is +composed of five B subunits and a single A subunit. +17.28). +• Diarrhea can be characterized as secretory,osmotic,malabsorp- +tive, or exudative. +• Environmental enteric dysfunction is prevalent in areas with +poor sanitation. +• Lactase deficiency causes an osmotic diarrhea due to the inability +to break down lactose. +coli; EIEC, enteroinvasive E. +coli; EHEC, enterohemorrhagic E. +coli; EPEC, enteropathogenic E. +coli; ETEC, +enterotoxigenic E. +coli; GI, gastrointestinal. +Chloride and sodium absorption are also inhibited by cAMP. +that draws water into the lumen and causes massive diarrhea. +Remarkably, mucosal biopsies show only minimal histologic +alterations. +Clinical Features +Most individuals exposed to V. +cholerae are asymptomatic +or develop only mild diarrhea. +The volumi- +nous stools resemble rice water and are sometimes described +as having a fishy odor. +Oral rehydration is often sufficient but is unfor- +tunately underutilized. +Flagella allow Campylobacter to be motile, which +facilitates adherence and colonization. +Some C. +jejuni lipopolysaccharide +cross-react with peripheral and central nervous system +gangliosides. +MORPHOLOGY +Campylobacter are comma-shaped, flagellated, gram-negative +organisms. +Diagnosis is primarily by stool culture, since biopsy +findings are nonspecific. +Importantly, crypt architecture +is preserved (Fig. +(A) Campylobacter jejuni infection produces acute, self-limited colitis. +(D) Enteroinvasive E. +coli infection is similar to other acute, self-limited colitides +such as those caused by C. +jejuni. +Clinical Features +Ingestion of as few as 500 C. +jejuni organisms can cause +disease after an incubation period of up to 8 days. +Patients +may shed bacteria for 1 month or more after clinical resolu- +tion. +Antibiotic therapy is generally not required. +coli. +Although humans are the only known reservoir, Shigella +spp. +Deaths are generally limited to children younger +than 5 years of age. +Pathogenesis +Shigella are resistant to gastric acid, thereby explaining the +low infective dose. +All Shigella spp. +This and other factors lead +to significant potential for confusion with inflammatory bowel +disease. +Duration of symptoms is typically +shorter in children, but severity is often much greater. +Confirmation of Shigella infection +requires stool culture. +S. +coli (EHEC) are more commonly responsible (Chapter 20). +Toxic megacolon and intestinal obstruction are uncommon +complications. +enteritidis. +Centralized food processing can lead to large outbreaks. +Vaccines are available for both humans and farm animals, +e.g., egg-laying hens. +Stool cultures are essential +for diagnosis. +Symptoms range +from loose stools to cholera-like profuse diarrhea to dys- +entery. +The disease +is caused by Salmonella enterica and its two subtypes, typhi +and paratyphi. +The majority of cases in endemic countries +are due to S. +typhi, while infection by S. +paratyphi is more +common among travelers, perhaps because they are often +vaccinated against S. +typhi. +Humans are the sole +reservoir for S. +typhi and S. +paratyphi; transmission occurs +from person to person or via food or contaminated water. +Gallbladder colonization with S. +typhi or S. +paratyphi may +be associated with gallstones and a chronic carrier state. +Pathogenesis +In contrast to S. +enteritidis, S. +Similar +to Shigella, S. +typhi are resistant to gastric acid and, initially, +invade via small intestinal M cells. +Draining mesenteric lymph nodes are +also enlarged. +Mucosal damage +creates oval ulcers, oriented along the axis of the ileum, that may +perforate. +In disseminated S. +Escherichia coli +E. +The latter are classified according to morphology, +pathogenesis, and in vitro behavior. +Subgroups with major +clinical relevance include enterotoxigenic E. +coli (ETEC), +enteropathogenic E. +coli (EPEC), enterohemorrhagic E. +coli +(EHEC), enteroinvasive E. +coli (EIEC), and enteroaggregative +E. +coli (EAEC). +Enterotoxigenic Escherichia coli. +ETEC are the principal +cause of traveler’s diarrhea and spread via contaminated food +or water. +In under-resourced countries, children younger than 2 +years of age are particularly susceptible. +ETEC are noninvasive +but produce heat-labile (LT) and heat-stable (ST) toxins. +Enteropathogenic Escherichia coli. +These proteins include Tir, which +is inserted into the intestinal epithelial cell plasma membrane. +EPEC strains do not produce Shiga toxins. +Enterohemorrhagic Escherichia coli. +EHEC are catego- +rized as E. +coli O157:H7 and non-O157:H7 serotypes. +E. +Contaminated milk and vegetables are +also vehicles for infection. +Both O157:H7 and non-O157:H7 +serotypes produce Shiga-like toxins, and therefore lesions +(see Fig. +17.29C) and clinical symptoms are similar to those +resulting from S. +dysenteriae infection. +Abdominal tenderness +may mimic appendicitis. +Rose spots, small erythematous +maculopapular lesions, develop on the chest and abdomen. +Symptoms abate after several weeks but relapse can occur. +Patients with sickle cell disease are particularly susceptible +to Salmonella osteomyelitis. +Blood cultures are positive in +more than 90% of affected individuals during the febrile +phase. +Antibiotic treatment can prevent disease progression. +Yersinia +Three Yersinia species are human pathogens. +Y. +enterocolitica +and Y. +pseudotuberculosis cause GI disease and are discussed +here; Y. +pestis, the agent of pulmonic and bubonic plague, +is discussed in Chapter 8. +coli, Klebsiella, Salmonella, and enterobacteria. +17.29B) and granulomas. +As with Shigella, these +factors can cause diagnostic confusion with Crohn disease. +Extraintestinal +symptoms of pharyngitis, arthralgia, and erythema +nodosum occur frequently. +Fever and diarrhea are less +common. +Yersinia can be detected by +stool culture on Yersinia-selective agar. +Enteroinvasive Escherichia coli. +17.29D). +Enteroaggregative Escherichia coli. +EAEC has a unique +“stacked brick” morphology when bound to epithelial +cells. +These organisms cause diarrhea in children and adults +worldwide, including traveler’s diarrhea. +difficile +causes pseudomembranous colitis. +Pathogenesis +Disruption of the normal colonic microbiota by antibiotics +allows C. +difficile overgrowth. +Toxins released by C. +A +B C +Figure 17.30 Clostridioides (formerly Clostridium) difficile colitis. +(B) +Pseudomembranes are easily appreciated on gross examination. +Clinical Features +Risk factors for C. +Individuals with C. +Protein loss can give rise +to hypoalbuminemia. +Fecal leukocytes and occult blood may +be present, but grossly bloody diarrhea is uncommon. +The diagnosis is usually made +by detection of C. +difficile toxin, rather than by culture, and +is supported by the characteristic histopathology. +difficile strains is increasing. +Recurrent C. +difficile–associated +colitis occurs in up to 40% of patients. +Pseudomembranes (Fig. +However, histopathology of C. +difficile–associated +colitis is pathognomonic. +The organism was identified as an actinomycete by PCR in +1992 and named Tropheryma whipplei. +Thus, the malabsorp- +tive diarrhea of Whipple disease is due to impaired lymph +drainage. +17.31B). +Intact rod-shaped bacilli can also be identified by electron +microscopy (Fig. +17.31D), and +the organisms are PAS-positive in both diseases. +The acid-fast +stain can be helpful, since mycobacteria stain positively (Fig. +17.31E), +while T. +whipplei does not. +B +D EC +Figure 17.31 Whipple disease and mycobacterial infection. +(B) Periodic acid–Schiff stain +highlights macrophage lysosomes full of bacilli. +Compare with (A). +(E) Unlike T. +whippelii, +mycobacteria are positive with stains for acid-fast bacteria. +(C, Courtesy +George Kasnic and Dr. +Viral Gastroenteritis +Symptomatic human infection is caused by many viruses. +The most common are discussed here. +Norovirus. +Approximately half of all gastroenteritis outbreaks world- +wide are thought to be due to norovirus. +They cause more +than 200,000 childhood deaths annually in under-resourced +countries. +Fecal-oral transmission is responsible for most sporadic +cases. +In these environments, vehicles +include airborne droplets, environmental surfaces, and +fomites. +The symptoms resolve within +2 to 3 days in most cases. +Norovirus infection in immunocompromised patients is +a significant problem. +As a result, a new pandemic strain +emerges every 2 to 4 years. +Rotavirus. +The WHO recommends that the first dose be +given at 6 weeks of age. +Adenovirus. +A common cause of pediatric diarrhea, adeno- +virus also affects immunocompromised patients. +Viral nuclear inclusions +are uncommon. +Fever and weight loss may +also be present. +Symptoms generally resolve within 10 days. +Ascaris lumbricoides. +This nematode infects 1 billion +individuals worldwide. +Ingested eggs hatch in the intestine, +and larvae penetrate the intestinal mucosa. +Approximately +3 weeks later, the larvae are coughed up and swallowed. +(B) Diffuse eosinophilic infiltrates in parasitic infection. +(C) Schistosomiasis can induce an inflammatory reaction to eggs trapped within the lamina propria. +(D) Entamoeba +histolytica in a colon biopsy specimen. +Note some organisms ingesting red blood cells (arrow). +17.32B) that can cause physical obstruction of +the intestine or biliary tree. +Larvae can also form hepatic +abscesses and cause pneumonitis. +Diagnosis is usually made +by detection of eggs in stool samples. +Strongyloides. +17.32B). +Strongyloides incite a strong +tissue reaction and peripheral eosinophilia. +Necator duodenale and Ancylostoma duodenale. +These +hookworms infect 1 billion people worldwide and cause +significant morbidity. +Infection is initiated by larval penetra- +tion through the skin. +After further development in the +lungs, they migrate up the trachea and are swallowed. +Worms +attach to the duodenal mucosa, suck blood, and reproduce. +Diagnosis can be made by detection of +the eggs in fecal smears. +Trichuris trichiura. +Whipworms primarily infect young +children. +Similar to Enterobius vermicularis, T. +trichiura does +not penetrate the intestinal mucosa and rarely causes serious +disease. +Heavy infections may cause bloody diarrhea and +rectal prolapse. +Enterobius vermicularis and Enterobius gregorii. +E. +Infection is primarily +by the fecal-oral route. +The eggs cause irritation and +rectal and perineal pruritus. +Schistosomiasis. +Eggs are trapped within +the mucosa and submucosa (Fig. +17.32C). +The resulting +immune reaction is often granulomatous and can cause +bleeding and even obstruction. +More details are presented in +Chapter 8. +Intestinal Cestodes. +Release of the larva allows attachment to the intestinal +mucosa through its head, or scolex. +Nevertheless, the parasite burden +can be staggering. +Clinical symptoms include abdominal pain, +diarrhea, and nausea, but most cases are asymptomatic. +Occasionally, D. +Identification of proglottids and eggs in stools is the most +efficient method of diagnosis. +Entamoeba histolytica. +This protozoan causes amebiasis +and is spread by fecal-oral transmission. +E. +E. +17.32D). +Amebae may also spread +to the kidneys and brain via the bloodstream. +Individuals with amebiasis may present with abdominal +pain, bloody diarrhea, or weight loss. +The parasites lack mitochondria +or Krebs cycle enzymes and are thus obligate fermenters +of glucose. +Giardia lamblia. +These organisms, also referred to as G. +duodenalis or G. +G. +Infection may occur +after ingestion of as few as 10 cysts. +Because cysts are resistant +to chlorine, Giardia are endemic in unfiltered public water +supplies. +Secretory +IgA and mucosal IL-6 responses are important for clearance +of Giardia infections. +Immunosuppressed, agammaglobu- +linemic, or malnourished individuals are often severely +affected. +Infection +is usually documented by immunofluorescent detection of +cysts in stool samples. +Oral antimicrobial therapy is effective, +but recurrence is common. +Cryptosporidium. +Like Giardia, cryptosporidia are an +important cause of diarrhea worldwide. +Crypto- +sporidiosis also causes persistent diarrhea in residents of +under-resourced countries. +Oocysts are +resistant to chlorine and may therefore persist in treated, +but unfiltered, water. +Contaminated drinking water continues +to be the most common means of transmission. +Like giardiasis, cryptosporidiosis +is readily spread to water sport participants. +Food-borne +infection occurs less frequently. +Humans are infected by several different Cryptosporidium +species, including C. +hominis and C. +parvum. +Once ingested, as few +as 10 encysted oocytes are sufficient to cause symptomatic +infection. +Sporozoites are released following protease activa- +tion by gastric acid. +17.32F). +Diagnosis is based on finding oocysts +in the stool. +Despite very real symptoms, the endoscopic and +microscopic evaluations are normal in IBS patients. +Thus, +the diagnosis depends on clinical symptoms and functional +testing. +Further, 5-HT3 receptor antagonists are effective +in many cases of diarrhea-predominant IBS. +Other causes, such as +enteric infection or inflammatory bowel disease, must be +excluded. +KEY CONCEPTS +INFECTIOUS ENTEROCOLITIS +• V. +• C. +Most +isolates are noninvasive. +• Salmonella and Shigella spp. +are invasive and associated with +exudative bloody diarrhea (dysentery). +• Salmonella enteritidis infection is a common cause of food +poisoning. +• S. +typhi cause systemic disease (typhoid fever). +• Pseudomembranous colitis is often triggered by antibiotic therapy. +The responsible organism, C. +These spread to form mucopurulent +pseudomembranes. +• Norovirus is a common cause of self-limited diarrhea in adults +and children. +It spreads from person to person in sporadic +cases and via contaminated water in epidemics. +Each +parasite has a distinctive life cycle and tissue reaction. +Those +that invade are typically associated with tissue and systemic +eosinophilia. +The +distinction between Crohn disease and ulcerative colitis is primarily based +on morphology. +Fat/vitamin +Yes No +malabsorption +Malignant +With colonic +involvement +potential +Yes +activation. +The two disorders that comprise IBD are ulcer- +ative colitis and Crohn disease. +17.33) and the morphologic expression of disease +(Table 17.8) at those sites. +Epidemiology. +This is at least partly due to genetic factors, as discussed +later. +inflammation in susceptible hosts. +• Mucosal immunity. +For example, NOD2 polymorphisms have not been associ- +ated with Crohn disease in Asian populations. +• Autophagy and cellular stress responses. +• Host-microbial interactions. +In general, the microbiome is populated by a small +number of species at birth. +Microbial complexity +then declines in old age. +This is one means by which the microbiome +can modulate mucosal immunity. +17.34A). +17.34B). +Edema and loss of the normal mucosal folds are common. +17.34B). +FissuresSmall intestine and colon 801 +granulomas (Fig. +17.35C) or uninvolved regions within any layer of +the intestinal wall (Fig. +17.35D). +Granulomas may also be present +in draining mesenteric lymph nodes. +Clinical Features +The clinical manifestations of Crohn disease are extremely +variable. +Unfortunately, +smoking cessation does not result in disease remission. +Perforation and peritoneal abscesses are +common. +Over the +last two decades, anti-TNF antibodies have revolutionized +treatment of Crohn disease. +A B +C D +Figure 17.34 Gross pathology of Crohn disease. +(A) Small intestinal +stricture. +(C) Perforation +and associated serositis. +(D) Creeping fat. +frequently develop and may extend deeply to become fistula +tracts or sites of perforation (Fig. +17.34C). +17.34A). +17.34D). +17.35A). +Epithelial metaplasia is +another consequence of chronic relapsing injury. +One form, +pseudopyloric metaplasia, refers to the presence of gastric +antral-appearing glands. +Paneth cell metaplasia may also occur +in the left colon, where Paneth cells are normally absent. +These +architectural and metaplastic changes may persist even when +active inflammation has resolved. +Mucosal atrophy, with loss of +crypts, may also occur after years of disease. +(A) Haphazard crypt organization results from repeated injury and regeneration. +(B) Noncaseating +granuloma. +(C) Active Crohn disease, with ulceration and purulent exudate. +(D) Transmural Crohn disease with submucosal and serosal granulomas +(arrows). +cases of pancolitis. +There can be an +abrupt transition between diseased and uninvolved colon (Fig. +17.36B). +Isolated islands of regenerating mucosa often bulge into the lumen +to create pseudopolyps (Fig. +17.36C), and the tips of these +polyps may fuse to create mucosal bridges (Fig. +17.36D). +Chronic +disease may lead to mucosal atrophy with a smooth mucosal +surface that lacks normal folds. +Unlike Crohn disease, ulcerative +colitis is not transmural. +17.37A), crypt distortion, and +pseudopyloric epithelial metaplasia (Fig. +17.37B). +Disease of the entire colon is termed pancolitis (Fig. +17.36A). +(B) Sharp demarcation between active ulcerative colitis (right) and normal mucosa (left). +(C) Inflammatory polyps. +(D) Mucosal bridges can join inflammatory polyps. +However, +infectious enteritis precedes disease onset in some cases. +These include +patchy histologic disease, a family history of Crohn disease, +and perianal lesions. +17.37C). +These symptoms may persist for +days, weeks, or months before they subside. +(A) Crypt abscess. +(B) Pseudopyloric metaplasia (right). +(C) Disease is limited to the mucosa (above the +arrow). +Compare to Fig. +17.35D. +often lacking in patients with ulcerative colitis and present +in those with Crohn disease. +Fortunately, overlap in medical management +allows indeterminate colitis to be treated effectively. +Risk increases sharply 8 to 10 years +after disease onset. +• Extent of the disease. +Patients with pancolitis are at greater +risk than those with only left-sided disease. +Crohn +disease patients without colonic involvement are not at +increased risk. +• Nature of the inflammatory response. +Dysplasia can develop in flat areas of mucosa +that are not grossly recognized as abnormal. +IBD-associated +dysplasia is classified histologically as low grade or high +grade (Fig. +17.38A, B) and may be multifocal. +High-grade +dysplasia may be associated with invasive carcinoma at +the same site (Fig. +17.38C) or elsewhere in the colon and +therefore often prompts colectomy. +(A) Dysplasia with extensive +nuclear stratification and marked nuclear hyperchromasia. +(B) Cribriform +glandular arrangement in high-grade dysplasia. +Also +seen are small invasive glands (arrowhead). +B C +Figure 17.39 Uncommon causes of colitis. +(A) Diversion colitis. +Note the +large lymphoid follicles with germinal centers. +(B) Collagenous colitis with +a dense subepithelial collagen band. +(C) Lymphocytic colitis. +Intraepithelial +lymphocytes can be recognized by their densely stained, small nuclei. +Colitis can develop within +the diverted segment. +17.39A). +Such enemas +are, however, used infrequently because of butyrate’s foul +odor. +Diversion colitis resolves after anastomosis and +restoration of fecal flow. +Radiologic and endoscopic studies are typically +normal. +17.39B). +17.39C). +Similar histologic +changes can be induced by NSAIDs and, possibly, proton +pump inhibitors. +The small bowel +and colon are involved in most cases. +Epithelial apoptosis, +particularly of crypt cells, is the most common histologic +finding. +The crypts may be completely destroyed in severe +cases. +The reasons for this dif- +ference in distribution are not well defined. +A +B C +Figure 17.40 Sigmoid diverticular disease. +(A) Stool-filled diverticula are +regularly arranged. +(B) Cross section showing the outpouching of mucosa +through the muscularis propria. +Perforation +can result in pericolonic abscesses, sinus tracts, and, occasionally, +peritonitis. +Patients sometimes experience alternating constipation and +diarrhea that mimics IBS. +Even when diverticulitis +occurs, it most often resolves spontaneously. +Surgical +intervention is generally reserved for those with severe or +recurrent diverticulitis. +17.40A). +These are most common in the +sigmoid colon, but other parts of the colon may be affected. +17.40B, C). +Diverticular obstruction +induces inflammation, termed diverticulitis. +These lesions are without malignant +potential. +the gut microbiome, abnormal GI motility, and increased enteric +sensory responses to GI stimuli. +• IBD is an umbrella term for ulcerative colitis and Crohn disease. +Involvement +is discontinuous, resulting in skip lesions. +In affected areas disease +can be transmural, affecting the full thickness of the entire +bowel wall. +Noncaseating granulomas are common. +• Diverticular disease of the sigmoid colon is common inWestern +populations older than age 60. +The causes include low-fiber +diets, colonic spasm, and the unique anatomy of the colon. +They are smooth, +nodular protrusions of the mucosa, often on the crests of mucosal +folds. +17.41). +Serration is typically restricted +to the upper third of the crypt. +Most, if not all, polyps begin as small eleva- +tions of the mucosa. +Polyps with stalks are termed +pedunculated. +In general, intestinal polyps can be classified +as nonneoplastic or neoplastic. +The most common neoplastic +polyp is the adenoma, which has the potential to progress +to cancer. +Nonneoplastic polyps can be classified as inflam- +matory, hamartomatous, or hyperplastic. +(A) Polyp surface with irregular tufting +of epithelial cells. +(B) Tufting results from epithelial overcrowding. +An inflammatory polyp may +ultimately form as a result of chronic cycles of injury and +healing. +Entrapment of this polyp in the fecal stream leads +to mucosal prolapse. +17.42). +Several +of these syndromes are discussed below and others are +summarized in Table 17.9. +Many juvenile polyps are located in the rectum +and cause rectal bleeding. +Sporadic juvenile polyps, which are also referred to +as retention polyps, are usually solitary. +MORPHOLOGY +Most juvenile polyps are less than 3 cm in diameter. +17.43). +The +muscularis mucosae may be normal or attenuated. +These patients often have both juvenile polyposis +and hereditary hemorrhagic telangiectasia. +Together +these mutations account for fewer than half of patients. +Thus, other genes responsible for autosomal dominant +juvenile polyposis remain to be discovered. +A B C +Figure 17.42 Solitary rectal ulcer syndrome. +(B) Epithelial +hyperplasia. +Dysplasia is rare in sporadic juvenile polyps. +These lesions are similar to +freckles but are distinguished by their presence in the buccal +mucosa. +Peutz-Jeghers polyps can initiate intussusception, +which is occasionally fatal. +Grossly, +the polyps are large and pedunculated with a lobulated contour. +17.44).810 CHAPTER 17 The Gastrointestinal Tract +A +A +B +B +Figure 17.44 Peutz-Jeghers polyp. +Figure 17.43 Juvenile polyposis. +(A) Juvenile polyp. +Note the surface +erosion and cystically dilated crypts. +(B) Inspissated mucus, neutrophils, +and inflammatory debris can accumulate within dilated crypts. +adenocarcinomas. +Adenomas develop in approximately 30% of adults living +in the Western world by age 60. +The preferred approach to surveil- +lance varies, but colonoscopy is the most frequent mode. +As the name implies, tubulovillous adenomas have a mixed +architecture. +17.46D). +These may extend into, but not through, the muscularis mucosae. +17.47A). +17.47B), +constitutes invasive adenocarcinoma and carries a risk of spread +to other sites. +MORPHOLOGY +Colorectal adenomas are characterized by the presence +of epithelial dysplasia. +Typical adenomas range from 0.3 to +10 cm in diameter and can be pedunculated (Fig. +17.45B). +17.46C). +Pedunculated adenomas +have slender fibromuscular stalks (Fig. +17.45C) containing prominent +blood vessels derived from the submucosa. +The stalk is usually +covered by nonneoplastic epithelium, but dysplasia can be present. +Adenomas can be classified as tubular, tubulovillous, or +villous based on their architecture. +17.46A). +Size is the most important characteristic that +correlates with risk of malignancy. +A B C +Figure 17.45 Colonic adenomas. +(A) Pedunculated adenoma (endoscopic view). +(B) Adenoma with a velvety surface. +(A) Tubular adenoma with a smooth surface and rounded glands. +(B) Villous adenoma with long, slender +projections that are reminiscent of small intestinal villi. +(C) Sessile serrated adenoma lined by goblet cells without cytologic features of dysplasia. +Compare to the +hyperplastic polyp in Fig. +17.41. +17.48). +As a result, prophylactic colectomy is +the standard of care. +Colectomy prevents colorectal cancer, +but patients remain at risk for neoplasia at other sites. +The +ampulla of Vater and the stomach are common extracolonic +sites of adenomas in FAP patients. +A +B +Figure 17.47 Adenoma with carcinoma. +(B) Invasive adenocarcinoma +(left) beneath a villous adenoma (right). +Patients with HNPCC inherit +one mutant gene and one normal allele. +A +B +Figure 17.48 Familial adenomatous polyposis. +(A) Hundreds of small +polyps are present throughout this colon with a dominant polyp (right). +(B) Three tubular adenomas are present in this single microscopic field. +This autosomal recessive disorder is +termed MUTYH-associated polyposis, or MAP. +In contrast to +FAP, MAP is characterized by fewer than 100 polyps, which +appear at later ages. +Colon cancer development is also +delayed. +Epidemiology. +Colorectal adenocarcinoma is responsible +for nearly 10% of all cancer deaths worldwide. +In contrast, rates +are lower in South America, India, Africa, and South Central +Asia. +Colorectal cancer incidence peaks at 60 to 70 years of +age. +In addition to dietary modification, pharmacologic +chemoprevention is possible. +Aspirin and other NSAIDs +have a protective effect. +17.49). +Telomerase expression also increases +as lesions become more advanced. +These are referred to as +MSI high, or MSI-H, tumors. +17.50). +Loss of one normal copy of the tumor suppressor gene APC +occurs early. +Individuals born with one mutant allele are therefore at increased risk of developing colon cancer. +Alternatively, inactivation of APC in colonic +epithelium may occur later in life. +This is the “first hit” according to the Knudson hypothesis (Chapter 7). +The loss of the intact second copy of APC +follows (“second hit”). +If these mutations affect genes involved in cell survival and proliferation, +cancer may develop. +Activating mutations in the oncogene +BRAF are common in these cancers. +In contrast, KRAS +and TP53 are not typically mutated. +• A small group of colon cancers display increased CpG island +methylation in the absence of MSI. +Many of these tumors +harbor KRAS mutations, but TP53 and BRAF mutations +are uncommon. +desmoplastic response, which is responsible for their characteristic +firm consistency. +Some poorly differentiated tumors form few +glands (Fig. +17.52B). +Uncommonly, tumors may be composed of signet- +ring cells similar to those in gastric cancer (Fig. +17.52C). +Unfortunately, colorectal cancers develop insidiously and +may go undetected for long periods. +17.53A). +Metastases may involve regional +lymph nodes, lungs (Fig. +17.53C). +The TNM classifica- +tion is used to define tumor stage (Table 17.12). +Five-year survival rates vary widely worldwide. +17.51), sometimes to the point of obstruction. +Both forms +grow into the bowel wall over time. +17.52A). +(A) Circumferential, ulcerated rectal +cancer. +Note the anal mucosa at the bottom of the image. +Areas of chalky necrosis are +present within the colon wall (arrow). +A B C +Figure 17.52 Histologic appearance of colorectal carcinoma. +(A) Well-differentiated adenocarcinoma. +Note the elongated, hyperchromatic nuclei. +Necrotic +debris, present in the gland lumen, is typical. +A B +C +Figure 17.53 Metastatic colorectal carcinoma. +(A) Lymph node +metastasis. +Note the glandular structures within the subcapsular sinus. +(B) +Solitary subpleural nodule of colorectal carcinoma metastatic to the lung. +(C) Liver containing two large and many smaller metastases. +Note the +central necrosis within metastases. +ranges from 90% to 40% depending on stage. +They have no +malignant potential and must be distinguished from sessile +serrated polyps. +• Inflammatory polyps form as a result of chronic cycles of injury +and healing. +• FAP is caused by APC mutations. +• HNPCC is caused by mutations in DNA mismatch repair +enzymes. +17.54B). +Alternatively, +basaloid differentiation may be mixed with mucinous dif- +ferentiation. +17.54C). +The major risk factor for these HPV associated +lesions is anal sex. +Hemorrhoids may +also develop secondary to portal hypertension. +Except +for pregnant women, hemorrhoids are rarely encountered +in persons younger than age 30. +Extensive or severe internal or external hemorrhoids may +be removed surgically by hemorrhoidectomy. +Acute +CpG island hypermethylation underlies most remaining colon +cancers. +TUMORS OF THE ANAL CANAL +The anal canal can be divided into thirds. +17.54A). +A B C +Figure 17.54 Anal tumors. +The +adjacent rectal mucosa is normal. +TUMORS OF THE APPENDIX +Several tumors occur in the appendix. +The most common is +the well-differentiated neuroendocrine (carcinoid) tumor. +Mucinous neoplasms of the appendix occur in adults, +most often in the sixth decade of life. +Mucin can dissect through the wall to the peritoneal +surface, causing appendiceal rupture. +KRAS mutations +are also common. +When confined to the appendix, +prognosis of LAMN is excellent. +Outcomes are more variable +in HAMN. +They also occur in portal hypertension. +• Acute appendicitis is most common in children and adolescents. +It is thought to be initiated by increased intraluminal pressure +and compromised venous outflow. +• Peritoneal dissemination of mucinous neoplasms can cause +pseudomyxoma peritonei. +Diagnosis of acute appendicitis requires neutrophilic infiltration +of the muscularis propria. +In more severe cases a prominent +neutrophilic exudate generates a serosal fibrinopurulent reaction. +Regrettably, classic signs and symptoms of acute appendi- +citis are often absent. +As +with other causes of acute inflammation, there is neutrophilic +leukocytosis. +Damage to the bowel wall may allow bacteria +to spread to the peritoneal cavity. +• Endometriosis, which causes hemorrhage into the peritoneal +cavity, that acts as an irritant. +• Ruptured dermoid cysts, which release keratins and induce +an intense granulomatous reaction. +E. +coli, streptococci, S. +aureus, +enterococci, and C. +perfringens are implicated most often. +Spontaneous bacterial peritonitis develops in the absence +of an obvious source of contamination. +coli, streptococci, and Klebsiella species +are the most frequently involved organisms. +by dense fibrosis that may extend to involve the mesentery. +Peritoneal mesotheliomas are almost always +associated with high levels of asbestos exposure. +The +most common of these is desmoplastic small round cell tumor. +This is an aggressive tumor that occurs in children and young +adults. +[Current analysis of trends +in gastrointestinal disease epidemiology and costs]. +[Review of short bowel syndrome and intestinal failure]. +[Review of mechanisms and emerging therapies in +Hirschsprung disease]. +[Review focusing on mechanisms +and treatment of pyloric stenosis]. +[Comprehensive review of achalasia]. +[Comprehensive +review of eosinophilic esophagitis]. +[Detailed approach to patients with +esophageal reflux]. +[Detailed +review of mechanisms underlying Barrett metaplasia]. +[Large clinical analysis of the +risk of dysplasia and cancer in Barrett esophagus]. +[Trends in +esophageal adenocarcinoma epidemiology]. +[Analysis +of current understanding and approaches in esophageal adenocarcinoma]. +[Detailed literature review with recom- +mendations regarding stress ulcer prophylaxis]. +[Analysis +of non-steroidal anti-inflammatory drugs and proton pump inhibitors in +gastric ulcers]. +Lanas A, Chan FKL: Peptic ulcer disease, Lancet 390:613–624, 2017. +doi:10.1093/jnci/djx262. +[Epidemiologic analysis of non-cardia +gastric cancer incidence and race]. +[Review of relationship between inflammatory cytokine responses and gastric +carcinogenesis]. +Crowe SE: Helicobacter pylori infection, N Engl J Med 380:1158–1165, +2019. +[Overarching review of Helicobacter pylori infection and gastritis +pathogenesis]. +[All-encompassing review of atrophic gastritis]. +[Analysis +of series of patients treated for Ménétrier disease]. +Simmons LH, Guimaraes AR, Zukerberg LR: Case records of the +Massachusetts General Hospital. +Case 6-2013. +A 54-year-old man +with recurrent diarrhea, N Engl J Med 368:757, 2013. +[Case report and +discussion of Zollinger-Ellison syndrome]. +[Updated discussion of +molecular diagnostics and treatment of gastrointestinal stromal tumors]. +[Perspective on +familial gastric cancer syndromes]. +Polk DB, Peek RM Jr: Helicobacter pylori: gastric cancer and beyond, +Nat Rev Cancer 10:403, 2010. +[Good review of Helicobacter pylori and +mechanisms by which it is linked to gastric cancer]. +[Discussion of gastric mucosa- +associated lymphoid tissue lymphoma pathogenesis]. +[Review of volvulus and its +complications]. +[Discussion of clinical approaches to lower gastrointestinal bleeding]. +[Review of angiodysplasia]. +[Physiology-oriented review of ion transport in +diarrhea]. +[Review of mechanisms underlying +growth failure (stunting)]. +[Review of obstruction and other +gastrointestinal complications of cystic fibrosis]. +[Expert review +of current and potential future means of managing celiac disease]. +[Review of secretory diarrhea with a view toward future, +targeted therapies]. +[Analysis of a Salmonella epidemic]. +[Study of cholera outbreak following the 2010 Haitian earthquake]. +DuPont HL: Acute infectious diarrhea in immunocompetent adults, +N Engl J Med 370:1532–1540, 2014. +[Expert discussion of acute infectious +diarrhea]. +[Review of current status of and future prospects for +therapeutic fecal transplantation]. +[Comprehensive review of irritable bowel +syndrome]. +[Overarching review of host–microbial +interactions focused on immune regulation]. +[Identification of monogenic causes of inflammatory +bowel disease]. +[Discussion of inflammatory and diarrheal diseases +associated with immunotherapy for cancers]. +Pardi DS: Diagnosis and management of microscopic colitis, Am J +Gastroenterol 112:78–85, 2017. +[Review of collagenous and lymphocytic +colitis pathobiology and diagnosis]. +[Prospective study of diet and diverticular +disease]. +Young-Fadok TM: Diverticulitis, N Engl J Med 380:500–501, 2019. +[Overarching review of diverticular disease]. +[Analysis of practice patterns and colonoscopy frequency]. +[Study of colorectal cancer risk as a function of +colonoscopy findings in nearly 16,000 patients]. +[Position statement on management of serrated +polyps]. +Sengupta S, Bose S: Peutz-Jeghers syndrome, N Engl J Med 380:472, +2019. +[Review of Peutz-Jeghers disease etiology and management]. +[Large study of relationship between adenoma detection rates and colon +cancer incidence]. +Medema JP: Targeting the colorectal cancer stem cell, N Engl J Med +377:888–890, 2017. +[Short review of potential new therapies in treating +colorectal cancer]. +Hemorrhoids +Jacobs D: Clinical practice. +Hemorrhoids, N Engl J Med 371:944–951, +2014. +[Clinically oriented review of hemorrhoid management]. +Acute Appendicitis and Tumors of the Appendix +Flum DR: Clinical practice. +[Discus- +sion of alternative approaches to management of acute appendicitis]. +[Overarching review of peritoneal +mesothelioma and evolving therapies]. +The lobule model provides one useful way to consider +the anatomic organization of the liver (Fig. +18.1). +In this +model, the liver is divided into 1- to 2-mm hexagonal lobules +a The contributions of Drs. +BD, Bile duct; HA, hepatic artery; PV, +portal vein. +that are oriented around the terminal tributaries of the hepatic +vein. +Each lobule can be further subdivided into six +triangular acini. +18.1). +Between the trabecular plates +of hepatocytes are vascular sinusoids. +Hepatocytes are thus +bathed on two sides by a mixture of portal venous and +hepatic arterial blood. +The sinusoids are lined by fenestrated +endothelium. +These channels +drain into the canals of Hering that, in turn, connect to bile +ductules. +The ductules empty into the interlobular bile ducts +within portal tracts. +When injury is irreversible, hepatocytes may die by +necrosis or apoptosis. +18.2). +These changes are a result of caspase cascades described in +detail in Chapter 2. +18.3). +This may be seen in acute toxic or ischemic injuries or in +severe viral or autoimmune hepatitis. +Confluent necrosis +may begin with hepatocyte dropout in zone 3 near the central +vein. +In pan-acinar necrosis, the entire lobule is obliterated. +In some cases, +there is scar regression (described in the next section). +When quiescent, the main +function of stellate cells is lipid storage, including vitamin +A. +In Asia, acute hepatitis B and E +are the predominant causes. +An etiology +cannot be established in about 15% of adult and 50% of +pediatric cases. +18.4).Affected +livers are small and shrunken. +Typically, serum liver transaminases +are markedly elevated. +• Coagulopathy. +Thus, with liver +failure, factor deficiencies and coagulopathy develops. +However, +patients with fulminant hepatic failure from any cause +may develop hepatorenal syndrome. +A +B +Figure 18.4 (A) Massive necrosis, cut section of liver. +The liver is small +(700 g), bile-stained, soft, and congested. +(B) Hepatocellular necrosis +caused by acetaminophen overdose. +Confluent necrosis is seen in the +perivenular region (zone 3) (large arrow). +Residual normal tissue is +indicated by an asterisk. +(Courtesy Dr. +Encephalopathy may progress over days, weeks, or +months following acute liver injury. +Associated fluctuat- +ing neurologic signs include rigidity and hyperreflexia. +Figure 18.5 Cirrhosis resulting from chronic viral hepatitis. +Relief may only be found in liver transplantation. +• Impaired estrogen metabolism leads to hyperestrogenemia, +which has several effects. +Each +angioma is a central, pulsating, dilated arteriole from +which small vessels radiate. +In males, hyperestrogenemia +may also produce hypogonadism and gynecomastia. +The dominant intrahepatic cause is +cirrhosis, accounting for most cases of portal hypertension. +18.5). +18.6A). +Morphologic features of regression include +thin incomplete scars (see Fig. +(A) Thick bands of collagen separate rounded cirrhotic +nodules. +(B) After 1 year of abstinence, most scars are gone. +(Masson trichrome stain) (Courtesy Drs. +This is caused +by arterial vasodilation, primarily in the splanchnic circula- +tion. +These +are illustrated in Fig. +18.7 and are described next. +Ascites +usually becomes clinically detectable when at least 500 mL +have accumulated. +The fluid may contain a +scant number of mesothelial cells and mononuclear leukocytes. +These shunts +microcirculation such as nodular regenerative hyperplasia +(discussed later). +Pulmonary Complications of Liver Failure and Portal +Hypertension. +Patients with this +syndrome have a poorer prognosis than patients without +hepatopulmonary syndrome. +• Portopulmonary hypertension refers to pulmonary arterial +hypertension arising in liver disease. +The most common clinical +manifestations are dyspnea on exertion and clubbing of +the fingers. +In such patients, there is often estab- +lished cirrhosis with extensive vascular shunting. +The short-term mortality of patients with +this form of liver failure is around 50%. +Other causes of decompensation are systemic rather than +intrahepatic insults. +In women, oligomenorrhea, +amenorrhea, and sterility as a result of hypogonadism are frequent. +Clinically significant findings are in boldface. +may appear wherever the systemic and portal circulations +share capillary beds (see Fig. +18.7). +Although hemorrhoidal bleeding may occur, +it is rarely massive or life threatening. +Each episode of bleeding is associated with ~30% +mortality. +Splenomegaly +Long-standing portal hypertension may cause congestive +splenomegaly. +and nurseries. +Water-borne epidemics can occur in places +with overcrowded, unsanitary conditions. +Sexual transmission may occur, +but maternal-fetal transmission does not. +Ultrastructurally, HAV is an icosahedral capside +that is 27 nm in diameter. +Clinical Features +The incubation period for HAV is 2 to 6 weeks. +IgM antibody +against HAV appears with the onset of symptoms and +persists for 3 to 6 months (Fig. +18.8). +HAV is shed in the stool for 2 to 3 weeks +before and 1 week after the onset of jaundice. +HAV vaccine is effective in preventing infection. +18.9). +In high-prevalence +regions, transmission during childbirth accounts for 90% +of cases. +• HBV polymerase (Pol), which exhibits both DNA poly- +merase and reverse transcriptase activities. +It has been implicated in the pathogenesis of HBV-related +hepatocellular carcinoma. +HBV replication occurs through reverse transcription via +an RNA intermediate. +The host immune response to the virus is the main +determinant of the outcome of the infection. +Clinical Features +HBV has a prolonged incubation period (4 to 26 weeks). +18.10. +By contrast, +HBsAg persists in cases that progress to chronicity. +18.10A). +18.10B). +In such patients, the HBeAg may be low or undetectable +despite the presence of serum HBV DNA. +In most cases, the infection is self-limited and resolves +without treatment. +The infection persists and becomes +chronic in 5% to 10% of infected individuals. +(A) Acute infection with resolution. +(B) Progression to chronic infection. +Transfusion-related transmission has largely +disappeared in the United States. +Perinatal transmission can +occur in children. +Pathogenesis +HCV, discovered in 1989, is a member of the Flaviviridae +family. +The role of these proteins in the life cycle of HCV is sum- +marized in Fig. +18.11. +Anti-HCV antibodies +emerge 3 to 6 weeks after infection. +18.12). +reason), persistent infection and chronic hepatitis are the usual +outcome. +(A) Acute infection with resolution. +(B) Progression to chronic +infection. +Those who develop cirrhosis +are at risk for development of hepatocellular carcinoma. +18.11). +HCV appears to be cured +in >99% of patients who achieve a sustained viral response. +HDV is uncommon in Southeast Asia +and China. +Pathogenesis +HDV, discovered in 1977, is a 35-nm, double-shelled particle. +Replication of the virus is through RNA- +directed RNA synthesis by host RNA polymerase. +• Co-infection occurs following exposure to serum containing +both HDV and HBV. +Co-infection can result in acute +hepatitis that is indistinguishable from acute hepatitis +B. +It is self -limited and is usually followed by clearance +of both viruses. +However, there is a higher rate of acute +hepatic failure in intravenous drug users. +• Superinfection occurs when a chronic carrier of HBV +is exposed to a new inoculum of HDV. +Co-infection with HDV and HBV increases the risk of +progression to cirrhosis and HCC. +Newer agents targeting viral +entry and replication are in clinical trials. +Vaccination for +HBV also prevents HDV infection. +IgM is replaced with persistent IgG +anti-HEV antibodies during recovery. +Chronic liver disease or persistent viremia in immuno- +competent patients is not observed. +Table 18.3 provides a summary of the salient features of +infection by various hepatitis viruses. +Acute infections by +all of the hepatotropic viruses can either be asymptomatic +or symptomatic. +From Washington K: Inflammatory and infectious diseases of the liver. +In contrast, HCV is notorious for progressing to +chronic infection. +HEV can cause acute liver failure in pregnant +women. +• Acute asymptomatic infection with recovery. +• Acute symptomatic infection with recovery. +The incubation period +for the different viruses is given in Table 18.3. +• Acute liver failure. +Viral hepatitis accounts for approxi- +mately 10% of cases of acute hepatic failure. +• Chronic hepatitis. +• Carrier state. +A “carrier” is an individual who harbors +and can transmit an organism, but has no symptoms. +In both cases, particularly +the latter, affected individuals constitute reservoirs of +infection. +18.11). +For HCV, a state equivalent to the HBV +“healthy carrier” is not recognized. +HIV is an important comorbid factor in hepatotropic +viral infections. +MORPHOLOGY +The general morphologic features of viral hepatitis are depicted +schematically in Fig. +18.4). +18.2 and 18.3), often +with pigmented macrophages scavenging the dead cell debris. +Liver failure can develop with +massive hepatic necrosis. +This may be accompanied by a variable degree of lobular +inflammation. +Fibrous septa +develop and lead to portoportal bridging fibrosis, and eventually +cirrhosis. +Immunostaining for hepatitis B surface and core antigens can +confirm the HBV infection (Fig. +18.14). +18.15). +Steatosis is common in +chronic hepatitis C, and can be marked with genotype 3 infection. +Bridging necrosis can occur in severe acute hepatitis, and +fibrosis is seen in chronic hepatitis. +Ductular reaction is often present in areas of fibrosis in chronic hepatitis. +Hydatid cysts are +usually caused by echinococcal infections (Chapter 8). +Hydatid cysts are uncom- +mon in high income countries. +There +is a female predominance (78%). +A +B +Figure 18.15 Chronic viral hepatitis due to hepatitis C virus. +(A) +Characteristic portal tract expansion by a lymphoid aggregate. +(B) Delicate +bridging fibrosis, seen later in the disease course. +When severe, +this may extend to the liver and produce intrahepatic +abscesses. +Liver abscesses are associated +with fever, right upper quadrant pain, and tender hepato- +megaly. +Jaundice may result from extrahepatic biliary +obstruction. +Numerous +plasma cells in clusters are typical (Fig. +18.16). +Compatible: Chronic hepatitis with lymphocytic infiltration without features +considered typical. +Atypical: Showing signs of another diagnosis like nonalcoholic fatty liver disease. +Figure 18.16 Autoimmune hepatitis. +A focus of lobular hepatitis with +prominent plasma cells typical for this disease is shown. +often at the interface, a curious phenomenon called emperipolesis. +Serum IgG is often elevated +in autoimmune hepatitis and may provide another clue to +the diagnosis. +Other immunosuppressants are used if the +side effects of steroids cannot be tolerated. +Liver transplantation may be +necessary for cirrhotic patients. +Based on U.S. +Pathogenesis +Principles of drug and toxic injury are discussed in Chapter +9. +In most instances, the injury is mediated by reactive +metabolites generated in the liver. +Drug-induced liver injury can be idiosyncratic (unpredict- +able) or dose-dependent (predictable). +It is +thought that there is genetic susceptibility in those who +have idiosyncratic reactions. +Modified from Washington K: Metabolic and toxic conditions of the liver. +While suicide attempts with acet- +aminophen are common, so are accidental overdoses. +• Correlation of temporal profile of drug intake and onset of +disease is necessary for diagnosis. +MORPHOLOGY +Drugs can lead to one or more patterns of injury. +Progression to +chronic hepatitis, and even cirrhosis, can be seen in a small minority +of cases. +Injury caused by intrinsic hepatotoxins is dominated by +necrosis with minimal inflammation. +Some agents produce other patterns of injury. +Pathogenesis +The pharmacokinetics and metabolism of alcohol are +described in Chapter 9. +However, +only 10% to 15% of alcoholics develop cirrhosis. +Thus, other +factors also influence the development and severity of +alcoholic liver disease. +These include: +• Gender. +• Ethnic and genetic differences. +Comorbid conditions. +Several factors appear to contribute to steatosis. +• CYP2E1 induction. +• Methoinine metabolism. +18.17). +Hepatic steatosis (fatty liver) +is an early, predictable effect of alcohol consumption. +After even +moderate intake of alcohol, lipid droplets accumulate in hepatocytes. +18.18). +Steatosis may be separated into microvesicular and macrovesicular +forms. +18.19). +18.19B). +Mallory hyaline may reflect a failed attempt to +sequester and degrade damaged cytoplasmic proteins. +• Inflammation and necrosis. +• Perivenular/pericellular fibrosis. +Steatohepatitis is often accompanied +by fibrosis. +18.18). +18.20). +Complete regression of alcoholic cirrhosis, although reported, +is rare. +Severe hepatic dysfunction is unusual. +Alcohol withdrawal +and consumption of an adequate diet are sufficient treat- +ment. +Some fibrosis (stained blue) +is present in a characteristic perisinusoidal chicken wire pattern. +(Masson +trichrome stain). +(Courtesy Dr. +Elizabeth Brunt, Washington University, St. +Mallory hyaline is present in another +hepatocyte (arrow). +(B) Alcoholic hepatitis with many ballooned hepatocytes (arrowheads). +Elizabeth Brunt, Washington +University, St. +Louis, Mo.) +than serum ALT levels by a ratio of 2 : 1 or greater. +This +finding can be particularly helpful in the setting of occult +alcoholism. +The outlook is unpredictable; each episode of hepatitis +incurs about a 10% to 20% risk of death. +With repeated +bouts, cirrhosis develops in about one-third of patients within +a few years. +Alcoholic hepatitis also may be superimposed +on established cirrhosis. +With proper nutrition and total +cessation of alcohol consumption, alcoholic hepatitis may +clear. +The manifestations of alcoholic cirrhosis are similar to +those of other forms of cirrhosis. +The long-term outlook for alcoholics with liver disease +is variable. +A +B +Figure 18.20 Alcoholic cirrhosis. +The greenish tint is caused by +cholestasis. +increases in mass but also becomes dysfunctional. +The dysfunctional +adipocytes also synthesize pro-inflammatory cytokines +such as TNF- α. +The net effect of these changes is to cause lipid to accu- +mulate in hepatocytes. +Pathogenesis +The precise mechanisms underlying NAFLD are unknown. +18.21). +Determination of the extent of fibrosis is important for clinical +management. +Pediatric NAFLD differs significantly from adult NAFLD. +Clinical Features +The varied clinical course of individuals with NAFLD is +summarized in Fig. +18.22. +Individuals with only steatosis +are generally asymptomatic. +Imaging studies may reveal fat accumulation in the +liver. +Liver biopsy is required for diagnosis of NASH and +aids in assessment of fibrosis. +Serum AST and ALT are elevated in most +patients with NASH. +Despite the enzyme elevations, patients +may be asymptomatic. +(A) Liver with mixed small +and large fat droplets as well as ballooned hepatocytes. +Note the resemblance to alcoholic hepatitis depicted in Fig. +18.18. +None to very minimal +progression to cirrhosis +2. +abnormalities in NASH. +Its histologic features +differ somewhat from those seen in adults. +The disease +typically manifests after 20 g of stored iron has accumulated. +18.23). +Due to these activities, an +increase in hepcidin lowers plasma iron levels. +Conversely, +an abnormal deficiency of hepcidin causes iron overload. +Other proteins involved in iron metabolism do so by regulat- +ing hepcidin levels. +The classification of the +various causes of iron overload is shown in Table 18.7. +Table 18.7 Classification of Iron Overload +I. +Hemochromatosis +TFR2 +TFR1 Iron +Enterocyte +Figure 18.24 Hereditary hemochromatosis. +In this Prussian blue–stained +section, hepatocellular iron appears blue. +The parenchymal architecture is +normal. +18.24). +Iron is a direct hepatotoxin, and inflammation +is characteristically absent. +The heart is often +enlarged and exhibits hemosiderosis, producing a striking brown +coloration. +Both organs may develop fibrosis. +The combination of these +pigments imparts a characteristic slate-gray color to the skin. +With hemosiderin deposition in joint linings, an acute synovitis +may develop. +This in turn +reduces efflux of iron from enterocytes. +Through these regulatory +interactions, normal iron absorption is maintained. +hepcidin synthesis. +Death may result +from cirrhosis or cardiac disease. +Fortunately, hemochromatosis is often diagnosed +before irreversible tissue damage has occurred. +Further evaluation +includes exclusion of secondary causes of iron overload. +With treatment, life expectancy is normal. +Ceruloplasmin accounts for 90% to 95% of plasma +copper. +Eventually cirrhosis supervenes. +Histochemical copper staining is not sensitive or specific for +diagnosis of Wilson disease. +Its clinical presentation +is extremely variable. +Some patients present with acute or +chronic liver disease. +Patients may also +have psychiatric symptoms. +Demon- +stration of Kayser-Fleischer rings by slit examination also +is diagnostically helpful. +lead to apoptosis (Chapter 2). +α1 AT is a small 394–amino acid plasma glycoprotein +synthesized predominantly by hepatocytes. +It is a member +of the serine protease inhibitor (serpin) family. +The most common genotype is PiMM, occurring in +90% of individuals (the “wild type”). +These individuals +are at high risk for developing clinical disease. +Among people of northern European descent, the +PiZZ state affects 1 in 1800 live births. +18.26). +(2) Extrahepatic bilirubin +is bound to serum albumin and delivered to the liver. +(5) Gut bacteria deconjugate the bilirubin +and degrade it to colorless urobilinogens. +The urobilinogens and the residue +of intact pigment are largely excreted in feces. +Jaundice becomes evident when the serum bili- +rubin levels rise above 2 to 2.5 mg/dL. +This form +is largely insoluble and cannot be excreted in the urine. +With this as an overview, we next discuss hepatobiliary +disorders that lead to hyperbilirubinemia. +Hence, transient and mild unconjugated +hyperbilirubinemia is nearly universal in the first week. +18.27). +Rupture of canaliculi can lead to extravasation of bile, which is +phagocytosed by Kupffer cells. +Cholangitis +usually presents with fever, chills, abdominal pain, and +jaundice. +Severe cases can result in abscess formation, sepsis, +and death. +18.28). +In ascending +cholangitis, the neutrophils also involve the bile duct epithelium +and lumens (Fig. +18.29). +Persistent obstruction leads to fibrosis, +which can eventually proceed to biliary cirrhosis (Fig. +18.30). +B +C +Figure 18.27 Cholestasis. +(A) Morphologic features of cholestasis (right) +and comparison with normal liver (left). +Cholestatic hepatocytes (1) are +enlarged with dilated canalicular spaces (2). +(B) Intracellular cholestasis showing the bile pigments in the cytoplasm. +(C) Bile plug (arrow) showing the expansion of bile canaliculus by bile. +to conjugated hyperbilirubinemia. +Both are autosomal +recessive disorders and clinically innocuous. +Figure 18.28 Acute large duct obstruction. +Neutrophils are seen within the bile duct epithelial lining and within the +lumen. +Figure 18.31 Ductular cholestasis of sepsis. +(Courtesy Dr. +18.31). +Inflammation and +hepatocellular injury is typically mild. +The disease is highly prevalent in East Asia, but is rare in +other parts of the world. +18.32).The ducts show chronic inflam- +mation, mural fibrosis, and peribiliary gland hyperplasia. +Obstruction +of extrahepatic ducts is not present. +B +Figure 18.30 Biliary cirrhosis. +Other +etiologies of obstructive biliary diseases like cystic fibrosis +also must be excluded. +Liver transplantation is the only option when surgical +intervention is not feasible. +Figure 18.32 Hepatolithiasis. +(Courtesy Dr. +Wilson M.S. +Infections, toxic agents, and +autoimmune injury have been invoked, but the cause is +unknown. +If left uncorrected, cirrhosis can develop by +3 to 6 months of age. +18.33). +Reactive Kupffer cells and extramedullary hematopoiesis +are usually present. +The features of these two conditions are +contrasted in Table 18.10. +Large intrahepatic ducts and the extrahepatic +biliary tree are not involved. +Family members +of PBC patients have an increased risk for development of +the disease. +Other autoantibodies against nuclear pore proteins +and centromeric proteins may also be present. +18.34). +Disease progression leads to +loss of small intrahepatic bile ducts (“ductopenia”). +PSC tends to occur in the +third through fifth decades and has a 2 : 1 male predominance. +Figure 18.34 Primary biliary cholangitis. +accumulation in PBC is not centrizonal, but is seen in periportal/ +periseptal regions. +End-stage disease +culminates in cirrhosis. +Hypercholesterolemia is +common. +Splenomegaly and jaundice are seen in advanced +disease. +For uncertain reasons, many +patients also have elevated serum levels of IgM antibody. +Lithiasis can develop +in the dilated ducts. +18.35), eventually +leading to obliteration by a “tombstone” scar. +Progression of cholestasis and fibrosis culminates in biliary cirrhosis. +The endoscope is visible, giving a +sense of scale. +(Courtesy Dr. +M. +Edwyn Harrison, MD, Mayo Clinic, +Scottsdale, Ariz.) +Figure 18.35 Primary sclerosing cholangitis. +A degenerating bile duct is +entrapped in a dense, “onion-skin” concentric scar. +Clinical Features +The most common presenting symptoms are fatigue, pruritus, +and jaundice. +Ascending cholangitis can also be the initial presentation. +Fibrosis and eventually cirrhosis can occur. +18.36). +This is referred to as small-duct PSC and can progress to +typical large-duct PSC. +In 5% to 10% of cases, autoimmune hepa- +titis is present along with PSC. +The disease typically follows a protracted course leading +to cirrhosis over 10 to 15 years. +The lifetime risk of developing +cholangiocarcinoma is 20%. +Liver transplantation is +the treatment of choice for end-stage liver disease. +Ascending cholangitis may develop. +Chronic obstruction can +lead to cirrhosis. +It predisposes to cholangiocarcinoma. +The diagnosis is established by +visualization of the biliary tree. +Patients are at risk for +developing cholangiocarcinoma. +Hepatic etiologies860 CHAPTER 18 Liver and Gallbladder +that are typical of biliary colic. +Approximately 20% of cases +become symptomatic only in adulthood. +The female-to-male ratio is 3 : 1 to 4 : 1. +There +also is an increased risk of developing bile duct carcinoma. +Lesions may be found +incidentally during radiographic studies, surgery, or autopsy. +Persons with fibropolycystic liver disease are at increased +risk for cholangiocarcinoma. +18.37). +Occasional von Meyenburg complexes are +common in otherwise normal individuals. +• Single or multiple intrahepatic or extrahepatic biliary cysts. +When present in isolation, these may be symptomatic +due to ascending cholangitis. +Multifocal cystic dilation +of the large intrahepatic bile ducts is referred to as Caroli +disease. +18.38). +Ducts may be cystically +dilated, but true cysts are also present. +These may be +intrahepatic cysts or choledochal cysts, as described +earlier. +18.39). +Figure 18.38 Congenital hepatic fibrosis with multiple biliary cysts. +Figure 18.37 Von Meyenburg complex (bile duct hamartoma). +Dilated +irregular bile ducts with curvilinear outlines thought to represent ductal +plate formation. +Figure 18.39 Congenital hepatic fibrosis. +Broad bands of fibrosis with +dilated remnants of ductal plates. +18.40). +18.41). +Underlying causes may include neoplasia, +polyarteritis nodosa (Chapter 11), or sepsis. +Figure 18.41 Liver infarct. +Many such patients have an +underlying thrombophilic genotype (e.g., Factor V Leiden, +Chapter 4). +It is +particularly common in India, although the incidence +appears to be declining. +Patients often present with upper +gastrointestinal bleeding. +The pathogenesis is unknown. +Lesions usually disappear after +correction of the underlying cause. +Obstruction of a single main hepatic +vein by thrombosis is clinically silent. +Hepatic damage is +the consequence of increased intrahepatic blood pressure. +18.43). +Pericentral/sinusoidal fibrosis develops in instances in +which thrombosis develops more slowly. +The major veins contain +thrombi showing various degrees of organization. +Clinical Features +The mortality of untreated acute hepatic vein thrombosis +is high. +Prompt surgery to create a portosystemic venous +Figure 18.42 Sickle cell crisis in liver. +The photomicrograph shows +several sinusoids containing “sickled” red cells (arrow). +Figure 18.43 Budd-Chiari syndrome. +The chronic form is far less +lethal, and more than two-thirds of patients are alive after +5 years. +The mortality rate is up to 80% in severe +disease. +Microscopically, there is congestion of dilated +centrilobular sinusoids. +18.45A). +This finding is known as nutmeg liver due to its resemblance +to the cut surface of a nutmeg. +18.44). +• The most common cause of impaired intrahepatic blood flow +is cirrhosis. +Figure 18.44 Sinusoidal obstruction syndrome. +In a +very small subgroup of pregnant women (0.1%), more serious +hepatic complications develop. +In extreme cases, +eclampsia and acute fatty liver of pregnancy may be fatal. +Here we focus on +the hepatic pathology of these entities. +AB hepatic rupture in eclampsia (Fig. +18.46). +Portal tracts and the periportal parenchyma are intact. +Mild cases may be managed +conservatively. +Termination of pregnancy is required in +severe cases. +Women who survive mild or severe preeclamp- +sia recover without sequelae. +Viral hepatitis (HAV, HBV, HCV, or HBV + HDV) +is the most common cause of jaundice in pregnancy. +The liver may also be secondarily +involved by other infections during pregnancy. +Figure 18.46 Eclampsia. +Subcapsular hematoma dissecting under Glisson +capsule in a fatal case. +(Courtesy Dr. +It is a +rare disease affecting approximately 1 in 16,000 pregnant +women. +Thus, this +may be a rare instance of the fetus causing metabolic disease +in the mother. +Cholestasis may also be present. +18.47A). +Most +lesions are 5 cm or less in diameter. +18.47B). +A prominent ductular +reaction is often present, but interlobular bile ducts are absent. +The primary +treatment is termination of pregnancy. +Affected women +present in the latter half of pregnancy, usually in the third +trimester. +In 20% to 40% of cases, the presenting +symptoms may be those of coexistent preeclampsia. +The level of bile salts is increased +greatly. +There +is a modest risk of fetal loss, and the condition may recur in +subsequent pregnancies. +FNH is a benign lesion and does +not need any treatment. +Resection is performed for large +symptomatic lesions. +Histologically, the tumor consists of dilated thin-walled +vascular channels (Fig. +18.48). +Most are asymptomatic and +are detected incidentally by imaging. +• Hepatocyte nuclear factor 1-alpha (HNF1 α)-inactivated +hepatocellular adenoma. +This subtype accounts for 40% to 50% of cases, +A +B +Figure 18.47 Focal nodular hyperplasia. +(A) Resected specimen showing +lobulated contours and a central stellate scar. +syndrome, hemangioma, and vascular malformations. +NRH can lead to portal +hypertension and mimic cirrhosis on imaging. +Both are asymptomatic and generally less than 2 cm. +The latter are thought to be a remnant +of ductal plate malformation. +Figure 18.48 Cavernous hemangioma. +Nearly 40% occur +in men. +18.50B). +18.50C). +Primary Malignant Neoplasms +Malignant tumors in the liver can be primary or metastatic. +Hepatoblastoma is a rare hepatocellular tumor that +occurs in the pediatric setting. +Nonepithelial tumors, such +as angiosarcoma, are exceedingly rare. +Hepatoblastoma +Hepatoblastoma is the most common liver tumor of early +childhood. +It rarely occurs over the age of 3 years, and its +incidence is increasing. +18.49). +18.50A). +A +B +Figure 18.49 Hepatocellular adenoma. +(A) Resected specimen showing a +well-define tan mass in the liver. +(A) HNF1α-inactivated hepatocellular adenoma. +(B) Hepatocellular adenoma with β-catenin +activation. +(C) Inflammatory hepatocellular adenoma. +The tumor is treated with surgical resection and chemo- +therapy, which has improved outcomes. +The overall 5-year +survival rate is approximately 80%. +18.52). +The tumor cells are arranged in sheets +and resemble embryonal and fetal hepatocytes. +MORPHOLOGY +A +Several precursor lesions for HCC have been described. +18.53). +18.53A). +18.53B). +More ominous are nodular lesions +B +Figure 18.52 Hepatocellular carcinoma. +(A) Liver removed at autopsy +showing a unifocal neoplasm replacing most of the right hepatic lobe. +A +such as hereditary hemochromatosis and α1-antitrypsin +deficiency, and alcoholic liver disease. +Nonalcoholic fatty +liver disease also increases the risk of HCC, even in the +absence of cirrhosis. +(A) Large cell change. +(B) Small cell change. +The abnormal cells have a high nuclear-to-cytoplasmic ratio and are +separated by thickened plates. +Normal-appearing hepatocytes are in the +lower-right corner. +(Courtesy Dr. +18.54), +which are often associated with small cell change. +18.54B). +HCC may form a single mass or multiple discrete masses, or +it may diffusely infiltrate the liver. +They may be pale and yellow +due to fatty change or green due to cholestasis. +A +B +Figure 18.55 Fibrolamellar carcinoma. +(A) Resected specimen showing a +well-demarcated nodule. +18.55). +Features of underlying chronic liver disease +can be present. +Ultrasonography is used for +screening high-risk patients such as those with cirrhosis. +Nodule-in-nodule growth suggests an evolving cancer. +(Courtesy Dr. +Masamichi Kojiro, Kurume University, Kurume, Japan.)The liver and bile ducts 871 +adequate function. +Liver transplantation is considered for +HCC in the setting of advanced cirrhosis. +Hematogenous metastases, +especially to the lung, tend to occur late in the disease. +Lymph node metastases occur in <5% of cases. +Intrahepatic cholangiocarcinoma +is the most common primary malignant tumor of the liver +after HCC. +Its incidence is rising in the United States. +It +accounts for 7.6% of cancer deaths worldwide and 3% of +cancer deaths in the United States. +KRAS mutations are common in both tumors. +Fusion genes involving +FGFR2 (fibroblast growth factor receptor 2) are also common. +A +B +C +Figure 18.56 Cholangiocarcinoma. +(B) Invasive malignant glands in a reactive, sclerotic stroma. +(A, Courtesy Dr. +Wilson M.S. +18.56) and typically forms a firm gray-white mass. +The liver weight can exceed several +kilograms. +Metastasis may also appear as a single nodule, +in which case it may be resected surgically. +Microscopically, both intrahepatic and extrahepatic tumors +show features of adenocarcinomas. +18.56B). +Lymphovascular and +perineural invasion (see Fig. +Tumor resection with negative margins and +absence of lymph node involvement are favorable factors. +Lymph node metastasis is present in 50% to 60% of patients +at presentation. +Adjuvant chemotherapy is commonly given +after resection, but tumor responses are usually transient. +Other Primary Hepatic Malignant Tumors +A number of other cancers may arise within the liver. +These tumors have the same risk factors +as HCC. +This tumor has become rare with reduced exposures to +these agents. +These tumors have a poor +prognosis. +Gallbladder +As much as 1 L of bile is secreted by the liver per day. +Between meals, bile is stored in the gallbladder, where it +is concentrated. +The adult gallbladder has a capacity of +about 50 mL. +A longitudinal or transverse septum may create +a bilobed gallbladder. +A +folded fundus is the most common anomaly, creating a +phrygian cap (Fig. +18.57). +• Acquired disorders. +• Hereditary factors. +sinensis increases the +Figure 18.57 Phrygian cap of the gallbladder; the fundus is folded inward. +CHOLELITHIASIS (GALLSTONES) +More than 95% of biliary tract disease is attributable to +gallstones. +Gallstones afflict 10% to 20% of adult populations +in high income countries. +Significant associations are +also seen with metabolic syndrome and obesity. +• Environmental factors. +The wall of the gallbladder is +thickened and fibrotic due to chronic cholecystitis. +Figure 18.59 Cholesterolosis. +Gallbladder mucosa demonstrates lamina +propria distended by foamy macrophages. +likelihood of pigment stone formation. +In hemolytic anemias, +the secretion of conjugated bilirubin into bile increases. +salts, while brown stones, which contain calcium soaps, are +radiolucent. +Mucin glycoproteins constitute the scaffolding and +interparticle cement of all types of stones. +Multiple stones are usually present that range up +to several centimeters in diameter. +Rarely, a very large stone may +virtually fill the fundus. +Surfaces of stones may be rounded or +faceted because of tight apposition to adjacent stones. +18.59). +Pigment gallstones are brown to black. +18.60), and are quite friable. +Their contours are +usually spiculated and molded. +Brown stones tend to be laminated +and soft and may have a soaplike or greasy consistency. +Gallstones also are associated with an increased risk of +gallbladder carcinoma (discussed later). +It almost always occurs in +association with gallstones. +In the United States, cholecystitis +is one of the most common indications for abdominal surgery. +Its epidemiology closely parallels that of gallstones. +The action of mucosal phospholipases hydrolyzes luminal +lecithins to toxic lysolecithins. +Acute acalculous cholecystitis is thought to result +from ischemia. +The cystic artery is an end artery without +a collateral circulation. +It usually occurs in acutely ill patients who are +hospitalized for unrelated conditions. +When the +exudate is virtually pure pus, the condition is referred to as +gallbladder empyema. +In mild cases, the gallbladder wall is +thickened, edematous, and hyperemic. +Neutrophils are typically sparse, unless there +is superimposed infection. +It is frequently associated with mild fever, +anorexia, tachycardia, sweating, nausea, and vomiting. +Mild +to moderate leukocytosis may be accompanied by modestly +elevated serum alkaline phosphatase. +Recurrence is common in patients who recover +without surgery. +In rare instances, primary bacterial infection +by agents such as S. +typhi and staphylococci can give rise +to acute acalculous cholecystitis. +Microorganisms, usually E. +coli and enterococci, are cultured +from the bile in about one-third of cases. +Unlike acute +calculous cholecystitis, obstruction of gallbladder outflow +is not a prerequisite. +The serosa is usually smooth +and glistening but may be dulled by subserosal fibrosis. +Dense +fibrous adhesions may be present that represent the sequelae of +prior acute inflammation. +On sectioning, the wall is variably +thickened and has an opaque gray-white appearance. +In uncom- +plicated cases, the lumen contains green-yellow, mucoid bile and +usually stones. +The mucosa itself is generally preserved. +On histologic examination, the degree of inflammation is +variable. +18.61A). +18.61B). +B +Figure 18.61 Chronic cholecystitis. +(A) The gallbladder mucosa is +infiltrated by inflammatory cells. +(B) Outpouching of the mucosa through +the wall forms Rokitansky-Aschoff sinus (contains bile). +recurrent attacks of either steady epigastric or right upper +quadrant pain. +Nausea, vomiting, and intolerance for fatty +foods are frequent accompaniments. +Approximately +6000 new cases of gallbladder cancer are diagnosed each +year in the United States. +As is typical of +TP53-mutated cancers, most gallbladder carcinomas exhibit +aneuploidy. +A +B +Figure 18.62 Gallbladder adenocarcinoma. +(A) The opened gallbladder +contains a large, exophytic tumor that virtually fills the lumen. +(B) +Malignant glands are seen infiltrating a densely fibrotic gallbladder wall. +Gallbladder cancers are mainly adenocarcinomas and are most +often detected in the fundus (Fig. +18.62). +and nausea and vomiting. +• Gallstones are common in Western countries. +The great majority +are cholesterol stones. +Pigmented stones containing bilirubin +and calcium are most common in Asian countries. +Gallstones are also a risk factor for gallbladder +cancer. +PubMed PMID: 18318440. +Lefkowitch JH: The pathology of acute liver failure, Adv Anat Pathol +23(3):144–158, 2016. +doi:10.1097/PAP.0000000000000112. +PubMed +PMID: 27058243. +Review, [An excellent review of the pathology of acute +liver failure]. +Expert Rev Gastroenterol +Hepatol 12(6):565–573, 2018. +[An excellent perspective on why +and how hepatitis C can be cured]. +[Review +of diagnosis, screening and treatment guidelines for hepatitis C]. +Joyce MA, Tyrrell DL: The cell biology of hepatitis C virus, Microbes +Infect 12:263, 2010. +[What we understand and do not understand about +hepatitis C virus and the cells it infects]. +[Review of +hepatitis B virus infection]. +doi:10.1016/j.humpath. +2019.10.003. +pii: S0046-8177(19)30179-0. +[Epub ahead of print], [Review +of hepatitis E virus infection]. +[Review of pathogenesis of AIH]. +[A still relevant set of criteria for +diagnosing autoimmune hepatitis]. +[Review of diagnosis +and treatment guidelines for PBC]. +[Review +of all aspects of PSC]. +[A comprehensive and +current review]. +[Recent review of the pathology of alcoholic liver +disease]. +[As authoritative as one can be on the topic]. +• Acute calculous cholecystitis is the most common reason for +emergency cholecystectomy. +• Gallbladder cancers are associated with gallstones in the vast +majority of cases. +Typically, they are detected late because of +nonspecific symptoms and hence carry a poor prognosis. +Koyama Y, Brenner DA: Liver inflammation and fibrosis, J Clin Invest +127(1):55–64, 2017. +doi:10.1172/JCI88881. +[Epub 2017 Jan 3]. +PubMed +PMID: 28045404. +Quaglia A, Alves VA, Balabaud C et al: International Liver Pathology +Study Group. +doi:10.1111/ +his.12957. +[Epub 2016 Apr 28]. +PubMed PMID: 26918878. +PubMed PMID: 10573521. +[The meticulous histopathologic identification +of a stem cell niche in liver]. +Wanless IR, Nakashima E, Sherman M: Regression of human cirrhosis. +Pathology history happening before your eyes]. +[An excellent clinical review]. +[About the +most common cause of acute liver failure leading to transplantation]. +Khungar V, Poordad F: Hepatic encephalopathy, Clin Liver Dis 16:301, +2012. +[A good overview of the one of the most ominous sequelae of all forms +of liver failure]. +[A classic paper in liver pathology]. +[A thorough overview of the most common features of liver +disease]. +[How bench-top work comes to exert +an impact on clinical medicine, sometimes slowly over decades]. +[Provides a review of the spectrum of histologic changes and a unifying +nomenclature]. +Adv Anat Pathol 25(4):254–262, 2018. +[Review of epidemiology ad trends in hepatocel- +lular carcinoma and cholangiocarcinoma]. +[Review of epidemiology, pathogenesis, and management of +cholangiocarcinoma]. +[Review of guidelines for diagnosis and management of HCC]. +19.1A). +The exocrine pancreas constitutes 80% to 85% of the +organ and is composed of acinar cells. +Islet cells secrete insulin, +glucagon, somatostatin, and pancreatic polypeptide. +Diseases of the endocrine +pancreas are described in detail in Chapter 24. +The pancreas normally arises from the fusion of dorsal and +ventral outpouchings of the foregut. +Pancreas Divisum. +19.1A). +Annular Pancreas. +Annular pancreas can +produce duodenal obstruction. +Ectopic Pancreas. +The favored sites for ectopia are +aI am grateful for the immense contributions of Ralph H. +Hruban +and Christine A. +Iacobuzio-Donahue, who authored this chapter +in the prior edition of this book. +Many of the photomicrographs +used in this chapter are contributed by Dr. +Hruban. +A. +Acute attacks may range +from mild and self-limited to life-threatening events. +Recur- +rent or persistent pancreatitis may lead to permanent loss +of pancreatic function. +Biliary tract disease +and alcoholism account for approximately 80% of these cases +(Table 19.1). +PANCREAS +DIVISUM +Minor +sphincter +Papilla +of Vater +Figure 19.1 Pancreatic ductal anatomy. +(A) Normal ductal anatomy. +(B) Ductal anatomy in pancreatic divisum. +Agenesis. +Very rarely the pancreas fails to develop (agen- +esis). +Under +normal circumstances, several factors protect the pancreas +from autodigestion. +Acinar +cells can be damaged by a variety of endogenous, exog- +enous, and iatrogenic insults. +Increased calcium flux is another important trigger +for inappropriate enzyme activation. +Calcium has a key +role in trypsin regulation. +Examples +include inherited abnormalities that affect calcium levels +(Table 19.2). +It is not clear if this mecha- +nism is relevant to human acute pancreatitis. +Thus, key aspects of the pathophysiology of alcohol- +induced pancreatitis remain obscure. +• Genetic lesions, as described below. +• Medications. +• Ischemic acinar cell injury due to shock, vascular thrombosis, +embolism, or vasculitis. +Three genes implicated in hereditary pancreatitis deserve +special note: PRSS1, SPINK1, and CFTR. +The extent of each of these depends on the duration and severity +of disease. +19.3). +In acute necrotizing pancreatitis, acini, ducts, and even +islets undergo necrosis. +19.4). +Glycosuria occurs in 10% of cases, and hypocalcemia may +result from saponification of necrotic fat. +Acute +respiratory distress syndrome and acute renal failure are +ominous complications. +Possible sequelae include sterile +pancreatic abscesses and pancreatic pseudocysts. +Systemic organ failure and pancreatic necrosis are +both adverse prognostic indicators. +Clinical Features +Abdominal pain is the cardinal manifestation of acute +pancreatitis. +The severity ranges from mild discomfort +to incapacitating pain. +Anorexia, nausea, and vomiting are +common. +Severe acute pancreatitis is a medical emergency. +19.5). +The most common cause of chronic +pancreatitis is long-term alcohol use. +19.6A). +In this case, an IgG4 stain confirmed abundant IgG4-expressing plasma cells. +(C, Photomicrograph courtesy Aatur D. +Visualization of calcifications within the +pancreas by CT and ultrasonography can be very helpful. +In other patients, severe, chronic pain is a dominant +problem. +Pancreatic pseudocysts (described later) develop in +about 10% of patients. +be atrophic, hyperplastic, or metaplastic (squamous). +19.6B). +19.6C).The last-mentioned may +also be seen in other organs. +Diagnosis of chronic pancreatitis requires a high degree +of suspicion. +During an attack there may be mild fever and +mild-to-moderate elevations of serum amylase. +NONNEOPLASTIC CYSTS +A variety of cysts can arise in the pancreas. +Most are non- +neoplastic pseudocysts, but congenital cysts and neoplastic +cysts also occur. +Cysts +in the kidney, liver, and pancreas frequently coexist in +polycystic kidney disease. +Traumatic +injury to the pancreas can also give rise to pseudocysts. +A +B +Figure 19.7 Pancreatic pseudocyst. +(A) Cross-section revealing a poorly +defined cyst with a necrotic brown-black wall. +(B) The cyst lacks a true +epithelial lining and instead is lined by fibrin and granulation tissue. +malignancies. +Endocrine tumors also occur in the pancreas +and are discussed in Chapter 24. +Serous cystic neoplasms usually occur in the tail of the +pancreas. +19.8). +Surgical resection is curative in the vast majority of +patients. +19.7A). +Pseudocysts are lined by fibrous tissue and granulation +tissue (Fig. +19.7B) and range in size from 2 to 30 cm in diameter. +NEOPLASMS +A broad spectrum of exocrine neoplasms arises in the +pancreas. +(A) Cross- +section through a microcystic serous cystic neoplasm. +Only a thin rim of +normal pancreatic parenchyma remains. +The cysts are relatively small and +contain clear, straw-colored fluid. +(B) The cysts are lined by cuboidal +epithelium without atypia. +B +Figure 19.9 Pancreatic mucinous cystic neoplasm with low-grade +dysplasia. +(A) Cross-section through a mucinous multiloculated cyst in +the tail of the pancreas. +The cysts are large and filled with tenacious +mucin. +(B) The cysts are lined by columnar mucinous epithelium with a +dense “ovarian” stroma. +on chromosome 3p is the most common genetic abnormality +in serous cystic neoplasms. +19.9). +Similar RNF43 +mutations also occur in colorectal cancers. +Up to 20% are multifocal. +19.10). +TP53 and SMAD4 +mutations typically occur only with transition to invasive +cancer. +The 5-year +survival rate is a dismal 10%. +19.11). +PanIN is often found in pancreatic parenchyma adjacent +to infiltrating carcinoma. +Gs α, are present in approximately two-thirds of IPMNs but +are not found in other pancreatic cysts. +Surgical resection is the treatment of choice and proves +curative in most patients. +KEY CONCEPTS +CYSTIC NEOPLASMS +• Virtually all serous cystic neoplasms are benign. +• Each of the major cystic neoplasms has a relatively specific +mutational profile. +19.12). +• SMAD4 (chromosome 18q) is inactivated in 55% of +pancreatic cancers. +SMAD4 is only +rarely inactivated in other cancer types. +• TP53 (chromosome 17p) is inactivated in 70% to 75% of +pancreatic cancers. +• DNA methylation (epigenetic) abnormalities. +DNA methyla- +tion abnormalities are widespread in pancreatic cancer. +Conversely, promoter hypomethylation leads +to overexpression of oncogenes such as GATA6 and BRD4. +• Transcriptomic profiles and pancreatic cancer subtypes. +How these subtypes respond +differentially to specific therapies is an area of active +investigation. +Epidemiology and Inheritance. +Pancreatic cancer is +primarily a disease of older adults, with 80% of cases +occurring after age 60. +Pancreatic cancer risk is also greater in those +with visceral obesity and high body mass index. +Diabetes +mellitus is also a modest risk factor. +19.13A). +Pancreatic cancers tend to grow along nerves and invade into +blood vessels and the retroperitoneum. +Perineural, lymphatic, and +large vessel invasion are common. +Distant metastases are principally +to the liver and lungs. +Survival after diagnosis of advanced pancreatic carcinoma +is typically short. +A +B +Figure 19.13 Carcinoma of the pancreas. +• Cigarette smoking is a significant cause of pancreatic cancer. +• Cancer-causing germline mutations are present in 10% of patients. +• Ductal adenocarcinomas are highly invasive and elicit an intense +desmoplastic response. +New-onset diabetes is detected in up to half of cases. +(Fig. +19.13B). +The poorly formed malignant glands are lined by +pleomorphic cuboidal-to-columnar epithelial cells. +They are malignant, but survival is better +than with pancreatic ductal adenocarcinomas. +[Discussion of pseudocysts by a leading +expert in pancreatic pathology]. +[Guidelines +on the clinical management of cysts]. +Kleeff J, Korc M, Apte M et al: Pancreatic cancer, Nat Rev Dis Prim +2:16022, 2016. +[Review of +the normal development of the pancreas and how development explains +anomalies]. +Lankisch PG, Apte M, Banks PA: Acute pancreatitis, Lancet 386:85–96, +2015. +Kleef J, Whitcomb DC, Shimosegawa T et al: Chronic pancreatitis, Nat +Rev Dis Primers 3:17060, 2017. +All the authors are world-renowned experts in this area]. +Majumder S, Chari ST: Chronic pancreatitis, Lancet 387:1957–1966, 2016. +Azotemia is a consequence of many +renal disorders, but it also arises from extrarenal disorders. +It is a typical feature of both acute and chronic kidney +injury. +Postrenal azotemia is seen +whenever urine flow is obstructed distal to the kidney. +Relief of the obstruction is followed by correction of the +azotemia. +It is the +classic presentation of acute poststreptococcal glomeru- +lonephritis. +The clinical features of +nephritis and the nephrotic syndrome are discussed in +more detail later. +In its most severe forms, it is manifested +by oliguria or anuria (reduced or no urine flow). +It can +result from glomerular, interstitial, vascular, or acute +tubular injury (ATI). +Renal diseases are responsible for a great deal of morbidity +and mortality. +According to the 2015 U.S. +For these reasons, recognizing the +early signs and symptoms is of particular clinical importance. +Some are uniqueGlomerular diseases 897 +cases. +It is the end result of all chronic renal parenchymal +diseases. +Chronic kidney +disease causes significant systemic abnormalities, which are +listed in Table 20.1. +It reflects a reduction in GFR. +• Kidney injury that results in azotemia can be either acute or +chronic. +factors and in the course of several systemic diseases. +These are termed secondary glomeru- +lar diseases. +We briefly review +the secondary forms covered in other parts of this book. +Type IV collagen forms a network +suprastructure to which other glycoproteins attach. +20.1). +20.2). +20.1). +Biologically, they are +most akin to vascular smooth muscle cells and pericytes. +They are important in many forms of glomerulonephritis. +20.1). +(B) Schematic representation of a glomerular lobe. +(A, Courtesy Dr. +• Infiltration of leukocytes, including neutrophils, monocytes, +and, in some diseases, lymphocytes. +• Formation of crescents. +Fibrin, amyloid, cryoglobulins, and abnormal fibrillary +proteins may also deposit in the GBM. +When +extensive, these deposits may obliterate the capillary lumens +of the glomerular tuft. +Sclerosis is characterized by deposition of extracellular +collagenous matrix. +Note the filtration slits (arrows) and diaphragm between the +foot processes. +(Courtesy Dr. +20.3. +CD2AP, CD2-associated protein.Glomerular diseases 901 +the capillary loops, or both. +Many primary glomerulopathies are classified by their +histology, as seen in Table 20.2. +We begin this +discussion with a review of antibody-instigated injury. +20.4B and E). +Glomerulo- +nephritis can be induced experimentally by antigen-antibody +reactions. +(D, Courtesy Dr. +J. +Kowalewska, Department of Pathology, University of Washington, +Seattle, Washington. +20.4A). +Some tumor antigens are also thought to cause +immune complex–mediated nephritis. +In many cases, the +inciting antigen is unknown. +Here we briefly review the salient features +that relate to glomerular injury. +Deposits +may be located at more than one site in a given case. +20.4D), in the mesangium, or in both locations. +Several factors affect glomerular localization of antigen, +antibody, or immune complexes. +The molecular charge and +size of these reactants are clearly important. +20.5). +This is discussed +later in the sections describing these diseases. +20.6). +• Platelets may aggregate in glomeruli during immune- +mediated injury. +Antiplatelet +agents have beneficial effects in both human and experi- +mental glomerulonephritis. +The +end result is the same as in classical pathway activation. +• Eicosanoids, nitric oxide, angiotensin, and endothelin are +involved in the hemodynamic changes. +• Chemokines such as monocyte chemoattractant protein 1 +promote monocyte and lymphocyte influx. +��� The coagulation system is also a mediator of glomerular +damage. +20.7). +20.7). +Such mutations are the cause +of rare hereditary forms of the nephrotic syndrome. +Glomerular sclerosis may be seen +even in cases in which the primary disease was nonglo- +merular. +It appears that proteinuria +also can cause direct injury to and activation of tubular cells. +The reduced GFR is mani- +fested clinically by oliguria, fluid retention, and azotemia. +The inciting +antigen may be exogenous or endogenous. +Immune complexes show a granular pattern of deposition +by immunofluorescence. +It usually appears 1 +to 4 weeks after a streptococcal infection of the pharynx or +skin (impetigo). +Skin infections are commonly associated +with overcrowding and poor hygiene. +Many lines of evidence support an immunologic basis +for poststreptococcal glomerulonephritis. +against one or more streptococcal antigens are present in a +great majority of patients. +20.8B). +(A) Normal glomerulus. +(C) Typical electron-dense subepithelial “hump” and a neutrophil in the lumen. +(A–C, Courtesy Dr. +H. +Rennke, Brigham and Women’s Hospital, Boston, Mass. +D, Courtesy D. +J. +20.8C), +presumably representing the antigen-antibody complexes at the +subepithelial cell surface. +What triggers the formation of these +autoantibodies is unclear in most patients. +In adults the disease is less benign. +Figure 20.9 Crescentic glomerulonephritis (periodic acid–Schiff stain). +(Courtesy Dr. +M. +A. +20.10). +Segmental glomerular necrosis and distinc- +tive crescents (Fig. +Neutrophils +and lymphocytes may be present. +The crescents may obliterate +the urinary space and compress the glomerular tuft. +Electron +microscopy discloses deposits in those cases due to immune +complex deposition. +Regardless of type, electron microscopy may +Figure 20.10 Crescentic glomerulonephritis. +Other forms of RPGN also respond well to steroids and +cytotoxic agents. +Increased renal catabolism +of filtered albumin also contributes to the hypoalbuminemia. +The generalized edema is a direct consequence of decreased +intravascular colloid osmotic pressure. +There is also sodium and +water retention, which aggravates the edema (Chapter 4). +If severe, it may also lead +to pleural effusions and ascites. +The genesis of the hyperlipidemia is complex. +Most affected children recover; the prognosis is worse in +adults. +Nephrotic Syndrome +Certain glomerular diseases virtually always produce the +nephrotic syndrome. +• Underlying malignant tumors, particularly carcinomas of +the lung and colon, and melanoma. +• SLE. +About 10% to 15% of glomerulonephritis in SLE is +of the membranous type. +Pathogenesis +Membranous nephropathy is a form of chronic immune +complex–mediated disease. +The antigens may +be endogenous or exogenous. +The endogenous antigens +may be renal or nonrenal (described later). +20.4C). +How does the glomerular capillary wall become leaky in +membranous nephropathy? +There is a paucity of neutrophils, +monocytes, or platelets in glomeruli. +How IgG4 may activate the complement system is not +clear. +The +most frequent systemic causes of the nephrotic syndrome +are diabetes, amyloidosis, and SLE. +These +three lesions are discussed individually in the following +sections. +Approximately +75% of cases of membranous nephropathy are primary. +Approximate prevalence of systemic disease = 5% in +children, 40% in adults. +20.11C). +20.11A). +20.11B +and D). +(A) Silver methenamine stain. +Note the effacement of foot processes overlying deposits. +(D) Diagrammatic representation of membranous +nephropathy. +CL, Capillary lumen; End, endothelium; Ep, epithelium; US, urinary space. +(A, Courtesy Dr. +Thus, defects in the charge barrier may contribute +to the proteinuria. +Hematuria and mild hypertension +are present in 15% to 35% of cases. +The course of the disease is variable but generally indolent. +The disease recurs in up to 40% of +patients who undergo transplantation for ESRD. +The peak +incidence is between 2 and 6 years of age. +The disease +sometimes follows a respiratory infection or routine pro- +phylactic immunization. +20.12A). +By +electron microscopy the GBM appears normal, and no electron- +dense material is deposited. +20.12B). +Immunofluorescence +studies show no Ig or complement deposits. +The +proteinuria usually is highly selective, most of the protein +being albumin. +A characteristic feature is its usually +dramatic response to corticosteroid therapy. +Most children +(>90%) with minimal change disease respond rapidly to +this treatment. +Although adults are slower to respond, their +long-term prognosis is also excellent. +It is sometimesGlomerular diseases 915 +A B +Figure 20.12 Minimal change disease. +(A) Glomerulus stained with periodic acid–Schiff. +Note normal basement membranes and absence of proliferation. +CL, Capillary lumen; M, +mesangium; P, podocyte cell body. +considered to be a primary disorder of podocytes, like +minimal change disease. +This epithelial +damage is the ultrastructural hallmark of FSGS. +Nephrin is a key component of the slit diaphragm (see +Fig. +20.3), the structure that controls glomerular perme- +ability. +Podocin has also been localized to the slit dia- +phragm. +Mutations in NPHS2 result in a syndrome of +steroid-resistant nephrotic syndrome of childhood onset. +• Mutations in the gene encoding TRPC6 have been found +in some kindreds with adult-onset FSGS. +Particularly +striking examples in which this occurs are reflux nephropathy +and unilateral agenesis. +These may lead to progressive +glomerulosclerosis and renal failure. +Such +a mechanism is suggested by experiments in rats subjected +to subtotal nephrectomy. +The sequence of events (Fig. +20.14A). +Lipid droplets and +foam cells are often present (Fig. +20.14B). +(A) Segmental sclerosis involves the upper half of both glomeruli. +In general, children have a better prognosis than +adults do. +Progression to renal failure occurs at variable +rates. +Recurrences are seen in +25% to 50% of patients receiving allografts. +The latter belong +to a group of disorders called C3 glomerulopathies. +The criteria +that define this group are still evolving. +Silver methenamine stain. +(Courtesy Dr. +In type II, C3 is present +on the GBM but not in the dense deposits. +MPGN accounts for up to 10% of cases of nephrotic +syndrome in children and young adults. +The antigens +involved in idiopathic MPGN are unknown. +Some patients develop numerous +crescents and a clinical picture of RPGN. +About 50% develop +chronic renal failure within 10 years. +The +glomeruli contain deposits of C3 and properdin but not +IgG. +Recall that in the alternative complement pathway, C3 +is directly cleaved to C3b (Fig. +20.18; see also Chapter 3, +MORPHOLOGY +The glomeruli are large and hypercellular. +20.16). +Such +interposition also gives rise to the appearance of “split” basement +membranes (Fig. +20.17A). +Crescents are present in many cases. +Type I MPGN is characterized by the presence of discrete +subendothelial electron-dense deposits. +Mesangial and +occasional subepithelial deposits may also be present (see Fig. +20.17A). +There are dense homogeneous deposits within the basement membrane. +In both, the basement membranes appear split when viewed in the light microscope. +CL, Capillary lumen. +(A, Courtesy Dr. +Jolanta +Kowalewska, Cedars-Sinai Medical Center, Los Angeles, Calif.) +Fig. +3.12). +This leads to the generation of C3bBb, the alternative +pathway C3 convertase. +20.18). +This favors persistent C3 activation and hypocomplement- +emia. +Clinically, +patients develop nephrotic syndrome, hematuria, and +progressive renal insufficiency. +The disease recurs in kidney +transplants. +It may be associated +with systemic infections. +It is associated with acquired +or genetic dysregulation of the alternate pathway of complement. +Dense deposit disease affects primarily children and young +adults. +The prognosis is poor, with +over one-half of patients progressing to ESRD. +The precise nature of the dense deposits is unknown. +20.17B). +C3 is also present in the mesangium +in characteristic circular aggregates (mesangial rings). +20.19). +A +B +Figure 20.19 IgA nephropathy. +(A) Light microscopy showing mesangial +proliferation and matrix increase. +may occasionally develop. +Rarely, patients may present with +crescentic GN. +Healing of the focal proliferative lesion may lead to secondary +focal segmental sclerosis. +The characteristic immunofluorescent +picture is of mesangial deposition of IgA (Fig. +20.19B), often +with C3 and properdin and lesser amounts of IgG or IgM. +Early +complement components are usually absent. +The hematuria typically lasts for several +days and then subsides, only to return every few months. +The subsequent course is highly variable. +Many patients +maintain normal renal function for decades. +Slow progression +to chronic renal failure occurs in 15% to 40% of cases over +a period of 20 years. +The disease is inherited +as an X-linked trait in approximately 85% of cases. +Approxi- +mately 90% of affected males progress to ESRD before 40 +years of age. +Missense and splice +site mutations, insertions, and deletions have all been identi- +fied. +Figure 20.20 Hereditary nephritis (Alport syndrome). +CL, Capillary lumen; +Ep, epithelium. +basket-weave appearance (Fig. +20.20). +Similar alterations can be +found in the tubular basement membranes. +There is also +absence of α5 staining in skin biopsy specimens from these patients. +Pro- +teinuria may develop later, and rarely, the nephrotic syn- +drome develops. +The auditory defects may be subtle, +requiring sensitive testing. +The abnormality is +estimated to affect 1% of the general population. +The disorder in homozygotes resembles +autosomal recessive Alport syndrome. +Homozygotes or +compound heterozygotes may progress to renal failure. +IgA is deposited in the glomerular mesangium +in a distribution similar to that of IgA nephropathy. +Most +children have an excellent prognosis. +The pathology and patho- +genesis of this disorder are discussed in Chapter 24. +Most of these diseases are +discussed elsewhere in this book. +Here we briefly recall +some of the lesions and discuss only those not considered +in other sections. +Lupus Nephritis +The various types of lupus nephritis are described in Chapter +6. +As discussed, SLE gives rise to a wide variety of renal +lesions and clinical presentations. +It is the most common cause of acute kidney injury. +• Direct toxic injury to the tubules. +ATI accounts for some 50% of cases of acute kidney injury +in hospitalized patients. +Other causes of acute renal failure +are discussed elsewhere in this chapter. +ATI is a reversible process that arises in a variety of +clinical settings. +This pattern is called +ischemic ATI. +In addition to its frequency, the +potential reversibility of ATI adds to its clinical importance. +Proper management can make the difference between +recovery and death. +20.21). +Initially, this response to +the increased sodium lowers the GFR to maintain distal +blood flow. +All of these effects, as shown in Fig. +20.21, +contribute to the decreased GFR. +20.22 and +20.23). +The distinct patterns of tubular injury in ischemic and +toxic ATI are shown in Fig. +20.22. +Figure 20.23 Acute tubular injury. +Tubuloin- +terstitial nephritis can be acute or chronic. +Here we discuss primary causes of +tubulointerstitial injury (Table 20.8). +Glomerular and vascular +abnormalities may also be present in advanced stages of +these diseases. +Toxic ATI is manifested by ATI, most obvious in the proximal +convoluted tubules. +Later, these cells become necrotic, are +desquamated into the lumen, and may undergo calcification. +The only +indication of renal involvement is a slight decline in urine +output with a rise in BUN. +At this point, oliguria could +be explained by a transient decrease in blood flow and +declining GFR. +With appropriate management, the patient +can overcome this oliguric crisis. +• Recovery phase is ushered in by a steady increase in urine +volume that may reach up to 3 L/day. +Hypokalemia, +rather than hyperkalemia, becomes a clinical problem. +There +is a peculiar increased vulnerability to infection at this +stage. +Eventually, renal tubular function is restored and +concentrating ability improves. +At the same time, BUN +and creatinine levels begin to return to normal. +The prognosis of ATI depends on the magnitude and +duration of injury. +With supportive care, +95% of those who do not succumb to the precipitating cause +recover. +This section deals principally +with pyelonephritis and drug-induced tubulointerstitial +nephritis. +It occurs in two forms. +By far the most common is Escherichia +coli, followed by Proteus, Klebsiella, and Enterobacter. +20.24). +Ascending infection is the most common cause of clinical +pyelonephritis. +coli +Proteus +Enterobacter +Figure 20.24 Schematic representation of pathways of renal infection. +Hematogenous infection results from bacteremic spread. +infection. +In +the presence of stasis, bacteria introduced into the bladder +can multiply unhindered. +• Vesicoureteral reflux. +20.26). +In the early stages, the neutrophilic infiltration is limited to +the tubules. +20.27). +Characteristically, glomeruli are relatively resistant to the +infection. +Three complications may be superimposed on acute +pyelonephritis. +Papillary necrosis +is usually bilateral but may be unilateral. +One or all of the pyra- +mids of the affected kidney may be involved. +20.28). +Dye injected into the bladder refluxes into both dilated +ureters, filling the pelvis and calyces. +20.25). +In addition, it may be acquired +by bladder infection itself. +Vesicoureteral reflux is estimated to affect 1% +to 2% of otherwise normal children. +• Intrarenal reflux. +20.25). +Figure 20.26 Acute pyelonephritis. +• Gender and age. +The diagnosis of +infection is established by quantitative urine culture. +coagulative necrosis, with preservation of outlines of tubules. +The leukocytic response is limited to the junctions between +preserved and destroyed tissue. +After the acute phase of pyelonephritis, healing occurs. +A B +Figure 20.28 Papillary necrosis. +Such bacteriuria then either disappears or may +persist, sometimes for years. +The superimposition of papillary necrosis +may lead to acute renal failure. +A viral pathogen causing pyelonephritis in kidney +allografts is polyomavirus. +20.29). +An interstitial +inflammatory response is invariably present. +Treatment +consists of a reduction in immunosuppression. +20.30). +The scars are usually polar and are associated +with underlying blunted calyces. +20.30 and 20.31A). +The kidneys usually +are irregularly scarred; if bilateral, the involvement is asymmetric. +In contrast, both kidneys in chronic glomerulonephritis are diffusely +and symmetrically scarred. +A B +Figure 20.29 Polyomavirus nephropathy. +(B) Intranuclear viral inclusions visualized by electron microscopy. +(Courtesy Dr. +The surface (left) is irregularly scarred. +The cut section (right) reveals blunting and loss of several papillae. +(B) Low-power view shows a corticomedullary renal scar with an underlying dilated deformed calyx. +Note the thyroidization of tubules in the cortex. +Obstructive lesions of the urinary tract are important predispos- +ing factors. +Significant +bacteriuria may be present, but it is often absent in the +late stages. +A rising serum creatinine or acute +kidney injury with oliguria develops in about 50% of cases. +Pathogenesis +Many features of the disease suggest an idiosyncratic immune +mechanism. +These +modified self antigens then become immunogenic. +(Courtesy Dr. +H. +Table 20.9 lists the main features of papillary necrosis in +these conditions. +• Acute hypersensitivity interstitial nephritis, resulting in renal +failure, as described earlier. +• Acute interstitial nephritis and minimal change disease. +Eosinophils and neutrophils may be present +(Fig. +Tubulitis, the infiltration of tubules by +lymphocytes, is common. +Variable degrees of tubular injury and +regeneration are present. +cortical atrophy and scarring. +The earliest functional defect is an inability to concentrate +the urine. +Other tubular defects, such as tubular acidosis and +salt-losing nephritis, may also occur. +With further damage, a +slowly progressive chronic kidney disease develops. +Precipitation of uric acid is favored by the acidic pH in +collecting tubules. +20.33). +The urate +deposits evoke a mononuclear response that contains +foreign-body giant cells. +• Light-chain deposition disease. +• Hypercalcemia and hyperuricemia are often present in these +patients. +The pathogenic mechanisms are unknown. +We limit the discussion +here to the tubulointerstitial lesions in multiple myeloma +patients. +Several factors contribute to renal damage: +• Bence-Jones proteinuria and cast nephropathy. +Two mechanisms seem to account for the renal toxicity +of Bence-Jones proteins. +20.34).The adjacent interstitial +tissue usually shows an inflammatory response and fibrosis. +Clinical Features +Clinically, the renal manifestations are of several types. +Another form occurs suddenly and is +manifested by acute kidney injury with oliguria. +This mechanism of injury is analogous to that with +monoclonal immunoglobulin and myoglobin casts. +VASCULAR DISEASES +Nearly all diseases of the kidney involve the renal blood +vessels secondarily. +Hypertension and diabetes, +however, increase the incidence and severity of the lesions. +20.35).The loss of mass is due mainly to cortical scarring and +shrinking. +20.36). +Figure 20.36 Hyaline arteriolosclerosis. +(Courtesy Dr. +M. +A. +Endothelial injury is a common pathogenic factor +in these disorders. +This occurs more frequently in men, and the incidence +increases with advancing age and diabetes. +The plaque is usually +concentrically placed, and superimposed thrombosis often occurs. +The second most frequent cause of stenosis is fibromuscular +dysplasia of the renal artery. +20.37). +The media shows marked fibrous thickening, and the +lumen is stenotic. +(Courtesy Dr. +On occasion, a bruit can be heard +on auscultation of the affected kidneys. +The cure rate after surgery is 70% to +80% in well-selected cases. +20.38). +Widespread “consumption” of platelets leads +to thrombocytopenia. +Endothelial Injury. +Platelet Aggregation. +However, due to underlying renal +damage, the long-term (15- to 25-year) outlook is more +guarded. +Autoantibodies against complement regulatory proteins +also result in atypical HUS. +The syndrome is described +in detail in Chapter 4. +In this setting, the microangiopathy +tends to follow a chronic course. +• Complications of pregnancy or the postpartum period. +The condition has a grave +prognosis, although recovery can occur in milder cases. +20.39). +most often caused by autoantibodies that inhibit ADAMTS13 +function. +Most cases occur +after intestinal infection with strains of E. +However, most cases of typical HUS caused by E. +coli are +sporadic. +Less commonly, infections by other agents, includ- +ing S. +dysenteriae, can give rise to a similar clinical picture. +Typical HUS can occur at any age, but children and older +adults are at highest risk. +Hypertension is +present in about half of patients. +Precisely how Shiga-like toxin exposure causes HUS is +not well understood. +In the +presence of cytokines such as TNF, Shiga-like toxin may +cause endothelial apoptosis. +But other possibilities remain. +(A) Fibrinoid necrosis of afferent arteriole (periodic acid–Schiff stain). +(B) Hyperplastic arteriolitis (onion-skin lesion). +(Courtesy Dr. +H. +• Irradiation of the kidney. +Regardless of the cause, most patients present +as adults younger than 40 years of age. +Less commonly, +patients inherit an inactivating mutation in ADAMTS13. +Figure 20.40 Diffuse cortical necrosis. +The pale ischemic necrotic areas +are confined to the cortex and columns of Bertin. +• In typical HUS, Shiga-like toxin produced by bacteria, most +commonly E. +coli strain O157:H7, is responsible for producing +platelet activation and thrombosis. +The glomerular +capillaries are distended and occluded by thrombi. +Interlobular arteries and arterioles often +show occlusive thrombi. +The renal cortex reveals various +degrees of scarring. +The morphologic lesions are similar to those seen in malignant +hypertension (Fig. +20.39). +The gross +alterations of massive ischemic necrosis are sharply limited to +the cortex (Fig. +20.40).The histologic appearance is that of acute +ischemic infarction. +20.41). +Frequently they are of no significance. +Many renal infarcts are clinically silent. +Figure 20.41 Atheroembolus with typical cholesterol clefts in an +interlobar artery. +The various manifestations are grouped under +sickle cell nephropathy. +The most common abnormalities are hematuria and a +diminished concentrating ability (hyposthenuria). +Proteinuria +is also common in sickle cell disease, occurring in about +30% of patients. +Renal Infarcts +The kidneys are common sites for the development of +infarcts. +About 10% of people are born with significant malformations +of the urinary system. +Renal dysplasias and hypoplasias +account for 20% of chronic kidney disease in children. +Here, we restrict the discussion to +structural anomalies involving primarily the kidney. +All +except horseshoe kidney are uncommon. +Anomalies of the +lower urinary tract are discussed in Chapter 21. +Agenesis of the Kidney. +Bilateral agenesis is incompatible +with life and usually encountered in stillborn infants. +It is +often associated with other congenital disorders (e.g., limb +defects, hypoplastic lungs). +Unilateral agenesis is uncommon +and compatible with normal life if no other abnormalities +exist. +The solitary kidney enlarges as a result of compensatory +hypertrophy. +Hypoplasia. +Hypoplasia refers to failure of the kidneys to +develop to a normal size. +Ectopic Kidneys. +The development of the metanephros into +the kidneys may occur in ectopic foci. +These kidneys lie either +just above the pelvic brim or sometimes within the pelvis. +Horseshoe Kidneys. +This anomaly is found in 1 in 500 to 1000 autopsies. +A useful classification of renal cysts +is summarized in Table 20.12. +The inheritance pattern is +autosomal dominant with high penetrance. +The disease is bilateral; reported unilateral cases probably +represent multicystic dysplasia. +• The PKD1 gene is located on chromosome 16p13.3. +Polycystin-1 is expressed in tubular epithelial cells, +particularly those of the distal nephron. +Mutations in PKD1 account for about 85% +of cases. +Polycystin-2 functions as a +Ca2+-permeable cation channel. +Overall, the disease is +less severe than that associated with PKD1 mutations. +20.42). +The cilia are +part of a system of organelles and cellular structures that +sense mechanical signals. +• Both polycystin-1 and polycystin-2 are localized to the +primary cilium. +On occasion, +papillary epithelial formations and polyps project into the lumen. +In others, hemor- +rhage or progressive dilation of cysts may produce pain. +Excretion of blood clots causes renal colic. +The enlarged +kidneys, usually apparent on abdominal palpation, may +induce a dragging sensation. +Both genetic and environmental factors influence disease +severity. +The kidney is +markedly enlarged and contains numerous dilated cysts. +(D) Liver cysts in adult PKD. +Individuals with polycystic kidney disease also tend +to have extrarenal congenital anomalies. +The cysts are derived from +biliary epithelium. +Cysts occur much less frequently in the +spleen, pancreas, and lungs. +The diagnosis is made by radiologic imaging +techniques. +The gene is highly expressed in adult and fetal kidney and +also in liver and pancreas. +The extracellular region contains +multiple copies of a domain forming an Ig-like fold. +This +complicates molecular diagnosis of the disorder. +MORPHOLOGY +The kidneys are enlarged and have a smooth external appearance. +20.43C). +In almost +all cases, the liver has cysts (Fig. +20.43D) associated with portal +fibrosis and proliferation of portal bile ducts. +In +older children, hepatic disease is the predominant clinical +concern. +Such patients may develop portal hypertension +with splenomegaly. +The +condition occurs in adults and is usually discovered radio- +graphically. +Renal function is usually normal. +The cysts are lined by +cuboidal epithelium or occasionally by transitional epithe- +lium. +Unless there is superimposed pyelonephritis, cortical +scarring is absent. +The pathogenesis is unknown. +Sodium wasting +and tubular acidosis are also prominent. +The expected +course is progression to ESRD in 5 to 10 years. +The NPHP2 gene product has been +Figure 20.44 Medullary cystic disease. +Cut section of kidney showing +cysts at the corticomedullary junction and in the medulla. +identified as inversin, which mediates left-right patterning +during embryogenesis. +20.44). +In general, glomerular +structure is preserved. +The kidney is usually enlarged, +extremely irregular, and multicystic (Fig. +20.45A). +The cysts +vary in size from several millimeters to centimeters in +diameter. +On histologic examination, they are lined by +flattened epithelium. +20.45B). +The main importance of cysts lies in their dif- +ferentiation from kidney tumors. +Fortunately, many causes of obstruction are surgically +correctable or medically treatable. +The common causes +are as follows (Fig. +Even with complete obstruction, glomerular filtration +B +Figure 20.45 Multicystic renal dysplasia. +(A) Gross appearance. +(A, Courtesy Dr. +D. +Schofield, Children’s Hospital, Los Angeles, +Calif.; B, courtesy Dr. +Most +are asymptomatic, but sometimes the cysts bleed, causing +hematuria. +Simple Cysts +Simple cysts may be single or multiple and usually involve +the cortex. +They are commonly 1 to 5 cm but may reach +10 cm or more in size. +They are translucent, lined by a gray, +glistening, smooth membrane, and filled with clear fluid. +Simple cysts are common postmortem findings without +clinical significance. +Progressive blunting of the apices of the pyramids occurs, and +these eventually become cupped. +Only later does the GFR +begin to fall. +20.8). +Most of the early +symptoms are produced by the underlying cause of the +hydronephrosis. +Sometimes its existence +first becomes apparent in the course of imaging studies. +Ultrasonography +is a useful noninvasive technique in the diagnosis of obstruc- +tive uropathy. +Hypertension is common. +20.47). +Curiously, after relief of complete +urinary tract obstruction, postobstructive diuresis occurs. +Men are affected +more often than women, and the peak age at onset is between +20 and 30 years. +Familial and hereditary predisposition to +stone formation has long been known. +A low urine +volume in some metabolically normal patients may also +favor supersaturation. +The resultant alkaline urine causes the precipitation of +magnesium ammonium phosphate salts. +These form some +of the largest stones, as the amount of urea excreted +normally is very large. +In contrast to the radiopaque calcium stones, uric +acid stones are radiolucent. +These stones also form at low urinary pH. +Cells may also +grow as tubules, glands, cords, and sheets of cells. +Figure 20.48 Nephrolithiasis. +A large stone impacted in the renal pelvis. +(Courtesy Dr. +E. +Ultrastructurally the eosinophilic +cells have numerous mitochondria. +There are some familial cases in which these +tumors are multicentric rather than solitary. +There are approximately 65,000 +new cases per year and 13,000 deaths from the disease. +Epidemiology +Tobacco is the most significant risk factor. +An international +MORPHOLOGY +Stones are unilateral in about 80% of patients. +The favored sites +for their formation are within the renal calyces and pelves (Fig. +20.48) and in the bladder. +Often many stones are found within one +kidney. +Larger stones often manifest themselves by hema- +turia. +NEOPLASMS OF THE KIDNEY +Both benign and malignant neoplasms occur in the kidney. +Malignant neoplasms are of great importance clinically. +• Von Hippel-Lindau (VHL) syndrome. +• Hereditary leiomyomatosis and renal cell cancer syndrome. +• Hereditary papillary carcinoma. +This autosomal dominant +form is manifested by multiple bilateral tumors with +papillary histology. +• Birt-Hogg-Dubé syndrome. +The major types of +tumor are as follows (Fig. +20.49): +• Clear cell carcinoma. +This is the most common type, +accounting for 70% to 80% of renal cell cancers. +The tumors +are made up of cells with clear or granular cytoplasm +and are nonpapillary. +They can be familial, but in most +cases (95%) are sporadic. +The deleted region harbors the VHL gene (3p25.3). +(Courtesy Dr. +• Papillary carcinoma accounts for 10% to 15% of renal +cancers. +These +tumors are not associated with 3p deletions. +MET is also mutated in a +small proportion of sporadic papillary carcinomas. +Unlike clear cell carcinomas, papillary +carcinomas are frequently multifocal in origin. +On cytogenetic examination, these +tumors show multiple chromosome losses and extreme +hypodiploidy. +Histologic distinction +from oncocytoma can be difficult. +• Xp11 translocation carcinoma is a genetically distinct subtype +of renal cell carcinoma. +The neoplastic cells consist of clear cytoplasm with a +papillary architecture. +They +arise from collecting duct cells in the medulla. +Figure 20.50 Renal cell carcinoma. +Typical cross-section of yellowish, +spherical neoplasm in one pole of the kidney. +Note the tumor in the +dilated thrombosed renal vein. +may show cystic as well as solid areas. +Interstitial foam cells are common in the papillary cores (see Fig. +20.51B). +Psammoma bodies may be present.The stroma is usually +scanty but highly vascularized. +20.51C). +They are bright yellow-gray-white +spherical masses of variable size that distort the renal outline. +The margins are +usually sharply defined and confined within the renal capsule (Fig. +20.50). +The pelvis has +been opened to expose the nodular irregular neoplasm, just proximal to +the ureter. +20.52). +They are almost invariably small when discovered. +These +tumors may block urinary outflow and lead to palpable +hydronephrosis and flank pain. +Urothelial tumors may occasionally be multiple, involving +the pelvis, ureters, and bladder. +(A) Clear cell type. +(B) Papillary type. +Note the papillae and foamy macrophages in the stalk. +(C) Chromophobe +type. +(Courtesy Dr. +A. +Infiltration of the wall of the pelvis and calyces is common. +[A current review of the clinicopathologic manifestations of these diseases]. +Roberts IS: Pathology of IgA nephropathy, Nat Rev Nephrol 10:445–454, +2014. +[An excellent review that details emerging concepts of the pathophysiol- +ogy of this disorder]. +Zuk A, Bonventre JV: Acute kidney injury, Annu Rev Med 67:293–307, +2016. +[A comprehensive review of acute kidney injury]. +[A review of the clinical and pathologic aspects of +pyelonephritis]. +[An excellent +review of the pathogenesis and clinical features of various forms of TMA]. +Chang A: Thrombotic microangiopathy and the kidney, Diagn Histopathol +23:101–108, 2017. +Hill GS: Hypertensive nephrosclerosis, Curr Opin Nephrol Hypertens +17:266–270, 2008. +[A review of the pathophysiologic underpinning of +hypertensive nephrosclerosis]. +Hildebrandt F, Benzing T, Katsanis N: Ciliopathies, N Engl J Med +364:1533–1543, 2011. +[An updated +pathologic classification of renal cell carcinoma]. +These tumors +have a poor prognosis. +[An outstanding +and comprehensive review of the immunopathogenesis of glomerular +diseases]. +[An excellent synopsis of alternations in podocytes +that underlie glomerular diseases]. +This epithelium +rests on a well-developed basement membrane, beneath +which is a lamina propria. +The ureters lie throughout their course in a retro- +peritoneal position. +Retroperitoneal tumors or fibrosis +may entrap and obstruct the ureters. +There is agenesis of the contralateral kidney +in a minority of cases. +In adults, UPJ obstruction is more +common in women and is most often unilateral. +Tumors and Tumor-Like Lesions +Primary tumors of the ureter are rare. +Benign tumors are +generally of mesenchymal origin. +The majority +are urothelial carcinomas (Fig. +21.1). +They commonly +occur concurrently with urothelial carcinomas of bladder +or renal pelvis. +The disorder occurs in middle +to late age and is more common in males than females. +(Courtesy Dr. +Cristina Magi-Galluzzi, The Johns Hopkins Hospital, +Baltimore, Md.) +other organs (Chapter 6). +Most, however, have no obvious cause and are +considered primary or idiopathic (Ormond disease). +• In children, congenital UPJ obstruction is the most common +obstructive lesion. +• Vesicoureteral reflux is the most common and serious +congenital anomaly. +As a result, +the bladder communicates directly with the abdominal +surface (Fig. +21.2). +Exstrophy is associated with an increased risk of +adenocarcinoma in the bladder remnant. +• Urachal anomalies. +Rarely, it remains fully or partially patent. +The +former creates a fistulous urinary tract connection between +the bladder and umbilicus. +The tied +umbilical cord is seen above the hyperemic mucosa of the everted bladder. +Below is an incompletely formed penis with marked epispadias. +(Courtesy +Dr. +Women are more likely to +develop cystitis as a result of their shorter urethras. +Tuberculous +cystitis is almost always a sequel to renal tuberculosis. +Viruses (e.g., adeno- +virus), Chlamydia, and Mycoplasma may also cause cystitis. +Adenovirus and BK virus infections may result in hemorrhagic +cystitis. +MORPHOLOGY +Most cases of cystitis produce nonspecific acute or chronic +inflammation of the bladder. +Other types of non-infectious cystitis include iatrogenic, fol- +licular, and eosinophilic cystitis. +Acute and chronic radiation cystitis may occur +following the irradiation of the bladder region. +These primary lesions must be corrected before +the cystitis can be relieved. +Interstitial Cystitis (Chronic Pelvic Pain Syndrome). +Inter- +stitial cystitis is a disorder of unknown etiology that occurs +most frequently in women. +Typical +cystoscopic findings include mucosal fissures and punctate +hemorrhages (glomerulations). +Treatment is largely empiric. +Late in the course, +transmural fibrosis may lead to a contracted bladder. +Malakoplakia. +It arises in the setting of chronic +bacterial infection, mostly by E. +A +B +Figure 21.3 Malakoplakia. +(A) Bladder involved by malakoplakia showing +the characteristic yellow-orange mucosal lesions. +(B) Periodic acid–Schiff +(PAS) stain. +macrophages with occasional multinucleate giant cells and lym- +phocytes. +21.3B). +21.3A). +His- +tologically, the lesion is composed of aggregates of large foamy +Polypoid Cystitis. +• Cystitis glandularis and cystitis cystica. +Both variants can arise in the setting +of inflammation and metaplasia. +Extensive and multifocal +intestinal metaplasia is a precursor to adenocarcinoma. +• Squamous metaplasia. +• Nephrogenic adenoma. +Nephrogenic adenoma is an unusual +lesion that may not be a form of true metaplasia. +It is the fourth most common cancer in American +men (7% of all new cases). +Many +of these tumors are multifocal at presentation. +21.4). +These tumors have a range of atypical changes +and are graded according to their biologic behavior. +Such lesions are considered to be high grade. +Once muscularis propria invasion +occurs, there is a 30% 5-year mortality rate. +Epidemiology. +About 80% of patients are +between 50 and 80 years of age. +Bladder cancer, with rare +exceptions, is not familial. +Between 50% and +80% of all bladder cancers among men are associated +with the use of cigarettes. +Cigars, pipes, and smokeless +tobacco are associated with a smaller risk. +Cancer appears 15 to 40 years after the first +exposure. +• Schistosoma haematobium infections in endemic areas (Egypt, +Sudan) are an established risk. +• Long-term use of analgesics is implicated, as it is in analgesic +nephropathy (Chapter 20). +21.5). +The majority of muscle-invasive bladder +cancers develop by progression from “flat” CIS. +MORPHOLOGY +The appearance of urothelial tumors varies from purely papillary +to nodular or flat. +21.6). +Multiple discrete tumors are +often present. +Table 21.3 lists the grading system of urothelial tumors. +Papil- +lomas represent 1% or less of bladder tumors and are often seen +in younger patients. +21.7A). +The lower section demonstrates multifocal +smaller papillary neoplasms. +(Courtesy Dr. +Fred Gilkey, Sinai Hospital, +Baltimore, Md.) +A B +C D +Figure 21.7 Papillary urothelial neoplasms. +(A) Papilloma consisting of small papillary fronds lined by normal-appearing urothelium. +(A) Normal urothelium with uniform nuclei and well-developed umbrella cell layer. +may occur. +21.7C). +These low-grade cancers may recur and, +infrequently, may also invade. +Only rarely do these tumors pose +a threat to life. +Some of the tumor cells are +highly anaplastic (Fig. +21.7D). +Mitotic figures, including atypical +ones, are frequent. +Architecturally, there is disarray and loss of +polarity. +21.8). +If untreated, 50% to 75% of CIS pro- +gresses to invasive cancer. +Invasive urothelial carcinoma (Fig. +21.9) may be associated +with papillary urothelial cancer, usually high grade, or adjacent +CIS. +few tumors (<10%) progress to higher-grade lesions. +Clinical Features +Painless hematuria is the most common symptom of bladder +cancer. +Frequency, urgency, and dysuria may accompany +hematuria. +Occasionally, obstruction of the ureteral orifice +may lead to pyelonephritis or hydronephrosis. +Initial treatment of non–muscle-invasive tumors is guided +by the pathologic findings. +Other recurrences are clonally distinct and represent +a second primary tumor. +Lymphoma may involve the bladder as a component of +systemic disease. +Metastatic spread of solid tumors to the +bladder may occur but is very rare. +Once bladder carcinoma metastasizes, treatment options +are limited. +Most are +invasive, fungating tumors or are infiltrative and ulcerative. +Mesenchymal Tumors +Benign Tumors. +Even collectively, they +are rare. +The most common is leiomyoma. +Sarcomas. +True sarcomas are distinctly uncommon in the +bladder. +Their soft, fleshy, gray-white +gross appearance suggests their mesenchymal nature. +The +most common bladder sarcoma in infancy or childhood is +embryonal rhabdomyosarcoma. +In some of these cases they +manifest as a polypoid grape-like mass (sarcoma botryoides). +21.9). +In the course of time, +crypts form and may be converted into diverticula. +The enlarged bladder may reach +the brim of the pelvis or even the level of the umbilicus. +Gonococcal urethritis is one of the earliest +manifestations of this venereal infection. +Nongonococcal +urethritis is common and can be caused by several different +organisms. +Mycoplasma +(Ureaplasma urealyticum) also accounts for symptoms of +urethritis in many cases. +Urethritis is often accompanied +by cystitis in women and by prostatitis in men. +In many +instances of suspected bacterial urethritis, no organism can +be isolated. +Some urethritis is truly noninfectious in origin. +Surgical excision +affords prompt relief and cure. +Primary carcinoma of the urethra is an +uncommon lesion (Fig. +21.10). +Adenocarcinomas are infrequent in the urethra and generally +occur in women. +Neoplasms of the prostatic urethra are +addressed later in the section on the prostate. +Hypospadias, the more common of +the two, occurs in approximately 1 in 300 live male births. +Only the nonspecific infections +causing so-called balanoposthitis are described here. +Balanoposthitis refers to infection of the glans and prepuce +caused by a wide variety of organisms. +Among the more964 CHAPTER 21 The Lower Urinary Tract and Male Genital System +common agents are C. +albicans, anaerobic bacteria, Gardnerella, +and pyogenic bacteria. +Tumors +Tumors of the penis are uncommon. +Figure 21.11 Carcinoma of urethra with typical fungating growth pattern +(arrow). +Treatments include surgery and injection of collagenase to +lyse the fibrous plaques. +These lesions are encompassed by the +umbrella term penile intraepithelial neoplasia (PeIN). +All are +squamous lesions confined to the epidermis by an intact +basement membrane. +PeIN may be HPV-related (undifferenti- +ated PeIN) or non–HPV-related (differentiated). +Penile lesions usually occur in the coronal sulcus +and inner surface of the prepuce. +21.11). +21.12A). +21.12B). +A B +Figure 21.12 Condyloma acuminatum of the penis. +(A) Low magnification reveals the papillary architecture and thickening of the epidermis. +E6 protein also stimulates telomerase expression, leading +to cellular immortalization. +Figure 21.13 Bowen disease (carcinoma in situ) of the penis. +the foreskin of older patients, and as the name implies retains +a degree of squamous maturation. +Both are associated with high-risk +HPV, most commonly HPV 16. +• Bowen disease most commonly affects the penile shaft and +scrotum of older men. +At these sites, it appears as a soli- +tary, thickened, gray-white, opaque plaque. +In less +common cases when it affects the glans, the lesion acquires +a velvety red appearance. +21.13). +Mitoses, some atypical, are +numerous. +In 10% of patients, Bowen disease gives rise +to infiltrating squamous cell carcinoma. +• Bowenoid papulosis occurs in sexually active adults. +Penile +carcinoma affects middle-aged and older patients (40 to +70 years of age). +In the United States, it accounts for less +than 1% of cancers in males. +Low income status and +poor hygiene habits are salient risk factors. +21.14). +• Two pathogenic pathways, one related to HPV and the other +unrelated to HPV. +TESTIS AND EPIDIDYMIS +Distinct pathologic conditions affect the testis and epididy- +mis. +It is found in approximately 1% +of 1-year-old boys. +Testicular descent occurs in two phases. +This phase is controlled by +the hormone müllerian-inhibiting substance. +locally along a broad pushing border, but rarely metastasizes. +The lesions are nonpainful until they undergo secondary +ulceration and infection. +As mentioned above, +prognosis is strongly correlated with tumor stage at diagnosis. +MORPHOLOGY +Cryptorchidism is usually unilateral,being bilateral in 25% of patients. +Cryptorchid testes are small and firm. +The histologic changes in +the malpositioned testis begin as early as 2 years of age. +Early on, +thickening of the basement membrane of the spermatic +tubules is seen (Fig. +21.15). +(A) Normal testis shows tubules with active spermatogenesis. +(B) Testicular atrophy in cryptorchidism. +The tubules show +Sertoli cells but no spermatogenesis. +There is thickening of basement membranes and an apparent increase in interstitial Leydig cells. +The +gross and microscopic alterations follow the pattern already +described for cryptorchidism. +In extreme cases there is +complete regression (“vanishing testis”). +Inflammation and Infections +Inflammatory disorders are distinctly more common in the +epididymis. +The cause of epididymitis varies with the age of the patient. +In +sexually active men younger than age 35 years, the sexually +transmitted pathogens C. +trachomatis and Neisseria gonorrhoeae +are most frequent. +In men older than age 35, common urinary +tract pathogens, such as E. +coli and Pseudomonas, are respon- +sible for most infections. +Current recommenda- +tions are for orchiopexy to be performed at 6 to 12 months +of age. +• The cryptorchid testis carries a three- to fivefold higher risk +for testicular cancer. +• Orchiopexy reduces but does not completely eliminate the +risk of sterility and cancer. +21.16). +There are two settings in which testicular torsion occurs. +Neonatal torsion occurs either in utero or shortly after birth. +It +often occurs without any inciting injury. +Contralateral orchiopexy is performed to prevent +recurrence in the unaffected testis. +Figure 21.16 Acute epididymitis caused by gonococcal infection. +The +epididymis is replaced by an abscess. +Normal testis is seen on the right. +to the testis, where it evokes a similar inflammatory reaction. +Histologically, +the orchitis is distinguished by granulomas restricted to +spermatic tubules. +Although +an autoimmune basis is suspected, the cause of these lesions +remains unknown. +In +severe cases epididymal abscesses may develop, leading to +extensive destruction and scarring. +The infection may also +spread to the testis and produce suppurative orchitis. +Mumps +Mumps is a systemic viral disease that most commonly +affects school-aged children. +Testicular involvement is +extremely uncommon in this age group. +In postpubertal +males, however, orchitis occurs in 20% to 30% of cases. +21.17). +In advanced stages, the swollen +testis consists entirely of soft, necrotic, hemorrhagic tissue. +Figure 21.17 Torsion of testis. +The most common benign paratesticular tumor is adeno- +matoid tumor. +Testicular Tumors +Testicular neoplasms span an amazing gamut of histologic +types. +The lifetime risk is highest in Northern Europe and New +Zealand and is lowest in Africa and Asia. +21.18). +Environmental Factors. +The role of environmental factors +is inferred in part from population migration studies. +Components of this +syndrome include cryptorchidism, hypospadias, and poor +sperm quality. +Genetic Factors. +Interestingly, these genes +are also thought to play a role in gonadal development. +Associations with variants in genes involved in sex hormone +metabolism have also been found. +Steps in the Development of Germ Cell Tumors. +Classification. +A simple classification of the most common +types of testicular tumors is presented in Table 21.7. +Two +broad groups are recognized. +Seminomatous tumors are +composed of cells that resemble primordial germ cells or +early gonocytes. +pale, fleshy, homogeneous mass on cut surface. +Seminoma +Seminoma is the most common type of GCT, making up +about 50% of these tumors overall. +The peak incidence is +in the fourth decade. +MORPHOLOGY +Seminomas produce bulky masses, sometimes ten times the size +of the normal testis. +21.19). +21.20B). +The +cytoplasm contains varying amounts of glycogen. +Approximately 15% +of seminomas contain syncytiotrophoblasts. +In contrast to other +GCTs, affected individuals are generally older (usual more +than 65 years old). +variation in cell and nuclear size and shape (pleomorphism). +Mitotic +figures and tumor giant cells are frequently seen. +Vascular-lymphatic +invasion is common. +In this age group it has +a very good prognosis. +21.21). +Histologically, the cells grow in alveolar or tubular +patterns, sometimes with papillary folds. +More undifferentiated +lesions may display sheets of cells with cleft-like spaces (Fig. +21.22). +In contrast to the seminoma +illustrated in Fig. +They may occur +at any age from infancy to adulthood. +Choriocarcinoma +Choriocarcinoma is a highly malignant type of GCT. +In its +pure form, choriocarcinoma is rare, constituting less than +1% of all GCTs. +Serum hCG is invariably elevated, often +markedly so. +Widespread metastasis, often associated with +hemorrhage at sites of involvement, may be seen. +21.24). +21.25). +Hemorrhage and necrosis are extremely +common. +21.23). +Figure 21.23 Choriocarcinoma. +Testicular tumors have a characteristic mode of spread. +Lymphatic spread is common to all forms. +In general, retro- +peritoneal para-aortic nodes are the first to be involved. +Subsequent spread may occur to mediastinal and supra- +clavicular nodes. +Hematogenous spread is primarily to the +lungs, but liver, brain, and bones may also be involved. +Metastases from seminomas typically involve lymph nodes. +Hematogenous spread occurs later in the course of dis- +semination. +Nonseminomatous GCTs tend to metastasize +earlier and more frequently via a hematogenous route. +The +histology of metastases and distant recurrences may differ +from that of the testicular lesion. +This is a reflection of the +fact that GCTs are derived from pluripotent germ cells. +Serum Biomarkers in Germ Cell Tumors. +Seminoma, which is radiosensitive and chemosensitive, +has the best prognosis. +Pure embryonal carcinoma behaves more aggressively than +mixed GCTs. +Pure choriocarcinoma and mixed GCT with +predominantly choriocarcinoma have a poor prognosis. +Figure 21.24 Teratoma of testis. +The variegated cut surface with cysts +reflects the presence of multiple tissue types. +adenocarcinoma, sarcoma, or other cancers. +Special +types include dermoid cysts, which typically contain hair, +teeth, and skin. +On rare occasions, prepubertal teratoma +may be admixed with yolk sac tumor. +Mixed Tumors +About 60% of GCTs are composed of more than one of the +above types. +Clinical Features of Testicular Germ Cell Tumors. +They +may arise in children or adults. +Approximately +10% of Leydig cell tumors in adults are malignant and can +produce metastases. +Histologically, the tumor cells +resemble their normal counterparts. +testicular neoplasm in men older than 60 years of age. +In +most cases, these are aggressive tumors that are disseminated +at the time of detection. +In contrast to GCTs, tumors are +frequently bilateral and involve the spermatic cord. +• Cryptorchidism, infertility, and prior history of GCT in contra- +lateral testis are risk factors. +• Germ cell neoplasia in situ is a precursor lesion associated +with most GCTs. +Seventy percent of patients with documented +germ cell neoplasia in situ will develop invasive GCTs. +Mixed tumors that contain more than one histologic type account +for 40% of GCTs. +• Clinically, testicular GCTs are divided into two groups: seminomas +and nonseminomatous tumors. +Seminomas spread mainly to +para-aortic nodes and are radiosensitive. +Nonseminomatous +tumors tend to spread earlier via lymphatic and hematogenous +routes. +These +neoplasms appear as firm, small nodules with a homogeneous +gray-white to yellow cut surface. +Most Sertoli cell tumors are +benign, but approximately 10% pursue a malignant course. +In some cases, the germ cell +component becomes malignant, giving rise to seminoma. +Hematocele is a collection of blood in the tunica vaginalis. +Varicocele +is a dilated vein in the spermatic cord. +21.26). +These zones are at risk for different types +of proliferative lesions. +Histologically, the prostate consists of glands separated +by abundant fibromuscular stroma. +21.27), which often contain small papillary infoldings. +We +begin our discussion with consideration of inflammatory +processes. +Figure 21.27 Normal prostate gland, with basal cell and secretory cell +layers. +Thus, +most cases are caused by various strains of E. +coli, other +gram-negative rods, enterococci, and staphylococci. +Clinically, acute bacterial +prostatitis is associated with fever, chills, and dysuria. +On rectal examination the prostate is exquisitely tender +and boggy. +The diagnosis can be established by urine +culture and clinical features. +The implicated +organisms are the same as those that cause acute prostatitis. +Fungal granulomatous prostatitis is typically +seen in immunocompromised hosts. +• Other forms of prostatitis. +Adenoviral and IGg4-associated +(Chapter 6) autoimmune prostatitis have also been +described. +It is not a premalignant lesion. +21.28A). +Estrogens +thus contribute to BPH pathogenesis by tipping the balance +toward proliferation (Fig. +21.28B). +(A) The central role of the stromal cells in generating dihydrotestosterone +(DHT) is depicted. +DHT may also be produced in skin and liver by both type 1 and type 2 5α-reductase. +(A) Well-defined nodules of BPH compress the urethra into a slit-like lumen. +may be seen. +21.29A). +21.29B). +Nodules composed primarily +of fibromuscular stroma are pale gray and firm. +21.29C), and infolding of the glands +may produce a papillary architecture. +DHT, an androgen derived from testosterone, +is the major hormonal stimulus for proliferation. +It is largely a disease of aging. +Epidemiology and Pathogenesis. +Environmental Factors. +21.30). +Inherited Genetic Factors. +Studies of twins and families +support the existence of important genetic predisposing +factors. +See text for details. +Androgens. +Unfortunately, most tumors eventually become resistant to +androgen blockade. +Acquired Genetic and Epigenetic Alterations. +Epigenetic events that modify gene expression are also +common in prostate cancer. +21.30. +Precursor Lesions. +Evidence in favor of stepwise develop- +ment of prostate cancer (as outlined in Fig. +Figure 21.31 Adenocarcinoma of the prostate. +21.31). +The +outer basal cell layer typical of benign glands is absent. +The cytoplasm of the tumor cells ranges from pale-clear to a +distinctive amphophilic appearance. +Nuclei are enlarged and often +contain one or more large nucleoli. +There is some variation in +nuclear size and shape, but in general pleomorphism is not marked. +Mitotic figures are uncommon. +Metastases spread via lymphatics to the obturator +nodes and eventually to the para-aortic nodes. +Hematogenous +spread occurs chiefly to the bones, particularly the axial +skeleton. +21.33). +A few findings are specific, +such as perineural invasion (Fig. +Compare to benign gland (left). +Figure 21.32 Metastatic osteoblastic prostatic carcinoma within vertebral +bodies. +21.33A and benign +hyperplastic glands in Fig. +21.29C with cancerous glands in Fig. +21.33B). +Such markers, while improving diagnostic accuracy, +Grading and Staging. +Grade and stage are the most +important prognostic factors in prostate cancer. +21.35A). +21.35C). +Other grades fall between +A B +Figure 21.33 Prostatic adenocarcinoma. +C +these extremes (Fig. +21.35B). +The two numeric grades +are then added to obtain a combined Gleason score. +Typically, a +transrectal needle biopsy is required to confirm the diagnosis. +PSA is a product of prostatic +epithelium and is normally secreted in the semen. +In normal men, only minute amounts of PSA +circulate in the serum. +Elevated blood levels of PSA occur +in association with localized as well as advanced cancer. +pathologic stage, margin status, and Gleason grade. +Metastatic carcinoma is treated with androgen deprivation +therapy. +KEY CONCEPTS +CARCINOMA OF THE PROSTATE +• Carcinoma of the prostate is very common in older men. +In +the United States, it is the most common malignancy in men. +Bone +metastases, often osteoblastic, typify advanced prostate cancer. +PSA is organ specific, but not cancer specific. +More than 90% of patients who +receive such therapy can expect to live for 15 years. +Currently, +the most common treatment is radical prostatectomy. +Ductal +adenocarcinomas are associated with a relatively poor +prognosis. +Almost +all cases of small-cell carcinoma are rapidly fatal. +The most common tumor to secondarily involve the +prostate is urothelial cancer. +Two distinct patterns of involve- +ment exist. +Large invasive urothelial cancers can directly +invade from the bladder into the prostate. +[Discussion of the pathophysiology of testicular +germ cell tumors and implications for therapy]. +[Review of salient +features of germ cell tumor biology and associated biomarkers]. +[Update +on the classification of bladder carcinoma]. +e25, 2017. +[A first look at the molecular characterization of invasive bladder +carcinoma]. +[Current recommendations for prostate cancer +grading]. +[Update +on classification of prostate and bladder carcinoma]. +[Review of the role of HPV in penile +carcinoma]. +[Update of the classification of penile +carcinoma]. +[Latest classification system for male urogenital neoplasms]. +22.1). +• Germ cells arise in the wall of the yolk sac by the fourth +week of gestation. +22.1A). +Further caudal growth brings these fused +ducts into contact with the urogenital sinus. +22.1B). +In the cervix +and vagina, these rests may be cystic and are termed +Gartner duct cysts. +INFECTIONS +A large variety of organisms can infect the female genital +tract. +HSVs are +DNA viruses that include two serotypes, HSV-1 and HSV-2. +By 40 years of age, approximately 30% of women are +seropositive for antibodies against HSV-2. +About one-third of newly infected individuals are +symptomatic. +Lesions around the urethra may +cause painful urination and urine retention. +As expected, recurrences +are much more common in immunosuppressed individuals. +Figure 22.2 Herpes simplex virus (HSV) infection (cervical smear). +The +cell in the center shows HSV cytopathic effect. +mother. +Cesarean delivery is warranted in such cases to +prevent transmission to the neonate. +The diagnosis is based on typical clinical findings and +HSV detection. +The purulent exudate is aspirated from the +lesions and inoculated into a tissue culture. +The viral +cytopathic effect can be seen after 48 to 72 hours, and the +virus can then be serotyped. +Individuals with primary, acute HSV infection do not have +serum anti-HSV antibodies. +Detection of anti-HSV antibodies +in the serum is indicative of recurrent/latent infection. +The +ultimate solution is an effective vaccine, a tantalizing goal +yet to be realized. +22.3A). +Molluscum may affect +any area of the skin but is most common on the trunk, +arms, and legs. +The average +MORPHOLOGY +By the time an HSV lesion is biopsied, it typically has ulcerated. +The epithelium is desquamated, and marked acute inflammation +is present in the ulcer bed. +22.2). +Condoms and antiviral +therapies reduce the risk of transmission, but do not prevent +it completely. +Previous infection with HSV-1 seems to reduce sus- +ceptibility to HSV-2 infection. +The gravest consequence of +HSV infection is transmission to the neonate during birth. +(A) Low-power appearance of a dome-shaped papule with dimpled center. +(B) High-power magnification +reveals intracytoplasmic viral inclusions. +incubation period is 6 weeks. +22.3B). +Severe +infection may result in mucosal ulcerations. +Patients typically present with thin, green-gray, +malodorous (fishy) vaginal discharge. +Bacterial cultures in such +cases reveal G. +In pregnant patients, bacterial vaginosis has +been implicated in premature labor. +• Chlamydia trachomatis infections mainly take the form of +cervicitis. +Chlamydia +infection is another well-recognized cause of PID. +With gonococcus, inflammatory changes start to appear +approximately 2 to 7 days after inoculation. +Pus fills the +center of the fallopian tube. +Such scarring may cause +infertility or ectopic tubal pregnancy. +channels rather than on the mucosal surfaces. +22.4A). +The infection may then spread to the ovary to create +a salpingo-oophoritis. +22.4B). +Nonspecific vulvitis is +particularly likely to occur in the setting of immunosup- +pression. +(A) Lichen sclerosus. +(B) Squamous cell hyperplasia, displaying thickened epidermis and hyperkeratosis. +These +cysts are usually lined by transitional or squamous epithelium. +They may become large, up to 3 to 5 cm in diameter, and +produce pain and local discomfort. +Bartholin duct cysts are +either excised or opened permanently (marsupialization). +Histologically, the lesion +is characterized by marked thinning of the epidermis (Fig. +The disease occurs in all age groups +but is most common in postmenopausal women. +It may +also be encountered elsewhere on the skin. +22.5B). +Lymphocytic +infiltration of the dermis is sometimes present. +The hyper- +plastic epithelium may show mitotic activity but lacks cellular +atypia. +(A) Low-power view showing exophytic, papillary architecture. +of sexually transmitted infections. +The etiology of +fibroepithelial polyps and squamous papillomas is unknown. +The lesions are +identical to those found on the penis and around the anus +in males (Chapter 21). +22.6A). +Condylomata acuminata are not precan- +cerous lesions. +years of age. +Squamous cell carcinoma is the most common +histologic type of vulvar cancer. +These are less +common (30% of cases) and occur in younger women +(average 60 years of age). +• Keratinizing squamous cell carcinomas are unrelated to HPV +infection. +These are more common (70% of cases) and +occur in older women (average 75 years of age). +Spontaneous regres- +sion of classic VIN has been reported, usually in younger +women. +No invasion is present. +There is a focus of necrosis (red area). +On histologic examination, basaloid +carcinoma (see Fig. +22.8A). +22.8B). +A B +Figure 22.8 Non–human papillomavirus (HPV) vulvar pre-neoplastic and malignant lesions. +No invasion is present. +The initial spread is to ingui- +nal, pelvic, iliac, and periaortic lymph nodes. +Ultimately, +hematogenous dissemination to the lungs, liver, and other +internal organs may occur. +GLANDULAR NEOPLASTIC LESIONS +Like the breast, the vulva contains modified apocrine sweat +glands. +These myoepithelial +elements are characteristic of sweat glands and sweat gland +tumors (Fig. +22.9). +In the vulva, it presents as a pruritic, red, crusted, maplike +area, usually on the labia majora. +In +the rare instances when invasion develops, the prognosis +is poor. +MORPHOLOGY +Paget disease is a distinctive intraepithelial proliferation of malignant +cells. +22.10A). +In addition, unlike squamous epithelium, the +cells express cytokeratin 7 (see Fig. +22.10B). +There is inflammation in the underlying dermis. +(B) Immunostaining for cytokeratin 7 highlights the intraepidermal Paget cells. +This is +normally replaced by squamous epithelium advancing +upward from the urogenital sinus. +They consist of 1- to 2-cm +fluid-filled submucosal cysts. +Infants may develop a unique, rare malignancy— +embryonal rhabdomyosarcoma (sarcoma botryoides). +22.11). +Rarely, +striations (indicative of muscle differentiation) can be seen +within the cytoplasm. +Such lesions can be mistaken for benign +inflammatory polyps. +(Courtesy +Dr. +The endocervix is lined by columnar, +mucus-secreting epithelium. +22.12). +In addition, at low +pH, lactobacilli produce bacteriotoxic hydrogen peroxide +(H2 O2). +Antibiotic therapy that suppresses lactobacilli +can also cause the pH to rise. +8 months, respectively). +Productive, persistent HPV infection requires viral entry +into immature basal epithelial cells. +22.12). +Although HPV infects immature squamous +cells, viral replication occurs in maturing squamous cells. +of other microorganisms, which may result in cervicitis or +vaginitis. +22.13). +Simple curettage +or surgical excision is curative. +The viral +DNA is integrated into the host cell genome in most cancers. +Hence a brief review +of the terminology is warranted. +Because the decision with regard to patient +management is two-tiered (observation vs. +replication, but only mild alterations in the growth of host +cells. +For these reasons, LSIL is not treated like a premalignant +lesion. +LSIL is approximately ten times more common +than HSIL. +By contrast to LSIL, HSIL is considered to be at high +risk for progression to carcinoma. +Nuclear alterations associated with perinuclear halos are termed +koilocytic atypia. +22.15). +The highest viral loads (assessed by in situ hybridization for HPV +DNA; see Fig. +22.15B) are found in maturing keratinocytes in the +upper half of the epithelium. +HPV E6 and E7 proteins prevent +cell cycle arrest. +22.15C), that are normally confined to the basal layer +of the epithelium. +22.15D). +common HPV type in both lesions. +Table 22.2 shows +rates of regression and progression of SILs within a 2-year +follow-up. +Progression +to invasive carcinoma, when it occurs, on average takes +place over several decades. +All of the aforementioned tumor +types are caused by high-risk HPVs. +The dark granular staining denotes HPV +DNA, which is most abundant in the superficial koilocytes. +a Progression within 2 to 10 years. +22.16A–B). +(B) Invasive adenocarcinoma. +(Fig. +22.17A–B). +Adenosquamous carcinoma is composed of +intermixed malignant glandular and squamous epithelium. +Lymphovascular invasion results in local and distant lymph +nodes metastases. +Distant metastases may also be found in the +liver, lungs, bone marrow, and other organs. +Carcinoma involves the vagina but not the lower +third. +Stage III—Carcinoma has extended to the pelvic wall. +These lesions shed abnormal cells that can be +detected on cytologic examination. +22.18. +The cytoplasmic staining of desquamated cells may be +either red or blue. +(A) Normal exfoliated superficial squamous cells. +(B) Low-grade squamous intraepithelial lesion—koilocytes. +(C) High-grade squamous +intraepithelial lesion (HSIL; cervical intraepithelial neoplasia [CIN] II). +(D) HSIL (CIN III). +(Courtesy Dr. +Edmund S. +HPV testing has a higher sensitivity but lower specificity, +as compared to the Pap test. +HPV DNA testing may be +added to cervical cytology for screening in women 30 years +of age or older. +Cervical cancer screening and preventive measures are +carried out in a stepwise fashion. +Abnormal appearing areas are biopsied. +Women with +biopsy-confirmed LSIL can be followed in a conservative +fashion. +HSIL is treated with +cervical conization (superficial excision). +Two HPV vaccines are now FDA-licensed. +The vaccines offer protection for up to 10 years; longer +follow-up studies are still pending. +HSIL may progress to invasive +carcinoma. +Mitotic figures are +numerous, and there is no evidence of mucus secretion +or vacuolation. +22.19A). +22.19B). +By the fourth week, the glands are tortuous, +producing a serrated appearance. +22.19). +(A) Proliferative phase with mitoses (arrow). +(B) Early secretory phase with subnuclear vacuoles (arrow). +(C) Late secretory exhaustion and predecidual changes (arrow). +(D) Menstrual endometrium with stromal breakdown (arrow) (see text). +22.19C). +22.19D). +They may also contribute to +the development of ectopic endometrial tissue and endo- +metrial cancer. +22.20C), submucosal +leiomyomas (see Fig. +This is a +clinical term for uterine bleeding that lacks an underlying +structural abnormality. +Note breakdown associated with proliferative glands. +(B) Chronic endometritis with plasma cells (arrow). +(C) Endometrial polyp. +(D) Submucosal leiomyoma with attenuation of the endometrial lining (arrow). +22.20A). +The inflammatory response +is chiefly limited to the stroma and is entirely nonspecific. +Endometrial +tuberculosis is rare in high income countries. +22.20B), +which are not seen in normal endometrium. +In about 15% +of cases, no cause is apparent. +The responsible organisms may not be detected by culture. +22.21). +A B +Figure 22.21 Endometriosis. +(A) Endometriosis involving the mucosa of the colon. +Molecular analyses have provided additional insights. +22.22). +These +factors may also contribute to avoidance of immune +clearance. +E, Estrogen. +inhibitors of aromatase are beneficial in the treatment of +endometriosis. +Deeply infiltrating endometriosis +can invade tissues and also cause fibrosis and adhesions. +22.21B), with or without the presence of +hemosiderin. +In rare cases only stroma is identified. +• It commonly results in dysmenorrhea, pelvic pain, and infertility. +Polyps may be asymptomatic or +may cause abnormal bleeding and infertility. +Polyps are responsive to +estrogen but show little or no response to progesterone (see +Fig. +22.20C). +However, tamoxifen has weak pro-estrogenic +effects in the endometrium. +Rarely, +adenocarcinoma arises within endometrial polyps. +Adenomyosis occurs in up to 20% of uteri. +It can +coexist with endometriosis. +When PTEN +function is lost, the PI3K/AKT pathway becomes overactive. +The glands show variation in size and shape and +may be dilated (Fig. +22.23B). +Hyperplasia may evolve into cystic atrophy when +estrogen is withdrawn. +A B +C D +Figure 22.23 Endometrial hyperplasia. +(A) Typical hyperplasia. +The glands are commonly back- +to-back and often have complex outlines due to branching +structures. +In addition, +the nuclei have open (vesicular) chromatin and conspicuous nucleoli. +22.23C–D). +• The PTEN tumor suppressor gene is mutated in approximately +20% of endometrial hyperplasias. +serous carcinomas, the most common morphologies of type +1 and type 2 tumors, respectively. +The +majority of these tumors fall in to the type I category. +It accounts for 7% of all invasive +cancer in women, excluding skin cancer. +In 2019 in the United States, 61,880 new +endometrial cancers and 12,160 deaths were predicted. +Worldwide there were over 380,000 new cases diagnosed +in 2018. +Most notable of these is obesity, +a rapidly increasing problem in high income countries. +22.24A). +22.25B), composed almost entirely of well-formed +glands; moderately differentiated (grade 2) (Fig. +22.25D), +characterized by greater than 50% solid growth pattern. +Up to 20% of endometrioid carcinomas contain foci of +squamous differentiation. +22.25A). +Invasion of the +broad ligaments may create a palpable mass. +Eventually, +A B +C D +Figure 22.25 Type I endometrial carcinoma. +(A) Endometrial adenocarcinoma presenting as a fungating mass in the fundus of the uterus. +22.26B and D). +All serous carcinomas belong to the copy number +high/serous-like molecular category. +As a result, they +have often spread outside of the uterus at the time of +diagnosis. +adenocarcinomas. +22.24B). +Serous tumors are considered type II tumors +and are by definition poorly differentiated (grade 3). +They +account for approximately 15% of cases of endometrial +carcinoma. +This subtype shows significant morphologic and +biologic overlap with ovarian serous carcinoma. +A B +C D +Figure 22.26 Type II endometrial carcinoma. +Treatment varies according to tumor type. +22.26C–D). +There is no +currently available screening test. +Stage II—Carcinoma involves the corpus and the cervix. +Stage III—Carcinoma extends outside the uterus but not +outside the true pelvis. +As mentioned, serous carcinoma has a propensity for +extrauterine (lymphatic or transtubal) spread. +Metastases usually +contain only epithelial components (see Fig. +22.27B). +Carcinosarcomas occur in postmenopausal women and +present with bleeding. +Outcome is determined primarily +by depth of invasion and stage. +(A) Micrograph showing both malignant epithelial and stromal components. +• There are two major types of endometrial carcinoma: type I +and type II. +• Four molecular subtypes of endometrioid and serous carcinoma +are currently recognized. +TP53 mutations are also found in precursor lesions. +malignant-appearing stroma, which coexists with benign +but abnormally shaped endometrial glands. +The principal diagnostic +dilemma is distinguishing these tumors from large benign +polyps. +The 5-year +survival rates average 50% for low-grade tumors and are +lower for high-grade tumors. +beneath the serosa (subserosal) (Fig. +22.28A). +Large tumors may develop +areas of yellow-brown to red softening. +22.28B). +Mitotic figures are scarce. +Both have a low mitotic index, +helping to distinguish these benign tumors from leiomyosarcoma. +Both +are considered benign despite their unusual behavior. +They are benign smooth +muscle neoplasms that may occur singly, but more often are +multiple. +Both genes encode closely related DNA-binding factors that +regulate chromatin structure. +Additionally, mutations in the +gene MED12 occur in roughly 70% of uterine leiomyomas. +Uterine leiomyomas, even when large or numerous, may +be asymptomatic. +Malignant transformation to leiomyosarcoma is +extremely rare. +Except in rare instances, +they are found within the myometrium of the corpus. +Only +infrequently do they involve the uterine ligaments, lower uterine +segment, or cervix. +(A) A large hemorrhagic tumor mass distends the lower corpus and is flanked by two leiomyomas. +(B) The tumor cells +are irregular in size and have hyperchromatic nuclei. +Numerous mitotic figures are present (arrows). +22.29A). +22.29B). +• High-grade stromal sarcoma shows marked atypia and is +associated with other gene fusions. +• Both low- and high-grade stromal sarcoma are prone to late +recurrences. +Dissemination throughout +the abdominal cavity is also encountered. +• Stromal nodules are benign, well-circumscribed tumors. +Historically, fallopian tube carcinoma was considered to +be a rare entity. +We will return to this issue when discussing ovarian +cancer in the next section. +abnormalities, polycystic ovaries, chronic anovulation, and +decreased fertility. +The etiology of PCOS +remains incompletely understood. +As the follicles +regress, the concentric theca-lutein hyperplasia may appear +nodular. +This change is not to be confused with true luteomas +of pregnancy (see later). +OVARIAN TUMORS +There are numerous types of ovarian tumors. +About 80% +are benign, and these occur mostly in young women between +20 and 45 years of age. +MORPHOLOGY +These cysts are usually multiple. +Malignant tumors are more common in women between 45 +and 65 years of age. +Some, principally epithelial tumors, are often bilateral. +Table +22.6 lists the tumors and their subtypes. +Epithelial Tumors +Most primary ovarian neoplasms arise from müllerian +epithelium. +These epithelial +proliferations are classified as benign, borderline, and +malignant. +The most intriguing risk factors are genetic. +Historically, the source +of these tumors was hypothesized to be cortical inclusion +cysts (Fig. +22.30). +These include +low-grade serous, endometrioid, and mucinous carcinomas. +They demonstrate high-grade +features and are most commonly of serous histology. +STIC, Serous tubal +intraepithelial carcinoma. +22.30). +About 70% are benign or +borderline, and 30% are malignant. +Benign and borderline +tumors are most common between 20 and 45 years of age. +Pathogenesis +Little is known about the risk factors for benign and bor- +derline tumors. +There is a higher frequency +of carcinoma in women with low parity. +Curiously, BRCA1 and BRCA2 mutations are rare in +sporadic high-grade serous carcinoma. +of the stroma is not seen (Fig. +22.33C). +22.33D). +22.32A) or as a mass projecting from the ovarian surface. +Borderline +tumors contain an increased number of papillary projections (Fig. +22.32A and C). +22.32B). +22.32C). +Microscopically, the cysts are lined by columnar epithelium. +In +benign tumors (Fig. +22.33A), the epithelial cells retain abundant +cilia, and microscopic papillae may be found. +(B) Carcinoma. +The cyst is opened to reveal a large, bulky tumor mass. +(A) Serous cystadenoma revealing stromal papillae with a columnar epithelium. +(C) Complex micropapillary growth defines a +low-grade “micropapillary” serous carcinoma. +(D) High-grade serous carcinoma of the ovary with invasion of underlying stroma. +of presentation, a picture associated with rapid clinical +deterioration. +Mucinous Tumors +Mucinous tumors account for about 20% to 25% of all ovarian +neoplasms. +They occur principally in middle adult life and +are rare before puberty and after menopause. +The vast +majority are benign or borderline tumors. +Thus, KRAS mutations may initiate +the development of these neoplasms. +22.34A). +22.34B). +(B) Columnar cells lining the cysts. +22.35). +Pseudomyxoma peritonei, +if extensive, may result in intestinal obstruction and death. +Pathogenesis +In about 15% to 20% of cases, endometrioid carcinoma +coexists with endometriosis. +Endometrioid carcinomas typically present +with solid and cystic areas of growth. +(A) View at laparotomy revealing +massive overgrowth of a gelatinous metastatic tumor. +(A, Courtesy Dr. +Paul H. +Clear cell tumors +of the ovary can be predominantly solid or cystic. +Clear cell carcinoma is treated like other types of ovarian +carcinoma. +They may contain +mucinous, serous, endometrioid, or transitional (Brenner +tumor) epithelium. +Uncommon transitional cell +carcinomas also occur in the ovary. +22.36B). +Most Brenner tumors are +benign, but borderline and malignant counterparts have been +reported. +Brenner tumors are often detected incidentally and even +when large behave in a benign fashion. +Benign lesions are easily resected and cured. +The +malignant tumors tend to cause progressive weakness, weight +loss, and cachexia. +Characteristically, +the ascitic fluid is filled with exfoliated tumor cells. +22.36A). +(B) Histologic detail of characteristic epithelial +nests within the ovarian stroma. +(Courtesy Dr. +M. +For these reasons, development +of new assays that permit early diagnosis is a top priority. +Prevention of ovarian cancer also remains an elusive goal. +Cystic teratomas are usually found in +young women. +KEY CONCEPTS +• Epithelial ovarian tumors are classified into benign, borderline, +or malignant. +• Benign tumors are composed of well-differentiated epithelial +cells with minimal proliferation. +Borderline tumors show +increased cell proliferation, but lack stromal invasion. +• Ovarian carcinomas are currently divided into type I (low-grade) +and type II (high-grade) tumors. +MORPHOLOGY +Benign teratoma is bilateral in 10% to 15% of cases. +Characteristi- +cally it consists of a unilocular cyst containing hair and sebaceous +material (Fig. +22.38). +22.39). +Dermoid cysts are sometimes incorporated +within the wall of a mucinous cystadenoma. +22.37). +Figure 22.38 Opened mature cystic teratoma (dermoid cyst) of the +ovary. +Grading is based on the proportion of the tumor that is comprised +of immature neuroepithelium (Fig. +22.40). +Figure 22.39 Benign cystic teratoma. +Low-power view of skin (right edge), +beneath which there is brain tissue (left edge). +Stage I +tumors, particularly those with low-grade (grade 1) histology, +have an excellent prognosis. +Higher-grade tumors confined +to the ovary are generally treated with adjuvant chemo- +therapy. +Dysgerminoma +Dysgerminoma is the ovarian counterpart of testicular +seminoma. +They may occur in childhood, but 75% occur in the +second and third decades of life. +Some occur in patients +with gonadal dysgenesis, including pseudohermaphroditism. +Most of these tumors have no endocrine function. +The origin of teratomas has been a matter of fascination +for centuries. +Some common beliefs blamed witches, night- +mares, or adultery with the devil. +The karyotype of almost +all benign ovarian teratomas is 46,XX. +They are always unilateral, although a contralateral +teratoma may be present. +Even rarer is strumal car- +cinoid, a combination of struma ovarii and carcinoid in the +same ovary. +Only about 2% of carcinoids in teratomas +metastasize. +The +tumor cells grow in sheets or cords separated by scant fibrous +stroma (Fig. +22.41), which is infiltrated by lymphocytes and may +contain noncaseating granulomas. +Figure 22.42 A Schiller-Duval body in a yolk sac carcinoma. +Overall survival exceeds 80%. +22.37). +Similar to +the normal yolk sac, the tumor cells elaborate α-fetoprotein. +22.42). +With combination chemotherapy, +there is greater than 80% survival, independent of disease +stage. +They +are histologically identical to the more common placental +lesions (described later). +KEY CONCEPTS +GERM CELL TUMORS +• Germ cell tumors constitute 15% to 20% of ovarian tumors. +• The majority are mature cystic teratomas (dermoid cysts) in +women of reproductive age. +• The remainder occur in young women and children; in these +age groups, malignant tumors dominate. +grow in anastomosing cords, sheets, or strands (Fig. +22.43A). +When these structures are evident, the diagnosis is +straightforward. +Although +they may be discovered at any age, approximately two-thirds +occur in postmenopausal women. +Occasionally, granulosa cell tumors produce androgens, +masculinizing the patient. +All granulosa cell tumors are potentially malignant. +It +is difficult to predict their biologic behavior from histology. +The likelihood of malignant behavior (recurrence, extension) +ranges from 5% to 25%. +The 10-year survival rate is approximately +85%. +Tumors composed predominantly of theca cells are +almost never malignant. +22.43B), and for monitoring patients being treated for these +neoplasms. +The granulosa cell component of these tumors has many +histologic patterns. +The small, cuboidal to polygonal cells may +A B +Figure 22.43 Granulosa cell tumor. +(A) Thecoma-fibroma composed of plump, differentiated stromal cells with thecal appearance. +(B) Large bisected fibroma +of the ovary apparent as a white, firm mass (right). +The fallopian tube is attached. +common in juvenile granulosa tumor, suggesting that it is +genetically distinct from the adult type. +22.44A). +Many +tumors contain a mixture of these cells and are termed +fibrothecomas. +Fibrothecomas and pure thecomas (a rare +subtype) may be hormonally active. +By contrast, pure +fibromas as a rule are hormonally inactive. +22.44B). +Focal areas of +thecal differentiation may be identified. +Uncommonly there is also a hydrothorax, usually only on +the right side. +Its +genesis is unknown. +The second association is with the basal +cell nevus syndrome, described in Chapter 25. +The vast +majority of fibromas, fibrothecomas, and thecomas are +benign. +They occur in women of all ages, although +the peak incidence is in the second and third decades. +MORPHOLOGY +These tumors are unilateral and may resemble granulosa cell +tumors grossly. +The cut surface is usually solid and varies from +gray to golden brown in appearance (Fig. +22.45A). +Microscopically, +A B +Figure 22.45 Sertoli cell tumor. +(A) Gross photograph illustrating characteristic golden-yellow appearance of the tumor. +(B) Photomicrograph showing +well-differentiated Sertoli cell tubules. +(Courtesy Dr. +It occurs in individu- +als with abnormal sexual development and in gonads +of indeterminate nature. +A coexistent dysgerminoma occurs in 50% of the +cases. +The prognosis is excellent if the tumor is completely +excised. +22.45B). +Leydig cells may be absent. +Heterologous elements, such as mucinous glands, bone, and +cartilage, may be present in some tumors. +The incidence of recurrence or metastasis by Sertoli-Leydig +cell tumors is less than 5%. +The tumors produce predomi- +nantly testosterone. +Treatment consists of surgical excision. +True hilus cell tumors are almost always benign. +• Pregnancy luteoma refers to a rare tumor that closely +resembles the corpus luteum of pregnancy. +These tumors +may produce virilization in pregnant patients and their +female infants. +• Pure thecomas are rare but may be hormonally active. +These +include selected disorders of early pregnancy, late pregnancy, +and trophoblastic neoplasia. +Understanding placental disorders requires a working +knowledge of normal placental anatomy. +The placenta is +composed of chorionic villi (Fig. +22.47). +Chorionic arteries branch further as they enter the villi. +Ascending infection is +particularly common in second-trimester losses. +Ectopic pregnancies account for +2% of confirmed pregnancies. +In some cases, however, the +fallopian tubes are apparently normal. +The host implantation site may also develop +decidual changes. +A +B +Figure 22.46 Normal placenta. +Rupture frequently results in massive intraperitoneal +hemorrhage, which sometimes is fatal. +Most of these +occur before 12 weeks. +Ten to fifteen percent of clinically +recognized pregnancies terminate in spontaneous abortion. +In most individual instances, +the mechanisms leading to early loss of pregnancy are +unknown. +However, multiple fetal and maternal causes of +spontaneous abortion have been identified. +Clinical Features +Rupture of a tubal pregnancy is a medical emergency. +Umbilical vessels branch and terminate in placental villi, where nutrient exchange takes place. +correlating with distention and then rupture of the fallopian +tube. +In such cases, the patient may rapidly develop hemor- +rhagic shock and signs of an acute abdomen. +There are three types of twin placentas (Fig. +(Modified from Gersell D, +et al: Diseases of the placenta. +Acute chorioamnionitis. +(A) On gross examination, the placenta +contains greenish opaque membranes. +(C) Acute +necrotizing intervillositis from Listeria infection. +The space between the villi is filled with blood and acute inflammatory cells (neutrophils). +The villi appear +necrotic. +Dichorionic placentation may occur with either +monozygotic or dizygotic twins and is not specific. +One complication of monochorionic twin pregnancy is +twin-to-twin transfusion syndrome. +If severe, it may result in the death of +one or both fetuses. +It is an +important cause of severe, potentially life-threatening +postpartum bleeding. +22.49A–B). +22.49C). +22.50). +• Endothelial dysfunction and imbalance of angiogenic and +antiangiogenic factors. +The result is defective vascular +development in the placenta. +Antihypertensive therapy does not affect +the disease course or improve outcome. +They are usually diagnosed during early pregnancy (average +9 weeks) by pelvic sonography. +For unknown reasons, the incidence varies considerably in +different parts of the world. +22.52A–B). +Partial Mole +Partial moles result from fertilization of an egg with two +sperm (see Fig. +22.52C). +In these moles, the karyotype is +triploid (e.g., 69,XXY) or occasionally tetraploid (92,XXXY). +Fetal tissues are typically present. +Figure 22.51 Acute atherosis of uterine vessels in eclampsia. +Note +fibrinoid necrosis of the vessel wall and subendothelial macrophages. +(Courtesy Dr. +Drucilla J. +22.51). +The kidney lesions are variable. +Immunofluorescent studies show abundant fibrin +deposition in glomeruli. +In advanced cases, fibrin thrombi are +present in the glomeruli and capillaries of the cortex. +Similar changes are +often found in the heart and the anterior pituitary gland. +Management of preeclampsia differs depending on the +gestational age and severity of disease. +For term pregnancies, +delivery is the treatment of choice regardless of disease +severity. +However, eclampsia, severe preeclampsia with1034 CHAPTER 22 The Female Genital Tract +A. +Complete mole +Chromosome +duplication +46XX +23X +Homozygous +Empty ovum +complete mole +B. +Note marked distention of +the uterus by enlarged, vesicular chorionic villi. +Adnexa (ovaries and +fallopian tubes) are visible on the left and right side of the uterus. +C. +The tumor manifests clinically with +vaginal bleeding and irregular uterine enlargement. +It is +always associated with a persistently elevated serum hCG. +(B) Less commonly, complete moles arise from dispermy in which two +sperm fertilize an empty ovum. +(C) Partial moles arise from two sperm +fertilizing a single ovum. +22.53 and 22.54). +Most moles are successfully removed by curettage. +Continuous +elevation of hCG may be indicative of persistent or invasive +mole (described next). +(A) Choriocarcinoma presenting as a bulky hemorrhagic mass invading the uterine wall. +(Courtesy Dr. +David R. +Genest, Brigham and Women’s Hospital, Boston, Mass.) +United States. +Rarely, nongestational choriocarcinoma develops +from germ cells in the ovaries or the mediastinum. +Many of the cured patients +have had normal subsequent pregnancies and deliveries. +The malignant trophoblastic cells typically +diffusely infiltrate the endomyometrium. +22.55A). +22.55B); chorionic villi +are absent. +Mitoses are abundant and sometimes abnormal. +Sometimes the tumor +does not appear until months after these events. +[An overview of HSV vaccine development]. +[A review of clinical outcomes in patients with intrauterine +DES exposure]. +[A review of current HPV vaccines]. +[A seminal study of HPV detection in cervical +carcinoma]. +[A comprehensive literature +review of the natural history of cervical intra-epithelial neoplasia]. +[A review of HPV-related cervical +carcinogenesis]. +[The epidemiology of HPV-related disease]. +[Current recom- +mendations for HPV testing]. +Uterus and Endometrium +Bulun SE: Endometriosis, N Engl J Med 360:268, 2009. +[A seminal review +of endometriosis pathogenesis]. +[A review +of the pathogenesis of leiomyomas]. +Giudice LC: Endometriosis, N Engl J Med 362:2389, 2010. +[A review of +the pathophysiology of endometriosis]. +[A review of stem cells in endometriosis]. +[A +comprehensive genomic study of endometrioid and serous endometrial +carcinoma]. +Ovary +Azzia R et al: Polycystic ovary syndrome, Nat Rev Dis Primers 11:16057, +2016. +[A comprehensive review of PCOS]. +[A landmark +study of mutations in non-epithelial ovarian tumors]. +[A detailed +review of the molecular genetics of ovarian germ cell tumors]. +[A recent +comprehensive review of the pathogenesis of ovarian cancer]. +Mathias-Guiu X, Stewart CJR: Endometriosis-associated ovarian +neoplasia, Pathology 17:30384, 2017. +[An overview of ovarian tumors +associated with endometriosis]. +[A review +of angiogenic alterations in preeclampsia]. +[A review of the clinicopathologic characteristics of molar +pregnancies]. +All of these features impact the origin, +presentation, and treatment of breast disease. +Each of +these elements is the source of both benign and malignant +lesions (Fig. +23.1). +23.1). +Changes in the female breast are most dynamic and +profound during the reproductive years. +Just as the endometrium grows and ebbs with each menstrual +cycle, so does the breast. +In the first half of the menstrual +cycle the lobules are relatively quiescent. +Upon menstruation, the fall in hormone +levels induces regression of the lobules. +Only with pregnancy does the breast completely mature +and become fully functional. +Lobules increase progressively +in number and size. +DCIS, Ductal carcinoma in situ. +and calories) over the next 10 days as progesterone levels +drop. +23.2A). +Greater than 90% of symptomatic breast +lesions are benign. +23.2B). +(B) Presentations of breast cancer. +cyclic pain may be due to premenstrual edema. +• Inflammation causes erythema and edema involving all +or part of a breast. +An impor- +tant mimic of reactive inflammation is inflammatory +breast carcinoma (discussed later). +• Nipple discharge may be normal when small in quantity +and bilateral. +Repeated nipple stimulation also may +induce lactation. +Galactorrhea is not a feature of malig- +nancy. +Bloody or serous discharges are most commonly +due to large duct papillomas and cysts. +During pregnancy, +rapid growth and remodeling of the breast may produce +a bloody discharge. +When pro- +nounced, imaging studies may be needed to exclude the +presence of a discrete mass. +The most common benign +masses are fibroadenomas and cysts. +23.2B). +The sensitivity and specificity of mammography increase +with age. +The principal mammographic +signs of breast carcinoma are densities and calcifications: +• Densities. +Breast lesions that replace adipose tissue with +radiodense tissue form mammographic densities. +• Calcifications. +Calcifications +associated with malignancy are usually small, irregular, +numerous, and clustered. +By the time +of detection, most (70% to 80%) cancers are invasive and +some have metastasized. +when the breast is most vulnerable due to cracks and fissures +in the nipples. +The breast is erythematous and painful, and fever is often +present. +At the outset only one duct system or sector of the +breast is involved. +If not treated, the infection may spread +to the entire breast. +Only rarely is surgical drainage required. +In +many affected women the nipple inverts due to traction +produced by inflammation and scarring. +More than 90% of +afflicted individuals are smokers. +23.3). +When squamous +metaplasia extends deep into a nipple duct, keratin becomes trapped and +accumulates. +dilation and eventually rupture of the duct. +Fat Necrosis +The presentations of fat necrosis are protean and may closely +mimic cancer. +About half of affected women have a history +of breast trauma or surgery. +If +secondary bacterial infection is present, antibiotics also have +a therapeutic role. +Pain and erythema are +uncommon. +This disorder tends to occur in the fifth or sixth +decade of life, usually in multiparous women. +Unlike +squamous metaplasia of lactiferous ducts, it is not associated +with cigarette smoking. +Ill-defined, firm, gray-white nodules containing small chalky-white +foci are seen grossly. +23.4). +Granulomas may form around cholesterol +deposits and secretions. +Subsequent fibrosis produces an irregular +mass with skin and nipple retraction. +Its only clinical +significance is that it must be distinguished from breast +cancer. +Granulomatous lobular mastitis is an uncommon +disease that occurs only in parous women. +These +histologic patterns may be manifestations of the same disease. +Treatment includes antibiotics and sometimes steroids. +Figure 23.4 Duct ectasia. +Chronic inflammation and fibrosis surround an +ectatic duct filled with inspissated debris. +C +Figure 23.5 Apocrine cysts. +(A) Clustered, rounded calcifications are +seen in a specimen radiograph. +(B) Gross appearance of typical cysts filled +with dark, turbid fluid contents. +(C) Cysts are lined by apocrine cells with +round nuclei and abundant granular cytoplasm. +Note the luminal +calcifications, which form on secretory debris. +Several other morphologic alterations fall into the category +of “nonproliferative” changes. +• Cysts. +Small cysts form by the dilation of lobules and in turn +may coalesce to form larger cysts. +Unopened cysts contain +turbid, semitranslucent brown- or blue-colored fluid (blue-dome +cysts) (Fig. +23.5B). +23.5C). +Calcifications are common (Fig. +23.5A). +• Fibrosis. +Cysts frequently rupture, releasing secretory material +into the adjacent stroma. +The resulting chronic inflammation +and fibrosis contribute to palpable nodularity of the breast. +• Adenosis. +Adenosis is defined as an increase in the number +of acini per lobule. +It is a normal feature of pregnancy. +(B) Epithelial hyperplasia. +The lumen is filled with a +heterogeneous, mixed population of luminal and myoepithelial cell types. +Irregular slit-like fenestrations are prominent at the periphery. +incidental findings in biopsies performed for other reasons. +These lesions are considered predictors of risk, rather than +direct precursors, of carcinoma. +23.6A). +Irregular lumens can often be discerned at the periphery +of the cellular masses (Fig. +23.6B). +Epithelial hyperplasia is usually +an incidental finding. +• Sclerosing adenosis. +23.7). +• Complex sclerosing lesion. +These lesions have components +of sclerosing adenosis, papilloma, and epithelial hyperplasia. +• Papilloma. +23.9). +Epithelial hyperplasia and apocrine metaplasia are frequently +present. +Large duct papillomas are situated in the lactiferous +Figure 23.7 Sclerosing adenosis. +Calcifications are present within some of the lumens. +sinuses of the nipple and are usually solitary. +Small duct papillomas +are commonly multiple and located deeper within the ductal +system. +Lobule formation is absent. +It presents as a button-like subareolar enlargement and may +be unilateral or bilateral. +23.10). +Lobule +formation is almost never observed. +Atypical lobular hyperplasia +Figure 23.9 Intraductal papilloma. +The papillae arborize within the lumen and are +biopsies. +lined by myoepithelial and luminal cells. +C +Figure 23.8 Radial sclerosing lesion. +(A) Radiograph shows an irregular +central mass with long radiodense projections. +These +features are highly atypical, but fall short of a diagnosis of ductal carcinoma in situ. +(B) Atypical lobular hyperplasia. +A population of monomorphic small, +round, loosely cohesive cells partially fills a lobule. +It is distinguished from DCIS in that it only partially fills +involved ducts (Fig. +23.11A). +23.11B). +Both breasts are at +increased risk. +• The majority are not precursors of cancer. +• These lesions are classified according to the subsequent risk +of cancer in either breast. +The lifetime risk of breast cancer is 1 in 8 for women +living to age 90 in the United States. +In this chapter, “luminal” cancers +are defined as being positive for ER and negative for HER2. +“Triple negative +breast cancers” (TNBCs) are cancers that are negative for +ER and HER2. +23.12). +Rates are per 100,000 women. +In contrast, luminal cancers show a marked +increase in incidence with age. +TNBC, +Triple negative breast cancer. +Breast cancer incidence and biology vary with ethnicity. +For Hispanic +women, the average age at diagnosis is 56, and 20% are +diagnosed at ages below 50. +The “excess” cancers in women +of European descent are mostly of luminal type (Fig. +23.12). +Surgical and medical interventions also can decrease risk. +Bilateral prophylactic mastectomy decreases risk by about +90%. +Chemoprevention using ER antagonists decreases +the incidence of ER-positive cancers. +These interventions +are mainly offered to women at very high risk for breast +cancer. +Gene expression (mRNA) profiling measures +relative levels of mRNA expression. +Red indicates a relative increase; green, a relative decrease; and black, no change in levels. +Genes are arrayed from top +to bottom and tumors from left to right. +All of these cancers express ER (an +estrogen-dependent transcription factor). +Biallelic +mutations cause a form +of Fanconi anemia. +ER, Estrogen receptor; TNBC, triple negative breast cancer. +Most of these genes play complex and interrelated roles +in maintaining genomic integrity. +BRCA1, BRCA2, and CHEK2 all have important functions +in repair of double-stranded DNA breaks. +23.14 and Table 23.4 and are described next. +DCIS +Figure 23.14 Major pathways of breast cancer development. +Three main pathways have been identified. +The most common pathway (yellow arrow) leads to +luminal (ER-positive) carcinomas. +The third pathway (green arrow) consists of +HER2-positive cancers. +Amplification of HER2 can occur in either ER-positive or ER-negative lesions. +A definite HER2-positive precursor lesion has not +been identified. +See text for other details. +DCIS, Ductal carcinoma in situ. +ER, Estrogen receptor; mRNA, messenger RNA; TNBC, triple negative breast cancer. +23.12). +These +are considered the earliest recognizable precursors of luminal +breast cancers. +23.13). +Recurrences after this time are rare. +HER2-positive cancers show a mixed pattern with both early and late +peaks. +or longer by treatment with antiestrogens (Fig. +23.15). +23.16). +23.15). +TNBC also shares other genetic features with serous +ovarian carcinoma. +In +familial breast cancer, this defect is often related to germline +BRCA1 and BRCA2 mutations. +The cancers that recur usually do so in the +first 8 years after diagnosis (see Fig. +23.15). +Metastases are +often to visceral sites and brain and frequently result in +death. +Patients who survive 10 years are likely cured, as +late recurrences are unusual. +Such +changes may set the stage for stromal invasion by breast +cancer cells. +With this as background, we next turn to discussion of +the pathology of breast cancer. +• The most important risk factors for sporadic cancers in women +are estrogenic stimulation and age. +duct lobular unit. +Ductal Carcinoma in Situ. +DCIS is almost always detected by mammography. +23.17). +Some +cases of DCIS have a single growth pattern, but most are comprised +of a mixture of patterns. +23.17A). +23.17B). +23.17C). +Micropapillary DCIS +produces complex bulbous protrusions without fibrovascular +cores (Fig. +23.17D). +Pruritus is common, +and the lesion may be mistaken for eczema. +(A and B) Comedo type. +(A) Specimen radiograph reveals linear and branching calcifications within the +ductal system. +(C) Cribriform DCIS. +Note +the round, regular (“cookie cutter”) spaces containing calcifying secretory material. +(D) Micropapillary DCIS. +The papillary projections lack fibrovascular +cores. +Paget cells are readily detected by nipple biopsy or cytologic +preparations of the exudate. +In contrast, the majority of women without a palpable +mass have only DCIS. +23.19A). +23.19B). +Necrosis and secretory activity are not seen, and thus calcifica- +tions are absent. +LCIS almost always expresses ER and PR and is +HER2-negative. +Duct involved +by DCIS +Figure 23.18 Paget disease of the nipple. +Death from +metastatic breast cancer after a diagnosis of DCIS occurs in +1% to 3% of women. +Mastectomy is curative in greater than 95% of women. +Trials +to identify patients who can safely undergo observation +rather than treatment are ongoing. +Lobular Carcinoma in Situ. +However, unlike DCIS, it is unclear if surgical removal of +the identified lesion lowers risk. +Invasive (Infiltrating) Carcinoma +Breast carcinoma has a wide variety of morphologic appear- +ances. +23.20). +They most commonly present +as a hard, irregular radiodense mass (Fig. +23.20A, B) associated +with a desmoplastic stromal reaction (Fig. +The underlying lobular architecture can still be recognized. +The cells extend into the adjacent duct by pagetoid spread. +Lobular carcinoma is the subtype with the clearest associa- +tion of phenotype and genotype. +Like LCIS, most cases show +biallelic loss of expression of CDH1, the gene that encodes +E-cadherin. +Of interest, this subtype +has a better prognosis than other poorly differentiated +carcinomas. +Many other special histologic types of breast cancer (too +numerous to list) have been described. +occasional foci of calcification. +Less commonly, tumors present as +deceptively well-circumscribed (Fig. +23.20D, E) masses composed +of sheets of tumor cells with scant stromal reaction (Fig. +23.20F) +or may be almost imperceptible (Fig. +23.20I). +Invasive carcinoma is graded using the Nottingham Histologic +Score. +Carcinomas are scored for tubule formation, nuclear +pleomorphism, and mitotic rate. +23.21A). +23.21B). +A high proliferative rate and areas of tumor necrosis are +common in high-grade tumors (Fig. +23.21C). +These include +lobular carcinoma, mucinous carcinoma, tubular carcinoma, and +papillary carcinoma. +Microscopically, such tumors are marked by an exuberant desmoplastic stromal +response (C). +Rarely, invasive cancers produce little or no stromal response. +Microscopically, tumor cells are found +scattered within normal-appearing fibroadipose tissue (I). +(B, Courtesy Dr. +23.22A). +Tubule formation +is absent. +The borders are pushing or circumscribed. +23.22B). +23.22C). +A cribriform pattern may also be +present. +Apocrine snouts are typical, and calcifications may be +present within the lumens. +Only rare mitoses are present. +Occasional mitotic figures are seen. +implies, produces true papillae, fronds of fibrovascular tissue lined +by tumor cells (Fig. +23.22D). +Two special histologic types frequently overexpress HER2. +The tumor cells of apocrine carcinoma resemble the cells that +line sweat glands. +23.22E). +23.22F). +TNBC (ER-negative, HER2-negative) often corresponds to one +of several special histologic types. +Chief among these is carcinoma +with medullary pattern. +23.22G). +DCIS is minimal or not seen. +23.22H). +These carcinomas rarely metastasize. +Another special subtype that merits mention is inflammatory +carcinoma. +It +presents as breast erythema, swelling, and skin thickening. +The presentation can be confused with a breast +infection, leading to delayed diagnosis. +These tumors are usually +of high grade but do not belong to any particular molecular +subtype. +The major prognostic factors are as follows (Table 23.5): +• Lymph node metastases. +(A) Lobular carcinoma. +(B) Mucinous carcinoma. +(C) Tubular carcinoma. +(D) Papillary carcinoma. +(E) Apocrine carcinoma. +(F) Micropapillary carcinoma. +(G) Carcinoma with medullary pattern. +(H) Secretory carcinoma. +See text for morphologic descriptions. +Histologic grade Survival diminishes with higher histologic grade. +Expression of +ER, PR, and +HER2 +in the absence of distant metastases. +Therefore, biopsy is necessary for accurate +assessment. +In these patients, metastasis +may occur via the internal mammary lymph nodes or +hematogenously. +• Distant metastases. +• Tumor size. +• Locally advanced disease. +• Lymphovascular invasion. +This finding is +strongly associated with the presence of lymph node +metastases. +• Inflammatory carcinoma. +The +3-year survival rate is only 3% to 10%. +Additional prognostic factors are related to tumor biology +(see Table 23.5). +A few other prognostic factors are clinically +useful and merit brief mention. +• Gene expression profiling. +Most are heavily weighted toward +inclusion of genes that are involved in proliferation. +• Response to neoadjuvant chemotherapy. +In +contrast, very few luminal cancers respond completely +to chemotherapy. +For many +luminal cancers, endocrine therapy is the best and most +effective therapeutic option. +Chemotherapy is used for highly +proliferative carcinomas, regardless of molecular subtype. +For +HER2 cancers, targeted therapy with HER2 antagonists has +markedly improved prognosis. +A multigene assay, when available, can be used to assign stage in this setting. +The survival estimates include the average survival for patients +with all biologic types of cancer. +disease, Klinefelter syndrome, and residency in Western +countries. +Approximately 6% +of male carriers develop breast cancer. +Dissemination follows +the same pattern as in women. +Most cancers are treated locally with +mastectomy and axillary node dissection. +• Effective treatment requires both local and systemic control +of disease. +There +are about 2670 cases and 500 deaths in the United States each +year. +Fibroadenoma +Fibroadenoma is the most common benign tumor of the +female breast. +Two-thirds of fibroadenomas harbor driver +mutations in MED12. +The pathogenesis of the remainder +is uncertain. +23.23B). +The delicate and often myxoid stroma +resembles normal intralobular stroma. +23.23C). +In older +women, the stroma typically becomes densely hyalinized and the +epithelium atrophic. +Figure 23.23 Fibroadenoma. +(A) Radiograph shows a characteristically +well-circumscribed mass. +The absence of adipose tissue accounts for the radiodensity of the lesion. +The border is sharply delimited from +the surrounding tissue. +Like fibroadenomas, the majority of phyllodes +tumors have MED12 mutations. +Rapid growth and +infarction during pregnancy may raise a false suspicion of +carcinoma. +Whether these lesions are true neoplasms or reactive +hyperplasias is unclear. +23.24). +Malignant Tumors of Interlobular Stroma +Malignant stromal tumors of the breast are rare. +Angiosarcoma of the breast may be +sporadic or arise as a complication of therapy. +Metastases to the breast are rare and most commonly arise +from melanomas and ovarian cancers. +Figure 23.24 Phyllodes tumor. +Low-grade (benign) lesions resemble fibroadenomas but +are more cellular and are mitotically active. +High-grade (malignant) +lesions may be difficult to distinguish from sarcomas. +Only the +stromal component metastasizes. +These include benign as well as malignant tumors, +all uncommon and hence considered briefly. +Lipomas +are often palpable and can also be detected mammographi- +cally as fat-containing lesions. +The only importance of these +lesions is to distinguish them from malignancies. +Fibromatosis is a clonal proliferation of fibroblasts and +myofibroblasts. +It presents as an irregular, infiltrating mass +that can involve muscle. +Though locally aggressive, this +lesion does not metastasize. +Some cases are associated with +prior trauma or surgery. +• Fibroadenomas are the most common benign tumor of the +breast. +[From Queen Atossa in Babylonia in 490 +BCE to Dr. +Yalom M: History of the breast, 1998, Ballantine Books. +Available +at https://www.cancer.org. +[Excellent resource for up-to-date information +about breast cancer.]. +International Association of Cancer Registries (IACR): GLOBOCAN, +2012. +Available at http://globocan.iarc.fr. +Large Internet Breast Cancer Datasets +The Cancer Genome Atlas project. +https://cancergenome.nih.gov. +(Accessed +1 January 2018). +https://icgc.org. +(Accessed +1 January 2018). +www.cbioportal.org. +(Accessed 1 January 2018). +This site also provides links to other databases].a +National Cancer Database (NCDB). +https://www.facs.org. +(Accessed 1 +January 2018). +http:// +seer.cancer.gov. +(Accessed 1 January 2018). +[Single-cell sequencing has shown +that every cell in a breast cancer may be genetically unique. +For example, tubule formation correlates +strongly with genes expressed by luminal cancers]. +[DNA sequencing and messenger RNA profiling provide only part of the +profile of a cancer cell. +Hortobagyi GN, Connolly JL, D’Orsi CJ et al: Breast. +(Accessed 23 December 2017). +[The American Joint Commission on +Cancer issues guidelines on cancer staging. +After publication of the book, +a significantly revised Breast Chapter was provided online. +Current +CAP protocols are available at www.cap.org]. +National Comprehensive Cancer Network (NCCN). +https://www +.nccn.org. +a The largest datasets with molecular information on breast cancer +include these. +An endocrine hormone is +frequently carried by the blood from its site of release to +its target. +24.1). +• Mammosomatotrophs produce GH and prolactin (PRL). +• Lactotrophs produce PRL. +• Thyrotrophs produce thyroid-stimulating hormone (TSH). +• Gonadotrophs produce follicle-stimulating hormone (FSH) +and luteinizing hormone (LH). +The same two hormones also regulate sper- +matogenesis and testosterone production in males. +24.2), which are carried to the anterior +pituitary by the portal venous plexus. +A +B +Figure 24.1 (A) Photomicrograph of a normal pituitary. +Synthetic oxytocin can be given to +pregnant women to induce labor. +An increase in plasma osmotic pressure detected +by osmoreceptors also triggers ADH secretion. +• Hyperpituitarism arises from excess secretion of trophic +hormones. +The symptoms of +hyperpituitarism are discussed later in the context of +individual tumors. +• Hypopituitarism results from deficiency of trophic hor- +mones. +• Symptoms related to local mass effects. +Null cell adenomas, by definition, only present with mass effects. +some hypothalamic disorders. +Pituitary adenomas are usually found in adults; the peak +incidence is from 35 to 60 years of age. +24.3), and β- and γ-subunits that noncovalently +bind α-subunits. +The α-subunit of Gs (Gs α) +is encoded by the GNAS gene, located on chromosome +20q13. +degradation. +MORPHOLOGY +The typical pituitary adenoma is soft and well-circumscribed. +24.4). +Such +lesions are termed aggressive adenomas. +GDP, Guanosine +diphosphate; GTP, guanosine triphosphate; Pi, inorganic phosphate. +See +Fig. +24.2 for other abbreviations. +Figure 24.4 Pituitary adenoma. +Acute +hemorrhage into an adenoma is sometimes associated with +pituitary apoplexy, as noted earlier. +The following is a description of the individual types of +tumors. +Figure 24.5 Pituitary adenoma. +Note also the absence of reticulin network. +24.5). +24.6A). +24.6B). +Local mass effects may be produced by any +type of pituitary tumor. +As mentioned earlier, these effects +AB +Figure 24.6 Ultrastructural features of prolactinoma. +(A) Electron micrograph of a sparsely granulated prolactinoma. +(B) Electron micrograph of +a densely granulated growth hormone–secreting adenoma. +The tumor cells are filled with numerous large, electron-dense secretory granules. +(Courtesy Dr. +Eva Horvath, St. +Lactotroph adenoma is the cause of almost one-fourth of +cases of amenorrhea. +Hyperprolactinemia may result from causes other than +prolactin-secreting pituitary adenomas. +Physiologic hyper- +prolactinemia occurs in pregnancy. +Other causes of hyperprolactinemia include renal failure +and hypothyroidism. +• If the levels of GH are increased after closure of the +epiphyses, acromegaly develops. +Bone density may increase (hyper- +ostosis) in both the spine and the hips. +Enlargement of +the jaw results in its protrusion (prognathism) and broaden- +ing of the lower face. +The feet and hands are enlarged, +and the fingers become thickened and sausage-like. +In +most instances, gigantism is also accompanied by evidence +of acromegaly. +The diagnosis relies on documenting elevated serum GH +and IGF-1 levels. +The causative pituitary +adenoma can be removed surgically or treated by pharma- +cologic means. +Thus, +accurate subtyping of somatotroph adenomas is of prognostic +importance. +MORPHOLOGY +Corticotroph adenomas are usually microadenomas at the time +of diagnosis. +Pituitary carcinoma is rare, accounting for less than 1% +of pituitary tumors. +The presence of craniospinal or systemic +metastases is a sine qua non of a pituitary carcinoma. +Metastases +usually appear late in the course, following multiple local +recurrences. +Pituitary blastoma presents with signs and +symptoms of Cushing disease. +granulated). +Nuclear TPIT is also +positive in the neoplastic cells, consistent with corticotroph lineage. +Because the adrenals are absent in persons with Nelson +syndrome, hypercortisolism does not develop. +They are a rare cause of hyperthyroidism. +Most are derived from cells of PIT-1–expressing lineage. +• Null cell adenomas do not express any markers of hormonal +or lineage differentiation. +• Pituitary adenomas can be macroadenomas (greater than 1 cm +in diameter) or microadenomas. +• Corticotroph adenomas secreteACTH and present with Cushing +syndrome and hyperpigmentation. +During +pregnancy, the anterior pituitary enlarges to almost twice +its normal size. +Classically, this occurs +in obese women with a history of multiple pregnancies. +Sometimes the loss of functioning +parenchyma is sufficient to produce hypopituitarism. +Hypothalamic insuf- +ficiency may also appear following irradiation of the +brain. +• Children can develop growth failure ituitary dwarfism) +(p +due to growth hormone deficiency. +• Prolactin deficiency results in failure of postpartum +lactation. +• Diabetes insipidus. +• Syndrome of inappropriate ADH (SIADH) secretion. +ADH +excess causes over-resorption of free water, resulting in +hyponatremia. +(Courtesy Dr. +“Palisading” of the squamous epithelium is frequently observed +at the periphery. +Compact, lamellar keratin formation (“wet +keratin”) is a diagnostic feature of this tumor (Fig. +24.7). +As +mentioned earlier, dystrophic calcification is a frequent finding. +Larger lesions are more invasive, but this does not impact +on the prognosis. +Cranio- +pharyngioma is thought to arise from vestigial remnants +of Rathke pouch. +These slow-growing tumors account for +1% to 5% of intracranial tumors. +24.8). +24.8). +The net +result is an increase in the basal metabolic rate. +Elevated T3 and T4 levels, in turn, +feed back to suppress the secretion of both TRH and TSH. +Figure 24.9 A person with hyperthyroidism. +most commonly by hyperfunction of the thyroid gland, it +is often referred to as hyperthyroidism. +• Excessive levels of thyroid hormone result in an increase +in the basal metabolic rate. +Heat intolerance is common. +Sweating is increased because of higher levels of calori- +genesis. +Heightened catabolic metabolism results in weight +loss despite increased appetite. +• Cardiac manifestations are among the earliest and most +consistent features. +Tachycardia, palpitations, and cardiomegaly are common. +Arrhythmias such as atrial fibrillation occur frequently, +particularly in older patients. +Congestive heart failure +may develop, especially in older adults with preexisting +cardiac disease. +Proximal muscle weak- +ness and decreased muscle mass are common (thyroid +myopathy). +Most patients +also develop some degree of fat malabsorption. +• Ocular changes often call attention to hyperthyroidism. +24.9). +• The skeletal system is also affected. +The net +effect is osteoporosis and an increased risk of fractures. +• Thyroid storm refers to the abrupt onset of severe hyper- +thyroidism. +Patients +are often febrile and present with tachycardia out of +proportion to the fever. +Thyroid storm is a medical +emergency. +A significant number of untreated patients +die of cardiac arrhythmias. +In these +cases, free T4 levels may be decreased, and direct measure- +ment of serum T3 is useful. +A +normal rise in TSH after administration of TRH excludes +secondary hyperthyroidism. +Hypothyroidism is a common disorder. +The prevalence increases with age, and +it is nearly 10-fold more common in women than in men. +Hypothyroidism can result from a defect anywhere in the +hypothalamic-pituitary-thyroid axis. +FOXE1, Forkhead box E1; PAX8, paired +box 8; THRB, thyroid hormone receptor β. +or as a result of pituitary and hypothalamic disease (Table +24.4). +Primary hypothyroidism can be congenital, autoimmune, +or iatrogenic. +• Congenital hypothyroidism. +• Autoimmune hypothyroidism. +The vast majority of cases +of autoimmune hypothyroidism are due to Hashimoto +thyroiditis. +• Iatrogenic hypothyroidism. +This can be caused by either +surgical or radiation-induced ablation. +Cretinism +Cretinism refers to hypothyroidism that develops in infancy +or early childhood. +It is now much less prevalent as a result of the +widespread supplementation of foods with iodine. +Normally, maternal T3 and T4 +cross the placenta and are critical for fetal brain development. +Myxedema +The term myxedema is applied to hypothyroidism develop- +ing in the older child or adult. +The clinical findings vary with age of onset. +Myxedema is marked by a slowing of physical and mental +activity. +Decreased sympathetic activity results in constipation and +decreased sweating. +The skin is cool and pale because of +decreased blood flow. +Measurement of the serum +TSH level is the most sensitive screening test for this +disorder. +T4 levels are decreased in individuals with hypo- +thyroidism of any origin. +Multiple immunologic mechanisms +may contribute to thyroid cell death, including (Fig. +The cut +surface is pale, yellow-tan, firm, and somewhat nodular. +There is +Figure 24.11 Hashimoto thyroiditis. +The thyroid parenchyma contains a +dense lymphocytic infiltrate with germinal centers. +Residual thyroid +follicles lined by deeply eosinophilic Hürthle cells are also seen. +24.11). +Pathogenesis +Granulomatous thyroiditis is believed to be triggered by a +viral infection. +In the typical case, +hypothyroidism develops gradually. +Histologic changes are patchy and depend on the stage of the +disease. +Multinucleate giant cells enclose pools of colloid (Fig. +24.12), +hence the designation granulomatous thyroiditis. +MORPHOLOGY +Except for possible mild symmetric enlargement, the thyroid +appears grossly normal. +Unlike Hashimoto thyroiditis, however, fibrosis and Hürthle cell +metaplasia are not prominent. +Clinical Features +Granulomatous thyroiditis is the most common cause of +thyroid pain. +There is variable enlargement of the gland. +Some +patients transition from hyperthyroidism to hypothyroidism +before recovery. +The disorder is most common between 40 and 50 years of +Figure 24.12 Granulomatous thyroiditis. +Nearly all patients have high serum +T4 and T3 levels and low serum TSH levels during this +phase. +After recovery, generally in 6 to 8 weeks, normal thyroid +function returns. +The +presence of a hard and fixed thyroid mass clinically simulates +a thyroid carcinoma. +It is another type +of autoimmune thyroiditis. +24.13A). +Increases in weight to over 80 g are not uncommon. +On cut section, the parenchyma has a soft, meaty appearance resem- +bling muscle. +24.13B). +Such papillae lack fibrovascular cores, in contrast to +those of papillary carcinoma (see later). +The colloid within the +follicle lumen is pale, with scalloped margins. +Germinal centers are common. +The +Graves disease is the most common cause of endogenous +hyperthyroidism. +Women are affected as much as 10 times more +frequently than men. +This disorder is said to affect 1.5% to +2% of women in the United States. +The most common1082 CHAPTER 24 The Endocrine System +A B +Figure 24.13 Graves disease. +(A) There is diffuse symmetric enlargement of the gland and a beefy deep red parenchyma. +Compare with gross photograph +of multinodular goiter in Fig. +24.15. +(B) Diffusely hyperplastic thyroid in a case of Graves disease. +The follicles are lined by tall, columnar epithelium. +The +crowded, enlarged epithelial cells project into the lumens of the follicles. +In addition, there is infiltration by lymphocytes and fibrosis. +Orbital muscles are edematous initially but may undergo fibrosis +late in the course of the disease. +Diffuse enlargement of the thyroid is present in all cases. +The extraocular muscles are often weak. +The basis of such localization is not clear, +and it is present only in a minority of patients. +Sometimes +individuals spontaneously develop thyroid hypofunction. +• Laboratory features include elevations in serum free T3 and T4 +and decreased serum TSH. +Goiters +can broadly be divided into two types: diffuse nontoxic and +multinodular. +This disorder occurs +in both an endemic and a sporadic distribution. +Native populations +subsisting on cassava root are particularly at risk. +• Sporadic goiter occurs less frequently than does endemic +goiter. +There is a striking female preponderance and a +peak incidence at puberty or in young adult life. +In most cases, however, the cause of sporadic +goiter is not apparent. +In these cases, the cut surface +of the thyroid is usually brown, somewhat glassy, and translucent. +Clinical Features +As stated earlier, most persons with simple goiters are clini- +cally euthyroid. +24.14). +Virtually all long-standing +simple goiters convert into multinodular goiters. +Single nodules are about four times more common in women +than in men. +The incidence of thyroid nodules increases +throughout life. +In fact, benign +neoplasms outnumber thyroid carcinomas by a ratio of +nearly 10 : 1. +24.15A). +24.15B). +A B +Figure 24.15 Multinodular goiter. +Note the absence of a prominent capsule, a +distinguishing feature from follicular neoplasms. +(B, Courtesy Dr. +The following sections consider the major +thyroid neoplasms. +This leads to +hyperthyroidism and produces a functional “hot” nodule +on imaging. +Overall, such mutations are present in 50% to +80% of toxic thyroid adenomas. +These are +discussed in further detail later in this chapter. +24.16A). +Follicular adenomas average about 3 cm +in diameter, but some are much larger (≥10 cm in diameter). +24.17). +(A) A solitary, well- +circumscribed nodule is seen. +We begin with a discussion of the molecular pathogenesis +of thyroid neoplasms. +Pathogenesis +Driver Mutations. +• Conventional papillary thyroid carcinomas. +24.18). +Figure 24.17 Hürthle cell (oxyphil) adenoma. +(Courtesy Dr. +Mary Sunday, Duke University, +Durham, NC.) +intact, well-formed capsule encircling the tumor. +Larger +masses may produce local symptoms, such as difficulty in +swallowing. +Suspected +adenomas of the thyroid are therefore removed surgically +to exclude malignancy. +Follicular adenomas do not recur +or metastasize and have an excellent prognosis. +• Follicular neoplasms. +24.18). +24.18). +• Poorly differentiated and anaplastic (undifferentiated) carcino- +mas. +• Medullary thyroid carcinomas. +Environmental Factors. +These rearrange- +ments also produce constitutively active NTRK1 fusion +proteins. +adjacent parenchyma and have ill-defined margins. +The tumors +may contain areas of fibrosis and calcification and are often cystic. +The cut surface sometimes reveals papillary foci that point to +the diagnosis. +The microscopic hallmarks of papillary neoplasms include the +following (Fig. +These +MORPHOLOGY +Conventional papillary carcinomas may be solitary or multifocal. +(B) This particular example contains well-formed papillae. +(D) Cells obtained by fine-needle aspiration of a papillary carcinoma. +Metastases to adjacent cervical lymph nodes occur in +up to one-half of cases. +The tall +cell variant has tall columnar cells with intensely eosinophilic +cytoplasm. +Lymph node metastases are present in +almost all cases. +24.20A). +Larger lesions may penetrate +the capsule and infiltrate into the adjacent neck. +Degenerative changes, +such as central fibrosis and foci of calcification, may be present. +24.20B). +24.21). +Unlike in papillary +cancers, lymphatic spread is uncommon in follicular cancers. +Hoarseness, dysphagia, +cough, or dyspnea suggests advanced disease. +Papillary +carcinomas are cold masses on scintigraphy. +The presence of vascular invasion is another feature of +follicular carcinomas. +Figure 24.20 Follicular carcinoma. +(A) Cut surface of a follicular +carcinoma with substantial replacement of the lobe of the thyroid. +The +tumor has a light-tan appearance and contains small foci of hemorrhage. +(B) A few of the glandular lumens contain recognizable colloid. +Clinical Features +Follicular carcinomas present as slowly enlarging painless +nodules. +The prognosis depends largely on the extent of inva- +sion and stage at presentation. +MORPHOLOGY +Sporadic medullary thyroid carcinomas present as a solitary nodule +(Fig. +24.22A). +In contrast, bilaterality and multicentricity are +common in familial cases. +There may be foci of hemorrhage and necrosis in larger lesions. +Small, more anaplastic cells are present in some +tumors and may be the predominant cell type. +Amyloid deposits +derived from calcitonin polypeptides are present in the stroma +in many cases (Fig. +24.22B). +24.23). +They account for approximately 5% of thyroid neoplasms. +Calcitonin +is a regulator of calcium metabolism. +About 70% of tumors +arise sporadically. +The remainder occur in the setting of +MEN-2A or MEN-2B syndromes. +A +B +Figure 24.22 Medullary carcinoma of the thyroid. +(A, Courtesy Dr. +• Multiple genetic pathways are involved in thyroid carcinogenesis. +Conventional papillary carcinomas harbor either fusions (RET/ +PTC, NTRK) or BRAF point mutations. +Progression to aggressive neoplasms is +associated with TP53, CTNNB1, and TERT mutations. +They are +highly aggressive, often lethal cancers. +Multicentricity and C cell hyperplasia are features of +familial cases. +Amyloid deposits are a characteristic histologic +finding. +Figure 24.23 Electron micrograph of medullary thyroid carcinoma. +Notably, hypocalcemia is not a +prominent feature, despite the presence of raised calcitonin +levels. +A sinus tract may persist +as a vestige of the tubular development of the thyroid gland. +Parts of this tube may be obliterated, leaving small segments +that form cysts. +These occur at any age and might not become +evident until adult life. +Characteristically, +subjacent to the lining epithelium, there is an intense +lymphocytic infiltrate. +The +four parathyroid glands are composed of two cell types: +chief cells and oxyphil cells. +Chief cells have secretory granules containing parathyroid +hormone (PTH). +Glycogen granules are also present in +these cells, but secretory granules are sparse or absent. +The function of the parathyroid glands is to regulate +calcium homeostasis. +Normally, decreased levels of free calcium stimulate +the synthesis and secretion of PTH. +Most +cases occur in the 50s or later in life. +24.24). +Between 10% and 20% of sporadic +parathyroid adenomas have this clonal rearrangement. +A +B +Figure 24.25 Parathyroid adenoma. +(B) High-power detail of a chief cell parathyroid +adenoma. +There is slight variation in nuclear size but no anaplasia and a +tendency for follicle formation. +capsule, is often visible at the edge of the adenoma. +In contrast to the normal +parathyroid parenchyma, adipose tissue is inconspicuous. +The combined weight of all glands rarely +exceeds 1 g and is often less. +As +in the case of adenomas, stromal fat is inconspicuous within +hyperplastic glands. +24.25). +These may resemble +Hürthle cell tumors in the thyroid. +24.26).The marrow spaces around the affected surfaces are +replaced by fibrovascular tissue. +26.13, Chapter 26). +• Asymptomatic hyperparathyroidism. +In fact, +primary hyperparathyroidism is the most common cause +of asymptomatic hypercalcemia. +• Symptomatic primary hyperparathyroidism. +a Primary hyperparathyroidism is the most common cause of hypercalcemia +overall. +Malignancy is the most common cause of symptomatic hypercalcemia. +Primary hyperparathyroidism and malignancy account for nearly 90% of cases of +hypercalcemia. +MORPHOLOGY +The parathyroid glands in secondary hyperparathyroidism are +hyperplastic. +As in primary hyperparathyroidism, the degree of +glandular enlargement may be asymmetric. +Fat cells +are decreased in number. +tend to be milder. +Parathyroidec- +tomy may be necessary to control the hyperparathyroidism +in such patients. +• Parathyroid adenomas are solitary, while hyperplasia typically +is a multiglandular process. +Renal +changes include nephrolithiasis (stones) and nephrocalcinosis. +HYPOPARATHYROIDISM +Hypoparathyroidism is far less common than is hyperpara- +thyroidism. +APS-1 is discussed further later in +this chapter. +Recall that loss-of- +function CASR mutations are a rare cause of familial +parathyroid adenomas. +The +classic findings on physical examination are Chvostek sign +and Trousseau sign. +• Ocular disease takes the form of calcification of the lens +and cataract formation. +• Dental abnormalities occur when hypocalcemia is present +during early development. +Indeed, +serum PTH levels are normal or elevated. +PTH resistance +is the most obvious clinical manifestation. +It presents as +hypocalcemia, hyperphosphatemia, and elevated circulat- +ing PTH. +The four main types are β, α, δ, +and PP (pancreatic polypeptide) cells. +24.27). +• The δ cells secrete somatostatin, which suppresses both +insulin and glucagon release. +These cells not only are present in +islets but also are scattered throughout the exocrine +pancreas. +• There are also two rare cell types, D1 cells and entero- +chromaffin cells. +The +α-cell granule shows a dense, round center. +(Electron micrographs courtesy Dr. +Arthur Like, University of Massachusetts Medical School, Worcester, Mass.) +commonly, both. +Diabetes and related disorders of glucose metabolism +are common. +Approximately 1.5 million +new cases of adult diabetes are diagnosed each year in the +United States. +Nonetheless, +diabetes remains in the top 10 “killers” in the United States. +Diagnosis +Blood glucose is normally maintained in a very narrow +range of 70 to 120 mg/dL. +According to the ADA and WHO, +diagnostic criteria for diabetes include the following: +1. +A fasting plasma glucose ≥126 mg/dL +2. +A fasting plasma glucose between 100 and 125 mg/dL +(“impaired fasting glucose”), +2. +Regulation of Insulin Release +Insulin is produced in the β cells of the pancreatic islets +(see Fig. +The most important stimulus for insulin synthesis and +release is glucose. +24.28). +The important similarities and differences between +T1D and T2D are summarized in Table 24.7. +Insulin and glucagon have opposing effects +on glucose homeostasis. +Thus, +fasting plasma glucose levels are determined primarily by +hepatic glucose output. +Insulin promotes glucose uptake and utilization in +tissues (discussed later). +This is one reason why exercise is beneficial +and obesity detrimental to glucose control. +In muscle cells, +glucose is either stored as glycogen or oxidized to generate +ATP. +24.30. +The insulin receptor is a tetrameric protein +composed of two α-subunits and two β-subunits. +The β- +subunit cytosolic domain possesses tyrosine kinase activity. +T1D most commonly +develops in childhood, becomes manifest at puberty, and +progresses with age. +Indeed, GLP-1 receptor agonists are also now +approved for treatment of obesity. +24.29). +The nature of these +environmental influences remains an enigma. +On the other hand, certain infections are +also thought to be protective against T1D. +Three +distinct stages of T1D are now recognized (Fig. +24.31). +Thus, autoreactive T cells not only +survive, but are poised to respond to self antigens. +The activated T cells +then traffic to the pancreas, where they cause β-cell injury. +IRS, Insulin receptor substrate; PI3K, +phosphoinositide 3-kinase. +(Modified from Brendan Manning, Harvard T.H. +Several non-HLA genes also confer susceptibility to T1D. +The mechanism +underlying this association is unknown. +Unlike T1D, there is no evidence of an autoimmune +basis. +subcutaneous]), islet β-cell function, and obesity. +In addition, GWAS +have shown an association between circadian-controlled +genes and T2D. +A variety of functional defects in the insulin-signaling +pathway underlie insulin resistance. +24.30). +The risk for +diabetes rises as the BMI increases. +Studies of +these so-called “metabolically healthy obese” individuals +is an emerging field. +Obesity can adversely impact insulin sensitivity in numer- +ous ways (see Fig. +24.32): +• Free fatty acids (FFAs). +Attenuated insulin signaling allows +phosphoenolpyruvate carboxykinase to “ramp up” +gluconeogenesis. +• Adipokines. +24.32). +Pancreatic β cells compensate +for insulin resistance by hypersecretion of insulin. +However, at some point, +β-cell compensation is followed by β-cell failure, and diabetes ensues. +Adiponectin levels are reduced in obesity, thus contribut- +ing to insulin resistance. +IL-1 and other cytokines act +on the major sites of insulin action to promote insulin +resistance. +This form of monogenic +diabetes is caused by a heterogeneous group of genetic +defects. +24.28). +Such patients often show a velvety +hyperpigmentation of the skin known as acanthosis nigricans. +T1D may arise at any age. +The assimilation of glucose into +muscle and adipose tissue is sharply diminished or abolished. +24.33). +Thus, intense thirst (polydipsia) appears. +A second major effect of insulin deficiency is increased +synthesis of ketone bodies. +When +these FFAs reach the liver, they are esterified to fatty acyl +coenzyme A. +Release of ketogenic amino acids by +protein catabolism aggravates the ketotic state. +Persistence of the ketotic state +eventually leads to depressed consciousness and coma. +hypoglycemia. +It is recommended +that HbA1c be maintained below 7% in patients with dia- +betes. +• Formation of advanced glycation end products. +The rate of AGE formation is accelerated by +hyperglycemia. +Proteins +cross-linked by AGEs are resistant to proteolytic digestion. +Thus, cross-linking decreases protein removal, enhancing +protein accumulation. +AGE-modified matrix components +also trap nonglycated plasma or interstitial proteins. +• Activation of protein kinase C. +• Oxidative stress and disturbances in polyol pathways. +Sorbitol accumulation in the lens contributes to cataract +formation. +• Hexosamine pathways and generation of fructose-6-phosphate. +As dis- +cussed earlier, these changes are seen in both T1D and T2D +(Fig. +24.34). +MORPHOLOGY +PANCREAS +Alterations in the pancreas are inconstant and often subtle. +Distinc- +tive changes are more commonly associated with T1D than with +T2D. +This is most +often seen in T1D, particularly with rapidly advancing disease. +Most of the islets are small and inconspicuous. +24.35A). +Lymphocytic infiltrates +may be present in T1D at the time of clinical presentation. +• Amyloid deposition within islets in T2D begins in and +around capillaries and between cells. +24.36). +The microangiopathy underlies the development of +islets may be virtually obliterated (see Fig. +24.35B); fibrosis may +also be observed. +Presumably, fetal islets undergo hyperplasia in response to the +maternal hyperglycemia. +Diabetic Macrovascular Disease +Diabetes exacts a heavy toll on the vascular system. +L, +Glomerular capillary lumen; U, urinary space. +(Courtesy Dr. +(B) Amyloidosis +of a pancreatic islet in type 2 diabetes. +(A, Courtesy Dr. +from this disease. +Capillary Basement Membrane Thickening. +Capillary +basement membrane thickening is best appreciated by +electron microscopy (Fig. +24.37). +24.38). +Figure 24.36 Severe renal hyaline arteriolosclerosis. +Note a markedly +thickened, tortuous afferent arteriole. +The amorphous nature of the +thickened vascular wall is evident (periodic acid–Schiff stain). +Diabetic Nephropathy +The kidneys are prime targets of diabetes. +Note the diffuse increase in mesangial matrix and +characteristic acellular PAS-positive nodules. +Diffuse Mesangial Sclerosis. +This lesion consists of diffuse +increase in mesangial matrix. +The matrix depositions are +PAS-positive (Fig. +24.39). +As the disease progresses, the +mesangial matrix deposits may take on a nodular appearance. +Nodular Glomerulosclerosis. +This is also known as +intercapillary glomerulosclerosis or Kimmelstiel-Wilson disease. +24.39) +or loops that are markedly dilated. +The loss of these support structures may lead to the formation +of capillary microaneurysms. +Both afferent and efferent +glomerular hilar arterioles show hyalinosis. +24.40). +Hyaline +arteriolosclerosis affects not only the afferent but also the +efferent arteriole. +in patients with diabetes than in the general population. +Diabetic Ocular Complications +The eye is profoundly affected by diabetes mellitus. +The +architecture and microanatomy of the eye are discussed in +Chapter 29. +The most profound ocular changes of diabetes are seen +in the retina. +This is discussed further in +Chapter 27. +Such infections cause +the deaths of about 5% of these patients. +The staggering societal and economic impact of diabetes +has already been discussed. +An elevated risk for cardiovascular +disease is even observed in patients with prediabetes. +Significantly, myocardial infarction is almost as common +in women with diabetes as in men. +In contrast, myocardial +infarction is uncommon in women of reproductive age +without diabetes. +• Diabetic nephropathy is a leading cause of end-stage +renal disease in the United States. +Approximately 30% to +40% of all patients with diabetes develop clinical evidence +of nephropathy. +maintained in noeplastic cells that do not express telom- +erase (Chapter 7). +Clinical manifestations include confusion, +stupor, and loss of consciousness. +PanNETs can occur anywhere within the pancreas +or in the immediate peripancreatic tissues. +These tumors may be +single or multiple and benign or malignant. +Unequivocal +criteria for malignancy include metastases, vascular invasion, +and local infiltration. +Fortunately, insulinomas are the +most common subtype of pancreatic endocrine neoplasms. +Most are solitary, although multiple tumors may +be encountered. +On rare occasions an insulinoma may arise in ectopic +pancreatic tissue. +In such cases, electron microscopy reveals the +distinctive granules of β cells (see Fig. +24.27). +Malignant +tumors are also well-differentiated, and they may be deceptively +encapsulated. +Deposition of amyloid is a characteristic feature +of many insulinomas (Fig. +24.41). +Hyperinsulinism may also be caused by focal or diffuse +hyperplasia of the islets. +This phenomenon is usually transient. +Total resection of the neoplasm, +when possible, eliminates the syndrome. +Figure 24.41 Pancreatic endocrine neoplasm (“islet cell tumor”). +The +neoplastic cells are monotonous and demonstrate minimal pleomorphism +or mitotic activity. +There is abundant amyloid deposition, characteristic of +an insulinoma. +Clinically, the patient had episodic hypoglycemia. +They may be very difficult to localize preoperatively. +High +plasma somatostatin levels are required for diagnosis. +Some of these tumors are locally invasive +and metastatic. +A VIP assay should be performed on +all patients with severe secretory diarrhea. +• Some pancreatic and extrapancreatic endocrine tumors +produce two or more hormones. +It is important to note that there are many other causes of +hypoglycemia besides insulinoma. +Adrenal Glands +structure, and function. +Beneath the capsule is the narrow layer of +zona glomerulosa. +An equally narrow zona reticularis abuts +the medulla. +Intervening is the broad zona fasciculata, which +makes up about 75% of the total cortex. +Catecholamines have many effects that allow +rapid adaptations to changes in the environment. +This variant of Cushing syndrome is +more common in men and usually occurs in the 40s and 50s. +Cortical carcinomas tend +to produce more marked hypercortisolism than adenomas +or hyperplasias. +Cushing syndrome can be broadly +divided into exogenous and endogenous causes. +ACTH-secreting pituitary adenomas account for 60% +to 70% of cases of endogenous hypercortisolism. +The +pituitary form of this syndrome is referred to as Cushing +disease. +In the vast majority of cases, it is caused by an +ACTH-producing pituitary microadenoma. +.. +.. +Cushing disease 60–70 .. +.. +.. +.. +.. +Ectopic ACTHa 5–10 .. +.. +.. +May respond to dexamethasone, CRH, +desmopressin +Occult neuroendocrine tumours ~2 .. +.. +.. +Ectopic CRH Very rare .. +.. +Causes pituitary corticotroph +hyperplasia +ACTH-Independent 20–30 .. +.. +.. +Unilateral adrenal .. +.. +.. +.. +.. +.. +.. +Autocrine ACTH production .. +.. +.. +.. +Sporadic or familial (ARMC5) .. +.. +.. +.. +Bilateral micronodular adrenal hyperplasias <2 .. +.. +.. +Isolated micronodular adrenocortical +disease +Very rare Infants .. +Nonpigmented adrenal micronodules +Primary bimorphic adrenocortical +disease +Very rare Infants .. +.. +MORPHOLOGY +The main lesions of Cushing syndrome are found in the pituitary +and adrenal glands. +24.42). +Both glands are enlarged, either +subtly or markedly, weighing up to 30 g. +24.43). +The +pigment is believed to be lipofuscin, a wear-and-tear pigment +(Chapter 2). +Primary adrenocortical neoplasms causing Cushing +syndrome may be malignant or benign. +Both the benign and malignant +lesions are more common in women in their 30s to 50s. +The carcinomas +associated with Cushing syndrome, by contrast, tend to be larger +than the adenomas. +Clinical Features +Cushing syndrome develops slowly and its onset may be +subtle. +Early stages may present with hypertension and +weight gain (Table 24.9). +The catabolic effects cause loss of collagen and resorption +of bones. +24.44). +24.43) in this gland from a patient with ACTH dependent +Cushing syndrome. +(Photographs courtesy Dr. +of cortisol secretion. +Hence, there is no reduction in urinary excretion of +17-hydroxycorticosteroids. +Hyperaldosteronism may be primary, or it may +be secondary to an extra-adrenal cause. +Primary hyperaldosteronism is caused by one of +three conditions (Fig. +ACTH +thus stimulates the synthesis of aldosterone synthase +from the chimeric gene. +They tend to occur in the +30s and 40s, and in women more often than in men. +24.51). +Therefore, the adjacent adrenal cortex and that of the contralateral +gland are not atrophic. +• Familial hyperaldosteronism accounts for ~5% of cases. +In primary hyperaldosteronism, the therapy varies +according to cause. +Adenomas are amenable to surgical +excision. +These patients are best +managed medically with an aldosterone antagonist such as +spironolactone. +Unlike gonadal androgens, +ACTH regulates adrenal androgen formation (Fig. +Such tumors are often also associated with +hypercortisolism (“mixed syndrome”). +They are morphologi- +cally identical to other cortical neoplasms and are discussed +later. +24.46). +Fig. +Thus, the level of testosterone is +increased, with resultant progressive virilization. +There +is only a partial deficiency of 21-hydroxylase, which +accounts for the later onset. +CAH also affects the function +of the adrenal medulla. +CAH should be suspected in any neonate with ambigu- +ous genitalia. +Mineralocorticoid +supplementation is required in the salt-wasting variants of +CAH. +Figure 24.47 Diffuse purpuric rash in a patient with Waterhouse- +Friderichsen syndrome. +APS-1 +is caused by mutations in the autoimmune regulator +(AIRE) gene on chromosome 21q22. +Self-reactive T cells +that recognize these antigens are eliminated (Chapter +6). +Overall, APS-2 is more prevalent than +APS-1. +The pathogenesis of +these other autoimmune polyendocrinopathies is not +understood. +• Metastatic neoplasms involving the adrenals are another +cause of adrenal insufficiency. +The adrenals are a fairly +common site for metastases in patients with disseminated +carcinomas. +Although adrenal function is preserved in +Figure 24.48 Waterhouse-Friderichsen syndrome. +underlying detail. +24.48). +The causes of +chronic adrenocortical insufficiency are listed in Table 24.10. +Death occurs rapidly unless +corticosteroid therapy begins immediately. +MORPHOLOGY +The anatomic changes in the adrenal glands depend on the underly- +ing disease. +24.49). +• Patients typically present with fatigue, weakness, and gastro- +intestinal disturbances. +Secondary +Figure 24.49 Autoimmune adrenalitis. +The +cortex may be reduced to a thin ribbon composed largely of +zona glomerulosa. +The medulla is not affected. +Adenomas and +carcinomas are about equally common in adults; in children, +carcinomas predominate. +However, +not all adrenocortical neoplasms elaborate steroid hormones. +24.50). +On cut surface, adenomas are +usually yellow to yellow-brown because of the presence of lipid. +24.51). +The adenoma is distinguished +from nodular hyperplasia by its solitary, circumscribed nature. +Figure 24.51 Histologic features of an adrenal cortical adenoma. +The +neoplastic cells are vacuolated because of the presence of intracytoplasmic +lipid. +There is mild nuclear pleomorphism. +Mitotic activity and necrosis are +not seen. +(in contrast to adrenocortical carcinomas). +24.52). +Larger +cysts may produce an abdominal mass and flank pain. +Figure 24.52 Adrenal carcinoma. +The hemorrhagic and necrotic tumor +dwarfs the kidney and compresses the upper pole. +a strong tendency to invade the adrenal vein, vena cava, and +lymphatics. +The median patient survival is about 2 years. +24.53), whichAdrenal glands 1127 +include the carotid bodies (Chapter 16). +The intravagal +paraganglia, as the term implies, are distributed along +the vagus nerve. +The organs of Zuckerkandl, close to the +aortic bifurcation, belong to this group. +Neuroblastomas and other neuroblastic tumors are +discussed in Chapter 10. +Traditionally, the features +of pheochromocytomas have been summarized by the “rule +of 10s”. +• Ten percent of adrenal pheochromocytomas are not associated +with hypertension. +One “traditional” 10% rule that has now been modified +pertains to familial cases. +VHL syndrome is associated with +a number of tumors, including pheochromocytomas and +paragangliomas. +Granules containing +catecholamine are not visible in this preparation. +It is not uncommon to +find bizarre cells, even in pheochromocytomas that are biologically benign. +(Courtesy Dr. +Jerrold R. +The tumor is enclosed within an +attenuated cortex and demonstrates areas of hemorrhage. +The comma- +shaped residual adrenal is seen below. +(Courtesy Dr. +Jerrold R. +Richly vascularized fibrous trabeculae within the tumor produce +a lobular pattern. +On section, the cut surfaces of smaller pheochromocytomas are +yellow-tan. +Larger lesions tend to be hemorrhagic, necrotic, and +cystic and typically efface the adrenal gland. +The histologic pattern in pheochromocytoma is quite variable. +24.55). +24.56). +Figure 24.56 Electron micrograph of pheochromocytoma. +This tumor +contains membrane-bound secretory granules in which catecholamines are +stored (30,000×). +Determining malignancy in pheochromocytomas can be vexing. +Even capsular and vascular invasion may be encountered in benign +lesions. +These episodes may also be associated with +pain in the abdomen or chest, nausea, and vomiting. +Multifocal lesions require long-term medical treatment for +hypertension. +• Tumors occur at a younger age than sporadic tumors. +• Even in one organ, the tumors are often multifocal. +• It is now recognized that the spectrum of this disease +extends beyond the three P’s. +Parathyroid abnormalities include both +hyperplasia and adenomas. +These tumors are usually aggressive and often present +with metastatic disease. +Medullary car- +cinomas of the thyroid occur in almost 100% of patients. +• MEN-2B has significant clinical overlap with MEN-2A. +However, unlike in +MEN-2A, primary hyperparathyroidism is not present. +• MEN-4 has emerged as a new entity in the past decade. +Smith TJ, Hegedus L: Graves’ disease, N Engl J Med 375:1552–1565, +2016. +Your one-stop shop for +this topic]. +Lee YS, Wollam J, Olefsky JM: An integrated view of immunometabo- +lism, Cell 172:22–40, 2018. +This review ties together how inflammation +eventually leads to metabolic deregulation]. +Pugliese A: Autoreactive T cells in type 1 diabetes, J Clin Invest +127:2881–2891, 2017. +These +tumors are rare and are described in specialized texts. +SUGGESTED READINGS +Pituitary +Asa SL, Mete O: What’s new in pituitary pathology? +Histopathology +72:133–141, 2018. +[A review on the updated WHO classification of pituitary +tumors and other non-neoplastic entities]. +[An updated review on the molecular mechanisms underlying diabetes +insipidus]. +Cabanillas ME, McFadden DG, Durante C: Thyroid cancer, Lancet +388:2783–2795, 2016. +[A clinically oriented review on diagnosis and +management of thyroid neoplasms]. +DeLeo S, Lee SY, Braverman LE: Hyperthyroidism, Lancet 388:906–918, +2016. +[A clinically oriented review on the causes and main therapeutic +avenues in hyperthyroidism]. +[A classic publication describing +the index case of the disease named after the author]. +[The original description of myxedema, +hence also known as “Gull disease”]. +[Dr. +A couple are included in the bibliography. +Take your pick!]. +[The original description of +Addison disease]. +Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency, +Lancet 383:2152–2167, 2014. +This review is a great place to get started]. +Rushworth RL, Torpy DJ, Falhammar H: Adrenal crisis, N Engl J Med +381:852–861, 2019. +[A review on the causes, pathophysiology, and treatment +of acute adrenal crises]. +Waterhouse R: A case of suprarenal apoplexy, Lancet 1:577–578, 1911. +Potential therapeutic +approaches are also discussed]. +25.1). +• Dendritic cells. +cells. +• Lymphocytes. +• Adnexal components. +Ingested +agents, such as therapeutic drugs, can cause an enormous +number of rashes or exanthems. +Skin conditions are very common, affecting about one- +third of the US population each year. +Thousands of diseases affect the skin. +Only those that +are common or that illustrate important pathologic mecha- +nisms are described here. +Macule, Patch Circumscribed, flat lesion distinguished from +surrounding skin by color. +Macules are 5 mm in +diameter or less; patches are greater than +5 mm. +Onycholysis Separation of nail plate from nail bed. +Papule, Nodule Elevated dome-shaped or flat-topped lesion. +Papules are 5 mm or less across; nodules are +greater than 5 mm in size. +Pustule Discrete, pus-filled, raised lesion. +Scale Dry, horny, plate-like excrescence; usually the +result of imperfect cornification. +Blister is the common term for either lesion. +Microscopic Lesions +Acanthosis Diffuse epidermal hyperplasia. +Dyskeratosis Abnormal, premature keratinization within cells +below the stratum granulosum. +Erosion Discontinuity of the skin showing incomplete loss +of the epidermis. +Exocytosis Infiltration of the epidermis by inflammatory cells. +Hypergranulosis Hyperplasia of the stratum granulosum, often due +to intense rubbing. +Lentiginous Linear pattern of melanocyte proliferation within +the epidermal basal cell layer. +Parakeratosis Keratinization with retained nuclei in the stratum +corneum. +On mucous membranes, +parakeratosis is normal. +Spongiosis Intercellular edema of the epidermis. +One answer appears to +lie in the phenomenon referred to as oncogene-induced +senescence. +Once present, freckles fade and darken in a cyclic fashion during +winter and summer, respectively. +This is not because of changes +in the number of melanocytes, but in the degree of pigmentation. +It occurs at +all ages, but most commonly appears in infants and children. +There is no sex or racial predilection, and the cause and +pathogenesis are unknown. +Unlike freckles, lentigines do not darken when +exposed to sunlight. +Melanocytic +nevi are thought to progress through a series of morphologic +changes over time. +25.2B). +25.3B). +In older lesions the epidermal nests may be lost entirely to form +pure intradermal nevi. +Compound and dermal nevi are often +more elevated than junctional nevi. +25.4). +25.4E). +Most of us have at least a few “moles” +and probably regard them as mundane and uninteresting. +Acquired melanocytic nevi are the most +common type and are found in virtually all individuals. +Several +lines of evidence support the concept that some dysplastic +nevi are precursors of melanoma. +(A) In contrast to the +junctional nevus, the compound nevus is raised and dome-shaped. +The +symmetry and uniform pigment distribution suggest a benign process. +Figure 25.2 Melanocytic nevus, junctional type. +(A) Grossly, lesions are +small, relatively flat, symmetric, and uniform. +AB CD E +Time +Figure 25.4 Maturation sequence of nondysplastic melanocytic nevi. +(A) Normal skin shows only scattered dendritic melanocytes within the epidermal +basal cell layer. +(B) Junctional nevus. +(C) Compound nevus. +(D) Dermal nevus. +(E) Dermal nevus with neurotization, a change that is also referred to as +maturation. +(A) Lentiginous melanocytic hyperplasia. +(B) Lentiginous junctional nevus. +(D) Early melanoma, or melanoma in radial growth +phase (large dark cells in epidermis). +(E) Advanced melanoma (vertical growth phase) with malignant spread into the dermis and vessels. +age 60, and at-risk individuals sometimes develop melanomas +at multiple sites. +What then distinguishes dysplastic +nevi from typical melanocytic nevi? +An important clue comes +from individuals with dysplastic nevus syndrome. +Such +individuals often have inherited loss-of-function mutations +in CDKN2A. +25.6A). +Most seem to be acquired rather than congenital. +Unlike +ordinary moles, dysplastic nevi occur on both sun-exposed and +protected body surfaces. +25.6A, B). +(A) Numerous atypical nevi on the back. +The dermis underlying the atypical cells characteristically shows linear, or lamellar, fibrosis. +related to a single predisposing environmental factor: UV +radiation exposure from sunlight. +CDKN2A is a +complex locus that encodes three different tumor sup- +pressors, p15, p16, and ARF. +contours; and hyperchromasia (Fig. +The +following comments apply to cutaneous melanomas. +Proteins indicated by asterisks are mutated in +melanoma. +Components of these pathways that are being targeted by drugs are indicated. +• Mutations that activate pro-growth signaling pathways. +25.7), which promote cell growth +and survival (Chapter 7). +PTEN is also silenced in +20% of melanomas arising in non–sun-exposed sites. +• Mutations that activate telomerase. +Rare melanoma-prone families have also been identified +that have germline TERT promoter mutations. +25.8A). +(A) Typical lesions are irregular in contour and pigmentation. +(C) Vertical growth phase demonstrating nodular +aggregates of infiltrating cells. +(D) High-power view of melanoma cells. +Even small numbers of malignant cells in a draining lymph node may confer a worse prognosis. +often notched, unlike the smooth, round, and uniform borders +of melanocytic nevi. +25.8B). +During this initial stage the +tumor cells seem to lack the capacity to metastasize. +25.8C). +25.8D). +The appearance of the +tumor cells is similar in the radial and vertical phases of growth. +25.8D, inset) confers a worse prognosis. +They often recapitulate the +structures from which they arise. +The majority of lesions +are greater than 10 mm in diameter at diagnosis. +The most +consistent clinical signs are changes in the color, size, or +shape of a pigmented lesion. +25.7). +25.9, inset). +It is uniformly tan to dark +brown and usually has a velvety to granular surface. +MORPHOLOGY +All forms of acanthosis nigricans have similar histologic features. +Figure 25.9 Seborrheic keratosis. +cells of the normal epidermis (Fig. +It is divided into two types based on +the underlying condition. +The most +common associations are with obesity and diabetes. +The lay term, wen, derives from +the Anglo-Saxon wenn, meaning a lump or tumor. +• Other appendage tumors are associated with germline mutations +in tumor suppressor genes. +In some such instances, the +disorder presents with multiple adnexal tumors that may +be disfiguring. +Some +have a predisposition to occur on specific body surfaces. +• Eccrine poroma occurs predominantly on the palms and +soles where sweat glands are numerous. +(A) Sebaceous adenoma; inset demonstrates sebaceous differentiation. +these tumors have a particularly high incidence in lightly +pigmented individuals. +Exposure to ionizing radiation, +industrial hydrocarbons, and arsenicals may induce similar +lesions. +dermal matrix (Fig. +25.10B). +25.10C, D). +25.11A). +25.11B). +Some lesions produce so much keratin +that a “cutaneous horn” develops (Fig. +Sun-exposed sites (face, arms, dorsum of hands) +are most frequently affected. +The lips may also develop similar +lesions (termed actinic cheilitis). +25.12B) +or, alternatively, with atrophy that results in thinning of the epi- +dermis. +The atypical basal cells usually have pink or reddish +cytoplasm due to dyskeratosis. +Although most appendage tumors are benign, malignant +variants exist. +Apocrine tumors are unusual in that malignant +forms appear to be more common than benign forms. +freezing, or topical application of chemotherapeutic agents. +susceptibility to cutaneous squamous cell carcinomas. +Except for lesions on the lower +legs, these tumors have a higher incidence in men than +in women. +Invasive squamous cell carcinomas are usually +discovered while they are small and resectable. +Tumor incidence is proportional to the degree of +lifetime sun exposure. +These are slow-growing tumors that rarely metas- +tasize. +The vast majority are recognized at an early stage +and cured by local excision. +Basal cell carcinoma occurs at sun-exposed sites in lightly +pigmented elderly adults. +Pathogenesis +Most basal cell carcinomas have mutations that lead to +unbridled Hedgehog signaling. +NBCCS is one of a number of cancer syndromes associated +with skin manifestations (Table 25.3). +25.13A). +25.12C). +Invasive squamous cell +carcinoma (Fig. +Basal cell +A B C +Figure 25.13 Invasive squamous cell carcinoma. +(A) Lesions are often nodular and ulcerated, as seen in this scalp tumor. +From Tsai KY, Tsao H: The genetics of skin cancer, Am J Med Genet C Semin Med Genet 131C:82, 2004. +mutation, usually caused by exposure to mutagens (par- +ticularly UV light). +Binding of SHH to PTCH releases SMO, which in turn +activates the transcription factor GLI1 (Fig. +25.14), thus +turning on the expression of genes that support tumor cell +growth and survival. +Mutations that activate Hedgehog signaling are also +prevalent in sporadic basal cell carcinomas. +tumors, explaining the archaic designation rodent ulcers. +Histologically, the tumor cells resemble those in the normal +basal cell layer of the epidermis. +They arise from the epidermis +or follicular epithelium and do not occur on mucosal surfaces. +25.15B). +In sections, the stroma retracts away from the carcinoma (Fig. +25.15A). +Left, Normally, PTCH and SMO form a receptor complex that can bind sonic hedgehog (SHH). +In the absence of SHH, PTCH blocks SMO activity. +burn sites, or in association with HPV infection in the setting +of immunosuppression. +Metastasis is very rare. +usually seen in adults and often occur on the legs of young +and middle-aged women. +Lesions are asymptomatic or +tender and may increase and decrease slightly in size over +time. +Their biologic behavior is indolent. +The cause of fibrous histiocytomas remains a mystery. +These tumors appear +to be composed at least partially of dermal dendritic cells. +These tumors are +MORPHOLOGY +These neoplasms appear as firm, tan to brown papules (Fig. +25.16A). +The most common form of fibrous histiocytoma is referred +to as a dermatofibroma. +25.16B, C). +A B C +Figure 25.16 Benign fibrous histiocytoma (dermatofibroma). +aggressive and can recur, they rarely metastasize. +Metastasis +most often is seen with tumors that exhibit greater cytologic +atypia. +While the primary mode of treatment is wide local +observed. +(A) The tumor consists of a flesh-colored fibrotic nodule on sectioning. +(C) Characteristic storiform (swirling) alignment of the spindled cells is apparent. +Mitoses are rare. +In contrast to dermatofibroma, the +overlying epidermis is generally thinned. +25.17B, C). +Raised, indurated, irregularly outlined erythe- +matous plaques may then supervene. +Development of +multiple tumor nodules correlates with systemic spread. +Sometimes the plaques and nodules ulcerate (Fig. +25.18A). +25.18B) and invade the +epidermis as single cells and small clusters (Pautrier microab- +scesses). +(A) Several erythematous plaques with scaling and ulceration are evident. +The resulting increase in KIT +signaling drives mast cell growth and survival. +MORPHOLOGY +The pathologic findings are highly variable. +25.19B). +Fibrosis, edema, +and eosinophils may also be present. +25.19C). +25.20A). +Most ichthyoses +become apparent either at or around the time of birth. +(A) Solitary mastocytoma in a 1-year-old child. +(C) Giemsa staining reveals purple “metachromatic” granules within the cytoplasm of the mast cells. +25.20B).There is generally little or no inflammation. +Discussed +here are examples of the more commonly encountered acute +dermatoses. +Figure 25.20 Ichthyosis. +Note prominent fish-like scales (A) and +compacted, thickened stratum corneum (B). +ichthyosis vulgaris, may be associated with lymphoid and +visceral malignancies. +This combination of effects produces pruritic +edematous plaques called wheals. +Angioedema is closely1154 CHAPTER 25 The Skin +Figure 25.21 Urticaria. +(A) Erythematous, edematous, often circular plaques are characteristic. +related to urticaria and is characterized by edema of the +deeper dermis and the subcutaneous fat. +Urticaria most often occurs between ages 20 and 40, but +all age groups are susceptible. +• Mast cell–dependent, IgE-independent. +• Mast cell–independent, IgE-independent. +These forms of +urticaria are triggered by local factors that increase +vascular permeability. +The precise +mechanism of aspirin-induced urticaria is unknown. +MORPHOLOGY +Lesions vary from small, pruritic papules to large edematous +plaques (Fig. +25.21A). +Eosinophils may also be present. +Collagen bundles +are more widely spaced than in normal skin, a result of dermal +edema (Fig. +25.21B). +Treatment involves a search for +offending substances that can be removed from the environ- +ment. +Topical steroids can be used to block the inflammatory +response. +acanthosis and hyperkeratosis and take on the appearance +of raised scaling plaques (Fig. +25.23A). +25.23B). +(B) Edema within the epidermis creates fluid-filled intraepidermal vesicles. +B +Figure 25.24 Erythema multiforme. +With +time, necrotic/apoptotic keratinocytes appear in the overlying epithelium (double arrow). +25.24A).The +lesions may occur in a variety of distributions. +25.24B).With time there is upward migration of lymphocytes +into the epidermis. +Discrete and confluent zones of epidermal +necrosis occur with concomitant blister formation. +Epidermal +sloughing leads to shallow erosions. +Psoriasis +Psoriasis is a chronic inflammatory dermatosis that appears +to have an autoimmune basis. +It is a common disorder, +affecting as many as 1% to 2% of people in the United States. +Persons of all ages develop the disease. +It can affect +any joint in the body and may be symmetric or asymmetric. +Psoriasis is one cause +of total body erythema and scaling known as erythroderma. +A B +Figure 25.25 Psoriasis. +25.25B). +The stratum granulosum is thinned +or absent, and extensive overlying parakeratotic scale +is seen. +scaling and crusting. +Fissures may also be present, particularly +behind the ears. +Dandruff is the common clinical expression of +seborrheic dermatitis of the scalp. +Resolution often leaves a residuum of postinflam- +matory hyperpigmentation. +Oral lesions, however, may +persist for years. +As in psoriasis, the Koebner phenomenon +may be seen in lichen planus. +Pathogenesis +The pathogenesis of lichen planus is not known. +Pathogenesis +The precise etiology of seborrheic dermatitis is unknown. +Increased sebum production, often in response to androgens, +is one possible contributory factor. +The glans penis is another common site of involvement. +insight into the pathogenic mechanisms. +25.28). +These disorders are usually benign, but in extreme +cases can be fatal without treatment. +Blisters in the various disorders occur +at different levels within the skin (Fig. +The major structural proteins of desmosomes and hemidesmosomes are +shown in the right panel. +A B C +Figure 25.29 Pemphigus vulgaris. +(A) Eroded plaques are formed following the rupture of confluent, thin-roofed bullae. +(C) Ulcerated blisters in the oral mucosa are also +common, as seen here on the lip. +mucosa and skin, especially on the scalp, face, axilla, +groin, trunk, and points of pressure. +It may present as oral +ulcers that may persist for months before skin involve- +ment appears. +25.29A). +(B) +Subcorneal separation of the epithelium is seen. +erythema and crusting; these represent superficial erosions +at sites of blister rupture (Fig. +25.30A). +25.31). +25.28). +(B) In pemphigus +foliaceus the immunoglobulin deposits and acantholysis are more +superficial. +In pemphigus vulgaris (see Fig. +In the vegetans +variant, there is also overlying epidermal hyperplasia. +Some patients +present with urticarial plaques and severe pruritus. +25.32B). +Most antibody deposition occurs +in a continuous linear pattern at the dermoepidermal junction +(Fig. +25.33B). +Ulcers form if +the blisters rupture. +(B) Electron micrograph showing the +ultrastructural features of the dermoepidermal junction. +AF, Anchoring fibrils; LD, lamina +densa. +(See also Fig. +25.31.)Blistering (bullous) diseases 1163 +Figure 25.34 Dermatitis herpetiformis. +(B) Selective deposition of IgA autoantibody at the tips of dermal papillae +is characteristic. +(B, Courtesy +Dr.Victor G. +Prieto, Houston, Tex.) +(see Fig. +25.29). +Antibodies against one such component +called BPAG2 are proven to cause blistering. +The disease affects +predominantly males, most often in the third and fourth +decades of life. +In some cases it occurs in association with +intestinal celiac disease (Chapter 17). +The plaques and vesicles +are extremely pruritic. +The resultant injury and inflammation produce a +subepidermal blister. +25.34C). +25.34A). +25.34B). +Two such disorders are epidermolysis bullosa and +porphyria. +Epidermolysis Bullosa. +(A) Junctional epidermolysis bullosa showing typical erosions in flexural creases. +(B) Subepidermal blister at the level +of the lamina lucida. +There is no associated inflammation. +in structural proteins that lend mechanical stability to the +skin. +This is the most common type of epider- +molysis bullosa, encompassing 75% to 85% of cases. +25.35; see Fig. +25.28). +�� Mixed types, marked by defects at several levels, are also +recognized. +Porphyria. +Porphyria refers to a group of uncommon inborn +or acquired disturbances of porphyrin metabolism. +Porphy- +rins are pigments that are normally present in hemoglobin, +myoglobin, and cytochromes. +The classification of porphyria +is based on both clinical and biochemical features. +porphyria, (4) porphyria cutanea tarda, and (5) mixed +porphyria. +25.36). +The pathogenesis +of these alterations is not understood. +Elimination of P. +acnes is the rationale +for administration of antibiotics to individuals with inflam- +matory acne. +MORPHOLOGY +Inflammatory acne is marked by erythematous papules, nodules, +and pustules (Fig. +25.37A). +Severe variants (e.g., acne conglobata) +result in sinus tract formation and dermal scarring. +25.37B, C). +Dermal abscesses may +form in association with rupture (Fig. +25.37B) and lead to +scarring. +Acne is seen in all races but is +usually milder in people of Asian descent. +Some +families seem to be particularly prone to acne, suggesting +a hereditary component. +Acne is divided into noninflammatory and inflammatory +types, although both types may coexist. +Noninflammatory +acne may take the form of open and closed comedones. +• Open comedones are small follicular papules containing +a central black keratin plug. +This color is the result of +oxidation of melanin pigment (not dirt). +• Closed comedones are follicular papules without a visible +central plug. +Pathogenesis +The pathogenesis of acne is incompletely understood and +is likely multifactorial. +population, with a predilection +for females. +Several microbial triggers +have been proposed, but none are proven. +(A) Inflammatory acne associated with erythematous papules and pustules. +(B) A hair shaft pierces the follicular epithelium, eliciting +inflammation and fibrosis. +(C) An open comedone. +Panniculitis often involves the lower legs. +Erythema +nodosum is the most common form and usually has a subacute +presentation. +A second somewhat distinctive form, erythema +induratum, also merits brief discussion. +Fever and malaise may accompany the +cutaneous signs. +MORPHOLOGY +The histopathology of erythema nodosum is distinctive. +Verrucae (Warts) +Verrucae are squamoproliferative lesions caused by human +papillomaviruses (HPVs). +They are common lesions of +children and adolescents, although they may be encountered +at any age. +Transmission of disease usually involves direct +contact between individuals or autoinoculation. +Verrucae +are generally self-limited, regressing spontaneously within +6 months to 2 years. +The +clinical variants of warts are often associated with distinct +HPV subtypes. +For example, anogenital warts are caused +predominantly by HPV types 6 and 11. +Viral typing can be accomplished +by either in situ hybridization (Fig. +25.38D) or polymerase +chain reaction. +MORPHOLOGY +The classification of verrucae is based largely on appearance and +location. +Verruca vulgaris is the most common type of wart. +(A) Multiple papules with rough pebble-like surfaces. +25.38A). +Verruca plana, or flat wart, is common on the +face or the dorsal surfaces of the hands. +Verruca plantaris and verruca palmaris occur +on the soles and palms, respectively. +Electron microscopy of these zones +reveals numerous HPV virions within nuclei. +25.38C). +Figure 25.39 Molluscum contagiosum. +Impetigo +Impetigo is a common superficial bacterial infection of skin. +The infection usually involves exposed skin, par- +ticularly that of the face and hands. +Over the past several decades a remarkable +shift in etiology has been observed. +aureus. +25.28). +Infection is usually +spread by direct contact, particularly among children and +young adults. +25.39). +Numerous virions are present within molluscum +bodies. +As pustules break, shallow erosionsSuggested readings 1169 +A B +Figure 25.40 Tinea. +(A) Characteristic plaque of tinea corporis. +Periodic acid–Schiff stain (inset) reveals deep red hyphae within the stratum corneum. +usually first appears on the upper inner thighs as moist, +red patches with raised scaly borders. +• Tinea pedis (athlete’s foot) affects 30% to 40% of the popula- +tion at some time in their lives. +There is diffuse erythema +and scaling, often initially localized to the web spaces. +Spread to (or +primary infection of the nails) is referred to as onycho- +mycosis. +This produces discoloration, thickening, and +deformity of the nail plate. +• Tinea versicolor usually occurs on the upper trunk and is +highly distinctive in appearance. +25.40A). +• Tinea cruris occurs most frequently in the inguinal areas +of obese men during warm weather. +Heat, friction, and +maceration all predispose to its development. +Special stains reveal the presence of bacteria +in these foci. +25.40B). +25.40B, +inset). +Cancer Genome Atlas Network: Genomic classification of melanoma, +Cell 16:1681, 2015. +“The B-K mole +syndrome.”, Arch Dermatol 114:732, 1978. +[Thorough +discussion of the causes and management of a common form of eczema]. +Nestle FO, Kaplan DH, Barker J: Psoriasis, N Engl J Med 361:496, +2009. +[Pathogenesis, clinical features, and targeted treatment options are +discussed]. +Schaefer P: Urticaria: evaluation and treatment, Am Fam Physician +83:1078, 2011. +[Practical discussion of the clinical evaluation and treatment +of urticaria]. +[Review of pathology and clinical +features, natural history, and treatment]. +doi:10.1155/2012/239691. +[Description of factors and disease +mechanisms underlying this rare disorder]. +[An update on basic +and clinical aspects of pemphigus]. +Ujiie H, Shibaki A, Nishie W et al: What’s new in bullous pemphigoid, +J Dermatol 37:194, 2010. +[Review of bullous pemphigoid pathogenesis]. +[Review of epidemiology, pathogenesis, and treatment of acne in the +United States]. +Elder DE: Dysplastic nevi: an update, Histopathology 56:112, 2010. +[Excellent review on immunotherapy using melanoma as a paradigm of a +responsive cancer]. +[Update on latest treatment agents and paradigms in melanoma]. +[Documents the key +molecular features of primary cutaneous melanoma progression]. +[Description of activating mutations in FGFR3 in seborrheic keratoses]. +[Documents key driver events in advanced cutaneous squamous cell +carcinoma]. +[epub ahead of print]. +Bone consists of extracellular matrix and several cell +types. +The latter, +The adult human skeleton is composed of 206 bones that +account for ~12% of body weight. +(B) Lamellar bone contrasts with the more cellular, disorganized appearance of woven bone. +Osteoid consists of type I collagen and smaller amounts +of glycosaminoglycans and other proteins. +Serum +osteopontin levels are used as a specific marker of osteoblast +activity. +Bone matrix can be woven or lamellar (Fig. +26.1). +Long bones are composed of a dense +outer cortex and a central medulla. +A +Cells +The cellular components of bone include osteoblasts, +osteocytes, and osteoclasts. +26.2A). +Osteoblast activity is tightly regulated +by hormonal and local mediators. +B +Figure 26.2 (A) Active osteoblasts synthesizing bone matrix. +The +surrounding spindle cells represent osteoprogenitor cells. +(B) Two +osteoclasts resorbing bone. +26.2B). +• Fibroblast growth factors (FGFs) are secreted by a variety +of mesenchymal cells. +26.4). +26.5). +The +cartilage mold (anlagen) is synthesized by mesenchymal +precursor cells. +This forms a primary center of ossification +resulting in radial bone growth. +26.3). +Chondrocytes within the growth plates undergo sequential +proliferation, hypertrophy, and apoptosis. +26.3). +Over time, this process produces +longitudinal bone growth. +1 +2 +3 +4 +5 +Figure 26.3 Active growth plate with ongoing endochondral ossification. +1, Reserve zone. +2, Zone of proliferation. +3, Zone of hypertrophy. +4, Zone +of mineralization. +26.5). +In contrast, acquired diseases +usually appear in adulthood. +Here we will categorize the +major diseases according to their pathogenesis. +More than 350 skeletal dysostoses and dysplasias are +recognized, most of which are extremely rare. +Osteoclasts are derived from the same +mononuclear cells that differentiate into macrophages. +RANK activation induces +precursor cells to become functional osteoclasts. +Consequently, OPG prevents bone resorption by inhibiting +osteoclast differentiation. +The balance between bone formation and resorption is +modulated by RANK and WNT signaling. +Each of these acts +by altering RANK/NF-κB and WNT/ β-catenin signaling. +BMP, Bone morphogenic protein; LRP5/6, +LDL receptor–related proteins 5 and 6. +FGF-mediated FGFR3 +activation normally inhibits endochondral growth. +This +effect is exaggerated by FGFR3 gain-of-function mutations. +Thanatophoric dysplasia is the most common lethal +form of dwarfism. +It is caused by mutations in +genes encoding the α1 and α2 chains of type I collagen. +The fundamental abnormality in OI is too little bone, +resulting in extreme skeletal fragility. +OI is separated into four major clinical subtypes of varying +severity (Table 26.2). +26.6). +Osteopetrosis due to CA2 +mutations is, therefore, accompanied by renal tubular aci- +dosis. +26.8). +Deposited bone is not remodeled and tends to be woven +rather than lamellar. +Figure 26.6 Skeletal radiograph of a fetus with lethal type 2 osteogenesis +imperfecta. +The compensa- +tory extramedullary hematopoiesis can lead to prominent +hepatosplenomegaly. +The normal osteoclasts produced from donor +stem cells reverse many of the skeletal abnormalities. +Mesenchymal +cells, particularly chondrocytes, degrade extracellular matrix +mucopolysaccharides. +In these diseases, mucopolysaccharides +accumulate within chondrocytes and induce apoptosis. +Extracellular mucopolysaccharide accumulation leads to +structural defects in articular cartilage. +Figure 26.7 Radiograph of the upper extremity in an individual with +osteopetrosis. +They manifest as absent, supernumerary, or +abnormally fused bones. +Global disorganization of bone and/or +cartilage is termed dysplasia. +Developmental abnormalities can +be categorized by the associated genetic defect. +Depending on the gene mutated, extraskeletal manifesta- +tions may also be present. +Figure 26.8 Section of proximal tibial diaphysis from a fetus with +osteopetrosis. +Fracture, anemia, and hydrocephaly are often seen, +resulting in postpartum mortality. +Osteopenia is +1 to 2.5 standard deviations below the mean. +Generalized +osteoporosis may be primary or secondary to a variety of +conditions (Table 26.3). +The following +discussion relates largely to these forms of osteoporosis. +Pathogenesis +Peak bone mass is achieved during young adulthood. +26.9). +Physical activity, muscle strength, +diet, and hormonal state also make important contributions. +This form of osteoporosis, known as senile +osteoporosis, is categorized as a low-turnover variant. +• Genetic factors such as single-gene defects are rare causes +of osteoporosis. +• Calcium nutritional state contributes to peak bone mass. +Adolescent girls (more than boys) tend to have insufficient +calcium intake in the diet. +• Hormonal influences. +26.10), +but certain bones tend to be more severely impacted. +26.11), leading +to microfractures and eventually to vertebral collapse. +Hyperparathyroidism +Hyperparathyroidism causes increased bone resorption. +PTH mediates the effect indirectly +by increasing RANKL expression on osteoblasts. +Inadequate vitamin D ultimately limits intestinal calcium +absorption. +Figure 26.13 Resected rib, harboring an expansile brown tumor adjacent +to the costal cartilage. +26.12). +Radiographically, dissecting osteitis is seen as decreased bone +density or osteoporosis. +26.13).The brown color reflects vascularity, hemor- +rhage, and hemosiderin deposition. +Bony changes regress or disappear completely when +hyperparathyroidism is controlled. +• Mixed pattern disease with areas of high turnover and low +turnover. +Pathogenesis +Kidney disease causes skeletal abnormalities through three +mechanisms (Fig. +26.14): +• Tubular dysfunction most commonly leading to renal +tubular acidosis. +26.15). +An intriguing aspect is the striking geographic variation in +its prevalence. +This results in hypocalcemia that contributes to second- +ary hyperparathyroidism. +Chronic renal failure disrupts this signaling +axis and contributes to osteopenia and osteomalacia. +• Osteomalacia is defined by the presence of bone that is insuf- +ficiently mineralized. +In the developing skeleton, this results in +rickets. +In high income +countries, where early diagnosis is the norm, these manifestations +are rare. +The bone changes stem from decreased tubular, +glomerular, and hormonal renal functions. +The prevalence in England is 2.5% for men and 1.6% for +women 55 years of age or older. +A decrease in new cases +has been observed in some countries over the past 30 years. +MORPHOLOGY +Paget disease shows remarkable histologic variation over time +and across sites. +Paget disease is monostotic +in about 15% of cases and polyostotic in the remainder. +The +axial skeleton or proximal femur is involved in up to 80% +of cases. +Most cases are asymptomatic and are discovered +as an incidental radiographic finding. +Chalk +stick–type fractures are common and usually involve the +long bones of the lower extremities. +Vertebral compression +fractures can result in spinal cord injury and kyphosis. +The diagnosis of Paget disease can be made radiographi- +cally. +Pagetic bone is typically enlarged with thick, coarsened +cortices and medulla (Fig. +26.17). +FRACTURES +Fractures are defined as loss of bone integrity. +They are +some of the most common pathologic conditions affecting +bone. +• Compound: the bone communicates with the skin surface. +• Comminuted: the bone is fragmented. +• Displaced: the ends of the bone at the fracture site are not +aligned. +• Greenstick: extending only partially through the bone, +common in infants when bones are soft. +The tibia is bowed. +• Pathologic: involving bone weakened by an underlying +disease process, such as a tumor. +Healing of Fractures +Bone has a remarkable capacity for repair. +26.18). +The healing process is +completed by restoration of the medullary cavity. +In such +settings, surgical immobilization is often needed for adequate +repair. +Other factors may also interfere with healing. +OSTEONECROSIS +(AVASCULAR NECROSIS) +Infarction of bone and marrow is relatively common. +It can +be limited to the medullary cavity or involve both the +medulla and cortex. +Figure 26.19 Femoral head with a subchondral, wedge-shaped pale area +of osteonecrosis. +changes supervene. +Subchondral infarcts often collapse, +resulting in secondary osteoarthritis. +Medullary infarcts are +usually small and clinically silent. +Pyogenic Osteomyelitis +Pyogenic osteomyelitis is almost always caused by bacterial +infection. +Staphylococcus aureus is responsible for 80% to 90% of +culture-positive pyogenic osteomyelitis. +Collateral blood flow usually limits +cortical involvement. +The slow pace of substitution in subchondral infarcts +(Fig. +Clinical Features +Symptoms depend on location and extent of infarction. +No specific organism is identified in nearly 50% +of patients. +In older children, involvement of the metaphysis is typical. +The combination of antibiotics and surgical +drainage is usually curative. +Acute osteomyelitis fails to resolve and persists as a +chronic infection in 5% to 25% of cases. +Forty percent of mycobacterial osteomyelitis cases involve +the spine (Pott disease). +Skeletal Syphilis +Syphilis (Treponema pallidum) and yaws (Treponema pertenue) +can involve bone. +MORPHOLOGY +Changes associated with osteomyelitis vary temporally and by +location. +In the acute phase, bacteria proliferate and recruit +neutrophils to the site. +Necrosis of bone cells and marrow ensues +within 48 hours. +Associated periosteal lifting further +impairs blood supply and contributes to the necrosis. +Dead bone, or seques- +trum, can crumble and release fragments into the sinus tract. +This new bone can form a living shell, or +involucrum, around the devitalized, infected bone (Fig. +26.20). +Figure 26.20 Resected femur in a person with draining osteomyelitis. +Most bone neoplasms have a propensity for the long +bones of the extremities. +The age groups and anatomic sites +affected are typical of specific tumor types. +For example, +osteosarcoma incidence peaks during adolescence and most +frequently involves the knee. +In contrast, chondrosarcoma +affects the pelvis and proximal extremities of older adults. +Benign bone tumors are often asymptomatic and identified +incidentally. +Others, however, produce pain, cause a slow- +growing mass, or produce a pathologic fracture. +Bone tumors are classified according to the normal cell +types recapitulated or matrix produced. +MORPHOLOGY +Spirochetes can be detected with silver stains or by immunohis- +tochemistry. +Primary bone tumors are rare and are vastly outnumbered +by metastases and hematopoietic tumors. +By definition, osteoid osteomas are +less than 2 cm in diameter. +A thick rim of reactive cortical bone +may be the only radiographic clue. +Figure 26.22 Specimen radiograph of intracortical osteoid osteoma. +26.21) and surrounded by loose connective tissue with many +dilated and congested capillaries. +26.22). +infarcts, and prior radiation (sometimes called secondary +osteosarcomas). +Men are affected slightly more often than +women (1.6 :1). +Osteosarcomas often present with pain, sometimes due +to pathologic fractures. +26.23). +Pathogenesis +The peak incidence of osteosarcoma is during the adolescent +growth spurt. +Abnormalities that interfere +with p53 function are common in sporadic osteosarcomas. +The age distribution of osteosarcoma is bimodal, +with 75% occurring before 20 years of age. +The tan-white tumor +fills most of the medullary cavity of the metaphysis and proximal diaphysis. +in individuals without overt metastases at initial diagnosis. +Osteosarcoma metastasizes hematogenously to the lungs, +bones, brain, and other sites. +Benign cartilage tumors are +much more common than malignant lesions. +Osteochondroma +Osteochondroma, or exostosis, is the most common benign +bone tumor. +26.24). +Extensive necrosis and +intravascular invasion are also common. +Men are affected three +times more often than women. +Osteochondromas develop +only in bones of endochondral origin. +In many cases, they are detected incidentally. +Reduced expression of +EXT1 or EXT2 has also been observed in sporadic osteo- +chondromas. +These genes encode enzymes that synthesize +heparan sulfate glycosaminoglycans. +(Fig. +26.26) and is covered by perichondrium. +26.27). +Enchondromas are most often diagnosed between 20 and +50 years of age. +When they involve large bones, enchon- +dromas are usually asymptomatic and detected incidentally. +(A) Radiograph of an osteochondroma arising from the distal femur (arrow). +Clinical Features +The growth potential of chondromas is limited. +Treatment +depends on the clinical situation and is usually observation or +curettage. +Chondrosarcoma +Chondrosarcomas are malignant cartilage-producing +tumors. +The clear cell and mesenchymal +variants occur in younger people, in their teens or 20s. +On +imaging, the calcified matrix of chondrosarcomas appears +as foci of flocculent densities. +The clear cell variant is unique in that it +originates in the epiphyses of long tubular bones. +Silencing of the CDKN2A tumor suppressor +Figure 26.27 Enchondroma of the proximal phalanx. +Occasionally, they can be painful or cause pathologic +fractures. +In enchondromatosis, the tumors may be numerous +and large, producing severe deformities. +Pathogenesis +Heterozygous mutations in the IDH1 and IDH2 genes are +present within enchondromas. +This “oncometabolite” +interferes with regulation of DNA methylation (Chapter +7). +26.28). +Approximately 80% of patients are younger +than 20 years of age. +26.29A). +Spotty calcifications are typically present, +and central necrosis may create cystic spaces. +Tumor spreads +through the cortex and into surrounding muscle and fat. +26.29B). +26.29C). +Clinical Features +Chondrosarcomas present as painful, progressively enlarging +masses. +The histologic grade correlates directly with biologic +behavior. +A B C +Figure 26.29 Chondrosarcoma. +26.30). +Fibrous septae may also be present, but there is +little stroma. +Geographic necrosis may be prominent. +A pathologic fracture is +also present. +joints, giant cell tumors may cause arthritis-like symptoms. +They can also present with pathologic fractures. +Chemotherapy- +induced necrosis is a positive prognostic indicator. +Although giant cell tumors are benign, +they can be locally aggressive. +This uncommon tumor usually +arises in the third through fifth decades of life. +Giant cell tumors develop within the epiphysis and may +extend into the metaphysis. +26.31). +Grossly, the tumors are large, red-brown masses +that frequently undergo cystic degeneration. +26.32). +The soft tissue component is +delineated by a thin rim of reactive subperiosteal bone. +(B) Axial magnetic resonance image demonstrating characteristic fluid levels (arrows). +Clinical Features +Giant cell tumors are treated by curettage, but 40% to 60% +recur locally. +Although up to 4% metastasize to the lungs, +these can regress spontaneously and are seldom fatal. +The +RANKL inhibitor denosumab has shown promise as an +adjuvant therapy. +All age groups are affected, but +most cases present in adolescence. +ABC develops most +frequently in the femur, tibia, and vertebral body posterior +elements. +26.33A). +Most show central lysis and a thin sclerotic +“eggshell” of reactive bone at the periphery. +26.33B). +26.34). +Bone deposition typically +follows the contours of fibrous septa. +Treatment +of ABC is by curettage or excision. +Recurrence occurs in +10% to 50% of cases. +The radiographic +findings are sufficiently specific that biopsy is rarely neces- +sary. +They are treated with curettage and may +require bone-grafting for proper healing. +These mutations occur early in embryogen- +esis, and affected individuals are genetic mosaics. +At one extreme, a mutation during early +embryogenesis produces McCune-Albright syndrome. +26.36). +Hemosiderin is commonly present. +Skeletal metastases are typically multifocal. +However, +carcinomas of the kidney and thyroid may present with +solitary lesions. +Some cancers are associated with predominantly +one pattern. +Goals of therapy are symptomatic relief and prevention of +further spread. +Periosteal +reaction usually is absent. +26.37). +Cystic +degeneration, hemorrhage, and foamy macrophages are also +common. +The femur, tibia, ribs, jawbones, and calvarium are most +commonly affected. +Growth +of the lesions may be reactivated during pregnancy. +Symp- +tomatic lesions are treated by curettage, but recurrence is +common. +The femur, skull, and tibia are +most frequently affected. +Bisphosphonates can be used to reduce +the severity of the bone pain. +Most primary bone +tumors are benign. +Metastases, especially adenocarcinomas, are +more common than primary bone neoplasms. +• Cartilage forming: Osteochondroma is a polypoid exostosis +with a cartilage cap. +Syndromic forms are most often associated +with mutations in EXT genes. +Chondrosarcomas are malignant tumors of cartilage +involving the axial skeleton in adults. +• Ewing sarcoma is an aggressive malignant small round cell tumor +associated with t(11;22). +Joints +Joints allow movement while providing mechanical stability. +They are classified as solid (nonsynovial) and cavitated +(synovial). +Immobile cartilaginous joints, or synchondroses, include +symphyses (manubriosternalis and pubic). +Synovial joints, +in contrast, have a joint space that allows for a wide range +of motion. +Synovial membranes are lined +by two types of cells arranged in one to four cell deep layers. +Type A synoviocytes are specialized macrophages with +phagocytic activity. +Type B synoviocytes are similar to +fibroblasts and synthesize hyaluronic acid and various +proteins. +Hyaline cartilage lacks blood +vessels, lymphatics, and nerves. +ARTHRITIS +Arthritis refers to inflammation of joints. +It is +the most common type of joint disease. +In these cases, the disease usually affects +few joints (oligoarticular) but may be generalized. +In these settings, the disease is +called secondary OA. +Gender has some influence on distribu- +tion. +The knees and hands are more commonly affected in +women and the hips in men. +26.38). +This leads to changes in proteoglycan +composition as the disease progresses. +Chondrocytes also +secrete matrix metalloproteases (MMPs) that degrade the type +II collagen network. +Advanced disease is characterized by chondrocyte loss and +severe matrix degradation. +synovial fluid to be forced into the subchondral regions. +As the +loculated fluid collection increases in size, fibrous-walled cysts form. +1. +CHONDROCYTE INJURY +Genetic +Biomechanical +Synovium +Chondrocytes +2. +(3) Late OA is evidenced by loss of both matrix and +chondrocytes with subchondral bone damage. +MORPHOLOGY +Chondrocytes proliferate and form clusters in early stages of +OA. +26.39B). +(A) Histologic demonstration of the characteristic fibrillation of articular cartilage. +Typically, only one or a few joints are involved, +except in the uncommon generalized variant. +The joints +commonly involved include the hips (Fig. +Heberden nodes, +prominent osteophytes at the distal interphalangeal joints, +are common in women. +Wrists, elbows, and shoulders are +usually spared. +26.41). +The prevalence of RA in the United States is +approximately 1%. +The incidence peaks in the second to +fourth decades. +RA is three times more common in women +than in men. +Pathogenesis +The autoimmune response in RA is initiated by CD4+ +helper T cells. +26.42). +• IL-17 from Th17 cells that recruits neutrophils and +monocytes. +• RANKL, which is expressed on activated T cells and +stimulates bone resorption. +Figure 26.40 Severe osteoarthritis of the hip. +Some +of these plasma cells secrete antibodies that recognize +self antigens. +IgM and IgA autoantibodies that bind +to IgG Fc regions are present in 80% of individuals. +The HLA-DR4 +allele is associated with ACPA-positive RA. +(A) Schematic view of the joint lesion. +(B) Low magnification reveals marked synovial hypertrophy with formation of +villi. +(C) At higher magnification, subsynovial tissue containing a dense lymphoid aggregate. +These small masses are +firm, nontender, and round to oval. +26.44). +Leukocytoclastic vasculitis produces purpura, +cutaneous ulcers, and nail bed infarction. +tuberculosis. +Involved joints are swollen, warm, and painful. +Unlike +OA, morning joint stiffness does not subside with activity. +26.45). +Unfortunately, individuals must +be maintained on anti-TNF therapy to avoid disease flares. +In +the United States, 30,000 to 50,000 individuals are affected. +Antinuclear antibody (ANA) seropositivity is typical, +but rheumatoid nodules are usually absent. +Approxi- +mately 90% of patients are HLA-B27 positive. +HLA-B27 is common in patients with reactive arthritis. +When active disease persists for +more than 6 months, the term chronic reactive arthritis is +used. +Inflammatory low back pain is a common accom- +panying symptom but is rarely the only symptom. +Synovitis of a digital tendon sheath produces “sausage” +finger or toe. +Fever, leukocytosis, and elevated sedimentation +rate are common. +Axial joint +involvement is most frequent in drug users. +Prompt recognition and effective +antimicrobial therapy can prevent joint destruction. +tuberculosis. +Onset is insidious and associated +with gradually increasing pain. +Systemic symptoms may +or may not be present. +Mycobacterial seeding of the joint +induces formation of confluent granulomas with caseous +necrosis. +Chronic disease results in fibrous ankylosis and obliteration +of the joint space. +Viral Arthritis +Arthritis can occur with a variety of viral infections. +The +manifestations range from acute to subacute arthritis. +It is the leading arthropod-borne disease +in the United States. +If left +untreated, arthritis (late disseminated stage) occurs months +after infection. +In neonates, contiguous spread from underlying +epiphyseal osteomyelitis is relatively common. +H. +influenzae +arthritis predominates in children younger than 2 years of +age. +S. +Arthritis may subsequently develop +at new sites. +In severe cases, the histopathology +mimics rheumatoid arthritis. +Elevated uric +acid can result from overproduction, reduced excretion, or +both (Table 26.6). +Uric acid levels are determined by several +factors: +• Uric acid production. +Urate synthesis is the end product of +purine catabolism. +• Uric acid excretion. +Asymptomatic hyperuricemia appears around puberty +in males and after menopause in females. +In primary gout, +hyperuricemia is usually due to reduced excretion. +26.46). +Macrophages +and neutrophils phagocytose the urate crystals. +Comple- +ment activation by the alternative pathway may also con- +tribute to leukocyte recruitment. +The resulting +acute arthritis typically remits spontaneously in days to +weeks. +26.47A). +The resulting pannus destroys the underlying cartilage and +leads to juxta-articular bone erosions. +In severe cases, fibrous or +bony ankylosis ensues, resulting in loss of joint function. +Tophi are the pathognomonic hallmark of gout. +(Fig. +26.47B–C).Tophi may appear in the articular cartilage, ligaments, +tendons, and bursae. +Less frequently they occur in soft tissues +(earlobes, fingertips) or kidneys. +Superficial tophi can ulcerate +through the overlying skin. +Generally, gout does not shorten the life +span, but it does impact quality of life. +Note that IL-1 stimulates the production of chemokines and other +cytokines from a variety of cells. +LTB4, Leukotriene B4. +and periarticular tissue as well as severe cartilage damage +that compromises joint function. +Only about 10% of individuals with hyperuricemia +develop gout. +There is no sex or racial predisposition. +CPPD is divided into sporadic (idiopathic), hereditary, and +secondary types. +These mutations are +distinct from those associated with craniometaphyseal dys- +plasia. +As in gout, inflammation is caused +by activation of the inflammasome in macrophages (see +Fig. +26.46). +26.48A). +Individual crystals are rhomboid, 0.5 +to 5 µm in greatest dimension (Fig. +26.48B), and birefringent. +Inflammation is usually milder than in gout. +A +Clinical Features +CPPD is frequently asymptomatic. +Ultimately, approximately +50% of affected individuals experience significant joint +damage. +Therapy is supportive to minimize symptoms. +There is no known treatment that prevents or slows crystal +formation. +The rare malignant +tumors are discussed with soft tissue tumors. +Despite +the name, the lesion is unrelated to ganglia of the nervous +system. +The cyst lining +resembles the synovium, and both cyst and synovium may +be hyperplastic. +Cyst fluid often contains inflammatory cells +and fibrin. +Both +variants are most often diagnosed in the 20s to 40s and +affect the sexes equally. +A +B +Figure 26.48 Pseudogout. +(A) Deposits are present in cartilage and +consist of amorphous basophilic material. +(B) Smear preparation of +calcium pyrophosphate crystals. +sacroiliac, vertebral joints and entheses and are associated with +HLA-B27. +• Suppurative arthritis describes direct infection of a joint space +by bacterial organisms. +• Lyme disease is a systemic infection by B. +MORPHOLOGY +Tenosynovial giant cell tumors are red-brown to orange-yellow. +26.49A); localized tumors are well circumscribed. +26.49B). +Older lesions +may become fibrotic. +They usually result from trauma +or degenerative processes and are much more common than +neoplasms. +(A) Excised synovium with fronds and nodules typical of diffuse tenosynovial giant cell tumor. +The +color and texture explain the old name of pigmented villonodular synovitis. +(B) Sheets of proliferating cells in tenosynovial giant cell tumor bulging the +synovial lining. +Clinical Features +Diffuse tenosynovial giant cell tumors present in the knee +in 80% of cases. +Sometimes a palpable mass is appreciated. +Recurrence +is common. +Bone erosion and recurrence are less common than in the +diffuse type. +Surgical excision is the mainstay of treatment. +Clinical trials using antagonists of M-CSF signaling have +had promising results. +Most soft tissue +tumors arise in the extremities, particularly the thigh. +Approximately 15% arise in children; the incidence increases +with age. +Pathogenesis +Most sarcomas are sporadic and have no known predispos- +ing cause. +Others are linked to known environmental +exposures such as radiation, burns, or toxins. +Some sarcomas reca- +pitulate a recognizable mesenchymal lineage (e.g. +Examples include Ewing sarcoma (discussed earlier) and +synovial sarcoma. +In others, the mechanisms are +unknown. +Oncogenic tumor-specific fusion proteins +represent potential targets for therapy. +Examples include leiomyosarcomas and undifferentiated +pleomorphic sarcoma. +The next section will consider representative soft +tissue tumors. +Pleomorphic liposarcomas have complex karyotypes +without reproducible genetic abnormalities. +26.50A). +26.50B). +MORPHOLOGY +The conventional lipoma is a well-encapsulated mass of mature +adipocytes. +It usually arises in the subcutis of the proximal extremi- +ties and trunk during middle adulthood. +Infrequently, lipomas are +large, intramuscular, and poorly circumscribed. +Lipomatosis +occurs when multifocal lipomas involve a limb. +Most lipomas are +soft, mobile, painless, and cured by simple excision. +Clinical Features +Liposarcomas recur locally, and often repeatedly, unless +adequately excised. +Clinical +subtypes include Dupuytren contracture, Ledderhose disease, +and Peyronie disease. +Incidence increases with age. +Eventually, it may cause abnormal curvature of the shaft +and constriction of the urethra. +Palmar and plantar fibromatoses progress in about 50% +of cases. +The remainder stabilize and do not progress; some +resolve spontaneously. +Nevertheless, recurrence is common, +even after excision. +They arise most frequently in the teens to 30s, pre- +dominantly in women. +The defect that prevents +neoplastic cells from becoming malignant has not been +defined. +Nodular fasciitis typically regresses spontaneously +and, if excised, rarely recurs. +MORPHOLOGY +Nodular fasciitis arises in the deep dermis, subcutis, fascia, or +muscle. +Mitoses are frequent, but atypical forms are +notably absent (Fig. +Storiform or fascicular patterns are +common in cellular areas. +It +affects males more frequently than females. +26.52). +The resulting histologic appearance can +resemble a scar. +Because they are infiltra- +tive, complete excision of deep fibromatosis can be difficult. +Recent efforts have concentrated on medical or radiation +therapy as alternatives to surgery. +A +rhabdomyoma, is frequently associated with tuberous +sclerosis (Chapter 28). +The remaining subtypes +of rhabdomyosarcoma are genetically heterogeneous. +B +Figure 26.53 Rhabdomyosarcoma. +(B) Alveolar rhabdomyosarcoma with +numerous spaces lined by discohesive, uniform round tumor cells. +at the periphery adhere to the septae. +Tumor cells are uniform +and round with little cytoplasm. +Cross-striations are uncommon +(Fig. +26.53B). +Rhabdomyoblasts are occasionally present. +Dense, collagenous, sclerotic stroma may be more common in +adults. +MORPHOLOGY +Embryonal rhabdomyosarcoma is a soft, gray, infiltrative mass. +26.53A). +Rhabdomyoblasts with visible +cross-striations may be present. +Individuals often present +with a deep-seated mass that has been present for several +years. +Tumor cells +have blunt-ended, elongated nuclei with minimal atypia +and few mitotic figures. +Solitary lesions are easily cured. +However, multiple tumors may be so numerous that surgical +removal is impractical. +It accounts for 10% to 20% +of soft tissue sarcomas. +They occur in adults and afflict +women more frequently than men. +A particularly deadly +form arises from the great vessels, often the inferior vena +cava. +Leiomyosarcomas have underlying defects in genomic +stability leading to complex genotypes. +MORPHOLOGY +Synovial sarcomas can be monophasic or biphasic. +26.54). +The 5-year survival varies from +25% to 62% and is related to tumor stage and patient age. +Common sites of metastases are the lung and, unusually +for sarcomas, regional lymph nodes. +MORPHOLOGY +Leiomyosarcomas present as painless firm masses. +Retroperitoneal +tumors may be large and bulky and cause abdominal symptoms. +Clinical Features +Leiomyosarcoma treatment depends on tumor size, loca- +tion, and grade. +Necrosis and hemorrhage common. +26.55). +Mitotic figures, including +atypical asymmetric forms, are abundant. +ACKNOWLEDGMENT +We thank Dr. +Andrew Rosenberg for his outstanding +contribution to previous editions of this chapter. +[A recent review of bone cell biology]. +Kogianni G, Noble BS: The biology of osteocytes, Curr Osteoporos Rep +5:81–86, 2007. +[A good review of the cellular basis of bone remodeling]. +Zaidi M: Skeletal remodeling in health and disease, Nat Med 13:791–801, +2007. +[An excellent review of the genetics and pathophysiology of skeletal +diseases]. +Skeletal Dysplasias +Krakow D, Rimoin DL: The skeletal dysplasias, Genet Med 12:327–341, +2010. +[A comprehensive summary of the dysplasias with a very useful +summary table]. +[An overview of the current classification of +osteogenesis imperfecta]. +Osteoporosis +Black DM, Rosen CJ: Clinical practice. +Postmenopausal osteoporosis, +N Engl J Med 374(3):254–262, 2016. +doi:10.1056/NEJMcp1513724. +Review. +Erratum in: N Engl J Med.;374(18):1797. +[A recent review of +postmenopausal osteoporosis]. +[A seminal paper elucidating the molecular pathways that underlie +osteoporosis]. +[A nice +summary of the effects of parathyroid hormone on calcium and bone +metabolism]. +Paget Disease +Cundy T: Paget’s disease of bone, Metabolism 80:5–14, 2018. +[A recent +update on the pathology, epidemiology, and biology of Paget disease]. +[A recent +update on the genetic contribution to Paget disease]. +601763. +[A summary of recent developments regarding the +pathophysiology of femoral head osteonecrosis]. +Despite this, prognosis is +generally poor. +Metastases occur in 30% to 50% of cases. +• Soft tissue tumors likely arise from pluripotent mesenchymal +stem cells rather than mature cells. +[A concise review of the biology of +osteosarcoma]. +[A recent update on the classification +of osteosarcoma]. +[A good review of the known +genetic abnormalities in cartilage tumors]. +[A seminal article identifying IDH mutations in +inherited cartilage tumors]. +[A discussion +of the genetic basis of multiple osteochondroma syndrome]. +[A review +of targets of the EWSR1-FLI1 fusion protein and therapeutic implications]. +[A recent review of RANK-RANKL interactions in the pathogenesis +of giant cell tumors]. +[A recent, nicely illustrated update on the pathogenesis of RA and +SLE]. +Scott DL, Wolfe F, Huizinga TW: Rheumatoid arthritis, Lancet +376:1094–1108, 2011. +[A review of the pathogenesis and treatment of +rheumatoid arthritis]. +[A recent +review of the diagnosis, classification, and treatment of spondyloarthritis]. +[A description of the +relationship among autoimmunity, HLA alleles, and microbes]. +[A recent, nicely illustrated, comprehensive review +of Lyme disease]. +Gout and Pseudogout +Dalbeth N, Merriman TR, Stamp LK: Gout, Lancet 388(10055):2039–2052, +2016. +[A comprehensive review of clinical, pathologic, and pathophysiologic +aspects of gout]. +[A seminal article identifying +clonal chromosomal rearrangement in tenosynovial giant cell tumor]. +[An excellent review of specificity (or lack thereof) of +genetic defects in soft tissue tumors]. +They +can be grouped according to anatomy, disease course, +and pathogenesis. +A discussion of neoplasms that arise from +peripheral nerves ends the chapter. +Injury to either of these components may +result in a peripheral neuropathy. +Myelin basic protein (MBP) is an intracellular protein +that has a role in myelin compaction. +the slowest conduction speeds due to their lack of myelin +and small axonal diameter. +27.1). +27.2). +27.3) and disintegrate into spherical structures (myelin +ovoids). +Macrophages are recruited and participate in the +removal of axonal and myelin debris. +Continuous pruning of the sprouting axons removes mis- +guided branches. +The regeneration is successful only if the two transected +ends remain closely approximated. +27.4). +As a result, degenerating and +regenerating axons coexist in a single biopsy. +With time, +damage tends to outpace repair, resulting in progressive +loss of axons. +(C) Regeneration of axons after injury (left axon) allows reinnervation of myofibers. +See Fig. +27.7 for comparison with reinnervation. +AB +Figure 27.3 Electron micrographs illustrating features of axonal degeneration. +Vasculitis is a common +cause of this pattern of injury. +27.2), whereas +axons are relatively preserved. +This definition is similar to +that of demyelinating diseases that affect the CNS (Chapter +28). +The overall annual +incidence is approximately 1 case per 100,000 persons. +Circulating +antibodies that cross-react with components of peripheral +nerves may also play a role. +Electron +microscopy has identified an early effect on myelin sheaths. +Ultimately, the remnants of the +myelin sheath are engulfed by the macrophages. +A B +Figure 27.5 Onion bulb neuropathy. +(B, Courtesy G. +Pathogenesis +T cells as well as antibodies are implicated in the inflamma- +tory process. +27.5). +Clinical Features +The clinical picture is dominated by ascending paralysis +and areflexia. +Deep tendon reflexes disappear early in +the process. +Many patients spend weeks in the +intensive care unit (ICU) before recovering normal function. +Perivascular +inflammatory infiltrates are often present. +Infectious Neuropathies +Many infectious processes affect peripheral nerves. +Each of these disorders is also discussed in more +detail in Chapter 8. +Thus, large traumatic ulcers may develop. +• Tuberculoid leprosy is characterized by an active cell- +mediated immune response to M. +leprae that usually +manifests as dermal nodules containing granulomatous +inflammation. +In tuberculoid leprosy, affected individuals have much +more localized nerve involvement. +These include +polyradiculoneuropathy and unilateral or bilateral facial +nerve palsies. +Diphtheria +Peripheral nerve dysfunction results from the effects of +the diphtheria exotoxin. +The mechanism of action of diphtheria toxin is +described in Chapter 8. +Following chickenpox, a +latent infection persists within neurons of sensory ganglia. +Most common is the involvement +of thoracic or trigeminal nerve dermatomes. +In a small proportion of patients, weakness +is also apparent in the same distributions. +Peripheral nerves show +degeneration of the axons that belong to the dead sensory +neurons. +Intranuclear inclusions +generally are not found in the peripheral nervous system. +Patients with both type 1 and type +2 diabetes are affected (Chapter 24). +Hyperglycemia causes the nonenzymatic +glycosylation of proteins, lipids, and nucleic acids. +cranial neuropathy, and radiculoplexus neuropathy. +It is often monophasic and can improve over +several months. +These asymmetric manifestations may be +caused by microvascular disease. +Most individuals with renal failure +have a peripheral neuropathy. +Regeneration and +recovery are common after dialysis. +• Thyroid dysfunction. +In rare cases, hyperthyroidism is associated +with a neuropathy resembling Guillain-Barré syndrome. +• Paraneoplastic neuropathies. +Nerve +biopsies show reduced numbers of axons. +27.6). +Paraneoplastic sensory neuronopathy +is most commonly associated with small cell lung cancer. +Sensory symptoms usually start distally +in an asymmetric and multifocal pattern. +• Neuropathies associated with monoclonal gammopathies. +Deposition of IgM can be seen ultrastructur- +ally between the membrane layers of the myelin sheath. +IgG or IgA paraproteins may also be associated with +peripheral neuropathy. +• Avulsion of a nerve may occur when tension is applied, +often to one of the limbs. +Women are +more commonly affected than men, and the problem +is frequently bilateral. +Now there is a +continuously growing list of altered genes that are linked +to these diseases. +27.1. +CMT1A accounts for some 55% of genetically defined +CMT. +• CMTX encompasses X-linked forms of CMT disease. +CMT1X is the most common of these, accounting for +15% of genetically defined cases of CMT. +CMT2A +is the most common subtype, accounting for 4% of all +CMT disease. +It is caused by mutations in the MFN2 +gene, which is required for normal mitochondrial fusion. +The phenotype is typically severe, with disease onset in +early childhood. +Loss of pain and temperature sensation is +the most common symptom. +The inability to sense pain +leads to traumatic injury of the hands and feet. +These are +typically axonal neuropathies. +Most are caused by +germline mutations of the transthyretin gene. +The clinical presentation is similar to +that of hereditary sensory and autonomic neuropathies. +Neuromuscular junctions are found midway along the +length of myofibers. +These receptors are responsible +for the initiation of signals leading to muscle contraction. +It has a prevalence of 150 to 200 per 1 million +and shows a bimodal age distribution. +In young adults, the +female-to-male ratio is 2:1, but in older adults there is a +male predominance. +The mechanism of action of the various autoantibodies +appears to differ. +This limits the ability of myofibers to respond +to ACh. +Autoantibodies directed against muscle-specific +receptor tyrosine kinase do not fix complement. +This peculiar condition is marked by +the appearance of B-cell follicles in the thymus. +Overall mortality has dropped from over +30% in the 1950s to less than 5% with current therapies. +Acetylcholinesterase inhibitors that increase the half-life of +ACh are the first line of treatment. +In contrast to +myasthenia gravis, rapid repetitive stimulation increases +muscle response. +Muscle strength is augmented after a few +seconds of muscle activity. +Patients typically present with +weakness of their extremities. +Symptoms may precede the diagnosis +of cancer, sometimes by years. +Patients without cancer often have other autoimmune +diseases, such as vitiligo or thyroid disease. +Botox acts by blocking the release of ACh from presynaptic +neurons (Chapter 8). +• Genetic defects in neuromuscular junction proteins give rise +to congenital myasthenic syndromes. +Skeletal Muscle Atrophy +Skeletal muscle atrophy is a common feature of many +disorders. +27.7). +• Perifascicular atrophy is seen in dermatomyositis (see later). +(B) Damage to innervating axons +leads to loss of trophic input and atrophy of myofibers. +Each type is +described next. +Neurogenic injuries lead to fiber type grouping and grouped +atrophy (see Fig. +27.7), both of which stem from the disruption +of muscle innervation. +Following +denervation, myofibers undergo atrophy, often assuming +a flattened, angulated shape. +These large motor units are also +susceptible to grouped atrophy if the innervating axon is +damaged. +Removal of the degenerated debris sets +the stage for regeneration. +Fusion of activated satellite +cells to damaged myofibers is an important step for +regeneration. +Eventually, new sarcomeres are generated, +and the continuity of the original myofiber is restored. +Depending on the nature of the primary insult, +atrophic myofibers may also be seen. +The histologic hallmark, discussed below, +is perifascicular atrophy. +With that, +polymyositis is a less common diagnosis than in the past. +Rarely certain +infectious agents can cause inflammation of skeletal muscle +(Chapter 8). +The prominence of this signature appears +to correlate with disease activity. +Direct immunologic injury +to the muscle fibers may also play a role. +A direct link between these autoantibodies and disease +pathogenesis has not yet been established. +27.8B). +Segmental fiber necrosis and regeneration may also be seen. +Clinical Features +Muscle weakness is slow in onset, symmetric, and often +accompanied by myalgias. +It typically affects the proximal +muscles first. +Note the heliotrope rash affecting the eyelids. +(B) Dermatomyositis. +The histologic appearance of muscle shows +perifascicular atrophy of muscle fibers and inflammation. +(Courtesy Dr. +Fine +movements controlled by distal muscles are affected only +late in the disease. +Cardiac involvement is common, but +rarely leads to cardiac failure. +Dermatomyositis may occur in adults or in children. +Dermatomyositis is the most common +inflammatory myopathy in children. +In many +patients, IMNM is associated with autoantibodies against +HMG-CoA reductase. +Descriptions of +other entities have made cases of polymyositis less common +as outlined above. +Dysphagia from esophageal and pharyngeal muscle +involvement is not uncommon. +It is present in about half of the patients and is +a useful marker of the disease. +Modified Gomori trichrome stain. +MORPHOLOGY +cases intravenous immunoglobulins (IVIG). +Among +prescription drugs, statins are among the leading culprits. +Myopathy is the most common complication of +statins (e.g., atorvastatin, simvastatin, pravastatin). +Cardiac muscle can also be affected by these drugs and can +exhibit similar pathologic changes. +It has +certain features in common with polymyositis, as discussed +earlier. +Thyroid dysfunction can lead to several types of myopa- +thy. +Hypothyroidism can cause cramping or aching +of muscles, and decreased movement. +Reflexes may be +slowed. +Alcohol can also be myopathic. +These categories should +largely be understood as illustrative of key concepts. +Included in the +group of inherited muscular disorders are the following. +They are often associated with distinct +structural abnormalities of the muscle. +These are exemplified by Ullrich congenital +muscular dystrophy (UCMD) and merosin deficiency. +UCMD +is characterized by hypotonia, proximal contractures, +and distal hyperextensibility. +• Conditions with abnormalities in receptors for extracellular +matrix. +27.10) by O-linked glycosylation. +Alpha-dystroglycan expression +is important for CNS and eye development. +Milder +forms may only cause skeletal muscle disease. +The following section focuses on the most common and +best understood forms of inherited myopathies. +As a result, these +diseases are sometimes referred to as dystrophinopathies. +The most common early-onset form is referred to as Duch- +enne muscular dystrophy. +It has an incidence of 1 per 3500 +live male births and has a severe progressive phenotype. +27.10). +Mutations in genes that encode these +glycosylation enzymes can cause myopathy as discussed below. +These +moieties are depicted as light blue branching structure. +The diagnosis is based on the history, physical examina- +tion, and laboratory studies. +The detection of a dystrophin mutation +offers definitive diagnosis. +Treatment of patients with dystrophinopathies is chal- +lenging. +Current treatment consists primarily of supportive +care. +Definitive therapy requires restoration of dystrophin +levels in skeletal and cardiac muscle fibers. +27.11). +Clinical Features +Boys with Duchenne muscular dystrophy appear normal at +birth. +Very early motor milestones are met, but walking is +often delayed. +The first indications of muscle weakness are +clumsiness and inability to keep up with peers. +Weakness +begins in the pelvic girdle muscles and then extends to the +shoulder girdle. +The mean age of wheelchair dependence is +around 9.5 years. +Dystrophin is also expressed in the heart and the CNS. +Histologic images of muscle biopsy specimens from two brothers. +(A and B) Specimens from a 3-year-old +boy. +(C) Specimen from his 9-year-old brother. +Their overall incidence is 1 in 25,000 to +50,000 individuals. +Both age of onset and +disease severity are highly variable. +It affects about +1 in 10,000 individuals. +Myotonia, a sustained involuntary +contraction of muscles, is a key feature of the disease. +Rarely, +patients present with “congenital myotonia,” marked by severe +manifestations in infancy. +They may also +influence gene expression by affecting chromatin organization +in the nucleus. +How defects in these proteins produce the +observed phenotypes is unknown. +It is an autosomal dominant disease affecting +about 1 in 20,000 individuals. +In others, there +is slowly progressive damage of muscle, without episodic +manifestations. +The defect in +this disorder impairs the transport of free fatty acids into +mitochondria. +Severe deficiency +results in the generalized glycogenosis of infancy, +Pompe disease (Chapter 5). +27.12). +By electron microscopy, morphologically abnormal mitochondria +may be seen. +• Myopathic disorders are often marked by degeneration and +regeneration of myofibers. +Immune damage to +small blood vessels and perifascicular atrophy are common +features. +• Polymyositis is an adult-onset myopathy caused by CD8+ T +cells. +Some of these diseases present in infancy, +others in adulthood. +They may be relentlessly progressive or +cause relatively static deficits. +The larger +fibers are those that are innervated and have undergone compensatory +hypertrophy. +27.13). +Most channelopathies are autosomal dominant disorders +with variable penetrance. +• CLC1: Mutations affecting this chloride channel cause +myotonia congenita. +As already discussed, CLC1 expres- +sion is decreased in myotonic dystrophy. +Other +rare tumors arising from nerves may show evidence of +perineurial cell differentiation. +Peripheral nerve sheath tumors have several unique +features. +Tumors with skeletal muscle differentiation +are discussed in Chapter 26. +Loss of +expression of the NF2 gene product, merlin, is a consistent +finding in all schwannomas. +As a result they can often be resected without sacrificing nerve +function. +Grossly, these tumors form firm, gray masses. +Palisading +of nuclei is common. +27.14B). +Electron microscopy shows basement +membrane deposits encasing single cells and collagen fibers. +Some large mitotically +active schwannomas lacking Antoni B areas can mimic a sarcoma. +from the acoustic portion of the nerve nor is it a neuroma. +Surgical removal is +curative. +Neurofibromas may be either sporadic or NF1-associated. +Different types of neurofibroma can be distinguished depend- +ing on their growth pattern. +Loss of the GTPase activity +causes RAS to be trapped in GTP bound active state. +Adnexal structures are sometimes entrapped at the edges of the +lesion. +(A and B) Schwannoma. +(C and D) Plexiform neurofibroma. +(C) Multiple nerve fascicles +are expanded by infiltrating tumor cells. +Diffuse neurofibroma. +Some of these neurofibromas can grow to large sizes. +Plexiform neurofibroma. +These tumors grow within and +expand nerve fascicles (Fig. +27.14C), entrapping associated axons. +The +tumor has cellular composition similar to that of other neurofi- +bromas. +The extracellular matrix varies from loose and myxoid +to more collagenous and fibrous. +Often the collagen is seen in +bundles likened to “shredded carrot” (Fig. +27.14D). +Sporadic cases +may arise de novo. +A wide range of histologic appearance can be +encountered. +spindle cells. +At low power the tumor often appears “marbleized” +due to variations in cellularity. +Mitoses, necrosis, and nuclear +anaplasia are common. +• Schwannomas are encapsulated benign tumors that can be +associated with NF2. +As +has been mentioned earlier, NF-1 protein has GTPase activity +that restrains RAS function. +In the absence of NF-1, RAS +remains trapped in its active state. +The disease has a high penetrance but variable expres- +sivity. +An +unfortunate subset has severe disease. +This disorder +is much less common than NF1, having a frequency of 1 +in 40,000 to 50,000. +Collins MP, Hadden RD: The nonsystemic vasculitic neuropathies, Nat +Rev Neurol 13:301, 2017. +Willison HJ, Jacobs BC, van Doorn PA: Guillain-Barré syndrome, Lancet +388:717, 2016. +[Review of the histomorphologic classification of inflammatory +myopathies]. +[Committee communication on classification and +diagnosis of congenital muscular dystrophies]. +Dalakas MC: Inflammatory muscle diseases, N Engl J Med 372(18): +1734–1747, 2015. +[Review on classification and clinical features of inflam- +matory myopathies]. +[Review +of the biologic mechanisms of facioscapulohumeral dystrophy]. +Dubowitz V, Sewry CA, Oldfors A: Muscle biopsy: a practical approach, +ed 4, Oxford, 2013, Elsevier. +[Overview of disorders affecting muscle]. +[Summary of the different +categories of limb-girdle muscular dystrophies]. +[Committee communication on classification and diagnosis of congenital +myopathies]. +[Review of possible +treatment strategies for myotonic dystrophy]. +Thornton CA: Myotonic dystrophy, Neurol Clin 32(3):705–719, 2014. +[Review of myotonic dystrophy]. +[Review of the pathologic +classification and features of peripheral nerve sheath tumors]. +In many +of these diseases, the predominant mechanism of cell death appears +to be apoptosis. +28.15A).“Red neurons” are evident +by 6 to 12 hours after an irreversible hypoxic/ischemic insult. +The astrocyte +derives its name from its star-shaped appearance. +Astrocytes act as metabolic buffers +and detoxifiers within the brain. +Figure 28.1 Reactive astrocytes. +Other types of astrocyte injury lead to the formation of +cytoplasmic inclusion bodies. +28.49C). +Figure 28.2 Hydrocephalus. +Dilated lateral ventricles seen in a coronal +CEREBRAL EDEMA, +section through the midthalamus. +28.2). +When hydrocephalus develops in infancy before closure +of the cranial sutures, the head enlarges. +There are two main +pathways of edema formation in the brain. +The +paucity of lymphatics greatly impairs the resorption of +excess extracellular fluid. +28.4). +due to distortion or tearing of penetrating veins and arteries +supplying the upper brainstem. +Hydrocephalus is an increase in CSF volume +within all or part of the ventricular system. +Myelomeningoceles occur most commonly in the +lumbosacral region (Fig. +28.5). +A range of different anatomic malformation patterns has +been defined. +Nodular +subcortical heterotopias may also be encountered. +Intrauterine +diagnosis of severe forms by ultrasonography is now +possible. +Holoprosencephaly is associated with trisomy +13 as well as other genetic syndromes. +28.6). +” +bundles of anteroposteriorly oriented white matter can +be demonstrated. +These may be accompanied by morphologic +changes in other regions of the brain. +28.7), and, almost invariably, hydrocephalus and a +lumbar myelomeningocele. +Disruption +of these processes can alter the size, shape, and organization +of the brain. +Different patterns of injury may occur. +Ultimately, the +infarcted areas develop into large cystic lesions (Fig. +Figure 28.7 Arnold-Chiari malformation. +The disease generally becomes manifest +in the second or third decade of life. +Although neurologic recovery is usually complete, +amnesia for the event often persists. +Hemorrhage can extend into the subarachnoid +space from these lesions. +The crests of gyri are most sus- +ceptible because this is where the direct force is greatest. +In general, if the +head is immobile at the time of trauma, only a coup injury +is found. +Figure 28.8 Chronic stage of periventricular leukomalacia. +A blow to the +head may be penetrating or blunt; it may cause either an +open or a closed injury. +The thickness of the cranial bones +varies; therefore, their resistance to fracture differs greatly. +Also, the relative incidence of fractures among skull bones +is related to the pattern of falls. +28.9A).The appearance of contusions is similar regardless of the +source of the trauma. +In the earliest stages, there is edema and +hemorrhage, which is often pericapillary. +Old traumatic lesions on the surface of the brain have a +characteristic gross appearance. +28.9B), can become epileptic foci. +In old +contusions, gliosis and residual hemosiderin-laden macrophages +predominate. +Axons are injured directly by mechanical +forces, with subsequent alterations in axoplasmic flow. +Traumatic Vascular Injury +Vascular injury is a frequent component of CNS trauma. +28.10). +These arteries, most notably the +middle meningeal artery, are vulnerable to traumatic injury. +28.11). +The expanding +hematoma compresses the underlying brain. +The +extravasated blood dissects through the two layers of the +dura, producing a subdural hematoma. +28.12).The underlying brain is flattened, +and the subarachnoid space is often clear. +Figure 28.11 Epidural hematoma covering a portion of the dura. +Also +present are multiple small contusions in the temporal lobe. +(Courtesy the +late Dr. +Raymond D. +A +Spinal Cord Injury +The spinal cord is vulnerable to trauma from its skeletal +encasement. +B +Figure 28.12 (A) Large organizing subdural hematoma attached to the +dura. +Clinical Features +Symptomatic subdural hematomas most often manifest +within 48 hours of injury. +Neurologic signs are attributable to the +pressure exerted on the adjacent brain. +Slowly progressive +neurologic deterioration is typical, but acute decompensation +may also occur. +The treatment of subdural hematomas is +to remove the blood and associated organizing tissue. +The +risk of repeat bleeding is greatest in the first few months +after the initial hemorrhage. +The general biochemical changes in cells resulting from +ischemia are discussed in Chapter 2. +When the ischemia is +sustained, infarction follows in the territory of the compro- +mised vessel. +• Embolism to the brain occurs from a variety of sources. +Emboli tend to lodge where +blood vessels branch or in areas of preexisting luminal +stenosis. +• Traumatic tearing of blood vessels leads to epidural or subdural +hematoma. +In the brain, +embolism is a more common cause of vascular occlusion +than thrombosis. +• Hemorrhage resulting from rupture of CNS vessels. +Primary angiitis of the CNS can also +develop in the absence of systemic vasculitis. +Brain infarcts are subdivided into two broad groups based +on the presence of secondary hemorrhage. +28.13B). +MORPHOLOGY +Both the gross and microscopic appearance of a nonhemorrhagic +infarct changes over time. +Grossly, there is little change in +appearance during the first 6 hours of irreversible injury. +28.14). +Microscopically, the tissue reaction evolves along the following +sequence: +• Acute infarct (Fig. +28.15A). +There is loss of the usual +tinctorial characteristics of white- and gray-matter structures. +Endothelial and glial cells, mainly astrocytes, swell, and myelinated +fibers begin to disintegrate. +• Subacute (evolving) infarct (Fig. +28.15B). +28.16). +On microscopic +Figure 28.14 Old cystic infarct showing cavitation from loss of brain +parenchyma. +A B C +Figure 28.15 Cerebral infarcts. +(A) Acute ischemic injury causes diffuse eosinophilia of neurons, which are beginning to shrink. +28.17) and is +often bilateral. +Figure 28.16 Lacunar infarcts in the caudate and putamen (arrows). +examination, there is tissue loss surrounded by gliosis. +In general, there is often slow improvement during +a period of months. +The clinical outcome varies with the severity and +length of the insult. +Other forms of hereditary small-vessel diseases of the +CNS have been identified. +28.18A). +Arteriolar walls affected by hyaline change (Fig. +28.18C). +(C, Courtesy Dr. +28.19); multiple aneurysms exist in 20% to +30% of cases based on autopsy series. +The neck of the aneurysm may be wide or +narrow. +Repeat +bleeding is common in survivors and unpredictable in timing. +With each episode of bleeding, the prognosis is worse. +(B) Dissected circle of Willis to show large aneurysm. +Foci of old hemorrhage, infarction, and +calcification frequently surround the abnormal vessels. +Males are affected twice +as frequently as females. +There are four principal routes by which +microbes enter the nervous system. +Meningoencephalitis refers to inflammation +of the meninges and brain parenchyma. +It occurs most often +with meningococcal and pneumococcal meningitis. +Particularly in untreated meningitis, Gram stain reveals variable +numbers of bacteria. +Leptomeningeal fibrosis may follow pyogenic meningitis and +cause hydrocephalus. +The viral aseptic meningitides are usually self-limited and +are treated symptomatically. +The spectrum of pathogens varies seasonally and +geographically. +28.22). +From +Figure 28.22 Pyogenic meningitis. +If untreated, focal neurologic signs, lethargy, and +coma may develop. +It +may involve the meninges or the brain. +28.23). +There may be discrete, white areas of inflammation scattered over +the leptomeninges. +Organisms can often be seen with acid-fast +stains. +Hydrocephalus may +result. +When the +process involves the spinal cord subarachnoid space, nerve +roots may also be affected. +MORPHOLOGY +Neurosyphilis presents in several distinct forms. +• Paretic neurosyphilis is caused by invasion of the brain by +T. +The spirochetes can, at times, be demonstrated in tissue +sections. +• Tabes dorsalis is the result of damage to the sensory axons +in the dorsal roots. +Organisms are not demonstrable in the cord lesions. +Involvement of the nervous system is referred to as +neuroborreliosis. +Some viruses have a propensity to infect the nervous +system. +All of these viruses have animal hosts and insect vectors. +neutrophils) (Fig. +28.24A). +Microglial cells form small aggregates, called microglial +nodules (see Fig. +28.24B). +In severe cases, there may be a necrotiz- +ing vasculitis with associated focal hemorrhages. +effective treatment in many cases, with a significant reduction +in the mortality rate. +28.25A). +The infection is necrotizing and +often hemorrhagic in the most severely affected regions. +28.25B). +The typical presenting symptoms are alterations in +mood, memory, and behavior. +(A, Courtesy Dr. +T.W. +Vaccination is now available to prevent these complications +of varicella-zoster virus reactivation. +The virus can also attack the lower spinal cord and roots, producing +a painful radiculoneuritis. +Any cell in the CNS (neurons, glia, +ependyma, or endothelium) may be infected. +A myocarditis sometimes com- +plicates the acute infection. +Postpolio syndrome can develop in +patients 25 to 35 years after resolution of the initial illness. +Exposure to certain species of +bats, even without a known bite, can also lead to rabies. +MORPHOLOGY +External examination of the brain shows intense edema and +vascular congestion. +28.26). +HIV can +be detected in CD4+ microglia and mononuclear or multinucleated +macrophages. +There are signs of meningeal +irritation and, as the disease progresses, flaccid paralysis. +Figure 28.27 HIV encephalitis. +28.28A). +28.28B). +Greatly enlarged oligodendrocyte +nuclei containing glassy amphophilic viral inclusions (Fig. +Infection of granule cell neurons in +the cerebellum has been demonstrated in rare instances. +The resultant vascular thrombosis produces +infarction that is often strikingly hemorrhagic. +The most commonly encountered +fungi that invade the brain are Candida and Cryptococcus. +The CSF may contain few cells but usually has +a high concentration of protein. +8.43). +Most cases of cryptococcal infection in immunosuppressed +individuals are caused by C. +neoformans. +Recently, a second +species, C. +Some case studies suggest that C. +(B) Microscopically, the lesions consists of areas of demyelination. +• Cerebral amebiasis. +The amebae may be +difficult to distinguish morphologically from activated +macrophages (Fig. +28.29). +• Cerebral malaria. +28.30B). +KEY CONCEPTS +INFECTIONS +• Pathogens from viruses through parasites can infect the brain. +Different pathogens use distinct routes to reach the brain and +cause different patterns of disease. +• Viral infections can cause meningitis or meningoencephalitis. +Several pathologic processes can cause loss of myelin. +separated in time and are attributable to patchy white +matter lesions that are separated in space. +Women are affected twice +as often as are men. +There is a strong association with a +DR haplotype of the major histocompatibility complex. +Environmental factors are also important. +Immune mechanisms that underlie the destruction of +myelin are the focus of much investigation. +The demyelination is caused by these +activated leukocytes and their injurious products. +Plaques can extend into gray +matter because myelinated fibers are present there as well. +28.32B), but axons are relatively preserved (Fig. +28.32C). +In +time, astrocytes undergo reactive changes. +Axons in old gliotic +plaques are usually greatly diminished in number. +(C) Relative preservation of axons is seen on the +neurofilament immunostain (brown). +agents, which may slow the progression of the disease but +are not curative. +Once considered a variant of MS, it is +clearly a distinct disorder. +Areas of demyelination in NMO show +loss of aquaporin-4, the major water channel of astrocytes. +White cells (often including neutrophils) are common in +the CSF. +The disease is fatal in many patients, with significant +deficits present in most survivors. +It appears that rapid increases in osmolality +damage oligodendrocytes through uncertain mechanisms. +Inflammation is absent from the lesions, and neurons and +axons are well preserved. +Secondary injury to axons typically emerges over +time. +However, only classic prion diseases +have been shown to be truly transmissible. +The basis +for aggregation varies from one disease to another. +Normal PrP +is a 30-kD cytoplasmic protein of unknown function. +The disease +has a peak incidence in the seventh decade. +The disease is uniformly +fatal; the average survival is only 7 months after the onset +of symptoms. +28.34A). +Inflammation is notably +absent. +Kuru plaques are extracellular deposits of aggregated abnormal +PrP. +They are Congo red– and PAS-positive and usually occur in +the cerebellum (Fig. +28.34B), but are abundant in the cerebral +cortex in cases of vCJD (Fig. +28.34C). +28.35). +(A) Spongiform change in the cerebral cortex. +Inset, High magnification of neuron with vacuoles. +(C) Cortical kuru plaques surrounded by spongiform change in variant +Creutzfeldt-Jakob disease. +abnormal deposits of tau in the brain is not a sufficient +stimulus to elicit deposition of Aβ. +28.35). +Point mutations in APP +are another cause of familial AD. +• Role of tau. +the course of the illness eventually appears to become +independent of the Aβ. +• Other genetic risk factors. +Three alleles +exist (ε2, ε3, and ε4) based on two amino acid polymor- +phisms. +• Role of inflammation. +• Basis for cognitive impairment. +• Biomarkers. +Neurofibrillary tangles are visible as basophilic fibrillary structures +with H&E staining (Fig. +28.37C) but are demonstrated much more +clearly by silver (Bielschowsky) staining (Fig. +28.37D) and with +tau immunohistochemistry (Fig. +Cerebral amyloid angiopathy (CAA) (Fig. +28.36). +28.37A). +(Courtesy the late Dr. +E.P. +(A) Plaques with dystrophic neurites +surrounding amyloid cores are visible (arrows). +(B) Plaque core and +surrounding neuropil are immunoreactive for Aβ. +(D) Silver stain highlights a neurofibrillary +tangle (black) within the neuronal cytoplasm. +Tau, +particularly when phosphorylated, has a propensity to +aggregate. +Two different types of tau mutations have been described. +Within each of these groups, there are heritable and +sporadic forms. +28.38A).These tangles may contain a +variety of tau isoforms. +Nigral degeneration may occur. +Inclusions +can also be found in glial cells in some forms of the disease. +28.38B). +Pathogenesis +Mutations in three different genes have been found in the +inherited forms of FTLD-TDP. +(A) FTLD-tau. +A tangle is present along with numerous tau-containing neurites. +(B) Pick +disease. +(C) FTLD-TDP. +(D) FLTD-TDP. +With progranulin mutations, the TDP-43– +containing inclusions are commonly intranuclear. +(discussed later). +How the repeat expansion results in +formation of aggregates of TDP-43 is a mystery at present. +Both loss of function and toxic gain of function +may contribute to this form of FTD. +There are forms of FTLD in which there are neither +tau- nor TDP-containing inclusions. +In the inclusions, TDP-43 is phos- +phorylated and ubiquitinated. +28.38D). +replacement therapy with L-DOPA (the immediate precursor +of dopamine). +Deep brain stimulation +has emerged over the past decade as a therapy for the motor +symptoms of PD. +This toxin has been used to generate animal +models of PD, which are used to test new therapies. +This protein is a major component +of the Lewy body, which is the diagnostic hallmark of PD. +This clinical impression is confirmed by symptomatic +response to L-DOPA replacement therapy. +A +MORPHOLOGY +A characteristic gross finding in PD is pallor of the substantia +nigra (compare Fig. +Lewy bodies (Fig. +Areas of neuronal loss also typically show gliosis. +Lewy neurites +are dystrophic processes that contain aggregated α-synuclein. +(A) Normal substantia nigra. +(B) +Depigmented substantia nigra in idiopathic Parkinson disease. +(C) Lewy +body in a substantia nigra neuron, staining bright pink (arrow). +Other +common symptoms include nuchal dystonia, pseudobulbar +palsy, and a mild progressive dementia. +The disease +is often fatal within 5 to 7 years of onset. +As with +PSP, cognitive decline may occur, typically later in the illness. +The same tau variant linked to PSP is also highly associated +with CBD. +In affected regions +of cortex, there is severe loss of neurons, gliosis, and “ballooned” +neurons. +Pathogenesis +As in PD, α-synuclein is the major component of the inclu- +sions. +Pathogenesis +HD is a prototypic polyglutamine trinucleotide repeat +expansion disease (Chapter 5). +The gene for HD, HTT, +located on chromosome 4p16.3, encodes a 348-kD protein +known as huntingtin. +In contrast to many other +degenerative diseases, there is no sporadic form of HD. +28.40B). +A B +Figure 28.40 Multiple system atrophy (MSA). +(A) Severe atrophy of the basis pontis in a case of MSA-C. +Motor symptoms often precede +the cognitive impairment. +Here we focus on the common varieties +of pathogenic mutations that are found in SCA. +Pathogenesis +The genes responsible for over half of the numerous SCAs +have been identified. +28.41A). +28.41, inset). +Figure 28.41 Huntington disease. +(Courtesy Dr. +• Expansion of noncoding repeats, similar to myotonic dys- +trophy. +The pathogenic +connection between expansion of these repeats and disease +is obscure. +• Other mutations. +Deep tendon reflexes are depressed or +absent, but an extensor plantar reflex is typically present. +Concomitant diabetes is found +in up to 25% of patients. +Clinical Features +The disease is relentlessly progressive, with death early in +the second decade. +Many affected individuals +develop lymphoid neoplasms, which are most often T-cell +leukemias. +Sporadic +ALS is more common than familial ALS, which may account +for up to 20% of cases. +A +MORPHOLOGY +The anterior roots of the spinal cord are thin (Fig. +Similar findings are seen in the hypoglossal, ambiguus, and +motor trigeminal cranial nerve nuclei. +Skeletal muscles innervated by the degenerated +lower motor neurons show neurogenic atrophy. +28.42B). +B +Figure 28.42 Amyotrophic lateral sclerosis. +of affected individuals are alive 2 years after diagnosis. +The +disease eventually involves the respiratory muscles, leading +to recurrent bouts of pneumonia. +Life span is normal. +Most SMN protein comes from mRNA transcripts derived +from the SMN1 gene on chromosome 5q. +• Prion diseases may be sporadic, familial, or transmissible. +The most common clinical presentation +is that of rapidly progressive dementia. +These disorders may be +caused by mutations in the mitochondrial or the nuclear +genomes. +The +following examples are representative of this spectrum of +disorders. +The +brain shows loss of myelin and oligodendrocytes (Fig. +28.43); a similar process affects peripheral nerves. +Neurons +and axons are relatively spared. +28.43, inset). +The most striking histologic finding is +demyelination with resulting gliosis. +Macrophages with +vacuolated cytoplasm are scattered throughout the white +matter. +In the typical form, young boys present with behavioral +changes and adrenal insufficiency. +Much of the white matter is gray/yellow +because of the loss of myelin. +Inset, “Globoid” cells are the hallmark of the +disease. +acids within peroxisomes, resulting in elevated serum +levels of these lipids. +The symptoms result from progres- +sive CNS, peripheral nerve, and adrenal disease. +In the +white matter, myelin loss is accompanied by gliosis and +extensive lymphocytic infiltration. +Adrenal cortical +atrophy explains the hypocortisolism. +A wide range of other leukodystrophies are recognized, +some with defects in lipid metabolism. +Ataxia, associated with neuronal loss from +the cerebellar system, is also common. +Most cases of +MERRF are associated with mutations in mitochondrial +tRNA genes. +A wide spectrum of nuclear and mitochondrial DNA +mutations has been identified. +Wernicke encephalopathy +is characterized by acute psychosis and ophthalmoplegia. +These symptoms are reversible when treated with thiamine. +The lesions +result from a defect in myelin formation; the mechanism +of this defect is not known. +Demy- +elination of white matter tracts may be a later event. +28.44). +The fetal alcohol syndrome is discussed in +Chapter 10. +Complete paraplegia may occur, usually only +later in the course. +Some regions of the brain are more sensitive to hypoglycemia +than others. +The affected individual +becomes dehydrated and develops confusion, stupor, and +eventually coma. +The fluid depletion must be corrected +gradually; otherwise, severe cerebral edema may follow. +Toxic Disorders +Cellular and tissue injury from toxic agents is discussed in +Chapter 9. +A unique pattern +Figure 28.44 Alcoholic cerebellar degeneration. +embryonal tumors, and a few less common categories. +In +addition, meningeal tumors and familial tumor syndromes +will be covered. +• Metabolic disturbances may disrupt brain function, often without +detectable morphologic changes. +Tumors of the CNS account +for nearly 20% of all cancers of childhood. +Even the +most highly malignant gliomas rarely metastasize outside +the CNS. +(Fig. +Individual tumor +cells infiltrate brain tissue some distance away from the main +lesion. +28.46). +28.47). +(B) Glioblastoma appearing as a necrotic, hemorrhagic, infiltrating mass. +grade. +28.46A). +These tumors constitute 5% to 15% of gliomas and are most +common in the fourth and fifth decades. +Patients may have +had several years of neurologic complaints, often includ- +ing seizures. +The lesions are found mostly in the cerebral +hemispheres and have a predilection for white matter. +WHO grade II astrocytomas may remain stable or +progress slowly; mean survival exceeds 5 years. +Inset, +Microvascular proliferation.1296 CHAPTER 28 The Central Nervous System +of 1p and 19q. +In contrast to high-grade astrocytic tumors, EGFR gene +amplification is not seen. +Pilocytic astrocytomas grow very slowly and can +often be treated by resection alone. +28.48). +Mitotic activity +and proliferation indices are low in low-grade (WHO grade II) +oligodendroglioma. +Such cases may arise de novo, +but more often progress from WHO grade II oligodendrogliomas. +28.49A), with a contrast-enhancing +mural nodule. +28.49B). +28.49C). +Progression +from low- to higher-grade lesions occurs, typically over a +period of 5 or more years. +Ependymomas do not share the +genetic alterations that are found in infiltrating gliomas. +MORPHOLOGY +Grossly and on MRI, ependymomas are solid (i.e., noninfiltrative) +masses. +In the posterior fossa, they typically arise from the floor of +Figure 28.48 Oligodendroglioma. +Similar to diffuse astrocytoma (see Fig. +(A) Grossly, this cerebellar tumor forms a mural nodule within a cyst. +the fourth ventricle (Fig. +28.50B); +more frequently present are perivascular pseudorosettes (Fig. +Two other variants of ependymoma merit brief mention. +Prognosis depends on completeness +of surgical resection. +A B +Figure 28.50 Ependymoma. +There are also “floating neurons” that sit in basophilic, +mucin-rich pools. +Rapid growth may occlude the flow of +CSF, leading to hydrocephalus. +They are usually asymptomatic and are incidental findings +at autopsy or imaging. +Despite the relationship of ependymomas to the +ventricular system, CSF dissemination is uncommon. +In general, neuronal tumors are +more often seen in children and young adults with epilepsy. +• Gangliogliomas (WHO grade I) are tumors composed of +a mixture of mature neuronal and glial cells. +Most +of these tumors are slow growing. +Gangliogliomas are most commonly found in the +temporal lobe and often have a cystic component. +The glial compo- +nent of these lesions most often resembles a pilocytic +astrocytoma. +28.51A). +In the classic subtype, tumor cells form Homer Wright +rosettes (Fig. +28.51C).The large cell/anaplastic variantTumors 1299 +AB +CD +Figure 28.51 Medulloblastoma. +28.51D). +Medulloblastomas have a propensity to spread to the sub- +arachnoid space. +Similarly, targeted therapies are being explored for +those with actionable molecular alterations. +28.52A). +28.52B). +Mitotic rates are often markedly elevated. +Clinical Features +Meningiomas are usually slow-growing tumors. +It is marked by +loss of sensory neurons and lymphocytic inflammation +in the dorsal root ganglia. +This +syndrome can also be seen in the absence of malignancy. +These disorders +are discussed in greater detail in Chapter 27. +Cysts may be found at various sites, including +the liver, kidneys, and pancreas. +Mutations in +TSC1 or TSC2 disrupt this control and lead to increased +and unregulated mTOR activity. +The disease frequency is 1 in 30,000 to 40,000. +VEGF leads +to excessive vessel growth, contributing to the development +of hemangioblastomas. +Ru W, Tang SJ: HIV-associated synaptic degeneration, Mol Brain 10:40, +2017. +Venkatesan A: Epidemiology and outcomes of acute encephalitis, Curr +Opin Neurol 28:277, 2015. +• Glial tumors are broadly classified into astrocytomas, oligoden- +drogliomas, and ependymomas. +Carcinomas are most common. +ACKNOWLEDGMENT +The contributions of Dr. +Matt Frosch to previous versions +of this chapter are gratefully acknowledged. +Epub ahead of print. +Lane CA, Hardy J, Schott JM: Alzheimer’s disease, Eur J Neurol 25:59, +2018. +Vision is a major quality-of-life issue. +Most individu- +als with AMD do not suffer from a total loss of vision—an +immersion into darkness. +The histopathology is unimpres- +sive: small scars develop in the macula. +But consider the +effect of these tiny scars in a retired schoolteacher with +AMD. +The central portion of her or his vision is lost. +The +faces of spouse or grandchildren are not visible. +He or she +cannot read a book or newspaper. +In short, this person is robbed +of the common joys that most of us take for granted. +To study the eye, one needs to comprehend all that has +come before. +However, the study of ocular pathology +does not merely repeat what has been presented thus far. +29.1). +forms of age-related neovascularization, result from patho- +logic angiogenesis. +This chapter is organized on the basis of ocular anatomy. +The orbital +contents are subject to the same disease processes that affect +other tissues. +Representative inflammatory conditions and +neoplasms of the orbit are discussed briefly next. +29.2). +Proptosis may be axial (directly forward) or positional. +These are described +in other chapters. +Neoplasms +may also invade from the sinuses into the orbit. +Note that the tendons of the muscles are spared. +(Courtesy Dr. +Ralph C. +Idiopathic orbital inflammation, also known as orbital +inflammatory pseudotumor (Fig. +29.3), is another inflam- +matory condition affecting the orbit. +29.4). +It may also +extend into the lacrimal gland ductules and thereby into the main +lacrimal gland. +the eyelid generate critical components of the tear film. +Figure 29.4 Anatomy of the conjunctiva and eyelids. +CONJUNCTIVA +Functional Anatomy +The conjunctiva is divided into zones (see Fig. +29.4), each +with distinctive histologic features and responses to disease. +The conjunctiva in the fornix is a pseudostratified +columnar epithelium rich in goblet cells. +Surprisingly, primary melanomas of the eyelid +skin are extremely rare. +Basal cell +carcinoma has a distinct predilection for the lower eyelid +and the medial canthus. +Sebaceous carcinoma +tends to spread first to the parotid and submandibular nodes. +The overall mortality rate can be as high as 22%. +Pagetoid +spread (Fig. +Neoplastic cells +with foamy cytoplasm are present within the epidermis (arrow). +29.1). +The conjunctiva, like the eyelid, is richly invested with +lymphatic channels. +Pterygium typically originates in the conjunctiva +astride the limbus. +29.6A, B). +The resultant +inflamed juvenile nevus is completely benign. +29.6C, D). +BRAF +V600 mutations may be identified in nearly 40% of conjunc- +tival melanomas. +The lesions tend to spread first to the parotid or +submandibular lymph nodes. +Approximately 25% of con- +junctival melanomas prove to be fatal. +(C, D) Conjunctival malignant melanoma. +29.7). +Anteriorly, the cornea is covered by epithelium that rests +on a basement membrane. +The sclera may appear “blue” in a variety of conditions. +• The sclera may appear blue in osteogenesis imperfecta. +The cornea is thin and +scarred (note the increased number of fibroblast nuclei). +Figure 29.7 Normal corneal microarchitecture. +The corneal tissue is +stained by periodic acid–Schiff (PAS) to highlight basement membranes. +A very thin +PAS-positive basement membrane separates the epithelium from the +Bowman layer. +Note that the Bowman layer is acellular. +The “holes” in the stroma are +artifactitious spaces between parallel collagenous stromal lamellae. +The specific forms +of keratitis may have certain distinctive features. +29.8). +Corneal +degenerations may be either unilateral or bilateral and are +typically nonfamilial. +By contrast, corneal dystrophies are +typically bilateral and are hereditary. +Band Keratopathies +Two types of band keratopathy serve as examples of corneal +degenerations. +Calcific band keratopathy is characterized by +deposition of calcium in the Bowman layer. +Such thinning results in a cornea that has a conical +rather than spherical shape. +This abnormal shape generates +irregular astigmatism that is difficult to correct with spec- +tacles. +The risk of corneal graft rejection increases +with stromal vascularization and inflammation. +A precise +alignment of collagen in the corneal stroma also contributes +to transparency. +Corneal vascularization may accompany chronic corneal +edema, inflammation, and scarring. +Scars may result from trauma or +inflammation. +The corneal endothelium is derived from neural crest and +is not related to vascular endothelium. +It rests on its basement +membrane, Descemet membrane. +Descemet membrane +increases in thickness with age. +It is the site of copper +deposition in the Kayser-Fleischer ring of Wilson disease +(Chapter 18). +Exudate1312 CHAPTER 29 The Eye +Figure 29.9 Keratoconus. +Figure 29.10 Fuchs dystrophy. +Numerous +drop-like excrescences—guttata—protrude downward from the Descemet +membrane. +Endothelial cell nuclei are not seen. +Epithelial bullae, not shown +in this micrograph, were present, reflecting corneal edema. +related to a primary loss of endothelial cells. +29.10). +Because of chronic edema, the stroma +may eventually become vascularized. +surface to the cornea and may provide refractive relief for +individuals with keratoconus. +Unlike many types of +degeneration, keratoconus is typically bilateral. +Keratoconus +is associated with Down syndrome, Marfan syndrome, and +atopic disorders. +29.9). +KEY CONCEPTS +• The cornea—not the lens—is the major refractive surface of +the eye. +• Corneal dystrophies are generally inherited and degenerations +are typically not inherited. +It is one of the principal +indications for corneal transplantation in the United States. +Neo- +plasms of the lens have not been described. +Cataract +The term cataract describes lenticular opacities that may be +congenital or acquired. +Age-related cataract typically results from opacification +of the lens nucleus (nuclear sclerosis). +Other physical changes in the lens may generate +opacities. +For example, the lens cortex may liquefy. +29.11). +The posterior chamber lies +behind the iris and in front of the lens. +Thus, the lens epithelium does not +exfoliate like the epidermis or a mucosal epithelium. +Note that the surface of the iris is highly textured with crypts and folds. +Lower left, Primary angle-closure glaucoma. +A prosthetic +intraocular lens is typically inserted into the eye. +As Fig. +With this background, glaucoma can be +classified into two major categories. +Both open-angle and angle-closure glaucoma can be +subclassified into primary and secondary types. +There are multiple causes of secondary open-angle glaucoma. +These anatomic changes provoke a marked elevation in +intraocular pressure (see Fig. +29.11). +This leads to minute anterior subcapsular +opacities that are visible by slit-lamp examination. +There are many causes of secondary angle-closure glaucoma. +29.11). +Necrotic tumors, especially +retinoblastomas, can also induce iris neovascularization and +glaucoma. +An anterior subcapsular +cataract (asc) has formed. +The radial folds in the lens are artifacts. +anterior subcapsular cataract (Fig. +29.12). +29.13). +• Glaucoma may develop in the context of either an open or +closed angle. +Open-angle and angle-closure glaucomas are further +subclassified into primary and secondary types. +Figure 29.13 Exogenous panophthalmitis. +This eye was removed after a +foreign body injury. +The central portion of the vitreous humor was extracted surgically +(by vitrectomy). +(From Folberg R: The +eye. +As will be described briefly, +uveitis is frequently accompanied by retinal pathology. +Examples +are described later. +Granulomatous uveitis is a common complication of sar- +coidosis (Chapter 15). +In the posterior segment, sarcoid +may involve the choroid and retina. +Thus, granulomas may +be seen in the choroid. +Numerous infectious processes can affect the choroid or +the retina. +Inflammation in one compartment is typically +associated with inflammation in the other. +Retinal toxoplas- +mosis is usually accompanied by uveitis and even scleritis. +Sympathetic ophthalmia is an example of noninfectious +uveitis limited to the eye. +The condition may develop from 2 weeks to many +years after injury. +Plasma cells are typically absent, but +eosinophils may be identified in the infiltrate (Fig. +29.14). +Sympathetic ophthalmia is treated by the administration of +systemic immunosuppressive agents. +The +Figure 29.14 Sympathetic ophthalmia. +The granulomatous inflammation +depicted here was identified diffusely throughout the uvea. +The uveal +granulomas may contain melanin pigment and may be accompanied by +eosinophils. +(C) Gross photograph +of a choroidal melanoma that has ruptured the Bruch membrane. +The overlying retina is detached. +(D) Epithelioid melanoma cells associated with an +adverse outcome. +29.15). +• The most common intraocular tumor of adults is metastasis +to the eye. +• The most common primary intraocular tumor of adults is uveal +melanoma. +The retina therefore +responds to injury by means of gliosis. +As in the brain, there +are no lymphatics. +29.16). +The location of the hemorrhage within the retina determines its +appearance by ophthalmoscopy. +Note that the outer segments of the photoreceptors +are missing (see Fig. +29.16 for orientation of layers). +The +photoreceptor outer segments are intact, illustrating an acute detachment. +Separation of the neurosensory +retina from the RPE defines a retinal detachment. +The RPE +has an important role in the maintenance of the outer seg- +ments of the photoreceptors. +The adult vitreous humor is avascular. +The vitreous humor can be +opacified by hemorrhage from trauma or retinal neovascu- +larization. +Rheg- +matogenous retinal detachment is associated with a full-thickness +retinal defect. +29.17). +29.18A). +Retinal arterioles and veins share a common +adventitial sheath. +29.18B). +In malignant hypertension, vessels in the retina and +choroid may be damaged. +29.18A). +29.19). +Diabetes Mellitus +The eye is profoundly affected by diabetes mellitus. +(A) The wall of the retinal arteriole (arrow) is thick. +Note the exudate (e) in the retinal outer plexiform layer. +(B) +The fundus in hypertension. +(B, Courtesy Dr. +Thomas A. +In addition, the number of pericytes relative to +endothelial cells diminishes. +Recall that VEGF was +initially called vascular permeability factor. +29.21C). +The web of +newly formed vessels is referred to as a neovascular membrane. +29.21B). +Figure 29.19 Nerve fiber layer infarct. +(Fundus +photograph, Courtesy Dr. +Thomas A. +29.20) and is reminiscent of similar changes in the glomerular +mesangium. +Figure 29.20 The ciliary body in chronic diabetes mellitus, periodic +acid–Schiff stain. +29.16 for a +schematic of retinal structure). +This is an example of intraretinal +angiogenesis known as intraretinal microangiopathy (IRMA). +Note the +retinal hemorrhage in the outer plexiform layer in the left half. +Absence of the ganglion cell and nerve fiber layers is a +hallmark of glaucoma. +The thin-walled +vessel to the right of the thin arrow is not invested with connective tissue. +Neovascular membrane contraction may create +sufficient force to cause retinal detachment. +The use of VEGF +inhibition in this condition is under investigation. +The final common +pathway in both types is vascular occlusion. +(A) Fundus photograph of the cherry-red spot in Tay-Sachs disease. +(A, Courtesy Dr. +Thomas A. +Total occlusion of a branch of retinal artery can produce a +segmental infarct of the retina. +Total occlusion of the central retinal artery can produce +a diffuse infarct of the retina. +Following an acute occlusion, +the retina appears relatively opaque by ophthalmoscopy. +29.22). +Retinal vein occlusion may occur with or without ischemia. +From the +name of this disorder, it is clear that advancing age is a risk +factor. +Loss of vision +may be severe in these individuals. +29.23). +Typically, both +rods and cones are lost to apoptosis, though in varying propor- +tions. +Loss of rods may lead to early night blindness and +constricted visual fields. +As cones are lost, central visual +acuity may be affected. +The +electroretinogram reveals abnormalities characteristic of this +disease. +RPE +BM +Figure 29.23 “Wet” age-related macular degeneration. +Note the blue discoloration of BM to the right of +the label, indicating focal calcification. +become situated directly beneath the neurosensory retina. +Photodynamic therapy +is also being evaluated for effectiveness. +The molecular genetics of retino- +blastoma are discussed in detail in Chapter 7. +In the sporadic cases, both RB alleles are lost +by somatic mutations. +Retinoblastomas arising in those +with germline mutations are often bilateral. +(A) Gross photograph of retinoblastoma. +Dystrophic calcification (black arrow) is present in the zones of tumor necrosis. +Focal zones +of dystrophic calcification are characteristic of retinoblastoma. +VEGF antagonists may prevent visual +loss in many of these conditions. +• Retinoblastoma is the most common primary intraocular tumor +of children. +• Primary retinal lymphoma is an aggressive tumor that often +involves the brain as well. +Retinoblastoma +tends to spread to the brain and bone marrow and seldom +disseminates to the lungs. +Primary +intraocular lymphoma tends to occur in older individuals +and may mimic uveitis clinically. +Most are diffuse large B-cell +lymphomas (Chapter 13). +Spread to the brain commonly +occurs via the optic nerve. +The diagnosis depends on a +demonstration of lymphoma cells in vitreous aspirates. +The pathology of the optic nerve +is similar to the pathology of the brain. +Zones of relative ischemia may +surround segmental infarcts of the optic nerve. +Optic nerve +function in these poorly perfused but not infarcted zones +may recover. +The optic nerve does not regenerate, and visual +loss from infarction is permanent. +29.25). +A B +C +Figure 29.25 The optic nerve in anterior ischemic optic neuropathy +(AION) and papilledema. +(A and B, +Courtesy Dr. +Sohan S. +Individuals may suffer severe visual compromise. +Leber optic neuropathy shows +maternal inheritance pattern typical of mitochondrial gene +mutations. +29.26), which can be +measured by optical coherence tomography. +See Fig. +29.16 for +orientation. +(C) The arrows point to the dura of the optic nerve. +Notice the wide +subdural space, a result of atrophy of the optic nerve. +NFL +GC IPL +IPL +females. +The usual age of onset is between 10 and 30 years. +It begins with clouding of vision that may progress to total +loss of vision. +One of the most important causes of optic +neuritis is multiple sclerosis (Chapter 28). +Indeed, optic +neuritis may be the first manifestation of this disease. +[This is an outstanding and +comprehensive review of the pathogenesis of diabetic retinopathy]. +Dimaras H, Kimani K, Dimba EOA et al: Retinoblastoma, Lancet 379:1436, +2012. +Dimras H, Corson TW, Cobrinik D et al: Retinoblastoma, Nat Rev Dis +Primers 2015. +Lim LS, Mitchell P, Seddon JM et al: Age-related macular degeneration, +Lancet 379:1728, 2012. +Rivera JC, Sapieha P, Joyal JS et al: Neonatology 100:343, 2011. +[This is +a comprehensive review of the pathogenesis of retinopathy of prematurity]. +Newman NJ: Treatment of hereditary optic neuropathies, Nat Rev Neurol +8:545, 2012. +Pau D, Al Dubidi N, Yalamanchili S et al: Optic neuritis, Eye (Lond) +25:833, 2011. +Smith DJ, Hagedüs L: Graves’ disease, N Engl J Med 375:1552, 2016. +[Another well-illustrated, concise, and com- +prehensive review]. +Pe’er J: Pathology of eyelid tumors, Indian J Ophthalmol 65:177, 2016. +[Well-illustrated, concise, and comprehensive review]. +[Keratoconus is a common indication for corneal transplant]. +[Fuchs endothelial +dystrophy is a major indication for corneal transplant. +This article reviews +the clinical features, genetics, and pathophysiology of this condition]. +Glaucoma +Jonas JB, Aung T, Bourne RR et al: Glaucoma, Lancet 390:2183, 2017. +Therapy +then becomes logical in this schema and the necessity +to regurgitate facts is minimized. +Cardiovascular surgery is presented in keeping with the +exponential strides recently achieved. +There are two major subdivisions to the text. +In the +first twelve chapters, subjects that transcend several organ +systems are presented. +The need for a +text such as we have envisioned is great and the goal +admittedly high. +It is our hope that this effort fulfills the +expressed demands. +Seymour I. +Hill, James Wu, Mark D. +Girgis, Danielle Hsu, +Areti Tillou, James Macho, Vishad Nabili, and +F. +DEFINITIONS OF LEADERSHIP +Many different definitions of leadership have been described. +. +. +1-1). +The great surgical pioneers, such as Hunter, Lister (Fig. +1-2), Halsted, von Langenbeck, Billroth, Kocher (Fig. +1-4), each possessed visions that revolutionized the field of +surgery. +The boy recov- +ered, and Lister gathered nine more patients. +Michael E. +7 Different leadership styles are tools to use based on the +team dynamic. +4 Surgical leaders have the willingness to commit to lifelong +learning. +5 Surgical leaders have the willingness to communicate +effectively and resolve conflict. +artery for arterial bypass operations, Dr. +Dr. +Leaders must learn to develop visions to provide direction +for their team. +Apollo 11 Lunar Module moon walk. +Astronaut Edwin +“Buzz” Aldrin walks by the footpad of the Apollo 11 Lunar Mod- +ule, July 1969. +(Reproduced with permission from AP Photo/NASA. +© 2014 The Associated Press.) +Figure 1-2. +(Copy- +right Bettmann/Corbis/AP Images.) +Figure 1-3. +Emil Theodor Kocher. +(Courtesy of the National +Library of Medicine.) +Figure 1-4. +Michael E. +DeBakey. +(Reproduced with permission +from AP Photo/David J. +Phillip. +To Lead. +A key characteristic of all great leaders is the will- +ingness to serve as the leader. +Dr. +1-5). +He +described this experience as “. +. +. +rough, really rough, the worst +time in my life . +. +. +. +I would go to work at 7 a.m. +and I’d get back +at 9 at night, and the kids would be in bed. +And I couldn’t +speak, I literally couldn’t, I was so exhausted . +. +. +. +Willingness to lead is a necessity in any individual who +desires to become a surgeon. +They do +so, believing fully in the improved quality of life that can be +achieved. +A tremendous +sacrifice is required for the opportunity to learn patient care. +To Learn. +Basic and translational science relating to surgical care +is growing at an exponential rate. +Dr. +Martin Luther King, Jr. +(Reproduced with +permission from AP Photo. +© 2014 The Associated Press.) +in new techniques using new skills and equipment. +To Communicate Effectively. +Effective communication +directly impacts patient care. +In 2000, the U.S. +One model to ensure open communication is through +standardization of established protocols. +A commonly accepted +protocol is the “Time Out” that is now required in the modern +operating room. +This +same standardization can be taught outside the operating room. +To Resolve Conflict. +Great leaders are able to achieve their +vision through their ability to resolve conflict. +Therefore, the tech- +niques for conflict resolution are essential for surgical leaders. +Introspection +allows the surgeon to understand the impact of his or her actions +and biases. +(3) A “differential diagnosis” is formed of possible root +causes of the conflict. +(4) The “assessment/plan” is developed +in the best interest of all involved parties. +(6) The +“operation” is the actual implementation of the agreed-upon +plan, including a time-out. +This seven-step method is an example of an objective, respect- +ful method of conflict resolution. +Time Management +It is important for leaders to practice effective time manage- +ment. +Time is the most precious resource, as it cannot be +bought, saved, or stored. +The effi- +cient use of one’s time helps to improve both productivity and +quality of life. +It is therefore critical that time be used wisely on effectively +achieving one’s goals. +Parkinson’s law, proposed in 1955 by the U.K. +Individuals list and assign relative +values to their tasks. +1-7). +Too often, surgeons spend a majority of their time attending to +Figure 1-6. +Surgery resident time-motion study. +H & +P = history and physical examination. +Figure 1-7. +Time management. +(From Covey S. +The Seven Habits +of Highly Effective People. +New York: Simon & Schuster; 1989.) +quadrant I (important and urgent) tasks. +A formal time management program is essential for +modern leadership. +Just as there are many definitions of leadership, many +classifications of styles exist as well. +Furthermore, it teaches when the situation may demand change +in style for the best outcome. +The Coercive leader demands immediate compliance. +This style reflects the command and control style that has +historically dominated surgery. +However, it is effective in times of crisis to deliver +clear, concise instruction. +This style should be used sparingly +and is best suited for emergencies. +This type of leader allows the team freedom to inno- +vate, experiment, and devise its own means. +Goleman’s research +indicates this style is often the most effective. +This is best +used when a shift in paradigm is needed. +The Affiliative leader creates harmony and builds emo- +tional bonds. +This requires employment of empathy, building +relationships, and emphasis on communication. +An affiliative +leader frequently gives positive feedback. +The Coaching style of leadership focuses on developing +people for the future. +Coaching is leadership through mentor- +ship. +The coach gives team members challenging tasks, coun- +sels, encourages, and delegates. +This leader- +ship style builds team capabilities by helping motivated learners +improve. +The Democratic leader forges consensus through partici- +pation. +This leadership style listens to and values each mem- +ber’s input. +It can also be exasperating if a +clear vision does not arise from the collaborative process. +The Pacesetter leader sets high standards for performance +and exemplifies them. +These leaders identify poor performers +and demand more from them. +Each of the above styles of leadership has strengths and +weakness. +Importantly, leaders who are the most successful do +not rely only on one leadership style alone. +They use several of +them seamlessly depending on the situation and the team +members at hand. +Physician leadership is a new mandate in surgical training. +Am J +Surg. +2004;187:328-331. +© Copyright Elsevier. +* P<0.001 by Student t test between mean importance and mean compe- +tence scores. +be taught to surgical trainees, and there are many validated tools +to measure outcomes. +Mentoring +A formal leadership training program for surgical trainees +should include mentoring. +A greater level +of trust and commitment distinguishes the mentor from the +teacher. +More than a teacher, a mentor is a coach. +The underlying prem- +ise is a limited level of advancement for the student. +Modern mentorship implies a partnership +between the mentor and the mentee. +Emeritus Chair of University of California, Los Ange- +les Head and Neck Surgery, Dr. +. +. +Ward embod- +ied the role as a surgeon’s coach. +Highly successful surgeons most often have had excellent sur- +gical mentors. +Effective leadership can +change surgical departments and improve patient care through +innovation. +Surgical leadership is bred through its training programs. +REFERENCES +Entries highlighted in blue are key references. +1. +Levinson W, Chaumeton N. +Communication between surgeons +and patients in routine office visits. +Surgery. +1999;125:127-134. +2. +Itani KM, Liscum K, Brunicardi FC. +Physician leadership +is a new mandate in surgical training. +Am J Surg. +2004; +187:328-331. +3. +Jensen AR, Wright A, Lance A, et al. +The emotional intel- +ligence of surgical residents: a descriptive study. +Am J Surg. +2008;195:5-10. +4. +Lee L, Brunicardi FC, 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+2005;115: +765-773. +43. +Accreditation Council for Graduate Medical Education. +Lead- +ership Skills for Chief Residents. +Available at: http://www. +acgme.org/acgmeweb/. +Accessed January 1, 2014. +44. +American College of Surgeons. +Surgeons as leaders: from oper- +ating room to boardroom. +Available at: http://www.facs.org/ +education/surgeonsasleaders.html. +Accessed January 1, 2014. +45. +Awad SS, Hayley B, Fagan SP, et al. +The impact of a novel +resident leadership training curriculum. +Am J Surg. +2004;188: +481-484. +46. +Horwitz IB, Horwitz S, Brandt M, et al. +Assessment of com- +munication skills of surgical residents using the Social Skills +Inventory. +Am J Surg. +2007;194:401-405. +47. +Horwitz IB, Horwitz S, Brunicardi F, et al. +Am J Surg. +2011;201:828-834. +48. +Barondess JA. +On mentoring. +J R Soc Med. +1997;90:347-349. +49. +Zuckerman H. +Scientific Elite: Nobel Laureates in the United +States. +New York, NY: Free Press; 1977:335. +50. +Sambunjak D, Straus SE, Marusic A. +Mentoring in academic +medicine: a systematic review. +JAMA. +2006;296:1103-1115. +Systemic Response to Injury and +Metabolic Support +Siobhan A. +Corbett* 2 +*This chapter is dedicated to its previous author, Dr. +Stephen Lowry, my mentor and friend. +Fur- +ther, trauma is the leading cause of mortality and morbidity for +individuals under age 45. +The resulting neuroendocrine reflex +plays an important modulatory role in the immune response. +We will also discuss how these events are +monitored and regulated by the central nervous system. +2-1). +Although the mechanisms for the sterile response are +Figure 2-1. +(Adapted with +permission from Guirao X, Lowry SF. +Biologic control of injury +and inflammation: Much more than too little or too late. +World J +Surg. +1996;20:437. +Trauma DAMPs are structurally diverse endogenous mol- +ecules that are immunologically active. +High-Mobility Group Protein B1. +HMGB1 +is highly evolutionarily conserved across species. +A Role for Mitochondrial DAMPs in the Injury-Mediated +Inflammatory Response. +How is it possible for biglycan to provide both sig- +nals? +The best-described ligands for these +receptors are microbial components, the PAMPs. +The best +described of these, the TLRs, NLRs, and CLRs, are discussed +in the following sections. +Toll-Like Receptors. +The first human TLR, TLR4, was identified +shortly thereafter. +TLRs are expressed on both immune and +nonimmune cells. +TLR expression is significantly +increased following blunt traumatic injury. +Nucleotide-Binding Oligomerization Domain-Like Recep- +tor Family. +The protein can then oligomerize and recruit +other complex members. +The net result is the autoactivation of +pro-caspase 1 to caspase 1. +C-Type Lectin Receptors. +In +this way, Mincle may contribute to local inflammation at sites +of tissue injury. +Soluble Pattern Recognition Molecules: The Pentraxins. +The best described +of the PRMs are the pentraxins. +The short pentraxin, C-reactive protein (CRP), was the +first PRM to be identified. +CRP and SAP plasma levels are +low (≤3 mg/L) under normal circumstances. +Thus, CRP is considered part of the +acute-phase protein response in humans. +Both molecules also participate in the activation and reg- +ulation of complement pathways. +PTX3 +plasma concentrations increase rapidly in various inflammatory +conditions, including sepsis. +This event is pivotal to all known inflamma- +some signaling pathways. +2-2). +How does +the CNS sense inflammation? +DAMPs and inflammatory +molecules convey stimulatory signals to the CNS via multiples +routes. +The Hypothalamic-Pituitary-Adrenal Axis. +This +action is mediated in part by circulating cytokines produced as +Figure 2-2. +Neural circuit relaying messages of localized injury to the brain (nucleus tractus solitarius). +This vagal response occurs in real time and is site specific. +EPI = epinephrine; IL-1 = interleukin-1; NOREPI = norepinephrine; TNF = +tumor necrosis factor. +(Adapted and re-created with permission from Macmillan Publishers Ltd. +Tracey KJ. +The inflammatory reflex. +Nature. +2002;420:853. +These include +TNF-α, IL-1β, IL-6, and the type I IFNs (IFN-α/β). +2-3). +Cortisol elicits its many actions through a cytosolic recep- +tor, the glucocorticoid receptor (GR). +2-4). +Steroid synthesis from +cholesterol. +Adrenocorticotropic hor- +mone (ACTH) is a principal regulator +of steroid synthesis. +The end products +are mineralocorticoids, glucocorti- +coids, and sex steroids. +These include IL-10 and IL-1 receptor +antagonist. +Growth Hormone, Insulin-Like Growth Factor, and Ghrelin. +GH promotes protein synthesis and insulin +resistance and enhances the mobilization of fat stores. +It also increases the +Figure 2-4. +Simplified schematic of +steroid transport into the nucleus. +Ste- +roid molecules (S) diffuse readily across +cytoplasmic membranes. +mRNA = messenger +RNA. +The Role of Catecholamines in Postinjury Inflammation. +Aldosterone. +Aldosterone is a mineralocorticoid released +by the zona glomerulosa of the adrenal cortex. +MRs have +also been shown to have effects on cell metabolism and immu- +nity. +Insulin. +RNS include +NO and nitrite. +Host cells are protected from the dam- +aging effects of ROS through a number of mechanisms. +Prolongation of the UPR, indicative of +irreversible cellular damage, can result in cell death. +For example, autopha- +gosomes can sequester and degrade pro-IL-1β and inflamma- +some components. +2-5). +Apoptosis during sepsis may influence the ultimate com- +petency of the acquired immune response. +Optimal signaling activity requires receptor trimerization. +(Adapted with permission from Lin E, Calvano SE, Lowry SF. +Tumor necrosis factor recep- +tors in systemic inflammation. +In: Vincent J-L (series ed), Marshall JC, Cohen J, eds. +Update in Intensive Care and Emergency Medicine: Vol. +31: +Immune Response in Critical Illness. +Berlin: Springer-Verlag; 2002:365. +The net result is +programmed necrosis (necroptosis). +The effect of cell death by +necroptosis on the immune response is not yet known. +A brief +discussion of the important cytokine molecules is included. +Tumor Necrosis Factor-α. +In particular, TNF elicits +many metabolic and immunomodulatory activities. +IL-1α and IL-1β share similar +biologic functions, but have limited sequence homology. +Thus, +IL-1Rα serves as a competitive antagonist for the receptor. +Both the precursor and mature forms of IL-1α +are active. +It can also be released directly from injured cells. +(TNF, IL-18) and foreign pathogens. +IL-1α or IL-1β itself can +also induce IL-1β transcription. +In contrast to IL-1α, IL-1β is +synthesized as an inactive precursor molecule. +Mature IL-1β +is then released from the cell via an unconventional secretory +pathway. +High doses of +either IL-1β or TNF are associated with profound hemodynamic +compromise. +There are two primary receptor types for IL-1: IL-1R1 +and IL-1R2. +IL-1R1 is widely expressed and mediates inflam- +matory signaling on ligand binding. +IL-1α or IL-1β binds first to +IL-1R1. +A complex is formed of IL-1R1 plus IL-1 plus the coreceptor. +These events culminate in the activation of NF-κB and +its nuclear translocation.70 +Interleukin-2. +Further, plasma levels of IL-6 are proportional to the degree of +injury. +The IL-10 family currently has six members including +IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26. +IL-10 is produced +by a variety of immune cells of both myeloid and lymphoid +origin. +Once receptor +ligation occurs, signaling proceeds by the activation of JAK1 +and STAT3. +IL-12 is unique among the cytokines in being +the only heterodimeric cytokine. +The individual +IL-12 family members are formed from various combinations of +the α and β subunits. +Ligation of the IL-12 receptors +initiates signaling events mediated by the JAK-STAT pathway. +IL-12 release is inhibited by IL-10. +IL-12 deficiency inhibits +phagocytosis in neutrophils. +In addition, IL-12 +enhances coagulation as well as fibrinolysis. +Interleukin-18. +IL-18 is a member of the IL-1 superfamily of +cytokines. +However, activated macrophages and Kupffer cells produce +large amounts of mature IL-18. +It then exits the cell through a nontra- +ditional secretory pathway. +Interferons are +categorized into three types based on receptor specificity and +sequence homology. +The two major types, type I and type II, +are discussed here. +IFN-γ stimulates the release of IL-12 +and IL-18. +Negative regulators of IFN-γ include IL-4, IL-10, +and glucocorticoids. +Granulocyte-Macrophage Colony-Stimulating Factor/ +Interleukin-3/Interleukin-5. +In this way, GM-CSF, IL-3, and IL-5 are able to +link the innate and acquired immune responses. +Eicosanoids +Omega-6 Polyunsaturated Fat Metabolites: Arachidonic +Acid. +2-6A). +Glucocor- +ticoids, nonsteroidal anti-inflammatory drugs, and leukotriene +Figure 2-6. +Schematic diagram of (A) arachidonic acid and (B) eicosapentaenoic acid metabolism. +The pro- +duction of eicosanoids is cell- and stimulus-specific. +Activation of BLT1 results in inhibition of adenyl- +ate cyclase and reduced production of cAMP. +The major direct dietary source of ara- +chidonic acid is from meat. +The second +major family of PUFAs is the ω-3 fatty acid. +2-6B). +In fact, key derivatives of ω-3 +PUFAs, termed resolvins, have been identified and synthesized. +Resolvins are now categorized as either E-series (from EPA) or +D-series (from DHA). +Many +lipid preparations are soy-based and thus primarily composed of +ω-6 fatty acids. +Complement activation proceeds via three different path- +ways. +C3a and C5a are +potent anaphylatoxins. +C3b acts as an opsonin, whereas C5b +initiates the formation of the membrane attack complex. +The latter rec- +ognizes several PAMPs and DAMPs on foreign and apoptotic +cells. +Kallikrein-Kinin System. +HK, produced by the liver, is cleaved by kalli- +krein to form bradykinin (BK). +They also increase renal vasodilation and consequently +reduce renal perfusion pressure. +Serotonin +is released at sites of injury, primarily by platelets. +Finally, survival +of lipopolysaccharide-induced endotoxic shock was reduced in +Tph1–/– mice. +H2R binding is +best described for its stimulation of gastric parietal cell acid +secretion. +Several of these receptors +have characteristic signaling pathways that are associated with +them. +These will be reviewed in the following sections. +2-7). +STAT molecules possess “docking” +sites that allow for STAT dimerization. +The STAT complexes +translocate into the nucleus and serve as gene transcription factors. +P = phosphate. +The +molecular implications for this in terms of cytokine signaling +are still being unraveled. +Interestingly, STAT-DNA binding can +be observed within minutes of cytokine binding. +STATs have +also been shown to modulate gene transcription via epigenetic +mechanisms. +PRRs, including both TLR and C-type lectin receptors, have also +been shown to activate SOCS. +The KIR domain binds with high affinity to the JAK +kinase domain to inhibit its activity. +2-8). +G-protein–coupled receptors are transmembrane proteins. +The G-protein receptors respond to ligands such as adrenaline and sero- +tonin. +The E component subsequently activates second messengers. +cAMP = cyclic adenosine triphosphate. +Finally, Gα12/13 appears to act through Rho- and +Ras-mediated signaling. +Optimal signaling activity +requires receptor trimerization. +An additional “common” Smad is +then recruited. +How does TGF-β inhibit immune responses? +One +of the most important effects is the suppression of IL-2 pro- +duction by T cells. +Moreover, +they occurred rapidly (within 4 to 12 hours) and were prolonged +for days and weeks. +2-9). +Gene expression and protein synthesis can occur +within a 24-hour period. +Rapid resynthesis of +I-κB is one method of inactivating the p50-p65 complex. +IL-1 = interleukin-1; P = phosphate; TNF = tumor necrosis factor. +2-10). +NF-κB +is composed of two smaller polypeptides, p50 and p65. +On release, NF-κB travels to the nucleus and promotes +gene expression. +NF-κB also stimulates the gene expression for +I-κB, which results in negative feedback regulation. +Additionally, I-BET conferred protection against +bacteria-induced sepsis. +2-11). +A healthy immune response depends on a balanced Th1/ +Th2 response. +As a consequence, both macrophage activation and +proinflammatory cytokine synthesis are inhibited. +What are the systemic mechanisms responsible for this +shift? +DCs are specialized antigen-presenting cells (APCs) +that have three major functions. +Eosinophils +Eosinophils are immunocytes whose primary functions are +antihelminthic. +Mast cells are also known to play an impor- +tant role in the anaphylactic response to allergens. +Interferon-γ (IFN-γ) +is a known inhibitor of the TH2 response. +(Adapted with permission from Lin E, Calvano SE, +Lowry SF. +Inflammatory cytokines and cell response in surgery. +Surgery. +2000;127:117. +In tissues, mononuclear phagocytes are quiescent. +M1 macrophages +promote a strong Th1 response. +Neutrophils are +circulating immunocytes with short half-lives (4 to 10 hours). +Neutrophils do facilitate the recruitment of monocytes into +inflamed tissues. +2-12). +There are more +than 50 different chemokines and 20 chemokine receptors that +have been identified. +The CXC chemokines are particu- +larly important for neutrophil (PMN) proinflammatory function. +NO can also +reduce microthrombosis by reducing platelet adhesion and +aggregation (Fig. +2-13) and interfering with leukocyte adhesion +to the endothelium. +There are two additional isoforms +of NOS: neuronal NOS (NOS1) and inducible NOS (iNOS/ +NOS2). +Prostacyclin +The immune effects of prostacyclin (PGI2) were discussed +earlier. +Prostacyclin is a potent vasodilator that also +inhibits platelet aggregation. +In the kidneys, PGI2 modulates renal blood flow and +glomerular filtration rate. +ETs are +21-amino-acid peptides derived from a 38-amino-acid precursor +molecule. +Atrial ETA receptor activation has +been associated with increased inotropy and chronotropy. +At low levels, in conjunction with +NO, ETs regulate vascular tone. +SLOW ROLLING +(10 to 20 μm/s) is predominantly mediated by P-selectins. +(Adapted with permission +from Lin E, Calvano SE, Lowry SF. +Selectin neutralization: does it +make biological sense? +Crit Care Med. +One of these is arachi- +donic acid, the precursor molecule for eicosanoids. +Another is +platelet-activating factor (PAF). +During acute inflammation, +PAF is released by immune cells following the activation of +PLA2. +Endothelial inter- +action with smooth muscle cells +and with intraluminal platelets. +2-14). +Figure 2-14. +RBC = red blood cell; WBC = white +blood cell. +(Adapted from Cahill GF: +Starvation in man. +N Engl J Med. +Body fuel reserves in a 70-kg man and +B. +Energy equivalent of substrate oxidation +A. +2-15). +2-16). +Alanine +within skeletal muscles can also be +used as a precursor for hepatic glu- +coneogenesis. +During starvation, +such fatty acid provides fuel sources +for basal hepatic enzymatic function. +RBC = red blood cell; WBC = white +blood cell. +Fuel utilization in extended starvation. +The brain uses ketones for fuel. +The kidneys become important participants in gluconeogenesis. +RBC = red blood cell; +WBC = white blood cell. +(Adapted from Cahill GF: Starvation in man. +N Engl J Med. +1970;282:668.) +46 +BASIC CONSIDERATIONS +PART + +I +ammonium ions. +Lipid stores within adipose tissue provide 40% or more of +caloric expenditure during starvation. +2-17). +2-18). +Oxidation of +1 g of fat yields approximately 9 kcal of energy. +Although the liver +is capable of synthesizing triglycerides from carbohydrates and +Figure 2-17. +Acute injury is asso- +ciated with significant alterations +in substrate utilization. +There is +enhanced nitrogen loss, indicative +of catabolism. +Fat remains the pri- +mary fuel source under these circum- +stances. +RBC = red blood cell; WBC = +white blood cell. +Figure 2-18. +Influence of injury severity on resting metabolism +(resting energy expenditure, or REE). +The shaded area indicates +normal REE. +(From Long CL, Schaffel N, Geiger J, et al. +JPEN J Par- +enter Enteral Nutr. +1979;3(6):452. +Copyright © 1979 by A.S.P.E.N. +2-19). +Lipolysis and Fatty Acid Oxidation. +Periods of energy +demand are accompanied by free fatty acid mobilization from +adipose stores. +2-20). +Free fatty acids absorbed by cells conjugate with acyl- +CoA within the cytoplasm. +2-21). +This accounts in part for the fact +that MCTs are more efficiently oxidized than LCTs. +Excess acetyl- +CoA molecules serve as precursors for ketogenesis. +An RQ of 0.85 suggests +the oxidation of equal amounts of fatty acids and glucose. +CoA = coenzyme A. +The rate of ketogenesis appears to be inversely related to the +severity of injury. +However, in minor stress states +ketogenesis does not exceed that in nonstressed starvation. +Fructose absorp- +tion, however, occurs by concentration-dependent facilitated +diffusion. +Discussion of carbohydrate metabolism primarily refers to +the utilization of glucose. +In starvation, glucose production occurs at the expense +of protein stores (i.e., skeletal muscle). +In cells, glucose is phosphorylated to form glucose-6- +phosphate. +Glucose-6-phosphate can be polymerized during gly- +cogenesis or catabolized in glycogenolysis. +2-22). +Fat mobilization in adipose tissue. +Triglycerides are serially hydrolyzed with resultant free fatty acid (FFA) release at +every step. +The FFAs diffuse readily into the capillary bed for transport. +Tissues with glycerokinase can use glycerol for fuel by forming +glycerol-3-phosphate. +Skeletal muscle and adipose cells have little glycerokinase and thus do not use glycerol for fuel. +Free fatty acids (FFAs) in the cells form fatty acyl- +coenzyme A (CoA) with CoA. +Once inside the mitochondria, carnitine +dissociates and fatty acyl-CoA is re-formed. +The carnitine molecule +is transported back into the cytosol for reuse. +“R” represents a part of the acyl group of +acyl-CoA. +Glucose- +6-phosphate becomes an important +“crossroad” for glucose metabolism. +50 +BASIC CONSIDERATIONS +PART + +I +peripheral insulin resistance. +Hydrophobic cell mem- +branes are relatively impermeable to hydrophilic glucose mol- +ecules. +There are two distinct classes of membrane glucose +transporters in human systems. +Numerous functional human GLUTs have been cloned +since 1985. +It is expressed on several other tis- +sues, but little is found in the liver and skeletal muscle. +GLUT2 is the major glucose +transporter of hepatocytes. +GLUT2 is important for +glucose uptake and release in the fed and fasted states. +GLUT4 +therefore plays a critical role in the regulation of whole-body +glucose homeostasis. +GLUT5 has been identified in several tis- +sues but is primarily expressed in the jejunum. +SGLT1 and SGLT2 are both associated with glucose reab- +sorption at proximal renal tubules. +2-23). +Severe trauma, burns, and +sepsis are associated with increased protein catabolism. +This state of pro- +tein catabolism may persist for as long as 3 to 7 weeks. +The effect of injury sever- +ity on nitrogen wasting. +(From Long CL, +Schaffel N, Geiger J, et al. +JPEN +J Parenter Enteral Nutr. +1979;3(6):452. +Copyright © 1979 by A.S.P.E.N. +Therefore, vitamins usu- +ally are not given in the absence of preoperative deficiencies. +Commercial enteral diets contain varying amounts of +essential minerals and vitamins. +Supplemental trace minerals may be given intravenously +via commercial preparations. +Adjusted lean body weight also can be cal- +culated. +A recent study +examined the use of trophic feedings in patients with acute lung +injury. +Guidelines have not yet been made with +regard to the fiber content of enteral formulas. +At present, the best-studied immunonutrients are glu- +tamine, arginine, and ω-3 PUFAs. +Of this, 75% is found within the +skeletal muscles. +Some of these studies +also provide in vitro evidence of enhanced immunocyte func- +tion. +Hence, there has been significant interest in reduc- +ing the ratio of ω-6 to ω-3 fatty acids. +Low-Residue Isotonic Formulas. +These contain no +fiber bulk and therefore leave minimum residue. +Isotonic Formulas with Fiber. +Isotonic formulas with fiber +contain soluble and insoluble fiber, which is most often soy +based. +Immune-Enhancing Formulas. +Calorie-Dense Formulas. +The primary distinction of calorie- +dense formulas is a greater caloric value for the same volume. +High-Protein Formulas. +These +formulas have nonprotein-calorie:nitrogen ratios between 80:1 +and 120:1. +Elemental Formulas. +Complex carbohydrates are limited, and fat content, in the form +of MCTs and LCTs, is minimal. +To date, there has been no evidence of their +benefit in routine use. +Renal Failure Formulas. +Pulmonary Failure Formulas. +Hepatic Failure Formulas. +Even in intubated patients, naso- +gastric feedings often can be recovered from tracheal suction. +Small-bowel feeding is more reliable for delivering nutri- +tion than nasogastric feeding. +It is also appropriate +for patients requiring passive gastric decompression. +Most tubes are 18F to 28F in size and may be +used for 12 to 24 months. +A 14-gauge angiocatheter is passed through the abdominal +wall into the fully insufflated stomach. +Percutaneous Endoscopic Gastrostomy-Jejunostomy and +Direct Percutaneous Endoscopic Jejunostomy. +This can be achieved by +endoscopic or fluoroscopic guidance. +Surgical Gastrostomy and Jejunostomy. +The only absolute contra- +indication to feeding jejunostomy is distal intestinal obstruction. +Needle-catheter +jejunostomies also can be done with a minimal learning curve. +In some instances, intravenous nutrition may +be used to supplement inadequate oral intake. +Patients with good nutritional status +5. +Early enteral feeding, compared with parenteral, reduces postop- +erative septic complications. +Ann Surg. +1992;216(2):172-183. +58 +BASIC CONSIDERATIONS +PART + +I +via peripheral veins. +Some nutrients cannot be supplemented +because they cannot be concentrated into small volumes. +There- +fore, PPN is not appropriate for repleting patients with severe +malnutrition. +Typi- +cally, PPN is used for short periods (<2 weeks). +Beyond this +time, TPN should be instituted. +Intravenous vitamin preparations also should be added to +parenteral formulas. +Vitamin deficiencies are rare occurrences +if such preparations are used. +Insulin may be supplemented +as necessary to ensure glucose tolerance. +In patients with diabetes mellitus, additional +insulin may be required. +In some cases as much as 240 mEq of +potassium ion daily may be required. +Hypokalemia may cause +glycosuria, which would be treated with potassium, not insulin. +This may require protocol-driven intrave- +nous insulin therapy. +The delivery of parenteral nutrition requires central intra- +venous access. +Complications of Parenteral Nutrition +Technical Complications. +Other causes of fever +should also be investigated. +If fever persists, the infusion cath- +eter should be removed and submitted for culture. +Some centers are now +replacing catheters considered at low risk for infection over a +guidewire. +This is most likely asso- +ciated with greater catheter manipulation and intensive use. +When catheters are indwelling for +<3 days, infection risks are negligible. +If indwelling time is 3 to +7 days, the infection risk is 3% to 5%. +Indwelling times of +>7 days are associated with a catheter infection risk of 5% to +10%. +All of these complications may be avoided by +strict adherence to proper techniques. +Intestinal Atrophy. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Minei JP, Cuschieri J, Sperry J, et al. +Crit 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Central Line-Associated Blood Stream Infec- +tions. +http://www.ahrq.gov/legacy/qual/clabsitools/ +clabsitoolshtm-purpose. +162. +Maecken T, Grau T. +Ultrasound imaging in vascular access. +Crit Care Med. +2007;35(5 Suppl):S178-S185. +This page intentionally left blank +Fluid and Electrolyte Management +of the Surgical Patient +G. +BODY FLUIDS +Total Body Water +Water constitutes approximately 50% to 60% of total body +weight. +Lean tissues such as muscle +and solid organs have higher water content than fat and bone. +This decreases +to approximately 65% by 1 year of age and thereafter remains +fairly constant. +3-1). +ECF +is measured using indicator dilution methods. +3-2. +The composition of +the plasma and interstitial fluid differs only slightly in ionic +composition. +Functional body fluid +compartments. +TBW = total body +water. +6 Most acute surgical illnesses are accompanied by some +degree of volume loss or redistribution. +For divalent ions such as magnesium, 1 mmol equals +2 mEq. +The movement of water across a cell membrane depends +primarily on osmosis. +This movement is determined by +the concentration of the solutes on each side of the membrane. +Chemical composition of +body fluid compartments. +active particles. +Conversely, +if the ECF concentration of sodium decreases, water will move +into the cells. +Sweat is hypotonic, and sweating usually results in only a small +sodium loss. +Both plasma and interstitial volumes usually are increased. +Symptoms are primarily pulmonary and cardiovascular (see +Table 3-2). +In fit patients, edema and hyperdynamic circula- +tion are common and well tolerated. +Volume Control +Volume changes are sensed by both osmoreceptors and baro- +receptors. +Concentration Changes +Changes in serum sodium concentration are inversely pro- +portional to TBW. +Therefore, abnormalities in TBW are +reflected by abnormalities in serum sodium levels. +Hyponatremia. +A low serum sodium level occurs when there +is an excess of extracellular water relative to sodium. +Extracel- +lular volume can be high, normal, or low (Fig. +3-3). +The elderly are particularly susceptible to drug- +induced hyponatremia. +A concomitant ECF volume deficit is common. +Oliguric renal failure also can be a rapid complication in the +setting of severe hyponatremia. +A systematic review of the etiology of hyponatremia +should reveal its cause in a given instance. +Next, depletional +versus dilutional causes of hyponatremia are evaluated. +Dilutional causes +of hyponatremia usually are associated with hypervolemic cir- +culation. +Hypernatremia. +Hypernatremia results from either a loss of +free water or a gain of sodium in excess of water. +3-3). +Urine +sodium concentration is typically >20 mEq/L, and urine osmo- +larity is >300 mOsm/L. +This can put traction on the cerebral vessels and lead to +subarachnoid hemorrhage. +Central nervous system symptoms +Figure 3-3. +Evaluation of sodium +abnormalities. +can range from restlessness and irritability to seizures, coma, +and death. +Composition Changes: Etiology and Diagnosis +Potassium Abnormalities. +Acute and chronic renal insufficiency also +impairs potassium excretion. +Symptoms of hyperkalemia are primarily GI, neuromus- +cular, and cardiovascular (Table 3-6). +GI symptoms include +nausea, vomiting, intestinal colic, and diarrhea. +Neuromuscu- +lar symptoms range from weakness to ascending paralysis to +respiratory failure. +Hypokalemia Hypokalemia is much more common than +hyperkalemia in the surgical patient. +Unlike changes in albumin, changes in pH will affect the +ionized calcium concentration. +Acidosis decreases protein bind- +ing, thereby increasing the ionized fraction of calcium. +Daily calcium intake is 1 to 3 g/d. +Most of this is excreted +via the bowel, with urinary excretion relatively low. +Pancreatitis +may sequester calcium via chelation with free fatty acids. +Hypocalcemia may lead to decreased +cardiac contractility and heart failure. +Serum phosphate levels are tightly +controlled by renal excretion. +Most cases of hyperphosphatemia +are seen in patients with impaired renal function. +Clinical manifestations of hypophosphatemia usually +are absent until levels fall significantly. +Magnesium Abnormalities. +Of the fraction found in the +extracellular space, one third is bound to serum albumin. +Mag- +nesium should be replaced until levels are in the upper limit of +normal. +The normal dietary intake is approximately 20 mEq/d +and is excreted in both the feces and urine. +The magnesium ion is essential for proper +function of many enzyme systems. +Depletion is characterized by +neuromuscular and central nervous system hyperactivity. +Severe deficiencies can +lead to delirium and seizures. +Acid-Base Balance +Acid-Base Homeostasis. +Significant compensation may not begin for 6 hours +and then may continue for several days. +↑ +aMeasured as standard bicarbonate, whole blood buffer base, CO2 content, or CO2 combining power. +N = normal; Pco2 = partial pressure of carbon dioxide. +increased loss of bicarbonate (Table 3-9). +Initially the urinary bicarbonate level is high in compensa- +tion for the alkalosis. +Hydrogen ion reabsorption also ensues, +with an accompanied potassium ion excretion. +Respiratory Derangements. +The principal causes are listed in Table 3-11. +Because +compensation is primarily a renal mechanism, it is a delayed +response. +Treatment of acute respiratory acidosis is directed +at the underlying cause. +Measures to ensure adequate ventila- +tion are also initiated. +Decreased glomerular filtration +2. +The most commonly +used solutions are listed in Table 3-12. +Lactated Ringer’s is slightly hypotonic in that +it contains 130 mEq of lactate. +Lactate is used rather than bicar- +bonate because it is more stable in IV fluids during storage. +A trial of 853 patients +receiving hypertonic saline versus hypertonic saline/dextran +70 vs. +Albumin (molecular weight 70,000) is prepared from +heat-sterilized pooled human plasma. +Because it is a +derivative of blood, it can be associated with allergic reactions. +Thus dextrans are used primar- +ily to lower blood viscosity rather than as volume expanders. +The molecular weights can range from 1000 to 3,000,000. +The +type of fluid used depends on the severity and ease of correc- +tion. +Caution also should be exercised when using 5% dextrose +in water to avoid overly rapid correction. +orally, in alert patients, or rectally. +Nebulized albuterol (10 to +20 mg) may also be used. +All of the aforementioned mea- +sures are temporary, lasting from 1 to approximately 4 hours. +Dialysis should be considered in severe hyperkalemia when +conservative measures fail. +Oral repletion is adequate for mild, asymptomatic +hypokalemia. +If IV repletion is required, usually no more than +10 mEq/h is advisable in an unmonitored setting. +Caution should be exercised when oliguria or impaired +renal function is coexistent. +Treatment +of hypercalcemia associated with malignancies is discussed +later in this chapter. +Hypocalcemia Asymptomatic hypocalcemia can be treated +with oral or IV calcium (see Table 3-15). +Associated +deficits in magnesium, potassium, and pH must also be corrected. +Hypocalcemia will be refractory to treatment if coexisting hypo- +magnesemia is not corrected first. +Calcium acetate tablets also are useful when +hypocalcemia is simultaneously present. +Dialysis usually is +reserved for patients with renal failure. +If elevated levels or symptoms persist, hemodialy- +sis may be necessary. +Hypomagnesemia Correction of magnesium depletion can +be oral if asymptomatic and mild. +This does not, however, include replenishment +of a pre-existing deficit or ongoing fluid losses. +Acute volume deficits should be corrected as much as +possible before the time of operation. +Close monitoring during this period is imperative. +Until the 1960s saline solutions were withheld during sur- +gery. +In the initial postoperative period, an +isotonic solution should be administered. +How- +ever, postoperative diuresis may require attention to replace- +ment of urinary potassium loss. +The earliest sign of volume +overload is weight gain. +Additional +signs of volume excess may also be present as listed in Table 3-2. +Hemoconcentration also may be present. +Treat- +ment will depend on the amount and composition of fluid lost. +In most cases, restriction of free water will improve +the hyponatremia. +Furosemide also can be used to induce free water loss. +Diabetes Insipidus. +However, volume +depletion can occur rapidly in patients incapable of oral intake. +In mild cases, free water replacement may be +adequate therapy. +In more severe cases, vasopressin can be +added. +The usual dosage of vasopressin is 5 U subcutaneously +every 6 to 8 hours. +Cerebral Salt Wasting. +However, severe +hyperglycemia may result from blunted basal insulin secretion. +Additionally, thiamine should be administered before the initia- +tion of feeding. +With the onset of renal fail- +ure, an accurate assessment of volume status must be made. +Oli- +guric renal failure requires close monitoring of serum potas- +sium levels. +Dialy- +sis may be required for severe hyponatremia. +Bicar- +bonate can be useful, but dialysis often is needed. +Cerebral salt +wasting also can occur in patients with intracerebral lesions. +Central +DI also can lead to hypernatremia in patients with central ner- +vous system lesions. +Tumor lysis syn- +drome can precipitate severe hyperkalemia from massive tumor +cell destruction. +Hypomagnesemia is a side effect of ifosfamide and +cisplatin therapy. +Humoral hypercalcemia +of malignancy is a common cause of hypercalcemia in cancer +patients. +Once an adequate volume status has been +achieved, a loop diuretic may be added. +Unfortunately, these +measures are only temporary, and additional treatment is often +necessary. +They have a slow onset of action, but +effects can last for 2 weeks. +It acts quickly, within 2 to 4 hours, but its use is limited by the +development of tachyphylaxis. +Gallium nitrates are potent inhibitors of +bone resorption. +They display a long duration of action but can +cause nephrotoxicity. +Tumor lysis syndrome most commonly develops during treat- +ment with chemotherapy or radiotherapy. +REFERENCES +Entries highlighted in blue are key references. +1. +Aloia JF, Vaswani A, Flaster E, et al. +Relationship of body +water compartment to age, race and fat-free mass. +J Lab Clin +Med. +1998;132:483. +2. +Bourque CW, Oliet SHR. +Osmoreceptors in the central ner- +vous system. +Annu Rev Physiol. +1997;59:601. +3. +Verbalis JG. +How does the brain sense osmolality? +J Am Soc +Nephrol. +2007;18(12):3056. +4. +Stauss HM. +Baroreceptor reflex function. +Am J Physiol Regul +Integr Comp Physiol. +2002;283:R284. +5. +Miller M. +Syndromes of excess antidiuretic hormone release. +Crit Care Clin. +2001;17:11. +6. +Kapoor M, Chan G. +Fluid and electrolyte abnormalities. +Crit +Care Clin. +2001;17:571. +7. +Adrogue HJ, Lederer ED, Suki WN, et al. +Determinants +of plasma potassium in diabetic ketoacidosis. +Medicine. +1986;65:163. +8. +Zietse R, Zuotendijk R, Hoorn EJ. +Fluid, electrolyte and acid- +base disorders associated with antibiotic therapy. +Nat Rev +Nephrol. +2009;5(4):193. +9. +Cobos E, Hall RR. +Effects of chemotherapy on the kidney. +Semin Nephrol. +1993;13:297. +10. +Gennari FJ. +Hypokalemia. +N Engl J Med. +1998;339:451. +11. +French S, Subauste J, Geraci S. +Calcium abnormalities in hos- +pitalized patients. +South Med J. +2012;105(4):231. +12. +Witteveen JE, van Theil S, Romijn JA. +Therapy of endo- +crine disease: hungry bone syndrome. +Eur J Endocrinol. +2013;168(3):R45. +13. +Bushinsky DA, Monk RD. +Calcium. +Lancet. +1998;352:306. +14. +Dunlay RW, Camp MA, Allon M, et al. +Calcitriol in prolonged +hypocalcemia due to tumor lysis syndrome. +Ann Intern Med. +1989;110:162. +15. +Reber PM, Heath H. +Hypocalcemic emergencies. +Med Clin +North Am. +1995;19:93. +16. +Tong GM, Rude RK. +Magnesium deficiency in critical illness. +J Intensive Care Med. +2005;20(1):3. +17. +Quamme GA. +Renal magnesium handling: new insights in +understanding old problems. +Kidney Int. +1997;52:1180. +18. +Marino PL. +Acid-base interpretations. +In: Marino PL, ed. +The +ICU Book. +2nd ed. +Baltimore: Williams & Wilkins; 1998:581. +19. +Gluck SL. +Acid-base. +Lancet. +1998;352:474. +20. +Kraut JA, Madias NE. +Treatment of acute metabolic acidosis: a +pathophysiologic approach. +Nat Rev Nephrol. +2012;8(10):589. +21. +Pal JD, Victorino GP, Twomey P, et al. +Admission serum +lactate levels do not predict mortality in the acutely injured +patient. +J Trauma. +2006;60:583. +22. +Koustova E, Standon K, Gushchin V, et al. +Effects of lactated +Ringer’s solution on human leukocytes. +J Trauma. +2002;53:782. +23. +Shires GT, Browder LK, Steljes TP, et al. +The effect of shock +resuscitation fluids on apoptosis. +Am J Surg. +2005;189:85. +24. +Roberts JS, Bratton SL. +Colloid volume expanders: problems, +pitfalls, and possibilities. +Drugs. +1998;55:621. +25. +Cottenceau V, Masson F, Mahamid E, et al. +J Neurotrauma. +2011;28(10):2003. +26. +Bulger EM, May S, Kerby JD, et al. +Ann Surg. +2011;253(3):431. +27. +Ley K. +Plugging the leaks. +Nat Med. +2001;7:1105. +28. +Conhaim RL, Watson KE, Potenza BM, et al. +Pulmonary cap- +illary sieving of hetastarch is not altered by LPS-induced sep- +sis. +J Trauma. +1999;46:800. +29. +Lucas CE. +The water of life: a century of confusion. +J Am +Coll Surg. +2001;192:86. +30. +de Jonge E, Levi M. +Effects of different plasma substitutes +on blood coagulation: a comparative review. +Crit Care Med. +2001;291:1261. +31. +Navickis RJ, Haynes GR, Wilkes MM. +J Thorac Cardiovasc Surg. +2012;144(4):223. +83 +Fluid and Electrolyte Management of the Surgical Patient +CHAPTER 3 +32. +Schortgen F, Lacherade JC, Bruneel F, et al. +Lancet. +2001;357:911. +33. +Zarychanski R, Abou-Setta AM, Turgeon AF, et al. +JAMA. +2013;309(7):678. +34. +Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al. +Anesth Analg. +1999;88:992. +35. +Boldt J, Haisch G, Suttner S, et al. +Br J Anaesth. +2002;89:772. +36. +Rittoo D, Gosling P, Bonnici C, et al. +Cardiovasc Surg. +2002;10:128. +37. +Coats TJ, Brazil E, Heron M, et al. +Impairment of coagulation +by commonly used resuscitation fluids in human volunteers. +Emerg Med J. +2006;23:846. +38. +Overgaard-Steensen C, Ring T. +Clinical Review: Practical +approach to hyponatremia and hypernatremia in critically ill +patients. +Crit Care. +2013;17(1):206. +39. +Norenberg MD. +Central pontine myelinolysis: historical and +mechanistic considerations. +Metab Brain Dis. +2010;25(1):97. +40. +Graff-Radford J, Fugate JE, Kauffmann TJ. +Clinical and radio- +logic correlations of central pontine myelinolysis syndrome. +Mayo Clin Proc. +2011;86(11):1063. +41. +American College of Surgeons. +Shock. +In: American College +of Surgeons Advanced Trauma Life Support Manual. +9th ed. +Chicago: American College of Surgeons; 2012. +42. +Shires GT, Williams J, Brown F. +Acute changes in extracel- +lular fluids associated with major surgical procedures. +Ann +Surg. +1961;154:803. +43. +Shires GT, Jackson DE. +Postoperative salt tolerance. +Arch +Surg. +1962;84:703. +44. +Shires GT III, Peitzman AB, Albert SA, et al. +Response +of extravascular lung water to intraoperative fluids. +Ann +Surg. +1983;197:515. +45. +Ellison DH, Burl T. +Clinical practice. +The syndrome of inap- +propriate antidiuresis. +N Engl J Med. +2007;356(20):2064. +46. +Tisdall M, Crocker M, Watkiss J, et al. +Disturbances of sodium +in critically ill adult neurologic patients: a clinical review. +J Neurosurg Anesthesiol. +2006;18(1):57. +47. +Yee AH, Burns JD, Wijdicks EF. +Cerebral salt wasting: patho- +physiology, diagnosis, and treatment. +Neurosurg Clin N Am. +2010;21(2):339. +48. +Kozar RA, McQuiggan MM, Moore FA. +Nutritional support +in trauma patients. +In: Shikora SA, Martindale RG, Schwait- +zberg SD, eds. +Nutritional Considerations in the Intensive +Care Unit. +1st ed. +Dubuque, IA: Kendall/Hunt Publishing; +2002:229. +49. +Boateng AA, Sriram K, Mequid MM, et al. +Nutrition. +2010;26(2):156. +50. +Glassford NJ, Bellomo R. +Acute kidney injury: how can we +facilitate recovery? +Curr Opin Crit Care. +2011;17(6):562. +51. +Kapoor M, Chan GZ. +Fluid and electrolyte abnormalities. +Crit +Care Clin. +2002;17:503. +52. +Clines GA. +Mechanisms and treatment of hypercalcemia of +malignancy. +Curr Opin Endocrinol Diabetes Obes. +2011; +18(6)339. +Holcomb, Matthew Pommerening, +Kenneth Jastrow, and Rosemary A. +The process is shown schematically in +Fig. +4-1. +Vascular Constriction +Vascular constriction is the initial response to vessel injury. +Vasoconstric- +tion is subsequently linked to platelet plug formation. +The extent of vasoconstriction varies with the degree of +vessel injury. +Platelet Function +Platelets are anucleate fragments of megakaryocytes. +The nor- +mal circulating number of platelets ranges between 150,000 and +400,000/μL. +Up to 30% of circulating platelets may be seques- +tered in the spleen. +4-2). +vWF binds to glycopro- +tein (GP) I/IX/V on the platelet membrane. +Up to +this point, this process is known as primary hemostasis. +Platelet +aggregation is reversible and is not associated with secretion. +Adenosine +diphosphate (ADP) and serotonin are the principal mediators in +platelet aggregation. +TXA2 has potent vasoconstriction and platelet aggrega- +tion effects. +Platelet factor 4 (PF4) and α-thromboglobulin are +also secreted during the release reaction. +PF4 is a potent heparin +antagonist. +Biology of hemostasis. +Key Points +1 The life span of platelets ranges from 7 to 10 days. +Common pathway +Intrinsic pathway +Clotting factors +VIII, IX, X, XI, XII +Fibrin +1. +Vascular phase +(Vasoconstriction) +2. +Platelet phase +(Platelets aggregate) +3. +Coagulation phase (Clot formation) +(Clot retraction) 4. +Platelets may also play a role in the initial +activation of factors XI and XII. +4-3). +Schematic of platelet activation and thrombus function. +Figure 4-3. +Schematic of the +coagulation system. +HMW = high +molecular weight. +TF binds to +VIIa, and this complex catalyzes the activation of factor X to Xa. +Factor IXa is responsible for the bulk +of the conversion of factor X to Xa. +The most potent mechanism +of thrombin inhibition involves the APC system. +APC forms a +complex with its cofactor, protein S, on a phospholipid surface. +This is of interest clinically in the form +of a genetic mutation, called factor V Leiden. +Patients with factor V Leiden are predisposed +to venous thromboembolic events. +Plas- +min formation occurs as a result of one of several plasminogen +activators. +Of note, the thrombin-TM complex +activates TAFI, leading to a mixed effect on clot stability. +Plasminogen is converted to plasmin by +one of several plasminogen activators, including tPA. +4-4). +tPA is synthesized by endothelial cells and released by the cells +on thrombin stimulation. +After plasmin is +generated, however, it cleaves fibrin somewhat less efficiently. +Figure 4-4. +Formation of fibrin degradation products (FDPs). +tPA = +tissue plasminogen activator. +Any circulating plasmin is also inhibited by α2-antiplasmin and +circulating tPA or urokinase. +Clot lysis yields FDPs including +E-nodules and D-dimers. +For factor IX replacement, the preferred products +are recombinant or high-purity factor IX. +For patients +with low titers, inhibitors can be overcome with higher doses of +factor VIII. +Menorrhagia is common in women. +vWD is classified into +three types. +For +bleeding, type I patients usually respond well to desmopressin +(DDAVP). +Type II patients may respond, depending on the par- +ticular defect. +Type III patients are usually unresponsive. +These +patients may require vWF concentrates.3 +Factor XI Deficiency. +Antifibrinolytics may +be useful in patients with menorrhagia. +Inher- +ited deficiencies of factors II, V, and X are rare. +These deficien- +cies are inherited as autosomal recessive. +Significant bleeding +in homozygotes with less than 1% of normal activity is encoun- +tered. +Bleeding with any of these deficiencies is treated with +FFP. +Similar to factor XI, FFP contains one unit of activity +of each per milliliter. +However, factor V activity is decreased +because of its inherent instability. +Prothrombin +complex concentrates can be used to treat deficiencies of pro- +thrombin or factor X. +Factor V deficiency may be coinherited with factor +VIII deficiency. +Factor VII Deficiency. +Inherited factor VII deficiency is a +rare autosomal recessive disorder. +Bleeding is uncommon unless the +level is less than 3%. +The half-life of factor VII in FFP is up to 4 hours. +Factor XIII Deficiency. +Umbilical stump bleeding is characteristic, and there is a high +risk of intracranial bleeding. +Replacement can be accomplished with FFP, +cryoprecipitate, or a factor XIII concentrate. +Levels of 1% to +2% are usually adequate for hemostasis. +The major surface protein abnormalities are +thrombasthenia and Bernard-Soulier syndrome. +This defect leads to faulty +platelet aggregation and subsequent bleeding. +The disorder was +first described by Dr. +Transfusion of normal +platelets is required for bleeding in these patients. +The most common intrinsic platelet defect is storage pool +disease. +Dense granule deficiency is the most +prevalent of these. +Bleed- +ing is variable, depending on the severity of the granule defect. +Bleeding is caused by the decreased release of ADP from these +platelets. +A few patients have been reported who have decreased +numbers of both dense and α-granules. +They have a more severe +bleeding disorder. +With +more severe bleeding, platelet transfusion is required. +The etiologies of both +qualitative and quantitative defects are reviewed in Table 4-1. +Table 4-1 +Etiology of platelet disorders +A. +Quantitative Disorders +1. +Failure of production: related to impairment in bone +marrow function +a. +Leukemia +b. +Myeloproliferative disorders +c. +B12 or folate deficiencies +d. +Chemotherapy or radiation therapy +e. +Acute alcohol intoxication +f. +Viral infections +2. +Decreased survival +a. +Disseminated intravascular coagulation (DIC) +c. +Related to platelet thrombi +1) Thrombocytopenic purpura (TTP) +2) Hemolytic uremic syndrome (HS) +3. +Sequestration +a. +Portal hypertension +b. +Sarcoid +c. +Lymphoma +d. +Gaucher’s Disease +B. +Qualitative Disorders +1. +Massive transfusion +2. +Therapeutic platelet inhibitors +3. +Disease states +a. +Myeloproliferative disorders +b. +Monoclonal gammopathies +c. +Corticosteroids: The majority of patients respond but +only a few long term + b. +Required in most patients + a. +Splenectomy: open or laparoscopic. +Criteria include +severe thrombocytopenia, high risk of bleeding, and +continued need for steroids. +Failure may be due to +retained accessory splenic tissue. +b. +Rituximab, an anti-CD 20 monoclonal antibody + c. +Thrombopoietin (TPO) receptor agonists such as +romiplostim and eltrombopag +Third Line. +To be used after failure of splenectomy and +rituximab + a. +TPO receptor agonists + b. +Immunosuppressive agents. +For failure of TPO receptor +agonists +quantitative Defects. +Large platelets are seen on peripheral smear. +Both gamma globulin and anti-D immunoglobulin are rapid +in onset. +Survival of the transfused platelets is usually short. +Primary immune thrombocytopenia is also known as +idiopathic thrombocytopenic purpura (ITP). +In children, it is +usually acute in onset, short lived, and typically follows a viral +illness. +In contrast, ITP in adults is gradual in onset, chronic +in nature, and has no identifiable cause. +Heparin-induced thrombo- +cytopenia (HIT) is a form of drug-induced immune thrombo- +cytopenia. +A negative ELISA, however, essentially rules out HIT. +The initial treatment of suspected HIT is to stop heparin +and begin an alternative anticoagulant. +Alternative anticoagulants are pri- +marily thrombin inhibitors. +The finding of schistocytes on a peripheral blood +smear aids in the diagnosis. +The metalloproteinase is normal in +these cases. +Neurologic symptoms are less frequent. +A number of patients +develop features of both TTP and HUS. +Discontinuation +of the involved drug is the mainstay of therapy. +Platelet +survival is mildly decreased. +A count of greater than 50,000/μL +generally requires no specific therapy. +qualitative Platelet Defects. +Impairment of ADP-stimulated aggregation occurs with +massive transfusion of blood products. +Uremia may be +associated with increased bleeding time and impaired aggrega- +tion. +If possible, surgery should be delayed until the +count has been decreased. +These patients are at risk for both +bleeding and thrombosis. +Acquired Hypofibrinogenemia +Disseminated Intravascular Coagulation (DIC). +As of yet, scoring systems for organ +failure do not routinely incorporate DIC. +Given the formation of microthrombi +in DIC, heparin therapy has also been proposed. +Primary Fibrinolysis. +In general, correction based solely on a low platelet count +should be discouraged. +Most often, treatment should be with- +held for invasive procedures and surgery. +Results are +mixed following insertion of a transjugular intrahepatic porto- +systemic shunt (TIPS). +Additionally, laboratory abnormalities may mimic those of +DIC. +Elevated D-dimers have been reported to increase the risk +of variceal bleeding. +The absorption of vitamin K is dependent +on bile production. +If the fibrinogen is less than 200 mg/dL, administration of cryo- +precipitate may be helpful. +Cryoprecipitate is also a source of +factor VIII for the rare patient with a low factor VIII level. +4-5, hypoperfusion causes activa- +tion of TM on the surface of endothelial cells. +These antibodies +may be associated with either venous or arterial thrombosis, +or both. +In fact, patients presenting with recurrent thrombosis +should be evaluated for APLS. +Therapeutic +anticoagulation is more reliably achieved with a low molecu- +lar weight heparin. +Medications that can alter warfarin requirements are +shown in Table 4-4. +Illustration of the pathophysiologic mechanism +responsible for the acute coagulopathy of trauma. +PAI-1 = plas- +minogen activator inhibitor 1; TAFI = thrombin-activatable fibri- +nolysis inhibitor. +More concerning is the absence of any +available reversal agent. +In most of these cases, reversal of +anticoagulation is the only treatment that is necessary. +Surgical intervention may prove necessary in patients +receiving anticoagulation therapy. +Certain surgical procedures should not be performed in +concert with anticoagulation. +Emergency +operations are occasionally necessary in patients who have been +heparinized. +The first step in these patients is to discontinue +heparin. +For more rapid reversal, protamine sulfate is effective. +The primary indication for this level of aggressiveness is +patients with mechanical heart valves. +Cardiopulmonary Bypass. +Significant surgical bleeding is usually +caused by ineffective local hemostasis. +Mechanical Procedures. +When a small vessel is transected, a simple ligature is usu- +ally sufficient. +However, for larger pulsating arteries, a transfix- +ion suture to prevent slipping is indicated. +Packing bone wax on the raw +surface to effect pressure can control bleeding from cut bone. +Thermal Agents. +A direct current also can result in hemostasis. +96 +BASIC CO +n +SIDERATIO +n +S +PART + +I +Topical Hemostatic Agents. +Levine and Stetson in 1939 followed with +the concept of Rh grouping. +Replacement Therapy +Typing and Cross-Matching. +Serologic compatibility for A, +B, O, and Rh groups is established routinely. +Rh-negative recipients should +be transfused only with Rh-negative blood. +However, this group +represents only 15% of the population. +In emergency situations, type O-negative blood may be +transfused to all recipients. +O-negative and type-specific red +blood cells are equally safe for emergency transfusion. +If these antibodies are present in high titer, hypother- +mia is contraindicated. +The use of autologous transfusion is growing. +Up to 5 units +can be collected for subsequent use during elective procedures. +Donations can be scheduled at intervals +of 3 to 4 days. +Banked Whole Blood. +Once the gold standard, whole +blood is rarely available in Western countries. +With sequen- +tial changes in storage solutions, the shelf life of red blood +cells is now 42 days. +Red Blood Cells and Frozen Red Blood Cells. +Red blood +cells are the product of choice for most clinical situations requir- +ing resuscitation. +The preparation reduces but does not elimi- +nate reactions caused by plasma components. +They are +used for patients who are known to have been previously sensi- +tized. +The red blood cell viability is improved, and the ATP and +2,3-DPG concentrations are maintained. +Leukocyte-Reduced and Leukocyte-Reduced/Washed Red +Blood Cells. +In most +Western nations, it is the standard red blood cell transfusion +product. +The shelf life of platelets is 120 hours from time of donation. +One unit of platelet concentrate has a volume of approximately +50 mL. +Fresh Frozen Plasma. +FFP car- +ries similar infectious risks as other component therapies. +FFP +can be thawed and stored for up to 5 days, greatly increasing +its immediate availability. +Tranexamic Acid. +16.0%, RR 0.91, confidence interval +[CI] 0.85–0.97; P = .0035). +184/2996 [6.1%], RR 0.79, CI 0.64–0.97; +P = .03). +Treatment given after 3 hours increased the risk of +death due to bleeding (144/3272 [4.4%] vs. +103/3362 [3.1%], +RR 1.44, CI 1.12–1.84; P = .004). +TXA is an inhibitor +of plasminogen activation and an inhibitor of plasmin activity. +This reduces +plasminogen activation to plasmin. +TXA is 10 times +more potent in vitro than aminocaproic acid. +It is excreted largely +unchanged in urine and has a half-life of about 2 hours in cir- +culation. +No adjustment is needed +for hepatic impairment. +Oxygen- +carrying capacity is primarily a function of the red blood cells. +Thus, transfusion of red blood cells should augment oxygen- +carrying capacity. +Measurements of hemoglobin +or hematocrit levels are frequently used to assess blood loss. +These measurements can be occasionally misleading in the face +of acute loss. +No quality clinical data supported this concept. +This definition is admittedly arbitrary. +This varia- +tion correlated with blood product ratios. +Source: Reproduced with permission from Salzman EW: Hemorrhagic disorders. +In: Kinney JM, Egdahl RH, Zuidema GD, eds. +Manual of Preoperative and Postoperative Care. +2nd ed. +Philadelphia: WB Saunders; +1971:157. +Copyright Elsevier. +100 +BASIC CO +n +SIDERATIO +n +S +PART + +I +Table 4-6 +Adult Transfusion Clinical Practice Guideline +A. +Initial Transfusion of Red Blood Cells (RBCs): +1. +Notify blood bank immediately of urgent need for RBCs. +O negative uncross-matched (available immediately). +As soon as possible, switch to O negative for females and O positive for males. +Type-specific uncross-matched (available in approximately 5–10 min). +Completely cross-matched (available in approximately 40 min). +2. +A blood sample must be sent to blood bank for a type and cross. +3. +The Emergency Release of Blood form must be completed. +If the blood type is not known and blood is needed immediately, +O-negative RBCs should be issued. +4. +RBCs will be transfused in the standard fashion. +All patients must be identified (name and number) prior to transfusion. +5. +B. +Adult Massive Transfusion Guideline: +1. +The Blood Bank should strive to deliver plasma, platelets, and RBCs in a 1:1:1 ratio. +Crystalloid infusion should be minimized. +2. +Every attempt should be made to obtain a 1:1:1 ratio of +plasma:platelets:RBCs. +3. +Once initiated, the MT will continue until stopped by the attending physician. +MT should be terminated once the patient is +no longer actively bleeding. +4. +5. +Pretreatment +with acetaminophen reduces the severity of the reaction. +Bacterial contamination of infused blood is rare. +Gram- +negative organisms, which are capable of growth at 4°C, are the +most common cause. +If the diagnosis is suspected, the trans- +fusion should be discontinued and the blood cultured. +Emer- +gency treatment includes oxygen, adrenergic blocking agents, +and antibiotics. +Allergic Reactions. +Allergic reactions are relatively frequent, +occurring in about 1% of all transfusions. +Reactions are usu- +ally mild and consist of rash, urticaria, and flushing. +In rare +instances, anaphylactic shock develops. +For every 6 red blood cells (RBCs), give +6 FFP (1:1 ratio). +Platelets For every 6 RBCs and plasma, give one +6 pack of platelets. +6 random-donor platelet +packs = 1 apheresis platelet unit. +Platelets are in every cooler. +Keep platelet counts >100,000. +Cryoprecipitate After first 6 RBCs, check fibrinogen +level. +If ≤200 mg/dL, give 20 units +cryoprecipitate (2 g fibrinogen). +Treatment and prophylaxis consist of the +administration of antihistamines. +In more serious cases, epi- +nephrine or steroids may be indicated. +Respiratory Complications. +Overload is manifest +by a rise in venous pressure, dyspnea, and cough. +Rales can gen- +erally be heard at the lung bases. +Symptoms are similar to circulatory overload with dyspnea +and associated hypoxemia. +Hemolytic Reactions. +Hemolytic reactions can be classified +as either acute of delayed. +Associated symptoms +include fever, respiratory distress, hypotension, and tachycardia. +In anesthetized patients, diffuse bleeding and hypotension are the +hallmarks. +A high index of suspicion is needed to make the diag- +nosis. +A positive Coombs’ test indicates +transfused cells coated with patient antibody and is diagnostic. +Delayed hemolytic transfusions may also be manifest by fever +and recurrent anemia. +Delayed hemolytic transfusion reac- +tions do not usually require specific intervention. +Transmission of Disease. +Malaria can be transmitted by +all blood components. +The species most commonly implicated +is Plasmodium malariae. +Cytomegalovirus (CMV) infection resembling +infectious mononucleosis also has occurred. +Improved donor selection and testing are responsible for +the decreased rates of transmission. +Common screening laboratory testing includes platelet +count, PT or INR, and aPTT. +The normal platelet count +ranges from 150,000 to 400,000/μL. +The +PT test measures the function of factors I, II, V, VII, and X. +To account for these variations, the INR is +now the method of choice for reporting PT values. +A template aids in administering a uniform test and +adds to the reproducibility of the results. +The normal clot goes through accel- +eration and strengthening phase. +The clot forming in the cuvette trans- +mits its movement onto the suspended piston. +4-6). +Coagulation +LY +Fibrinolysis +R MA K +Angle +Figure 4-6. +Illustration of a thromboelastogram (TEG) tracing. +K = +clot kinetics; LY = lysis; MA = maximal amplitude; R = reaction time. +104 +BASIC CO +n +SIDERATIO +n +S +PART + +I +Several parameters are generated from the TEG tracing. +As +such, the k-time is prolonged with hypofibrinogenemia and sig- +nificant factor deficiency. +Prolonged r-value and k-time are com- +monly addressed with plasma transfusions. +The alpha or angle +(∝) is the slope of the tracing and reflects clot acceleration. +The +angle reflects the interactions of clotting factors and platelets. +The slope is decreased with hypofibrinogenemia and platelet +dysfunction. +Decreased angles are treated with cryoprecipitate +transfusion or fibrinogen administration. +The maximal ampli- +tude (mA) is the greatest height of the tracing and represents clot +strength. +Its height is reduced with dysfunction or deficiencies in +platelets or fibrinogen. +The LY30 represents clot +stability and when increased fibrinolysis is present. +Massive blood transfusion is a well-known cause of throm- +bocytopenia. +The first sign of a transfusion reaction may be +diffuse bleeding. +Transfusion purpura occurs when the donor platelets are +of the uncommon PlA1 group. +This is an uncommon cause of +thrombocytopenia and associated bleeding after transfusion. +The platelets sensitize the recipient, who makes antibody to the +foreign platelet antigen. +The antibody then destroys the +recipient’s own platelets. +The resultant thrombocytopenia and +bleeding may continue for several weeks. +Corticosteroids may be of some help +in reducing the bleeding tendency. +Hemolysis appears to be one mechanism in sepsis leading +to defibrination. +REFEREnCES +Entries highlighted in blue are key references. 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+This page intentionally left blank +Shock +Brian S. +Zuckerbraun, Andrew B. +Peitzman, and +Timothy R. +Hypovolemic +shock, the most common type, results from loss of circulating +blood volume. +This categorization of shock based on etiology persists +today (Table 5-1). +This includes +etiologies such as pulmonary embolism or tension pneumo- +thorax. +2 A central component of shock is decreased tissue perfusion. +This led to new methods of prolonged +mechanical ventilation. +Our current concept of ARDS is a com- +ponent in the spectrum of multiple organ system failure. +Thus both +inadequate and uncontrolled volume resuscitation is harmful. +5-1). +Furthermore, the pathophysiologic responses vary with +time and in response to resuscitation. +This represents the compensated phase of shock. +Ischemia/reperfusion injury will often exacerbate the +initial insult. +5-2). +Persistent +hypoperfusion results in further hemodynamic derangements +and cardiovascular collapse. +5-3). +Pathways leading to +decreased tissue perfusion and shock. +3 +112 +BASIC CONSIDERATIONS +PART + +I +Figure 5-2. +Figure 5-3. +The percentages shown above the curve +represent survival rates. +Shock. +1998;10:343- +346. +Peripheral vasoconstriction occurs, and +fluid excretion is inhibited. +The initial stimulus is loss of circulat- +ing blood volume in hemorrhagic shock. +The initial inciting event usually is loss of +circulating blood volume. +Baroreceptors also are an important afferent pathway in +initiation of adaptive responses to shock. +They become activated +with low volume hemorrhage or mild reductions in right atrial +pressure. +These receptors normally inhibit induction of the ANS. +Hemorrhage results in +diminished venous return to the heart and decreased cardiac +output. +These are compared +in Table 5-2. +The arte- +rial vasoconstriction is not uniform; marked redistribution of +blood flow results. +Increased sympathetic output induces catecholamine +release from the adrenal medulla. +Catecholamine levels peak +within 24 to 48 hours of injury and then return to baseline. +Hormonal Response. +ACTH subsequently +stimulates the adrenal cortex to release cortisol. +Cortisol acts +synergistically with epinephrine and glucagon to induce a +catabolic state. +Cortisol causes retention of sodium +and water by the nephrons of the kidney. +The renin-angiotensin system is activated in shock. +Potassium +and hydrogen ions are lost in the urine in exchange for sodium. +Epinephrine, angiotensin II, pain, and hyperglycemia +increase production of ADH. +Vasopressin also increases hepatic gluconeo- +genesis and increases hepatic glycolysis. +Proinflammatory cytokines +also contribute to arginine vasopressin release. +At rest, the majority of the blood volume is within the +venous system. +This increases venous return to the heart, thus maintain- +ing ventricular filling. +Most alterations in cardiac output in the normal heart are +related to changes in preload. +These relatively slow responses maintain preload by +altering circulating blood volume. +Ventricular Contraction. +This relationship is based on force of contraction being deter- +mined by initial muscle length. +Afterload. +Afterload is the force that resists myocardial work +during contraction. +Arterial pressure is the major component +of afterload influencing the ejection fraction. +This vascular +resistance is determined by precapillary smooth muscle sphinc- +ters. +Blood viscosity also will increase vascular resistance. +Microcirculation. +The result is a loss of extracellular fluid volume. +This occurs via the breakdown of cellular glyco- +gen stores to pyruvate. +This is compared to complete +oxidation of 1 mol of glucose that produces 38 mol of ATP. +There are numerous consequences secondary to these met- +abolic changes. +The depletion of ATP potentially influences all +ATP-dependent cellular processes. +Furthermore, acido- +sis leads to changes in calcium metabolism and calcium signal- +ing. +Compounded, these changes may lead to irreversible cell +injury and death. +Epinephrine and norepinephrine have a profound impact +on cellular metabolism. +Cortisol, +glucagon, and ADH also contribute to the catabolism during +shock. +Under normal circumstances, cells can +“repay” the O2 debt during reperfusion. +The magnitude of +the O2 debt correlates with the severity and duration of hypo- +perfusion. +5-1). +5-4). +5-5). +Together these signals amplify the immune response +Figure 5-4. +Cells require multiple inputs and stimuli before activation of a +full response. +Multiple mediators have been implicated in the host +immune response to shock. +A more comprehensive review can be +found in Chap. +2. +Monocytes, macro- +phages, and T cells release this potent proinflammatory cyto- +kine. +During the stress response, TNF-α contributes to the +muscle protein breakdown and cachexia. +Interleukin-1 (IL-1) has actions similar to those of +TNF-α. +This cytokine +also augments the secretion of ACTH, glucocorticoids, and +β-endorphins. +Signaling via the pattern recognition receptor TLR4. +LPS signaling via TLR4 requires the cofactors LPS binding protein (LBP), +MD-2, and CD14. +Shock. +IL-6 is elevated in response to hemorrhagic shock, major +operative procedures, or trauma. +Elevated IL-6 levels correlate +with mortality in shock states. +Chemokines bind to specific chemokine +receptors and transduce chemotactic signals to leukocytes. +Activation of the comple- +ment cascade can contribute to the development of organ +dysfunction. +Activated complement acts synergistically +with endotoxin to induce the release of TNF-α and IL-1. +However, activated PMNs and their products +may also produce cell injury and organ dysfunction. +Ischemia-reperfusion activates PMNs and causes PMN-induced +organ injury. +Interactions between endothelial cells and leukocytes are +important in the inflammatory process. +Cell Signaling +A host of cellular changes occur following shock. +119 +S +HOCK +CHAPTER 5 +intracellular energy metabolism. +Intracellular calcium (Ca2+) +homeostasis and regulation represent one such pathway. +5-6). +These changes increase vaso- +constriction and peripheral arterial resistance. +Diagnosis. +Treatment of shock is initially empiric. +Such apparent clinical shock results +from at least 25% to 30% loss of the blood volume. +(Reproduced with +permission from Xiao W, Mindrinos MN, Seok J, et al. +A genomic +storm in critically injured humans. +J Exp Med. +2011;208:2581– +2590. +© 2011 Xiao et al. +doi: 10.1084/jem.20111354.) +120 +BASIC CONSIDERATIONS +PART + +I +to bleeding (e.g., β-blockers). +However, only 59% of patients achieved a heart rate +greater than 120 bpm. +The relationship between systolic blood pressure and mortality in trauma patients with hemorrhage. +Base deficit (BD) is also shown on this graph. +ED = emergency department. +J Trauma. +2007;63:291–297.) +with hemorrhage following trauma (Fig. +Patients with penetrating +injuries who are in shock usually require operative intervention. +In the nontrauma patient, the GI tract must always be considered +as a site for blood loss. +Direct pressure must be applied and +Figure 5-8. +(From +Peitzman et al,7 with permission. +The relationship between base deficit (negative base excess) and mortality in trauma patients. +BEA = base excess arterial; +ECF = extracellular fluid. +(Reproduced with permission from Siegel JH, Rivkind AI, Dalal S, et al. +Early physiologic predictors of injury +severity and death in blunt multiple trauma. +Arch Surg. +1990;125:498. +Copyright © 1990 American Medical Association. +All rights reserved.) +sustained to minimize ongoing blood loss. +In +a more stable patient, a chest radiograph may be obtained to +look for evidence of hemothorax. +Intraperitoneal hemorrhage is probably the most com- +mon source of blood loss inducing shock. +Treatment. +This probability increased approximately 1% for each 3 +minutes in the emergency department. +Initial resuscitation +is limited to keep SBP around 80 to 90 mmHg. +This prevents +renewed bleeding from recently clotted vessels. +In this setting, an SBP of 110 mmHg would seem to be more +appropriate. +Mortality is inevitable once the patient manifests +shock in its terminal stages. +Unfortunately, this is often diag- +nosed in retrospect. +5-11). +Figure 5-10. +RBC = red blood cell. +J +Trauma. +Treatment of +OR (95% CI) of tranexamic acid +Ti +me +to + tr +eatment (h) +0.5 +8 +7 +6 +5 +4 +3 +2 +1 +0 +1. +01 .5 2.0 2.5 3.0 +Figure 5-11. +Early treatment (within 3 hours) of trauma patients with +tranexamic acid reduces mortality. +However, later treatment exacer- +bated outcome. +OR = odds ratio. +The Lancet. +2011;377:1096- +1101. +This is not the characteristic response in vasodila- +tory shock. +The most frequently encoun- +tered form of vasodilatory shock is septic shock. +iNOS produces large quan- +tities of nitric oxide for sustained periods of time. +Diagnosis. +Hypoperfusion with signs of +organ dysfunction is termed severe sepsis. +Treatment. +This resuscitation should be at +least 30 mL/kg within the first 4 to 6 hours. +These situ- +ations may require multiple operations to ensure proper wound +hygiene and healing. +Occasionally, patients +with septic shock will develop arterial resistance to catechol- +amines. +Mortality in this group is high. +33.3%) compared to the +standard therapy group. +10.3%). +103 mg/dL). +Surviving Sepsis Campaign Bundles +Figure 5-12. +Updated bundles of care +from the Surviving Sepsis Campaign +2012. +(From Dellinger RP, Levy MM, +Rhodes A, et al. +Intensive Care Med. +2013;39:165- +228, Figure 1. +10 ± 11 days; P = .007). +Cardiogenic shock complicates 5% to 10% of acute MIs. +Although shock +may develop early after MI, it typically is not found on admis- +sion. +Prevention of infarct extension is a critical component. +Myocardial diastolic function is +impaired in cardiogenic shock as well. +Diagnosis. +Cardiac +exam may include dysrhythmia, precordial heave, or distal heart +tones. +Rela- +tively few patients with blunt cardiac injury will develop cardiac +pump dysfunction. +Those who do generally exhibit cardiogenic +shock early in their evaluation. +Treatment. +Electrolyte +abnormalities, commonly hypokalemia and hypomagnesemia, +should be corrected. +Pain is treated with IV morphine sulfate +or fentanyl. +Titration of both dopamine and dobutamine infusions +may be required in some patients. +Inva- +sive monitoring generally is necessary in these unstable patients. +Anticoagulation and aspirin are given for acute MI. +The major determinant of the +degree of hypotension is the pericardial pressure. +Diagnosis and Treatment. +The diagnosis of tension pneu- +mothorax should be made on clinical examination. +Immediate return of air should be encountered with +rapid resolution of hypotension. +Hyperresonance may be diffi- +cult to appreciate in a noisy resuscitation area. +Jugular venous +distention may be absent in a hypovolemic patient. +Tracheal +deviation is a late finding and often is not apparent on clinical +examination. +A high index of suspicion is warranted to +make a rapid diagnosis. +The indi- +cations for this maneuver are discussed in Chap. +7. +Beck’s triad consists of hypotension, muffled heart +tones, and neck vein distention. +Echocardiogra- +phy has become the preferred test for the diagnosis of cardiac +tamponade. +Pericardiocentesis to diagnose pericardial blood and potentially +relieve tamponade may be used. +The procedure is best performed in the operating room +under general anesthesia. +It can be performed through either the +subxiphoid or transdiaphragmatic approach. +Diagnosis. +Treatment. +With prolonged anaerobic metabolism, tissue +acidosis and O2 debt accumulate. +Clinical confirmation of this endpoint remains +a challenge. +In addi- +tion, mortality was fourfold higher in patients who developed +infections. +Direct measure- +ment of the O2 debt in the resuscitation of patients is difficult. +Lactate. +Base Deficit. +Gastric Tonometry. +Lactate and base deficit indicate global +tissue acidosis. +With heterogeneity of blood flow, regional tissue +beds may be hypoperfused. +Gastric tonometry has been used +to assess perfusion of the GI tract. +The NIR probe +emits multiple wavelengths of light in the NIR spectrum (650 +to 1100 nm). +Photons are then either absorbed by the tissue or +reflected back to the probe. +13%).111,112 +Tissue PH, Oxygen, and Carbon Dioxide Concentra- +tion. +Right Ventricular End-Diastolic Volume Index. +RVEDVI is a param- +eter that seems to correlate with preload-related increases in +cardiac output. +1. +Gross S. +A System of Surgery: Pathologic, Diagnostic, Thera- +peutic and Operative. +Philadelphia: Lea and Febiger; 1872. +2. +Bernard C. +Lecons sur les Phenomenes de la Via Communs +aux Animaux et aux Vegetaux. +Paris: JB Ballieve; 1879. +3. +Cannon W. +Traumatic Shock. 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1016-1007. +105. +Zipnick RI, Scalea TM, Trooskin SZ, et al. +Hemodynamic +responses to penetrating spinal cord injuries. +J Trauma. +1993; +35(4):578-582; discussion 582-583. +106. +Abou-Khalil B, Scalea TM, Trooskin SZ, Henry SM, Hitch- +cock R. +Hemodynamic responses to shock in young trauma +patients: need for invasive monitoring. +Crit Care Med. +1994; +22(4):633-639. +107. +Claridge JA, Crabtree TD, Pelletier SJ, Butler K, Sawyer RG, +Young JS. +J Trauma. +2000;48(1):8-14; discussion 14-15. +108. +Ivatury RR, Simon RJ, Havriliak D, Garcia C, Greenbarg +J, Stahl WM. +J Trauma. +1995;39(1):128-134; discussion 134-126. +109. +Maynard N, Beale R, Smithies M, Bihari D. +Gastric intramu- +cosal pH in critically ill patients. +Lancet. +1992;339(8792): +550-551. +110. +Gomersall CD, Joynt GM, Freebairn RC, Hung V, Buckley +TA, Oh TE. +Crit Care Med. +2000;28(3):607-614. +111. +Cairns CB, Moore FA, Haenel JB, et al. +J Trauma. +1997;42(3):532-536. +112. +Cohn SM, Crookes BA, Proctor KG. +Near-infrared spectros- +copy in resuscitation. +J Trauma. +2003;54(5 Suppl):S199-202. +113. +Knudson MM, Bermudez KM, Doyle CA, Mackersie RC, +Hopf HW, Morabito D. +Use of tissue oxygen tension measure- +ments during resuscitation from hemorrhagic shock. +J Trauma. +1997;42(4):608-614; discussion 614-606. +114. +McKinley BA, Marvin RG, Cocanour CS, Moore FA. +J Trauma. +2000;48(4):637-642. +115. +Cheatham ML, Nelson LD, Chang MC, Safcsak K. +Crit +Care Med. +1998;26(11):1801-1806. +116. +Chang MC, Meredith JW, Kincaid EH, Miller PR. +J Trauma. +2000;49(1):26-33; discussion 34-37. +Surgical Infections +Greg J. +Beilman and David L. +In 1846, Ignaz Semmelweis, a Magyar physician, +took a post at the Allgemein Krankenhaus in Vienna. +In 1861, he published his classic +work on childbed fever based on records from his practice. +He died +shortly thereafter. +His achievements were only recognized after +Pasteur’s description of the germ theory of disease. +In spite of initial resis- +tance, his methods were quickly adopted throughout Europe. +He used +these same techniques to identify the organisms responsible for +cholera and tuberculosis. +2 Source control is a key concept in the treatment of most surgi- +cally relevant infections. +Delays in adequate source control are associated with wors- +ened outcomes. +Barrier function, however, is not solely limited +to physical characteristics. +Host barrier cells may secrete sub- +stances that limit microbial proliferation or prevent invasion. +In the upper +respiratory tract, respiratory mucus traps larger particles, includ- +ing microbes. +This results in recruitment +and proliferation of inflammatory cells. +Macrophage cytokine +synthesis is upregulated. +A chronic abscess also may +intermittently drain and/or be associated with bacteremia. +Infection is defined by the presence of microorganisms +in host tissue or the bloodstream. +6-1). +1 +139 +S +URGICAL + I +N +fe +CTIONS +CHAPT +e +R 6 +figure 6-1. +Relationship between infection and +systemic inflammatory response syndrome (SIRS). +Other conditions +may cause SIRS as well (trauma, aspiration, etc.). +Severe sepsis (and septic shock) are both subsets +of sepsis. +above normal value +Plasma procalcitonin >2 s.d. += standard deviations; Svo2 = venous oxygen +saturation; WBC = white blood cell count. +Bacteria +Bacteria are responsible for the majority of surgical infections. +Specific species are identified using Gram’s stain and growth +characteristics on specific media. +tetani, C. +septicum +Peptostreptococcus spp. +Gram-negative +Bacteroides fragilis +Fusobacterium spp. +niger, A. +terreus, A. +flavus +Blastomyces dermatitidis +Candida albicans +Candida glabrata, C. +paropsilosis, C. +Other acid-fast bacilli +include Nocardia spp. +37°C). +Agents currently available for antifungal therapy are +described in Table 6-3. +Prophylactic and therapeutic use of antiviral +agents is discussed in Chap. +11. +Guidelines for prophylaxis are provided in Table 6-5. +Initial drug +selection must be based on initial evidence (Gram-positive vs. +This is safe, and may facilitate earlier discharge. +PYOGeNeS mSSA mrSA S. +ePIDermIDIS eNTerOCOCCUS Vre e. +COlI P. +PYOGeNeS mSSA mrSA S. +ePIDermIDIS eNTerOCOCCUS Vre e. +COlI P. +1 = Reliable activity; +/– = variable activity; 0 = no activity. +The sensitivities presented are generalizations. +Allergy to antimicrobial agents must be considered prior +to prescribing them. +Penicillin allergy is quite common, the reported inci- +dence ranging from 0.7% to 10%. +Each of these factors has been directly correlated +with overall drug administration. +Prolonged +treatment associated with drains and tubes has not been shown +to be beneficial. +Table 6-6 lists risk factors for development of +SSIs. +Class I D wounds are similar except that a prosthetic device +(e.g., mesh or valve) is inserted. +Several of these +organizations are noted in Table 6-8. +However, the effect of +this approach on the incidence of SSIs is not known at this time. +figure 6-2. +6-2). +The treatment of organ/space infections is +discussed in the following section. +These infections invariably are monomi- +crobial and rarely require surgical intervention. +In +patients without this risk factor organisms can include E. +coli, +K. +pneumoniae, pneumococci, and others, although many +different pathogens can be causative. +Candida albicans and other related yeast cause the majority +of fungal hepatic abscesses. +Splenic +abscesses are extremely rare and are treated in a similar fashion. +6-3). +Mortal- +ity in 65 patients in 9 case series reported was 6% overall. +Debridement of necrosis through a lumbar approach has +been advocated by a number of authors. +Patients receive +transgastric or preferably retroperitoneal drainage of the seques- +trum. +6-4). +69%), with comparable mortality rate, +hospital, and ICU lengths of stay. +Furuncles +or boils may drain spontaneously or require surgical incision and +drainage. +Infected pancreatic necrosis. +(A) Open necrosectomy +specimen with pancreatic stent in situ. +(C) Retroperitoneal cavity seen through endoscope during VARD. +exogenous microbes, the result can be devastating. +Not surprisingly, patients often develop sepsis syndrome +or septic shock without an obvious cause. +The extremities, +perineum, trunk, and torso are most commonly affected, in that +order. +6-5). +During the procedure a Gram’s stain should be performed +on tissue fluid. +If so, additional resection of infected tis- +sue and debridement should take place. +The patient succumbed to his disease after 16 hours despite aggressive debridement. +Cellulitis on right anterior thigh is +outlined. +(C) Classic dishwater edema of tissues with necrotic fascia. +(D) Right lower extremity after debridement of fascia to viable muscle. +or >105 CFU/mL in asymptomatic individuals. +Coli, K. +pneumonia) that achieves +high levels in the urine is appropriate. +Prolonged mechanical ventilation is associated with nos- +ocomial pneumonia. +This rate is expected to increase as the +population of aged in the United States increases. +As discussed earlier, one exception is that of +infected pancreatic necrosis. +The current +first-line agent for treatment of hypotension is norepinephrine. +However, a recent randomized trial +failed to show survival benefit. +Resistant Organisms: In the 1940s, penicillin was first pro- +duced for widespread clinical use. +There are two major components that are responsible +for antibiotic resistance. +Target resuscitation to normalize lactate in patients with elevated lactate levels. +Diagnosis: Obtain appropriate cultures prior to antibiotics but do not delay antibiotic therapy. +Use rapid antigen assays in patients +with suspected fungal infection. +Imaging studies should be performed promptly to confirm a source of infection. +Discontinue antibiotics in 7–10 d for most infections, stop antibiotics for noninfectious issues. +Remove intravascular access devices if potentially infected. +Infection prevention: Selective oral and digestive tract decontamination. +Phenylephrine is +not recommended in treatment of septic shock. +Dobutamine infusion can be used in setting of myocardial dysfunction. +Do not use +strategy of targeting supranormal cardiac index. +Use positive end-expiratory pressure to avoid lung collapse. +Use a weaning protocol to evaluate the +potential for discontinuing mechanical ventilation. +Pulmonary artery catheter is not indicated for routine monitoring. +Sedation: Minimize sedation using specific titration endpoints. +Adapted from Dellinger et. +al13 +the antibiotic will not be effective against this organism. +The second com- +ponent driving resistance is that related to antibiotic selection. +This has led to antibiotic resistance described +in all classes of antibiotics in common use today. +Resistance mechanisms are varied, and include one of +three routes. +There are several drug resistant organisms of interest to +the surgeon. +The +appropriate antibiotic choice in this setting is a carbepenem. +Hepatitis B virus (HBV) is a DNA virus that affects only +humans. +This virus is confined to humans and +chimpanzees. +Several potential +agents are discussed in the following sections. +A key aspect +in establishing the diagnosis is eliciting an exposure history. +Rapid antigen tests are currently under development for iden- +tification of this gram-positive rod. +Yersinia pestis (Plague) +Plague is caused by the Gram-negative organism Yersinia pes- +tis. +The naturally occurring disease in humans is transmitted via +flea bites from rodents. +Postexposure prophylaxis for +patients exposed to plague consists of doxycycline. +The fatality rate may reach 30%. +After inoculation, this organism proliferates within +macrophages. +Enlarged +lymph nodes occur in approximately 85% of patients. +RefeReNCeS +Entries highlighted in bright blue are key references. +1. +Nuland SB. +The 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incisions: primary or delayed +primary closure? +A randomized trial. +Surg Infect (Larchmt). +2009:10(2):129-136. +50. +Margenthaler JA, Longo WE, Virgo KS, et al. +Risk factors for +adverse outcomes after the surgical treatment of appendicitis in +adults. +Ann Surg. +2003;238:59-66. +51. +McManus LM, Bloodworth RC, Prihoda TJ, et al. +J Leukoc Biol. +2001;70:395-404. +52. +Richards JE, Kauffmann RM, Obremskey WT, May AK. +J Orthop Trauma. +2013;27(1):16-21. +53. +Ata A, Lee J, Bestle SL, et al. +Postoperative hyperglycemia and +surgical site infection in general surgery patients. +Arch Surg. +2010;145(9):858-864. +54. +Greif R, Akca O, Horn EP, et al. +Supplemental perioperative +oxygen to reduce the incidence of wound infection. +N Engl J +Med. +2000;342:161-167. +55. +Kao LS, Millas SG, Pedroza C, et al. +Should perioperative supple- +mental oxygen be routinely recommended for surgery patients? +A Bayesian meta-analysis. +Ann Surg. +2012;256(6):894-901. +56. +Grubbs BC, Statz CL, Johnson EM, et al. +Salvage therapy of +open, infected surgical wounds: a retrospective review using +Techni-Care. +Surg Infect. +2000;1:109-114. +159 +S +URGICAL + I +N +fe +CTIONS +CHAPT +e +R 6 +57. +Roberts DJ, Zygun DA, Grendar J, et al. +J Trauma Acute Care Surg. +2012;73(3):629-639. +58. +Solomkin JS, Mazuski JE, Baron EJ, et al. +Clin Infect +Dis. +2003;37:997-1005. +59. +Solomkin JS, Dellinger EP, Christou NV, et al. +Ann Surg. +1990;212:581-591. +60. +Solomkin JS, Yellin AE, Rotstein OD, et al. +Protocol 017 Study +Group. +Ann Surg. +2003;237:235-245. +61. +Chromik AM, Meiser A, Hölling J, et al. +J Gastrointest Surg. +2009;13(7): +1358-1367. +62. +Pang TC, Fung T, Samra J, et al. +Pyogenic liver abscess: an +audit of 10 years’ experience. +World J Gastroenterol. +2011; +17(12):1622-1630. +63. +Bradley EL III, Allen K. +Am J Surg. +1991;161:19. +64. +Charbonney E, Nathens AB. +Severe acute pancreatitis: a review. +Surg Infect (Larchmt). +2008;9(6):573-578. +65. +Freeman ML, Werner J, van Santvoort HC, et al. +Interventions +for necrotizing pancreatitis: summary of a multidisciplinary +consensus conference. +Pancreas. +2012;41(8):1176-1194. +66. +Wysocki AP, McKay CJ, Carter CR. +Infected pancreatic necro- +sis: minimizing the cut. +ANZ J Surg. +2010;80(1-2):58-70. +67. +Haghshenasskashani A, Laurence JM, Kwan V, et al. +Endo- +scopic necrosectomy of pancreatic necrosis: a systematic +review. +Surg Endosc. +2011; 25(12):3724-3730. +68. +Bakker OJ, van Santvoort HC, van Brunschot S, et al. +JAMA. +2012;307(10): +1053-1061. +69. +Fink D, Soares R, Matthews JB, Alverdy JC. +History, goals, and +technique of laparoscopic pancreatic necrosectomy. +J Gastroin- +test Surg. +2011;15(7):1092-1097. +70. +van Santvoort HC, Bakker OJ, Bollen TL, et al. +A Conserva- +tive and Minimally Invasive Approach to Necrotizing Pan- +creatitis Improves Outcome. +Gastroenterology. +2011;141(4): +1254-1263. +71. +van Santvoort HC, Besselink MG, Bakker OJ, et al. +A step- +up approach or open necrosectomy for necrotizing pancre- +atitis. +N Engl J Med. +2010;362(16):1491-1502. +72. +Beilman GJ, Sandifer G, Skarda D, et al. +Surg +Infect (Larchmt). +2005;6(1):87-92. +73. +Kao LS, Lew DF, Arab SN, et al. +Am J Surg. +2011; 202(2): +139-145. +74. +George ME, Rueth NM, Skarda DE, et al. +Hyperbaric oxygen +does not improve outcome in patients with necrotizing soft tis- +sue infection. +Surg Infect (Larchmt). +2009;10(1):21-28. +75. +Klompas M. +Does this patient have ventilator-associated pneu- +monia? +JAMA. +2007 11;297(14):1583-1593. +76. +Riaz OJ, Malhotra AK, Aboutanos MB, et al. +Am Surg. +2011;77(3): +297-303. +77. +O’Grady NP, Alexander M, Burns LA, et al. +Guidelines for +the prevention of intravascular catheter-related infections. +Clin +Infect Dis. +2011; 52(9): e162–e193. +78. +Safdar N, Maki DG. +Chest. +2005;128(2);489-495. +79. +Marr KA, Sexton DJ, Conlon PJ, et al. +Ann Intern Med. +1997;127:275. +80. +Broom JK, Krishnasamy R, Hawley CM, et al. +BMC Nephrol. +2012;13:146. +81. +Moore LJ, Moore FA. +Epidemiology of sepsis in surgical +patients. +Surg Clin North Am. +2012;92(6):1425-1443. +82. +Otero RM, Nguyen HB, Huang DT, et al. +Chest. +2006;130(5) +1579-1595. +83. +Miller LG, McKinnell JA, Vollmer ME, Spellberg B. +Infect Control Hosp Epidemiol. +2011;32(4):342-350. +84. +Han JH, Nachamkin I, Zaoutis TE, et al. +Infect Control Hosp Epidemiol. +2012;33(12):1242-1245. +85. +Calfee DP. +Curr Opin Infect Dis. +2012;25(4):385-394. +86. +Centers for Disease Control and Prevention. +Accessed March 3, 2013. +87. +Goldberg D, Johnston J, Cameron S, et al. +Risk of HIV trans- +mission from patients to surgeons in the era of post-exposure +prophylaxis. +J Hosp Infect. +2000;44:99-105. +88. +Recommended Adult Immunization Schedule-United States. +Available at: http://www.cdc.gov/vaccines/schedules/hcp/adult. +html Accessed March 4, 2013. +89. +Centers for Disease Control. +Hepatitis B vaccination–United +States, 1982–2002. +MMWR. +2002;51:549. +90. +Accessed March 3, 2013. +91. +MacCannell T, Laramie AK, Gomaa A, Perz JF. +Clin Liver Dis. +2010;14(1):23-36. +92. +Katz LH, Goldvaser H, Gafter-Gvili A, Tur-Kaspa R. +Cochrane Database Syst Rev. +2012;9:CD008516. +93. +Inglesby TV, O’Toole T, Henderson DA, et al. +Anthrax as a +biological weapon, 2002: updated recommendations for man- +agement. +JAMA. +2002;287:2236-2252. +94. +Inglesby TV, Dennis DT, Henderson DA, et al. +Plague as a bio- +logical weapon; medical and public health management. +Work- +ing group on civilian biodefense. +JAMA 2000;283:2281-2290. +95. +Russell PK, Gronvall GK. +U.S. +medical countermeasure devel- +opment since 2001: a long way yet to go. +Biosecur Bioterror. +2012;10(1):66-76. +96. +DeClercq E. +Cidofovir in the treatment of poxvirus infections. +Homicides, suicides, and other causes are responsible for +another 50,000 deaths each year. +However, death rate under- +estimates the magnitude of the societal toll. +For these reasons, trauma must be considered +a major public health issue. +The ATLS +format and basic tenets are followed throughout this chapter, +with some modifications. +Soft collars do not effectively immo- +bilize the cervical spine. +7 The abdomen is a diagnostic black box. +Altered +mental status is the most common indication for intubation. +Options for endotracheal intubation include nasotracheal, +orotracheal, or operative routes. +Nasotracheal intubation can +be accomplished only in patients who are breathing spontane- +ously. +Orotracheal +intubation is the preferred technique used to establish a defini- +tive airway. +13). +Crico- +thyroidotomy (Fig. +The +cricothyroid membrane is verified by digital palpation and +opened in a horizontal direction. +Cricothyroidotomy is recommended for emergent +surgical establishment of a patent airway. +Hemorrhage from these vessels obscures +vision and prolongs the procedure. +A. +Use of +a tracheostomy hook stabilizes the thyroid cartilage and facilitates +tube insertion. +B. +A 6.0 endotracheal tube is inserted after digital +confirmation of airway access. +of the airway. +7-2). +All +injured patients should receive supplemental oxygen and be +monitored by pulse oximetry. +All of these diag- +noses should be made during the initial physical examination. +7-3). +A +B +164 +BASIC CONSIDERATIONS +PART + +I +accumulate in the pleural space. +7-4). +Flail chest occurs when three or more contiguous ribs are +fractured in at least two locations. +However, the additional work of breathing +Figure 7-3. +A. +B. +Heavy scissors +are used to cut through the intercostal muscle into the pleural space. +C. +D. +A 28F chest tube is directed superiorly and posteriorly with the aid +of a large clamp. +Figure 7-4. +A. +Full-thickness loss of the chest wall results in an +open pneumothorax. +B. +and chest wall pain caused by the flail segment is rarely suf- +ficient to compromise ventilation. +Pulmonary contusion often progresses during the first +12 hours. +Resultant hypoventilation and hypoxemia may require +intubation and mechanical ventilation. +7-5); close monitoring and frequent +clinical re-evaluation are warranted. +Massive air leak occurs from major tracheobronchial +injuries. +Bronchoscopy confirms diagnosis +and directs management. +An initial approximation of the patient’s cardiovascular +165 +T +RAUMA +CHAPTER 7 +Figure 7-5. +A. +Admission chest film may not show the full extent +of the patient’s pulmonary parenchymal injury. +B. +Figure 7-6. +A. +The proximal tibia is the preferred location. +Alterna- +tively, the distal femur can be used if the tibia is fractured. +B. +The +needle should be directed away from the epiphyseal plate to avoid +injury. +Figure 7-7. +Saphenous vein cutdowns are excellent sites for fluid +resuscitation access. +A. +The vein is consistently found 1 cm ante- +rior and 1 cm superior to the medial malleolus. +B. +Proximal and +distal traction sutures are placed with the distal suture ligated. +C. +A 14-gauge IV catheter is introduced and secured with sutures and +tape to prevent dislodgment. +status can be obtained by palpating peripheral pulses. +Saphenous +vein cutdowns at the ankle provide excellent access (Fig. +7-7). +The saphenous vein is reliably found 1 cm anterior and 1 cm +superior to the medial malleolus. +Figure 7-8. +More than 1500 mL of blood in the pleural space is considered a massive hemothorax. +Chest film findings reflect the positioning +of the patient. +A. +B. +In the upright position, blood is visible dependently in the right pleural space. +7-8). +After pen- +etrating trauma, a great vessel or pulmonary hilar vessel injury +should be presumed. +This ultimately leads to decreased right ventricular out- +put. +Diagnosis of hemopericardium is best achieved by bedside +ultrasound of the pericardium (Fig. +7-9). +7-10). +Subxiphoid pericardial ultrasound reveals a large peri- +cardial fluid collection. +Figure 7-10. +Pericardiocentesis is indicated for patients with evidence of pericardial tamponade. +A. +B. +Seldinger technique +is used to place a pigtail catheter. +Blood can be repeatedly aspirated with a syringe or the tubing may be attached to a gravity drain. +The utility of RT has been debated for decades. +For all +penetrating wounds, survival rate is 15%. +7-11). +7-12). +7-13). +Scores range +from 3 (the lowest) to 15 (normal). +Scores of 13 to 15 indicate +mild head injury, 9 to 12 moderate injury, and ≤8 severe injury. +No +Tamponade? +ECG = electrocardiogram; OR = operating room; SBP = systolic blood pressure. +Neurologic evaluation is critical before administration of +neuromuscular blockade for intubation. +Deterioration in mental status may be subtle and may +not progress in a predictable fashion. +The goal of fluid +resuscitation is to re-establish tissue perfusion. +The details of a MTP are discussed later. +A. +B and C. +D. +Figure 7-13. +Urine output is a quantitative, reliable indicator of organ per- +fusion. +There are several caveats to be considered when evaluating +the injured patient for shock. +Scores range from 3 (the lowest) to 15 (normal). +This group of patients can be challenging to triage for definitive +management. +Evaluation of the CVP may further assist in distinguish- +ing between these two categories. +A patient with distended neck +veins and a CVP of >15 cm H2O is likely to be in cardiogenic +shock. +Air embolism is a frequently overlooked lethal complica- +tion of pulmonary injury. +7-14). +Persistent hypotension due to uncontrolled hemorrhage is +associated with high mortality. +Type-specific RBCs should be +administered as soon as available. +A. +B. +patient transported to the OR immediately. +7-15). +Fracture-related blood loss, when additive, may +Figure 7-15. +This dilemma is becoming less common in +many trauma centers where CT scanning is done in the ED. +Gross hematuria demands evaluation of the genitourinary sys- +tem for injury. +For patients with +severe blunt trauma, chest and pelvic radiographs should be +obtained. +Limited one-shot extremity radio- +graphs also may be taken. +For +less severely injured patients only a complete blood count and +urinalysis may be required. +Repeat FAST is performed if there are any signs of +abdominal injury or unexplained blood loss. +Many trauma patients cannot provide specific information +about the mechanism of their injury. +For patients with stab wounds, the length and type +of object is helpful. +Finally, some patients experience a com- +bination of blunt and penetrating trauma. +High-velocity gun- +shot wounds (bullet speed >2000 ft/s) are infrequent in the +civilian setting. +Shotgun injuries are divided into close-range +(<20 feet) and long-range wounds. +Hemodynamic, respiratory, and men- +tal status will determine the most appropriate course of action. +With these issues in mind, additional diagnostic tests are dis- +cussed on an anatomic basis. +A lateral canthotomy may be needed to relieve +periorbital pressure. +Anterior facial structures should be examined to rule out +fractures. +Nasal packing or balloon tamponade may +be necessary to control bleeding. +7-16). +Hemorrhage into the subarachnoid space may cause vasospasm +and further reduce cerebral blood flow. +Intraparenchymal hema- +tomas and contusions can occur anywhere within the brain. +7-17). +During cervi- +cal examination one must maintain cervical spine precautions +Figure 7-16. +Figure 7-17. +A. +A right middle +cerebral infarct noted on a computed +tomographic scan of the head. +B. +An inter- +nal carotid artery pseudoaneurysm +documented by angiography. +BA +and in-line stabilization. +Spinal cord injuries can vary in severity. +Complete injuries +cause either quadriplegia or paraplegia, depending on the level +of injury. +Significant +neurologic recovery is rare. +Central cord syndrome typically occurs in older persons +who experience hyperextension injuries. +Some functional recov- +ery usually occurs, but is often not a return to normal. +Prognosis for recovery is poor. +A more sub- +tle injury that may not be identified is a fracture of the larynx +due to blunt trauma. +Signs and symptoms include hoarseness, +subcutaneous emphysema (Fig. +7-18), and a palpable fracture. +The management +Figure 7-18. +Figure 7-19. +Algorithm for the management of penetrating neck injuries. +CT = computed tomography; CTA = computed tomographic +angiography; GSW = gunshot wound. +7-20). +Figure 7-21. +I +II +III +Figure 7-20. +For the purpose of evaluating penetrating injuries, +the neck is divided into three zones. +Zone I is to the level of the +clavicular heads and is also known as the thoracic outlet. +Zone II is +located between the clavicles and the angle of the mandible. +Zone +III is above the angle of the mandible. +7-21). +7-22). +Other chest radiographic findings suggestive of an +aortic tear are summarized in Table 7-5 (Fig. +7-23). +7-24). +Injuries of the +esophagus and trachea are exceptions. +Widened mediastinum +2. +Abnormal aortic contour +3. +Tracheal shift +4. +Nasogastric tube shift +5. +Left apical cap +6. +Left or right paraspinal stripe thickening +7. +Depression of the left main bronchus +8. +Obliteration of the aorticopulmonary window +9. +Left pulmonary hilar hematoma +Figure 7-22. +Figure 7-23. +179 +T +RAUMA +CHAPTER 7 +and directs angiography or endoscopy as appropriate. +Abdomen The abdomen is a diagnostic black box. +Fortunately, +with few exceptions, it is not necessary to determine in the +Figure 7-24. +The diagnostic approach differs for penetrating trauma +and blunt abdominal trauma. +As a rule, minimal evaluation is +7 +180 +BASIC CONSIDERATIONS +PART + +I +Figure 7-25. +Algorithm for the evaluation of penetrating abdominal injuries. +7-25). +Laparoscopy is another option to assess peritoneal +penetration for tangential wounds. +If there is doubt, however, +it is always safer to explore the abdomen. +** A positive local wound exploration is defined as violation of the posterior fascia. +CT +Scan +Left-sided thoracoabdominal DPL vs. +Penetrating thoracoabdominal wounds may cause occult +injury to the diaphragm. +7-26). +7-27) in Morrison’s pouch, +the left upper quadrant, and the pelvis. +7-28). +Algorithm for the initial evaluation of a patient with suspected blunt abdominal trauma. +stable patients for whom the physical examination is unreliable. +If DPL is +pursued, an infraumbilical approach is used (Fig. +7-29). +The aspirate is considered to show positive find- +ings if >10 mL of blood is aspirated. +If <10 mL is withdrawn, a +liter of normal saline is instilled. +Values representing positive find- +ings are summarized in Table 7-6. +Pelvis Blunt injury to the pelvis may produce complex frac- +tures with major hemorrhage (Fig. +7-30). +Sharp spicules of bone can lac- +erate the bladder, rectum, or vagina. +CT cystography is performed if the urinalysis findings are +positive for RBCs. +Bony fractures or +knee dislocations should be realigned before definitive vascular +examination. +7-31). +It is known that some of these patients +will have arterial injuries that require repair. +The most common +Figure 7-27. +Focused abdominal sonography for trauma imaging detects intra-abdominal hemorrhage. +If the difference is >10%, +CT angiography or arteriography is indicated. +If hemorrhage occurs from +these injuries, compartment syndrome and limb loss may occur. +partial nephrectomy. +Specific transfusion triggers +Figure 7-29. +A. +The linea alba is sharply incised, and the catheter is directed into the pelvis. +B. +The abdominal contents should initially be aspirated +using a 10-mL syringe. +for individual blood components exist. +However, these guidelines have +been replaced by TEG and ROTEM criteria in many trauma +centers. +7-32). +Massive transfusion +185 +T +RAUMA +CHAPTER 7 +Figure 7-30. +This concept has been termed . +Extended postoperative antibiotic therapy is adminis- +tered only for contaminated open fractures. +Tetanus prophylaxis +is administered to all patients according to published guidelines. +Trauma patients are at risk for venous thromboembolism +and its associated morbidity and mortality. +Morbidly obese patients and those over 55 years of age are at +additional risk. +A final prophylactic measure that is usually not consid- +ered is thermal protection. +Each shipment’s quantity +can be doubled at the request of Surgery or Anesthesia. +Shipments > 4 are determined by patient’s clinical course +and lab values. +Shipment PRBCs FFP Platelets Cryo +14 +2 +3 4 +44 +4 2 +2 +2 +2 +1 +1 +10 +10 +Figure 7-32. +Denver Health Medical Center’s Massive Transfusion Protocol. +187 +T +RAUMA +CHAPTER 7 +problem. +Hypothermia aggravates coagulopathy and provokes myocar- +dial irritability. +7-33). +Figure 7-33. +A. +B. +C. +Further exposure is facilitated by resection of the posterior belly of the +digastric muscle. +7-33). +The glossopharyngeal and vagus +nerves are also mobilized and retracted as necessary. +If acces- +sible, the styloid process and attached muscles are removed. +At +this point anterior displacement of the mandible (subluxation) +may be helpful. +In desperate situations, the vertical ramus of the +mandible may be divided. +The location of the incision is in the +fifth interspace, in the inframammary line (Fig. +7-34). +7-35). +If the sternum is divided, the +internal mammary arteries should be ligated to prevent blood +loss. +Emergent median sternotomy is +limited to anterior stab wounds to the heart. +Patients in extremis, however, should undergo +anterolateral thoracotomy. +1 +2 +3 +B +Figure 7-34. +Figure 7-35. +A. +A “clamshell” thoracotomy provides exposure to +bilateral thoracic cavities. +B. +For children under the age of 6, a transverse +incision may be advantageous. +7-36). +7-37). +Similarly, clamping +the splenic hilum may more effectively control bleeding than +packing alone. +7-38). +The first decision is whether the patient +has a supracolic or an infracolic vascular injury. +7-39). +The left +Figure 7-36. +A sagittal view of packs placed to control hepatic +hemorrhage. +Lap = laparotomy. +Figure 7-37. +Figure 7-38. +With complete mobilization, the spleen can reach the +level of the abdominal incision. +The operative approach for +SMA injuries is based on the level of injury. +More distal SMA injuries, Fullen zones III and IV, +are approached directly within the mesentery. +Inferior vena cava injuries are approached by +a right medial visceral rotation (Fig. +7-40). +A Satinsky +clamp can be used to control anterior caval wounds. +Tamponade with a folded laparotomy pad +Figure 7-39. +A left medial visceral rotation is used to expose the +abdominal aorta. +Figure 7-40. +A right medial visceral rotation is used to expose the +infrahepatic vena cava. +Figure 7-41. +Pelvic vascular isolation. +A. +B. +Alter- +natively, complete pelvic vascular isolation (Fig. +7-42). +Associated hematomas +should be unroofed to rule out adjacent bowel injury. +Duodenal injuries should be evaluated with a wide Kocher +maneuver. +The skin is closed selectively based on +the amount of intra-abdominal contamination. +Ragged +edges of the injury site should be débrided using sharp dissec- +tion. +Figure 7-42. +Options for the treatment of vascular injuries are listed +in Table 7-9. +In the lower extremities, +at least one artery with distal runoff should be salvaged. +Follow-up imag- +ing is performed 1 to 2 weeks after injury to confirm healing. +The SMV should be repaired optimally, but +>80% of patients will survive following ligation. +The type of operative repair for a vascular injury is based +on the extent and location of injury. +Lateral suture repair is pre- +ferred for arterial injuries with minimal loss of tissue. +7-43). +7-44). +Larger arteries (e.g., subclavian, innomi- +nate, aorta, common iliac) are bridged by PTFE grafts. +Figure 7-44. +Traction +must be maintained on both ends of the suture to prevent loosening +and leakage of blood. +Six stitches should be placed before the graft +is pulled down to the artery. +Figure 7-43. +Small arteries repaired with an end-to-end anastomo- +sis are prone to stricture. +A curved +hemostat is a useful adjunct to create the curve. +7-45). +Injuries of the common and external +iliac arteries can be handled in a similar fashion (Fig. +7-46), +while maintaining flow in at least one internal iliac artery. +Venous injuries are inherently more difficult to reconstruct +due to their propensity to thrombose. +Small injuries without loss +of tissue can be treated with lateral suture repair. +In the remainder of venous +injuries the vein may be ligated. +Controlling surgical bleeding while +preventing ischemia is of utmost importance during DCS. +Aor- +tic injuries must be repaired using an interposition PTFE graft. +Venous injuries are Figure 7-45. +Figure 7-46. +A. +Right common iliac artery transposed to left common iliac artery. +B. +Left +internal iliac artery transposed to the distal right common iliac artery. +C. +Right internal iliac artery transposed to the right external iliac artery. +The bloody vicious cycle. +FFP = fresh-frozen plasma; RBC = red blood cell. +tamponade bleeding (see Fig. +7-36). +7-48). +For thoracic injuries requiring DCS several options exist. +For +Figure 7-48. +A. +B. +Once placed inside the injury tract, the balloon is inflated +with saline until hemorrhage stops. +C. +In penetrating injuries, pulmonary trac- +totomy is used to divide the parenchyma (Fig. +Pledgeted repair should be +performed for the relatively thin right ventricle. +The second key component of DCS is limiting enteric +content spillage. +Alternatively, open ends of +the bowel may be ligated using umbilical tapes to limit spill- +age. +Urologic injuries +may require catheter diversion. +Before the patient is returned +to the SICU, the abdomen must be temporarily closed. +7-50). +Figure 7-49. +The opened track permits direct +access to injured vessels or bronchi for individual ligation. +The burr +hole is made on the side of the dilated pupil to decompress the +intracranial space. +Resuscitation efforts aim for a euvolemic state and an SBP of +>100 mm Hg. +A burr hole is made for decompression of an epidural +hematoma as a life-saving maneuver. +No attempt should be made to control intracranial hemor- +rhage through the burr hole. +Figure 7-52. +(Image used with permission from Vincent D. +Eusterman, +MD, DDS.) +posterior nasal bleeding, and oropharyngeal packing. +Prompt +angioembolization will halt exsanguinating hemorrhage. +7-52). +Urgent decompression in acute cervical spinal cord +injury is safe. +Prompt revascularization of the internal carotid artery, using a +Figure 7-53. +The Denver grading scale for blunt cerebrovascular injuries. +Grade III: pseudoaneurysm. +Grade IV: vessel occlusion. +Grade V: vessel transection. +CAI = carotid +artery injury; VAI = vertebral artery injury. +temporary Pruitt-Inahara shunt, should be considered in patients +arriving in profound shock. +Currently, we +administer heparin with an ACT target of 250 sec. +Screening and treatment algorithm for blunt cerebrovascular injuries (BCVIs). +(aspirin 325 mg/d or clopidogrel 75 mg/d). +Aerodigestive Subclinical fractures of the larynx and trachea +may manifest as cervical emphysema. +Fractures documented by +CT scan are usually repaired. +More than +85% of patients can be definitively treated with a chest tube. +One caveat concerns +the patient who presents after a delay. +7-55). +Descending thoracic aortic injuries may require urgent +if not emergent intervention. +A. +Angiography reveals a 1-cm pseudoaneurysm of the innominate artery origin. +B. +C. +The origin of the innominate is then oversewn at its base to exclude the pseudoaneurysm. +While +endograft sizing has improved, the major question is long-term +outcome in younger patients. +7-56). +However, primary arterial repair should be done when possible. +LA +Figure 7-56. +Figure 7-57. +A variety of techniques +may be necessary to repair cardiac +wounds. +Generally, pledget support +is used for the relatively thin-walled +right ventricle. +Principles of repair are similar to those +for repair of cervical tracheal injuries. +The most common complication after thoracic injury is +development of an empyema. +While fibrinolytics +are often used for empyema there is a paucity of data to support +their use. +Operative options are +based on the extent and location of esophageal injury. +Early institution of effective pain control +is essential. +The current role of opera- +tive rib fixation remains controversial. +7-58). +1 polypropylene +suture. +The only absolute contraindication to nonopera- +tive management is hemodynamic instability. +With extensive injuries and +major hemorrhage a Pringle maneuver should be done immedi- +ately. +Intermittent release of the Pringle is helpful to attenuate +hepatic cellular loss. +Hemorrhage from most major hepatic injuries can be controlled +with effective perihepatic packing. +7-36). +A Pringle maneuver can help delineate the source of hemor- +rhage. +Injuries of the portal triad vasculature should be addressed +immediately. +In general, ligation from the celiac axis to the +Figure 7-58. +If the right hepatic artery is +ligated, cholecystectomy also should be performed. +Place- +ment of a hepatic vein stent by interventional radiology may +be considered. +Minor lac- +erations may be controlled with manual compression applied +directly to the injury site. +Caution must be used to prevent hepatic +necrosis. +Omen- +tum can be used to fill large defects in the liver. +Additionally, the omentum can provide buttressing support for +parenchymal sutures. +Injuries +of the extrahepatic bile ducts are a challenge due to their small +size and thin walls. +These factors may preclude primary repair. +Venovenous bypass permits hepatic vascular isola- +tion with continued venous return to the heart. +IMV = inferior mes- +enteric vein; IVC = inferior vena cava; SMV = superior mesenteric +vein. +Alternatively, the duct can be ligated +if the opposite lobe is normal and uninjured. +Earlier exploration may be indi- +cated in patients with evidence of ongoing hemorrhage. +Alternatively, angioembolization is appropri- +ate for complex injuries. +Although febrile patients should be +Figure 7-60. +7-60). +Bilomas are loculated collections of bile, which may or may not +be infected. +If infected, they should be treated like an abscess +via percutaneous drainage. +Primary +repair of the injured intrahepatic duct is unlikely to be success- +ful. +Pseudoaneurysms and biliary fistulas are rare complica- +tions in patients with hepatic injuries. +Spleen Until the 1970s, splenectomy was considered manda- +tory for all splenic injuries. +The authors use autotrans- +plantation of splenic implants (Fig. +Drains are not used. +Hemorrhage from the raw splenic +Figure 7-61. +Figure 7-62. +Interrupted pledgeted sutures may effectively control +hemorrhage from the cut edge of the spleen. +7-62). +Gastric wounds can be oversewn +with a running single-layer suture line or closed with a stapler. +The most commonly missed gastric injury is the poste- +rior wound of a totally penetrating injury. +Alternatively, air can be introduced via the NG +tube with the abdomen filled with saline. +26). +Following repair of GI tract injuries, there is an obligatory +postoperative ileus. +Return of bowel function is indicated by a +decrease in gastrostomy or nasogastric tube output. +The topic of +nutrition is well covered in other chapters, but a few issues war- +rant mention. +The wound should be closed in a direc- +tion that results in the largest residual lumen. +Challenges arise +when there is a substantial loss of duodenal tissue. +7-63). +Otherwise, +208 +BASIC CONSIDERATIONS +PART + +I +Figure 7-64. +Figure 7-63. +cholangiography, optimally via the cystic duct, is diagnostic. +7-64). +In these cases of extensive injuries, damage +control principles are often employed. +Several options exist for treating injuries of the +pancreatic body and tail. +In stable patients, spleen-preserving +distal pancreatectomy should be performed. +An alternative, +209 +T +RAUMA +CHAPTER 7 +Figure 7-65. +A. +B and C. +The authors frequently use needle-catheter jejunostomy tube feedings for these patients. +Application of fibrin glue over the stump may be advantageous. +A gastrojejunos- +tomy restores GI tract continuity. +Vagotomy is not necessary +because a risk of marginal ulceration has not been documented. +Perhaps surprisingly, the sutures maintain diversion for only 3 +to 4 weeks. +Complications should be expected after major pancreati- +coduodenal injuries. +33). +33). +Intra-abdominal abscesses are common and routinely managed +with percutaneous drainage. +All sutur- +ing and anastomoses are performed using a running single-layer +technique (Fig. +Diverting ileostomy with colocolostomy, however, +is used for most other high-risk patients. +Therefore, indirect +treatment with intestinal diversion usually is required. +The cur- +rent options are loop ileostomy and sigmoid loop colostomy. +7-67). +7-67). +29). +Due to lack +of mobility of the abdominal aorta, few injuries are amenable +to primary repair. +Figure 7-66. +Technique for bowel repair and anas- +tomosis. +A. +The running, single-layer suture is started +at the mesenteric border. +B. +C. +The continuous suture is tied near the antimesenteric +border. +Patients requiring +Figure 7-67. +Loop colostomy will completely divert +the fecal flow, allowing the low rectal injury to heal. +ligation of an inferior vena cava injury often develop marked +bilateral lower extremity edema. +Consequently, long-term administration of antiplatelet +agents or antithrombotics is not routine. +7-68). +Arterial reconstruction using +graft interposition should be attempted for renal preservation. +Over 90% of blunt renal injuries are treated nonopera- +tively. +Vascular occlusion con- +trols bleeding and permits adequate +visualization. +B. +The renal capsule is +carefully preserved. +C. +The collect- +ing system is closed separately with +absorbable suture. +D. +The preserved +capsule is closed over the collecting +system repair. +irrigation to dispel blood clots is warranted. +The renal arteries +and veins are uniquely susceptible to traction injury caused +by blunt trauma. +The renal vein may be torn or completely +avulsed from the vena cava due to blunt trauma. +Typically, the +large hematoma causes hypotension, which leads to operative +intervention. +Techniques of repair and hemostasis are similar to +those described earlier. +An +injury may not be identified until a complication (i.e., a uri- +noma) becomes apparent. +Laparoscopic repair is becoming common in +patients not requiring laparotomy for other injuries. +Extraperito- +neal ruptures are treated nonoperatively with bladder decompres- +sion for 2 weeks. +Strictures are not uncommon but can be managed electively. +Female Reproductive Tract Gynecologic injuries are rare. +Occasionally the vaginal wall will be lacerated by a bone frag- +ment from a pelvic fracture. +Although repair is not mandated, +it should be performed if physiologically feasible. +7-69). +In high risk patients, (e.g. +7-70). +Pelvic packing also eliminates the often +difficult decision by the trauma surgeon: OR vs. +interventional +radiology? +Currently, angiography is reserved for patients with evidence of +Figure 7-69. +Management algorithm for patients with pelvic fractures with hemodynamic instability. +Another clinical challenge is the open pelvic fracture. +To reduce +the risk of infection, performance of a diverting sigmoid colos- +tomy is recommended. +Vascular injuries, either isolated or in combination with +fractures, require emergent repair. +Controversy exists regarding which +should be done first, fracture fixation or arterial repair. +For subclavian or axillary artery repairs, 6-mm PTFE +Figure 7-70. +A. +B. +C. +215 +T +RAUMA +CHAPTER 7 +graft and RSVG are used. +The injured vessel segment is excised, and +an end-to-end interposition RSVG graft is performed. +Close monitoring for calf compartment syndrome +is mandatory. +7-71). +Rarely, with +open wounds a straight posterior approach with an S-shaped +incision can be used. +For an isolated popliteal +artery injury, RSVG is performed with an end-to-end anastomosis. +Paresthesias may +also be described. +Progression to paralysis can +occur, and loss of pulses is a late sign. +In comatose or obtunded +patients, the diagnosis is more difficult to secure. +7-72). +Step 2: Intra-arterial nitroglycerin 200 μg/20 mL bolus +Repeat same dose once as needed. +If spasm continues, proceed to step 3. +Step 3: Inter-arterial verapamil 10 mg/10 mL bolus +If spasm continues, proceed to step 4. +Step 4: Inter-arterial papaverine drip 60 mg/50 mL given + over 15 min +Figure 7-71. +A. +B. +Alternatively, a medial approach with two incisions may be used. +216 +BASIC CONSIDERATIONS +PART + +I +and priorities. +In fact, optimizing crystalloid administra- +Figure 7-72. +A. +Care must be +taken to avoid the superficial pero- +neal nerve running along the raphe. +B. +The role of rela- +tive adrenal insufficiency is another controversial area. +The goal is to normalize lactate within 24 hours. +The most common intra-abdominal complica- +tions are anastomotic failure and abscess. +The most +common technique is to measure the patient’s bladder pressure. +Increased abdominal pressure affects multiple organ sys- +tems (Fig. +7-73). +Organ failure can occur over a wide range +of recorded bladder pressures. +This method is particularly applicable for +nonoperative management of major liver injuries. +7-50). +Several management points deserve attention. +Patients with an open abdomen lose between +500 and 2500 mL per day of abdominal effluent. +colloid). +The advent of VAC +technology has revolutionized fascial closure. +7-74). +128 The +authors’ success rate with this approach exceeds 95%. +These include intra-abdominal abscess, enteric fistula, +and bowel perforations (Fig. +7-75). +SPECIAL POPULATIONS +Pregnant Patients +During pregnancy, 7% of women are injured. +Pregnancy results in physiologic changes that may impact +postinjury evaluation (Table 7-13). +Consequently +a pregnant woman may lose 35% of her blood volume before +exhibiting signs of shock. +Other physiologic changes during pregnancy affect the GI, +renal, and hematologic systems. +Liver function test values increase, with the alkaline phos- +phatase level nearly doubling. +The authors’ sequential closure technique for the open abdomen. +A. +Interrupted No. +B. +C and +D. +E. +F. +Plasma albumin level decreases from a normal +of around 4.3 g/dL to an average of 3.0 g/dL. +The uterus +may also compress the ureters and bladder, causing hydrone- +phrosis and hydroureter. +Assessment of the fetal heart rate is +the most valuable information regarding fetal viability. +Amniotic sac rupture can result +in prolapse of the umbilical cord with fetal compromise. +Determin- +ing fetal age is key for considerations of viability. +Discrepancy in dates and size may be due to uter- +ine rupture or hemorrhage. +DPL can be performed in pregnant women via +a supraumbilical, open technique. +Trauma radiography of preg- +nant patients presents a conundrum. +If clinically warranted, however, a +radiograph should be obtained. +The vast majority of injuries are treated similarly whether +the patient is pregnant or not. +A particular challenge in the +pregnant trauma patient is a major pelvic fracture. +Fetal +loss may be related to both maternal shock and direct injury +to the uterus or fetal head. +Penetrating injuries in this patient +population also carry a high risk. +On the other hand, stab wounds do not often +penetrate the thick wall of the uterus. +They should be counseled regarding warning signs that +mandate prompt return to the ED. +Early monitoring of arterial blood gas values will identify occult +shock. +First, outcomes +are worse in this age group than in their younger counterparts. +One of the most common sequelae of blunt thoracic +trauma is rib fractures. +In the aging population, perhaps due to +osteoporosis, less force is required to cause a fracture. +Upon the pediatric +patient’s arrival, the basic tenets of the ABCs apply, with some +caveats. +Additionally, the child’s tongue is much larger in +relation to the oropharynx. +Administration +of atropine before rapid-sequence intubation will prevent bra- +dycardia. +In children older than 11 years, standard cricothy- +roidotomy is performed. +Alternatively, tracheostomy may be performed. +As is true in adults, the vast majority of thoracic trauma +is also blunt. +However, because a child’s skeleton is not com- +pletely calcified, it is more pliable. +Significant internal organ +damage may occur without overlying bony fractures. +The evaluation for abdominal trauma in the pediatric +patient is similar to that in the adult. +44%).139 +REFERENCES +Entries highlighted in bright blue are key references. +1. +Minino AM, Heron MP, Murphy SL, et al. +Deaths: final data +for 2004. +Natl Vital Stat Rep. +55, August 21, 2007; 55(19): +1-120. +Available at http://www.cdc.gov/nchs/data/nvsr/ +nvsr55/nvsr55_19.pdf [accessed October 29, 2012]. +2. +National Center for Injury Prevention and Control: CDC +Injury Fact Book. +Atlanta: Centers for Disease Control and +Prevention, November 2006. +Available at http://www.cdc. +gov/ncipc/fact_book/InjuryBook2006.pdf [accessed October +29, 2012]. +3. +Esposito TJ and Brasel KJ. +Epidemiology. +Mattox KL, Moore +EE, Feliciano DV (eds): Trauma, 7th ed. +New York: McGraw- +Hill, 2013. +4. +Eastman AB. +Wherever the dart lands: toward the ideal trauma +system. +J Am Coll Surg. +2010;211(2):153-168. +5. +MacKenzie EJ, Rivara FP, 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+J Trauma +2009;66(4):1040-1044. +21. +Kliegel A, Losert H, Sterz F, et al. +Serial lactate determina- +tions for prediction of outcome after cardiac arrest. +Medicine +(Baltimore) 2004;83(5):274-279. +22. +Cohn SM, Nathens AB, Moore FA, et al. +J Trauma. +2007;62:44-54. +23. +Clancy K, Velopulos C, Bilaniuk JW, et al. +J Trauma Acute Care +Surg. +2012;73:S301-S306. +24. +Velmahos GC, Karaiskakis M, Salim A, et al. +J Trauma. +2003;54(1):45-50. +25. +Ferrada P, Murthi S, Anand RJ, Bochicchio GV, Scalea T. +J Trauma. +2011;70:56-62. +26. +Arntfield RT, Millington SJ. +Curr Cardiol Rev. +2012;8(2):98-108. +27. +Dolich MO, McKenney MG, Varela JE, et al. +2,576 ultra- +sounds for blunt abdominal trauma. +J Trauma. +2001; 50: +108-112. +28. +Sondeen JL, Coppes VG, Holcomb JB. +Blood pressure at +which rebleeding occurs after resuscitation in swine with aor- +tic injury. +J Trauma. +2003; 54(Suppl):S110-S117. +29. +J Neurotrauma 24(Suppl):S1, 2007. +30. +Ryb GE, Dischinger PC, Kufera JA, et al. +J Trauma. +2007;63:1000-1005. +31. +Ivascu FA, Howells GA, Junn FS, Bair HA, Bendick PJ, +Janczyk RJ. +J +Trauma. +2008;65(4):785-788. +32. +Moore MM, Pasquale MD, Badellino M. +J Trauma Acute +Care Surg. +2012;73(1):126-130. +33. +Diaz JJ Jr., Aulino JM, Collier B, et al. +J Trauma. +2005; +59:897-903. +34. +Sekharan J, Dennis JW, Veldenz HC, et al. +J Vasc Surg. +2000;32:483-489. +35. +Inaba K, Branco BC, Menaker J, et al. +J Trauma Acute Care Surg. +2012;72:576-583. +36. +Fabian TC, Richardson JD, Croce MA, et al. +J Trauma Trauma. +1997;42:374-380, + 37. +Dyer DS, Moore EE, Ilke DN, et al. +A prospective study of 1,561 +patients. +J Trauma. +2000;48:673-682. +38. +Siegel JH, Smith JA, Siddiqi SQ. +A Crash Injury Research Engineering +Network (CIREN) study. +J Trauma 2004;57(4):760-777. +39. +Flowers JL, Graham SM, Ugarte MA, et al. +Flexible endos- +copy for the diagnosis of esophageal trauma. +J Trauma. +1996; +40:261-265. +40. +Cox CS Jr., Allen GS, Fischer RP, et al. +Blunt vs. +penetrat- +ing subclavian artery injury: Presentation, injury pattern, and +outcome. +J Trauma .1999;46:445-449. +41. +Demetriades D, Hadjizacharia P, Constantinou C, et al. +Selec- +tive nonoperative management of penetrating abdominal solid +organ injuries. +Ann Surg. +2006; 244:620-628. +42. +Biffl WL, Cothren CC, Brasel KJ, et al. +J Trauma. +2008; 64:250. +43. +Biffl WL, Kaups KL, Pham TN, et al. +J Trauma. +2011;71(6):1494-1502. +44. +Ochsner MG, Knudson MM, Pachter HL, et al. +J Trauma. +2000; 49:505-510. +45. +Yu J, Fulcher AS, Turner MA, Cockrell C, Halvorsen RA. +Blunt bowel and mesenteric injury: MDCT diagnosis. +Abdom +Imaging. +2011;36(1):50-61. +46. +LeBedis CA, Anderson SW, Soto JA. +CT imaging of blunt +traumatic bowel and mesenteric injuries. +Radiol Clin North +Am. +2012;50(1):123-136. +47. +Fox N, Rajani RR, Bokhari F, et al. +J Trauma Acute Care Surg. +2012;73:S315-S320. +48. +Burch JM, Franciose RJ, Moore EE, et al. +Single-layer con- +tinuous vs. +two-layer interrupted intestinal anastomosis—a +prospective randomized study. +Ann Surg. +2000; 231:832-837. +49. +Moore EE. +Thomas G. +Am J Surg. +1996;172:405-410. +50. +Gonzalez E, Pieracci FM, Moore EE, Kashuk JL. +Coagulation +abnormalities in the trauma patient: the role of point-of-care +thromboelastography. +Semin Thromb Hemost. +2010;36:723-737. +51. +Cohen MJ, Call M, Nelson M, et al. +Ann Surg. +2012;255(2): +379-385. +52. +Cotton BA, Harvin JA, Kostousouv V, et al. +J Trauma Acute Care Surg. +2012;73(2):365-370. +53. +Hebert PC, Wells G, Blajchman MA, et al. +New Engl J Med. +1999; 340:409-417. +54. +West MA, Shapiro MB, Nathens AB, et al. +IV. +Guidelines for transfusion in the trauma +patient. +J Trauma. +2006; 61:436-439. +55. +Toy P, Popovsky MA, Abraham E, et al. +Transfusion-related +acute lung injury: definition and review. +Crit Care Med. +2005; +33:721-726. +56. +Moore FA, Moore EE, Sauaia A. +Blood transfusion: an inde- +pendent risk factor for postinjury multiple organ failure. +Arch +Surg. +1997;132:620-624. +57. +Kashuk JL, Moore EE, Sauaia A, et al. +J Trauma. +2008;65:261-270. +58. +Davenport R, Curry N, Manson J, et al. +Hemostatic effects of +fresh frozen plasma may be maximal at red cell ratios of 1:2. +J Trauma. +2011;70(1):90-95. +59. +Stanworth SJ, Morris TP, Gaarder C, et al. +Reappraising +the concept of massive transfusion in trauma. +Crit Care. +2010;14(6):R239. +60. +Dzik WH, Blajchman MA, Fergusson D, et al. +Crit Care. +2011;15(6):242. +61. +Menaker J, Stein DM, Scalea TM. +Incidence of early pulmo- +nary embolism after injury. +J Trauma. +2007; 63:620-624. +62. +Prager M, Polterauer P, Böhmig HJ, et al. +Collagen vs. +gelatin-coated Dacron vs. +Surgery. +2001;130(3):408-414. +63. +Mattox KL. +Red River anthology. +J Trauma. +1997;42(3): +353-368. +64. +Richardson JD, Bergamini TM, Spain DA, et al. +Opera- +tive strategies for management of abdominal aortic gunshot +wounds. +Surgery. +1996;120(4):667-671. +65. +Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch +JM, Galloway B. +J Trauma. +1997;42(5):857-861. +66. +Maegele M, Spinella PC, Schöchl H. +The acute coagulopathy +of trauma: mechanisms and tools for risk stratification. +Shock. +2012;38(5):450-458. +67. +Nirula R, Millar D, Greene T, et al. +J +Trauma, in press. +68. +Cooper DJ, Rosenfeld JV, Murray L, et al. +Decompressive craniectomy in diffuse +traumatic brain injury. +N Engl J Med. +2011;364(16):1493-1502. +69. +Rinker C, McMurry F, Groeneweg V, et al. +Emergency cra- +niotomy in a rural level III trauma center. +J Trauma. +1998; +44:984-989. +70. +Hutchison JS, Ward RE, Lacroix J, et al. +Hypothermia therapy after traumatic brain +injury in children. +N Engl J Med. +2008;358(23):2447-2456. +71. +Kramer C, Freeman WD, Hoffman-Snyder C, et al. +Therapeu- +tic hypothermia for severe traumatic brain injury: a critically +appraised topic. +Neurologist. +2012;18(3):173-177. +225 +T +RAUMA +CHAPTER 7 + 72. +Pieracci FM, Moore EE, Beauchamp K, et al. +A cost- +minimization analysis of phenytoin vs. +levetiracetam for early +seizure pharmacoprophylaxis after traumatic brain injury. +J Trauma Acute Care Surg. +2012;72(1):276-281. +73. +Cogbill T, Cothren CC, Ahearn MK, et al. +J Trauma. +2008; 64:250. +74. +Bracken MB, Shepard MJ, Holford TR, et al. +Results of the Third National Acute Spinal Cord Injury Ran- +domized Controlled Trial. +National Acute Spinal Cord Injury +Study. +JAMA. +1997;277:1597-1604. +75. +Stahel PF, Vanderheiden T, Finn MA. +Management strategies +for acute spinal cord injury: current options and future per- +spectives. +Curr Opin Crit Care. +2012;18(6):651-660. +76. +Spine. +2006; 31:S28,-S35. +77. +Biffl WL, Moore EE, Offner PJ, et al. +Blunt carotid arterial +injuries: implications of a new grading scale. +J Trauma. +1999; +47:845-853. +78. +Burlew CC, Biffl WL, Moore EE, Barnett CC, Johnson JL, +Bensard DD. +J Trauma +Acute Care Surg. +2012;72(2):330-335. +79. +Cothren CC, Moore EE, Biffl WL, et al. +Anticoagulation is +the gold standard therapy for blunt carotid injuries to reduce +stroke rate. +Arch Surg. +2004; 139:540-545. +80. +Edwards NM, Fabian TC, Claridge JA, et al. +J Am +Coll Surg. +2007; 204:1007-1013. +81. +Bladergroen M, Brockman R, Luna G, et al. +A twelve- +year study of cervicothoracic vascular injuries. +Am J Surg. +1989;157:483-486. +82. +Johnston RH, Wall MJ, Mattox KL. +Innominate artery trauma: +a thirty-year experience. +J Vasc Surg. +1993; 17:134-139. +83. +Fabian TC, Davis KA, Gavant ML, et al. +Ann Surg. +1998;227:666. +84. +Karmy-Jones R, Nicholls S, Gleason TG. +The endovascular +approach to acute aortic trauma. +Thorac Surg Clin. +2007; +17:109-128. +85. +Demetriades D, Velmahos GC, Scalea TM, et al. +Diagnosis +and treatment of blunt thoracic aortic injuries: changing per- +spectives. +J Trauma. +2008;64(6):1415-1418. +86. +Moore EE, Burch JM, Moore JB. +Ann Surg. +2004; 240:38-43. +87. +Wall MJ, Tsai P, Mattox KL. +Heart and Thoracic Vascular +Injury. +Mattox KL, Moore EE, Feliciano DV (eds): Trauma, +7th ed. +New York: McGraw-Hill, 2013. +88. +Jones EL, Burlew CC, Moore EE. +J Trauma Acute Care Surg. +2012;72(3):796-798. +89. +Cothren CC, Moore EE. +Traumatic ventricular septal defect. +Surgery. +2007;142:776-777. +90. +Wall MJ Jr., Hirshberg A, Mattox KL. +Pulmonary tractotomy +with selective vascular ligation for penetrating injuries to the +lung. +Am J Surg. +1994; 168:665-669. +91. +Cothren C, Moore EE, Biffl WL, et al. +J Trauma +2002;53:483-487. +92. +Cryer HG, Mavroudis C, Yu J, et al. +Shock, transfusion, +and pneumonectomy. +Death is due to right heart failure +and increased pulmonary vascular resistance. +Ann Surg. +1990;212:197-201. +93. +Luo L, Yin L, Liu Z, Xiang Z. +Posttraumatic pulmonary pseu- +docyst: Computed tomography findings and management in +33 patients. +J Trauma and Acute Care Surg. +2012;73(5): +1225-1228. +94. +Moore HB, Moore EE, Burlew CC, et al. +J Trauma Acute Care +Surg. +2012;73: 1372-1379. +95. +de Souza A, Offner PJ, Moore EE, et al. +Optimal management +of complicated empyema. +Am J Surg. +2000; 180:507-511. +96. +Truitt MS, Murry J, Amos J, et al. +Continuous intercos- +tal nerve blockade for rib fractures: ready for primetime? +J +Trauma. +2011;71(6):1548-1552. +97. +Kozar RA, Moore FA, Cothren CC, et al. +Risk factors for +hepatic morbidity following nonoperative management: mul- +ticenter study. +Arch Surg. +2006; 141:451-458. +98. +Malhotra AK, Fabian TC, Croce MA, et al. +Blunt hepatic +injury: a paradigm shift from operative to nonoperative man- +agement in the 1990s. +Ann Surg . +2000;231:804-813. +99. +Peitzman AB, Marsh JW. +Advanced operative techniques +in the management of complex liver injury. +J Trauma Acute +Care Surg. +2012;73(3):765-770. +100. +Biffl WL, Moore EE, Franciose RJ. +J Trauma. +1998; 45:400-403. +101. +Poggetti RS, Moore EE, Moore FA, et al. +Balloon tamponade +for bilobar transfixing hepatic gunshot wounds. +J Trauma. +1992; 33:694-697. +102. +Delis SG, Bakoyiannis A, Selvaggi G, et al. +Liver transplanta- +tion for severe hepatic trauma: experience from a single cen- +ter. +World J Gastroenterol. +2009;15(13):1641-1644. +103. +Lillemoe KD, Melton GB, Cameron JL, et al. +Postoperative +bile duct strictures: management and outcome in the 1990s. +Ann Surg. +2000;232:430-441. +104. +Pickhardt B, Moore EE, Moore FA, et al. +Operative splenic +salvage in adults: a decade perspective. +J Trauma. +1989; 29: +1386-1391. +105. +Feliciano DV, Spjut-Patrinely V, Burch JM, et al. +Splenor- +rhaphy: the alternative. +Ann Surg. +1990; 211:569-580. +106. +Stassen NA, Bhullar I, Cheng JD, et al. +J Trauma and Acute Care Surg. +2012;73(5):S294-S300. +107. +McIntyre LK, Schiff M, Jurkovich GJ. +Failure of nonoperative +management of splenic injuries: Causes and consequences. +Arch Surg. +2005;140:563-568. +108. +Smith HE, Biffl WL, Majercik SD, et al. +Splenic artery embo- +lization: have we gone too far? +J Trauma. +2006; 61:541-546. +109. +Toutouzas KG, Velmahos GC, Kaminski A, et al. +Leukocy- +tosis after posttraumatic splenectomy: a physiologic event or +sign of sepsis? +Arch Surg. +2002; 137:924-928. +110. +Howdieshell TR, Heffernan D, Dipiro JT. +Therapeutic Agents +Committee of the Surgical Infection Society. +Surgical infec- +tion society guidelines for vaccination after traumatic injury. +Surg Infect (Larchmt). +2006;7(3):275-303. +111. +Burch JM, Franciose RJ, Moore EE, et al. +Single-layer con- +tinuous vs. +two-layer interrupted intestinal anastomosis: +a prospective randomized trial. +Ann Surg Surg. +2000;231: +832-837. +112. +Todd SR, Kozar RA, Moore FA. +Nutrition support in adult +trauma patients. +Nutr Clin Pract. +2006; 21:421-429. +113. +Burlew CC, Moore EE, Cuschieri J, et al; the WTA Study Group. +Who should we feed? +J Trauma Acute Care Surg. +2012;73:1380-1387. +226 +BASIC CONSIDERATIONS +PART + +I +114. +Sharpe JP, Magnotti LJ, Weinberg JA, et al. +Impact of a +defined management algorithm on outcome after traumatic +pancreatic injury. +J Trauma Acute Care Surg. +2012;72: +100-105. +115. +Vaughn GD, Frazier OH, Graham D, et al. +The use of pyloric +exclusion in the management of severe duodenal injuries. +Am +J Surg. +1977;134:785. +116. +Nelson R, Singer M. +Primary repair for penetrating colon inju- +ries. +Cochrane Database Syst Rev 3:CD002247, 2003. +117. +Asensio JA, Britt LD, Borzotta A, et al. +Multi-institutional +experience with the management of superior mesenteric artery +injuries. +J Am Coll Surg. +2001;193:354-356. +118. +Burch JM, Richardson RJ, Martin RR, et al. +Penetrating iliac +vascular injuries: experience with 233 consecutive patients. +J Trauma. +1990; 30:1450-1459. +119. +Mullins RJ, Lucas CE, Ledgerwood AM. +The natural his- +tory following venous ligation for civilian injuries. +J Trauma. +1980;20:737-743. +120. +Roth SM, Wheeler JR, Gregory RT, et al. +Blunt injury of the +abdominal aorta: a review. +J Trauma. +1997; 42:748-755. +121. +Jurkovich GJ, Hoyt DB, Moore FA, et al. +Portal triad injuries. +J Trauma. +1995;39:426-434. +122. +Voelzke BB, McAninch JW. +Renal gunshot wounds: clinical +management and outcome. +J Trauma. +2009;66(3):593-600. +123. +Knudson MM, Harrison PB, Hoyt DB, et al. +Outcome after +major renovascular injuries: A Western trauma association +multicenter report. +J Trauma. +2000; 49:1116-1122. +124. +J Trauma. +62:834-839. +125. +Burlew CC, Moore EE, Smith WR, et al. +J Am Coll Surg. +2011;212(4):628-635. +126. +Bosse MJ, MacKenzie EJ, Kellam JF, et al. +An analysis of +outcomes of reconstruction or amputation of leg-threatening +injuries. +N Engl J Med . +2002;347:1924-1931. +127. +Moore FA, McKinley BA, Moore EE, et al. +III. +Guidelines for shock resuscitation. +J Trauma, 2006;61:82-89. +128. +Burlew CC, Moore EE, Biffl WL, Bensard DD, Johnson JL, +Barnett CC. +J Trauma Acute Care Surg. +2012;72(1):235-241. +129. +Sela HY, Weiniger CF, Hersch M, Smueloff A, Laufer N, +Einav S. +The pregnant motor vehicle accident casualty: adher- +ence to basic workup and admission guidelines. +Ann Surg. +2011;254(2):346-352. +130. +ACOG Committee on Obstetric Practice: ACOG Commit- +tee Opinion. +Number 299, September 2004. +Guidelines +for diagnostic imaging during pregnancy. +Obstet Gynecol +2004;104:647-651. +131. +Morris JA, Rosenbower TJ, Jurkovich GJ, et al: . +Infant sur- +vival after cesarean section for trauma. +Ann Surg. +1996;223: +481-488. +132. +Curet MJ, Schermer CR, Demarest GB, et al. +J Trauma. +2000;49:18-24. +133. +Davis JW, Kaups KL. +Base deficit in the elderly: a marker of +severe injury and death. +J Trauma. +1998; 45:873-877. +134. +Reynolds FD, Dietz PA, Higgins D, et al. +J Trauma. +2003;54:492-496. +135. +Bulger EM, Arneson MA, Mock CN, et al. +Rib fractures in the +elderly. +J Trauma 2000;48:1040-1046. +136. +Bergeron E, Lavoie A, Clas D, et al. +Elderly trauma patients +with rib fractures are at greater risk of death and pneumonia. +J Trauma. +2003;54:478-485. +137. +Tepas JJ. +The national pediatric trauma registry: a legacy of +commitment to control childhood injury. +Semin Pediatr Surg. +2004;13:126-132. +138. +Partrick DA, Bensard DD, Moore EE, et al. +J Trauma. +1998;45:57-63. +139. +Partrick DA, Bensard DD, Moore EE, et al. +J Pediatr Surg. +1999;34: +1695-1699. +Burns +Jonathan Friedstat, Fred W. +Endorf, +and Nicole S. +BACKGROUND +Burn injury historically carried a poor prognosis. +Anticipating the need for intubation and establishing an +early airway are critical. +A primary sur- +vey should be conducted in accordance with Advanced Trauma +Life Support guidelines. +Hypothermia is a common pre- +hospital complication that contributes to resuscitation failure. +Patients should be wrapped with clean blankets in transport. +Cooling blankets should be avoided in patients with moderate +or large (>20% TBSA) burns. +A tetanus +booster should be administered in the emergency room. +However, we +must also consider treatment of long-term anxiety. +The “rule of nines” is a crude but quick and effective method +of estimating burn size (Fig. +8-1). +The importance of an accurate burn size assessment cannot +be overemphasized. +2 Never administer prophylactic antibiotics other than tetanus +vaccination. +3 Early excision and grafting of full-thickness and deep partial- +thickness burns improve outcomes. +soiled skin with burns. +Hydrofluoric acid is a particu- +larly common offender due to its widespread industrial uses. +The concept behind continuous fluid requirements is +simple. +As in any critically ill patient, a target +MAP of 60 mmHg ensures optimal end-organ perfusion. +Goals for urine output should be 30 mL/h in adults and +1 to 1.5 mL/kg/h in pediatric patients. +The use of colloid as part of the burn resuscitation has gen- +erated much interest over the years. +Determining patient +cardiac function and volume status may guide fluid resuscita- +tion. +a traditional transfusion trig- +ger of 10 g/dL. +The physiologic effects of smoke inhalation are numer- +ous. +Silver sulfadiazine is one of the most widely used in +clinical practice. +It has the +added benefits of being inexpensive and easily applied and has +soothing qualities. +It is not significantly absorbed systemically +and thus has minimal metabolic derangements. +Also, silver sulfadiazine may retard epithelial migration +in healing partial-thickness wounds. +Mafenide acetate, either in cream or solution form, is an +effective topical antimicrobial. +Use of mafenide acetate may +be limited by pain with application to partial-thickness burns. +Silver nitrate has broad-spectrum antimicrobial activity as +a topical solution. +A rare complication is methemo- +globinemia. +All three have been reported to +cause nephrotoxicity and should be used sparingly in large +burns. +This formula estimates caloric needs to be +25 kcal/kg/d plus 40 kcal/%TBSA/d. +One study of HIT in burn patients showed +an incidence of 1.6% in heparinized burn patients. +Excision to +fat or fascia may be necessary in deeper burns. +In larger burns, meshed + autografted skin provides a larger area of wound coverage. +The search for a perfect permanent synthetic skin substi- +tute remains elusive. +Immediate +and ongoing physical and occupational therapy is mandatory to +prevent functional loss. +This includes patients with burns over joints, such as with +hand burns. +Patients should be taught exercises they can do them- +selves to maintain full range of motion. +Whether they prevent hypertrophic scar +formation has been long debated. +However, they do provide vas- +cular support that many patients find more comfortable. +Laser-based therapies provide addition treatment options +for symptomatic hypertrophic scars. +Lasers are believed to help with scar remodel- +ing and collagen reorganization. +Outpatient and office-based +treatment sessions are tolerated well by most patients. +Psychological rehabilitation is equally important in the +burn patient. +First, the proximity to the +detonated bomb directly impacted mortality. +Of the survivors, 79,130 +people were injured and 118,613 remain uninjured. +A 20-kiloton nuclear device generates +180 mph winds 0.8 miles from the epicenter. +The explosion +results in a direct pressure wave and an indirect wind drag. +Decontamination and triage are vital to maximize the num- +ber of survivors. +Initial decontamination requires removal of +clothing and washing wounds with water. +Irrigation fluid should +be collected to prevent radiation spread into the water supply. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Baxter CR, Shires T. +Physiological response to crystalloid +resuscitation of severe burns. +Ann N Y Acad Sci. +1968;150:874. +2. +Janzekovic Z. +A new concept in the early excision and imme- +diate grafting of burns. +J Trauma. +1970;10(12):1103-1108. +3. +Practice Guidelines for Burn Care. +J Burn Care Rehabil. +2001;22:1S. 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injuries. +J Burn Care Res. +2007;28(3):396-400. +90. +Cartotto R, Ellis S, Gomez M, et al. +Burns. +2004;30:453-463. +91. +Patton ML, Simone MR, Kraut JD, et al. +Successful utilization +of ECMO to treat an adult burn patient with ARDS. +Burns. +1998;24:566. +92. +Schmalstieg FC, Keeney SE, Rudloff HE, et al. +Ann Surg. +2007;246(3):512-521; discussion 521-523. +93. +Hart DW, Wolf SE, Mlcak R, et al. +Persistence of muscle +catabolism after severe burn. +Surgery. +2000;128(2):312-319. +94. +Hart DW, Wolf SE, Chinkes DL, et al. +Determinants of +skeletal muscle catabolism after severe burn. +Ann Surg. +2000;232(4):455-465. +95. +Gottschlich MM, Jenkins ME, Mayes T, et al. +The 2002 clini- +cal research award: an evaluation of the safety of early vs. +J Burn Care Rehabil. +2002;23(6):401-415. +96. +Hart DW, Wolf SE, Chinkes DL, et al. +J Trauma. +2003; +54(4):755-764. +97. +Jeschke MG, Herndon DN, Ebener C, et al. +Arch Surg. +2001;136(11):1301-1306. +98. +Sefton EJ, Boulton-Jones JR, 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+106. +Murphy KD, Thomas S, Mlcak RP, et al. +Effects of long- +term oxandrolone administration in severely burned children. +Surgery. +2004;136(2):219-224. +107. +Demling RH, DeSanti L. +Burns. +2003;29:793. +108. +Jeschke MG, Finnerty CC, Suman OE, et al. +Ann +Surg. +2007;246(3):351-360; discussion 360-362. +109. +Van den Berghe G, Wouters P, Weekers F, et al. +Intensive insulin +therapy in critically ill patients. +N Engl J Med. +2001;345:1359-1367. +110. +Thomas SJ, Morimoto K, Herndon DN, et al. +The effect of +prolonged euglycemic hyperinsulinemia on lean body mass +after severe burn. +Surgery. +2002;132(2):341-347. +111. +Jeschke MG, Klein D, Herndon DN. +Insulin treatment +improves the systemic inflammatory reaction to severe +trauma. +Ann Surg. +2004;239(4):553-560. +112. +Gore DC, Wolf SE, Sanford A, et al. +Ann Surg. +2005;241(2):334-342. +113. +Pham TN, Neff MJ, Simmons JM, et al. +The clinical pulmo- +nary infection score poorly predicts pneumonia in patients +with burns. 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+DiCarlo AL, Maher C, Hick JL, et al. +Disaster Med Public Health Prep. +2011;5(Suppl 1):S32-S44. +144. +Palmer JL, Deburghgraeve CR, Bird MD, et al. +Development +of a combined radiation and burn injury model. +J Burn Care +Res. +2011;32(2):317-323. +145. +Barber RC, Aragaki CC, Chang LY, et al. +CD14-159 C allele +is associated with increased risk of mortality after burn injury. +Shock. +2007;27(3):232-237. +146. +Barber RC, Chang LY, Arnoldo BD, et al. +Innate immunity +SNPs are associated with risk for severe sepsis after burn +injury. +Clin Med Res. +2006;4(4):250-255. +147. +Moore CB, Medina MA, van Deventer HW, et al. +Downregu- +lation of immune signaling genes in patients with large surface +burn injury. +J Burn Care Res. +2007;28(6):879-887. +148. +Xiao W, Mindrinos MN, Seok J, et al. +Inflammation and host +response to injury large-scale collaborative research program. +A genomic storm in critically injured humans. +J Exp Med. +2011;208(13):2581-2590. +149. +Klein MB, Silver G, Gamelli RL, et al. +Inflammation and the +Host Response to Injury Investigators. +J Burn +Care Res. +2006;27(4):448-451. +This page intentionally left blank +Wound Healing +Adrian Barbul, David T. +Efron, and +Sandra L. +The 1650 +b.c. +These +same properties are still considered essential in contemporary +daily wound management. +He emphasized the importance of maintaining a +moist environment to ensure adequate healing. +Joseph Lister probably +made one of the most significant contributions to wound healing. +The 1960s and 1970s led to the development of polymeric +dressings. +semiocclusive), varying degrees of absorbency, and differ- +ent physical forms. +It is the combination of all these modali- +ties that enables optimal wound healing. +. +. +An approximate timeline of these events is +depicted in Fig. +9-1. +The cellular, biochemical, and +mechanical phases of wound healing. +9-2A). +Cellular infiltration after injury follows a characteristic, +predetermined sequence (see Fig. +9-1). +PMNs are the first infil- +trating cells to enter the wound site, peaking at 24 to 48 hours. +The postulated primary role of neutrophils is phagocytosis +of bacteria and tissue debris. +The phases of wound healing viewed histologically. +A. +The hemostatic/inflammatory phase. +B. +Latter inflammatory phases +reflecting infiltration by mononuclear cells and lymphocytes. +C. +The +proliferative phase, with associated angiogenesis and collagen synthesis. +9-2B). +9-2B,C). +244 +BASIC CONSIDERATIONS +PART + +I +Figure 9-3. +The steps of collagen synthesis. +mRNA = messenger RNA. +9-2C). +It is dur- +ing this phase that tissue continuity is re-established. +Endothelial cells migrate from intact venules +close to the wound. +Type I collagen is the major component of extracellular matrix +in skin. +Biochemically, each chain of collagen is composed of a +glycine residue in every third position. +9-3). +At both ends, this struc- +ture contains nonhelical peptide domains called registration +peptides. +Proteoglycan Synthesis. +Rarely found free, they couple with proteins to form proteoglycans. +The major glycosaminoglycans present in wounds are der- +matan and chondroitin sulfate. +The interaction between collagen and proteo- +glycans is being actively studied. +The mechanical strength of the scar never achieves that of +the uninjured tissue. +Collagenolysis is the result of collagenase activity, +a class of MMPs that require activation. +Both collagen synthesis +and lysis are strictly controlled by cytokines and growth factors. +Some factors affect both aspects of collagen remodeling. +9-4). +The healing by epithelialization of superficial cutane- +ous wounds. +Growth factors act on cells via surface receptor binding. +Wound Contraction +All wounds undergo some degree of contraction. +Small blood vessels are +fragile, making suturing difficult during surgery. +Inguinal her- +nias in these children resemble those seen in adults. +Great care +should be taken to avoid tearing the skin and fascia. +The trans- +versalis fascia is thin, and the internal ring is greatly dilated. +248 +BASIC CONSIDERATIONS +PART + +I +of the ascending aorta. +Patients who suffer from this syndrome also +are prone to hernias. +OI is a result of a mutation in type I collagen. +There +are four major OI subtypes with mild to lethal manifestations. +Patients experience dermal thinning and increased bruisability. +Scarring is normal, and the skin is not hyperextensible. +Source: Reproduced and updated with permission from Phillips et al.31 Copyright © Elsevier. +skin layers; the last can present as multiple blisters throughout +different layers of skin. +Characteristic features of EB are blistering and ulceration. +Surgical interventions include esophageal dilata- +tion and gastrostomy tube placement. +Diagnosis is con- +firmed by the presence of an abnormally low blood zinc level +(>100 mg/dL). +The gross anatomic features of the GI tract are remarkably +constant throughout most of its length. +Injuries to all parts of the GI tract undergo the same +sequence of healing as cutaneous wounds. +However, there are +some significant differences (Table 9-5). +Mesothelial (serosal) +and mucosal healing can occur without scarring. +9-5). +Collagen synthesis in the GI tract is carried out by +both fibroblasts and smooth muscle cells. +stapled, continuous vs. +interrupted sutures, absorbable +vs. +nonabsorbable sutures, or single- vs. +two-layer closure). +(Reproduced with permission from Hunt +TK, Van Winkle W Jr. +Wound healing: normal repair. +In: Dunphy +JE, ed. +Fundamentals of Wound Management in Surgery. +This +is similar to the formation of granulation tissue in soft tissue. +The soft callus is formed externally along the bone shaft +and internally within the marrow cavity. +Clinically, this phase is +characterized by the end of pain and inflammatory signs. +This may take up to +2 to 3 months and leads to complete bony union. +The healing response of cartilage depends on the depth of +injury. +In contrast to superficial injuries, deep injuries involve +the underlying bone and soft tissue. +They consist +of parallel bundles of collagen interspersed with spindle cells. +Due to the mobility +of the underlying bone or muscles, the damaged ends usually +separate. +As the collagen fibers are organized, +transmission of forces across the damaged portion can occur. +Restoration of the mechanical integrity may never be equal to +that of the undamaged tendon. +Tendon vasculature has a clear effect on healing. +Schwann +cells ensheathe and help in remyelinating the regenerating axons. +Functional units are formed when the regenerating axons connect +with the appropriate end targets. +This complex interplay of growth factors +and adhesion molecules helps in nerve regeneration. +Wound Environment. +Different clinical approaches to the closure and heal- +ing of acute wounds. +Figure 9-7. +The acquisition of wound mechanical strength over +time in normal, delayed, and impaired healing. +Growth Factors. +Fetal wounds are notable for the absence of +TGF-β, which may have a significant role in scarring. +Wound Matrix. +Acute wounds +heal in a predictable manner and time frame. +The process occurs +with few, if any, complications, and the end result is a well-healed +wound. +Surgical wounds can heal in several ways. +An incised +wound that is clean and closed by sutures is said to heal by pri- +mary intention. +9-6). +The healing spectrum of acute wounds is broad (Fig. +9-7). +Normal healing is affected by both systemic and local factors +(Table 9-6). +Factors Affecting Wound Healing +Advanced Age. +Clinical experience with elderly patients tends +to support this belief. +Hypoxia, Anemia, and Hypoperfusion. +Low oxygen tension +has a profoundly deleterious effect on all aspects of wound heal- +ing. +Uremia also has been associated with disordered +wound healing. +Obesity is the largest growing public health problem in +the United States and the world. +Over 60% of Americans are +overweight or obese. +Many of these molecules have +effects on cells participating in the healing response. +The mechanism by which obesity +impairs wound healing awaits complete delineation. +Nutrition. +9-8). +Effect of malnutrition on collagen deposition in exper- +imental human wounds. +OHP = hydroxyproline. +following diverse surgical procedures. +Arginine appears most active in terms of enhancing wound +fibroplasia. +The vitamins most closely involved with wound healing +are vitamin C and vitamin A. +The recommended dietary allowance is +60 mg daily. +This provides a considerable safety margin for most +Figure 9-9. +*P < .05. +(Reproduced with +permission from Williams JZ, Abumrad NN, Barbul A. +Effect of a +specialized amino acid mixture on human collagen deposition. +Ann +Surg. +2002;236:369.) +5 +4 +3 +2 +1 +ASP LYSO HP +Experimental +Control +αAN +healthy nonsmokers. +Serious injury or stress leads to increased vitamin A +requirements. +In the severely injured patient, supplemental doses +of vitamin A have been recommended. +Doses ranging from +25,000 to 100,000 IU per day have been advocated. +Frequently, +deficiencies are multiple and include macronutrient deficien- +cies. +Clinically, +preventing deficiencies is often easier to accomplish than diag- +nosing them. +It is essential for wound healing in animals and humans. +These defects are reversed by zinc supplementation. +Cosmetically, infections can lead to disfig- +uring, unsightly, or delayed closures. +Many factors +contribute to the development of postoperative wound infec- +tions. +There has been much debate about the actual definition +of wound infection. +This causes minimal if any discomfort to +the patient. +Most intra-abdominal infections do not, +however, communicate with the wound. +Deep infections present +with fever and leukocytosis. +Sometimes wound dehiscence will occur. +The most dangerous of the deep infections is necrotizing +fasciitis. +It results in high mortality, particularly in the elderly. +This is an invasive process that involves the fascia and leads +to secondary skin necrosis. +The aim of surgical treatment +is thorough removal of all necrosed skin and fascia. +aureus, S. +epidermidis Cefazolin 1–2 g IV2 +Ophthalmic S. +epidermidis, S. +aureus, streptococci, +enteric gram-negative bacilli, +Pseudomonas spp. +epidermidis Cefazolin16 or Vancomycin2,16 1–2 g IV2, 1 g IV +Thoracic (noncardiac) S. +aureus, S. +There seems to be +confusion as to what exactly constitutes wound infection. +aureus, S. +aureus, S. +2The recommended dose of cefazolin is 1 g for patients who weigh 80 kg and 2 g for those >80 kg. +Morbidly obese patients may need higher doses. +Fluoroquinolones should not be used for prophylaxis in cesarean section. +8Cefotetan, cefoxitin, and ampicillin/sulbactam are reasonable alternatives. +or 2 g of neomycin plus 2 g of metro- +nidazole at 7 p.m. +and 11 p.m. +the day before an 8 a.m. +operation. +10Due to increasing resistance of E. +11For a ruptured viscous, therapy is often continued for about 5 d. +13Shock wave lithotripsy, ureteroscopy. +If manipulation of +bowel is involved, prophylaxis is given according to colorectal guidelines. +15Divided into 100 mg before procedure and 200 mg after. +10(122):73. +www.medicalletter.org. +As discussed previously, neutrophils play a major role in +preventing wound infections. +Surgeons become involved when +the patient develops infectious or obstructive complications. +The nitroblue tetrazolium (NBT) reduction test is used to +diagnose CGD. +Wound +complications, mainly infection, are common. +Sutures should +be removed as late as possible since the wounds heal slowly. +Thomas K. +The majority of wounds that have not healed +in 3 months are considered chronic. +9-10). +Cancers arising de novo in chronic +wounds include both squamous and basal cell carcinomas. +Ischemic Arterial Ulcers. +These wounds occur due to a lack +of blood supply and are painful at presentation. +After establishing adequate blood +supply, most such wounds progress to heal satisfactorily. +A strategy of prevention is extremely important in the +approach to patients with limb ischemia. +Venous +hypertension and capillary damage lead to extravasation of hemo- +globin. +The products of this breakdown are irritating and cause +pruritus and skin damage. +Venous stasis occurs due to the incompetence of either the +superficial or deep venous systems. +The wound usually is shal- +low with irregular margins and pigmented surrounding skin. +Compression can be accomplished via rigid or +flexible means. +The most commonly used method is the rigid, +zinc oxide–impregnated, nonelastic bandage. +Ten percent to 25% of diabetic patients +run the risk of developing ulcers. +The neuropathy is both sensory and motor and is secondary +to persistently elevated glucose levels. +There is also severe micro- and +macrovascular circulatory impairment. +Once ulceration occurs, the chances of healing are poor. +Wide débridement of all necrotic or infected +tissue is another cornerstone of treatment. +Pressure +ulcer formation is accelerated in the presence of friction, shear +forces, and moisture. +Typical appearance of the malignant transformation of a long-standing chronic wound. +(Photos used with permission by +Dr. +Robert S. +9-11). +Men and women are equally affected. +They vary in size from a few millimeters to large, +Figure 9-11. +Recurrent keloid on the neck of a 17-year-old patient +that had been revised several times. +(Reproduced with permission +from Murray JC, Pinnell SR. +Keloids and excessive dermal scar- +ring. +In: Cohen IK, Diegelmann RF, Lindblad WJ, eds. +Wound +Healing: Biochemical and Clinical Aspects. +Philadelphia: WB +Saunders; 1993. +Copyright Elsevier.) +pedunculated lesions with a soft to rubbery or hard consistency. +They rarely occur on eyelids, genitalia, palms, soles, +or across joints. +There is an abundance of collagen and glycoprotein depo- +sition. +In HTS, the collagen +bundles are flatter and more random, and the fibers are in a wavy +pattern. +This perturbed synthetic activity is mediated by altered +growth factor expression. +The underlying mechanisms that cause HTSs and keloids +are not known. +Much is inferred from the presence of various +immune cells in HTSs and keloids. +HTSs have higher T lymphocyte and Langerhans +cell contents. +It may +be secured with tape or worn beneath a pressure garment. +Intralesional injections are more effective on +younger scars. +Success is enhanced when used +in combination with surgical excision. +Serial injections every +2 to 3 weeks are required. +Complications include skin atrophy, +hypopigmentation, telangiectasias, necrosis, and ulceration. +It is more effective when combined +with surgical excision. +Pressure aids collagen maturation, flattens scars, and +improves thinning and pliability. +External +compression is used to treat HTSs, especially after burns. +Scars older than 6 to 12 months respond poorly. +Peritoneal Scarring. +Operations in the lower abdomen have +a higher chance of producing small bowel obstruction. +Fibrin deposition occurs between the damaged but +opposed serosal surfaces. +9-12). +Fewer adhesions +form with laparoscopic surgical techniques due to reduced tis- +sue trauma. +Fibrin formation and degradation in peritoneal tis- +sue repair and adhesion formation. +264 +BASIC CONSIDERATIONS +PART + +I +TREATMENT OF WOUNDS +Local Care (Fig. +The history is fol- +lowed by a meticulous examination of the wound. +Figure 9-13. +Algorithm for management of acute +wounds. +Management of acute wounds +1. +Examination +a) Depth? +Underlying structures injured +b) Configuration? +c) Nonviable tissue? +4. +Follow-up +a) Cellulitis/drainage? +b) Suture removal + -4–5 days for face + -7–10 days other skin +3. +This +is particularly important for wounds that cross the vermilion +border, eyebrow, or hairline. +Drains may be placed in areas at risk of +forming fluid collections. +Intradermal +absorbable sutures do not require removal. +Use of skin tapes +alone is only recommended for closure of the smallest superfi- +cial wounds. +These new glues are less prone +to brittleness and have superior burst-strength characteristics. +Antibiotics +Antibiotics should be used only when there is an obvious wound +infection. +Most wounds are contaminated or colonized with bac- +teria. +The presence of a host response constitutes an infection +and justifies the use of antibiotics. +Signs of infection to look for +include erythema, cellulitis, swelling, and purulent discharge. +In addition, appli- +cation of compression provides hemostasis and limits edema. +It also allows transfer of gases and water vapor from +the wound surface to the atmosphere. +Dressings can be classified as primary or secondary. +Many types of dress- +ings exist and are designed to achieve certain clinically desired +endpoints. +Absorbent Dressings. +Accumulation of wound fluid can lead +to maceration and bacterial overgrowth. +Nonadherent Dressings. +Occlusive and Semiocclusive Dressings. +Hydrophilic and Hydrophobic Dressings. +These dressings +are components of a composite dressing. +Hydrocolloid and Hydrogel Dressings. +Hydrocolloid and +hydrogel dressings attempt to combine the benefits of occlusion +and absorbency. +Hydrogel is a cross-linked polymer that has +high water content. +Alginates. +The ratios of these sugars vary with the species +of algae used, as well as the season of harvest. +The +polymers gel, swell, and absorb a great deal of fluid. +Absorbable Materials. +Medicated Dressings. +Medicated dressings have long been +used as a drug-delivery system. +These agents have been shown to increase epi- +thelialization by 28%. +The type of dressing to be used depends on the amount +of wound drainage. +A nondraining wound can be covered with +semiocclusive dressing. +Drainage of less than 1 to 2 mL/d may +require a semiocclusive or absorbent nonadherent dressing. +Mechanical Devices. +The continuous nega- +tive pressure is very effective in removing exudates from the +wound. +Conventional Skin Grafts. +Skin grafts have long been used to +treat both acute and chronic wounds. +Split-thickness grafts require less +blood supply to restore skin function. +Tem- +porary placement of allografts or xenografts may be used to +prepare the wound bed. +Skin Substitutes. +Cultured epithelial autografts (CEAs) represent expanded +autologous or homologous keratinocytes. +CEAs are available from cadavers, unrelated adult donors, +or neonatal foreskins. +Cost +Short shelf life +True engraftment questionable +Growth Factor Therapy. +Growth factors for clinical use may be either recombi- +nant or homologous/autologous. +Gene or Cell Therapy. +Elaborate systems have been created for topical use as on/off +switches for genes. +What, if any, are the deficiencies in gene expression or 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+Guidelines for +the prevention of venous ulcers. +Wound Repair Regen. +2008;16:147. +112. +Steed DL, Attinger C, Colaizzi T, et al. +Guidelines for treat- +ment of diabetic ulcers. +Wound Repair Regen. +2006;14:680. +113. +Jeffcoate WJ, Harding KG. +Diabetic foot ulcers. +Lancet. +2003;361:1545. +114. +Steed DL, Attinger C, Brem H, et al. +Guidelines for the +prevention of diabetic ulcers. +Wound Repair Regen. +2008;16:169. +115. +Whitney J, Phillips L, Aslam R, et al. +Guidelines for +the treatment of pressure ulcers. +Wound Repair Regen. +2006;14:663. +116. +Stechmiller JK, Cowan L, Whitney J, et al. +Guidelines for +the prevention of pressure ulcers. +Wound Repair Regen. +2008;16:151. +117. +Niessen FB, Spauwen PH, Schalkwijk J, et al. +On the nature of +hypertrophic scars and keloids: a review. +Plast Reconstr Surg. +1999;104:1435. +118. +Marneros AG, Norris JE, Olsen BR, et al. +Clinical genetics of +familial keloids. +Arch Dermatol. +2001;137:1429. +119. +Gauglitz GG, Korting HC, Pavicic T, et al. +Mol Med. +2011;17:113-125. +120. +Butler PD, Longaker MT, Yang GP. +Current progress in +keloid research and treatment. +J Am Coll Surg. +2008;206:731. +271 +W +OUND + H +EALING +CHAPTER 9 +121. +Mustoe TA. +Evolution of silicone therapy and mecha- +nism of action in scar management. +Aesthetic Plast Surg. +2008;32:82. +122. +Dijkstra FR, Nieuwenhuijzen M, Reijnen MM, et al. +Scand +J Gastroenterol Suppl. +2000;232:52. +123. +Cheong YC, Laird SM, Shellton JB, et al. +The correlation of +adhesions and peritoneal fluid cytokine concentrations: a pilot +study. +Hum Reprod. +2002;17:1039. +124. +Zeng Q, Yu Z, You J, Zhang Q. +World J Surg. +2007;31:2125. +125. +Armstrong DG, Lavery L. +Lancet. +2005;366:1704. +126. +Martinez-Zapata MJ, Marti-Carvajal AJ, Sola I, et al. +Autol- +ogous platelet-rich plasma for treating chronic wounds. +Cochrane Database Syst Rev. +2012;10:CD006899. +The surgeon often is responsible for the +initial diagnosis and management of solid tumors. +The primary goal of surgical and radiation therapy is +local and regional control. +Recent advances in molecular biology are revolutionizing +medicine. +2 Understanding cancer biology is essential to successfully +implement personalized cancer therapy. +Incidence is usually expressed as the number of new cases +per 100,000 persons per year. +Incidence and mortality data are +usually available through cancer registries. +The incidence of cancer varies by geography. +nonsmokers). +The results are expressed in terms of an odds ratio, or +relative risk. +Prostate cancer rates rapidly increased and +decreased between 1995 and 1998. +Reprogramming of energy metabolism and evading +immune destruction. +Source: Modified with permission from John Wiley and Sons: Siegel R et al. +Cancer statistics, 2013. +CA: a cancer journal for clinicians. +2013;63:11. +© 2013 +American Cancer Society, Inc. +male lung cancer and more than 40% for prostate cancer. +10-3). +The mortality rates for different cancers +also vary significantly among countries. +The incidence of stomach cancer varies significantly among dif- +ferent regions of the world. +Cancer statistics, 2013. +CA: a cancer journal for clinicians. +2013;63:11. +Stomach cancer is the second +leading cause of cancer death in both sexes worldwide. +Overall, the incidence of breast cancer is rising in most +countries. +Low rates are estimated in developed +regions, with the exception of Southern Europe. +The geographical distribution of the mortality rates is similar to +that observed for incidence. +This is due in part to genetic differ- +ences, including racial and ethnic differences. +Human cells require several genetic changes for neo- +plastic transformation. +Cell type–specific differences also exist +for tumorigenic transformation. +Rates are age adjusted to the 2000 U.S. +standard population. +(Modified with permission from John Wiley and Sons: Siegel +R et al. +Cancer statistics, 2013. +CA: a cancer journal for clinicians. +2013;63:11. +Cancer statistics, 2013. +CA: a cancer +journal for clinicians. +2013;63:11. +© 2013 American Cancer Society, Inc. +Thus, many normal-appearing +cells may have an increased malignant potential. +This is referred +to as a field effect. +Subsequent events can lead to accumula- +tions of additional deleterious mutations in the clone. +Fearon and Vogelstein proposed the model for colorec- +tal tumorigenesis presented in Fig. +There are several controls at each level. +The cell cycle is divided into four phases (Fig. +Oncogenes +Normal cellular genes that contribute to cancer when abnor- +mal are called oncogenes. +The normal counterpart of such a +gene is referred to as a proto-oncogene. +Oncogenes are usu- +ally designated by three-letter abbreviations, such as myc or ras. +More than 100 oncogenes have +been identified. +Persistent overexpression +Figure 10-3. +Estimated cancer incidence worldwide in 2008. +(Modified with permission from Ferlay, IARC)4 +All cancers +< 11.2 +< 0.3 < 0.5 < 0.7 < 1. +0< 11.2 < 0.4 < 0.7< 1. +0< 1. +Protein tyrosine kinases account for a large por- +tion of known oncogenes. +One of the best-studied oncogenes, +HER2 is discussed as an example later. +Hallmarks of cancer and their therapeutic implications. +The drugs +listed are illustrative examples.(Modified with permission from Hanahan et al. +A genetic model for colorectal tumorigenesis. +Individuals with familial adenomatous polyposis (FAP) inherit a mutation on chromosome arm 5q. +The chromosome +arms most frequently deleted include 5q, 17p, and 18q. +DCC = deleted in +colorectal cancer gene. +(Modified with permission from Fearon et al. +Unlike other recep- +tor tyrosine kinases, HER2/neu does not have a direct soluble +ligand. +10-7). +Schematic representation of the phases of the cell +cycle. +Mitogenic growth factors can drive a quiescent cell from G0 +into the cell cycle. +The DNA is replicated in S phase, and the +chromosomes are condensed and segregated in mitosis. +Cell-cycle checkpoints have been identified in +G1, S, G2, and M phases. +CDK = cyclin-dependent kinase. +In animal models, HER2 increases tumorigenic- +ity, angiogenesis, and metastasis. +These results all suggest that +HER2 plays a key role in cancer biology. +More recently HER2 +mutations have also been reported in human cancer. +All of these mutations were sensitive to the irreversible kinase +inhibitor, neratinib. +Cancer cells must avoid apoptosis if tumors are to arise. +Apoptosis is distinguished from necrosis because +it leads to several characteristic changes. +Apoptotic cells are then engulfed and +degraded by phagocytic cells. +Another regulatory group is the FADD-like +interleukin-1 protease-inhibitory proteins (FLIPs). +FLIPs have +homology to caspase 8; they bind to the DISC and inhibit the +activation of caspase 8. +The HER2 signaling pathway. +Cell-to-cell adhesion in normal cells involves interactions +between cell-surface proteins. +Integrins are a family of glycoproteins that form heterodi- +meric receptors for ECM molecules. +Serine, cysteine, and aspartic proteinases and MMPs have +all been implicated in cancer invasion. +Plasmin, in return, can +degrade several ECM components. +Plasmin also may activate +MMPs. +uPA has been more closely correlated with tissue inva- +sion and metastasis than tPA. +MMPs comprise a family of metal-dependent endopepti- +dases. +Upon activation, MMPs degrade a variety of ECM com- +ponents. +For example, collagenase-1 is now referred to +as MMP-1. +The MMPs are further classified as secreted and +membrane-type MMPs. +MMPs are upregulated in almost every type of cancer. +This neovascularization is essential +for tumor growth and metastasis. +Finally, sprouting tips anastomose to +form a vascular network surrounded by a basement membrane. +A schematic representation of the metastatic process. +A. +The metastatic process begins with an in situ cancer surrounded by an +intact basement membrane. +B. +C. +Metastasizing cells can enter the circulation via the lymphatics. +D. +They can also directly enter +the circulation. +E. +Intravascular survival of the tumor cells and extravasation of the circulatory system follow. +F. +Metastatic single cells can +colonize sites and remain dormant for years as occult micrometastases. +G. +(Adapted by permission from Macmillan Publishers Ltd. +Steeg PS. +Metastasis suppressors alter the signal transduction of cancer cells. +Nat Rev Cancer. +2003;3:55. +Ang-1, via the Tie-2 +receptor, induces remodeling and stabilization of blood vessels. +Therefore the balance between these factors determines the +angiogenetic capacity of a tumor. +Tumor angiogenesis is regulated by several factors in a +coordinated fashion. +Such inhibitors of +angiogenesis include thrombospondin 1 and angiostatin. +Angio- +genesis is a prerequisite not only for primary tumor growth +but also for metastasis. +Expression of angiogenic factors +such as VEGFs has had prognostic value in many studies. +These +findings further emphasize the importance of angiogenesis in +cancer biology. +The +metastatic process consists of a series of steps that need to be +completed successfully (Fig. +After the cancer +cells are shed into the circulation, they must survive. +Metastases can sometimes arise several years after the +treatment of primary tumors. +Several types of tumors metastasize in an organ-specific +pattern. +Metastasis also may involve the loss +of metastasis-suppressor genes. +Currently available drugs can +shrink metastatic tumors but often cannot eradicate them. +Therapeutic approaches +targeting stem cells specifically are under study. +Accumulation of somatic mutations acquired by the cancer cell. +Other processes +such as example DNA repair defects may contribute to the mutational burden. +Stratton MR, Campbell PJ, Futreal PA. +The cancer genome. +Nature. +2009;458:719. +Copyright © 2009.)37 +or to a loss of function by tumor-suppressor genes. +Somatic mutations in a +cancer genome may consist of several classes of DNA sequence +changes. +Somatic mutations in a cancer cell genome have accumu- +lated over the lifetime of the patient (Fig. +10-9).37 DNA in normal +cells is continuously damaged by internal and external mutagens. +Most of this damage is repaired; however, a small fraction may +remain as fixed mutations. +This is clearly the case for some cancers. +The most common cancer genes are protein kinases. +The remainder of mutations are “bystanders” or “pas- +sengers” that do not confer growth advantage. +It is likely that +most somatic mutations are passenger mutations. +10-10). +287 +ONCOLOGY +CHAPTER 10 +Hereditary:N onhereditary: +Tumor Tumor +Figure 10-11. +“Two-hit” tumor formation in both hereditary +and nonhereditary cancers. +(Adapted by permission from Macmillan +Publishers Ltd. +Knudson AG. +Two genetic hits (more or less) to +cancer. +Nat Rev Cancer. +2001;1:157. +Molecular subsets of lung adenocarcinoma. +Pao W, Hutchinson KE. +Chipping away at the lung cancer +genome. +Nat Med. +2012;18:349. +The following factors may suggest the presence of a +hereditary cancer49: +1. +Tumor development at a much younger age than usual +2. +Presence of bilateral disease +3. +Presence of multiple primary malignancies +4. +Presentation of a cancer in the less affected sex (e.g., male +breast cancer) +5. +Clustering of the same cancer type in relatives +6. +Some of the more commonly encountered +hereditary cancer syndromes are discussed here. +rb1Gene. +The retinoblastoma gene rb1 was the first tumor +suppressor to be cloned. +These findings led to the theory that a single +mutation is not sufficient for tumorigenesis. +p53 and Li-Fraumeni Syndrome. +Tumor heterogeneity. +A. +Cells within the primary tumor can acquire or lose genomic alterations in metastatic sites. +C. +Futreal PA et al. +A census of human cancer genes. +Nat Rev Cancer. +2004;4:177. +Copyright © 2004. +Of the known genes in human cancer, p53 is the most com- +monly mutated. +It is estimated that 5% to 10% of breast cancers are +hereditary. +BRCA2, mapped to +13q12.3, was reported shortly afterward. +The polyps usually appear in adoles- +cence and, if left untreated, progress to colorectal cancer. +Mismatch Repair Genes and Hereditary Nonpolyposis +Colorectal Cancer. +These errors are corrected through a process +referred to as mismatch repair. +The “hot spot” for PTEN mutations has been identified in +exon 5. +This suggests that the PTEN catalytic activity is vital +for its biologic function. +Breast cancer develops in 25% to 50% of +affected women.78 +p16 and Hereditary Malignant Melanoma. +E-cadherin and Hereditary Diffuse Gastric Cancer. +Mutations in the RET gene have also been +identified in half of sporadic medullary thyroid cancers. +Genetic Modifiers of Risk. +Chemicals are clas- +sified into three groups based on how they contribute to tumor +formation. +Group 3 agents are not classifiable, +and Group 4 agents are probably not carcinogenic to humans. +H. +The long fibers support cell proliferation and +have been shown to preferentially induce tumors. +Therefore, physical car- +cinogens may be synergistic with chemical carcinogens. +Within the next 20 years, a large number of radiation-related +skin cancers were reported. +It is thought that +radiation may initiate cancer by inactivating tumor-suppressor +genes. +Activation of oncogenes appears to play a lesser role in +radiation carcinogenesis. +Strong* +4,4’-Methylenebis(2-chloroaniline) .. +See text*§ +3,3’,4,4’,5-Pentachlorobiphenyl (PCB-126) .. +See text*§ +Ethylene oxide .. +*Agents classified in Group 1 on the basis of mechanistic information. +†Weak evidence in workers, but strong evidence for some chemicals in this industry. +‡Due to the diversity and complexity of these exposures, other mechanisms may also be relevant. +§Strong evidence for an aryl hydrocarbon receptor (AhR)-mediated mechanism. +¶Particularly myeloid leukemia. +||After maternal exposure (before or during pregnancy, or both). +**New epidemiological findings. +Source: Adapted from Baan et al 2009. +Patients with ataxia telangiectasia mutated syndrome also have +a radiation-sensitive phenotype. +Oncogenic viruses +may be RNA or DNA viruses. +Oncogenic RNA viruses are ret- +roviruses and contain a reverse transcriptase. +Oncogenic transforming retroviruses +carry oncogenes derived from cellular genes. +These genes +are required for viral replication using the host cell machinery. +Like other types of carcinogenesis, viral carcinogenesis +is a multistep process. +Furthermore, some viruses encode genes that suppress or delay +apoptosis. +When cancer does develop, it usually occurs +several years after the viral infection. +Source: Modified from Butel JS. +Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. +Carcinogenesis. +2000;21:405. +By permission of Oxford University Press. +297 +ONCOLOGY +CHAPTER 10 +and over her lifetime (to age 90 years). +Similar models are in development or are +being validated for other cancers. +CANCER SCREENING +Early detection is the key to success in cancer therapy. +The consequences of a false-positive screen- +ing test result also need to be considered. +Among women +for whom biopsy specimen is recommended, 25% to 40% will +have a breast cancer. +Beginning in +their early 20s, women should be told about the benefits +and limitations of BSE. +Women at any age should not be +screened annually by any screening method. +Guaiac-based toilet bowl FOBT tests also are +not recommended. +There is no justification for +repeating FOBT in response to an initial positive finding. +Stool DNA testb, or Interval uncertain, starting at age 50 y. +FSIG, or Every 5 y, starting at age 50 y. +DCBE, or Every 5 y, starting at age 50 y. +Colonoscopy Every 10 y, starting at age 50 y. +CT colonography Every 5 yr, starting at age 50 y. +These guidelines need to be modified for patients +who are at high risk. +Screening should not be +viewed as an alternative to smoking cessation. +Prostate cancer screening should not occur +without an informed decision-making process. +aBeginning at age 40 y, annual CBE should ideally be performed prior to mammography. +Source: Modified with permission from John Wiley and Sons: Smith RA et al. +CA: a cancer +journal for clinicians. +2013;63:87. +© 2013 American Cancer Society, Inc. +FDG PET assesses the rate of glycolysis. +The TNM staging applies only to tumors that have been +microscopically confirmed to be malignant. +Standard TNM +staging (clinical and pathologic) is completed at initial diag- +nosis. +If even one lymph node is involved by tumor, the N com- +ponent is at least N1. +NX indicates that the lymph nodes cannot +be fully assessed. +N Engl J Med. +2004;351:281. +Copyright © 2004 Massachusetts Medical Society. +The +RS was indeed able to stratify patients by freedom from distant +recurrence (Fig. +Unfor- +tunately, identification of serum markers of clinical value has +been challenging. +More- +over, tumor marker levels can be elevated in benign conditions. +In spite of these +many clinical limitations, several serum markers are in clinical +use. +A few of the commonly measured serum tumor markers are +discussed in the following sections. +Prostate-Specific Antigen. +PSA is normally present in low concentrations +in the blood of all adult males. +Carcinoembryonic antigen +(CEA) is a glycoprotein found in the embryonic endoder- +mal epithelium. +CEA measurement is most commonly used in the man- +agement of colorectal cancer. +However, the appropriate use of +CEA testing in patients with colorectal cancer has been debated. +Use of CEA level as a screening test for colorectal cancer is +not recommended. +Preoperative elevation of CEA level is an +indicator of poor prognosis. +Alpha-fetoprotein (AFP) is a glyco- +protein normally produced by a developing fetus. +AFP levels +decrease soon after birth in healthy adults. +Rarely, other types of cancer +such as gastric are associated with an elevated AFP level. +Cancer Antigen 19-9. +The CA +15-3 epitope is recognized by two monoclonal antibodies in a +sandwich radioimmunoassay. +CA 15-3 levels are infrequently elevated +in early-stage breast cancer. +Another methodology used to detect cancer cells in the periph- +eral blood is RT-PCR. +In a prospective +multicenter trial, the number of CTCs (≥5 CTCs vs. +This +technology, known as CellSearch, has been approved by the +FDA for clinical use. +An example +of this is toilet mastectomies for large ulcerated breast tumors. +The traditional Halsted +view states that lymphadenectomy is important for staging and +survival. +The effect of appropriate +staging on survival is twofold. +Clearly the impact of lymphadenectomy on +survival will not be easily resolved. +Moreover, the utility of sentinel +node biopsy specimen in other cancer types is being explored. +The first node to receive drainage from the tumor site is +termed the sentinel node. +Lymphatic mapping and sen- +tinel lymph node biopsy specimen for breast +cancer. +A. +Peritumoral injection of blue dye. +B. +Blue dye draining into the sentinel lymph +node. +(Modified with permission from Meric F, +Hunt KK. +Careful manual palpation is a crucial part of the +procedure to minimize the false-negative rate. +Another area of active investigation is the prognostic value +of minimal nodal involvement. +All +patients underwent breast-conserving surgery and tangential +whole-breast irradiation. +The role of completion lymph node +dissections in melanoma is under investigation. +Patient selection is the key to the success of surgical ther- +apy for distant metastases. +The cancer type is a major deter- +minant in surgical decision making. +The goal +of therapy in this setting is to decrease the tumor burden, thus +prolonging survival. +It is rare to achieve cure with chemother- +apy for metastatic disease for most solid tumors. +Preoperative chemotherapy has three potential advantages. +There are some potential disadvantages to preoperative +chemotherapy, however. +Anticancer Agents +Alkylating Agents. +The damage to the +DNA prevents cell division and, if severe enough, leads to apopto- +sis. +Antitumor Antibiotics. +Antitumor antibiotics are the prod- +ucts of fermentation of microbial organisms. +Like the alkylat- +ing agents, these agents are cell-cycle nonspecific. +Antimetabolites. +These drugs +are most effective, therefore, in tumors that have a high growth +fraction. +The +antimetabolites include folate antagonists, purine antagonists, +and pyrimidine antagonists. +Plant Alkaloids. +Combining cell-cycle–specific and cell-cycle– +nonspecific agents may be especially advantageous. +However, it +increases the drug’s toxicity to a wide range of organs through- +out the body. +Hormonal therapy pro- +vides a highly tumor-specific form of therapy in sensitive tis- +sues. +Androgen +receptor is also being pursued as a therapeutic target for breast +cancer treatment. +These drugs +work by targeting bcr-abland c-kit (imatinib) and HER2 and +Braf, respectively. +Sequencing of the human genome has revealed approxi- +mately 500 protein kinases. +Some other agents, such as sunitinib, are +multi-targeted kinase inhibitors. +Selected FDA-approved targeted +therapies are listed in Table 10-11. +Finally, most biologic +agents are cytostatic, not cytotoxic. +Several antitumor strategies are under investigation. +An +alternate strategy is the use of autologous tumor vaccines. +Targeting PI3K/Akt/mTOR signaling. +(Modified with permission from McAuiliffe et al. +Thus +both anti-PD1 and anti-PD-L1 strategies are actively being pur- +sued for cancer therapy. +Several vector systems are under study for gene ther- +apy; however, none is considered ideal. +Tumor size is +another important variable. +Because of the larger proportion of cells divid- +ing, smaller tumors may be more chemosensitive. +For +example, cells in the G0 phase are resistant to drugs active in +the S phase. +For +drug-sensitive cancers, another factor limiting optimal killing is +improper dosing. +One mechanism is +through the loss of the target. +Gamma rays are photons that are released from the +nucleus of a radioactive atom. +X-rays are photons that are created +electronically, such as with a clinical linear accelerator. +Currently, +high-energy radiation is delivered to tumors primarily with linear +accelerators. +Gamma rays typically are produced by radioac- +tive sources used in brachytherapy. +The dose of radiation absorbed correlates with the energy +of the beam. +One gray is equivalent to 100 rads, the unit of radiation mea- +surement used in the past. +The mechanism +of DNA damage differs by the type of radiation delivered. +Radiation damage is manifested primarily by the loss of +cellular reproductive integrity. +Some cell types, however, undergo apoptosis. +The extent of DNA damage after radiation exposure is +dependent on several factors. +The most important of these is cel- +lular oxygen. +Hypoxic cells are significantly less radiosensitive +than aerated cells. +Conventional fractionation is 1.8 to 2 Gy/d, administered +5 days each week for 3 to 7 weeks. +In these cases, radiation is +recommended for symptomatic metastases only. +The goal of adjuvant radiation therapy is to decrease local- +regional recurrence rates. +Preoperative radiation therapy has several advantages. +Further, the +radiation therapy can be modified on the basis of margin status. +Another mode of postoperative radiation therapy is +brachytherapy. +The radiation source may be cesium, gold, iridium, +or radium. +Several additional studies of +adjuvant IORT also are ongoing internationally. +It is thought that chemotherapy given concurrently with +radiation improves survival rates. +10-16).160 +A minimum dose of radiation must be given before any response +is seen. +The response to radiation then increases slowly with +an increase in dose. +The side effects depend on the tissue included in the target + volume. +The probability of tumor control and of complica- +tions at different radiation doses. +A. +At lower doses, the probability +of complications is low, with a moderate chance of tumor control. +B. +(Modified with +permission from Eisbruch A, Lichter AS. +In selected circumstances, the risk of cancer is high +enough to justify surgical prevention. +Further, the conservative options of close surveillance +and chemoprevention need to be discussed. +One of the critical changes expected is earlier +detection of cancers. +Another area of rapid development is the identification of +serum markers. +Surgical Therapy +The current trend in surgery is toward more conservative resec- +tions. +With earlier identification of tumors, more conservative +operations may be possible. +The goal, however, is always to +remove the tumor en bloc with wide 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Kuff D, Pollock R, eds. +Cancer Medi- +cine. +Hamilton B.C. +Decker Inc; 2000:465. +159. +Raju MR, Carpenter SG. +A heavy particle comparative study. +Part IV: acute and late reactions. +Br J Radiol. +1978;51:720-727. +160. +Eisbruch A, Lichter AS. +What a surgeon needs to know about +radiation. +Ann Surg Oncol. +1997;4:516-522. +161. +Hartford AC, Galvin JM, Beyer DC, et al. +Am J Clin Oncol. +2012;35:612-617. +162. +McCarthy K, Pearson K, Fulton R, Hewitt J. +Pre-operative +chemoradiation for non-metastatic locally advanced rectal +cancer. +Cochrane Database Syst Rev. +2012;12:CD008368. +163. +Evans DB, Varadhachary GR, Crane CH, et al. +J Clin Oncol. +2008;26:3496-3502. +164. +Courrech Staal EF, Aleman BM, Boot H, van Velthuysen ML, +van Tinteren H, van Sandick JW. +BrJSurg. +2010;97:1482-1496. +165. +Daly J, Bertagnolli M, DeCosse J. +Oncology. +In: Schwartz S, +Spencer F, Galloway A, eds. +Principles of Surgery. +New York: +McGraw-Hill; 1999:297. +166. +Fisher B, Costantino JP, Wickerham DL, et al. +J Natl Cancer +Inst. +1998;90:1371-1388. +167. +Vogel VG, Costantino JP, Wickerham DL, et al. +JAMA. +2006;295:2727-2741. +168. +Lippman SM, Batsakis JG, Toth BB, et al. +Comparison of +low-dose isotretinoin with beta carotene to prevent oral carci- +nogenesis. +N Engl J Med. +1993;328:15-20. +169. +Hong WK, Lippman SM, Itri LM, et al. +N Engl J Med. +1990;323:795-801. +170. +Sidransky D. +Emerging molecular markers of cancer. +Nat Rev +Cancer. +2002;2:210-219. +171. +Meric-Bernstam F, Hung MC. +Advances in targeting human +epidermal growth factor receptor-2 signaling for cancer ther- +apy. +Clin Cancer Res. +2006;12:6326-6330. +172. +Pao W, Hutchinson KE. +Chipping away at the lung cancer +genome. +Nat Med. +2012;18:349-351. +Transplantation +Angelika C. +Gruessner, Tun Jie, Klearchos Papas, +Marian Porubsky, Abbas Rana, M. +Cristy Smith, +Sarah E. +Yost, David L. +Dunn, and Rainer W.G. +But the success of transplantation has created new chal- +lenges. +11-1). +11-2). +HISTORY +Over the centuries, multiple references to transplantation can +be found in the literature. +Two major events preceded the rise of +transplantation. +322 +Figure 11-1. +Patients on the waiting list and the +number of organ transplants performed, 2000 to +2009. +(U.S. +data from the Scientific Registry of +Transplant Recipients Annual Report, http://srtr. +Second, the findings of British scientist Sir Peter B. +Other centers performed similar trans- +plants and could reproduce the good results. +Ultimately, attempts were made to perform kidney trans- +plants between nonidentical individuals. +Dramatic changes occurred with the further develop- +ment of immunosuppression. +The gradual increase in the organ shortage led to innova- +tive surgical techniques. +For example, deceased donor split-liver +Figure 11-2. +Patients on the waiting list and +the number of organ transplants performed, +2009. +KP = kidney and pancreas. +(U.S. +Murray Boston, MA +Liver 1963 Thomas E. +Starzl Denver, CO +Lung 1963 James D. +Hardy Jackson, MS +Pancreas 1966 Richard C. +Lillehei Minneapolis, MN +Heart 1967 Christiaan N. +Barnard Cape Town, South Africa +Small intestine 1967 Richard C. +Lillehei Minneapolis, MN +Heart/lung 1981 Bruce Reitz Stanford, CA +Multivisceral 1989 Thomas E. +Similarly, living donor intestine and pan- +creas techniques have been developed. +TRANSPLANT IMMUNOBIOLOGY +The outcomes of early transplants were unsatisfactory. +The +limiting factor was the lack of understanding of immunologic +processes. +Irreversible rejection was the reason for graft loss in +the vast majority of recipients. +In humans, these antigens make up the +human leukocyte antigen (HLA) system. +The antigen-encoding +genes are located on chromosome 6. +Two major classes of HLA +antigens are recognized. +They differ in their structure, function, +and tissue distribution. +Class I antigens (HLA-A, HLA-B, and +HLA-C) are expressed by all nucleated cells. +This leads to +recognition and elimination of the foreign antigen with great +specificity. +HLA molecules play a crucial role in transplant +recipients as well. +They can trigger rejection of a graft via two +different mechanisms. +This process is called +allorecognition, with T cells playing the crucial role. +This +interaction causes transmission of the signal into the cell, named +signal 1. +However, this signal alone is not sufficient to activate +the T cell. +An additional costimulatory signal is required, named +signal 2. +Two well-characterized costimulatory interactions are +the CD40/CD154 and B7/CD28 pathways. +Rejection is a result of an attack of acti- +vated T cells on the transplanted organ. +The end result is graft damage caused by inflam- +matory injury. +It is triggered by preformed antibodies +against the donor’s HLA or ABO blood group antigens. +Chronic +Chronic rejection is a slow type of rejection. +Immunosuppressive regimens are very +important to graft and patient survival posttransplant. +Certain regimens may involve withdrawal, +avoidance, or minimization of certain classes of drugs. +Char- +acteristics of the most common immunosuppressive agents are +listed in Table 11-3. +One dose +alone (30 mg) depletes 99% of lymphocytes. +Moreover, they are often the +first-line agents in the treatment of acute rejection. +AZA decreases T-lymphocyte +activity and decreases antibody production. +The most significant side effect of AZA, often dose- +related, is bone marrow suppression. +Leukopenia is often +reversible with dose reduction or temporary cessation of the +drug. +Mycophenolate is the prodrug of mycophenolate acid, derived +from Penicillium fungi. +The other important side effects are leukopenia, anemia, and +thrombocytopenia (Table 11-4). +Sirolimus is a substrate for CYP3A4/4 +and has many significant drug interactions (see Table 11-4). +Sandim- +mune, an older, oil-based formulation, has poor bioavailabil- +ity and variable absorption. +The newer formulations, Gengraf +and Neoral, are microemulsified with improved bioavailability. +They also can cause hyperkalemia and +hypomagnesemia. +It is associated +with a higher incidence of hypertension and hyperlipidemia than +is tacrolimus. +Tacrolimus causes a higher incidence of new-onset dia- +betes posttransplant than does cyclosporine. +It is a high- +avidity molecule with slower dissociation rates. +Recent trials have compared the use of belatacept vs. +The FDA recommends the use of +belatacept only in seropositive recipients. +Studies in liver trans- +plant recipients were halted early because of increased mortality +rates. +The CD20 antigen is expressed early in the B-cell cycle but +is absent on mature plasma cells. +It can directly target plasma cells. +It blocks the activation of the terminal complement +cascade. +Infections +Transplant recipients are predisposed to a variety of infec- +tions. +Immunosuppression is the obvious reason. +Posttransplant, they continue to have significant +comorbid conditions. +Early. +Infections during +this period can be devastating. +It is imperative to differentiate between medical and +surgical infections. +Surgical infections are the most common +and require expedient surgical intervention. +In liver and pancreas recipients, surgical infections are +most severe. +Furthermore, pretrans- +plant infections can re-emerge or worsen. +Treatment entails a prompt return to the operating room. +Common fungal isolates are Can- +dida albicans, Candida krusei, and Candida glabrata. +Local- +ized infections or abscesses can be treated with percutaneous +drainage and antibiotics. +Medical infections include respiratory, urinary tract, +and bloodstream infections. +Late. +Pretransplant exposure to viruses may confer immunity. +Infections +usually occur 3 to 6 months posttransplant or during treatment +for rejection. +It results from the +proliferation of EBV-positive B cells in immunosuppressed +patients. +Among patients with early lesions, the +first line of treatment is to reduce immunosuppression. +For those +with more advanced PTLD, rituximab is used. +Diagnosis is con- +firmed by biopsy; the preferred treatment is IV amphotericin B. +It is +endemic in the Southwest, Northern Mexico, and various parts +of Central and South America. +This infection can be resilient +and difficult to treat. +The first line of treatment is high-dose +amphotericin B. +Treatment consists of pro- +longed (3 to 13 months) administration of oral itraconazole. +Patients with invasive Candida or Aspergillus infec- +tions have a 20% mortality rate. +The standardized incidence ratio was 2.10 (as +compared with the general population). +The nation- +wide “Organ Donation Breakthrough Collaborative,” sponsored +by the U.S. +How- +ever, a severe donor shortage remains. +The number of living +organ donors peaked in 2007 and has declined since. +Deceased Donors +Most transplants today utilize organs from deceased donors. +Formerly, death was determined by the cessation of both cardiac +and respiratory function. +Donation after Brain Death. +The medical history and social history are obtained from the +available family members. +11-3). +Exposure for thoracic and abdominal organ +procurement. +preserved. +The common bile duct is transected at the superior mar- +gin of the head of the pancreas. +The gallbladder is incised and +flushed with ice-cold saline to clear the bile and sludge. +If the +pancreas is to be procured, the duodenum is flushed with anti- +microbial solution. +The tho- +racic organs, liver, pancreas, and kidneys are then removed. +Donation after Cardiac Death. +After the cessation of cardiac and respiratory +function, organ procurement commences. +The surgical team must be +familiar with, and respect, the local protocol. +The initial experience with organs procured using ECMO has +been encouraging. +Surgical Technique. +Alternatively, the NHBD is transported +to the operating room after declaration of cardiac death. +A midline incision is used to rapidly gain entry into the +abdominal cavity. +A +short segment of the distal aorta is dissected out from the retro- +peritoneum. +A moist umbilical tape is passed around the aorta, +which is used to secure a cannula. +The distal aorta is clamped. +Next, a cannula is passed cephalad through an aortotomy and +secured. +The portal flush is +then instituted. +It is the fiduciary duty of +transplant professionals to explain the risks of organ donation. +Any decision to donate should be uncoerced, and no entice- +ments should be offered. +The use of living donors offers numerous advantages for +recipients in need. +Receiving an organ from a closely matched +relative may also have immunologic benefits. +The major disadvantage is the risk to the living donor. +Medically, there is no possibility of benefit to the donor, only +the potential for harm. +The risk of death associated with dona- +tion depends on the organ being removed. +The risk of surgical and medical +complications also depends on the procedure being performed. +The guiding prin- +ciple should be minimization of risk to the donor. +The donor’s left kidney is usually +preferable because of the long vascular pedicle. +11-4). +11-5). +Such solutions help prevent cellular swelling +and the loss of cellular potassium. +Laparoscopic left donor nephroureterectomy. +A. +Takedown of splenic flexure of colon to expose the left renal hilum. +B. +Dis- +section of left ureter off the psoas muscle. +C. +Dissection of left renal vein and gonadal vein. +Left ureter seen lateral to the dissection. +D. +Dissection of left renal artery. +Lumbar veins clipped and divided. +E. +Endo-TA stapler transection of the left renal artery. +F. +Placement of +ports and Pfannenstiel incision for the donor kidney extraction. +Figure 11-5. +Donor hepatectomy (right hepatectomy). +A. +The liver parenchymal transection line (c, the Cantlie line) marked with cautery. +Right portal vein (p) and right hepatic artery (a) isolated. +b = bile duct. +Cystic duct was cannulated for intraoperative cholangiography. +B. +Exposure of hepatic veins after transection of the parenchyma. +In the case of heart and lung recipients, ischemic times should +be under 6 hours. +All of those times assume the use of normal +donors. +This +infrastructure later became the blueprint for other countries to +follow. +As a result, organ transplantation is the most transparent +field of medicine. +The meeting is coordinated by +a transplant physician or surgeon. +In an open forum format, +important decisions such as type of donor (living vs. +deceased) +are discussed. +4 +335 +T +RANSPLANTATION +CHAPTER 11 +Medical Evaluation +Cardiovascular Disease. +Diabetes and hypertension are the +leading causes of chronic renal disease. +Concomitant cardiovas- +cular disease (CVD) is a common finding in this population. +The perioperative risk assessment is based on +patient symptoms and exercise tolerance. +Malignancies. +Transplant candidates should undergo routine tuberculosis +(TB) screening. +In such +candidates, obtaining a liver biopsy is essential to assess the +disease severity. +Transplant candidates with chronic HCV infection often +have HCV-related glomerulonephritis. +In +patients with evidence of cirrhosis, a combined liver-kidney trans- +plant should be considered. +In appropriate candidates, pretrans- +plant antiviral treatment with interferon-α may be considered. +Kidney Disease. +Adjuvant therapy with rituximab +recently has been proposed.80 +Hypercoagulopathy. +Surgical Evaluation +Urologic Evaluation. +Vascular Evaluation. +Careful physical examination often reveals significant central +and/or peripheral vascular disease. +Immunologic Evaluation. +ABO blood typing and HLA typ- +ing (HLA-A, -B, and -DR) are required before a kidney trans- +plant. +Psychosocial Evaluation. +Recipient Operation +Kidney allografts usually are transplanted heterotopically. +The rectus muscle can be easily mobilized medially +without being divided. +11-6). +The retroperitoneal space of the iliac fossa is entered by +mobilizing the peritoneum medially. +A self-retained retractor is used to expose +the surgical field. +The iliac vessels should be dissected with +great care. +11-7). +Incision and exposure for kidney transplant. +A. +Mark for the skin incision. +B. +Anterior rectus sheath incised obliquely. +The +abdominal muscle transected lateral to the rectus muscle. +C. +External iliac artery and vein dissected. +Figure 11-7. +Vascular anastomoses of kidney transplant. +A. +B. +AB +the anastomosis. +11-8). +Therefore, reconstruction of the en bloc graft pretransplant is +key to a successful transplant. +The donor’s suprarenal vena +cava and aorta are oversewn. +The lumbar branches of the cava +and aorta are ligated. +Dissection around the renal hilum should +be avoided. +The orientation of the cava and aorta should be +AB +Figure 11-8. +Arterial and venous reconstruction. +A. +Two renal arteries combined into a single Carrel patch (arrow). +Right renal vein exten- +sion conduit constructed with stapled caval patch. +IVC = inferior vena cava; R = right renal vein. +B. +Three renal arteries anastomosed to +external iliac artery separately. +AB +Figure 11-9. +En bloc kidney transplant (3-month-old donor kidneys). +A. +En bloc kidneys benched. +Vascular integrity tested with methylene +blue (blue hue look of the kidneys). +B. +En bloc kidneys transplanted in to a 62-year-old woman. +clearly marked, in order to avoid torsion of the anastomosis. +11-9). +Electrolyte +panels should be checked. +The crucial elements include hemodynamic stability +and fluid and electrolyte balance. +Hypotension is an unusual event immediately posttrans- +plant. +Immediate +action should be taken to avoid life-threatening complications. +Postoperatively, urine output is used as a surrogate marker +to monitor graft function. +Suddenly decreased or minimal urine output requires +immediate attention. +Postoperative bleeding is an uncommon event after a kid- +ney transplant. +Recipients on anticoagulation or antiplatelet +treatments are at increased risk. +Doppler +ultrasound is useful to establish the underlying cause. +Surgical +exploration seldom is required, because the accumulated hema- +toma tamponades the bleed. +One of the most devastating postoperative complications +in kidney recipients is graft thrombosis. +It is rare, occurring in +fewer than 1% of recipients. +Graft thrombosis usually occurs +within the first several days posttransplant. +Doppler ultrasound may help +confirm the diagnosis. +Urologic complications are seen in up to 5% of recipi- +ents. +Late +urinary obstruction is often related to ischemia. +The appear- +ance of hydronephrosis on ultrasound is a good initial indicator. +Treatment includes percutaneous placement of a nephrostomy +and ureteral stenting. +Results +A kidney transplant remains the most common solid organ +transplant in the world today. +According to a recent analysis of +more than 250,000 U.S. +An estimated 10% to 15% of the U.S. +population is +affected by it; of all diabetic patients, 10% have early-onset dis- +ease. +It is one of the most common causes of death, along +with myocardial infarction and stroke. +Diabetes significantly +decreases not only the quality of life but also life expectancy. +Almost 80% of pancreas +transplants are performed in this category. +A successful SPK +transplant renders the recipient dialysis-free and insulin- +independent. +•    Pancreas after kidney (PAK) transplant in diabetic and +posturemic patients. +Approximately 15% of all pancreas +transplants fall into this category. +•    Pancreas transplant alone (PTA) in nonuremic patients +with brittle diabetes mellitus. +Only about 8% of all pan- +creas transplants are in this category. +11-10). +The splenic artery +is divided close to its origin and is retained with the pancreas. +The SMA is also procured with an aortic Carrel patch and is +retained with the pancreas. +Simultaneous pancreas, in situ +split-liver, and intestine procurement. +(Repro- +duced from Gruessner RWG, Sutherland DER, +eds. +Transplantation of the Pancreas. +New York: +Springer, 2004; Color Plate VI, Figure 8.1.3.11. +Back table preparation is carried out in a basin filled +with chilled preservation solution. +11-11). +11-12 and 11-13). +For venous drainage, systemic +venous drainage is preferred over portal venous drainage. +Venous and arte- +rial anastomoses are performed end-to-side. +After restoration of +SA +IIA +EIA +SMA SMA +Figure 11-11. +Posterior view of the pancreas graft with Y-graft +reconstruction. +(Reproduced from Gruessner RWG, Sutherland DER, eds. +Trans- +plantation of the Pancreas. +New York: Springer, 2004; Color Plate +VII, Figure 8.1.3.13[B]. +With kind permission of Springer Science ++ Business Media.) +Figure 11-12. +Whole-organ transplant with systemic +vein and bladder exocrine drainage. +(Reproduced from +Gruessner RWG, Sutherland DER, eds. +Transplanta- +tion of the Pancreas. +New York: Springer, 2004; Color +Plate XIV, Figure 8.2.2.2[B]. +The pancreas usually is placed with the +pancreatic head and duodenum pointing caudally. +Bladder drainage has +two main advantages. +Amylase levels are measured routinely in the recipient’s urine. +In the absence of hyperglycemia, more +than 90% of pancreas rejection episodes are reversible. +Second, +bladder drainage avoids the bacterial contamination that occurs +with enteric drainage. +Enteric drainage is more physiologic and has advantages +as well. +Whole-organ transplant with systemic vein and +enteric exocrine drainage. +(Reproduced from Gruessner RWG, +Sutherland DER, eds. +Transplantation of the Pancreas. +New York: +Springer, 2004; Color Plate XIV, Figure 8.2.2.2[A]. +Bleeding frequently +requires relaparotomy. +Thrombosis usually occurs within the first week posttrans- +plant. +Surgi- +cal exploration in recipients with thrombosis usually requires a +graft pancreatectomy. +The most common nonsurgical complication posttrans- +plant is rejection. +The incidence of rejection is about 30% within +the first year. +In enteric- +drained recipients, one must rely on serum amylase and lipase +levels only. +The diagnosis of +rejection should be confirmed by a percutaneous pancreas graft +biopsy. +Bladder-drained pancreas recipients may experience an +array of unique urologic complications. +In particular, patients with high PRA levels should be +considered for a living donor transplant. +11-14). +Ste- +roid avoidance has increased over time in all three recipient +categories. +These changes have led to improved patient and graft +survival rates. +Like- +wise, the 1-year immunologic graft loss rate has also decreased, +ranging from 2% to 6%. +The 1-year patient survival rates now +exceed 90% in all three recipient categories. +The 1-year pancreas graft sur- +vival rate is 80% in PAK recipients and 78% in PTA recipients. +Figure 11-14. +Segmental transplant with systemic vein and blad- +der exocrine drainage. +The splenic artery anastomosis is lateral and proximal +to the splenic vein anastomosis. +A two-layer ductocystostomy is +constructed. +(Reproduced from Gruessner RWG, Sutherland DER, +eds. +Transplantation of the Pancreas. +New York: Springer, 2004; +Color Plate XVI, Figure 8.2.2.4. +The quality of the deceased donor +graft is of paramount importance. +Islet vs. +Islet transplants rarely maintain long-term insulin +independence. +The full potential of islet transplants remains to be real- +ized, but the future is exciting. +History +The first experimental liver transplants in dogs are often attrib- +uted to C. +Stuart Welch in 1955 and then Jack Cannon in 1956. +The +advent of better immunosuppressive drugs was instrumental. +In +1978, cyclosporine was introduced clinically in England. +It was +soon combined with prednisone to great effect. +The arrival of +tacrolimus in the 1990s further improved graft survival. +Technical advances were also significant. +Improvements in portosystemic shunting and perioperative criti- +cal care also were contributory. +Chronic alcoholic disease and HCV +are the most common indications in the United States. +Furthermore, most transplant centers recommend rehabilitation +and Alcoholics Anonymous programs. +Once recur- +rence occurs, treatment methods are limited. +Posttransplant outcomes for such +patients have been excellent. +Hemochromatosis, an inherited disorder, +results in excessive intestinal iron absorption. +Iron deposition +can cause cirrhosis and severe cardiomyopathy. +Careful cardiac +evaluation is necessary pretransplant. +Careful pul- +monary evaluation is necessary pretransplant. +Patients can +develop significant neurologic complications and cirrhosis. +Resection is the first +line of treatment if possible, but often, cirrhosis is too advanced. +If the tumor meets the Milan criteria, a liver transplant can be +performed. +A significant +number of patients will recover with supportive care. +They are +susceptible to infections, which are frequently overwhelming. +Recipient Selection +The diagnosis of cirrhosis itself is not an indication for a trans- +plant. +The early stages result in sleep disturbances and depression. +Hyperammonemia suggests worsening liver +function and bypass of portal blood flow around the liver. +GI +bleeding and infection can exacerbate hepatic encephalopathy. +coli, although Gram stain +and culture results should be used to guide therapy. +Portal hypertensive bleeding can be a devastating event +for patients with cirrhosis. +Only 50% of bleeding events cease spontaneously, +so treatment must be expedient. +The initial medical treatment +is with vasopressin and octreotide. +The initial intervention is +endoscopy with sclerotherapy and band ligation of bleeding +varices. +Hepatorenal syndrome is a form of acute renal failure that +develops as liver disease worsens. +Candidates should have +a normal ejection fraction. +If coronary arterial disease is pres- +ent, they should undergo revascularization pretransplant. +Severe +chronic obstructive pulmonary disease (COPD) with oxygen +dependence is a contraindication. +Candidates with pulmonary hypertension should be +evaluated with a right heart catheterization. +Fungal and multidrug-resistant bacterial infections +are relative contraindications. +Some centers require an extended +period of treatment and documented eradication pretransplant. +A bilateral subcostal incision with midline extension is used. +Mechanical retraction spreads the rib cage to allow access. +The ligamentous attachments of the liver are dissected free. +11-15). +The bile duct, portal structures, and vena cava are +divided, completing the hepatectomy (Fig. +After the liver is removed, the anhepatic phase begins. +Significant hemodynamic instability and increased +variceal bleeding can occur. +The donor liver is placed in the orthotopic position. +Coagulopathy also can worsen because of +these byproducts as well as fibrinolysis. +Of course, many variations +are possible. +After arterial reperfusion, the bile duct anastomosis +Figure 11-15. +Cirrhotic liver immobilized in preparation for com- +plete hepatectomy. +Figure 11-16. +If necessary for technical reasons, +the recipient common duct can be joined to a Roux-en-Y limb. +The piggyback technique is a common variation of the +standard technique. +The recipient’s IVC is preserved by care- +fully dissecting off the posterior aspect of the liver. +The recipient’s liver is +removed by dividing it at the confluence of the hepatic veins. +The most common indication is biliary atresia. +The surgical procedure is similar to the adult procedure. +As a result, surgical +complications are much more common in pediatric recipients. +Hepatic artery thrombosis is about three times more common. +11-17). +Both techniques have simi- +lar outcomes. +11-18). +Donation +by an adult living donor to a pediatric recipient requires the left +lateral lobe (Fig. +11-19). +Donor safety is paramount. +Donor and recipient procedure for living donor liver +transplant into a pediatric recipient. +A separate donor team should serve as the +donor advocate and thoroughly explain all risks. +Careful recipient selection is essential. +Postoperative Care +A liver transplant imposes significant trauma on the major +organ systems. +Immediately posttransplant, the first goal is +to stabilize those systems. +350 +BASIC CONSIDERATIONS +PART + +I +Figure 11-18. +A. +Hepatic transection completed for right lobe removal. +B. +Implantation of the donor right lobe with the MHV. +CHA = common hepatic artery. +(Reproduced with permission +from Gruessner RWG, Benedetti E, eds. +Living Donor Organ Transplantation. +New York: McGraw-Hill, 2008. +R.P .A. +RHD +C.A. +C.D. +Careful attention needs to be paid to ongoing +bleeding. +Appropriate hemoglobin levels should be main- +tained. +Evaluation of Graft Function +Evaluation of the graft begins in the operating room. +A. +Hepatic transection completed for removal of +left lateral segments (S2 and S3). +Bile ducts to segments 2 and +3 divided; vascular structures still intact. +B. +Implantation of the +donor left lobe. +(Reproduced with permission from Gruessner +RWG, Benedetti E, eds. +Living Donor Organ Transplantation. +New +York: McGraw-Hill, 2008. +Transaminases usually +peak by postoperative day 2. +An aspartate transaminase (AST) +level greater than 2500 IU/L is suggestive of significant injury. +Cholestasis usually peaks from postoperative day 7 to 12. +The +INR should improve shortly after reperfusion. +The most common vascular complication is hepatic artery +thrombosis. +Diagnostic imaging with ultrasound has more +than 90% sensitivity and specificity. +If hepatic artery thrombosis +is identified, urgent re-exploration is needed. +Thrombosis of the portal vein is very uncommon. +Signs of +early thrombosis include liver dysfunction, ascites, and variceal +bleeding. +Upon diagnosis, an operative thrombectomy should +be attempted. +Signs include fever and abdominal pain, with bilious drainage +from surgical drains. +Diagnosis is made with cholangiography. +Complications manifest themselves as leaks or stric- +tures. +Two common reconstructions are +choledochostomy and choledochojejunostomy. +Some centers +also routinely use T-tube stents or internal stents. +Consensus +has not been reached as to which reconstruction technique is +superior. +Intra- +abdominal infections should raise concerns of a possible bile +leak. +Fungal infections are often associated with poor graft +function. +Acute rejection occurs in approximately 20% of liver +recipients. +Maintenance immunosuppression consists of a +corticosteroid, tacrolimus, and mycophenolate. +Over the first two decades, the results were dismal. +High levels +of immunosuppression are needed, yet the rejection rate is still +high. +Intestine failure is typically multifactorial. +Indications for a transplant differ between the adult and +pediatric population. +The leading causes of intestine failure are +summarized in Table 11-7. +Liver failure is often seen in patients on long-term +TPN. +Both vessels are isolated at the root of the +mesentery. +Figs. +11-20 to +11-22 show these three main types of transplants. +The vast majority of intestine transplants use a deceased +donor organ. +11-24). +Similarly, the recipient operation also varies by the organs +transplanted. +The +diversion of splanchnic flow into the systemic venous circulation +Figure 11-20. +Isolated intestine transplant. +Figure 11-21. +Combined liver-intestine transplant. +Figure 11-22. +Multivisceral transplant. +Once the recipient recovers, the ileostomy +can be taken down. +Broad-spectrum antibiotics are an integral +component of care. +Of all solid organ transplants, intestine transplants have +the highest rate of rejection. +Rejection leads to structural damage of the intes- +tinal mucosa. +Translocation of endoluminal pathogens into the +circulation can cause systemic infections. +Immediately posttransplant, recipients are maintained +on TPN. +Enteral nutrition is initiated as early as possible, but +is advanced very cautiously. +Despite all the recent advances, the complication rate +posttransplant remains high. +A. +Donor operation. +B. +Recipient operation. +(Reproduced with permission from Gruessner RWG, +Benedetti E, eds. +Living Donor Organ Transplantation. +New York: McGraw-Hill, 2008. +Hardy performed the first human lung transplant in +1963, although the patient lived only 18 days. +The first suc- +cessful long-term lung transplant was performed in 1983 in +Toronto. +The 1980s +marked the start of the modern age of thoracic transplants. +Heart Transplants +Indications. +About 3000 patients are +added to the waiting list each year. +Evaluation. +Procedure. +Heart transplants are most often performed ortho- +topically (Fig. +11-25). +The recipient’s native heart is removed, +Figure 11-24. +Recipient operation. +A very short Roux-en-Y loop (10 to +20 cm) is anastomosed to the donor’s bile duct(s). +(Reproduced with +permission from Gruessner RWG, Benedetti E, eds. +Living Donor +Organ Transplantation. +Color Plates, Figure IN-6. +New York: +McGraw-Hill, 2008. +© 2008 by The McGraw-Hill Companies, Inc.) +Figure 11-25. +A donor’s heart brought forward for anastomosis. +Usually the left atrial cuff +is anastomosed first, providing left heart inflow. +11-26). +Posttransplant Care. +Patient survival rates for heart recipi- +ents differ slightly after primary transplants vs. +retransplants. +Heart recipients must be monitored for both early and late +complications. +Both T-cell–mediated (cellular) and +B-cell–mediated (antibody-mediated) rejection are monitored. +Figure 11-26. +Other immunosuppressive agents can be used, depending on the +needs of individual recipients. +Coronary artery disease can +begin to develop as early as 1 year posttransplant. +Its pathogen- +esis is unknown, but it is believed to be immunologic. +Lung Transplants +Indications. +The next most common diagnosis +among patients on the waiting list is cystic fibrosis. +A lung allo- +cation score (LAS) was instituted in 2005. +Evaluation. +Potential lung donors are also screened for blood type +and size match. +Living donors +can donate a single lobe to a smaller recipient, such as a child. +Procedure. +11-27). +The pulmonary veins and +main pulmonary artery are encircled outside the pericardium. +The bronchial anastomosis +(Fig. +11-28) is performed first and then covered with peribron- +chial tissue or pericardium. +The pulmonary artery and, finally, +the vein are anastomosed. +All clamps are removed, and the lung is aerated. +At least +two chest tubes are left in place. +Posttransplant Care. +Patient survival rates for lung recipients +vary significantly after primary vs. +redo transplants. +Postoperative care of lung recipients can be very labor- +intensive. +Most patients are extubated within the first 24 to +48 hours. +Early complications include technical complications, +graft dysfunction, infections, and rejection. +In up to 20% of recipi- +ents, primary early graft dysfunction can occur with no obvious +cause. +Rejec- +tion is monitored by biopsies and treated as needed. +Strictures are treated with bronchoscopic dilation +and intervention. +All recipients should be +taught to perform microspirometry at home as a screening +Figure 11-27. +Clamshell incision. +Bronchial anastomosis with +ligated pulmonary arteries and veins. +Figure 11-28. +Bronchial anastomosis. +358 +BASIC CONSIDERATIONS +PART + +I +tool posttransplant. +Biopsies are performed to confirm the diag- +nosis of any complication and, if possible, the cause. +Heart-lung candidates are often younger than their single-organ +counterparts. +The patient survival rates at 1, 3, and 5 years are +66%, 48%, and 39%, respectively. +Often, lung 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al. +Hepatitis C virus +kinetics during and immediately after liver transplantation. +Hepatology. +2002;35(3):680-687. +130. +Berenguer M, Prieto M, Rayon JM, et al. +Hepatology. +2000;32(4 Pt 1): +852-858. +131. +Lake JR, Shorr JS, Steffen BJ, Chu AH, Gordon RD, Wiesner +RH. +Am J Transplant. +2005;5(3):549-557. +132. +Neff GW, Montalbano M, O’Brien CB, et al. +Transplantation. +2004;78(9):1303-1307. +133. +Lee J, Belanger A, Doucette JT, Stanca C, Friedman S, Bach +N. +Transplantation trends in primary biliary cirrhosis. +Clin +Gastroenterol Hepatol. +2007;5(11):1313-1315. +362 +BASIC CONSIDERATIONS +PART + +I +134. +Liermann Garcia RF, Evangelista Garcia C, McMaster P, +Neuberger J. +Hepa- +tology. +2001;33(1):22-27. +135. +Campsen J, Zimmerman MA, Trotter JF, et al. +Liver Transplant. +2008;14(2): +181-185. +136. +Schilsky ML, Scheinberg IH, Sternlieb I. +Liver transplantation +for Wilson’s disease: indications and outcome. +Hepatology. +1994;19(3):583-587. +137. +Medici V, Mirante VG, Fassati LR, et al. +Liver Transplant. +2005;11(9):1056-1063. +138. +Mazzaferro V, Regalia E, Doci R, et al. +N Engl J Med. +1996;334(11): +693-699. +139. +Heimbach JK, Haddock MG, Alberts SR, et al. +Transplanta- +tion for hilar cholangiocarcinoma. +Liver Transplant. +2004;10 +(10 Suppl 2):S65-S68. +140. +O’Grady JG, Alexander GJ, Hayllar KM, Williams R. +Early +indicators of prognosis in fulminant hepatic failure. +Gastroen- +terology. +1989;97(2):439-445. +141. +Boyer TD, Haskal ZJ. +Hepatology. +2010;51(1):306. +142. +Kamath PS, Wiesner RH, Malinchoc M, et al. +A model to +predict survival in patients with end-stage liver disease. +Hepa- +tology. +2001;33(2):464-470. +143. +Wiesner R, Edwards E, Freeman R, et al. +Model for end-stage +liver disease (MELD) and allocation of donor livers. +Gastro- +enterology. +2003;124(1):91-96. +144. +Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port +FK, Wolfe RA. +The survival benefit of liver transplantation. +Am J Transplant. +2005;5(2):307-313. +145. +Safdar K, Neff GW, Montalbano M, et al. +Liver transplant for +the septuagenarians: importance of patient selection. +Trans- +plant Proc. +2004;36(5):1445-1448. +146. +Bellamy CO, DiMartini AM, Ruppert K, et al. +Transplantation. +2001;72(4):619-626. +147. +Vagefi PA, Parekh J, Ascher NL, Roberts JP, Freise CE. +Arch Surg. +2011;146(9):1052-1059. +148. +Brown RS Jr., Russo MW, Lai M, et al. +A survey of liver +transplantation from living adult donors in the United States. +N Engl J Med. +2003;348(9):818-825. +149. +Bilzer M, Gerbes AL. +Preservation injury of the liver: mech- +anisms and novel therapeutic strategies. +J Hepatol. +2000; +32(3):508-515. +150. +Jaeschke H. +Preservation injury: mechanisms, prevention, and +consequences. +J Hepatol. +1996;25(5):774-780. +151. +Serracino-Inglott F, Habib NA, Mathie RT. +Hepatic ischemia- +reperfusion injury. +Am J Surg. +2001;181(2):160-166. +152. +Drazan K, Shaked A, Olthoff KM, et al. +Am Surg. +1996;62(3):237-240. +153. +Tzakis AG, Gordon RD, Shaw BW Jr., Iwatsuki S, Starzl +TE. +Transplantation. +1985;40(6):667-671. +154. +Grant D, Abu-Elmagd K, Reyes J, et al. +2003 report of the +intestine transplant registry: a new era has dawned. +Ann Surg. +2005;241(4):607-613. +155. +Abu-Elmagd K, Mazariegos G, Bond G, et al. +Intestinal +transplantation: current status and future considerations. +Am J Gastroenterol. +2006;101(9):S145-S146. +156. +Yersiz H, Renz JF, Hisatake GM, et al. +Multivisceral and +isolated intestinal procurement techniques. +Liver Transplant. +2003;9(8):881-886. +157. +Bueno J, Abu-Elmagd K, Mazariegos G, Madariaga J, Fung +J, Reyes J. +J Pediatr Surg. +2000;35(2):291-295; discussion +95-96. +158. +Farmer DG, McDiarmid SV, Edelstein S, et al. +Improved out- +come after intestinal transplantation at a single institution over +12 years. +Transplant Proc. +2004;36(2):303-304. +159. +Tzakis AG, Kato T, Levi DM, et al. +100 multivisceral trans- +plants at a single center. +Ann Surg. +2005;242(4):480-490; dis- +cussion 91-93. +160. +Gruessner RWG, Sharp HL. +Living related intestinal +transplantation: first report of a standardized surgical +technique. +Transplant. +1997;64:1605-1607. +161. +Kouchoukos NT, Blackstone EH, Doty DB. +Heart failure. +In: Kouchoukos NT, Blackstone EH, Doty DB, et al, eds. +Cardiac Surgery. +3rd ed. +New York: Kirklin/Barratt-Boyes; +2003:1725. +162. +First human heart transplant. +The History Channel website. +163. +Meyers BF, Patterson GA, Haverich A, Harringer W. +Lung +transplantation, heart-lung transplantation. +In: Pearson FG, +Cooper JD, Deslauriers J, et al, eds. +Thoracic Surgery. +2nd ed. +New York: Churchill-Livingston; 2002:1085-1131. +164. +Costanzo MR, Dipchand A, Starling R, et al. +J Heart Lung Transplant. +2010;29(8):914-956. +165. +National Transplant Data. +UNOS/HRSA website. +Retrieved +October 12, 2012, from http://www.optn.transplant.hrsa.gov/ +latestData. +166. +Esker B, Cooper DKC. +Overcoming the barriers to xenotrans- +plantation: prospects for the future. +Exp Rev Clin Immunol. +2010;6(2):219-230. +167. +Schuurman HJ. +Clin Transplant. +2011;25(4):E415-E421. +168. +Dooldeniya MD, Warrens AN. +Xenotransplantation: where +are we today? +J R Soc Med. +2003;96:111. +169. +Thompson P, Badell IR, Lowe M, et al. +Am J +Transplant. +2012;12(7):1765-1775. +170. +Hering BJ, Cooper DKC, Cozzi E, et al. +Xenotransplantation. +2009;16:196-202. +171. +Schuurman HJ. +Regulatory aspects of pig-to-human islet +transplantation. +Xenotransplantation. +2008;15(2):116-120. +172. +Schuurman HJ. +Xenotransplantation. +2009;16(4):215-222. +173. +Dorling A. +Clinical xenotransplantation: pigs might fly? +Am J +Transplant. +2002;2:695. +174. +Greenstein JL, Schuurman H-J. +Solid organ xenotransplanta- +tion: progress, promise, and regulatory issues. +J Comm Bio- +tech. +2001;8:15-29. +363 +T +RANSPLANTATION +CHAPTER 11 +175. +Thompson P, Badell IR, Lowe M, et al. +Islet xenotransplanta- +tion using gal-deficient neonatal donors improves engraftment +and function. +Am J Transplant. +2011;11:2593-2602. +176. +Rood PPM, Cooper DKC. +Islet xenotransplantation: are +we really ready for clinical trials? +Am J Transplant. +2006; +6(6):1269-1274. +177. +Mihalicz D, Rajotte R, Rayat G. +Porcine islet xenotransplan- +tation for the treatment of type I diabetes. +In: Type I Diabe- +tes: Pathogenesis, Genetics and Immunotherapy. +New York: +InTech; 2011:479-502. +178. +Beckwith J, Nyman JA, Flanagan B, et al. +A health-economic +analysis of porcine islet xenotransplantation. +Xenotransplan- +tation. +2010;17:233-242. +179. +Elliot RB, Living Cell Technologies, Ltd. +Towards xenotrans- +plantation of pig islets in the clinic. +Curr Opin Organ Trans- +plant. +2011;16(2):195-200. +180. +Marigliano M, Bertera S, Grupillo M, et al. +Pig-to-nonhuman +primate pancreatic islet xenotransplantation: an overview. +Curr Diab Rep. +2011;11(5):402-412. +181. +Dufrane D, Gianello P. +Transplant Rev (Orlando). +2012;26: +183-188. +This page intentionally left blank +Patient Safety +Catherine L. +Chen, Michol A. +Cooper, +Mark L. +Shapiro, Peter B. +Angood, and Martin +A. +A single error can even destroy a surgeon’s +career. +Other +high-risk industries have managed to maintain an impeccably +low error rate. +For example, one of the highest risk systems in +existence today, the U.S. +Navy’s nuclear submarine program, +has an unmatched safety record. +• People trust one another. +• People have friendly, open relationships emphasizing cred- +ibility and attentiveness. +The IOM report brought much-needed attention to the +field of patient safety. +7 Patient rapport is the most important determinant of + malpractice claims against a surgeon. +Her father, Sidney +Zion, a lawyer and columnist for the N.Y. +These recommendations +were adopted by New York State in 1989. +Context: Are we improving the safety culture? +Outcome Process +Structure +Figure 12-1. +Donebedian model for measuring quality. +(From +Makary et al,6 with permission.) +and evidence-based medicine). +Intimidation of other OR personnel by surgeons +was historically accepted as the norm. +This can prevent nurses +and other OR staff from pointing out potential errors or mis- +takes. +Moreover, this culture is not limited to the OR. +The +hospital was sued by the two women’s families and by one +of the doctors disciplined. +• I am encouraged by my colleagues to report any patient safety +concerns I may have. +• The culture in this clinical area makes it easy to learn from +the mistakes of others. +• Medical errors are handled appropriately in this clinical area. +• I know the proper channels to direct questions regarding +patient safety in this clinical area. +• I receive appropriate feedback about my performance. +• I would feel safe being treated here as a patient. +• In this clinical area, it is difficult to discuss mistakes. +Scores can be compared to those of +other participating institutions to compare safety climates. +Teamwork is dependent on the underlying culture and patterns +of communication. +12-2). +Root causes of sentinel events 2004 to +2012. +(From Makary et al,17 with permission from Else- +vier. +It is +also associated with higher job satisfaction ratings and less sick +time taken from work. +12-3). +Similar +discrepancies have been found in ICUs. +Differences in teamwork perceptions between sur- +geons and operating room (OR) nurses. +(From Makary et al,17 with +permission. +CRNA = certified registered nurse anesthetist. +Source: From Makary et al,17 with permission from Elsevier. +©2006 by the American College of Surgeons. +Table 12-3 +Five-point operating room briefing +What are the names and roles of the team members? +Is the correct patient/procedure confirmed? +(The Joint + Commission Universal Protocol [TIME-OUT]) +Have antibiotics been given? +(if appropriate) +What are the critical steps of the procedure? +What are the potential problems for the case? +Source: From Makary et al,19 with permission from Elsevier. +©2007 by +the American College of Surgeons. +Briefings often are locally adapted to the specific needs +of the specialty. +Figure 12-5. +Incidence of identification errors +observed per 1000 specimens (n = 21,351). +(From Makary et al,22 with permission. +Copy- +right Elsevier.) +Figure 12-4. +World Health Organization surgical safety checklist. +(Reproduced with permission from World Health Organization Safe Sur- +gery Saves Lives. +Available at: http://www.who.int/patientsafety/safesurgery/en/. +Yes +Is the site marked? +Yes +Not applicable +Yes +Yes +No +Yes +Difficult airway or aspiration risk? +No +Yes, and equipment/assistance available +Risk of >500ml blood loss (7ml/kg in children)? +Confirm the patient’s name, procedure, +and where the incision will be made. +Has antibiotic prophylaxis been given within +the last 60 minutes? +How long will the case take? +What is the anticipated blood loss? +To Anaesthetist: +Are there any patient-specific concerns? +To Nursing Team: +Has sterility (including indicator results) +been confirmed? +Are there equipment issues or any concerns? +This checklist is not intended to be comprehensive. +Additions and modifications to fit local practice are encouraged. +Not applicable +Is the anaesthesia machine and medication +check complete? +Is the pulse oximeter on the patient and +functioning? +Known allergy? +This makes sign outs +a very vulnerable process of care, which can lead to catastrophic +events. +Sign outs +should occur whenever a patient’s care setting or provider is +changing. +. +12-6). +She spent 10 days in the pediatric intensive care unit and was well on her way to recovery. +Around 1 p.m. +the next day, a nurse came to Josie’s bedside with a syringe of methadone. +Josie’s heart stopped, and her +eyes became fixed. +She was moved to the pediatric intensive care unit and placed on life support. +Two days later, on February 22, +2001, she died from severe dehydration. +Figure 12-6. +Impact of operating room briefings on team- +work and communication. +(From Makary et al,19 with per- +mission from Elsevier. +Decision making +utilized input +from relevant +personnel. +Surgery and +anesthesia +worked together +as a well- +coordinated +team. +They can identify potential +safety problems that merit further investigation. +These process and +outcome measures are detailed in Table 12-5. +hospitals participate in the program. +Several insights about patient safety have arisen as a result +of NSQIP. +This survey is conducted in 41 regions that +cover over half of the U.S. +population and 62% of all hospital +beds in the country. +In 2011, more than 1200 urban, suburban, +and rural hospitals participated in the survey. +This +information can be viewed at hospitalsafetyscore.org. +Coronary artery bypass graft ≥450/100 +2. +Percutaneous coronary intervention ≥400/75 +3. +Abdominal aortic aneurysm repair ≥50/22 +4. +Aortic valve replacement ≥120/22 +5. +Pancreatic resection ≥11/2 +6. +Esophagectomy ≥13/2 +7. +Bariatric surgery >100/20 +Source: From The Leapfrog Group,34 with permission. +The second Global Patient Safety Challenge focuses +on improving the safety of surgical care. +Criteria for inclusion as a “never event” are +listed below. +Source: From National Quality Forum,36 with permission. +But the program was shut +down by this event. +Of these, mortality was reported in 6.6%, permanent +injury in 33%, and temporary injury in 59%. +The cost of the +never events totaled $1.3 billion. +The decision to remove these retained needles +depends on symptoms and patient preference. +Retained +surgical sponges should always be removed. +It is difficult +to determine the true incidence of wrong-site surgery for several +reasons. +Another factor is that wrong-site surgery is underreported +by healthcare providers. +Finally, the total number of potential +opportunities for each type of wrong-site error is unknown. +The protocol has been endorsed by more +than 50 professional associations and organizations. +Through this, over the next year, most hospitals +decreased their mortality rate to below 2%. +Transparency in healthcare is becoming central to the +healthcare quality discussion. +• Perform an operating room briefing (checklist) to identify +and mitigate hazards early. +• Promote a culture of speaking up about safety concerns. +• Use a screening x-ray to detect foreign bodies in high-risk +cases. +• Begin patient sign-outs with the most likely immediate +safety hazard. +Source: Reproduced with permission from Michaels RK, et al. +Ann Surg 245:526, 2007. +Most surgical errors occur in +the OR and are technical in nature. +Physicians’ fear of litigation represents +a major barrier to error disclosure. +Its average payout in 2005 was $16,000 per +settlement, vs. +This model also was replicated at +the University of Michigan Health System with similar results. +In addition, University of +Michigan doctors, patients, and lawyers are happier with this +system. +Individual errors can cause minor or major com- +plications during or after a surgical procedure. +Complications in Minor Procedures +Central Venous Access Catheters. +Complications of central +venous access catheters are common. +• Experienced personnel should insert the catheter or should +supervise the insertion. +• Use proper positioning and sterile technique. +• Ultrasound is recommended for internal jugular vein insertion. +• All central catheters should be removed as soon as possible. +Common complications of central venous access include +the following. +Prevention +requires proper positioning of the patient and correct insertion +technique. +If the patient is symptomatic, a thoracostomy tube should +be placed. +This +usually creates sufficient compromise that a tube thoracostomy +is required. +A prompt chest x-ray and close monitoring of the +patient until retrieval are indicated. +Treatment may prove +futile if the air bolus is larger than 50 mL, however. +Nearly 15% of hospital- +ized patients will acquire central venous line sepsis. +The required treatment +is 4 to 6 weeks of tailored antibiotic therapy. +Arterial Lines. +Arterial lines are placed to facilitate arterial +blood gas sampling and hemodynamic monitoring. +Although complications occur less than 1% of the time, they +can be catastrophic. +Pseudoaneurysms and arteriovenous fistulae can also occur. +Endoscopy and Bronchoscopy. +The principal risk of gas- +trointestinal (GI) endoscopy is perforation. +In +obtunded or elderly patients, a change in clinical status may take +24 to 48 hours. +When diagnosed in a timely fashion, they are rarely life +threatening. +If biopsies have been performed, +the risk for these complications increases. +Tracheostomy. +A recent literature review examining early +(<3–7 days) vs. +Complications and outcomes between the +two different methods remain largely equivalent. +The most dramatic complica- +tion of tracheostomy is tracheoinnominate artery fistula (TIAF) +(Fig. +12-7).58,59 This occurs rarely (~0.3%) but carries a 50% to +80% mortality rate. +TIAFs can occur as early as 2 days or as +late as 2 months after tracheostomy. +A sentinel bleed occurs in +50% of TIAF cases, followed by a large-volume bleed. +This illustration depicts improper positioning of the +percutaneous needle. +the innominate artery while preparation for a more definitive +approach is organized. +Percutaneous Endogastrostomy. +Tube Thoracostomy. +Chest tube insertion is performed for +pneumothorax, hemothorax, pleural effusions, or empyema. +Complications of Angiography. +Invasive or noninvasive +imaging studies confirm the suspected problem. +Initial management is direct compression at +the access site and resuscitation as indicated. +Renal complications of angiography occur in 1% to 2% +of patients. +Nonionic contrast also may be of benefit +in higher-risk patients. +Complications of Biopsies. +Bleeding at a biopsy +site usually can be controlled with direct pressure. +Organ System Complications +Neurologic System. +The nerve injury may be a stretch injury or an +unintentionally severed nerve. +Mental status changes in the postoperative patient can +have numerous causes (Table 12-12). +Mental status changes +must be continually assessed. +A noncontrast CT scan should be +used early to detect new or evolving intracranial causes. +Neurologic consultation should be obtained immediately to +confirm the diagnosis. +DESs do require systemic +antiplatelet therapy due to the alternative coagulation path- +way. +Duration of antiplatelet therapy of 1 year is routine. +Eyes, Ears, and Nose. +Corneal abrasions are unusual, but +are due to inadequate protection of the eyes during anesthesia. +Overlooked contact lenses in patients occasionally may cause +conjunctivitis. +The use of antibiotics for posterior +packing is controversial. +External otitis and otitis media occasionally occur post- +operatively. +Thyroid and Parathyroid Glands. +Recurrent laryngeal nerve (RLN) injury occurs in less than +5% of patients. +Of those with injury, approximately 10% are +permanent. +Dissection near the inferior thyroid artery is a com- +mon area for RLN injury. +The cord on the affected side will be in the paramedian +position. +With bilateral RLN injury, the chance of a successful +extubation is poor. +If paralysis of the cords is not permanent, +function may return 1 to 2 months after injury. +Respiratory System. +Hypotension, hypoxemia, and tracheal deviation +away from the affected side may be present. +A tension pneumo- +thorax can cause complete cardiovascular collapse. +Treatment +is by needle thoracostomy, followed by tube thoracostomy. +The +chest tube is inserted at the fifth intercostal space in the anterior +axillary line. +Hemothoraces should be evacuated completely. +Delay in +evacuation of a hemothorax leaves the patient at risk for empy- +ema and entrapped lung. +Fiberoptic bronchoscopy can be useful to clear +mucous plugs and secretions. +Aspiration complications include pneumonitis and pneu- +monia. +Antibiotics +are not indicated. +Not all patients can be weaned easily from mechanical +ventilation. +o2). +Lipids, carbohydrates, and protein have dif- +fering effects on CO2 production. +Patients consuming a diet of +mostly carbohydrates have an RQ of 1 or greater. +Ideally, an RQ of 0.75 to 0.85 suggests +adequate balance and composition of nutrient intake. +The occurrence of PE is probably underdiagnosed. +Its + etiology is thought to stem from DVT. +The Greenfield filter has +been most widely studied, and it has a failure rate of less than +4%. +Retrievable filters, +however, must be considered as permanent. +In most studies, the +actual retrievable rate only reached about 20%. +However, IVC filters do not prevent +PEs that originate from DVTs of the upper extremities. +Cardiac System. +Ventricular arrhythmias and other tachyarrhythmias may +occur in surgical patients as well. +Cardiac ischemia is a cause of postoperative mortality. +The workup to rule out an AMI includes an ECG and cardiac +enzyme measurements. +The patient should be transferred to a +monitored (telemetry) floor. +Gastrointestinal System. +These have lower leak rates, but leaks result in +mediastinitis and can be difficult to control. +Postoperative ileus is related to dysfunction of the neural +reflex axis of the intestine. +Excessive narcotic use may delay +return of bowel function. +Erythromycin is a motilin +agonist that works throughout the stomach and bowel. +When it does occur, adhesions are usu- +ally the cause. +Internal and external hernias, technical errors, +and infections or abscesses are also causative. +GI bleeding can occur perioperatively (Table 12-14). +Errors in surgery that cause hyperbilirubinemia largely +involve missed or iatrogenic injuries. +The presence of cirrhosis predisposes to postoperative +complications. +Abdominal or hepatobiliary surgery is problem- +atic in the cirrhotic patient. +Spirono- +lactone with other diuretic agents may be helpful in the post- +operative care. +The treatment is long-term +antibiotics with percutaneous drainage of large abscesses. +Pancreatitis can occur following injection of contrast dur- +ing cholangiography and ERCP. +A pancreatic fistula may +respond to antisecretory therapy with a somatostatin analogue. +The majority of pancreatic fistulae +will eventually heal spontaneously. +Renal System. +The +most common cause is a misplaced or clogged urinary catheter. +Oliguria is initially evaluated by flushing the urinary cath- +eter using sterile technique. +Urine electrolytes should also be +measured (Table 12-15). +A hemoglobin and hematocrit level +should be checked immediately. +Hepatobiliary-Pancreatic System. +Complications involv- +ing the hepatobiliary system are usually due to technical errors. +The recommended treatment +is a Roux-en-Y hepaticojejunostomy. +These patients may +present with abdominal pain and hyperbilirubinemia. +The diag- +nosis of a biliary leak can be confirmed by CT scan, ERCP, or +radionuclide scan. +Intrinsic renal +failure and subsequent ATN are often the result of direct renal +toxins. +Contrast-induced nephropathy usually leads to a subtle or +transient rise in creatinine. +Mannitol and furosemide are not +recommended. +Patients who do not respond to resuscitation are +at risk for needing renal replacement therapy. +Fortunately, most +of these patients eventually recover from their renal dysfunction. +Musculoskeletal System. +A compartment syndrome can +develop in any compartment of the body. +Compartment syn- +drome of the extremities generally occurs after a closed fracture. +Routine skin care and turning of the patient +help ensure a reduction in skin ulceration. +This can be labor +intensive, and special mattresses and beds are available to help. +The treatment of a decubitus ulcer in the noncoagulopathic +patient is surgical débridement. +Earlier rates were +erroneously reported higher due to lack of contemporary technology. +bHBV is reported with pre-nucleic acid amplification technology. +HBV = hepatitis B virus; HCV = hepatitis C virus. +dressings with frequent dressing changes is the alternative and is +labor intensive. +Expensive topical enzyme preparations are also +available. +If the wounds fail to respond to these measures, soft +tissue coverage by flap is considered. +Contractures are the result of muscle disuse. +Hematologic System. +Transfusion reactions are common complications of blood +transfusion. +These can be attenuated with a leukocyte filter, but +not completely prevented. +Severe transfusion reactions are rare but +can be fatal. +One unit of platelets will +increase the platelet count by 5000 to 7500 per mL in adults. +It is important to delineate the cause of the low platelet count. +Rarely, it is due to heparin-induced thrombocytopenia I +and II. +The treatment is +anticoagulation with synthetic agents such as argatroban. +Factor VIIa use may also be limited due to its potential throm- +botic complications. +Other blood dyscrasias seen by surgeons include hyper- +coagulopathic patients. +Abdominal Compartment Syndrome. +Wounds, Drains, and Infection +Wound (Surgical Site) Infection. +Prophylactic use of antibiotics should sim- +ply not be continued beyond this time. +Overtreating colonization is just as injurious as undertreating +infection. +The strict definition of wound (soft tissue) infection is +more than 105 CFU per gram of tissue. +Drain Management. +They prevent premature closure of an abscess cavity +in a contaminated wound. +The risk of surgery is far greater than the +placement of an image-guided drain. +Urinary Catheters. +The most frequent nosocomial infection is urinary tract +infection (UTI). +These infections are classified into compli- +cated and uncomplicated forms. +The uncomplicated type is a +UTI that can be treated with outpatient antibiotic therapy. +The interpretation of urine culture results of less +than 100,000 CFU/mL is controversial. +Undertreatment or misdiagnosis +of a UTI can lead to urosepsis and septic shock. +Recommendations are mixed on the proper way to treat +Candida albicans fungal bladder infections. +Replacement of +the urinary catheter and a course of fluconazole are appropriate +A +B +Figure 12-8. +treatments, but some infectious disease specialists claim that +C. +albicans in the urine may serve as an indication of fungal +infection elsewhere in the body. +Empyema. +One of the most debilitating infections is an +empyema, or infection of the pleural space. +Once the specific +organisms are confirmed, anti-infective agents are tailored +appropriately. +Refractory empyemas require specialized surgical +approaches. +Abdominal Abscesses. +Necrotizing Fasciitis. +septicum, carry a mortality +of 30% to 70%. +S. +Systemic Inflammatory Response Syndrome, Sepsis, +and Multiple-Organ Dysfunction Syndrome. +SIRS is the result of proin- +flammatory cytokines related to tissue malperfusion or injury. +Sepsis is categorized as sepsis, severe sepsis, and septic +shock. +Sepsis is SIRS plus infection. +Severe sepsis is sepsis +plus signs of cellular hypoperfusion or end-organ dysfunction. +Septic shock is sepsis plus hypotension after adequate fluid +resuscitation. +Nutritional and Metabolic Support +Complications +Nutrition-Related Complications. +Slow progression of the enteral feeding administration rate +can avoid this complication. +Common TPN problems are mostly related to electrolyte +abnormalities that may develop. +Glycemic Control. +In addi- +tion, some studies find no relationship between glycemic control +and improved outcomes. +When +this is performed, glycemic control is enhanced and hypoglyce- +mia is avoided. +Metabolism-Related Complications. +A rapid provocative +test with synthetic adrenocorticotropic hormone may confirm +the diagnosis. +After a baseline serum cortisol level is drawn, +250 μg of cosyntropin is administered. +Problems with Thermoregulation +Hypothermia. +Bradycardia occurs with temperatures below 30°C +(86°F). +It is well known that hypothermia may induce CO2 +retention, resulting in respiratory acidosis. +Whether this is a worthwhile practice or not may be contro- +versial. +Hyperthermia. +Aggressive cooling meth- +ods are also implemented, such as an alcohol bath, or packing +in ice. +In cases of severe malignant hyperthermia, the mortality +rate is nearly 30%. +Thyrotoxicosis can occur after surgery due to undiag- +nosed Graves’ disease. +As +the name suggests, these patients are usually toxic and require +supportive measures as well. +1. +Bierly PE III, Spender JC. +Culture and high reliability orga- +nizations: the case of the nuclear submarine. +J Manage. +1995;21:639. +2. +Ruchlin HS, Dubbs NL, Callahan MA. +The role of leadership +in instilling a culture of safety: lessons from the literature. +J 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+2013;12(6):546-553. +144. +Georgiou AP, Manara AR. +Br J Anaesth. +2013;110(3):357-367. +145. +Peterson K, Carson S, Carney N. +Hypothermia treatment for +traumatic brain injury: a systematic review and meta-analysis. +J Neurotrauma. +2008;25(1):62-71. +146. +Schulman CI, Namias N, Doherty J, et al. +Surg Infect. +2005;6(4):369-375. +147. +O’Donnell J, Axelrod P, Fisher C, et al. +Use and effectiveness +of hypothermia blankets for febrile patients in the intensive +care unit. +Clin Infect Dis. +1977;24:1208. +This page intentionally left blank +Physiologic Monitoring of the +Surgical Patient +Louis H. +Alarcon and Mitchell P. +Also presented is a brief look at emerging techniques +that may soon enter into clinical practice. +Delivery of oxygen +to mitochondria may be insufficient for several reasons. +These factors include the hor- +monal milieu and mechanical workload of contractile tissues. +Arterial blood pressure is a complex function of +both cardiac output and vascular input impedance. +Several +methods exist for this purpose. +Systolic pressure is defined as the pressure in the cuff when tap- +ping sounds are first audible. +Diastolic pressure is the pressure +in the cuff when audible pulsations first disappear. +Unfortunately, this approach is neither accurate nor reliable. +A number of automated devices are capable of repetitively +measuring blood pressure noninvasively. +Therefore, the width of the cuff should be approximately +40% of its circumference. +This could +result in the use of monitoring data to make inappropriate +clinical decisions. +Under +these conditions, the pressure in the cuff reflects the pressure +in the digital artery. +Digital values for systolic and diastolic pressure +also are displayed. +Other sites include +the femoral and axillary artery. +Distal ischemia is an uncommon complication of intra- +arterial catheterization. +Catheter-related +infections can occur with any intravascular monitoring device. +The limb leads are defined as lead I (LA-RA), +lead II (LL-RA), and lead III (LL-LA). +To detect 95% +of the ischemic episodes, two or more precordial leads were +necessary. +determinants of Cardiac Performance +Preload. +Thus, cardiac preload is determined by end-diastolic vol- +ume (EDV). +The presence of atrioventricular +valvular stenosis may alter this relationship. +Ventricular compliance +is altered by various pathologic conditions and pharmacologic +agents. +Afterload. +Contractility. +Contractility is defined as the inotropic state +of the myocardium. +These end-systolic points on the pres- +sure vs. +volume diagram describe a straight line, known as the +end-systolic pressure-volume line. +A steeper slope of this line +indicates greater contractility. +One channel terminates in a balloon at the tip of +the catheter. +Prior to insertion of the PAC, the integrity of the +balloon should be verified by inflating it. +One of these channels terminates at the tip of the catheter. +The +other terminates 20 cm proximal to the tip. +Placement of a PAC requires access to the central venous +circulation. +Percutaneous placement through either the jugular or +subclavian vein generally is preferred. +A small-bore needle is +inserted through the skin and subcutaneous tissue into the vein. +A dilator/introducer sheath is passed over +the wire, and the wire and the dilator are removed. +The equations used to calculate the derived +parameters are summarized in Table 13-2. +Measurements of +QT using the thermodilution technique are simple and reasonably +accurate. +The measurements can be performed repetitively and +the principle is straightforward. +to zero. +In +clinical practice, the Stewart-Hamilton equation is solved by a +microprocessor. +Changes in blood tem- +perature and QT during the respiratory cycle can influence the +measurement. +The Fick equation +can be rearranged as follows: CVO2 = Cao2 – VO2/QT. +Thus it can be seen that SVO2 is a func- +tion of VO2 (i.e., metabolic rate), QT, Sao2, and Hgb. +Therefore for practical purposes, mea- +surements of SVO2 can be performed only intermittently. +By adding a fifth channel to the PAC, it has become pos- +sible to monitor SVO2 continuously. +There was a significantly higher rate of pul- +monary emboli in the PAC group (0.9% vs. +0%). +There +was no difference in hospital mortality between the 2 groups +(with PAC 68% vs. +without PAC 66%, p = 0.39). +Clearly, these were critically ill patients, as noted by the high +hospital mortality rates. +There was no +formal treatment protocol, but inotropic support was discouraged. +Substantial reduction in symptoms, jugular venous pressure, and +edema was noted in both groups. +without PAC 9%). +Adverse events were more common among +patients in the PAC group (21.9% vs.11.5%; P = 0.04). +There was a 1% rate of crossover from +CVC-guided therapy to PAC-guided therapy. +Certainly, given the available evidence, routine use +2 of the PAC cannot be justified. +Defining what constitutes the optimum cardiac output, +however, has proven to be difficult. +As a +result, the marginal benefit now available by placing a PAC may +be quite small. +Less invasive modalities are available that may +provide clinically useful hemodynamic information. +Several approaches +have been developed, which have achieved variable degrees of +success. +doppler ultrasonography. +Therefore, measurements of the +Doppler shift can be used to calculate red blood cell velocity. +Two approaches have been developed for using Dop- +pler ultrasonography to estimate QT. +A second more promising, albeit more invasive, approach +has been introduced. +FTc is a function of preload, +contractility, and vascular input impedance. +This methodology is called impedance cardiog- +raphy. +The vast majority of +pulsatile flow is related to blood moving within the aorta. +Partial carbon dioxide +(CO2) rebreathing uses the Fick principle to estimate QT non- +invasively. +TEE requires that the patient +be sedated and usually intubated for airway protection. +Doppler techniques allow estimation of atrial filling +pressures. +Assessing Preload Responsiveness. +Thus, if QT +is low, some other means must be employed to estimate pre- +load. +Many clinicians assess the adequacy of cardiac preload by +determining CVP or PAOP. +StO2 and BD were +also comparable in predicting mortality. +Many of +these patients require mechanical ventilation. +When indicated, carboxyhemoglobin and methemoglobin levels +also can be measured. +Continuous monitor- +ing, however, is expensive and is not widely employed. +DO2 also is dependent on QT +and Hgb. +Thus, when Sao2 is low, the clinician has only a limited +number of ways to improve this parameter. +It is considered one of the most important and +useful technologic advances in patient monitoring. +Under normal circumstances, the contributions of carboxyhe- +moglobin and methemoglobin are minimal. +Capnometry is most commonly +measured by infrared light absorption. +CO2 absorbs infrared light +at a peak wavelength of approximately 4.27 μm. +Capnometers are configured with either an in-line sensor or +a sidestream sensor. +The in-line devices +are bulky and heavier, but are less likely to become clogged. +A number of situations can be promptly detected +with continuous capnography. +Causes of +an increase in Petco2 include reduced minute ventilation or +increased metabolic rate. +With a patent Foley catheter, urine output is a gross +indicator of renal perfusion. +Oligu- +ria is a cardinal sign. +While the diagnosis of ACS is a clinical +one, measuring IAP is useful to confirm the diagnosis. +CPP is equal to the difference between MAP and ICP: +CPP = MAP – ICP. +These devices can be placed in the +intraventricular, parenchymal, subdural, or epidural spaces. +It is especially useful in obtunded and comatose patients. +They also can provide prognostic data +in posttraumatic coma. +Normal +values for PbtO2 are 20 to 40 mm Hg, and critical levels are +8 to 10 mm Hg. +Goals of therapy +in both groups included maintaining an ICP <20 mm Hg and +a CPP >60 mm Hg. +Among patients with PbtO2 monitoring, +therapy also was directed at maintaining PbtO2>25 mm Hg. +The +groups had similar mean daily ICP and CPP levels. +REFERENCEs +Entries highlighted in bright blue are key references. +1. +Bur A, Herkner H, Vlcek M, et al. +Crit Care Med. +2003;31(3):793-799. +2. +Fischer MO, Avram R, Carjaliu I, et al. +Br J Anaesth. +2012;109(4):514-521. +3. +Traore O, Liotier J, Souweine B. +Crit Care Med. +2005;33(6):1276-1280. +4. +Landesberg G, Mosseri M, Wolf Y, Vesselov Y, Weissman C. +Anesthesiology. +2002;96(2):264-270. +5. +Yu H, Pi-Hua F, Yuan W, et al. +J Electrocardiol. +2012;45(1): +60-65. +6. +Chen WL, Tsai TH, Huang CC, Chen JH, Kuo CD. +Resuscitation. +2009;80(10)1114-1118. +7. +Hravnak M, Edwards L, Clontz A, et al. +Arch Intern +Med. +2008;168(12):1300-1308. +8. +Hayashi H, Amano M. +Does ultrasound imaging before puncture 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Trauma F, American Association of Neurological S, Con- +gress of Neurological S, et al. +Guidelines for the management of +severe traumatic brain injury. +IX. +Cerebral perfusion thresholds. +J Neurotrauma. +2007;24 Suppl: 1S59-1S64. +58. +Cremer OL, van Dijk GW, van Wensen E, et al. +Crit Care Med. +2005;33(10):2207-2213. +59. +Sigl JC, Chamoun NG. +An introduction to bispectral analysis for +the electroencephalogram. +J Clin Monit. +1994;10(6):392-404. +60. +Gan TJ, Glass PS, Windsor A, et al. +BIS Utility Study +Group. +Anesthesiology. +1997;87(4):808-815. +61. +Simmons LE, Riker RR, Prato BS, Fraser GL. +Crit Care +Med. +1999;27(8):1499-1504. +62. +Qureshi AI, Sung GY, Razumovsky AY, et al. +Crit Care Med. +2000;28(4):984-990. +63. +Czosnyka M, Matta BF, Smielewski P, Kirkpatrick PJ, Pick- +ard JD. +J Neurosurg. +1998;88(5):802-808. +64. +Feldman Z, Robertson CS. +Monitoring of cerebral hemodynam- +ics with jugular bulb catheters. +Crit Care Clin. +1997;13(1):51-77. +65. +Vigue B, Ract C, Benayed M, et al. +Early SjvO2 monitor- +ing in patients with severe brain trauma. +Intens Care Med. +1999;25(5):445-451. +66. +Murkin JM, Arango M. +Near-infrared spectroscopy as an index +of brain and tissue oxygenation. +Br J Anaesth. +2009;103 Suppl: +1i3-li13. +67. +Stiefel MF, Spiotta A, Gracias VH, et al. +J Neurosurg. +2005;103(5):805-811. +Spight, John G. +Hunter, and Blair A. +It is not a discipline unto itself, but more a philosophy of +surgery, a way of thinking. +As public awareness has grown, so too has its spread outside of +larger institutions. +The primary advantage of SILS is the +reduction to one surgical scar. +Clinically the +transvaginal approach has been studied the most extensively. +Subsequently, CO2 and N2O were used for inflating the +abdomen. +N2O had the advantage of being physiologi- +cally inert and rapidly absorbed. +As such, caution should be exercised when perform- +ing laparoscopic cancer surgery with this agent. +Finally, the +safety of N2O pneumoperitoneum in pregnancy has yet to be +elucidated. +14-1). +CO2 is rapidly absorbed across the +peritoneal membrane into the circulation. +means of performing procedures that previously required a celi- +otomy. +Moreover, MRI magnets +are bulky and limit the surgeon’s access to the patient. +(Reproduced with +permission from Hunter JG, ed. +Bailliere’s Clinical Gastroenterol- +ogy Laparoscopic Surgery. +London/Philadelphia: Bailliere Tindall; +1993:758. +The most common arrhythmia created by laparoscopy is brady- +cardia. +The pathophysiology and management are +discussed at the end of this section. +Endocrine responses to laparoscopic surgery are not +always intuitive. +Immune suppression +also is less after laparoscopy than after open surgery. +Thoracoscopy +The physiology of thoracic MIS (thoracoscopy) is different +from that of laparoscopy. +By collapsing the ipsilateral lung, working space +within the thorax is obtained. +14-2). +Balloons are used to create extra-anatomic working +spaces. +influence cardiovascular performance by reducing or removing +the CO2 pneumoperitoneum. +MIS procedures +are often outpatient procedures, so short-acting anesthetic agents +are preferable. +The video monitor(s) should be set across the operating table +from the surgeon. +14-3). +Patient Positioning +Patients usually are placed in the supine position for laparo- +scopic surgery. +The legs may be elevated in Allen stirrups +or abducted on leg boards to achieve this position. +14-4). +Once the robot is docked to the patient, the bed cannot +be moved without undocking. +Figure 14-3. +An example of a typical minimally invasive surgery +suite. +All core equipment is located on easily movable consoles. +The nares, mouth, urethra, +and anus are used to access the respiratory, GI, and urinary sys- +tems. +The advantage of using these points of access is that no +incision is required. +The disadvantages lie in the long distances +between the orifice and the region of interest. +Similarly, the peritoneal cavity may be reached through the side +wall of the stomach or colon. +vessel, usually in the groin. +In these procedures, +general anesthesia and single lung ventilation are essential. +14-5). +The umbilicus usually is selected as the preferred +Figure 14-5. +A. +B. +The abdomen is inflated +with a pressure-limited insufflator. +CO2 gas usually is used, with +maximal pressures in the range of 14 to 15 mmHg. +14-6). +After peritoneal insufflation, direct access to the abdomen +is obtained with a 5- or 10-mm trocar. +A fin- +ger is placed into the abdomen to make sure that there is no +adherent bowel. +14-7). +Rapid insufflation can make up for some of the time lost with +the initial dissection. +It is essential to be able to interpret the insufflator +pressure readings and flow rates. +These readings indicate proper +intraperitoneal placement of the Veress needle. +Figure 14-7. +It is generally agreed that 5-mm trocars need no site sutur- +ing. +For retroperitoneal locations, balloon dissection is effec- +tive. +The balloon is inflated in the extraperitoneal +space to create a working chamber. +Higher gas pressures force CO2 into the soft tissues and may +contribute to hypercarbia. +14-8).45,46 Once the saphenous vein is +A +B +Figure 14-8. +A. +B. +Harvest of muscle, nerve, fascia, and vein. +In: Bostwick J III, Eaves +FE III, Nahai F, eds. +Endoscopic Plastic Surgery. +St Louis: Qual- +ity Medical Publishing, Inc.: Quality Medical Publishing, Inc.; +1995:542. +A small incision above the knee also can be +used to ligate perforating veins in the lower leg. +It is easier to hide several 5-mm incisions than one +long incision. +Some prefer gas insufflation of these soft tissue planes. +14-9). +Remaining trocars are 8 mm. +The ease of decontamination, +entry, and closure of these structures create variable challenges. +The esophagus can be traversed to +enter the mediastinum. +14-10). +Closure has been performed using endo- +scopic clips or sutures with advanced endoscopic platforms. +The advantage of this tech- +nique is that conventional laparoscopic tools can be employed. +This is an example of hand-assisted laparoscopic surgery during left colectomy. +This +technique is particularly useful in the region of the transverse colon. +Figure 14-10. +Submucosal tunnel technique for transesophageal mediastinoscopy. +(Reproduced with permission from Khashab MA, Kalloo +AN. +NOTES: current status and new horizons. +Gastroenterology. +2012;142:704-710. +© 2012 by the AGA Institute.) +C +D +E +AB +is needed. +14-11A,B). +The major disad- +vantage is cost. +14-12). +As a result, the surgeon must often work in a crossed hands fash- +ion (Fig. +14-13). +A. +Specialized multilumen trocars can facilitate instrument placement. +B. +(Illustration by Corinne Sandone. +© 2014 JHU. +The distance between the left and the right +hand is also ideally 10 to 15 cm. +In this “baseball diamond” con- +figuration, the surgical target occupies the second base position. +Figure 14-13. +(Illustration +by Corinne Sandone. +© 2014 JHU. +Reprinted with permission.) +426 +BASIC CONSIDERATIONS +PART + +I +Figure 14-14. +A. +The laparoscope tips come in a variety of +angled configurations. +All laparoscopes have a 70° field of view. +Video cameras come in two basic designs. +To enjoy the benefit of the +clarity of HD video imaging, HD monitors also are necessary. +Without the first +two attributes, video surgery is unsafe. +Rigid telescopes may have a flat or angled end. +14-14A); rotating an angled telescope changes +the field of view. +Flexible tip +laparoscopes offer even greater optical freedom. +Light is delivered to the endoscope through a fiber-optic +light cable. +14-15). +The larger the number of line pairs per +millimeter, the sharper and more detailed the image. +Most +high- resolution monitors have up to 700 horizontal lines. +However, this technology has not yet been widely adopted. +Interest in three-dimensional (3-D) laparoscopy has waxed +and waned. +Single-incision laparoscopy presents new challenges to +visualization of the operative field. +In the traditional laparo- +scope, the light source enters the scope at a 90° angle. +That +position coupled with a bulky scope handle creates crowding in +an already limited space. +With bipolar electrosurgery, the electrons flow between +two adjacent electrodes. +The tissue between the two electrodes +is heated and desiccated. +14-16). +In addition, the integrity of the +Figure 14-15. +The video +camera is placed on the eyepiece to provide the working image. +The image is only as clear as the weakest link in the image chain. +CCD = +charge-coupled device. +An example of bipolar coagulation devices. +insulation must be maintained and assured. +14-17A). +This may result in +thermal necrosis and a delayed fecal fistula. +14-17B). +Another method of delivering RF electrosurgery is argon +beam coagulation. +Bipolar electrocoagulation is used primarily for thermal +hemostasis. +The next +most popular laser is the neodymium yttrium-aluminum garnet +(Nd:YAG) laser. +Nd:YAG laser light is 1.064 μm (1064 nm) +in wavelength. +14-18). +A disadvantage is that the deep tissue heating +may cause perforation of a hollow viscus. +When it is desirable to coagulate flat lesions in the cecum, +a different laser should be chosen. +The depth of tissue heating is intermediate, between +those of the CO2 and the Nd:YAG lasers. +A. +B. +(Reproduced with permission from Odell.58) +Figure 14-18. +(Reproduced with +permission from Hunter JG, Sackier JM, eds. +Minimally Invasive +Surgery. +Two days after administration, the drug is +endoscopically activated using a laser. +The activated porfimer +sodium generates oxygen free radicals, which kill the tumor +cells. +The tumor is later endoscopically débrided. +These devices also are inserted through thin probes for endoscopic +application. +Methods of producing shock waves or heat with ultrasonic +energy are also of interest. +Techniques such as mucosotomy, hydrodissection, and +clip application require specialized training. +14-19). +14-20). +Robotic instruments and hand controls. +Figure 14-20. +Room setup and position of surgeon and assistant for robotic surgery. +(©2013 Intuitive Surgical, Inc. +Female pelvic surgery with the da Vinci robot is also +reaching wide appeal. +14-21). +14-23). +The deployment of a metal stent across an isolated +vessel stenosis is illustrated. +(Reproduced with permission +from Hunter JG, Sackier JM, eds. +Minimally Invasive Surgery. +New York: McGraw-Hill; 1993:235.) +432 +BASIC CONSIDERATIONS +PART + +I +Figure 14-22. +Figure 14-23. +Covered self-expanding metal stents. +These devices +can be placed fluoroscopically or endoscopically. +was added to coronary stents several years ago to decrease +endothelial proliferation. +Endovascular stenting of aortic aneurysms has +nearly replaced open surgery for this condition. +14-24). +The scope is advanced +4 +433 +Minimally Invasive Surgery +CHAPTER 14 +Figure 14-24. +(Illustration by Jennifer Fairman. +© 2007 JHU. +The mucosotomy is then closed using endoscopic clips +(Fig. +14-25). +Over 1000 clinical POEM cases have been per- +formed worldwide. +14-26). +14-11). +Ports typically contain three or four +channels. +The latter often affords the ability to place a dedicated +retractor. +There are many challenges faced by the operating surgeon +in SILS procedures. +5 +434 +BASIC CONSIDERATIONS +PART + +I +A +B +Figure 14-25. +A. +Peroral endoscopic esophageal myotomy for the +treatment of achalasia. +B. +(A. +From Inoue +H, Minami H, Kobayashi Y, et al. +Peroral endoscopic myotomy +(POEM) for esophageal achalasia. +Endoscopy. +2010;42:265- +271. +Thieme. +B. +From Rieder E, Dunst CM, Kastenmeier AS, et +al. +Development and technique of peroral endoscopic myotomy +(POEM) for achalasia. +Eur Surg. +2011;43/3:140-145. +14-27). +A low-profile HD scope with or without a +deflectable tip can improve visualization greatly. +Contraindications include those true of traditional lapa- +roscopy. +Relative contraindications include previous surgery +and high body mass index (BMI). +Patients with a high BMI or +Figure 14-26. +Transanal endoscopic microsurgery scope. +(Illustration by Corinne Sandone. +© 2014 JHU. +Reprinted with +permission.) +Figure 14-27. +Example of curved instruments used in single-incision +laparoscopic surgery. +(©2013 Intuitive Surgical, Inc. +Current status of single- +incision laparoscopic surgery: European experts’ views. +Surg Laparosc +Endosc Percutan Tech. +2012;22(3):194-199. +Size and morphology of +the target organ should always be considered when doing SILS. +This is in large part due to the already improved benefits of +laparoscopic surgery. +14-28). +However, laparoscopy in +the infant and young child requires specialized instrumenta- +tion. +The instruments are shorter (15–20 cm), and many are 3 +mm in diameter rather than 5 mm. +Current status of single- +incision laparoscopic surgery: European experts’ views. +Surg Laparosc +Endosc Percutan Tech. +2012;22(3):194-199. +DVT +is rare in children, so prophylaxis against thrombosis probably +is unnecessary. +A and B. +Robotic single-incision surgery platform. +(©2013 Intuitive Surgical, Inc. +Reprinted with permission.) +436 +BASIC CONSIDERATIONS +PART + +I +20 weeks. +Fetal acidosis induced by maternal hyper- +carbia also has been raised as a concern. +Protection of the fetus against intraoperative x-rays is impera- +tive. +MIS +techniques also have been used in the staging of cancer. +All of the major abdominal cancer opera- +tions have been performed with laparoscopy. +The advantage of MIS lies in what happens after the +operation. +Much of the morbidity of surgery in the elderly is +a result of impaired mobility. +Additionally, ascitic +leak from a port site may occur, leading to bacterial peritonitis. +Therefore, a watertight port site closure should be carried out +in all patients. +This training occurred on patients. +Although such a paradigm +did not compromise patient safety, learning in the OR is costly. +Clearly, +there was a need for developing a less invasive approach +(Fig. +14-29). +The third step is in vivo stud- +ies in the most appropriate animal model. +1880 1900 1920 1940 1960 1980 1985 1990 1995 2000? +? +Open surgery +Laparoscopic surgery +Seamless surgery +Progress in Surgery +Figure 14-29. +The progress of general sur- +gery can be reflected by a series of performance +curves. +Video +optics allowed the development of minimally +invasive surgery over the last 25 years. +These steps often are called the +preclinical phase of procedure development. +The decision as to when such procedures are ready to +come out of the lab is a difficult one. +Once these three criteria are reached, +the time for human application has arrived. +Cer- +tainly if a dying cancer patient has a chance with a new drug, this +makes sense. +This may take +10 procedures, or it may take 50 procedures. +This will complete phase +I of the procedure development. +In phase II, the efficacy of the procedure is tested in a non- +randomized fashion. +These same requirements may be applied to the introduction +of new technology into the OR. +In phase III, a +randomized trial pits the new procedure against the old. +If not, further observation and assistance from the +experts are required. +Although this approach may sound obvi- +ous, it is fraught with difficulties. +Would I consider undergoing this procedure if +I developed a surgical indication? +Is the procedure as good as +or better than the procedure it is replacing? +Answering these questions in +the affirmative should be a professional obligation. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Hopkins HH. +Optical principles of the endoscope. +In: Berci +G, ed. +Endoscopy. +New York: Appleton-Century-Crofts; +1976:3. +2. +Katzir A. +Optical fibers 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H. +C. +Within cells, DNA is packed tightly into chromosomes. +15-1). +15-2). +The nucleotides are joined together by phosphodiester bonds. +The flow of genetic information from DNA to pro- +tein to cell functions. +Key historical events +concerning genetics are outlined in Table 15-1. +Figure 15-2. +Schematic representation of a DNA molecule form- +ing a double helix. +DNA is made of four types of nucleotides, +which are linked covalently into a DNA strand. +The diagram at the bot- +tom left of the figure shows the DNA molecule straightened out. +(Republished with permission of Garland Publishing, +Inc. +from Alberts B, Johnson A, Lewis J, et al. +Molecular Biology +of the Cell, 5th ed. +New York: Garland Science; 2008. +446 +BASIC CONSIDERATIONS +PART + +I +Figure 15-4. +Four major steps in the control of eukaryotic gene expression. +Note that posttranscriptional and posttranslational controls consist of several steps. +DNA replication. +In this way, double-helical DNA +can be copied precisely. +(Republished +with permission of Garland Publishing, +Inc. +from Alberts B, Johnson A, Lewis J, +et al. +Molecular Biology of the Cell, +5th ed. +New York: Garland Science; 2008. +Before a +cell divides, DNA must be precisely duplicated. +15-3). +Proofreading mechanisms ensure +that the replication process occurs in a highly accurate man- +ner. +15-4). +However, gene regulation is far more com- +plex, particularly in eukaryotic organisms. +For example, many +gene transcripts must be spliced to remove the intervening +sequences. +Transcription. +A promoter region is the +DNA region upstream of the transcription initiation site. +Consequently, few +nucleotides can be base-paired with the DNA template to begin +transcription. +Once transcription begins, the σ factor is released. +The growing RNA chain may begin to peel off as the chain +elongates. +In this way, the protein products are synthesized +in a coordinated manner. +The precursor is +then modified and/or processed into its final functional form. +(d) +RNA is made in the nucleus and transported into cytoplasm, +where translation occurs. +Therefore, unlike bacteria, eukaryotes +undergo uncoupled transcription and translation. +Translation. +DNA directs the synthesis of RNA; RNA in turn +directs the synthesis of proteins. +The process of decoding information on mRNA to synthesize +proteins is called translation (see Fig. +15-1). +Translation takes +place in ribosomes composed of rRNA and ribosomal proteins. +Because of this +decoding, the information carried on mRNA relies on tRNA. +Translation involves all three RNAs. +A codon, a triplet of three bases, codes for +one amino acid. +In this case, random combinations of the four +bases form 4 × 4 × 4, or 64 codes. +The +codons on mRNA are sequentially recognized by tRNA adaptor +proteins. +Specific enzymes termed aminoacyl-tRNA synthetases +link a specific amino acid to a specific tRNA. +Protein synthesis proceeds in the amino-to- +carboxy-terminus direction. +The biologic versatility of proteins is astounding. +They also +transport ions and various small molecules across plasma mem- +branes. +The unique functional properties of proteins are largely deter- +mined by their structure (Fig. +15-5). +Regulation of Gene Expression. +For +example, muscle and bone express different genes or the same +genes at different times. +15-4). +Each of the steps during transcription is properly regulated in +eukaryotic cells. +Letter in [ ] indicates single letter code for amino acid. +Figure 15-5. +Maturation of a functional protein. +Transcriptional control by RNA polymerase. +DNA +is packaged into a chromatin structure. +Coactivator or +corepressor is a factor linking the TF with the Pol II complex. +TF +Coactivator or +Corepressor +Pol II +Holoenzyme +TBP TBP +TATA +TFBS +dependent. +However, there is a common scheme that applies +to transcription at the molecular level (Fig. +15-6). +Human Genome +Genome is a collective term for all genes present in one organ- +ism. +15-1). +Although the potential of this field of study is vast, it is in its +early stages. +Thus, +the cell cycle is the fundamental mechanism to maintain tissue +homeostasis. +15-7). +Early G1 cyclin +D/CDK4/6 or late G1 cyclin E/CDK2 controls the G1-S transi- +tion. +The cell cycle is connected with signal transduction path- +ways as well as gene expression. +Growing cells proliferate only when supplied with +appropriate mitogenic growth factors. +Cells become committed +to entry of the cell cycle only toward the end of G1. +Meanwhile, cells also +receive antiproliferative signals such as those from tumor sup- +pressors. +For example, when DNA is damaged, cells will repair the +damage before entering the S phase. +Therefore, G1 contains one +of the most important checkpoints for cell cycle progression. +Accelerated proliferation or improper cell cycle progression with +damaged DNA would be disastrous. +In addition to cell cycle control, cells use genetically pro- +grammed mechanisms to kill cells. +15-8). +However, recent +advances in apoptosis research suggest an interconnection of +the two pathways. +The complex machinery of apoptosis must be tightly controlled. +Perturbations of this process can cause neoplastic transforma- +tion or other diseases. +15-9). +All cells have the ability to sense +changes in their external environment. +Other substances bind directly +with a transmembrane protein (cell-surface receptor). +Figure 15-7. +The cell cycle and its control system. +A complex of cyclin and cyclin- +dependent kinase (CDK) controls specific events of each phase. +Without cyclin, CDK is inactive. +Different cyclin/CDK complexes +are shown around the cell cycle. +A, B, D, and E stand for cyclin A, +cyclin B, cyclin D, and cyclin E, respectively. +A simplified view of the +apoptosis pathways. +Cell-surface and intracellular receptor pathways. +The +receptor serves as the receiver, and in turn activates the downstream +signals in the cell. +Either extracellular or intracel- +lular signals often reach the nucleus to control gene expression. +In a given cell, many signaling pathways operate +simultaneously and crosstalk with one another. +Signaling pathways often are grouped according to the +properties of signaling receptors. +Members of this superfamily share a characteristic +seven-transmembrane configuration. +Structurally, these receptors usually have only one +transmembrane-spanning domain. +Insulin is a peptide hormone that +is secreted by the β-cell of the pancreas. +Insulin +binding to InsR activates the kinase activity of InsR. +15-10). +Type 2 diabetes +accounts for about 90% of all cases of diabetes. +Although insulin and many mitogenic +Figure 15-10. +Insulin-signaling pathway. +Inactivation of the +insulin pathway can lead to type 2 diabetes. +TGF-β is one of them. +15-11). +The com- +plex consists of transmembrane serine/threonine kinases. +The +outcome of the altered gene expression leads to the inhibition +of cell cycle progression. +Resistance to TGF-β’s anticancer action is one hall- +mark of human cancer cells. +TGF-β receptors and SMADs are +identified as tumor suppressors. +Some lose TGF-β responsiveness through +downregulation or mutations of their TGF-β receptors. +The locus +encoding cell cycle inhibitor p15INK4B may be deleted. +Finally, functional pRb, the end target of this pathway, +may be lost through mutation of its gene. +Cancer is a complex disease, involving uncontrolled +growth and spread of tumor cells (Fig. +15-12). +TGF-β signaling pathway. +The TGF-β family has +at least 29 members encoded in the human genome. +They are also +peptide growth factors. +Meta- +static cancer cells that enter the bloodstream can reach virtu- +ally all tissues of the body. +Bones are one of the most common +places for these cells to settle and start growing again. +Bone +metastasis is one of the most frequent causes of pain in people +with cancer. +It also can cause bones to break and create other +symptoms and problems for patients. +The progression in the knowledge of cancer biology +has been accelerating in recent years. +As a result of +explosive new discoveries, some modern treatments were devel- +oped. +Immunotherapy. +The growth of the body is controlled by +many natural signals through complex signaling pathways. +Tumor clonal evolution and metastasis. +A tumor +develops from mutant cells with multiple genetic mutations. +The expanded lymphocyte +pool enables recognition of the antigen on cancer cells. +Chemotherapy. +In CML, +STI571 is targeted at the Bcr-Abl kinase, an activated oncogene +product in CML (Fig. +15-13). +Gene Therapy. +Several problems must be resolved to transform it into a +clinically relevant form of therapy. +Adju- +vant therapy was first tested and found to be effective in breast +cancer. +It was later adopted for use in other cancers. +Many of these +tumors can be cured today by combination chemotherapy. +As +Figure 15-13. +Mechanism of STI571 as a +molecular drug. +PO4 = phos- +phate; Tyr = tyrosine. +This can lead to subtle changes in func- +tion or dramatic results that cause pathology. +This results in a shift in the oxygen- +hemoglobin dissociation curve to the left, causing hypoxia. +Stem cells are +endowed with two remarkable properties (Fig. +15-14). +Second, they have the abil- +ity to differentiate into many specialized cell types. +There are +two groups of stem cells: embryonic stem (ES) cells and adult +stem cells. +Adult stem cells are present in and can +be isolated from adult tissues. +For example, hema- +topoietic stem cells are adult stem cells. +It is believed that dis- +covery of the signals that control self-renewal vs. +Stem cells. +15-15). +The process of molecular cloning +involves several steps of manipulation of DNA. +The +vector and the DNA fragment are then joined in vitro by a DNA +ligase. +Precautions must be taken in +every step of cloning to generate the desired DNA construct. +The selection of desired recombinant plasmid-bearing +E. +coli normally is achieved by the property of drug resistance +conferred by the plasmid vectors. +The resulting plasmid vec- +tor can be amplified in E. +Detection of Nucleic Acids and Proteins +Southern Blot Hybridization. +15-16).26 Southern +blotting is named after E. +M. +Southern, who in 1975 first +described the technique of DNA analysis. +Southern blotting is com- +posed of several steps. +The DNA gel is stained with a dye, usually ethidium +Figure 15-15. +Generation of recombinant DNA. +The vector is a circular DNA molecule that is capable of replicating in Escherichia coli cells. +Ligated +DNA (i.e., the recombinant plasmid DNA) is then transformed into E. +coli cells, where it replicates to produce recombinant progenies. +E. +coli +E. +coli containing +recombinant plasmid +Propagation +E. +coli containing +recombinant plasmid +Figure 15-16. +Southern blotting. +DNA is digested with +restriction enzymes. +DNA fragments are denatured +and separated by gel +electrophoresis. +DNA fragments are transferred +to a membrane filter. +The filter is hybridized with +a radioactive DNA probe. +DNA fragment that is hybridized +to the radioactive DNA is detected +by autoradiography. +The DNA gel then is treated so the DNA fragments are dena- +tured (i.e., strand separation). +Northern Blot Hybridization. +Polymerase Chain Reaction. +It is simple, yet robust, +speedy, and most of all, flexible. +As a recombinant DNA tool, +it underlies almost all of molecular biology. +Immunoblotting and Immunoprecipitation. +Analyses of +proteins are primarily carried out by antibody-directed immu- +nologic techniques. +Immunoblotting refers to the process of identifying a pro- +tein from a mixture of proteins (Fig. +15-18). +diseased tissues is possible. +15-19). +The purified protein can +then be analyzed by a number of biochemical methods. +DNA Microarray. +Amplification of DNA using the polymerase chain reaction (PCR) technique. +A. +B. +(Republished with permission of Garland Publishing, Inc. +from Alberts B, Johnson A, Lewis J, et al. +Molecular Biology of the Cell, +5th ed. +New York: Garland Science; 2008. +Permission conveyed through Copyright Clearance Center, Inc.) +Etc. +Immunoblotting. +The massive scale of micro- +array experiments requires the aid of computers. +For example, analysis +of genomic DNA detects amplifications and deletions found +in human tumors. +The fluorescent +make a human being. +461 +MOLECULAR AND GENOMIC SURGERY +CHAPTER 15 +Figure 15-19. +Immunoprecipitation. +Proteins +prepared from cells or tissues can be enriched +using an antibody directed against them. +The anti- +body is first conjugated to agarose beads and then +incubated with protein mixture. +The immunoprecipitated protein can then be +analyzed by immunoblotting. +DNA microarrays. +DNA microarray is used to comparatively analyze gene expression +in different cells or tissues. +The two fluorescent cDNA +probes are mixed and hybridized to the same DNA microarrays. +Yellow spots represent +equal expression of the gene in both cell samples. +BS-seq is commonly used to identify DNA +methylation on the genome (5-methylcytosine [5mC]). +Thus, 5mC and cytosine are distinguished +by this way. +Usually, cDNA +that is reversely transcribed from extracted RNA is used to gen- +erate libraries. +Depending on the needs, mRNA and ncRNA can +be enriched in different protocols for RNA extraction. +ChIP-seq +is always used to map the location of a DNA-binding protein in +the genome. +First, POI +and DNA are cross-linked before sonication. +Then, a specific +antibody is used to pull down POI and attached DNA fragments. +Figure 15-21. +Cell culture and +transfection. +A. +Primary cells can be +isolated from tissues and cultured in +medium for a limited period of time. +B. +15-21). +immortalized/transformed cells). +If +cultured cells grow continuously in suspension, they are split or +subcultured by dilution. +The common procedure to use is cryo- +preservation. +Cell Transfection. +Cells are cultured for two reasons: to main- +tain and to manipulate them (see Fig. +15-21). +DNA transfec- +tion has become an important tool for studying the regulation +and function of genes. +These methods have shown variable success when attempting +to transfect a wide variety of cells. +Transfection can be per- +formed in the presence or absence of serum. +Depending on the transfection method, DNA expression +can be transient or stable. +Stable cell clones can be selected +when plasmids carry an antibiotic-resistant marker. +In all cases, the gene to be manipulated must first be +cloned. +Transgenic Mice. +15-22). +These animals, called transgenic, contain for- +eign DNA within their genomes. +Figure 15-22. +Transgenic mouse tech- +nology. +The +microinjected egg develops offspring +mice. +The design of a transgene construct is +a simple task. +Overexpression of the transgene normally +represents gain-of-function mutations. +The second application of the trans- +genic expression is to analyze the gene promoter of interest. +Concentration of DNA should be accu- +rately determined. +Mice that develop from injected eggs often +are termed founder mice. +Depending on the +promoter and the transgene, phenotypes can be predictable or +unpredictable. +Gene Knockout in Mice. +The first recorded knockout mouse +was created by Mario R. +Capecchi, Sir Martin J. +Evans, and +Oliver Smithies in 1989. +They were awarded the 2007 Nobel +Prize in Physiology or Medicine. +15-23). +Excellent protocols +are available in public domains or in mouse facilities in most + institutions. +To alter the genome of ES cells, the targeting vector DNA +then is transfected into ES cells. +Electroporation is the most +widely used and the most efficient transfection method for ES +cells. +Similar procedures for stable cell transfection are used for +Figure 15-23. +Knockout mouse technology. +Summary of the procedures used for making gene replacements in mice. +Some of these mice also will contain germline cells that contain the altered gene. +These defects are carefully analyzed to help decipher the normal function of the missing gene. +(Republished with permission of Garland Publishing, Inc. +from Alberts B, Johnson A, Lewis J, et al. +Molecular Biology of the Cell, 5th ed. +New York: Garland Science; 2008. +Stable ES cells +are selected in the presence of a positive selectable antibiotic +drug. +Positive ES colonies are then expanded and used for +creation of chimeras. +RNA Interference. +15-24). +The antisense siRNA strand is fully complementary to +the mRNA target sequence. +Target sequences for an siRNA are +identified visually or by software. +Those sequences that appear +to be specific to the GOI are the potential siRNA target sites. +A few of these target sites are selected for siRNA design. +The +antisense siRNA strand is the reverse complement of the target +sequence. +The sense strand of the siRNA is the same sequence +as the target mRNA sequence. +There are two ways to introduce siRNA to knock down +gene expression in human cells: +1. +RNA transfection: siRNA can be made chemically or +using an in vitro transcription method. +Like DNA oligos, +chemically synthesized siRNA oligos can be commercially +ordered. +In vitro transcription provides a more +economic approach. +Both short and long RNA can be syn- +thesized using bacteriophage RNA polymerase T7, T3, or +SP6. +Transfection of siRNA directly into primary +cells may be difficult. +2. +15-24). +There are two advan- +tages of the siRNA expression vectors over siRNA oligos. +First, it is easier to transfect DNA into cells. +Therefore, +the applications of RNAi to human health are enormous. +Practical applications of RNAi will possibly result in new +therapeutic interventions. +RNAi +has been shown to antagonize the effects of hepatitis C virus +in mouse models. +Finally, siRNA also has potential applications for some +dominant genetic disorders. +However, this knowledge +has not been effectively or reproducibly clinically translated. +Figure 15-24. +RNA interference in mammalian cells. +Small interfering RNA (siRNA) can be produced from a polymerase III–driven expres- +sion vector. +siRNA can be chemically +synthesized and directly introduced into the target cell. +A phase I clinical trial (BB-IND 14205) involving 52 cancer +patients was recently completed. +No toxic effect was identified. +Expected survival +of similar patients is historically less than 1 year. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Watson JD, Crick FH. +Molecular structure of nucleic acids: a +structure for deoxyribose nucleic acid. +Nature. +1953;171:737. +2. +Alberts B, Johnson A, Lewis J, et al. +Molecular Biology of the +Cell. +4th ed. +New York: Garland Science; 2002. +3. +International Human Genome Sequencing Consortium. +Finish- +ing the euchromatic sequence 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cancer. +Cancer. +2011; +117(4):723-733. +42. +Templeton NS, Lasic DD, Frederik PM, et al. +Improved DNA: +liposome complexes for increased systemic delivery and gene +expression. +Nat Biotechnol. +1997;15(7):647-652. +43. +Nemunaitis J, Rao DD, Liu SH, Brunicardi FC. +Personalized +cancer approach: using RNA interference technology. +World J +Surg. +2011;35(8):1700-1714. +Khan, Jonathan Bank, David H. +Song, and +Eugene A. +Accounting for +approximately 15% of total body weight, it is the largest organ +in the human body. +Enabled by an array of tissue and cell types, +intact skin protects the body from external insults. +16-1). +Ninety to ninety-five percent of these +epithelial cells are ectodermally derived keratinocytes. +16-1). +Transit time (kera- +tinization) is approximately 30 days. +Epidermal Components +Keratinocytes. +Melanosomes are positioned +over the nucleus. +2 Dermal fibers are predominantly made of type I and III col- +lagen in a 4:1 ratio. +They are responsible for the mechanical +resistance of skin. +3 Staphylococcus aureus is the most common isolate of all skin +infections. +Cautery and ablation, cryotherapy, +drug therapy, and radiation therapy are alternative treatments. +Key Points +conferring mechanical resistance to the epidermis as a whole. +Proliferation occurs at this cell layer. +Spinosum layer keratinocytes are polygonal, with an eosinophilic +cytoplasm. +Langerhans Cells. +474 +Figure 16-1. +Schematic representation of the skin and +its appendages. +Note that the root of the hair follicle may +extend beneath the dermis into the subcutis. +Melanocytes express the bcl-2 oncoprotein, S100 protein, and +vimentin. +Merkel Cells. +Merkel cells display both neuroendocrine and epi- +thelial features. +Lymphocytes. +They express predominantly a T-memory/effector + phenotype.3 +Toker Cells. +Appendages serve +functions that include lubrication, sensation, contractility, and +heat loss. +Sweat Glands. +Sweat glands are tubular exocrine glands, con- +sisting of a secretory coil and an excretory duct. +These glands are found in the axillary, anogenital, +and nipple regions. +A third type of sweat gland was more recently described +in the axillary region. +Their size and morphology are +variable (terminal, vellus, lanugo, and intermediary hair). +Nails. +The nails overlie the dorsal aspect of the distal phalanges +of the fingers and toes. +Dermis +Architecture. +It consists of cells, fibrous +molecules, and a ground substance. +The elastic network is +also thicker in this layer. +Dermal Fibers. +Collagen +accounts for 98% of the total mass of dry dermis. +This core is surrounded by a varying number of microfibrils +made of fibrillin. +Cells. +Dermal dendrocytes +complement the immunologically functional cells of the epider- +mis. +Cutaneous Vasculature. +The skin contains a rich and com- +plex enervation, consisting of an afferent and an efferent limb. +The diagnosis is made clinically without the +need for imaging or laboratory tests. +Treatment varies depending on disease severity and extent. +Antiandrogens have an equivo- +cal role in therapy. +Skin grafting has a faster heal- +ing rate compared with secondary wound closure. +Secondary infec- +tion is common. +PG is more common in women and peaks in +the third to sixth decades of life. +Lesion borders are purplish in +color with erythematous edges. +Five clinical types are identi- +fied: ulcerative, pustular, bullous, vegetative, and peristomal. +Treatment +of PG combines systemic, topical, and surgical modalities. +16-2). +The process progresses for 7 to 10 days; re-epithelialization +occurs over 1 to 3 weeks. +Mucosal and ocular surfaces may be +involved in a similar fashion. +Immunosuppressed patients are +at higher risk. +Less than 10% of total body surface area is involved +with this disease. +Blisters on the forearm of a patient several days after +exposure to vancomycin. +surface area. +Despite drug withdrawal, noxious metabolites +may persist. +A Wood’s lamp exami- +nation every 1 hour should be performed to look for corneal +sloughing. +There are mixed reports of +IVIG treatment efficacy. +Surgeons must be aware of the role radiation plays in +oncologic multidisciplinary care. +Acute skin changes are the result of injury to the basal +epithelium in the radiated region. +Within weeks, this manifests +as erythema, edema, and alopecia. +Histologically, the epidermis appears +thickened, but the functional integrity is compromised. +UVB radiation reaches the +earth in relatively low amounts but is highly energetic. +Seasonal, +temporal, geo-orbital, and environmental parameters affect solar +irradiance. +UVA rays are more penetrant, with 20% to 30% reach- +ing the deep dermis. +The major chromophores are nucleic acids, +aromatic amino acids, and melanin. +Short-term solar radiation effects include erythema and +pigmentation. +Pigmentation occurs as a result of photo- +oxidation of melanin by UVA. +Partial fading occurs rapidly +within 1 hour after the end of exposure. +For higher UVA doses, +a stable residual pigmentation is observed after the transient +effect. +It becomes visible after about +72 hours. +UVB pigmentation results in a +homogeneous tan and UVA protection. +Trauma-Induced Injuries +Mechanical Injury. +Clean lacerations may be closed primarily after irrigation, +debridement, and exploration. +Bite Wounds. +Early pre- +sentation bite wounds yield polymicrobial cultures. +Capnocytophaga canimorsus bacteria after a dog bite +are rare. +Bacteria colonizing human bites are those present on the +skin or in the mouth. +Antibiotic +coverage must cover gram-positive and anaerobic organisms. +Most wounds are amenable to standard wound care protocols. +Larger wounds with signs of infection will +require pulse irrigation. +Rapid quantitative cultures should be used +to guide treatment in wounds with suspected infection. +Human +bites typically are characterized by higher bacteria load (>105). +In devel- +oping countries, dog bites remain the most common source of +rabies. +Management of this is beyond the scope of this chapter. +This limits subsequent tissue penetration. +16-4). +This permits further penetration of the unattached molecules, +causing further tissue destruction. +The clinician observes and treats based on the +degree of presentation. +Surgery is indicated for tissue +necrosis, uncontrolled pain, or deep-tissue damage. +Antibiot- +ics should not be administered unless signs of infection are +present. +Topical calcium carbonate gel and quaternary +AB +Figure 16-3. +A. +Dog bite to the face involving the lip and left oral commissure. +B. +Primary closure following debridement and irrigation. +Closure was performed due to aesthetic and functional considerations. +480 +SPECIFIC CONSIDERATIONS +UNIT + +II +PART II + ammonium compounds detoxify fluoride ions. +16-5). +Initial presentation may include ery- +thema, blistering, and pain. +Injury to deeper structures should be excluded. +Topical antimicrobial therapy is encouraged until +surgery is possible. +The depth and extent of injury are dependent on the +duration and temperature of the exposure. +The pathophysiol- +ogy and management are discussed elsewhere in this book. +16-6). +Self-inflicted alkali burn with cleaner fluid. +481 +THE SKIN AND SUBCUTANEOUS TISSUE +CHAPTER 16 +AB +C +Figure 16-5. +A. +Potassium chloride intravenous infiltrate in a critically ill patient on multiple vasopressors. +B. +Following operative debride- +ment to paratenon layer. +C. +Temporary coverage with Integra skin substitute. +Frequent or pro- +longed ischemic insults will ultimately result in tissue damage +(Fig. +16-7). +Stage 2 and 3 ulcers may be left to +heal secondarily after debridement. +A. +Pressure wound after removal of a poorly padded +cast. +Stage cannot be determined until debridement but is at least a +grade 2 lesion. +B. +Decubitus ulcer of the sacral region, stage 4, to +the tendinous and bone layers. +Figure 16-6. +Scald burn of upper arm, back, and buttock. +Biobrane +is a silicon and nylon mesh layer bound with porcine collagen. +The more superficial silicon layer +can be removed, and an autograft can subsequently be applied. +Several other skin substitutes are +also available. +Folliculitis and furuncles resolve with adequate hygiene and +warm soaks. +Need +for empiric coverage for streptococci is unlikely. +Clindamycin, +trimethoprim-sulfamethoxazole, linezolid, and tetracyclines are +options. +The infections can be managed on an outpatient basis +in the vast majority of cases. +Aspirated fluid from suspected infected collection +should be cultured. +Empiric MRSA coverage is warranted in all other +complicated skin and subcutaneous infections. +Clindamycin is also approved for +S. +These signs are late findings and are +frequently absent. +Common sites of origin are the genitalia, perineum +(Fournier’s gangrene), and abdominal wall. +16-8). +Necrotizing +myositis primarily involves the muscle but can spread to sur- +rounding tissue as well. +Three types of necrotizing infections can be distinguished +based on the organisms involved. +Type 3 +A +B +Figure 16-8. +A. +Initial presentation of necrotizing soft issue infec- +tion in an obese, diabetic patient. +B. +Following operative debride- +ment to muscle layer. +is a rare but fulminant subset resulting from a V. +vulnificus +infection of traumatized skin in sea divers. +Laboratory findings are nonspecific. +Leukocytosis, low +calcium, and elevated lactate, creatine kinase, and creatinine +may be seen. +Advanced illness may bring on coagulopathy and +acidemia. +Blood cultures may or may not be positive. +If the diagnosis is clear, +operative exploration and debridement should not be delayed. +Surgery is the definitive treatment. +Necrotic tissue will appear dull, gray, and avas- +cular and should be excised. +Characteristic “murky dishwater”– +like fluid may be encountered at the affected sites. +Borders for +debridement are where tissue planes cease to readily separate. +Revision surgery should be +planned (“second look”) within 24 to 48 hours. +Wound closure is performed once +bacteriologic, metabolic, and nutritional balances are obtained. +Mortality ranges from 25% to 40% and is higher in truncal and +perineal cases. +Oral infection may spread to the hypopharynx, +larynx, trachea, salivary glands, and sinuses. +Treatment consists of a +combination of penicillin therapy and surgical debridement. +[C10]AUTHOR: “infection” okay as added +here? +Cutaneous manifestations of HPV can vary. +Plane warts occur on the face, dorsum of hands, and shins. +They regress spontaneously. +There is a 30% to 50% risk of squamous cell carcinoma (SCC) +transformation. +If these fail, cryotherapy may be considered. +Kaposi’s sarcoma may precede the onset of immunosuppression. +Recurrent +and persistent mucocutaneous candidiasis is common in patients +with HIV infection. +Bacterial infections such as impetigo and +folliculitis may be more persistent and widespread. +Approximately 6% of HIV +patients will develop a cutaneous malignancy over a 7.5-year +period. +In +both of these cases, resection is also indicated. +Systemic pred- +nisone and interferon-α can impede tumor progression. +They are most commonly +acquired, and most involute after migration into the dermis. +All clinically +appear as a white, creamy substance-containing subcutaneous, +thin-walled nodule. +The eyebrow is the most frequent site of +presentation. +After the acute phase subsides, the entire cyst should +be removed to prevent recurrence. +Keratosis +Actinic Keratosis. +In fact, 60% to 65% of SCCs are +believed to originate from these precursor lesions. +Seborrheic Keratosis. +Untreated BCC can result in significant morbidity. +This variant tends to develop +in sun-exposed areas of individuals over the age of 60. +Treatment options include Moh’s microsurgery, exci- +sional surgery, and cautery and destruction. +Lastly, topical photodynamic therapy +has shown some benefit in treatment as well. +16-9). +In situ disease presents as well-delineated pink +Figure 16-9. +Squamous cell carcinoma forming in a chronic +wound. +Bleeding of the lesion with +minimal trauma is not uncommon, and pain is rare. +Surgical excision is the treatment of choice, when feasi- +ble. +Management of lymph +node disease involves surgical resection and/or radiation ther- +apy. +6 +488 +SPECIFIC CONSIDERATIONS +UNIT + +II +PART II +Melanoma +Background. +A well-known environmental risk factor is exposure to solar +UV radiation. +The most common +subtype is superficial spreading, accounting for 70% of cases +(Fig. +16-10). +These melanomas are found anywhere on the body +Figure 16-11. +Nodular melanoma seen in the leg of a 55-year-old +male. +Figure 16-10. +Primary cutaneous melanoma seen in the scalp of +a 61-year-old male. +with the exception of the hands and feet. +16-11). +Diagnosis and Staging. +Workup should begin with a history +and physical exam. +Suspicious lymph nodes should undergo fine-needle aspiration +(FNA). +16-12 and 16-13). +The radioactive tracer-dye combination +allows the sentinel node to be identified in 98% of cases. +16-14). +Surgical Management of the Primary Tumor and Lymph +Nodes. +The appropriate excision margin is based on primary +tumor depth. +A. +B. +C. +ANT = anterior; INJ = injection; +POST = posterior. +Figure 16-13. +Technique of sentinel lymph +node biopsy for cutaneous melanoma. +(From Ger- +shenwald JE, Ross MI. +Sentinel-lymph node +biopsy for cutaneous melanoma. +N Engl J Med. +2011;364:1738-1745. +Copyright © 2011 Mas- +sachusetts Medical Society. +A trial from +the Swedish Melanoma Study Group supported the WHO trial. +74%; P = .88) +or overall survival (75% vs. +74%; P = .77) between the groups. +77%; P = .074) or local recur- +rence (2.1% vs. +2.6%) between the two cohorts. +Technically challenging locations should be treated +in a similar fashion. +when it was delayed until the +patients presented with clinical findings. +Several studies evaluated the indications and benefit +for extended lymphadenectomy. +If metastatic workup including PET-CT excludes +AB +Figure 16-14. +Operation of sentinel lymph node biopsy for cutaneous melanoma. +An incision is made directly overlying the lymph node basin in the posterior axillary space. +The sentinel lymph nodes +are identified and excised. +Nonmeta- +static, in-transit disease should undergo excision to clear mar- +gins when feasible. +16-15). +Radiotherapy for symptomatic +bony or brain metastases provides palliation in diffuse disease. +Adjuvant and Palliative Therapies. +Most patients with metastatic melanoma will not be sur- +gical candidates. +Special Circumstances. +The prognosis +of pregnant patients is similar to women who are not pregnant. +Mela- +noma of the mucous membranes most commonly presents in +Figure 16-15. +Isolated limb infusion. +Sche- +matic of isolated limb infusion of lower +extremity. +(From Testori A, Verhoef C, +Kroon HM, et al. +J Surg Oncol. +2011;104:397-404. +Copyright 2011 John +Wiley and Sons. +Generally speaking, lymph node +dissection should be avoided because the benefit is unclear. +16-16). +Risk factors include UV radiation, +PUVA, and immunosuppression. +A rapidly growing, flesh-colored papule or plaque +characterizes the disease. +Merkel cell carcinoma seen just above the left knee +in a 44-year-old female. +Elective lymph +node dissection may decrease regional nodal recurrence and +in-transit metastases. +Patients with clinically positive nodes +should have an FNA to confirm disease. +Moh’s microsurgery may play +a role to ensure negative margins. +Clinically, Kaposi’s +sarcoma appears as multifocal, rubbery blue nodules. +Tumor depth is the most important +prognostic variable. +Recurrent +tumors should be resected whenever possible. +They present as solitary, soft to firm, skin-colored subcutane- +ous nodules. 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the +common clinical features. +Theories +espoused by Galen dominated medicine until the Renaissance. +Tulp, Observationes medicae 1652). +However there were no new theories espoused in +relation to cancer. +The 17th century saw the +start of the Age of Enlightenment which lasted until the 19th +century. +Halsted and Meyer advocated complete dissection of axillary +lymph node levels I to III. +17-1) when normal regression fails. +Each breast develops +when an ingrowth of ectoderm forms a primary tissue bud in +the mesenchyme. +The primary bud, in turn, initiates the devel- +opment of 15 to 20 secondary buds. +Epithelial cords develop +from the secondary buds and extend into the surrounding mes- +enchyme. +Major (lactiferous) ducts develop, which open into a +shallow mammary pit. +During infancy, a proliferation of mes- +enchyme transforms the mammary pit into a nipple. +If there is +failure of a pit to elevate above skin level, an inverted nipple +results. +This congenital malformation occurs in 4% of infants. +These transitory events occur in +response to maternal hormones that cross the placenta. +However, the breasts remain incom- +pletely developed until pregnancy occurs. +Symmastia is a rare +anomaly recognized as webbing between the breasts across the +midline. +Accessory axillary breast tissue is uncommon and +usually is bilateral. +Functional Anatomy +The breast is composed of 15 to 20 lobes (Fig. +It extends transversely from the lateral +border of the sternum to the anterior axillary line. +The axillary tail of Spence extends +laterally across the anterior axillary fold. +The breast has a protuberant conical form. +The +base of the cone is roughly circular, measuring 10 to 12 cm in +diameter. +The nulliparous +breast has a hemispheric configuration with distinct flattening +above the nipple. +Figure 17-2. +Anatomy of the breast. +Tangential and cross-sectional +(sagittal) views of the breast and associated chest wall. +(Reproduced +with permission from Romrell LJ, Bland KI. +Anatomy of the +breast, axilla, chest wall, and related metastatic sites. +In: Bland +KI, Copeland EMI, eds. +The Breast: Comprehensive Management +of Benign and Malignant Diseases. +Philadelphia: Saunders, 2009. +Copyright Elsevier.) +501 +T +HE + B +REAST +CHAPTER 17 +Nipple-Areola Complex. +The epidermis of the nipple-areola +complex is pigmented and is variably corrugated. +During +puberty, the pigment becomes darker and the nipple assumes +an elevated configuration. +Throughout pregnancy, the areola +enlarges and pigmentation is further enhanced. +Inactive and Active Breast. +17-2). +In the inactive breast, the epithelium is +sparse and consists primarily of ductal epithelium (Fig. +17-3). +In the early phase of the menstrual cycle, minor ducts are cord- +like with small lumina. +When the hormonal stimulation decreases, the alveolar epithe- +lium regresses. +With pregnancy, the breast undergoes proliferative and +developmental maturation. +Inactive human breast (100x). +The epithelium, which +is primarily ductal, is embedded in loose connective tissue. +Dense +connective tissue surrounds the terminal duct lobular units (TDLU). +(Photo used with permission of Dr. +Sindhu Menon, Consultant His- +topathologist & Dr. +Active human breast: pregnancy and lactation (160x). +The alveolar epithelium becomes conspicuous during the early pro- +liferative period. +The alveolus is surrounded by cellular connective +tissue. +(Photo used with permission of Dr. +Sindhu Menon, Consul- +tant Histopathologist & Dr. +The +minor ducts branch and alveoli develop. +17-4). +Blood Supply, Innervation, and Lymphatics. +17-5). +It also +gives rise to lateral mammary branches. +Lymph vessels generally parallel the course of +blood vessels. +These +branches exit the intercostal spaces between slips of the serratus +anterior muscle. +The six axillary lymph node +groups recognized by surgeons (Figs. +Lymphatic pathways of the breast. +Arrows indicate +the direction of lymph flow. +(Visual Art: © 2012. +The University +of Texas MD Anderson Cancer Center.) +Figure 17-7. +Axillary lymph node groups. +(Visual Art: © 2012.The +University of Texas MD Anderson Cancer Center.) +Figure 17-5. +Arterial supply to the breast, axilla, and chest wall. +(Reproduced with permission from Romrell LJ, Bland KI. +Anat- +omy of the breast, axilla, chest wall, and related metastatic sites. +In: Bland KI, Copeland EMI, eds. +The Breast: Comprehensive +Management of Benign and Malignant Diseases. +Philadelphia: +Saunders, 2009. +Overview of the neuroendocrine con- +trol of breast development and function. +(Reproduced with permission from Kass R et al. +Breast physiology: normal and abnormal develop- +ment and function. +In: Bland KI, Copeland EMI, +eds. +The Breast: Comprehensive Management of +Benign and Malignant Diseases. +Philadelphia: +Saunders, 2009. +Copyright Elsevier.) +GRF +LH-RH +Dopamine Oxy/ADH +TRH +CRF +- +group of lymph nodes. +The +axillary lymph nodes usually receive >75% of the lymph drain- +age from the breast. +It upregulates hormone receptors and stimu- +lates epithelial development. +17-9A). +These physiologic events initiate +A +B +C +D +Figure 17-9. +The breast at different physi- +ologic stages. +The central column contains +three-dimensional depictions of microscopic +structures. +A. +Adolescence. +B. +Pregnancy. +C. +Lactation. +D. +Senescence. +In the first and second trimesters, the minor ducts branch and +develop. +In late pregnancy, prolactin stimulates the synthesis +of milk fats and proteins. +After weaning of the infant, +prolactin and oxytocin release decreases. +17-9C). +17-9D). +In contrast, +senescent gynecomastia is usually bilateral. +Mammography and ultrasonography are used to differentiate +breast tissues. +Gynecomastia generally does not +predispose the male breast to cancer. +Refeeding gynecomastia +Table 17-1 +Pathophysiologic mechanisms of gynecomastia +I. +Estrogen excess states +A. +Gonadal origin +1. +True hermaphroditism +2. +Gonadal stromal (nongerminal) neoplasms of the +testis +a. +Leydig cell (interstitial) +b. +Sertoli cell +c. +Granulosa-theca cell +3. +Germ cell tumors +a. +Choriocarcinoma +b. +Seminoma, teratoma +c. +Embryonal carcinoma +B. +Nontesticular tumors +1. +Adrenal cortical neoplasms +2. +Lung carcinoma +3. +Hepatocellular carcinoma +C. +Endocrine disorders +D. +Diseases of the liver—nonalcoholic and alcoholic +cirrhosis +E. +Nutrition alteration states +II. +Androgen deficiency states +A. +Senescence +B. +Hypoandrogenic states (hypogonadism) +1. +Primary testicular failure +a. +Klinefelter’s syndrome (XXY) +b. +Reifenstein’s syndrome +c. +Rosewater-Gwinup-Hamwi familial +gynecomastia +d. +Kallmann syndrome +e. +Kennedy’s disease with associated +gynecomastia +f. +Eunuchoidal state (congenital anorchia) +g. +Hereditary defects of androgen biosynthesis +h. +Adrenocorticotropic hormone deficiency +2. +Secondary testicular failure +a. +Trauma +b. +Orchitis +c. +Cryptorchidism +d. +Irradiation +C. +Renal failure +III. +Pharmacologic causes +IV. +Androgen deficiency may initiate gyne- +comastia. +This senescent gynecomastia usually occurs in men aged +50 to 70 years. +Hypoandrogenic states can be from primary tes- +ticular failure or secondary testicular failure. +Secondary testicular failure may result +from trauma, orchitis, and cryptorchidism. +Renal failure, regard- +less of cause, also may initiate gynecomastia. +When it +is caused by medications, then these are discontinued if possi- +ble. +When endocrine defects are responsible, then these receive +specific therapy. +Techniques include local excision, liposuction or sub- +cutaneous mastectomy. +Breast infections +may be chronic, possibly with recurrent abscess formation. +Uncommon organ- +isms may be encountered, and long-term antibiotic therapy may +be required. +Epidemic puerperal mastitis is initiated +by highly virulent strains of methicillin-resistant S. +Purulent fluid may +be expressed from the nipple. +The addition of antibiotic therapy results in a satisfactory out- +come in >95% of cases. +Pus mixed with blood may be +expressed from sinus tracts. +Antifungal agents can be adminis- +tered for the treatment of systemic (noncutaneous) infections. +Scrapings from the lesions demonstrate fungal +elements (filaments and binding cells). +Involvement of the axillary skin is often multifo- +cal and contiguous. +Antibiotic therapy with incision and drain- +age of fluctuant areas is appropriate treatment. +Excision of the +involved areas may be required. +A tender, +firm cord is found to follow the distribution of one of the major +superficial veins. +This benign, self-limited disorder is not indicative of a can- +cer. +The process usually resolves within 4 to 6 weeks. +In: Mansel RE, et al, eds. +Hughes, Mansel & Webster’s Benign Disorders and Diseases of the Breast. +London: Saunders, 2009. +Copyright Elsevier. +The vertical component indi- +cates the period during which the condition develops. +Early Reproductive Years. +The precise etiology of adolescent +breast hypertrophy is unknown. +A spectrum of changes from +limited to massive stromal hyperplasia (gigantomastia) is seen. +Later Reproductive Years. +Painful nodularity that +persists for >1 week of the menstrual cycle is considered a disor- +der. +Involution. +Involution of lobular epithelium is dependent +on the specialized stroma around it. +The macrocysts are com- +mon, often subclinical, and do not require specific treatment. +Periductal fibro- +sis is a sequela of periductal mastitis and may result in nipple +retraction. +About 60% of women ≥70 years of age exhibit some +degree of epithelial hyperplasia (Fig. +17-11). +The classification +Figure 17-11. +A. +Ductal epithelial hyperplasia. +B. +Lobular hyperplasia. +(Photos used with permission of Dr. +R.L. +Hackett.) +Figure 17-10. +Fibroadenoma (40x). +(Photo used with permission of Dr. +Sindhu +Menon, Consultant Histopathologist & Dr. +N Engl J Med 312:146, 1985. +Calcium deposits are frequently encountered in the breast. +Most are benign and are caused by cellular secretions and +debris or by trauma and inflammation. +Fibroadenomas have +abundant stroma with histologically normal cellular elements. +They may be divided into tubular +adenomas and lactating adenomas. +Arch Pathol Lab Med. +1986;110:171. +diameter, firm, and sharply circumscribed. +Fibrocystic Disease. +The term fibrocystic disease is nonspe- +cific. +Benign calcifications are often associated with +this disorder. +Florid duc- +tal epithelial hyperplasia occupies at least 70% of a minor duct +lumen. +Intraductal papillomas arise in the major +ducts, usually in premenopausal women. +They generally are +<0.5 cm in diameter but may be as large as 5 cm. +A common +presenting symptom is nipple discharge, which may be serous +or bloody. +Lobular carcinoma in situ (100x). +(Photo used with permission of +Dr. +Sindhu Menon, Consultant Histopathologist & Dr. +17-12). +There is a variant of +LCIS that has been termed pleomorphic LCIS. +Treatment of Selected Benign Breast +Disorders and Diseases +Cysts. +The volume of a typical +cyst is 5 to 10 mL, but it may be 75 mL or more. +After aspiration, the breast is carefully palpated to exclude +a residual mass. +When cystic fluid is bloodstained, fluid +can be sent for cytologic examination. +Fibroadenomas. +Careful ultrasound examination with core-needle +biopsy will provide for an accurate diagnosis. +Larger lesions are often still +best removed by excision. +Sclerosing Disorders. +The clinical significance of sclerosing +adenosis lies in its imitation of cancer. +Periductal Mastitis. +Antibiotics are then +continued based on sensitivity tests. +Ultrasound will accurately delineate its extent. +Recurrent abscess with fistula is a difficult problem. +London: +WB Saunders, 2000, p 162. +Copyright © Elsevier. +Nipple Inversion. +Finally, there is an association between +obesity and increased breast cancer risk. +Nonhormonal risk factors include radiation exposure. +Risk Assessment Models +The average lifetime risk of breast cancer for newborn U.S. +There are several risk assessment models +available to predict the risk of breast cancer. +The output is a +five-year risk and a lifetime risk of developing breast cancer. +N Engl J Med. +342:564, 2000. +Furthermore, +these hormone supplements were thought to reduce coronary +artery disease as well. +benefits of postmenopausal +hormone replacement therapy. +They found an +increased risk of breast cancer with ever use of estrogen replace- +ment therapy. +In addition, a clini- +cal breast examination by a health professional is recommended +annually. +Chemoprevention. +There have been 4 prospective +studies published evaluating tamoxifen vs. +placebo for reducing +the incidence of invasive breast cancer for women at increased +risk. +Cataract surgery is required almost +twice as often among women taking tamoxifen. +The +trial randomized 4,560 women to exemestane 25 mg daily vs. +placebo for five years. +Preventive Services Task Force. +Risk-reducing Surgery. +BRCA Mutations +BRCA1. +More +than 500 sequence variations in BRCA1 have been identified. +Approximately 50% of children of carriers inherit the +trait. +Several founder mutations have been identified in BRCA1. +BRCA2 is located on chromosome arm 13q and spans +a genomic region of approximately 70 kb of DNA. +The mutational spec- +trum of BRCA2 is not as well established as that of BRCA1. +To date, >250 mutations have been found. +Approximately 50% of children of carriers inherit +the trait. +A number of founder mutations +have been identified in BRCA2. +BRCA Mutation Testing. +This person undergoes complete +sequence analysis of both the BRCA1 and BRCA2 genes. +If a +mutation is identified, relatives are usually tested only for that +specific mutation. +In addition, no BRCA muta- +tion can be passed on to the woman’s children. +Overall, the false-negative rate for BRCA mutation testing is +<5%. +This is because single base-pair changes do not always result in +a nonfunctional protein. +Indeterminate genetic +variance currently accounts for 12% of the test results. +Cancer Prevention for BRCA Mutation Carriers. +Risk man- +agement strategies for BRCA1 and BRCA2 mutation carriers +include the following: +1. +Risk-reducing mastectomy and reconstruction +2. +Risk-reducing salpingo-oophorectomy +3. +Intensive surveillance for breast and ovarian cancer +4. +Risk-reducing salpingo- +oophorectomy is a reasonable prevention option in mutation car- +riers. +Hormone replacement therapy is dis- +cussed with the patient at the time of oophorectomy. +For 2002 to 2008 rates were 92% and 78%, respectively. +There is a 10-fold variation in breast cancer incidence +among different countries worldwide. +The incidence rates of breast cancer increased in most +countries through the 1990s. +It was predicted that there would be approxi- +mately 1.4 million new cases in 2010. +These are features that characterize many +underdeveloped nations and also many eastern nations. +The +median survival of this population was 2.7 years after initial +diagnosis (Fig. +17-13).117 The 5- and 10-year survival rates +Figure 17-13. +Survival of women with untreated breast cancer +compared with natural survival. +(Reproduced with permission +from Bloom HJG, Richardson WW, Harries EJ. +Br Med J. +Only +0.8% survived for 15 years or longer. +Almost 75% of the women +developed ulceration of the breast during the course of the +disease. +The longest surviving patient died in the nineteenth +year after diagnosis. +Primary Breast Cancer. +Localized edema (peaud’orange) +develops when drainage of lymph fluid from the skin is dis- +rupted. +With continued growth, cancer cells invade the skin, and +eventually ulceration occurs. +As new areas of skin are invaded, +small satellite nodules appear near the primary ulceration. +17-14). +Axillary Lymph Node Metastases. +Eventually the lymph +nodes adhere to each other and form a conglomerate mass. +17-14A). +Distant Metastases. +These cells are scavenged by natural killer +lymphocytes and macrophages. +A. +Overall survival for women with breast can- +cer according to axillary lymph node status. +The time periods +are years after radical mastectomy. +Analysis of 716 consecutive patients. +Cancer. +1978;11:1170. +Copyright © American Cancer Society. +Risk of metastases according to +breast cancer volume and diameter. +(Reproduced with permission +from Koscielny S et al. +Br J Cancer. +Before the widespread use +of mammography, diagnosis of breast cancer was by physical +examination. +Table 17-8 lists +the clinical and pathologic characteristics of DCIS and LCIS. +Lobular Carcinoma In Situ. +LCIS originates from the termi- +nal duct lobular units and develops only in the female breast. +Cytoplasmic mucoid globules are +a distinctive cellular feature. +Invasive +breast cancer develops in 25% to 35% of women with LCIS. +Philadelphia: WB +Saunders;1998:1020. +Copyright Elsevier. +Ductal Carcinoma In Situ. +Published series suggest a detection frequency of 7% in all +biopsy tissue specimens. +Calcium deposition +occurs in the areas of necrosis and is a common feature seen +on mammography. +Based +on multiple consensus meetings, grading of DCIS has been rec- +ommended. +17-15A and B). +bSolid, cribriform, papillary, or focal micropapillary. +PPO Updates 10:1, 1996. +521 +T +HE + B +REAST +CHAPTER 17 +invasive ductal carcinoma of no special type (NST). +These can- +cers generally have a worse prognosis than special-type cancers. +Paget’s disease of the nipple +2. +Medullary carcinoma, 4% +4. +Mucinous (colloid) carcinoma, 2% +5. +Papillary carcinoma, 2% +6. +Tubular carcinoma, 2% +7. +Invasive lobular carcinoma, 10% +8. +A palpable mass +may or may not be present. +Paget’s disease +may be confused with superficial spreading melanoma. +This cancer occurs most +frequently in perimenopausal or postmenopausal women in the +Figure 17-15. +Ductal carcinoma in situ (DCIS). +A. +Craniocaudal mammographic view shows a poorly defined mass containing microcalci- +fications. +(Photo used with permission of Dr. +Anne Turnbull, Consultant Radiologist/Director of Breast Screening. +Royal Derby Hospital.) B. +Sindhu Menon, +Consultant Histopathologist & Dr. +17-16A +and B). +Grossly, the can- +cer is soft and hemorrhagic. +A rapid increase in size may occur +secondary to necrosis and hemorrhage. +On physical examina- +tion, it is bulky and often positioned deep within the breast. +Bilaterality is reported in 20% of cases. +In rare circumstances, +mesenchymal metaplasia or anaplasia is noted. +The cut +surface of this cancer is glistening and gelatinous in quality. +Fibrosis is variable, and when abundant it imparts a firm consis- +tency to the cancer. +Typically, papillary car- +cinomas are small and rarely attain a size of 3 cm in diameter. +These cancers are defined by papillae with fibrovascular stalks +and multilayered epithelium. +Distant metastases are +rare in tubular carcinoma and invasive cribriform carcinoma. +Long-term survival approaches 100%. +Invasive lobular carcinoma accounts for 10% of breast +cancers. +17-17). +At presentation, invasive +Figure 17-17. +Lobular carcinoma (100×). +(Used with permission of Dr. +Sindhu +Menon, Consultant Histopathologist & Dr. +Invasive ductal carcinoma with productive fibrosis (scirrhous, simplex, no special type) A. +100x and B. +200x. +(Used with +permission of Dr. +Sindhu Menon, Consultant Histopathologist & Dr. +It is frequently multifocal, multicentric, and bilateral. +Breast pain usually is associated with benign disease. +Examination +Inspection. +The surgeon inspects the woman’s breast with +her arms by her side (Fig. +17-18A), with her arms straight up +in the air (Fig. +Palpation. +As part of the physical examination, the breast is +carefully palpated. +With the patient in the supine position (see +Fig. +The breast may be cupped or molded in the +surgeon’s hands to check for retraction. +A systematic search for +lymphadenopathy then is performed. +Figure 17-18D shows the +position of the patient for examination of the axilla. +By support- +ing the upper arm and elbow, the surgeon stabilizes the shoul- +der girdle. +Careful palpation +Figure 17-18. +Examination of the breast. +A. +Inspection of the +breast with arms at sides. +B. +Inspection of the breast with arms +raised. +C. +Palpation of the breast with the patient supine. +D. +Palpa- +tion of the axilla. +of supraclavicular and parasternal sites also is performed. +17-19). +Imaging Techniques +Mammography. +By comparison, chest radiography delivers 25% of this +dose. +Screening mammography is used to detect unexpected +breast cancer in asymptomatic women. +In this regard, it supple- +ments history taking and physical examination. +17-20A and B) and the mediolat- +eral oblique (MLO) view (Fig. +17-20 C and D). +17-21C). +A breast examination record. +A-D. +Mammogram of a premenopausal +breast with a dense fibroglandular pattern. +E-H. +Mam- +mogram of a postmenopausal breast with a sparse +fibroglandular pattern. +(Photos used with permission of +Dr. +(Continued ) +microcalcifications. +Mammogram revealing a small, spiculated mass in the right breast A. +A small, spiculated mass is seen in the right breast with +skin tethering (CC view). +B. +Mass seen on oblique view of the right breast. +C. +Spot compression mammography view of the cancer seen in +A and B. +The spiculated margins of the cancer are accentuated by compression. +(Photos used with permission of Dr. +This is especially useful in women with dense breasts +and women <50 years of age. +Recently, investigators directly +compared digital vs. +Ductography. +Intraductal papillomas are +seen as small filling defects surrounded by contrast media +(Fig. +17-22). +Cancers may appear as irregular masses or as mul- +tiple intraluminal filling defects. +Ultrasonography. +17-23). +Breast cancer +characteristically has irregular walls (Fig. +17-25) but may have +smooth margins with acoustic enhancement. +17-26). +There is current interest in the use of MRI to screen the +Figure 17-22. +Ductogram. +(Photos used with permission of B. +Steinbach.) +BA +breasts of high-risk women and of women with a newly diag- +nosed breast cancer. +17-27). +17-28). +The use of dedicated breast coils is mandatory in the MRI +imaging of the breast. +Breast cyst. +A. +Simple cyst. +B. +Complex solid and cystic mass. +(C) Complex solid and cystic mass characteristic of intracystic papillary tumor. +(Photos used with +permission of Dr. +Figure 17-24. +Ultrasonography images of benign breast tumors. +A. +Fibroadenoma. +B. +Intraductal papilloma. +(Photos used with permission +of Dr. +Breast Biopsy +Nonpalpable Lesions. +The com- +bination of diagnostic mammography, ultrasound or stereotactic +A +B +CD +Figure 17-25. +Ultrasonography images of malignant breast lesions. +A. +25 mm irregular mass. +B. +Ultrasound 30 mm mass anterior to an +implant. +C. +Ultrasound breast cancer with calcification. +D. +Ultrasound 9 mm spiculated mass with attenuation. +(Photos used with permission +of Dr. +Palpable Lesions. +Ultrasonography images of lymph nodes. +A. +Normal axillary lymph node. +B. +Indeterminate axillary lymph node. +C. +Malignant +appearing axillary lymph node. +(Photos used with permission of Dr. +(Photo used with permission of Dr. +MRI imaging of the breast revealing multifocal tumors not detected with standard breast imaging. +(Photo used with permission +of Dr. +The cellular material is then expressed onto microscope +slides. +Both air-dried and 95% ethanol–fixed microscopic sec- +tions are prepared for analysis. +Automated devices also are avail- +able. +Tissue specimens are placed in formalin and then +processed to paraffin blocks. +The clinical, radiographic, and pathologic findings should be +in concordance. +17-14B). +Biomarkers +Breast cancer biomarkers are of several types. +Size +should be measured to the nearest millimeter. +In general, pathologic determination should take precedence over clinical determination of T size. +ITCs may be detected by +routine histology or by immunohistochemical (IHC) methods. +** RT-PCR: reverse transcriptase/polymerase chain reaction. +New York: Springer; 2010:358-361. +Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. +–The designation pM0 is not valid; any M0 should be clinical. +–Postneoadjuvant therapy is designated with “yc” or “yp” prefix. +New York: Springer; +2010:360-361. +Used with permission of the American Joint Committee +on Cancer (AJCC), Chicago, Illinois. +Steroid Hormone Receptor Pathway. +Hormones play an +important role in the development and progression of breast +cancer. +Breast cancer risk is related to estrogen exposure over +time. +Growth Factor Receptors and Growth Factors. +Patients +whose tumors overexpress HER-2/neu are candidates for anti– +HER-2/neu therapy. +Trastuzumab (Herceptin) is a recombinant +humanized monoclonal antibody directed against HER-2/neu. +Indices of Angiogenesis. +Antiangiogenesis breast +cancer therapy is now being studied in human trials. +Bevaci- +zumab (a monoclonal antibody to VEGF) was approved by the +U.S. +Indices of Apoptosis. +Coexpression of Biomarkers. +Adjuvant! +Adjuvant! +New York: +Springer-Verlag;2003:112. +With kind permission of Springer Science + +Business Media. +Source: Adapted from Carlson RW, et al: Breast cancer, in NCCN Prac- +tice Guidelines in Oncology. +Fort Washington, PA: National Compre- +hensive Cancer Network, 2006. +537 +T +HE + B +REAST +CHAPTER 17 +course of treatment. +17-29). +For women with limited +disease, lumpectomy and radiation therapy are generally rec- +ommended. +Specimen mammography is performed to ensure that all +visible evidence of cancer is excised. +Adjuvant tamoxifen ther- +apy is considered for DCIS patients with ER-positive disease. +AB +Figure 17-29. +Extensive DCIS seen on mammography. +A. +Extensive calcifications are seen throughout the breast on this CC view. +B. +Mag- +nification view of calcifications. +Due to the extent of the disease the patient is not a good candidate for breast conserving surgery. +(Photos +used with permission of Dr. +Women treated with +mastectomy have local recurrence and mortality rates of <2%. +There is no randomized trial comparing mastectomy vs. +About +45% of these recurrences will be invasive cancer when radia- +tion therapy is not used. +In contrast, patients with high grade +DCIS had an unacceptably high local recurrence rate. +lumpectomy with whole breast +irradiation. +The role of axillary staging in patients with DCIS +is limited. +One consideration is for patients undergoing mastec- +tomy. +13.4%, P = 0.0009). +5.2%, P<0.001). +However it should be noted that +there were several criteria in the B-06 study. +There was a specific +lymphadenopathy exclusion criteria. +All patients +received adjuvant tamoxifen. +Although there were fewer local +recurrences with radiation (1% vs. +4%, P<0.001), there were no +differences in DFS and OS. +Mean age was 68 years, and 80% of women had +ER-positive tumors. +Again, local recurrence rates were lower +in women who received radiation (0.6% vs. +1.3% with +EBRT, a 2% increased recurrence risk. +Immediate reconstruction allows for skin-sparing, thus optimiz- +ing cosmetic outcomes. +standard axillary surgery. +A total of 26% of these clini- +cally node-negative patients had a positive SLN. +Patients with 1 or 2 positive SLNs were randomized to +completion ALND or no further surgery. +Adjuvant systemic +therapy recommendations were left to the treating clinicians. +The morbidity of SLN dissection alone vs. +those who had no further axillary surgery. +These issues have thus far lim- +ited the uptake of the results of Z0011 by some centers. +Patients with SLN +micrometastases were randomized to ALND vs. +no further sur- +gery. +Unlike Z0011, the 23-01 trial did not exclude patients +treated with mastectomy. +Approximately 9% of patients ran- +domized to each study arm underwent mastectomy. +17-31). +Indeed, a previous +AB +Figure 17-30. +Locally advanced breast cancer. +A. +Mammography of the right breast reveals a large tumor with enlarged axillary lymph +nodes. +B. +Imaging of the left breast is normal. +(Photos used with permission of Dr. +Treatment pathways for stage IIIA and +stage IIIB breast cancer. +However, the Oxford overview of all randomized +studies of neoadjuvant therapy (vs. +adjuvant therapy) reported a +hazard ratio of 1.5 (i.e., 50% increase) in local recurrence rates. +In both stage IIIA and IIIB disease, sur- +gery is followed by adjuvant radiation therapy. +Symptoms per se (e.g., breathlessness) are not in themselves an +indication for chemotherapy. +The same approach should be taken to other +symptoms such as pain. +A randomized trial is currently underway through ECOG to +address this question. +Chemo- +therapy and antiestrogen therapy are considered. +Data have been collected since 1973 +and is updated at regular intervals. +Today it is +AB +Figure 17-32. +Lesion to be targeted to excisional +biopsy. +A. +B. +Oblique +view demonstrating target lesions. +(Photos used +with permission of Dr. +mastectomy with or without reconstruction) and the need for +nodal assessment with SLN dissection. +17-32). +In +the lower half of the breast, the use of radial incisions typically +provides the best outcome. +The biopsy tissue specimen is orientated for +the pathologist using sutures, clips, or dyes. +Electrocautery or +absorbable ligatures are used to achieve wound hemostasis. +Wound drainage is usually not required. +The lesion can also be +targeted by sonography in the imaging suite or in the operating +room. +17-33). +17-34). +Although limited data are available, SLN +Figure 17-33. +Wire localization procedure. +(Photos used with permission of Dr. +Subdermal +injections are given in proximity to the cancer site or in the +subareolar location. +Specimen mammography. +(Photos +used with permission of Dr. +The use +of radioactive colloid is safe, and radiation exposure is very low. +A hand-held gamma counter is used to transcutaneously +identify the location of the SLN. +This can help to guide place- +ment of the incision. +The gamma probe is used to facilitate the dissection and to +pinpoint the location of the SLN. +Before the SLN is removed, a 10-second in vivo radioactivity +count is obtained. +A search is made for +additional SLNs if the counts remain high. +Finally, removal of a larger number +of SLNs at surgery appears to reduce the false-negative rate. +This was significantly +influenced by the site of radioisotope injection. +Radial incisions are preferred when +the tumor is in the lower aspect of the breast. +Specimen orientation is performed by the surgeon. +Requests for determination of +ER, PR, and HER-2 status are conveyed to the pathologist. +It is the surgeon’s responsibility to ensure complete +removal of cancer in the breast. +Cancer size and the extent +of skin excision are not significant factors in this regard. +If clear margins are not obtainable with re-excision, mastectomy +is required. +SLN is performed before removal of the primary +breast tumor. +The overall goal is to achieve the best possible aes- +thetic result. +Modified radical mastectomy: eleva- +tion of skin flaps. +Skin flaps are 7 to 8 mm in thick- +ness, inclusive of the skin and telasubcutanea. +(Visual +Art: © 2012. +The University of Texas MD Anderson +Cancer Center.) +Figure 17-36. +Modified radical mastectomy after +resection of breast tissue. +The pectoralis major muscle +is cleared of its fascia as the overlying breast is elevated. +The latissimus dorsi muscle is the lateral boundary of the +dissection. +(Visual Art: © 2012.The University of Texas +MD Anderson Cancer Center.) +pectoral nerve. +17-35). +17-36). +Subsequently, an axillary lymph node dissection is per- +formed. +Care +is taken to preserve the thoracodorsal neurovascular bundle. +In Patey’s modified radi- +cal mastectomy he removed the pectoralis minor muscle. +The use of closed-system suction drainage reduces +the incidence of this complication. +Catheters are retained in the +wound until drainage diminishes to <30 mL per day. +Figure 17-37. +Modified radical mastectomy (Patey): axillary lymph node dissection. +Care is +taken to preserve the thoracodorsal artery, vein, and nerve in the deep axillary space. +The superomedial limit +of this dissection is the clavipectoral fascia (Halsted’s ligament). +Inset depicts division of the insertion of the pectoralis minor muscle at the +coracoid process. +The surgeon’s finger shields the underlying brachial plexus. +(Reproduced with permission from Bland KI, et al. +Modified +radical mastectomy and total (simple) mastectomy. +In: Bland KI, Copeland EMI, eds. +The Breast: Comprehensive Management of Benign +and Malignant Diseases. +Philadelphia: Saunders, 2009. +The free TRAM +flap uses microvascular anastomoses to establish blood supply +to the flap. +Chemotherapy Adjuvant +Chemotherapy. +Table 17-14 lists the frequently used chemotherapy +regimens for breast cancer. +Neoadjuvant (Preoperative) Chemotherapy. +Source: Adapted from Carlson RW, et al: Breast cancer, in NCCN Prac- +tice Guidelines in Oncology. +Fort Washington, PA: National Compre- +hensive Cancer Network, 2006. +Neoadjuvant Endocrine Therapy. +Neoadjuvant endocrine +therapy has not been based on randomized controlled trials. +Antiestrogen Therapy +Tamoxifen. +The analysis +also showed a 39% reduction in the risk of cancer in the con- +tralateral breast. +Thrombotic events occur in <3% of treated women. +Cataract surgery is more frequently performed in patients +receiving tamoxifen. +A long-term risk of tamoxifen use is +endometrial cancer. +This +approach has not been universally accepted. +Aromatase inhibitors. +5 years of tamoxifen and this is irrespective of +absolute risk. +The risk of osteoporosis +can be averted by treatment with bisphosphonates. +Joint pains +are a side effect which affects a significant number of patients. +Oopho- +rectomy was used in premenopausal breast cancer patients. +For +both groups, the response rates were nearly 30%. +Dose-dependent and transient side effects include ataxia, dizziness, +and lethargy. +Neither permanent adrenal insufficiency nor acute crises have +been observed. +Patients with HER-2-positive tumors +benefit if trastuzumab is added to paclitaxel chemotherapy. +It was approved for use with capecitabine in patients +with HER-2-positive metastatic disease. +In this circumstance, +mammography and ultrasound are indicated for further evalu- +ation. +Nipple discharge associated with a cancer may be clear, +bloody, or serous. +A 3.0 lacrimal +duct probe can be used to identify the duct that requires exci- +sion. +Another approach is to inject methylene blue dye within +the duct after ductography. +Suspicious findings on mammography, ultra- +sonography, or MRI necessitate breast biopsy. +Chemotherapy and +endocrine therapy should be considered. +Fewer than 25% of the breast nodules +developing during pregnancy and lactation will be cancerous. +Ultrasonography and needle biopsy specimens are used in the +diagnosis of these nodules. +Lactation +is suppressed. +Jewish and African American males have the +highest incidence. +Male breast cancer is preceded by gyneco- +mastia in 20% of men. +Breast cancer is rarely seen in young +males and has a peak incidence in the sixth decade of life. +A +firm, nontender mass in the male breast requires investigation. +Skin or chest wall fixation is particularly worrisome. +DCIS makes up <15% of male breast cancer, whereas +infiltrating ductal carcinoma makes up >85%. +Special-type can- +cers, including infiltrating lobular carcinoma, have occasionally +been reported. +Borderline tumors have a greater +potential for local recurrence. +Cystic areas represent sites of +infarction and necrosis. +Most malignant phyllodes tumors (Fig. +Small +phyllodes tumors are excised with a margin of normal-appearing +breast tissue. +Large phyllodes tumors may require mastectomy. +Axillary dis- +section is not recommended because axillary lymph node metas- +tases rarely occur. +There may be +an associated breast mass (Fig. +17-39). +Inflammatory breast cancer also +may be mistaken for a bacterial infection of the breast. +A positron emission +A +B +Figure 17-38. +A. +Malignant phyllodes tumor (cystosarcoma- +phyllodes). +B. +Histologic features of a malignant phyllodes tumor +(hematoxylin and eosin stain, ×100). +Figure 17-39. +Inflammatory breast carcinoma. +Table 17-15 +Inflammatory vs. +Inflammatory changes are +present without dermal lymph +vessel invasion. +Cancer is not sharply +delineated. +Cancer is better delineated. +Erythema and edema +frequently involve >33% of +the skin over the breast. +Erythema is usually confined +to the lesion, and edema is +less extensive. +Lymph node involvement is +present in >75% of cases. +Lymph nodes are involved +in approximately 50% of the +cases. +Distant metastases are present +in 25% of cases. +Distant metastases are less +common at presentation. +Distant metastases are +more common at initial +presentation. +Philadelphia: WB Saunders;1998;1281. +Copyright +Elsevier. +This multimodal +approach results in 5-year survival rates that approach 30%. +Patients with inflammatory breast cancer should be encouraged +to participate in clinical trials. +Rare Breast Cancers +Squamous Cell (Epidermoid) Carcinoma. +Adenoid Cystic Carcinoma. +Adenoid cystic carcinoma is very +rare, accounting for <0.1% of all breast cancers. +It is typically +indistinguishable from adenoid cystic carcinoma arising in sali- +vary tissues. +These cancers are generally 1 to 3 cm in diameter +at presentation and are well circumscribed. +Axillary lymph node +metastases are rare, but deaths from pulmonary metastases have +been reported. +Apocrine Carcinomas. +There is a very low mitotic rate and little +variation in cellular features. +However, apocrine carcinomas +may display an aggressive growth pattern. +Sarcomas. +Sarcomas of the breast are histologically similar +to soft tissue sarcomas at other anatomic sites. +The +clinical presentation is typically that of a large, painless breast +mass with rapid growth. +Diagnosis is by core-needle biopsy or by +open incisional biopsy. +Primary treatment is wide local excision, which may necessitate +mastectomy. +Axillary dissection is not indicated unless there is +biopsy proven lymph node involvement. +Sixty percent of +women developing this cancer have a history of adjuvant radia- +tion therapy. +Lymphomas. +Primary lymphomas of the breast are rare, and +there are two distinct clinicopathologic variants. +The second +type is seen in women ≥40 years of age and is usually of the +B-cell type. +Breast involvement by Hodgkin’s lymphoma has +been reported. +An occult breast lymphoma may be diagnosed +after detection of palpable axillary lymphadenopathy. +Treat- +ment depends on the stage of disease. +Lumpectomy or mas- +tectomy may be required. +Axillary dissection for 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Clin Oncol. +2002;20:3095-3105. +300. +Volpi A, De Paola F, Nanni O, et al. +Breast Cancer Res Treat. +63:181-192. +301. +Buzdar AU, Ibrahim NK, Francis D, et al. +J Clin Oncol. +2005; 23:3676-3685. +302. +Buzdar AU, Valero V, Ibrahim NK, et al. +Clin Cancer Res. +2007;13:228-233. +303. +Tench DW. +The unknown primary presenting with axillary +lymphadenopathy. +In: Bland KI, Copeland EMI, eds. +The +Breast: Comprehensive Management of Benign and Malignant +Diseases. +Philadelphia: WB Saunders;1998:1447. +304. +Robinson DS, Sundaram M, et al. +Carcinoma of the breast in +pregnancy and lactation. +In: Bland KI, Copeland EMI, eds. +The +Breast: Comprehensive Management of Benign and Malignant +Diseases. +Philadelphia: WB Saunders;1998:1433. +305. +Giordano SH, Buzdar AU, Hortobagyi GN: Breast cancer in +men. +Ann Intern Med. +2002;137:678-687. +306. +Wilhelm MC. +Cancer of the male breast. +In: Bland KI, +Copeland EMI, eds. +The Breast: Comprehensive Management +of Benign and Malignant Diseases. +Philadelphia: WB Saun- +ders; 1998:1416. +307. +Khan SA, Badve S. +Phyllodes tumors of the breast. +Curr Treat +Options Oncol. +2001;2:139-147. +308. +Chittoor SR, Swain SM. +Locally advanced breast cancer: Role +of medical oncology. +In: Bland KI, Copeland EMI, eds. +The +Breast: Comprehensive Management of Benign and Malignant +Diseases. +Philadelphia: WB Saunders;1998:1403. +309. +Mies C. +Mammary sarcoma and lymphoma. +In: Bland KI, +Copeland EMI, eds. +The Breast: Comprehensive Management +of Benign and Malignant Diseases. +Philadelphia: WB Saun- +ders;1998:307. +310. +Stewart FW, Treves N. +Cancer. +1948;1:64-81. +Disorders of the Head and Neck +Richard O. +Wein, Rakesh K. +Chandra, +C. +René Leemans, and Randal S. +Infected, desquamated debris accumulates within the canal. +For this +reason, the patient should also be instructed to keep the ear dry. +In addition to the previ- +ously mentioned findings, cranial neuropathies may be observed. +Patients who do not respond to medical management require +surgical debridement. +In its acute phase, otitis media typically implies a bacterial +infection of the middle ear. +Long-term car- +diovascular problems are a significant concern in these patients. +Most cases occur before 2 years +of age and are secondary to immaturity of the Eustachian tube. +18-1). +If the process lasts 3 to 8 weeks, it is deemed +subacute. +Acute otitis media. +Figure 18-2. +Myringotomy and tube. +dysfunction, and other factors. +The exact role of bacteria in the pathophysiol- +ogy is controversial. +The patient experiences otalgia, ear full- +ness, and conductive hearing loss. +Bubbles may be seen behind the +retracted membrane. +Treatment for uncomplicated otitis media is oral antibiotic +therapy. +Chronic otitis media is frequently treated with myringotomy +and tube placement (Fig. +18-2). +7 Disorders of the head and neck can cause significant cos- +metic and functional impairment. +The practitioner must be +empathetic to the effect of these morbidities on quality of +life. +567 +DISORDERS OF THE HEAD AND NECK +CHAPTER 18 +fluid and middle ear ventilation. +Chronic otitis media, however, may be associated with +nonhealing tympanic membrane perforations. +Patients may have +persistent otorrhea, which is treated with topical drops. +Squamous epithelium may also migrate into the middle ear via a +perforation. +The mastoid air cells +coalesce into one common space filled with pus. +These diagnoses are confirmed by +computed tomographic (CT) scan. +Labyrinthitis refers to inflam- +mation of the inner ear. +Most cases are idiopathic or are second- +ary to viral infections of the endolymphatic space. +Labyrinthitis associated +with middle ear infection may be serous or suppurative. +Total recovery is +eventually possible after the middle ear is adequately treated. +This condition +may hallmark impending meningitis and must be treated rapidly. +Meningitis is the most common intracranial complica- +tion. +Otologic meningitis in children is most commonly associ- +ated with a H. +influenzae type B infection. +Mastoidectomy and neurosurgical consultation may be +necessary. +Historically, Bell’s +palsy was synonymous with “idiopathic” facial paralysis. +Treatment +includes oral steroids plus antiviral therapy (i.e., valacyclovir). +Traumatic facial nerve injuries may occur secondary to +accidental trauma or surgical injury. +Complete recovery of nerve +function is uncommon in these cases. +The classification of sinusitis as acute vs. +This may be accomplished by +endoscopic or radiologic examination (i.e., CT scan). +This results in stasis of secretions, tis- +sue hypoxia, and ciliary dysfunction. +These conditions promote +bacterial proliferation and acute inflammation. +pneumoniae, +H. +influenzae, and M. +catarrhalis. +Nosocomial acute sinusitis +frequently involves Pseudomonas or S. +aureus, both of which +may also exhibit significant antibiotic resistance. +Nasal endoscopy is a critical element of the diagnosis of +chronic sinusitis. +18-3 +and 18-4). +In this setting, purulence +may represent an acute exacerbation of chronic sinusitis. +Overall, S. +Endoscopic view of purulence within a surgically +opened maxillary sinus cavity. +Figure 18-4. +Endoscopic image of a nasal polyp. +Figure 18-5. +POC-CT system. +All components can be fit within an +8' × 10' room in an outpatient office setting. +sinusitis. +Thus, the increased prevalence of community acquired +methicillin resistant S. +CT scan has excellent negative predictive value when per- +formed in the setting of active symptoms. +18-5). +One theoretical +shortcoming of this technology is that it does not permit soft tis- +sue imaging. +This is seldom a concern in sinonasal evaluation, as +this is typically undertaken in bone windows. +18-6 and 18-7). +Inspis- +sated mucin or pus is drained and cultured. +The role of fungi in sinusitis is an area of active investiga- +tion. +Fungal sinusitis may take on both noninvasive and invasive +forms. +Polyps in the ethmoid cavity are seen on the endoscope image. +570 +SPECIFIC CONSIDERATIONS +UNIT + +II +PART II +subtle and limited to a single sinus. +Fungus balls represent a + significant proportion of isolated sphenoid sinus pathology +(Fig. +18-7). +Oral antifungal +therapy is sometimes indicated as well. +The mucosa of the +posterior and lateral pharyngeal walls is also rich with lym- +phoid cells. +In the vast majority of cases, infectious pharyngitis is viral +rather than bacterial in origin. +Most cases resolve without com- +plication from supportive care and possibly antibiotics. +Patients +with tonsillitis typically present with sore throat, dysphagia, +and fever. +The mucosa is inflamed. +Tonsillar exudates and +cervical adenitis may be seen, especially when the etiology is +bacterial. +If adenoiditis is present, symptoms may be similar to +those of sinusitis. +Tonsillitis and adenoiditis may follow acute, recurrent +acute, and chronic temporal patterns. +When the patient also has hoarseness, rhinorrhea, +Figure 18-7. +Sphenoid sinus fungal ball. +pneumoniae, and group C and G streptococci.13 +H. +influenzae and anaerobes also have been implicated. +Some experts advocate culture only when these +are negative. +Complications of S. +The incidence of glomerulonephritis +is not influenced by antibiotic therapy. +Scarlet fever results from +production of erythrogenic toxins by streptococci. +The so-called strawberry +tongue also is seen. +Locoregional complications include peri- +tonsillar abscess and, rarely, deep-neck space abscess. +Candida albicans is the most common fungal organism +to cause pharyngitis. +Whitish-cheesy or +creamy mucosal patches are observed with underlying erythema. +Progression of the clinical picture +reveals lymphadenopathy, splenomegaly, and hepatitis. +Noninfectious causes of pharyngitis must also be consid- +ered. +There is no consensus as to the best +method. +Adenoidectomy +is also the first line of surgical management for children with +chronic sinusitis. +In both procedures, there is risk +of velopharyngeal insufficiency. +In the latter condition, nasal +regurgitation of liquids and hypernasal speech are experienced. +In OSA, polysom- +nogram demonstrates at least 10 episodes of apnea or +hypopnea per hour of sleep. +These episodes occur as a +result of collapse of the pharyngeal soft tissues during sleep. +This can be accomplished with cold steel, laser, and/or cau- +tery. +Patients with moderate to severe sleep apnea frequently mani- +fest involvement of the tongue base. +Figure 18-8. +Laryngeal granuloma. +These “social snorers” may pursue elective +procedures that stiffen the uvula and soft palate. +Elec- +tive uvulopharyngoplasty may also be a consideration in this +population. +The princi- +pal symptom of these disorders, at least when a mass lesion +is present, is hoarseness. +Other vocal manifestations include +hypophonia or aphonia, breathiness, and pitch breaks. +Many +cases resolve after puberty, but the disorder may progress into +adulthood. +The diagnosis +can be established with office endoscopy. +Currently, there is no +“cure” for RRP. +Therefore, surgery has an ongoing role for palliation +of the disease. +Multiple procedures are typically required over +the patient’s lifetime. +18-8). +Effective management requires identifica- +tion of the underlying cause(s). +Patients report pain (often with +swallowing) more commonly than vocal changes. +The +management of vocal cord paresis/paralysis is discussed later in +this section. +The +superficial lamina propria just underlies the vibratory epithelial +surface. +Patients report progressive development of a rough, low- +pitched voice. +Use +of anticoagulant or antiplatelet drugs may be a risk factor. +Notably, top- +ical and systemic steroids are ineffective for these conditions. +Focal polyps may be excised superficially under microlaryn- +goscopy. +Postoperative voice therapy is usually +indicated. +Large cyst of vocal cord. +as the supraglottic larynx. +Cysts may present in a variety of ways +depending on the size and site of origin (Fig. +18-9). +Cysts observed in children can be quite +large, thus compromising the airway. +Lesions of the true vocal +cord usually present with hoarseness. +Treatment again depends +on the size and site of the cyst. +Lesions exhibiting hyperplasia have a 1% to 3% risk +of progression to malignancy. +In contrast, that risk is 10% to +30% for those demonstrating dysplasia. +Features of ulceration and erythropla- +sia are particularly suggestive of possible malignancy. +A history +of smoking and alcohol abuse should also prompt a malignancy +work-up. +In the absence of suspected malignancy, conserva- +tive measures are used for 1 month. +Antireflux therapy, including proton +pump inhibitors, may be prescribed. +Investigational therapies, +including retinoids, also have been attempted. +Any lesions that +progress, persist, or recur should be considered for excisional +biopsy specimen. +The cause remains idiopathic in up to 20% of adults +and 35% of children. +Some patients do well +with this modality alone. +This +technique also is useful for vocal cord atrophy, which may occur +with aging. +18-10).26 This may be +combined with procedures to adduct the vocal process of the +arytenoids. +Figure 18-10. +Cross-section of the larynx demonstrating the prin- +ciple of medialization laryngoplasty. +An implant is used to push the +paralyzed vocal cord toward the midline. +While 40% of cases will resolve completely, the remainder +will require intervention. +Subcu- +taneous interferon-α-2a may also be used for this purpose. +Capillary malformations +usually involve the midline neck or forehead, and may fade +with age. +Venular malformations are also known as port-wine +stains. +These lesions often follow facial dermatomes and usu- +ally thicken with age. +Venous malformations are composed of +ectatic veins within the lips, tongue, or buccal area. +These may +present as purple masses or subcutaneous/submucosal nodules. +Those +arising above the hyoid bone tend to be microcystic and have an +infiltrative quality. +Lymphangiomas may become secondarily +infected and may rapidly enlarge, causing airway compromise. +These lesions may also be associated with feeding difficulties +and failure to thrive. +Capillary hemangiomas and superficial port-wine stains +are effectively treated by FPDL. +The KTP or Nd:YAG laser is +used for deeper port-wine stains. +Arteriovenous malformations require formal surgical resection +with negative margins. +Preoperative angiographic embolization +is frequently used to facilitate surgery. +This often is difficult for microcystic cases +given the infiltrative nature. +Head and neck soft tissues have the benefit of a robust +blood supply. +A pressure dressing is also +applied. +These measures are employed to avoid a pincushion +deformity (Fig. +18-11). +Sutures are removed after 4 to 5 days, but may be removed +earlier in thin-skinned areas. +The chosen antibiotic should cover S. +aureus. +The gray line (conjunctival margin; Fig. +18-12) must +Figure 18-11. +Figure 18-12. +Alignment of the gray line is the key step in the +repair of eyelid lacerations. +Management of lip injuries follows the same principle. +The orbicularis oris must be closed, and the vermilion bor- +der carefully approximated (Fig. +18-13). +These injuries must be repaired so that the cartilage is +covered. +A pressure dress- +ing is frequently advocated after closure of an ear laceration. +Soft- +tissue injuries occurring in the midface may involve distal facial +nerve branches. +If neural segments are missing, cable +Figure 18-13. +Approximation of the vermilion border is the key +step in the repair of lip lacerations. +3% +3% +36% +2% +20% +21% 14% +Figure 18-14. +Sites of common mandible fractures. +Injuries to +the buccal branch should alert the examiner to a possible parotid +duct injury. +The duct should be repaired +over a 22-gauge stent or marsupialized into the oral cavity. +Facial bone fractures most commonly involve the man- +dible. +18-14). +Currently, arch bars and IMF are performed to establish occlu- +sion. +The fracture is then exposed and reduced, using transoral +approaches where possible. +Rigid fixation is then accomplished by the application of plates +and screws. +Midface fractures are classically described in three pat- +terns: Le Fort I, II, and III. +A full understanding of midface +structure is first necessary (Fig. +18-15). +Le Fort I fractures occur transversely across the alveolus, +above the level of the teeth apices. +The +nasal dorsum, palate, and medial part of the infraorbital rim are +mobile. +The Le Fort III fracture is also known as craniofacial +disjunction. +The frontozygomaticomaxillary, frontomaxillary, +and frontonasal suture lines are disrupted. +The entire face is +mobile from the cranium. +It is convenient to conceptualize com- +plex midface fractures according to these patterns (Fig. +18-16); +however, in reality, fractures reflect a combination of these three +types. +Also, the fracture pattern may vary between the left and +right sides of the midface. +Lateral blows to the cheek may be +associated with isolated zygoma fractures. +Major buttresses of the midface. +III +II +I +Figure 18-16. +Classic Le Fort fracture patterns. +Figure 18-17. +18-17). +This may be associated with enophthalmos or entrap- +ment of the inferior oblique muscle. +The latter results in diplopia +upon upward gaze. +Temporal bone fractures occur in approximately one fifth +of skull fractures. +Unfortunately, the incidence of temporal bone +fracture from gunshot wounds to the head is rising. +Fractures are +divided into two patterns (Fig. +18-18), longitudinal and trans- +verse, based on the clinical picture and CT imaging. +In practice, +most fractures are oblique. +The facial nerve is injured in approximately 20% of cases. +The facial nerve is injured in 50% of cases. +Hemotympanum may be +observed. +A cerebrospinal fluid (CSF) leak must be suspected +in temporal bone trauma. +This resolves with conservative mea- +sures in most cases. +Delayed or partial paralysis will almost always resolve +with conservative management. +View of cranial surface of skull base. +Longitudinal +(left) and transverse (right) temporal bone fractures. +for nerve decompression. +This is because the majority of malignancies of +this region are represented by this pathology. +The selection of treatment protocols varies for each site +within the upper aerodigestive tract. +The importance of multi- +disciplinary management cannot be underestimated. +The future of the treatment of head and neck +cancer lies within the field of molecular biology. +This relationship is +synergistic rather than additive. +This increased +risk rises to > threefold for heavy drinkers. +Smokers presented more +frequently with tumors of the larynx, hypopharynx, and floor +of mouth. +The nut is +chewed in combination with lime and cured tobacco as a mix- +ture known as a quid. +The risk of hard +palate carcinoma is 47 times greater in reverse smokers com- +pared to nonsmokers. +Environmental ultraviolet light exposure has been associated +with the development of lip cancer. +In addition, pipe smoking also has been +associated with the development of lip carcinoma. +Oral cavity landmarks. +18-19). +The pharynx is divided into three regions: nasopharynx, +oropharynx, and hypopharynx. +The inferior margin of the nasophar- +ynx is the superior surface of the soft palate. +The adenoids, typi- +cally involuted in adults, are located with the posterior aspect +of this site. +Retropharyngeal metastatic lymphatic +spread may occur with oropharyngeal lesions. +The larynx is divided into three regions: the supraglot- +tis, glottis, and subglottis. +Overexpression of mutant p53 is associated with carcino- +genesis at multiple sites within the body. +Point mutations in p53 +have been reported in up to 45% of head and neck carcinomas. +These two events also are known +as initiation and promotion. +The overall rate of second primary tumors is approxi- +mately 14%. +The prevalence of synchronous tumors is +approximately 3% to 4%. +Additionally, +barium swallow has been used instead of esophagoscopy as a +preoperative evaluation. +Table 18-1 demonstrates TNM +staging for oral cavity lesions. +The N classification system is +uniform for all head and neck sites except for the nasopharynx. +Upper Aerodigestive Tract +Lip. +Basal cell carcinoma presents more fre- +quently on the upper lip than lower. +Clinical findings in lip cancer include an ulcerated lesion on +the vermilion or cutaneous surface. +Careful palpation is impor- +tant in determining the actual size and extent of these lesions. +Lip cancer results in fewer than 200 patient deaths annu- +ally and is stage dependent. +Early diagnosis coupled with ade- +quate treatment results in a high likelihood of disease control. +Lymph node metastasis occurs in +fewer than 10% of patients with lip cancer (Fig. +18-20). +The +primary echelon of nodes at risk is in the submandibular and +submental regions. +In the presence of clinically evident neck +metastasis, neck dissection is indicated. +The typical lip length is 6 to 7 cm. +Resection with primary closure is possible with +a defect of up to one third of the lip (Fig. +18-21). +Lymphatics of the lip. +Figure 18-21. +Wedge resection of lower lip squamous cell + carcinoma. +18-22). +Microstomia is a potential complication with these +types of lip reconstruction. +The majority of tumors in the +oral cavity are squamous cell carcinomas (>90%). +Each site is +briefly reviewed with emphasis placed on anatomy, diagnosis, +and treatment options. +Oral Tongue. +The oral tongue is a muscular structure with +overlying nonkeratinizing squamous epithelium. +The tumors may present as ulcerations or as exophytic +masses (Fig. +18-24). +18-25). +The CO2 laser may be used for excision +Figure 18-22. +A-C. +Karapandzic labiaplasty for lower lip carcinoma. +Figure 18-23. +Oral tongue squamous cell carcinoma. +Figure 18-24. +Primary lymphatics for regional +spread of oral cavity malignancies. +The ostia of the submaxillary and sublingual glands are con- +tained in the anterior floor of mouth. +Invasion into these muscles can result in decreased +tongue mobility and poor articulation. +18-26). +Figure 18-25. +A and B. +Anatomy of the floor of +mouth and submandibular space. +a. += artery; m. += +muscle; n. += nerve. +A +B +Submandibular gland +Digastric m. +(anterior belly) +Myohyoid m. +Stylopharyngeus, +stylohyoid and +styloglossus mm. +Digastric muscle +(posterior belly) +Styloid +process +Hypoglossal n. +Middle +constrictor m. +External +carotid a. +Hyoid bone +Hyoglossus m. +Lingual n. +Deep lingual a. +Dorsal lingual a. +Genioglossus m. +Geniohyoid m. +Sublingual a. +Lingual n. +Hyoid bone +Hypoglossal n. +18-27) and immediate recon- +struction. +Composite resection specimen of a T4 floor of +mouth squamous cell carcinoma. +Figure 18-26. +A and B. +Differences in +the transoral resection of a floor of mouth +and alveolar ridge lesion. +AB +Incision +Tissue excised +muscular bed. +Alveolus/Gingiva. +The alveolar mucosa overlies the bone of +the mandible and maxilla. +It extends from the gingivobuccal +sulcus to the mucosa of the floor of mouth and hard palate. +Although access for such a procedure can be per- +formed by using an anterior mandibulotomy (Fig. +For radiographic +evaluation of the mandible, Panorex views demonstrate gross +cortical invasion. +MRI is the best modality for demonstrating +invasion of the medullary cavity of the mandible. +Patients with N0 disease had a 5-year survival rate +of 69%.52 +Buccal Mucosa. +Tumors in this area have a propensity to +spread locally and to metastasize to regional lymphatics. +Lymphatic drainage is to the facial +and the submandibular nodes (level I). +Anterior mandibulotomy with mandibular swing to +approach a posterior lesion. +cheek may require through-and-through resection. +Palate. +Most squamous cell +carcinomas of the hard palate are caused by habitual tobacco +and alcohol use. +Chronic irritation from ill-fitting dentures +also may play a causal role. +Treatment is symptomatic and biopsy specimen +confirms its benign nature. +Mucosal melanoma may occur on the palate and presents +as a nonulcerated, pigmented plaque. +Kaposi’s sarcoma of the +palate is the most common intraoral site for this tumor. +Tumors +may present as either an ulcerative, exophytic, or submucosal +mass. +Minor salivary gland tumors tend to arise at the junc- +tion of the hard and soft palate. +Squamous cell carcinoma of the hard palate is treated +surgically. +Adjuvant radiation is indicated for advanced staged +tumors. +Involvement of the periosteum requires +removal of a portion of the bony palate. +Oropharynx. +Oropharyngeal cancer may present as an ulcerative lesion +or an exophytic mass. +Tumor fetor from necrosis is common. +Dysphagia and weight loss are common symptoms. +The incidence of regional metas- +tases from cancers of the oropharynx is high. +The etiology for this rise has been attributed to the HPV-16 +related development of malignancy. +Patients were treated +with sequential chemoradiation for advanced stage disease. +HPV positivity was found in 57% of all oropharyngeal can- +cers in the study. +HPV-positive cancers demonstrated a higher +response rate to induction chemotherapy (82% vs. +55%) +and improved 2-year survival (95% vs. +62%). +Extensive oropharyngeal cancers may require surgical +resection and postoperative radiotherapy. +Nasal regurgitation of air and liquids can be decreased with use. +Preoperative planning can +result in the creation of a defect that better tolerates obturation. +Hypopharynx and Cervical Esophagus. +18-29). +Squamous cancers of the hypopharynx frequently +present at an advanced stage. +Relationship of nasopharynx, oropharynx, and +hypopharynx. +18-30). +Resection of the primary tumor and surrounding pha- +ryngeal tissue is performed en bloc. +When total laryngopharyngoesoph- +agectomy is necessary, gastric pull-up is performed. +Cervical esophageal cancer may be managed surgically or +by concomitant chemoradiation. +Larynx. +18-31). +The lateral limits of the larynx are the ary- +epiglottic folds. +The larynx is composed of three regions: the +supraglottis, the glottis, and the subglottic (Fig. +18-32). +The epi- +glottis and the vocal cords are lined by stratified, nonkeratinizing +squamous epithelium. +The subglottic mucosa is pseudostratified, +ciliated respiratory epithelium. +Minor salivary glands are also +found in the supraglottic and subglottic. +Tumors of the laryngeal framework include synovial +sarcoma, chondroma, and chondrosarcoma. +Endoscopic view of a laryngeal squamous carcinoma. +Referred +otalgia or odynophagia is encountered with advanced supraglottic +cancers. +Bulky tumors of the supraglottic may result in airway +compromise. +Decreased vocal cord mobility may be caused by direct muscle +invasion or involvement of the RLN. +Superficial tumors that are bulky may appear +to cause cord fixation through mass effect. +Lymph node metastasis may be defined more +readily with the use of imaging studies. +Lymphatic drainage of the larynx is distinct for each sub- +site. +Limited glottic +cancers typically do not spread to regional lymphatics (1%–4%). +In contrast, more +advanced tumors may require partial laryngectomy (Fig. +18-33) or +even total laryngectomy (Fig. +18-34).65 Further complicating the +Perichondrium +Unilateral +lesion +Thyroid +cartilage +Figure 18-33. +Example of the resection of a vertical partial laryn- +gectomy for an early stage glottic carcinoma. +Figure 18-34. +591 +DISORDERS OF THE HEAD AND NECK +CHAPTER 18 +Figure 18-35. +resection. +Use +of an operative microscope aids the precision of such dissec- +tions. +Open laryngofissure and cordectomy may be reserved for +more invasive tumors. +The risk for aspiration is high following certain partial lar- +yngectomies. +Patient selection is vital to successful application +of these techniques. +Presurgical pulmonary assessment may be +necessary. +One simple measurement of functional reserve is to +have the patient climb two flights of stairs. +Close follow-up +examinations and smoking cessation are mandatory adjuncts of +therapy. +18-35) or free flap reconstruction is +required for lesions with pharyngeal extension. +Speech and Swallowing Rehabilitation. +The sounds produced can be articulated into words. +Unfortunately, less than 20% of postlaryngectomy patients +develop fluent esophageal speech. +The valve prevents retrograde passage of food or saliva +into the trachea. +The vibrations create sound waves that the +patient articulates into words. +A disadvantage of the electro- +larynx is the mechanical quality of the sound produced. +This +device is most useful in the postoperative period before training +for esophageal speech. +Unknown Primary Tumors. +Example of the Ohngren’s line and the relationship +to the maxilla. +patients previously considered to have an unknown primary. +Symptoms associated with sinonasal tumors +are subtle and insidious. +They include chronic nasal obstruc- +tion, facial pain, headache, epistaxis, and facial numbness. +As +such, tumors of the paranasal sinuses frequently present at an +advanced stage. +Orbital invasion can result in proptosis, diplo- +pia, epiphora, and vision loss. +Malignant tumors of the sinuses are predominantly squa- +mous cell carcinomas. +Metasta- +ses from the kidney, breast, lung, and thyroid may also present +as an intranasal mass. +The site of origin, involved bony structures, and the presence of +vascularity should be assessed. +A meningocele or encephalocele +will present as a unilateral pulsatile mass. +Biopsy of a unilat- +eral nasal mass should be deferred until imaging studies are +obtained. +An untimely biopsy specimen can result in a CSF leak. +Each team member is necessary to facilitate the goal of safe +and complete tumor removal. +Prognosis is dependent on tumor location and extension to +the surrounding anatomy. +If there is invasion of the orbital fat, exenteration +of the orbital contents is required. +The head and neck surgeon and neurosurgeon work in con- +cert to perform this procedure. +Chemotherapy has a limited application and may be used for +specific indications. +Rhabdomyosarcoma is primarily treated +with chemotherapy followed by radiation therapy. +Surgery is +reserved for persistent disease after chemoradiation. +Risk factors for nasopharyngeal carcinoma include area +of habitation, ethnicity, and tobacco use. +Cra- +nial nerve involvement is indicative of skull base extension and +advanced disease. +Lymphatic spread occurs to the posterior +cervical, upper jugular, and retropharyngeal nodes. +Bilateral +regional metastatic spread is common. +Distant metastasis is +present in 5% of patients at presentation. +Evaluation with +imaging studies is important for staging and treatment planning. +The status +of the cavernous sinus and optic chiasm should also be assessed. +Endoscopic removal is also +possible in selected cases. +The most +common histology is squamous cell carcinoma. +In the pediatric population, tumors of the temporal bone +are most commonly soft-tissue sarcomas. +For extensive, +pinna-based lesions, procedures such as auriculectomy may +be required. +advanced skin cancer with positive margins, perineural spread, +or multiple involved lymph nodes. +Temporal bone resec- +tions are classified as lateral or subtotal (Fig. +18-37). +It is indicated for malignant tumors +extending into the middle ear. +The differential diagnosis of a neck mass +is dependent on its location and the patient’s age. +In children, +most neck masses are inflammatory or congenital. +The use of imaging (CT and/or MRI) is dictated by the patient’s +clinical presentation. +Patterns of Lymph Node Metastasis. +The regional lym- +phatic drainage of the neck is divided into seven levels. +18-38). +Levels of the neck denoting lymph node bearing +regions. +Primary tumors within the oral cavity and lip metastasize to the +nodes in levels I, II, and III. +18-39). +18-40). +18-41). +This may be in the form of elective neck irradiation +or elective neck dissection. +Figure 18-39. +Shaded region indicates the region included in a +supraomohyoid neck dissection. +Figure 18-40. +Shaded region indicates the region included in a +lateral neck dissection. +For clinically N+ necks, frequently the surgical treat- +ment of choice is the MRND or RND. +Surgically debulking +metastatic disease does not improve survival and is not advo- +cated. +Parapharyngeal Space Masses. +18-42), dysphagia, cranial nerve dysfunction, +Horner’s syndrome, or vascular compression. +Figure 18-41. +Shaded region indicates the region included in a +posterolateral neck dissection. +Lymph node metas- +tases and primary lymphoma represent 15% of lesions. +Surgical access to these tumors may require a trans- +mandibular and/or lateral cervical approach. +Benign Neck Masses. +A number of benign masses of the +neck occur that require surgical management. +Many of these +masses are seen in the pediatric population. +They present as a midline or paramedian +cystic mass adjacent to the hyoid bone. +After an upper respira- +tory infection, the cyst may enlarge or become infected. +There are several types, numbered according to their cor- +responding embryologic branchial cleft. +18-43). +The removal of +Figure 18-43. +CT scan demonstrating a branchial cleft cyst with operative specimen. +They +typically present as mobile, fluid-filled masses. +Recurrence and re-growth occur with incomplete removal. +Deep Neck Fascial Planes. +The deep cervi- +cal fascia is composed of three layers. +These are the investing +(superficial deep), pretracheal, and the prevertebral fascias. +This layer surrounds the SCM muscle and cov- +ers the anterior and posterior triangles of the neck. +This fascia blends laterally to the carotid sheath. +The major sali- +vary glands are the parotid, submandibular, and sublingual glands. +About 85% of salivary gland neoplasms arise within +the parotid gland (Fig. +18-44). +Tumors arising from minor salivary gland tissue carry +an even higher risk for malignancy (75%). +Salivary gland tumors are usually slow growing and +well circumscribed. +Additional findings ominous for malignancy include skin inva- +sion and fixation to the mastoid tip. +Anterior facial v. +Temporal +branches +Posterior belly +of digastric m. +Cervical +branch +Masseter m. +Zygomatic branch +Parotid duct +Buccal +branch +Mandibular +branch +Figure 18-44. +Example of a tumor in the parotid with the pattern +of the facial nerve and associated anatomy. +m. += muscle; n. += nerve; +v. += vein. +tumor and possible fixation to the mandible or involvement of the +tongue. +Parotid gland malignancies can metastasize to the +intra- and periglandular nodes. +The next echelon of lymphat- +ics for the parotid is the upper jugular nodal chain. +Tumors arising in patients of advanced age +also tend to have more aggressive behavior. +Diagnostic imaging is standard for the evaluation of sali- +vary gland tumors. +Diagnosis of salivary +gland tumors is frequently aided by the use of FNA. +The final histopathologic diagnosis is confirmed by +surgical excision. +Nonepithelial benign lesions include +hemangioma, neural sheath tumor, and lipoma. +Tumor spillage of a +pleomorphic adenoma during removal can lead to problematic +recurrences. +Malignant epithelial tumors range in aggressiveness from +low to high grade. +The most common malignant epithelial neoplasm of the salivary +glands is mucoepidermoid carcinoma. +The primary treatment of salivary malignancies is surgi- +cal excision. +Radical resection is indicated with tumors that +invade the mandible, tongue, or floor of mouth. +Tumor surgery frequently +necessitates removal of structures related to speech and swal- +lowing. +It is important to remember that the most com- +plex procedure is not always the most appropriate. +Full-thickness grafts are used on the face when local rotational +flaps are not available. +These grafts have less contracture over +time than split-thickness grafts. +Several myocutaneous flaps exist for head and neck recon- +struction. +This flap is ideal for +reconstruction of scalp and lateral skull base defects. +The latter vessel may be sacrificed to +increase the arc of rotation. +The latissimus dorsi flap provides a large source of soft +tissue and has a wide arc of rotation. +The flap is based on the +thoracodorsal vasculature. +This flap can be used as a regional +rotational flap or as a free flap. +The natural shape of this donor +site bone is similar to the mandibular angle. +However, for lengthy mandibular defects (>10 cm), the fibular +flap usually is chosen. +The scapular flap can +provide approximately 12 cm of scapula bone and is based on +Figure 18-45. +Radial forearm free flap before harvest +from the arm. +602 +SPECIFIC CONSIDERATIONS +UNIT + +II +PART II +the circumflex scapular artery. +Placement of a tracheostomy does not obligate a patient +to loss of speech. +Such a patient may require dilatation and/ +or placement of a gastrostomy tube for nutrition. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Kaushik V, Malik T, Saeed SR. +Interventions for acute otitis +externa. +Cochrane Database Syst Rev. +2010 Jan 20;(1):CD004740. +2. +Carfrae MJ, Kesser BW. +Malignant otitis externa. +Otolaryngol +Clin North Am. +2008; 41(3):537-549. +3. +Ann Otol Rhinol Laryngol 2000;109:24. +4. +Cunningham M, Guardiani E, Kim HJ, et al. +Otitis media. +Future Microbiol. +2012 7(6):733-753. +5. +Otolaryngol Head Neck Surg 1999;120:350. +6. +Gantz BJ, Rubinstein 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et al. +Evidence for treat- +ment strategies in sinonasal adenocarcinoma. +Head Neck. +2012; +34(8):1168-1178. +71. +Reiersen DA, Pahilan ME, Devaiah AK. +Meta-analysis +of treatment outcomes for sinonasal undifferentiated carcinoma. +Otolaryngol Head Neck Surg. +2012;147(1):7-14. +72. +Eggesbø HB. +Imaging of sinonasal tumours. +Cancer Imaging. +2012;12:136-152. +73. +Robbins KT, Ferlito A, Silver CE, et al. +Contemporary manage- +ment of sinonasal cancer. +Head Neck. +2011;33(9):1352-1365. +74. +Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy +vs. +J Clin Oncol. +1998;16:1310-1317. +75. +Kuhel W, Hume CR, Selesnick SH: Cancer of the external +auditory canal and temporal bone. +Otolaryngol Clin North Am. +1996;29:827-852. +76. +Morris LG, Mehra S, Shah JP, et al. +Predictors of survival and +recurrence after temporal bone resection for cancer. +Head Neck. +2012; 34(9):1231-1239. +77. +Wang Y, Ow TJ, Myers JN. +Pathways for cervical metastasis +in malignant neoplasms of the head and neck region. +Clin Anat. +2012;25(1):54-71. +78. +Laryngoscope. +1984;94:942-945. +79. +Medina JE, Byers RM: Supraomohyoid neck dissection: +rationale, indications and surgical technique. +Head Neck. +1989;11:111-122. +80. +Eicher SA, Weber RS: Surgical management of cervical lymph +node metastases. +Curr Opin Oncol. +1996;8:215-220. +81. +J Am +Coll Surg. +2001;193:91-102. +82. +Head Neck. +1997;19:14-19. +83. +Strojan P, Ferlito A, Langendijk JA, et al. +Indications for radio- +therapy after neck dissection. +Head Neck. +2012; 34(1):113-119. +84. +Eisele DE, Netterville J, Hoffman H, et al: Parapharyngeal +space masses. +Head Neck. +1999;21:154-159. +85. +Laryngoscope. +2011;121(8):1702-1707. +86. +Arch Otolaryngol Head Neck Surg. +1990;116:1055-1060. +87. +Head Neck. +1997;19:620-628. +88. +Agrawal A, Husein OF, Schuller DE. +Esophageal reconstruc- +tion with larynx preservation using forearm-free flap. +Laryngo- +scope. +2008;118(10):1750-1752. +89. +Fujiwara T, Shih HS, Chen CC, et al. +Laryngoscope. +2011;121(2):289-293. +90. +Arch Otolaryngol Head Neck Surg. +1998;124:46-56. +91. +1996. +Also see http://www.headandneckcancer.org/ +clinicalresources/docs/oralcavity.php. +Chest Wall, Lung, Mediastinum, +and Pleura +Katie S. +Nason, Michael A. +Maddaus, and +James D. +The cricoid cartilage consists +of an anterior arch and a posterior broad-based plate. +Articulat- +ing with the posterior cricoid plate are the arytenoid cartilages. +The vocal cords originate from the arytenoid cartilages and then +attach to the thyroid cartilage. +19-2). +8 The assessment of patient risk before thoracic resection +is based on clinical judgment and data. +11 Treatment of pulmonary aspergilloma is individualized. +Asymptomatic patients can be observed without any +additional therapy. +High cuff +pressures can cause ischemia of the contiguous airway wall in +as short as 4 hours. +Avoidance requires careful cuff management to keep pressures +Epiglottis +Aryepiglottic m. +Transverse, oblique +arytenoid mm. +Lateral +cricoarytenoid m. +Posterior +cricoarytenoid m. +Thyroid cartilage + facet +Recurrent +laryngeal n. +Internal +laryngeal n. +Thyroepiglottic m. +Thyroarytenoid m. +Cricothyroid m. +(cut) +Inferior +thyroid a. +Branch from +internal thoracic a. +Superior bronchial a. +Middle bronchial a. +1 +Lateral longitudinal +anastomosis +3 +2 +Figure 19-1. +Anatomy of the larynx and upper trachea. +m. += muscle; n. += nerve. +Figure 19-2. +Arterial blood supply to the larynx and upper trachea. +a. += artery. +Mild +ulceration and stenosis are frequently seen after tracheostomy +removal. +Stridor and dyspnea on exertion are the primary symptoms +of tracheal stenosis. +19-3). +Acute Management. +A comprehensive bronchoscopic evalua- +tion is critical in the initial phase of evaluation. +Rarely, if ever, is +tracheostomy necessary. +Resection typically involves 2 to 4 cm of trachea +for benign stenosis. +It is critical to fully resect all inflamed and +scarred tissue. +This removes all +Figure 19-3. +Diagram of the principal postintubation lesions. +A. +A circumferential lesion at the cuff site after the use of an endotracheal +tube. +B. +Potential lesions after the use of tracheostomy tubes. +Anterolateral stenosis can be seen at the stomal level. +Circumferential stenosis +can be seen at the cuff level (lower than with an endotracheal tube). +The segment in between is often inflamed and malacotic. +C. +Damage to +the subglottic larynx. +D. +E. +Tracheoinnominate artery fistula. +(Adapted with permission from Grillo H. +Surgical treatment of postintubation tracheal injuries. +J +Thorac Cardiovasc Surg. +1979;78:860. +Tracheal Fistulas +Tracheoinnominate Artery Fistula. +Most cuff-induced fistulas will develop +within 2 weeks after placement of the tracheostomy. +Clinically, tracheoinnominate artery fistulas present with +bleeding. +With significant +609 +Chest Wall, Lung, Mediastinum, and Pleura +CHAPTER 19 +Figure 19-4. +Steps in the emergency +management of a tracheoinnominate +artery fistula. +bleeding, the tracheostomy cuff can be hyperinflated to tempo- +rarily occlude the arterial injury. +19-4). +The patient can then be orally intubated, +and the airway suctioned free of blood. +Tracheoesophageal Fistula. +Clinically, airway suctioning +reveals saliva, gastric contents, or tube feedings. +Gastric insuf- +flation, secondary to positive pressure ventilation, can occur. +Alternatively, esophagoscopy demonstrates the cuff of +the endotracheal tube in the esophagus. +The cuff of the endotracheal tube should be placed below the +fistula, avoiding overinflation. +If aspira- +tion persists, esophageal diversion with cervical esophagostomy +can be performed. +Their biologic behavior is similar to that of squamous +cell carcinoma of the lung. +Esophagus +Figure 19-5. +Single-stage operation for clo- +sure of a tracheoesophageal fistula and tra- +cheal resection. +A. +The fistula is divided and +the trachea is transected below the level of +damage. +B. +The damaged trachea +segment is resected. +C. +View of completed +tracheal anastomosis. +m. += muscle. +(CT) and rigid bronchoscopy. +19-6). +Up to 50% of the length of the trachea can be +resected with primary anastomosis. +Nodal positivity does not seem to be associated with worse sur- +vival. +LUNG +Anatomy +Segmental Anatomy. +19-7). +Note the continuity of the pulmonary +parenchyma between adjacent segments of each lobe. +Lymphatic Drainage. +19-8). +Algorithm for eval- +uation and treatment of tracheal +neoplasm. +PET = positron emis- +sion tomography. +19-9). +The N2 lymph nodes consist of four main groups. +19-10). +Ciliated cells predominate. +Two cell types, called type I and type II pneumocytes, +make up the alveolar epithelium. +Apical +2. +Posterior +3. +Anterior +4. +Lateral +5. +Medial +6. +Superior +7. +Medial Basal * +8. +Anterior Basal +9. +Lateral Basal +10. +Segmental anatomy of the lungs and bronchi. +Figure 19-8. +The location of regional lymph node stations for lung cancer. +(Reproduced with permission from Mountain CF, Dresler CM. +Regional lymph node classification for lung cancer staging. +Chest. +1997;111:1718.) +613 +Chest Wall, Lung, Mediastinum, and Pleura +CHAPTER 19 +Figure 19-9. +Figure 19-10. +Normal lung histology. +A. +Pseudostratified ciliated columnar cells and mucous cells normally line the tracheobronchial tree. +B. +A Kulchitsky cell is depicted (arrow). +B +A +capable of regeneration because they have no mitotic potential. +In addition, +clusters of neuroendocrine cells are seen in the alveolar spaces. +Three precancerous lesions of the respiratory tract are currently +recognized. +1. +Squamous dysplasia and carcinoma in situ. +Gradations are considered mild, moderate, or +severe. +Carcinoma in situ represents carcinoma still con- +fined by the basement membrane. +2. +Atypical adenomatous hyperplasia (AAH). +3. +Diffuse idiopathic pulmonary neuroendocrine cell hyper- +plasia. +Lesions over 5.0 mm in size or that +breach the basement membrane are carcinoid tumors. +Non–Small Cell Lung Carcinoma. +J Thorac Oncol. +2011;6:244. +aNumbers represent the percentage of cases that are reported to be positive. +including large cell, squamous cell, and adenocarcinoma. +Adenocarcinoma. +It +occurs more frequently in females than in males. +1 +2 +3 +615 +Chest Wall, Lung, Mediastinum, and Pleura +CHAPTER 19 +1. +Adenocarcinoma in situ (AIS). +They are very rarely mucinous, consisting of type II pneu- +mocytes or Clara cells. +Mucinous AIS is more likely +to appear solid or to have the appearance of consolida- +tion. +2. +Minimally invasive adenocarcinoma (MIA). +J Thorac +Oncol. +2011;6:244. +As with AIS, MIA is very +rarely mucinous. +3. +Lepidic predominant adenocarcinoma (LPA). +4. +Invasive adenocarcinoma. +19-11).Subtypes include: +a. +Lepidic predominant +b. +Acinar predominant +c. +Papillary predominant +d. +Micropapillary predominant +e. +Pleural retraction is +also a poor prognostic indicator. +5. +616 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Figure 19-11. +Major histologic patterns of invasive adenocarcinoma. +A. +B. +C. +Area of invasive acinar adenocarcinoma (same tumor as in A and B). +D. +Acinar adenocarcinoma consists +of round to oval-shaped malignant glands invading a fibrous stroma. +E. +F. +G. +H. +Solid adenocarcinoma +with mucin. +(Reproduced with +permission from Travis W, Brambilla E, Noguchi M, et al. +J Thorac Oncol. +2011;6:244.) +Squamous Cell Carcinoma. +Histologically, cells develop a pattern +of clusters with intracellular bridges and keratin pearls. +Such cavities may +become infected, with resultant abscess formation. +Large Cell Carcinoma. +Salivary Gland–Type Neoplasms. +The two most common are adenoid cystic +carcinoma and mucoepidermoid carcinoma. +Both tumors occur +centrally due to their site of origin. +Neuroendocrine Neoplasms. +It +occurs primarily in younger patients. +Histologically, tumor cells +are arranged in cords and clusters with a rich vascular stroma. +Histologic findings may include areas of necrosis, +nuclear pleomorphism, and higher mitotic rates. +Lymph node +metastases are found in 30% to 50% of patients. +At diagnosis, +25% of patients already have remote metastases. +They are often large with central necrosis and a high mitotic +rate. +These +cancers also arise primarily in the central airways. +Evaluation includes expert +pathology review and comprehensive evaluation for metastatic +disease. +These tumors are the leading pro- +ducer of paraneoplastic syndromes. +19-12). +13.8% +for men), younger age (5-year survival of 22.8% for those <45 +years vs. +13.7% for those >65 years), and white race (5-year sur- +vival of 16.1% for whites vs. +12.2% for blacks). +According to the U.S. +Note: Due to changes in ICD coding, numerator information has changed over time. +Leading new cancer cases and deaths: 2012 estimates. +*Excludes basal and squamous cell skin cancers and in situ carcinomas +except urinary bladder. +(Modified with permission from John Wiley and Sons: Siegel R, Naishadham D, Jemal A. +Cancer statistics, 2013. +CA Cancer J Clin. +2012;62:10. +© 2012 American Cancer Society, Inc.) +Figure 19-13. +Age-adjusted cancer death rates. +A. +Males by site, United States, 1930 to 2008. +B. +Females by site, United States, 1930 to +2008. +*Per 100,000, age adjusted to the 2000 U.S. +standard population. +(Modified with permission from John Wiley and Sons: Siegel R, +Naishadham D, Jemal A. +Cancer statistics, 2013. +CA Cancer J Clin. +2012;62:10. +†Uterus cancer death rates are for uterine cervix and uterine corpus combined. +Note: Due to changes in ICD coding, numerator information has changed over time. +cancer increases with longer duration and higher level of +exposure to environmental tobacco. +Source: Reprinted by permission from Macmillan Publishers Ltd. +Sun S, Schiller JH, Gazdar AF. +Lung cancer in never smokers–a different disease. +Nat Rev Cancer. +2007;7:778 Copyright © 2007. +First, there was a 7% false-positive rate in this +trial. +About 150,000 solitary nodules are found incidentally +each year. +The clinical significance of such a lesion depends on +whether or not it represents a malignancy. +It is also more likely to be +AB +CD +Figure 19-14. +Spiral computed tomography scan showing normal transverse chest anatomy at four levels. +A. +At the level of the tracheal +bifurcation, the aorticopulmonary window can be seen. +B. +The origin of the left pulmonary artery can be seen at a level 1 cm inferior to A. +C. +The origin and course of the right pulmonary artery can be seen at this next most cephalad level. +The left upper lobe bronchus can be seen at +its origin from the left main bronchus. +D. +Cardiac chambers and pulmonary veins are seen in the lower thorax. +malignant if it is symptomatic or the patient is older, male, or +has had occupational exposures. +19-14). +For assessing the trachea and central bronchi, +collimation of 3 to 5 mm is recommended. +19-15). +Calcification that is stippled, amorphous, or eccentric is usually +associated with cancer. +Growth over time is an important characteristic for dif- +ferentiating benign and malignant lesions. +One must always entertain the possibility that a +single new lesion is a primary lung cancer. +The probability of +a new primary cancer vs. +metastasis in patients presenting with +solitary lesions depends on the type of initial neoplasm. +The registry +A +B +C +Figure 19-15. +Computed tomography scan images of solitary +pulmonary nodules. +A. +The corona radiata sign demonstrated by +a solitary nodule. +B. +A +biopsy-proven adenocarcinoma demonstrating spiculation. +C. +About 88% of patients underwent complete +resection. +When any or all of these optimal charac- +teristics are absent, survival progressively declines. +The general principles of patient selection for metasta- +sectomy are listed in Table 19-6. +The technical aim of pulmo- +nary metastasectomy is complete resection of all macroscopic +tumors. +Multiple lesions and/or hilar lesions may require lobectomy. +Pneumonectomy is rarely justified or employed. +Pulmonary Symptoms. +Pulmonary symptoms result from the +direct effect of the tumor on the bronchus or lung tissue. +Nonpulmonary Thoracic Symptoms. +Other specific nonpulmonary thoracic symptoms include: +1. +Pancoast’s syndrome. +2. +Phrenic nerve palsy. +3. +Recurrent laryngeal nerve palsy. +4. +Superior vena cava (SVC) syndrome. +(Reprinted with +permission from Pastorino, U. +(2010). +The Development of an International Registry. +J Thorac Oncol. +5(6): S196-S197) +625 +Chest Wall, Lung, Mediastinum, and Pleura +CHAPTER 19 +and conjunctival edema. +It is seen most commonly with +NEC grade IV (small cell) lung cancer. +5. +Pericardial tamponade. +6. +Back pain. +Results from direct invasion of a vertebral body +and is often localized and severe. +If the neural foramina are +involved, radicular pain may also be present. +7. +Other local symptoms. +Primary tumor must already be controlled. +2. +3. +Metastases must be completely resectable based on +computed tomographic imaging. +4. +There is no evidence of extrapulmonary tumor burden. +5. +Alternative superior therapy must not be available. +Their presence does not influence resectability or +treatment options. +1. +Hypertrophic pulmonary osteoarthropathy (HPO). +Often severely debilitating, symptoms of HPO may ante- +date the diagnosis of cancer by months. +Clubbing of the digits may +occur in up to 30% of patients with grade IV NEC (Fig. +19-17). +2. +Hypercalcemia. +Hypertrophic pulmonary osteoarthropathy associated with small cell carcinoma. +A. +Painful clubbing of the fingers. +B. +Painful +clubbing of the toes (close-up). +C. +The arrows point to new bone formation on the femur. +disease is not present. +Unfortunately, tumor recurrence is extremely +common and may manifest as recurrent hypercalcemia. +3. +Hyponatremia. +Another cause of +hyponatremia can be the ectopic secretion of atrial natri- +uretic peptide (ANP). +4. +Cushing’s syndrome. +5. +Peripheral and central neuropathies. +Other metastatic dis- +ease leading to disability must also be excluded. +6. +Lambert-Eaton syndrome. +Therapy is directed at the primary +tumor with resection, radiation, and/or chemotherapy. +Many patients have dramatic improvement after successful +therapy. +Unlike with myasthenia gravis +patients, neostigmine is usually ineffective. +Symptoms Associated with Metastatic Lung Cancer. +Bony metastases are +identified in 25% of all patients with lung cancer. +Liver metastases are most often an incidental finding on CT +scan. +Adrenal metastases are also typically asymptomatic and +are usually discovered by routine CT scan. +They may lead to +adrenal hypofunction. +Nonspecific Cancer-Related Symptoms. +Lung Cancer Management +Role of Histologic Diagnosis and Molecular Testing. +19-18). +In many cases, tumor morphology differentiates +adenocarcinoma from the other histologic subtypes. +EGFR, KRAS, and EML4-ALK fusion gene). +Patient Evaluation. +Assessment of the Primary Tumor. +Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology. +If all markers are negative, the tumor is classified as NSCLC-NOS. +In NSCLC-NOS, if +EGFR mutation is positive, the tumor is more likely to be ADC than SQCC. +(Reproduced with permission from Travis W, Brambilla E, Noguchi M, et al. +J Thorac Oncol. +2011;6:244. +This is +especially true if the use of iodine contrast material is contra- +indicated. +Options for Tissue Acquistion. +Diagnostic tissue from +bronchoscopy can be obtained by one of four methods: +1. +Brushings and washings for cytology +2. +Direct forceps biopsy of a visualized lesion +3. +For central lesions, direct forceps biopsy by bron- +choscopic visualization is often possible. +Surgical risk acceptable? +Consider XRT or monitor +for symptoms and +palliate as necessary. +(Reproduced +with permission from the American College of Chest Physicians from Gould MK, et al. +(2nd edition) Chest. +Lesions +most suitable for VATS are those that are located in the outer +one third of the lung. +A thoracotomy is occasionally necessary to diagnose and +stage a primary tumor. +Assessment for Metastatic Disease. +Distant metastases are +found in approximately 40% of patients with newly diagnosed +lung cancer. +The presence of lymph node or systemic metasta- +ses may imply inoperability. +This is particularly true +for patients with a significant tobacco history. +The skin should +be thoroughly examined. +Mediastinal Lymph Nodes. +Any CT finding of metastatic nodal involvement +must be confirmed histologically. +However, the false-negative rate +increases to nearly 30% with centrally located and T3 tumors. +Therefore, all such patients should undergo mediastinoscopy. +Mediastinal lymph node staging by PET scanning appears +to have greater accuracy than CT scanning. +PET staging of +mediastinal lymph nodes has been evaluated in two meta-analyses. +It understaged the tumor in 12 patients and over- +staged it in 16 patients. +PET correctly identified the nodal stage +in 59 patients (87%). +It understaged the tumor in five patients +and overstaged it in four. +CT scan alone yielded 75%, 63%, and 68%, respectively. +There are several options for invasive +mediastinal staging: +1. +Like mediastinoscopy, EBUS does +not allow assessment of level 3, 5, or 6 nodal stations. +2. +19-8). +Using FNA or core-needle +biopsy, samples of lymph nodes or primary lesions can be +obtained. +3. +19-20). +4. +19-8). +If the index of suspicion is high, the VATS biopsy is per- +formed as a separate procedure. +Pleural Effusion. +The presence of pleural effusion on radio- +graphic imaging should not be assumed to be malignant. +Figure 19-20. +Cervical mediastinoscopy. +Table 19-10 +Indications for prethoracotomy biopsy of station 5 and +6 lymph nodes +1. +Enrollment criteria for induction therapy protocol require +pathologic confirmation of N2 disease. +2. +3. +Cytology reveals malignant cells in 50% +of malignant effusions. +Distant Metastases. +Currently, chest CT and PET are rou- +tine in the evaluation of patients with lung cancer. +19-21). +Tumor, Node, and Metastasis: Lung Cancer Staging. +Therapeutic plans are generated based on +clinical stage. +The staging of solid epithelial tumors is based on the TNM +staging system. +19-8). +A. +CT of the chest showing a tumor in the left upper lobe. +B. +PET scan of the chest at the identical cross-sectional level. +C. +Coregistered PET-CT scan clearly showing tumor invasion (con- +firmed intraoperatively). +(Reprinted with permission from Lardi- +nois D, Weder W, Hany TF, et al. +N Engl J Med. +2003;348:2504. +Copyright © +2003 Massachusetts Medical Society.) +sis status. +Although they do not affect +the stage grouping, they indicate cases +needing separate analysis. +Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. +of the TNM descriptors currently used in staging NSCLC and +the overall stage classifications. +Staging for small cell lung cancer (SCLC) is typically +based on the extent of disease. +Limited disease must be treatable within a tolerable +field of radiation. +Using AJCC descriptors, this includes any +T stage, any N stage, without metastatic disease (M0). +Metastases to brain, bone, bone marrow, and the +pleural and pericardial spaces are common. +Assessment of Functional Status. +A sequential process of evaluation then +unfolds. +A patient’s history is the most important tool for gauging +risk. +Specific questions regarding performance status should be +routinely asked. +Current smoking status and sputum production are also +pertinent. +Nevertheless, abstinence for at least 2 +weeks before surgery should be encouraged. +Sputum culture, +antibiotic administration, and bronchodilators may be warranted +preoperatively. +It +must be emphasized that these are guidelines only. +For example, with a planned right upper lobectomy, a total +of three segments will be removed. +At presentation, the patient was dyspneic +with ambulation, and the FEV1 was 1.38 L. +Six months prior, +this patient could walk up two flights of stairs without dyspnea. +Solid line indicates logistic regression model; dashed +lines indicate 95% confidence limits. +(Adapted with permission from +Wang J, Olak K, Ferguson M. +J Thorac Cardiovasc Surg. +1999;117:582. +Copyright Elsevier.) +6 +637 +Chest Wall, Lung, Mediastinum, and Pleura +CHAPTER 19 +Figure 19-23. +Chest computed tomography scan of an obstructing right main stem lung tumor. +Arrow indicates location of right main bron- +chus. +The right lung volume is much less than the left lung volume. +postoperative value would be 27%, and pneumonectomy would +pose a significantly higher risk. +The risk assessment of a patient is an amalgam of clinical +judgment and data. +Early-Stage Non–Small Cell Lung Cancer. +(2nd edition) Chest. +2007;132:161S. +(2nd edition) Chest. +The latter cir- +cumstance occurs with bulky adenopathy or with extracapsular +nodal spread. +Management of Early-Stage Lung Cancer in the High-Risk +Patient. +Rationale for Limited Resection in Early-Stage Lung Cancer. +1. +Radiofrequency ablation. +In lung tumors, the electrodes are typically inserted into +the tumor mass under CT guidance. +19-24). +OF LIMITED +RESECTIONS +NO. +bOnly intentional resection. +cIncluding 13 pneumonectomies. +Survival +following lobectomy vs limited resection for stage I lung cancer: a meta-analysis. +Br J Cancer. +2005;92:1033. +Copyright © 2005. +2. +Stereotactic body radiotherapy. +Failure in regional +node basins was seen in two patients. +Chemotherapy and surgery versus surgery alone in non- +small cell lung cancer. +Cochrane Database Syst Rev. +2007:CD006157. +John Wiley & Sons, Ltd. +Copyright Cochrane Collaboration. +Evaluation and Management of Locally Advanced +NSCLC. +This is particularly +true in regions with high incidence of granulomatous diseases. +Surgery in T4 and Stage IV Disease. +Survival rates remain extremely low +for these patients. +Simlarly, the treatment of patients with stage +IV disease is chemotherapy. +Surgery for Management of Pancoast’s Tumor. +Treatment algorithm for Pancoast’s tumors. +Complete resection was achieved in 76%. +Five-year +survival was 44% overall and 54% when complete resection +was achieved. +19-25. +Preoperative (Induction) Chemotherapy for NSCLC. +2. +The primary tumor may be downstaged, enhancing resect- +ability. +3. +4. +It functions as an in vivo test of the primary tumor’s sensi- +tivity to chemotherapy. +5. +Response to chemotherapy can be monitored and used to +guide decisions about additional therapy. +6. +Systemic micrometastases are treated. +7. +Potential disadvantages include: +1. +2. +Postoperative (Adjuvant) Chemotherapy for NSCLC. +In the situa- +tion where the margins of resection are positive, re-resection +is recommended. +Definitive Nonsurgical Treatment for NSCLC. +Once a treatment plan has been devised, two strategies +for delivery are available. +5 mo (DFS; P = .006) 22 vs. +10 mo (P = .005) 16% vs. +0% +Roth et al90 60 (60) Cyclophosph +amide +Etoposide +Cisplatin +35 NR 39% vs. +31% Not reached vs. +9 mo +(P = .006) +64 vs. +11 mo (P = .008) 56% vs. +15%a +Pass et al91 27 (27) Etoposide +Cisplatin +62 8 85% vs. +86% 12.7 vs. +5.8 mo (P = .083) 28.7 vs. +15.6 mo (P = .095) NR +Nagai et al92 62 (62) Cisplatin +Vindesine +28 0 65% vs. +77% NR 17 vs. +16 mo (P = .5274) 10% vs. +22% +Gilligan et al93 519 (80) Platinum basedb 49 4 82% vs. +80% NR 54 vs. +55 mo (P = .86) 44% vs. +45% +Depierre et al94 355 (167) Mitomycin +Ifosfamide +Cisplatin +64 11 92% vs. +86% 26.7 vs. +12.9 mo (P = .033) 37 vs. +26 mo (P = .15) 43.9% vs. +35.3%c +Pisters et al95 354 (113)d Carboplatin +Paclitaxel +41 NR 94% vs. +89% 33 vs. +21 mo (P = .07) 75 vs. +46 mo (P = .19) 50% vs. +43% +Sorensen et al96 90 (NR) Paclitaxel +Carboplatin +46 0 79% vs. +70% NR 34.4 vs. +22.5 mo (NS) 36% vs. +24% (NS) +Mattson et al97 274 (274) Docetaxel 28 NR 77% vs. +76%e 9 vs. +7.6 mo (NS) 14.8 vs. +12.6 mo (NS) NR +a3-year survival. +c4-year survival. +d113 patients (32%) were reported to have stage IIB or IIIA disease. +e22 patients in the chemotherapy arm and 29 patients in the control arm had resectable disease. +Source: Reproduced with permission from JNCCN—Journal of the National Comprehensive Cancer Network. +(Reproduced with +permission from Demmy TL, Nwogu C. +Is video-assisted thoracic +surgery lobectomy better? +Quality of life considerations. +Ann Tho- +rac Surg. +2008;85:S719. +Source: Reproduced with permission from Demmy TL, Nwogu C. +Is video-assisted thoracic surgery lobectomy better? +Quality of life considerations. +Ann +Thorac Surg. +2008;85:S719. +Copyright © Elsevier. +Copyright Elsevier. +and altered fractionation. +Subjective measures of quality +of life after VATS, such as pain (Fig. +Finally, recovery of respiratory function occurs earlier in VATS +patients. +Table 19-16 provides a summary of pop- +ulations that may benefit from VATS approaches. +Video-Assisted Thoracoscopic Surgery. +The incision location +varies according to the procedure. +Selected video-assisted thoracic surgery lobectomy maneuvers. +All the maneuvers are shown with the patient positioned in +the left lateral decubitus position. +The same maneuvers can be performed in mirror image for left-sided work. +A. +Medial viewing and inferior +holding of lung to allow dissection through the access incision. +Example shows dissection of the apical hilum. +B. +Medial viewing and access +holding of lung to allow stapling of hilar structures from below. +C. +Example shows use of stapler to divide pulmonary artery to right lower lobe. +D. +This method is commonly used to dissect the pul- +monary artery in the major fissure. +Example shows inferior pulmonary vein after the pulmonary ligament was divided using this maneuver. +E. +Standard viewing and use of access incision to deliver stapler to divide fissures. +Example shows division of the posterior fissure between +the right lower lobe and the upper lobe. +19-27). +Open approaches to Thoracic Surgery. +19-28). +The anterolateral thoracotomy has +traditionally been used in trauma victims. +This approach allows +quick entry into the chest with the patient supine. +The posterolateral thoracotomy incision. +A. +Skin incision from the anterior axillary line to the lower extent of the scapula +tip. +B and C. +Division of the latissimus dorsi and shoulder girdle musculature. +D. +centers. +A hypesthetic nipple +is a frequent complication of this approach. +19-29). +Postoperative Care +Chest Tube Management. +At the conclusion of most thoracic +operations, the pleural cavity is drained with a chest tube(s). +After chest tube placement, the +lung is re-expanded with positive-pressure ventilation. +atrial +appendage +R. +ventricle +Preperitoneal +fat Diaphragm +L. +atrial +appendage +Aortic arch +Innominate v. +Pulmonary a. +Figure 19-29. +The median sternotomy incision. +A. +Skin incision +from the suprasternal notch to the xiphoid process. +B. +Exposure of +the pleural space. +a. += artery; v. += vein. +If the lung is well- +expanded, the chest tube can remain to water seal drainage. +These catheters are also +prone to kinking at the insertion site into the skin. +If bubbles pass through the water seal cham- +ber, an air leak is presumed. +Pain Control. +The most common techniques of pain management are epidural, +paravertebral, and intravenous. +Combinations +of narcotic and topical analgesia are then infused as with the +epidural catheter. +Motor function, however, remains +649 +Chest Wall, Lung, Mediastinum, and Pleura +CHAPTER 19 +intact. +Dosing must be titrated to balance the +degree of pain relief with the degree of sedation. +Respiratory Care. +Post- +operatively, proper pain control (as outlined earlier) is essential, +without oversedation. +This +catheter is well-tolerated by most patients and allows regular +and convenient suctioning. +Clinically, +symptoms of respiratory distress manifest hours to days after +surgery. +Radiographically, diffuse interstitial infiltration or +frank alveolar edema is seen. +Treatment consists of ventilatory sup- +port, fluid restriction, and diuretics. +Extracorporeal membrane +oxygenation may be life-saving in centers where this option is +available. +The syndrome reportedly has a nearly 100% mortality +rate despite aggressive therapy. +Other postoperative complications include air leak and +bronchopleural fistula. +Although these are two very differ- +ent problems, distinguishing between them may be difficult. +Patients often have concomitant empyema, and +open drainage may be necessary. +The most com- +mon cause is rupture of an apical subpleural bleb. +Treatment is +generally chest tube insertion with water seal. +Pulmonary Infections +Lung Abscess. +Less often, there may be multiple, +smaller cavities (<2 cm). +In that case, the infection is typically +referred to as a necrotizing pneumonia. +An abscess that is pres- +ent for more than 6 weeks is considered chronic. +Direct extension from +a contiguous site is less frequent. +Most primary lung abscesses +are suppurative bacterial infections secondary to aspiration. +Infected cysts or bullae +are not considered true abscesses. +Microbiology. +Clinical Features and Diagnosis. +Severe complications +Table 19-17 +Causes of lung abscess +I. +Primary +A. +Necrotizing pneumonia +1. +Staphylococcus aureus, Klebsiella, Pseudomonas, +Mycobacterium +2. +Bacteroides, Fusobacterium, Actinomyces +3. +Entamoeba, Echinococcus +B. +Aspiration pneumonia +1. +Anesthesia +2. +Stroke +3. +Drugs or alcohol +C. +Esophageal disease +1. +Achalasia, Zenker’s diverticulum, +gastroesophageal reflux +D. +Immunodeficiency +1. +Cancer (and chemotherapy) +2. +Diabetes +3. +Organ transplantation +4. +Steroid therapy +5. +Malnutrition +II. +Secondary +A. +Bronchial obstruction +1. +Neoplasm +2. +Foreign body +B. +Systemic sepsis +1. +Septic pulmonary emboli +2. +Seeding of pulmonary infarct +C. +Complication of pulmonary trauma +1. +Infection of hematoma or contusion +2. +Contaminated foreign body or penetrating injury +D. +Direct extension from extraparenchymal infection +1. +Pleural empyema +2. +Mediastinal, hepatic, subphrenic abscess +Source: Adapted with permission from Rusch VW, et al. +Chest wall, +pleura, and mediastinum. +In: Schwartz SI, et al, eds. +Principles of Sur- +gery. +7th ed. +New York: McGraw-Hill; 1999:735. +The CXR is the primary tool for diagnosing a lung abscess +(Fig. +19-30). +Its distinguishing characteristic is a density or mass +with a relatively thin-walled cavity. +A cavi- +tating lung carcinoma is frequently mistaken for a lung abscess. +Ideally, the specific etiologic organism is identified before +antibiotic administration. +Actinomycosis lung infection typically +begins as acute pneumonitis after an aspiration. +Actinomyces israelii is the most common +cause of disease among the Actinomyces species. +In some cases, empyema also develops. +Management of Lung Abscess. +Systemic antibiotics directed +against the causative organism represent the mainstay of therapy. +Oral therapy can then be used to complete the +course of therapy. +Clindamycin +is also a primary therapeutic agent. +Indications for intervention are listed in Table 19-18. +Sur- +gical resection is required in fewer than 10% of lung abscess +patients. +Lobectomy is the preferred intervention for bleeding +from a lung abscess or pyopneumothorax. +Surgical treatment has a 90% success rate, with +an associated mortality of 1% to 13%. +Bronchiectasis. +Pathogenesis. +Development of bronchiectasis can be attributed +to either congenital or acquired causes. +Congenital causes tend to produce +a diffuse pattern of bronchial involvement. +Acquired causes +are categorized broadly as infectious and inflammatory. +Lung abscess resulting from emesis and aspiration after an alcoholic binge. +A. +Chest x-ray showing an abscess cavity in the +left upper lobe. +B. +A coronal tomogram highlights the thin wall of the abscess. +C. +Healing of the abscess cavity after 4 weeks of antibiotic +therapy and postural drainage. +Thus chronic airway inflam- +mation is the essential pathologic feature of bronchiectasis. +The saccular type is the most common after bronchial obstruc- +tion or infection (Fig. +19-31). +Clinical Manifestations and Diagnosis. +Other patients +Table 19-18 +Indications for surgical drainage procedures for lung +abscesses +1. +Failure of medical therapy +2. +Abscess under tension +3. +Abscess increasing in size during appropriate treatment +4. +Contralateral lung contamination +5. +Abscess >4–6 cm in diameter +6. +Necrotizing infection with multiple abscesses, +hemoptysis, abscess rupture, or pyopneumothorax +7. +Inability to exclude a cavitating carcinoma +Figure 19-31. +may appear asymptomatic or have a dry nonproductive cough +(“dry bronchiectasis”). +These patients are prone to have involve- +ment of the upper lobes. +The clinical course is characterized +by progressive symptoms and respiratory impairment. +Increas- +ing resting and exertional dyspnea are the result of progressive +airway obstruction. +Acute exacerbations may be triggered by +viral or bacterial pathogens. +Massive bleeding +may result from erosion of the hypertrophied bronchial arteries. +Sputum culture may identify +characteristic pathogens. +Management of Bronchiectasis. +Mycobacterial Infections +Epidemiology. +Tuberculosis is a widespread problem that +affects nearly one third of the world’s population. +HIV infection is the strongest risk factor +for developing active tuberculosis. +Microbiology. +Mycobacterial species are obligate aerobes. +They +are primarily intracellular parasites with slow rates of growth. +It is estimated that 9% of all MDRTB cases are +extensively drug resistant. +The more important NTM organisms include Mycobacte- +rium kansasii, M. +avium and M. +intracellulare complex (MAC), +and M. +fortuitum. +The highest incidence of M. +kansasii infec- +tion is in midwestern U.S. +cities among middle-aged males from +good socioeconomic surroundings. +MAC organisms are impor- +tant infections in elderly and immunocompromised patient +groups. +M. +fortuitum infections are common complications of +underlying severe debilitating disease. +None of these organisms +are as contagious as M. +tuberculosis. +Pathogenesis and Pathology. +The main route of transmission +is via airborne inhalation of viable mycobacteria. +Three stages +of primary infection have been described. +In the first stage, +alveolar macrophages become infected through ingesting the +bacilli. +Activated macrophages acquire +an increased capacity for bacterial killing. +Reactivation tuberculosis may occur after hydrolytic +enzymes liquefy the caseum. +Edema, hemorrhage, and mononuclear +cell infiltration are also present. +The pathologic changes caused by NTM organisms are +similar to those produced by M. +tuberculosis. +M. +Cavitary dis- +ease is infrequent, although nodules may be noted. +Clinical Presentation and Diagnosis. +About +80% to 90% of tuberculosis patients present with clinical dis- +ease in the lungs. +After primary infection, pulmonary tuberculosis is fre- +quently asymptomatic. +Systemic symptoms of low-grade fever, +malaise, and weight loss are subtle and may go unnoticed. +A +productive cough may develop, usually after tubercle cavita- +tion. +Extrapulmonary involvement is due to +hematogenous or lymphatic spread from pulmonary lesions. +The pleura, chest wall, and +mediastinal organs may all be involved. +For pulmonary tuberculosis, +sputum examination is inexpensive and has a high diagnostic +yield. +Chest CT +scan can delineate the extent of parenchymal disease. +Management. +A +current treatment algorithm is outlined in Fig. +19-32. +Gener- +ally, therapy lasts about 18 months. +The overall response rate is +satisfactory in 70% to 80% of patients with M. +kansasii infec- +tion. +In con- +trast, pulmonary M. +Scattered nodular disease may be left intact, given its low +mycobacterial burden. +Pulmonary Fungal Infections. +Patients receiving high-dose, intensive +antibiotic therapies are also susceptible. +Serologic testing to identify mycotic-specific antibodies +may also be useful. +Aspergillosis. +The species most commonly +responsible for clinical disease include A. +fumigatus, A. +flavus, +A. +niger, and A. +terreus. +Aspergillus is a saprophytic, filamen- +tous fungus with septate hyphae. +Treatment algorithm for tuberculosis. +A repeat smear and cul- +ture should be performed when 2 months of treatment has been completed. +*EMB may be discontinued when results +of drug susceptibility testing indicate no drug resistance. +†PZA may be discontinued after it has been taken for 2 months (56 doses). +§Therapy should be extended +to 9 months if results of 2-month culture are positive. +(Reproduced with permission of the American Thoracic Society. +Copyright © American +Thoracic Society. +Blumberg HM, et al. +Am J Respir Crit Care Med. +Complications resulting from previous thoracic surgery to +treat tuberculosis +2. +Need for tissue acquisition for definitive diagnosis +4. +Extrapulmonary thoracic involvement +6. +Pleural tuberculosis +7. +19-33). +This form is the most common presentation of non- +invasive pulmonary aspergillosis. +The natural history varies greatly between patients and, +therefore, treatment is individualized. +Asymptomatic patients can be observed without any additional +therapy. +Antifungals have limited utility due to the poor blood +supply to the aspergilloma. +Operative intervention may be required for recurrent hemoptysis, +A +C +B +Figure 19-33. +Pulmonary aspergilloma. +A. +B. +A cut section shows the “fungus ball” occupying an old, fibrotic cavity. +C. +Histologic stain reveals +characteristic Aspergillus hyphae invading the wall of the cavity. +Long-term follow-up is neces- +sary, given that the recurrence rate after surgery is about 7%. +They may also have pleuritic chest pain, cough, dyspnea, or +hemoptysis. +Characteristic signs on CT scan include the halo +sign and cavitary lesions. +In addition, +the patient should no longer be immunosuppressed. +Cryptococcosis. +Cryptococci are typi- +cally present in soil and dust contaminated by pigeon droppings. +Symptoms +are nonspecific, as are the radiographic findings. +Multiple antifungal agents are +effective against C. +neoformans, including amphotericin B and +the azoles. +The choice of antifungal and duration of treatment +depend on the severity of disease. +Duration of therapy is longer +in patients who are immunocompromised. +Candidiasis. +The fungi of this genus are common +hospital and laboratory contaminants. +Other potentially pathogenic Candida species +include C. +tropicalis, C. +glabrata, and C. +krusei. +Historically, +C. +albicans was the most common pathogen to cause invasive +candidal infection. +However, more recent reports suggest that +other Candida species, particularly C. +glabrata and C. +krusei, +are becoming more prevalent and now account for between 40% +and 50% of all cases. +Pulmonary candidal infections typically result in +an acute or chronic granulomatous reaction. +Treatment for candidal infection includes both fungicidal +and fungistatic agents. +For funge- +mia, an eye examination should be performed. +Treatment should +continue for at least 2 weeks after the last positive blood culture. +Mucormycosis. +Infection occurs via +inhalation of spores. +Tissue destruction is significant, +along with cavitation and abscess formation. +Lipid formulations of amphotericin B are recom- +mended at this time. +Primary Fungal Pathogens +Histoplasma capsulatum. +The clinical presentation depends on the inoculum size +and on host factors. +CXRs may be normal or may +show mediastinal lymphadenopathy and patchy parenchymal +infiltrates. +Most patients improve in a few weeks; mild to mod- +erate disease can be treated with itraconazole. +Central and concentric +calcification may occur; if so, no further treatment is required. +Typical symptoms include +cough, hemoptysis, and dyspnea. +Life-threatening complica- +tions include massive hemoptysis or bronchoesophageal fistula. +In addition to radiography, bronchoscopy should be performed +to aid in diagnosis. +Endobronchial debridement is not advised as this +can result in massive, fatal bleeding. +A trial of itraconazole is +worthwhile, although it is not proven to be effective. +In the majority of patients, how- +ever, antifungal therapy has not been proven effective. +There +is no role for corticosteroids at this time or for antifibrotics. +Occasionally, intravascular stents have been helpful for severe +vascular compromise. +Chest radiography may reveal +intrapulmonary cavitation and scarring. +Occasionally, partial +resolution of the inflammatory changes may be observed. +Itra- +conazole provides effective therapy, but must be given for 12 +to 24 months. +Vori- +conazole and posaconazole have been found to be useful for +salvage therapy. +Serum itraconazole levels should be monitored +to ensure that the drug is being absorbed. +Occasionally, lipid- +associated amphotericin B is necessary for more severe infec- +tions. +Coccidioides immitis. +Inhalation of the fungus causes pulmonary involvement +in 95% of patients with symptomatic disease. +Primary pulmonary +coccidioidomycosis occurs in about 40% of people who inhale +spores. +The other 60% will remain asymptomatic and develop +life-long immunity. +Pathologic findings of infection in normal and immunocompromised hosts. +A. +The exudate consists mostly of mononuclear phagocytes, lymphocytes, and occasional plasma cells. +Many of the alveolar walls are +markedly thickened (hematoxylin and eosin stain [H&E], ×50). +B. +C. +D. +E. +A few multinucleated macrophages are present. +A thin layer of fibroblasts circumscribes the lesion. +Yeasts +of H. +Lesions of this type often undergo necrosis to become necrotizing granulomas +(H&E, ×50). +F. +Necrotizing (sometimes referred to as caseating) granuloma from the same lung as in E. +A prominent giant +cell is present in the lower left of the granuloma (at approximately 8 o’clock). +Microorganisms are usually present only in relatively small +numbers in these types of lesions. +There are several relative indications for surgery in pulmo- +nary coccidioidomycosis. +Amphotericin B deoxycholate or the triazoles continue to be +the primary antifungal medications. +Intrathecal amphotericin B +can also be administered in some cases. +Blastomyces dermatitidis. +It resides in the soil as a nonmotile spore called +conidia. +Exposure occurs when contaminated soil is disturbed +and the conidia are aerosolized. +B. +Symptoms are nonspecific and con- +sistent with chronic pneumonia in 60% to 90% of patients. +Pulmonary parenchymal abnormalities in the upper lobe(s) may +be noted. +Mass lesions similar to carcinoma are frequent, +and lung biopsy is frequently used. +It is a medi- +cal emergency associated with a mortality rate of 30% to 50%. +First, it is difficult for the +patient or caregivers to quantify the volume of blood being lost. +Anatomy. +The lungs have two sources of blood supply: the +pulmonary and bronchial arterial systems. +Causes. +Significant hemoptysis occurs as a result of pulmo- +nary, extrapulmonary, and iatrogenic causes. +Table 19-20 +summarizes the most common causes of hemoptysis. +Most +are secondary to inflammatory processes. +Hemoptysis due to lung cancer is usually mild, result- +ing in blood-streaked sputum. +Although rare, +it is often a terminal event. +Management. +Achieve respiratory stabilization and prevent +asphyxiation. +2. +Localize the bleeding site. +3. +Control the hemorrhage. +4. +Determine the cause. +5. +Definitively prevent recurrence. +Scenario 1: Significant, Persistent, but Nonmassive Bleeding. +A CXR is the first test and often proves to be the most +revealing. +Chest CT scan provides more +detail and is nearly always performed if the patient is stable. +Pathologic areas may be obscured by blood soiling. +Flexible bronchoscopy is the next step in evaluating the +patient’s condition. +Some clinicians argue that rigid bronchos- +copy should always be performed. +Scenario 2: Significant, Persistent, and Massive Bleeding. +Life-threatening bleeding requires emergency airway control +and preparation for potential surgery. +Such patients are best +cared for in an operating room equipped with rigid bronchos- +copy. +Immediate orotracheal intubation may be necessary to +gain control of ventilation and suctioning. +However, rapid trans- +port to the operating room with rigid bronchoscopy should be +facilitated. +The best option is to +place a bronchial blocker in the affected bronchus with inflation. +Surgical Intervention. +A chest CT scan and +pulmonary function studies should be obtained preoperatively. +General indications for urgent +surgery are presented in Table 19-22. +End-Stage Lung Disease +Lung Volume Reduction Surgery. +Operative mortality in the initial experience was 16.9%, +with a 1-year mortality of 23%. +surgical management after a 10-week pretreatment pulmonary +rehabilitation program. +After 2 years, functional improvements began to +decline toward baseline. +Similar parameters in medically treated +patients steadily decline below baseline. +The most common indications for +lung transplant are COPD and idiopathic pulmonary fibrosis +(IPF). +Most patients with IPF and older patients with COPD are +offered a single-lung transplant. +Table 19-22 +General indications for urgent operative intervention +for massive hemoptysis +1. +Presence of a fungus ball +2. +Presence of a lung abscess +3. +Presence of significant cavitary disease +4. +Patients with significant pulmonary +hypertension should be listed earlier. +19-35 and 19-36. +The mortality of +patients while waiting for transplants is about 10%. +Recipient outcomes are similar to those with cadaver donors in +carefully selected patients. +19-37). +Episodes of acute rejection are the major risk factors for develop- +ing BOS. +The overall survival rate after lung transplantation +at the University of Minnesota. +Survival +123 +BOS-free survival +1.0 +0.8 +0.6 +0.4 +0.2 +Years posttransplant +Figure 19-36. +All chest wall tumors should be consid- +ered malignant until proven otherwise. +Complete resection is imperative if there is any hope for +cure and/or long-term survival. +A general approach is outlined +in Figs. +19-38 and 19-39. +With Ewing’s +sarcoma, fever and malaise may also be present. +Overall, between 50% and 80% +of chest wall tumors are malignant. +Evaluation and Management. +Laboratory evaluations are +useful in assessing chest wall masses for the following: +1. +2. +Osteosarcoma: Alkaline phosphatase levels may be elevated. +3. +Ewing’s sarcoma: Erythrocyte sedimentation rates may be +elevated. +Radiography. +Biopsy. +The first step in the management of all chest wall +tumors is to obtain a tissue diagnosis. +CT = computed tomography; +MRI = magnetic resonance imaging. +Figure 19-39. +Systematic approach for evaluating a chest wall +mass for which the diagnosis is not unequivocal. +A tissue diagno- +sis is critical for effective management of chest wall masses. +CT +computed tomography; MRI magnetic resonance imaging; PNET +primitive neuroectodermal tumor. +1. +2. +3. +Benign Chest Wall Neoplasms +1. +Chondroma. +Chondromas may grow to huge +sizes if left untreated. +Treatment is surgical resection with a +2-cm margin. +Fibrous dysplasia. +Radiographically, an expansile mass is present, +with cortical thinning and no calcification. +Local excision +with a 2-cm margin is curative. +3. +Osteochondroma. +Osteochondromas in the thorax arise +from the rib cortex. +When part of this syndrome, osteochondromas +have a high rate of degeneration into chondrosarcomas. +Local excision of a benign +osteochondroma is sufficient. +If malignancy is determined, +wide excision is performed with a 4-cm margin. +4. +Eosinophilic granuloma. +Eosinophilic granulomas are +benign osteolytic lesions. +The cause is +unknown. +They are diagnosed primarily in children between the ages +of 5 and 15 years. +5. +Desmoid tumors. +Desmoid +tumors possess alterations in the adenomatous polyposis +coli (APC)/β-catenin pathway. +The tumor is usually fixed to the chest wall, but not to the +overlying skin. +A +margin of less than 1 cm results in much higher local recur- +rence rates. +19-40). +All sarcomas have a +propensity to spread to the lungs. +In fact, patients receiving surgical intervention +have significantly better overall survival. +Chest computed tomography scan +showing a right chest wall tumor (arrow). +Tissue +diagnosis revealed that this mass was a leiomyosar- +coma. +The following is an overview of several chest wall sarcomas. +1. +Chondrosarcoma. +Chondrosarcomas are the most com- +mon primary chest wall malignancy. +As with chondro- +mas, they usually arise anteriorly from the costochondral +arches. +19-41). +The involved bony structures are also +destroyed. +Chondrosarcomas +are not sensitive to radiation or chemotherapy. +Prognosis is +determined by tumor grade and extent of resection. +2. +Osteosarcoma. +Osteosarcomas +are potentially sensitive to chemotherapy. +Currently, pre- +operative chemotherapy is common. +Source: Reproduced with permission from Gutierrez et al.152 Copyright Elsevier. +Malignant fibrous histiocytoma. +The typical age at presentation is between +age 50 and 70 years. +Presentation is pain, with or without a +palpable mass. +Radiographically, a mass is usually evident, +with destruction of surrounding tissue and bone. +Treatment +is wide resection with a margin of 4 cm or more and recon- +struction. +Over two thirds of patients suffer from distant +metastasis or local recurrence. +4. +Liposarcoma. +Liposarcomas make up 15% of chest wall +sarcomas. +They typically present as a painless mass. +Treat- +ment is wide resection and reconstruction. +Local recurrence can be treated with re-excision, with +occasional use of radiotherapy. +5. +Fibrosarcoma. +Local and systemic +recurrence is frequent. +Patient survival at 5 years is about +50% to 60%. +6. +Rhabdomyosarcoma. +Rhabdomyosarcomas are rare tumors +of the chest wall. +Microscopically, they are a spindle cell +tumor. +The diagnosis often depends on immunohistochemi- +cal staining for muscle markers. +Rhabdomyosarcomas are +sensitive to chemotherapy. +Treatment consists of preopera- +tive chemotherapy with subsequent surgical resection. +Other Tumors of the Chest Wall +1. +Primitive neuroectodermal tumors (PNETs) and +Ewing’s sarcoma. +Systemic symptoms of malaise and fever are often +present. +Evidence of bony destruction is also com- +mon. +The diagnosis can be made by a percutaneous needle +biopsy or an incisional biopsy. +Figure 19-41. +Chest computed tomography scan showing a right posterior lung tumor. +Increasing tumor size is asso- +ciated with decreasing survival. +2. +Plasmacytoma. +Plain radiographs show an osteolytic +lesion in the region of the pain. +As with other chest wall +tumors, a needle biopsy under CT guidance is performed +for diagnosis. +Histologically, the lesion is identical to mul- +tiple myeloma, with sheets of plasma cells. +It occurs at an +average age of 55 years. +If the results of these studies are negative, then +a solitary plasmacytoma is diagnosed. +19-42). +Anteriorly based lesions contiguous with the sternum require +partial sternectomy. +Primary malignant tumors of the sternum +may require complete sternectomy. +19-42). +There are +several properties that make Gore-Tex an excellent material for +AB +Figure 19-42. +Principles of reconstruction after resection of a chest wall tumor (osteogenic sarcoma) are shown. +A. +The resected +specimen is shown. +B. +A prosthesis has been sewn in place. +In the lower third of the prosthesis, the line of diaphragm reattachment is seen. +The skin defect was closed with a myocutaneous flap from the ipsilateral rectus muscle. +19-43). +The visceral or middle compartment is located +between the great vessels and the trachea. +The thymus gland is large dur- +ing childhood, occupying the entire anterior mediastinum (Fig. +19-45). +Numerous pathologic +variants may be present in the various compartments, with much +overlap. +Thymoma in child- +hood is rare (Table 19-26). +Anatomic division of the mediastinum. +Thymus +Figure 19-44. +Normal appearance of the thymus +gland in childhood. +Ao = aorta; PA = pulmonary +artery; VC = vena cava. +of mediastinal tumors are malignant. +Pediatric tumors will be +discussed in Chapter 39. +When symptomatic, these +tumors are significantly more likely to be malignant. +The patient in Fig. +672 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Figure 19-45. +Computed tomography scan showing +the normal appearance of an involuted thymus gland +in an adult. +The mediastinum and its compartments. +In: Shields TW, ed. +Mediastinal Surgery. +Philadelphia: +Lea & Febiger; 1991:5. +If an endocrine origin is suspected, several other imaging +modalities are available (Table 19-29). +The sestamibi scan may be useful for +diagnosing and localizing a mediastinal parathyroid gland. +The use of serum markers to evaluate a mediastinal mass can +be invaluable in some patients. +In over 90% of nonseminomatous germ cell tumors, +either the AFP or the hCG level will be elevated. +Results are +close to 100% specific if the level of either AFP or hCG is +greater than 500 ng/mL. +Mediastinal masses. +Surg Clin North Am. +1980;60:760. +Copyright +Elsevier. +Primary lesions of the mediastinum +and their investigation and treatment. +In: Shields TW, ed. +General +Thoracic Surgery, 4th ed. +Baltimore: Lippincott Williams & Wilkins; +1994:1731. +Figure 19-46. +Finally, core-needle +biopsy was better at diagnosis for benign diseases compared +to FNA. +Recently, core-needle biopsy with EBUS +became possible with release of a EBUS-core needle device. +At the time of sternotomy, if +the lesion is easily resectable, it should be completely removed. +Masses in the paratracheal region are eas- +ily biopsied by mediastinoscopy. +Source: Reproduced with permission from McGinnis KM, et al. +Markers of the mediastinum. +In: Pearson FG, et al, eds. +Thoracic Surgery. +2nd ed. +New +York: Churchill Livingstone; 2002:1675. +Copyright Elsevier. +Other minimally invasive approaches are under study. +Mediastinal Neoplasms +Thymic Hyperplasia. +The role of PET +scanning is unclear. +Thymoma. +Most patients with thy- +moma are asymptomatic. +The diagnosis may be suspected based on CT scan and +history, but imaging alone is not diagnostic. +Biopsy should +be avoided in cases where imaging is highly suggestive of thy- +moma. +Grossly, +many thymomas remain well encapsulated. +19-47). +The goal for surgical resection should be complete exci- +sion of the mass with total thymectomy. +The role of adjuvant or neoadjuvant therapies for +advanced-stage tumors remains unclear. +Stage-specific survival for thymomas. +Cisplatin/doxorubicin-based regimens appear to yield the +best results. +Massive thymolipoma that was asymp- +tomatic in an 18-year-old female. +the surgeon and radiation oncologist can ensure appropriate +radiation treatment. +Thymic Carcinoma. +Thymic carcinomas are unequivocally +malignant at the microscopic level. +Malignant pleural and pericardial effu- +sions occur frequently. +Five-year survival rates are between 30% and 50%. +The prognosis of patients with thymic +cancer remains poor. +Thymolipoma. +Thymolipomas are rare benign tumors that +may grow to a very large size prior to diagnosis. +19-48). +Resection is recommended for large +masses. +Neurogenic Tumors. +The +incidence, cell types, and risk of malignancy strongly correlate +with patient age. +Tumors of nerve sheath origin predominate in +adults. +Most present as asymptomatic incidental findings, and +most are benign. +Nerve sheath tumors account for 20% of +all mediastinal tumors. +More than 95% of nerve sheath tumors +are benign neurilemomas or neurofibromas. +Malignant neuro- +sarcomas are much less common. +Neurilemoma. +Neurilemomas, also called schwannomas, arise +from Schwann cells in intercostal nerves. +They are firm, well- +encapsulated, and generally benign. +Antoni type A regions contain compact spindle +cells with twisted nuclei and nuclear palisading. +19-49). +Neurofibroma. +Figure 19-49. +Complete surgical resection is the mainstay of treatment. +Ganglion Cell Tumors. +Ganglioneuroma. +Ganglioneuroblastoma. +Ganglioneuroblastomas contain a +mixture of benign ganglion cells and malignant neuroblasts. +The distribution of these cells within the tumor is predictive of +the clinical course. +Ganglioneuroblastomas arise most frequently in +infants and children <3 years old. +The majority are resectable, +with 80% 5-year survival. +Neuroblastoma. +Highly malignant, neuroblastomas are the +most common extracranial solid malignancy of childhood. +Paraganglionic Tumors. +Only 10% of all pheochromocytomas are located in +an extra-adrenal site. +Intrathoracic pheochromocytomas are +one of the rarest tumors. +Localization +is by CT scan, aided by MIBG scintigraphy. +These tumors tend to +be highly vascular and should be approached with care. +They rarely secrete +catecholamines and are malignant in up to 30% of patients. +Lymphoma. +Overall, lymphomas are the most common malig- +nancy of the mediastinum. +The posterior compartment +is rarely involved. +Mediastinal Germ Cell Tumors. +Germ cell tumors are +uncommon neoplasms, with only about 7000 diagnosed each +year. +However, they are the most common malignancy in young +men 15 to 35 years of age. +Previously, most +mediastinal germ cell tumors were thought to be metastatic. +Two thirds are nonseminomatous +tumors or teratomas. +Treatment and prognosis vary consider- +ably within these two groups. +In 10% of seminomas, hCG levels may be slightly ele- +vated. +FNA findings, along with high hCG and AFP levels, can +accurately diagnose nonseminomatous tumors. +Thoracoscopy is the most frequent diagnostic +surgical approach. +Seminoma. +Complete responses +have been reported in over 75% of patients treated with these +regimens. +Surgical resection of residual masses after chemo- +therapy may be indicated. +Nonseminomatous germ cell tumors. +Lactate dehydrogenase (LDH), AFP, and hCG levels are +frequently elevated. +With this regimen, survival is 67% at 2 years and 60% at +5 years. +Surgical resection of residual masses is indicated, as it +may guide further therapy. +Therapy for mature, benign teratomas is surgical +resection, which confers an excellent prognosis. +For most simple, asymptomatic pericardial cysts, +observation alone is recommended. +Surgical resection or aspira- +tion may be indicated for complex cysts or large symptomatic +cysts. +Bronchogenic cyst. +Approximately 15% occur within the pulmonary +parenchyma. +They may +communicate with the tracheobronchial tree. +Symptoms +include chest pain, cough, dyspnea, and fever. +Thoracoscopic exploration and resection are possible for +small cysts with minimal adhesions. +Enteric cyst. +Thus, +surgical resection is the treatment of choice in both adults and +children. +Thymic cyst. +Generally asymptomatic, thymic cysts are often +discovered incidentally. +Simple cysts are of no consequence; +however, the occasional cystic neoplasm must be ruled out. +Cystic components occasionally are seen in patients with thy- +moma and Hodgkin’s disease. +Ectopic endocrine glands. +Usually nontoxic, over 95% can be completely +resected through a cervical approach. +True ectopic thyroid tis- +sue of the mediastinum is rare. +Location can generally be pin- +pointed by a combination of CT scan and Sestamibi scans. +Mediastinitis +Acute Mediastinitis. +Antibiotics, fluid resuscitation, and other sup- +portive measures are also important. +Blood cell counts and serial CT +scans may also be required. +Persistent sepsis or collections on +CT scan may require further radical surgical debridement. +Chronic Mediastinitis. +There is no defini- +tive treatment. +Infections +of the mediastinum. +In: Pearson FG, et al, eds. +Thoracic Surgery. +2nd ed. +New York: Churchill Livingstone; 2002:1604. +Copyright Elsevier. +achieve vascular reconstruction. +In one series +of 22 patients, ketoconazole was effective in controlling progres- +sion. +In another series of 71 patients, 30% died during long-term +follow-up. +A network of somatic, sympa- +thetic, and parasympathetic fibers innervates the parietal pleura. +Normally, 15 to 20 mL of pleural fluid is present +at any given time. +Any disturbance in these forces can lead to +imbalance and accumulation of pleural fluid. +19-50). +Pleural effusion. +N Engl J Med 2002;346:1971. +Copyright © Massachusetts Medical Society. +All rights reserved. +Adapted from Light RW. +Approach to the patient. +In: Light RW, ed. +Pleural Diseases. +5th ed. +Philadelphia: Lippincott Williams & +Wilkins; 2007:111. +Figure 19-50. +Techniques for aspiration and drainage of a pleural effusion. +A. +Needle aspiration. +Large volumes of fluid can be removed with a little patience +and a large-bore needle. +B. +Chest tube insertion. +A 28F to 32F tube is adequate for most situations. +A 36F tube is preferred for hemothorax or for a +viscous empyema. +Many surgeons prefer a very small tube (16F–20F) for drainage of simple pneumothorax. +C. +The tube is connected to a +water-seal drainage system. +demonstrated to be free-flowing. +If the +effusion is loculated, CT- or ultrasound-guided drainage may +be indicated. +Complications of Pleural Drainage. +Sometimes bleeding may be the result +of an underlying coagulopathy or anticoagulant therapy. +For this reason, it is recom- +mended to drain only up to 1500 mL initially. +Pleural Fluid Analysis. +Pleural fluid collections are generally +classified as transudates and exudates (Table 19-34). +On gross visual inspection, a transudative effusion +is generally clear or straw-colored. +Grossly, they are often turbid, +bloody, or purulent. +Transudates and exudates can be differentiated using +Light’s criteria. +If criteria suggest an exudate, further diagnostic +studies may be helpful. +Effusion size and degree of associated dyspnea influ- +ence management. +Patient preference is +also considered, as is their life expectancy. +The choice of +sclerosant includes mechanical, talc, bleomycin, or doxycycline. +Success rates range from 60% to 90% and are highest with talc. +Figure. +19-51 presents a decision algorithm for +the management of malignant pleural effusion. +Empyema +Thoracic empyema is defined by a purulent pleural effusion. +Pathophysiology. +The spectrum of organisms +involved in pneumonic processes that progress to empyema is +changing. +Cases +involving mycobacteria or fungi are rare. +Multiple organisms +may be found in up to 50% of patients. +Transudative pleural effusions +A. +Congestive heart failure +B. +Cirrhosis +C. +Nephrotic syndrome +D. +Superior vena caval obstruction +E. +Fontan procedure +F. +Urinothorax +G. +Peritoneal dialysis +H. +Glomerulonephritis +I. +Myxedema +J. +Cerebrospinal fluid leaks to pleura +K. +Hypoalbuminemia +L. +Pulmonary emboli +M. +Sarcoidosis +II. +Exudative pleural effusions +A. +Neoplastic diseases +1. +Metastatic disease +2. +Mesothelioma +3. +Body cavity lymphoma +4. +Pyothorax-associated lymphoma +B. +Infectious diseases +1. +Tuberculosis +2. +Other bacterial infections +3. +Fungal infections +4. +Parasitic infections +5. +Viral infections +C. +Pulmonary embolization +D. +Gastrointestinal disease +1. +Pancreatic disease +2. +Subphrenic abscess +3. +Intrahepatic abscess +4. +Intrasplenic abscess +5. +Esophageal perforation +6. +After abdominal surgery +7. +Diaphragmatic hernia +8. +Endoscopic variceal sclerosis +9. +After liver transplantation +E. +Heart diseases +1. +After coronary artery bypass graft surgery +2. +Post-cardiac injury (Dressler’s) syndrome +3. +Pericardial disease +F. +Obstetric and gynecologic diseases +1. +Ovarian hyperstimulation syndrome +2. +Fetal pleural effusion +3. +Postpartum pleural effusion +4. +Megis’ syndrome +5. +Endometriosis +G. +Collagen vascular diseases +1. +Rheumatoid pleuritis +2. +Systemic lupus erythematosus +3. +Drug-induced lupus +4. +Immunoblastic lymphadenopathy +5. +Sjögren’s syndrome +6. +Familial Mediterranean fever +7. +Churg-Strauss syndrome +8. +Wegener’s granulomatosis +H. +Drug-induced pleural disease +1. +Nitrofurantoin +2. +Dantrolene +3. +Methysergide +4. +Ergot alkaloids +5. +Amiodarone +6. +Interleukin-2 +7. +Procarbazine +8. +Methotrexate +9. +Clozapine +I. +Miscellaneous diseases and conditions +1. +Asbestos exposure +2. +After lung transplantation +3. +After bone marrow transplantation +4. +Yellow nail syndrome +5. +Sarcoidosis +6. +Uremia +7. +Trapped lung +8. +Therapeutic radiation exposure +9. +Drowning +10. +Amyloidosis +11. +Milk of calcium pleural effusion +12. +Electrical burns +13. +Extramedullary hematopoiesis +14. +Rupture of mediastinal cyst +15. +Acute respiratory distress syndrome +16. +Whipple’s disease +17. +Iatrogenic pleural effusions +J. +Hemothorax +K. +Approach to the patient. +In: Light RW, ed. +Pleural Diseases. +5th ed. +Philadelphia: Lippincott Williams +& Wilkins; 2007:110. +These +mechanisms lead to variable degrees of endothelial injury and +capillary instability. +This process overwhelms the normal +pleural lymphatic drainage. +This early effusion is watery and +free-flowing in the pleural cavity. +free-flowing purulent fluid). +Cancer. +1985;56:905. +Cancer. +1985;56:905. +Treatment decision algorithm for the management of malignant pleural effusion (MPE). +CT = computed tomography; VATS = +video-assisted thoracic surgery. +The chest drain was clamped for 1 hour after +injection and released. +Management. +If there is a residual space, persistent pleural +infection is likely to occur. +If the space is small +and well-drained by a chest tube, a conservative approach may +be possible. +19-52). +If the mediastinal pleura +are disrupted on both sides, bilateral chylothoraces may occur. +Pathophysiology. +19-52). +The duct continues superiorly, lying just +to the right of the vertebral column. +Thoracentesis is usually +grossly suggestive, revealing milky, nonpurulent pleural fluid. +Empyema and +bronchopleural fistula. +In: Pearson FG, et al, eds. +Thoracic Surgery. +2nd ed. +New York: Churchill Livingstone; 2002:1177. +Copyright Elsevier. +686 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +fluid may not be grossly abnormal. +If the triglyceride level is less than 50 mg/mL, there is +only a 5% chance of chylothorax. +Management. +19-53). +The pleura. +In: Sabiston DC, et al, eds. +Surgery of the Chest. +6th ed. +Philadelphia: +Elsevier; 1995. +Copyright Elsevier. +Thoracic d. +Cisterna chyli +Figure 19-52. +Normal thoracic duct anatomy. +Somatostatin has been advocated by some authors, +with variable results. +Malignant Mesothelioma. +Male predominance is 2:1, and it occurs most commonly +after the age of 40. +Algorithm for the manage- +ment of chylothorax. +NPO = nothing by mouth. +Other risk factors +include radiation exposure. +Clinical Presentation. +Most patients present with dyspnea and +chest pain. +Over 90% have a pleural effusion, but thoracentesis +is diagnostic in less than 10% of patients. +Sarcomatous and mixed tumors share a more +aggressive course. +Management. +The treatment of malignant mesotheliomas +remains controversial. +Whenever +possible, patients are referred for 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+2005;23:3495. +213. +Fletcher CDM, Unni KK, Mertens F. +World Health Organization +Classification of Tumours. +Pathology and Genetics of Tumours of +Soft Tissue and Bone. +Lyon, France: IARC Press; 2002. +214. +England DM, Hochholzer L, McCarthy MJ. +Localized benign +and malignant fibrous tumors of the pleura. +A clinicopatho- +logic review of 223 cases. +Am J Surg Pathol. +1989;13:640. +Congenital Heart Disease +Tara Karamlou, Yasuhiro Kotani, and +Glen A. +Van Arsdell 20 +INTRODUCTION +Congenital heart surgery is a dynamic and evolving field. +Embryology. +The atrial and ventricular septa form between +the third and sixth weeks of fetal development. +Anatomy. +20-1).1 +Pathophysiology. +This shift occurs because the resistance of the downstream +vascular beds changes after birth. +New monitoring devices and periopera- +tive strategies are currently under investigation. +Figure 20-1. +The anatomy of atrial septal defects. +B. +Secundum +defects generally occur as isolated lesions. +C. +(Reproduced with permission from +Greenfield LJ, Mulholland MW, Oldham KT, et al, eds. +Surgery: +Scientific Principles and Practice. +3rd ed. +Patients at this stage +have a balanced circulation and may deceptively appear less + symptomatic. +Diagnosis. +Patients with ASDs may present with few physi- +cal findings. +The electrocardiogram shows +right axis deviation with an incomplete bundle-branch block. +In general, ASDs are closed when patients are between +4 and 5 years of age. +Patients who are symptomatic may +require repair earlier, even in infancy. +The details of the repair itself are +generally straightforward. +The caudal end of the transected +cava is oversewn. +The cranial end of the transected cava is anas- +tomosed to the auricle of the right atrium. +Inside the atrium, a +patch is used to redirect pulmonary venous blood flow to the +left atrium. +698 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Results and Complications of Surgical ASD Closure. +New and Future Approaches to Traditional Surgical ASD +Closure. +Operative precision must be maintained with limited exposure +in any minimally invasive technique. +Certain approaches have a specific +patient population in whom they are applicable. +Aortic Stenosis +Anatomy and Classification. +20-2). +Associated left- +sided lesions are often present. +Endocardial fibroelastosis also is common among infants with +critical aortic stenosis (AS). +In severe cases, a +reversal of flow may occur, causing right ventricular volume +loading. +Those infants with mild-to-moderate AS +in whom LV function is preserved are asymptomatic at birth. +The anatomy of the types of congenital aortic ste- +nosis. +A. +Valvar aortic stenosis. +B. +Supravalvar aortic stenosis +and its repair (insert). +C. +Tunnel-type subvalvar aortic stenosis. +D. +Membranous subvalvar aortic stenosis. +(Reproduced with + permission from Greenfield LJ, Mulholland MW, Oldham KT, +et al, eds. +Surgery: Scientific Principles and Practice. +3rd ed. +Diagnosis. +A systolic click +correlates with a valvular etiology of obstruction. +As LV +dysfunction progresses, evidence of congestive heart failure +occurs. +Treatment. +20-3). +The infant +with severe AS requires urgent intervention. +Exposure is attained with placement of a retractor +into the right coronary sinus. +20-4). +Induction of +more than moderate aortic regurgitation is poorly tolerated in +Figure 20-3. +VSD += ventricular septal defect. +(From Alsoufi B, et al. +Eur J Cardiothorac Surg. +2007;31:1013. +Fig 1. +Aortic valvotomy with cardiopulmonary bypass. +Exposure is accomplished with placement of a retrac- +tor into the right coronary sinus. +(Reproduced with permission from Doty DB. +Cardiac +Surgery: A Looseleaf Workbook and Update Service. +Chicago: +Year Book; 1986. +In general, catheter-based balloon valvotomy has sup- +planted open surgical valvotomy. +20-5). +The placement of a +pulmonary conduit, which does not grow and becomes calcified +Figure 20-5. +A through C. +The pulmonary auto- +graft for aortic valve replacement. +The pulmonary valve and main pulmonary artery +are excised and transferred to the aortic position. +The coronary buttons are then attached to the +neoaortic root. +A pulmonary allograft is inserted +to re-establish the right ventricular outflow tract. +(From Kouchokos NT, Davila-Roman VG, Spray +TL, et al. +N Engl J Med. +20-6). +20-7). +The signs and symptoms of supravalvular AS are similar +to other forms of LVOT obstruction. +An asymptomatic murmur +is the presenting manifestation in approximately half of these +patients. +Syncope, poor exercise tolerance, and angina may all +occur with nearly equal frequency. +A gradient of 50 mmHg or greater is an indication +for operation. +In the normal fetal cardiovascular +Figure 20-6. +nonautograft) for a hypo- +thetical patient of 3 years undergoing AVR in 1990. +AoV = aortic valve. +(Reproduced with permission from Karam- +lou T, et al. +Circula- +tion. +Natural History. +Clinical Manifestations and Diagnosis. +Unrestrictive ductal flow may lead +to pulmonary hypertension within the first year of life. +Auscultation demonstrates +a systolic or continuous murmur, often termed a machinery + murmur. +Cyanosis is not present in uncomplicated isolated PDA. +Figure 20-7. +A. +B. +C. +A separate peri- +cardial patch closes the right ventriculotomy. +(Reproduced with permission from Misbach +GA, Turley K, Ullyot DJ, et al. +Left ventricular +outflow enlargement by the Konno procedure. +J Thorac Cardiovasc Surg. +1982;84:696. +Cardiac cath- +eterization is necessary only when pulmonary hypertension is +suspected. +Therapy. +Surgical closure can be achieved via either open or +video-assisted approaches. +The lung +is then retracted anteriorly. +In the neonate, the PDA is sin- +gly ligated with a surgical clip or permanent suture. +In older +patients, the PDA is triply ligated. +Care must be taken to +avoid the recurrent laryngeal nerve, which courses around +the PDA. +In this case, division between +vascular clamps with oversewing of both ends is advisable +(Fig. +20-8). +In extreme cases, the use of CPB to decompress +the large ductus during ligation is an option. +A. +Surgeon’s perspective of infant patent ductus arteriosus exposed via a left thoracotomy. +B. +The pleura over the aortic isth- +mus is incised and mobilized. +C and D. +Technique of triple ligation. +a. += artery; n. += nerve. +(From Castaneda AR, Jonas RA, Mayer JE, et al. +Cardiac Surgery of the Neonate and Infant. +Philadelphia: W.B. +Saunders; 1994:208, with permission. +Copyright Elsevier.) +A +B +C +D +Pulmonary a. +Aorta +Recurrent +laryngeal n. +Vagus n. +In older +infants and children, mortality is less than 1%. +Bleeding, chylo- +thorax, vocal cord paralysis, and the need for reoperation occur +infrequently. +This narrowing is most commonly located distal +to the left subclavian artery. +The embryologic origin of COA +is a subject of some controversy. +In addition, detailed information regard- +ing other associated anomalies can be gleaned. +Aortography is +reserved for those cases in which the echocardiographic find- +ings are equivocal. +Therapy. +Hypertension is also well recognized following repair of +COA. +Both balloon dilatation and primary stent +implantation have been used successfully. +These patients +may be ideal candidates for primary stent placement. +Truncus Arteriosus +Anatomy. +Figure 20-9. +Type I is the +same as A1. +(Reproduced with permission from Fyler DC. +Truncus arteriosus. +In: +Fyler DC, ed. +Nadas’ Pediatric Cardiology. +Philadelphia: Hanley & Belfus; 1992:676. +Copyright Elsevier. +As adapted with permission from +Hernanz-Schulman M, Fellows KE. +Persistent truncus arteriosus: pathologic, diagnostic and therapeutic considerations. +Semin Roentgenol. +1985;20:121. +The ECG is usually nonspecific, demonstrating normal +sinus rhythm with biventricular hypertrophy. +The presence of truncus is an indication for surgery. +Repair should be undertaken in the neonatal period or as soon as +the diagnosis is established. +Repair. +The results of complete repair of truncus have steadily +improved. +Unique to this lesion is the absence of a definitive form of +palliation. +Anatomy and Embryology. +Accordingly, the pulmonary veins +drain to the heart through a systemic vein (Fig. +20-10). +This invari- +ably occurs via a nonrestrictive patent foramen ovale. +Therapy. +The ASD can then +be closed with an autologous pericardial or synthetic patch. +20-11). +20-12). +4 +Figure 20-10. +(From Castaneda +AR, Jonas RA, Mayer JE, et al. +Cardiac +Surgery of the Neonate and Infant. +Phila- +delphia: W.B. +Saunders; 1994:158, with +permission. +(From Castaneda +AR, Jonas RA, Mayer JE, et al. +Cardiac Sur- +gery of the Neonate and Infant. +Philadelphia: +W.B. +Saunders; 1994:161, with permission. +Results. +In the sutureless techniques, there are no sutures +placed in the fragile veins themselves. +Early and late extrinsic stenosis are thought to be reduced +using this latter technique. +Hyde et al80 similarly reported that connec- +tion type was not related to outcome. +20-13). +Cor Triatriatum +Anatomy. +20-14). +Pathophysiology and Diagnosis. +Cor triatriatum results +in obstruction of pulmonary venous return to the left atrium. +a. +b. +(Reproduced with permission from +Karamlou T, et al. +Circulation. +Therapy. +Operative treatment for cor triatriatum is fairly + simple. +CPB and cardioplegic arrest are used. +20-15). +Pathophysiology and Diagnosis. +Figure 20-14. +A. +Common chamber draining +to right atrium directly. +B. +Common chamber +draining into systemic venous circulation via +anomalous vein. +RA = right atrium. +(Adapted +with permission from Krabill KA, Lucas RV +Jr. +Abnormal pulmonary venous connec- +tions. +In: Emmanouilides GC, ed. +Moss and +Adams’ Heart Disease in Infants, Children, +and Adolescents. +5th ed. +Echocar- +diography can detect the defect and also provide information +about associated anomalies. +Retrograde aortography will con- +firm the diagnosis but is rarely necessary. +Therapy. +All infants with APW require surgical correction +once the diagnosis is made. +Repair is undertaken through +a median sternotomy and the use of CPB. +The coronary ostia +must be carefully visualized and included on the aortic side +of the patch. +A through C. +Classification of aortopulmonary win- +dow. +(Reproduced with permission from Mori K, Ando M, Takao A. +Distal type of aortopulmonary window: report of 4 cases. +Br Heart +J. +1978;40:681. +20-16).86 +Results. +This results +in discontinuity between the right atrium and RV. +The RV is +generally hypoplastic, and left-heart filling is dependent on an +ASD. +Anatomy. +An unrestrictive ASD is usually +present. +20-17). +Pathophysiology. +As the ductus +begins to close shortly after birth, infants become intensely + cyanotic. +Pulmonary hypertension is unusual in +tricuspid atresia. +Two-patch repair of aor- +topulmonary window. +A. +The ductus arteriosus (when +present) can be ligated. +The aorta is +cross-clamped and the heart arrested +with cardioplegia. +B. +A piece of previously prepared pul- +monary homograft material is used to +patch the aortic defect. +In older children, +polytetrafluoroethylene material can be +safely used. +C. +D. +Diagnosis. +When +pulmonary blood flow is provided through a VSD, there may be +a prominent systolic murmur. +This is often +related to excessive flow across a VSD. +Chest radiography will +show decreased pulmonary vascularity. +Two-dimensional +echocardiography readily confirms the diagnosis and the ana- +tomic subtype. +Treatment. +20-18). +Multiple modifications of this initial repair were per- +formed over the next 20 years. +This repair became known as the modified Fontan +operation. +20-19).96 +Figure 20-17. +Classification of tricuspid +atresia. +(Repro- +duced with permission from Tricuspid +atresia. +In: Mavroudis C, Backer CL, +eds. +Pediatric Cardiac Surgery. +2nd ed. +St. +Louis: Mosby; 1994:381.) +714 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Figure 20-18. +Superior vena cava–pulmonary artery +shunts. +A. +Classic Glenn shunt. +B. +C. +D. +(Reproduced with permission from Tricuspid atresia. +In: +Mavroudis C, Backer CL, eds. +Pediatric Cardiac Surgery. +2nd ed. +St. +Louis: Mosby; 1994:383.) +Figure 20-19. +The fenestrated Fontan proce- +dure. +(Reproduced with +permission from Kopf GS, Kleinman CS, Hijazi +ZM, et al. +J +Thorac Cardiovasc Surg. +1992;103:1039. +Competing risks depiction of events after diagnosis in 150 patients with tricuspid atresia. +At any point in time, the sum of +proportions of children in each state is 100%. +(From Karamlou et al,99 Fig. +1, with permission. +20-20). +Anatomy. +Closure of the ductus is incompatible with life in +these neonates. +Neonates with severe HLHS receive all pulmonary, sys- +temic, and coronary blood flow from the RV. +Treatment. +20-21). +Unfortunately, in +717 +C +ONGENITAL + H +EART + D +ISEASE +CHAPTER 20 +Figure 20-21. +Current techniques for first-stage palliation of the hypoplastic left-heart syndrome. +A. +Incisions used for the procedure, +incorporating a cuff of arterial wall allograft. +The distal divided main pulmonary artery may be closed by direct suture or with a patch. +B. +Dimensions of the cuff of the arterial wall allograft. +C. +D and E. +The procedure is completed +by atrial septectomy and a 3- to 5-mm modified right Blalock shunt. +F. +a. += artery. +(From Castaneda AR, Jonas RA, Mayer JE, et al. +Cardiac Surgery of the Neonate and Infant. +Philadelphia: +W.B. +Saunders; 1994:371, with permission. +Copyright Elsevier.) +A +B +C +D +EF +Homograft +Aorta +Main pulmonary a. +64%, P = .01). +20-22). +Not all patients with HLHS require this three-stage pallia- +tive repair. +In this group, a +two-ventricle repair can be achieved with reasonable outcome. +Technique of a bidirectional +Glenn shunt. +(From Castaneda +AR, Jonas RA, Mayer JE, et al. +Cardiac Surgery +of the Neonate and Infant. +Philadelphia: W.B. +Saunders; 1994:376, with permission. +Outcomes for HLHS are still significantly worse +than those for other complex cardiac defects. +DEFECTS THAT MAY BE PALLIATED OR +REPAIRED +Ebstein’s Anomaly +Anatomy. +This is a rare defect, occurring in less than 1% +of CHD patients. +The atrialized RV is usually +thin and dilated. +There is commonly an +ASD present, which results in a right-to-left shunt at the atrial +level. +Occasionally, there is true anatomic pulmonary atresia +or milder forms of RVOT obstruction. +Diagnosis. +The ECG may show right bundle- +branch block and right axis deviation. +A score of greater +than 1 translates into uniformly fatal outcome. +Treatment. +720 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Neonatal Ebstein’s anomaly is a separate entity. +Results. +Supraventricular +tachycardia also has been problematic postoperatively. +There are few published reports of outcomes, due to the +rarity of this defect. +Pathophysiology. +This causes left atrial enlargement and a left-to-right shunt via +the patent foramen ovale. +Postnatally, the LV does not hypertrophy because it is not +subjected to systemic afterload. +Clinical Manifestations and Diagnosis. +Surgical Repair. +20-24). +Figure 20-23. +The Senning operation. +A. +B. +C. +D. +(Reproduced with permission from D-Trans- +position of the great arteries. +In: Mavroudis C, Backer CL, eds. +Pediatric Cardiac Surgery. +2nd ed. +St. +Double-Outlet Right Ventricle +Anatomy. +The noncom- +mitted VSD (10%–20%) exists when the VSD is remote from +the great vessels. +20-25). +Clinical Manifestations and Diagnosis. +Therapy. +In patients without pulmonary stenosis who +Figure 20-24. +A. +A and B. +(Reproduced with permission from +Backer CL, Idriss FS, Mavroudis C. +In: Mavroudis C, Backer CL, eds. +Arterial Switch. +Cardiac Surgery: State of the Art +Review. +Vol. +5, no. +1. +Philadelphia: Hanley & Belfus; +1991:108. +A. +Subaortic VSD without pulmonary stenosis. +B. +Subaortic VSD +with pulmonary stenosis. +C. +Subpulmonary VSD (Taussig-Bing +malformation). +D. +Doubly committed VSD. +E. +Noncommitted +(remote) VSD. +F. +Intact interventricular septum. +(Adapted with permission from +Zamora R, Moller JH, Edwards JE. +Double-outlet right ventricle. +Chest. +Tetralogy of Fallot +Anatomy. +20-26). +Pathologic specimen of the heart in a patient with +tetralogy of Fallot. +(From Van Praagh et al,141 with permission. +© Elsevier Ltd.) +Pathophysiology and Clinical Presentation. +Occasion- +ally, aortography is necessary to delineate the coronary artery +anatomy. +Treatment. +20-27). +Results. +This may be partly +explained by a higher chance of postoperative complications in +neonates. +Figure 20-27. +The free +edge of the tricuspid leaflets is shown by dashed lines. +A. +B. +The same perspective without the +outline of the tricuspid valve leaflets. +C. +D. +E. +The repair of the ventricular septal +defect is completed. +ant. += anterior; +ML = mitral leaflet; post. += posterior; TV = tricuspid +valve. +4th ed. +Philadelphia: Elsevier, 2013, p 1384. +Copyright Elsevier.) +Parietal +extension Amputation +Transection +TV post. +leaflet +TV ant. +Clinical events were reported in 12% +of patients at 35 years after repair. +Ventricular Septal Defect +Anatomy. +VSD refers to a hole between the LV and RV. +20-28). +The supracristal or outlet VSD results from a defect within +the conal septum. +These are surrounded by muscle and can occur anywhere +Figure 20-28. +Classic anatomic types of ventricular +septal defect (VSD). +A. +Type I (conal, infundibular, +supracristal, subarterial) VSD. +B. +Type II or peri- +membranous VSD. +C. +Type III VSD (atrioventricu- +lar canal type or inlet septum type). +D. +Type IV VSD +(single or multiple). +(Reproduced with permission +from Ventricular septal defect. +In: Mavroudis C, +Backer CL, eds. +Pediatric Cardiac Surgery. +2nd ed. +St. +Pathophysiology and Clinical Presentation. +The size of +the VSD determines the initial pathophysiology of the dis- +ease. +Diagnosis. +Treatment. +Repair of isolated VSDs requires the use of CPB with +moderate hypothermia and cardioplegic arrest. +20-29). +Atrioventricular Canal Defects +Anatomy. +20-30).156 +Pathophysiology and Diagnosis. +Left-to-right shunting predominates as +long as pulmonary vascular resistance remains low. +(Reproduced from Feldt +RH, Porter CJ, Edwards WD, et al. +Defects +of the atrial septum and the atrioventricular +canal. +In: Adams FH, Emmanouilides GC, +eds. +Moss’ Heart Disease in Infants, Children, +and Adolescents. +4th ed. +Baltimore: Lippincott +Williams & Wilkins; 1989. +© Mayo Clinic ID +#: CP1214116B-2. +Used with permission of +Mayo Foundation for Medical Education and +Research.) +Figure 20-29. +A. +Stay sutures have been placed to slightly evert the atrial wall. +Note that initially, the superior edge of this typical peri- +membranous defect is not visible. +B and C. +(Reproduced with permission +from Walters HL, Pacifico AD, Kirklin JK: Ventricular septal defects. +In: Sabiston DC, Lyerly HK, eds. +Textbook of Surgery: The Biologic +Basis of Modern Surgical Practice. +Philadelphia: W.B. +Saunders; 1997:2014. +Physical examination may reveal a right ventricular heave +and a systolic murmur. +The management of patients with AV canal +defects can be especially challenging. +Timing of operation is +individualized. +Results. +IAA is classified based on the location of the interruption +(Fig. +20-31). +RPA +Ao +IA LC +LS IA LC +LS +MPA +LPA +PDA IA +LC LS +PDA +A B C +Figure 20-31. +Anatomic types of interrupted aortic arch. +A. +Inter- +ruption distal to the left subclavian artery. +B. +Interruption between +the left subclavian and left carotid arteries. +C. +Interruption between +the left carotid and innominate arteries. +(Reproduced with permission from Jonas RA. +Interrupted aortic arch. +In: Mavroudis C, Backer CL, eds. 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+Ann Thorac Surg. +2002;73:58. +155. +Rastelli G, Kirklin JW, Titus JL. +Mayo Clin +Proc. +1966;41:296. +156. +Ungerleider RM. +Atrial septal defects, ostium primum defects, +and atrioventricular canals. +In: Sabiston DC, Lyerly HK, eds. +Textbook of Surgery: The Biologic Basis of Modern Surgical +Practice. +Philadelphia: W.B. +Saunders; 1997:1993. +157. +Kouchoukos NT, Blackstone EH, Doty DB, et al. +Coarcta- +tion of the aorta and interrupted aortic arch. +In: Kouchoukos +NT, Blackstone EH, Doty DB, et al, eds. +Kirklin/Barrat-Boyes +Cardiac Surgery. +3rd ed. +Philadelphia: Churchill Livingstone; +2003:1353. +158. +Ungerleider RM, Kisslo JA, Greeley WJ, et al. +J Thorac Cardiovasc +Surg. +1989;98:1146. +159. +Roussin R, Belli E, Lacour-Gayet F, et al. +Aortic arch recon- +struction with pulmonary autograft patch aortoplasty. +J Tho- +rac Cardiovasc Surg. +2002;123:443. +This page intentionally left blank +Acquired Heart Disease +Shoichi Okada, Jason O. +Robertson, +Lindsey L. +Saint, and Ralph J. +Damiano, Jr. +This discomfort may radiate to the left +arm, neck, mandible, or epigastrium. +Left heart +failure manifests as dyspnea, usually with exertion. +However, +most cardiac pathologies do result in fatigue or exercise intoler- +ance of some degree. +Recent results +for destination therapy have approached those of cardiac +transplantation. +mitral stenosis. +Patients typically describe palpitations as a “skipped beat” +or “racing heart”. +Clinically significant +arrhythmias, however, require thorough investigation. +It results in an irregu- +lar, and at times, rapid heartbeat. +Syncope associated with heart disease results from abrupt +reduction of cerebral perfusion. +Any episode +of syncope warrants a thorough evaluation and search for the +root cause. +Functional Disability and Angina. +With regard to heart fail- +ure, functional capacity is strongly correlated with mortality. +The general appearance of a patient is important in the +clinical assessment. +II Comfortable at rest. +Slight limitation of physical +activity. +Fatigue, palpitations, or dyspnea with +ordinary physical activity. +III Comfortable at rest. +Marked limitation of physical +activity. +Fatigue, palpitations, or dyspnea with +less than ordinary physical activity. +IV Inability to carry out any physical activity. +Symptoms may be present at rest and increase +with activity. +Angina occurs with +strenuous, rapid, or prolonged exertion during +work or recreation. +II Slight limitation of ordinary activity. +Walking more than 2 blocks or +climbing one flight of stairs causes angina. +IV Inability to carry out any physical activity without +discomfort. +Angina may be present at rest. +hypertrophy or parasternal heaves seen in right ventricular over- +load. +Murmurs +are characterized by their location, timing, quality, and radia- +tion. +A rub +due to pericardial friction is specific and virtually pathogno- +monic for pericarditis. +Auscultation of the lung fields may reveal rales in +patients with pulmonary edema. +The work of breathing may also +be assessed simply by observing the patient. +Jugular venous dis- +tention and hepatosplenomegaly are seen in right heart failure. +3–5 Pursue further testing if it will advance +management. +Diagnostic Studies +Electrocardiogram and Chest X-ray. +Echocardiography. +Posterior structures such as the mitral +valve and left atrium are particularly well visualized. +Radionuclide Studies. +In the +past, planar imaging with three separate two-dimensional views +of the heart were obtained. +Territories that do not show uptake at rest or during stress +are likely to be nonviable scar. +This study is also useful in revealing +hypokinetic segments of the myocardium. +Cardiac Catheterization. +Right- +sided pressures and structures are assessed in a similar fashion +as in the left heart. +(Fig. +Multislice computed +tomography (CT) imaging can be used to assess the coronary +vasculature. +Cardiac catheterization angiography. +A. +Stenosis of +right coronary artery indicated by the arrow. +B. +Still image of a +normal left ventriculogram. +asystole and hypothermia. +The early bubble oxygenators have evolved into the modern +membrane oxygenators. +Once the appropriate cannulations +and connections are complete, CPB is commenced. +Venous +return is initiated followed by arterial flow while monitoring +systemic blood pressures. +Once +the heart is decompressed and hemodynamics are acceptable, +ventilation is stopped. +The oxygenator is adjusted to maintain +a PaO2 of 150 mm Hg and normocarbia. +The venous return to the CPB machine is gradually +reduced allowing the heart to fill. +Inotropic and vasopressor support may be +used to augment cardiac function and treat hypotension. +Once +CPB has been stopped and stable hemodynamics achieved, the +cannulae are removed. +Generation of thrombin +plays a major role in both thrombotic and bleeding phenomena +during CPB. +Platelets are activated by the converging hemostatic pathways +and are consumed. +This can be a problem particularly with the cerebral, +renal, and mesenteric circulations. +There are controversies regarding the method (antegrade +retrograde vs. +both), type (crystalloid vs. +blood), temperature +(cold vs. +warm vs. +tepid), and interval (continuous vs. +inter- +mittent) of cardioplegia delivery. +The optimal combination is +beyond the scope of this text. +However, most surgeons in the +United States favor cold blood potassium cardioplegia. +The use of vein +patches to repair the arteriotomy sites was described by Sen- +ning in 1961. +Beta-blockers are to be considered in patients +with LV dysfunction and following MI or ACS. +The variety +of presentations can make myocardial ischemia difficult to diag- +nose. +Typical angina is relieved by rest and/or use of sublingual +nitroglycerin. +This +may be silent and need not be preceded by angina. +The ischemic insults from CAD may lead to congestive +heart failure. +The initial myocardial damage sets off a cascade +of responses, both local and systemic. +Heart failure should be suspected in patients who present +dyspnea, orthopnea, fatigue, and edema. +Arrhythmias may also be a sequela of CAD. +Ischemic eti- +ologies should be investigated in patients who present with new +arrhythmias. +Coronary angiography is the primary diagnostic tool. +A stress ECG is frequently used as a screening tool +with a high sensitivity. +The positive predict value is 90% in +patients with ST-segment depression >1mm. +Some of the representative studies +are summarized here. +The New York State Study (2005). +Of these, +37,212 patients received a CABG and the others underwent a +PCI. +Revascularization strategies, CABG vs. +CABG was performed on 86,244 patients and 103,549 +underwent PCI. +Operative Techniques and Results +Bypass Conduit Selection. +The most important criterion in +conduit selection is graft patency. +The radial artery is another frequently used conduit. +This artery can also be harvested using an +endoscopic technique. +745 +Acquired Heart Disease +CHAPTER 21 +Figure 21-2. +Coronary artery bypass grafting. +A. +B. +Anastomotic site is shown +by the arrow. +Conventional Coronary Artery Bypass Grafting. +Tradi- +tionally, CABGs are performed with the patient lying supine +through a median sternotomy. +After the patient is heparinized, +cardiopulmonary bypass is initiated. +The aorta is cross-clamped +and cardioplegia is delivered. +(Fig. +Once all grafts are in place, the patient is +weaned from bypass. +The mortality and morbidity of the procedure itself has +changed over time. +With OPCAB the heart is left beating. +(Fig. +This occlu- +sion causes temporary ischemia, and if not tolerated, coronary +shunts can be employed. +Minimally Invasive Direct Coronary Artery Bypass. +Epicardial stabilizing device used during off-pump +coronary anastomosis. +MIDCAB Results A review of 411 patients undergoing MID- +CAB quotes an operative mortality >1%. +Transmyocardial Laser Revascularization. +New Developments +Regenerative Medicine and Tissue Engineering. +Diastolic +and continuous murmurs, on the other hand, are frequently +pathologic in nature. +748 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Table 21-7 +Classification of cardiac murmurs. +Table 21-8 +Hemodynamic alterations in cardiac murmur intensity. +INTERVENTION EFFECT +Respiration Right-sided murmurs increase with inspiration. +Left-sided murmurs increase with expiration. +Valsalva maneuver Most murmurs decrease in length and intensity. +The murmur of HCM becomes louder, and the +murmur of MVP becomes louder and longer. +The murmurs of MR, VSD, and AI also increase with isometric exercise. +Systolic murmurs of +atrioventricular valve regurgitation do not change. +The response in MVP is +biphasic (softer then louder than control). +tissue valve prosthesis. +Current options for mechanical valve replacement include +tilting disc valves and bileaflet valves. +Mechanical Valves. +The first bileaflet valve was introduced in +1977. +21-4). +Tissue Valves. +21-5). +This effect is most pronounced in patients with small prosthetic +Figure 21-4. +St. +Jude bileaflet mechanical valve. +(Photo repro- +duced with permission of St. +Jude Medical, Inc., St. +Paul, MN. +All +rights reserved.) +Figure 21-5. +Edwards’ Magna Ease stented porcine bioprosthesis. +Homografts. +Autografts. +Valve Repair. +MITRAL VALVE DISEASE +Mitral Stenosis +Etiology. +Pathology. +21-6). +Mitral stenosis. +The thickened, fused leaflets of the +diseased mitral valve are viewed through a left atriotomy. +(Image +courtesy of the Centers for Disease Control and Prevention, Edwin +P. +Ewing, Jr.) +752 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +against a fixed obstruction. +Clinical Manifestations. +The murmur, classically known as the +auscultatory triad, is best heard at the apex. +Hemoptysis, and pulmonary edema may develop +as the venous hypertension worsens. +Diagnostic Studies. +In most cases further examinations are not necessary. +Pathophysiology. +Clinical Manifestations. +As mentioned previously, patients may present with AF due to +dilatation of the left atrium. +Findings consistent with pulmonary +hypertension frequently indicate late-stage disease. +Diagnostic Studies. +However, TTE +may underestimate lesion severity due to inadequate views of +the color flow jet. +Commissurotomy. +Upon opening the left atrium, the MV is +visualized and the left atrium is examined for thrombus. +The anterior leaflet is grasped with forceps +and brought through its complete range of motion. +Occasionally, the leaflets can be debrided carefully +to increase mobility. +Valve replacement may be more appropri- +ate if extensive secondary mobilization is required. +21-7). +Mitral Valve Repair. +Mitral valve replacement. +A St. +Jude bileaflet +mechanical valve is viewed through a left atriotomy. +5 +756 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +intraoperative assessment of valvular pathology. +The +commissures are examined for evidence of prolapse, fusion, +and malformation. +Leaflet +perforations are generally repaired primarily, or with a peri- +cardial patch. +The degree of annular dilation is also noted. +Recent trends have been toward leaflet preservation. +One of the mainstays of MV repair is triangular resection +of the posterior leaflet. +If focal insufficiency +is identified in other areas, additional procedures are performed. +Chordal shortening +has generally been abandoned in favor of chordal replacement. +While some groups report excellent late +results, its use remains controversial. +Mitral valve repair. +AORTIC VALVE DISEASE +Aortic Stenosis +Etiology. +21-9). +Pathology. +Pathophysiology. +Aortic stenosis. +(Image courtesy of the Centers for Disease +Control and Prevention, Edwin P. +Diagnostic Studies. +Any abrupt change in signs or symptoms in +a patient with AS is an indication for TTE examination. +Additional preoperative studies may be necessary in some +patients. +Pathology. +Depending on the severity +of AI, the left atrium may undergo dilation and hypertrophy as +well. +There are also many primary valvular diseases that cause +AI, generally in association with AS. +Pathophysiology. +115,117 +Eventually, left ventricular compensatory mechanisms fail +and systolic dysfunction ensues. +Clinical Manifestations. +Diagnostic Studies. +Aortic Valve Replacement. +The annulus is thoroughly debrided of calcium deposits. +After +the calcium has been removed, the ventricle is copiously irri- +gated with saline. +At this point, the annulus is sized and an +appropriate prosthesis is selected. +21-10). +For +Figure 21-10. +Aortic valve replacement. +The stented porcine bio- +prosthesis as viewed through an aortotomy. +hemorrhagic complications for biological and mechanical +valves, respectively. +Aortic Valve Repair. +90%, +P=0.03; and 100% vs. +77%, P=0.002, respectively) at midterm +follow-up. +123 +Ross Procedure. +Transcatheter Aortic Valve Replacement. +The transaortic approach is usually done through a min- +isternotomy. +30.7%, P = <0.001), +the rate of death from cardiovascular causes (41.9% vs. +19.6%, +p = <.001), and the rate of repeat hospitalization (44.1% vs. +4.5%, P = 0.04), major vascular complications (16.8% vs. +2.2%, P = <.001), and major bleeding events (22.3% vs. +5 days, +P = <0.001), and a shorter index hospitalization (8 vs. +12 days, +P = <.001). +4.3%, P = 0.04), and major vascular complications (11.3% +vs. +3.5%, P = <.001) at one year. +TRICUSPID VALVE DISEASE +Tricuspid Stenosis and Insufficiency +Etiology. +This is most commonly caused by MV disease. +Pathology. +Clinical Manifestations. +In the absence of pulmonary hypertension, +dyspnea is not a prominent feature of tricuspid disease. +Diagnostic Studies. +Indications for Operation. +As an isolated lesion, mild or +moderate TV disease does not require surgical correction. +Operative Techniques and Results. +Most surgeons favor ring over suture +annuloplasty. +The choice of +prosthetic valve is also somewhat controversial. +Etiology and Pathophysiology +Heart failure can be classified as acute vs. +chronic, genetic vs. +acquired, left-sided vs. +right-sided and systolic vs. +diastolic +dysfunction. +The underlying causes and treatments for each of +these vary considerably. +It is most successful when treating +hibernating as opposed to infarcted myocardium. +Entry criteria included an EF ≤35% with +CAD and anatomy suitable for CABG. +16%, p<0.0001). +77%, P = 0.02). +71%, +P = NS). +53%, +p<0.05), as well as worse 5-year freedom from recurrent CHF +(85% vs. +3% in patients without significant dyssynchrony +(p<0.001). +with end-stage heart failure who present with low EF and lim- +ited myocardial viability. +Mitral valve repair is the procedure of choice when surgery +is indicated for secondary MR. +Outcomes from surgery vary between centers and amongst +patients in this heterogeneous group. +This usually occurs 4 to 8 weeks +following the infarct. +The rest are inferior in location and the result of circumflex +or right coronary occlusion. +Clinical Presentation and Diagnosis. +Rupture is extremely uncommon. +Patients generally present for coronary artery bypass or during +evaluation of CHF or arrhythmias. +21-11A & B). +Figure 21-11. +Surgical ventricular restoration of a ventricular aneurysm using the Dor Procedure. +A. +B. +These patients should also be candidates +for repair of any other concomitant cardiac disease. +With respect to VT, Dor et al. +Mechanical Circulatory Support +Intra-aortic Balloon Pump. +The +device is inserted percutaneously through the femoral artery +into the thoracic aorta. +This is the most serious complication of IABP +placement. +Ventricular Assist Device Indications and Cannula- +tion. +Left Ventricular Assist Devices. +The first generation +LVADs were pulsatile devices. +These devices are +smaller, quieter, and durable enough for long term support. +21-12A & B, 21-13A & +B). +These devices are com- +monly used in either post-MI or postcardiotomy heart failure. +Bridge to Recovery. +The HeartMate II LVAD viewed from the (A) outside and (B) inside. +The device is an axial flow, rotary pump that produces +no pulsatile action. +(Images reprinted with the permis- +sion of Thoratec Corporation.) +AB +Figure 21-13. +The HeartWare HVAD system. +A. +B. +Similar to the HeartMate II, it can deliver a flow rate of up to 10 L/min. +At 3 months, 81% of patients were in class I +or II heart failure. +Destination Therapy. +24%, P=0.008) and adverse event rates were significantly lower. +There is currently no destination +therapy device for biventricular failure. +Unlike ven- +tricular assist devices, the TAH replaces the entire heart. +Medical Management. +Restoration of normal sinus rhythm has several potential +benefits over other strategies 198-200. +Indications for Surgical Management. +The Cox-Maze IV Procedure. +In 2002, the Cox-Maze IV, +was introduced. +21-14). +Results from the Cox-Maze IV procedure have been excel- +lent. +The Cox-Maze IV Lesion Set. +A. +B. +(From Weimar T, Bailey MS, Watanabe Y, et al. +J Interv Card Electrophysiol. +2011;31: +47-54. +Although, +there is seldom justification for limited lesion sets in experienced +hands. +Pulmonary vein isolation is ubiquitously performed, and the +LAA is often excised. +Pulmonary Vein Isolation. +These include staplers and epicardial clips that +can be placed without the need for CPB. +However, it may be monophasic or biphasic in up to +50% of patients. +Table 21-16 +Features of acute pericarditis. +Treatment. +The preferred treatment depends on the underly- +ing cause of the pericarditis. +Some patients may require judicious use of +steroids or IV antibiotics. +More +commonly, surgical intervention is required to manage recur- +rent disease. +Relapsing +pericarditis normally responds to a longer course of NSAIDS +± colchicine. +No perioperative deaths were observed, and +only 2 patients (3%) had major complications. +Chronic Constrictive Pericarditis +Etiology, Pathology, and Pathophysiology. +In many +patients, these symptoms develop insidiously over a course +of years. +Clinical and Diagnostic Findings. +Several findings are characteristic on noninvasive and +invasive testing. +CVP is often elevated 15 to 20 mm Hg or +higher. +Pericardial adhesions may also +be seen on tagged cine MRI studies. +Surgical Treatment. +These patients +are best treated with medical therapy alone. +Surgical Results. +Despite the risks, many patients experience significant +benefits from surgical treatment. +Clinical Presentation. +Arrhythmias and pericardial effusions are very rare in +this population. +Diagnosis and Characterization of Cardiac Masses. +Delayed enhance- +ment cMRI is the best modality to separate these two entities. +Myxoma +Pathology and Genetics. +18%) +or one of the ventricles (25% vs. +0%), more often multicentric +(33% vs. +6%) and more likely to recur (20% vs. +3%).238 They +also present earlier at an average age of 24 years old (range +4–48 years). +Pathophysiology. +21-15). +Treatment. +In order to prevent +recurrence, a full thickness excision of the attachment site is +Figure 21-15. +Massive left atrial myxoma. +A. +B. +The +resected specimen. +The neck of the mass that was obstructing the mitral orifice is clearly delineated. +Rhabdomyomas are myocardial hamar- +tomas that are often multicentric in the ventricles. +They frequently invade nearby car- +diac structures and are multicentric in 60% of cases. +Workup is simi- +lar to other cardiac tumors. +Treatment is generally with com- +bined chemotherapy and radiation and is rarely effective. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Braunwald E, Bonow RO. +Braunwald’s heart disease: a +textbook of cardiovascular medicine. +9th ed. +Philadelphia: +Saunders; 2012. +2. +Lee DH, Buth KJ, Martin 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647. +241. +Gammie JS, Abrishamchian AR, Griffith BP. +Cardiac auto- +transplantation and radical bi-atrial resection for recurrent +atrial myxoma. +Ann Thorac Surg. +2007;83:1545-1547. +242. +Goldstein DJ, Oz MC, Michler RE. +Radical excisional therapy +and total cardiac transplantation for recurrent atrial myxoma. +Ann Thorac Surg. +1995;60:1105-1107. +243. +Putnam JB Jr., Sweeney MS, Colon R, Lanza LA, Frazier +OH, Cooley DA. +Primary cardiac sarcomas. +Ann Thorac Surg. +1991;51:906-910. +244. +Neragi-Miandoab S, Kim J, Vlahakes GJ. +Malignant tumours +of the heart: a review of tumour type, diagnosis and therapy. +Clin Oncol (R Coll Radiol). +2007;19:748-756. +This page intentionally left blank +Thoracic Aneurysms and Aortic +Dissection +Scott A. +LeMaire, Raja R. +Gopaldas, and Joseph S. +22-1). +The proximal aortic segment includes the ascending aorta and +the transverse aortic arch. +The ascending aorta begins at the aor- +tic valve and ends at the origin of the innominate artery. +The aortic +root joins the tubular portion of the ascending aorta at the sino- +tubular ridge. +The transverse aortic arch is the area from which +the brachiocephalic branches arise. +The distal aortic segment +includes the descending thoracic aorta and the abdominal aorta. +Aneurysms can be localized to a single +aortic segment, or they can involve multiple segments. +Fusiform +aneurysms are more common and can be described as symmetri- +cal dilatations of the aorta. +Saccular aneurysms are localized +outpouchings of the aorta. +These include rupture, which is usually a fatal event. +Therefore, +aggressive treatment is indicated in all but the poorest surgical +candidates. +2 The clinical progression of an aortic aneurysm is continued +expansion and eventual rupture. +5 Ascending aortic aneurysms that are symptomatic or +>5.5 cm should be repaired. +This threshold is lowered for +patients with connective tissue disorders. +Figure 22-1. +Illustration of normal thoracic aortic anatomy. +nancy. +An emergency operation is performed for any patient in +whom a ruptured aneurysm is suspected. +Patients with thoracic aortic aneurysm often have coexist- +ing aneurysms of other aortic segments. +Therefore, staged repair of multiple +aortic segments often is necessary. +Causes and Pathogenesis +General Considerations. +Any alteration in this delicate +balance can lead to aortic disease. +Thoracic aortic aneurysms have a variety of causes +(Table 22-1). +Hemodynamic factors clearly contribute to the process +of aortic dilatation. +Turbulent blood +flow is also recognized as a factor. +Hemodynamic +derangements, however, are only one piece of a complex puzzle. +Atherosclerosis is commonly cited as a cause of thoracic +aortic aneurysms. +Nonspecific Medial Degeneration. +Nonspecific medial +degeneration is the most common cause of thoracic aortic dis- +ease. +The underlying causes of medial +degenerative disease remain unknown. +Aortic Dissection. +This event profoundly weakens the outer wall. +Genetic Disorders. +Loeys-Dietz Syndrome Loeys-Dietz syndrome is phenotypi- +cally distinct from Marfan syndrome. +It is characterized as an +aneurysmal syndrome with widespread systemic involvement. +The subtypes represent differing defective steps of +collagen production. +Infection. +Primary infection of the aortic wall resulting in +aneurysm formation is rare. +The ascend- +ing aorta and arch are the most commonly involved areas. +Aortitis. +The cause of the intense inflammatory reaction is unknown. +Systemic autoimmune disorders also cause thoracic aor- +titis. +Pseudoaneurysms. +As expected, aortic diam- +eter was a strong predictor of rupture, dissection, and mortality. +One common clinical scenario deserves special attention. +The clinical history of these ectatic ascend- +ing aortas has been defined by several studies. +Therefore, patients often are asymptom- +atic at the time of diagnosis. +Local Compression and Erosion. +Initially, aneurysmal +expansion and impingement on adjacent structures causes mild, +chronic pain. +Pulmonary or air- +way erosion presents as hemoptysis. +Compression and erosion +of the esophagus cause dysphagia and hematemesis, respec- +tively. +Jaundice due to compression of the liver or porta +hepatis is uncommon. +Aortic Valve Regurgitation. +In response +to the volume overload, the heart remodels and becomes +increasingly dilated. +Distal Embolization. +Rupture. +Whenever possible, +all results should be compared to those of prior imaging studies. +Plain Radiography. +Ascending aortic +aneurysms produce a convex shadow to the right of the cardiac +silhouette. +Aortic root aneurysms, for +example, often are hidden within the cardiac silhouette. +22-2). +Echocardiography and Abdominal Ultrasonography. +Computed Tomography. +A. +Anteroposterior +view. +B. +Lateral view. +Magnetic Resonance Angiography. +Invasive Aortography and Cardiac Catheterization. +Proximal aortography carries a 0.6% to 1.2% +risk of stroke. +Treatment +Selecting the Appropriate Treatment. +None- +theless, endoluminal stenting is approved by the U.S. +Determination of the Extent and Severity of Disease. +A CT +scan can reveal detailed information about aortic calcification +and luminal thrombus. +These details are important in preventing +embolization during surgical manipulation. +Indications for Operation Thoracic aortic aneurysms are +repaired to prevent fatal rupture. +In contrast, patients who present +with symptoms may need urgent operation. +Symptomatic +patients are at increased risk of rupture and warrant expedi- +tious evaluation. +The majority +of hybrid approaches involve repairing the aortic arch. +These patients also have a mortal- +ity rate that is significantly higher than normal. +Operative Repair. +The spectrum of operations +(Fig. +22-4) ranges from simple graft replacement of the tubular +portion of the ascending aorta (Fig. +Mechanical prosthe- +ses necessitate following a lifelong anticoagulation regimen. +Illustrations of proximal aortic repairs in which the native aortic root is left intact. +A. +Graft replacement of the tubular portion +of the ascending aorta with the aortic arch left intact. +B. +C. +A modified hemiarch with additional graft replacement of the innominate artery. +D. +Patch repair of the aortic arch. +E. +F. +G. +The elephant +trunk approach with a concomitant island brachiocephalic artery reattachment. +Contemporary Y-graft arch repairs include H. +the single +Y-graft approach, I. +the double Y-graft approach, J. +the elephant trunk approach with a single Y-graft, and K. +the elephant trunk approach +with a double Y-graft. +The aortic wall was then wrapped around the graft +to establish hemostasis. +22-6). +22-4). +This permits +the distal anastomosis to be brought forward and aids in hemo- +stasis. +aortic +root aneurysm. +B. +The diseased aortic tissue (including the sinuses of Valsalva) is excised. +Buttons of surrounding tissue are used to mobi- +lize the origins of the coronary arteries. +C. +A synthetic graft is sewn to the distal ascending aorta with continuous suture. +D. +E. +F. +The annular sutures +are then tied. +G. +Each of the three commissures is then secured near the top of the graft. +H. +The supra-annular aortic tissue is sewn to the graft +in continuous fashion. +I. +J. +The +two aortic grafts are sewn together with continuous suture. +K. +L. +22-7). +Illustration of a modified Bentall procedure for +replacing the aortic root and ascending aorta. +by using a hybrid endovascular approach (Fig. +22-8) in certain +settings. +This provides constant perfusion of the brain and +other vital organs during the repair. +Although its use was +cumbersome in the past, contemporary ACP techniques (Fig. +Upon initiation, cold blood +is delivered into the brain via the right common carotid artery. +Illustration of a contemporary Y-graft approach to total arch replacement for aortic arch aneurysm. +A. +The proximal portions +of the brachiocephalic arteries are exposed. +B. +The proximal ends of the transected brachiocephalic arteries are ligated. +C. +D. +The proximal aspect of the Y-graft is clamped. +This directs +flow from the axillary artery to all three brachiocephalic arteries. +The arch is then replaced with a collared elephant trunk graft. +E. +The collared +graft accommodates any discrepancy in aortic diameter. +F. +(Adapted from LeMaire et al,73 Fig. +2. +Used with permission. +Copyright The Society of Thoracic Surgeons.) +arena, although they remain controversial. +22-10). +The branches +of the graft are then sewn to the arch vessels. +Once the arch +is “debranched,” the arch aneurysm can be excluded with +an endograft. +Commonly, a zone 0 approach (Fig. +Illustration of Borst’s elephant trunk technique using a contemporary Y-graft approach. +A. +A section of the graft is left sus- +pended within the proximal descending thoracic aorta. +B. +Stage 2: The distal repair uses the floating “trunk” for the proximal anastomosis. +C. +An alternate “hybrid” approach may be used in patients with less extensive distal aortic disease. +Endovascular stent grafts are placed within +the elephant trunk to complete the repair. +(Used with permission of Baylor College of Medicine.) +Figure 22-9. +A. +B. +(Images adapted from Gravlee GP, Davis RF, Stammers AH, et al, eds. +Cardiopulmonary Bypass: Principles +and Practice, 3rd ed. +Philadelphia: Lippincott Williams & Wilkins; 2008, Chap. +32, Fig. +1A,B. +Illustration of a hybrid arch repair. +A. +B. +C. +The completed repair. +The proximal landing zone of the endograft is within zone 0. +Zone 0 +includes the ascending aorta and the origin of the innominate artery. +Zone 1 includes the origin of the left common carotid artery. +Zone +2 includes the left subclavian artery origin. +22-12). +Extent IV repairs begin at the +diaphragmatic hiatus and often involve the entire abdominal aorta. +Descending thoracic aortic aneurysms are repaired through +a left thoracotomy. +Clamping the descending thoracic aorta causes ischemia +of the spinal cord and abdominal viscera. +(Reproduced with permission from Coselli et al,232 +Fig. +1. +Copyright The Society of Thoracic Surgeons.) +operations. +A. +Stage 1: The distal aorta is repaired through a left thoracoabdominal approach. +Proximal intercostal arteries are oversewn. +B. +C. +Stage 2: The proximal aorta is repaired through a median sternotomy. +The aortic arch is opened under hypothermic circulatory arrest. +The +“trunk” is pulled out and used to replace the aortic arch and ascending aorta. +This eliminates the need for a new distal anastomosis and simpli- +fies the procedure. +Circulatory arrest and operative time, along with their attendant risks, are reduced. +D. +The completed two-stage repair of +the entire thoracic aorta. +Ann Thorac Surg 2005; 80:2166, Figs. +2, 3, 7, and 8. +The most common complication of extensive +repairs is pulmonary dysfunction. +Injury +to the esophagus during the proximal anastomosis can have +catastrophic consequences. +Myo- +cardial perfusion is maintained through the carotid- +subclavian bypass graft. +(Reproduced with permission +from Jones et al,96 Fig. +2. +If the femoral artery will not accommodate the nec- +essary sheath, then an iliac artery is exposed. +The endograft is then advanced +into the aorta and suitably positioned. +An aortogram is then +taken to rule out any endoleak, and protamine is administered. +This allows the distal end of the trunk to be identified via fluo- +roscopy. +Occasionally, the wire must be advanced in an antegrade +fashion from a brachial artery. +Hybrid Repair As discussed previously, hybrid aortic repairs are +extremely heterogeneous. +22-16). +805 +T +HORACIC + A +NEURYSMS + +AND + A +ORTIC + D +ISSECTION +CHAPTER 22 +Figure 22-15. +Illustration of a hybrid repair of the proximal descending thoracic aorta. +A. +B. +After the bypass is completed, the left subclavian artery is ligated proximal to the graft. +C. +(Reproduced with permission from Bozinovski +et al,103 Figs. +9, 10, and 11. +dure or develop over time. +As the separation of the layers of the media propagates, +at least two channels form (Fig. +The dissecting mem- +brane separates the true and false lumens. +The extensive disruption of the aortic wall has severe +anatomic consequences (Fig. +22-18). +Dissection vs. +Aneurysm. +The relationship between dissec- +tion and aneurysmal disease requires clarification. +In most cases, dissection occurs in +patients without aneurysms. +The subsequent progressive dilata- +tion of the weakened outer aortic wall results in an aneurysm. +The overused term dissecting aneurysm +should be reserved for this specific situation. +Classification. +Normal aorta Aortic dissection Intramural hematoma Penetrating aortic ulcer +Figure 22-17. +Illustration of longitudinal sections of the aortic wall and lumen. +Blood flows freely downstream in normal aortic tissue. +In each of these conditions, the outer aortic wall is severely +weakened and prone to rupture. +Dissection is considered +808 +SPECIFIC CONSIDERATIONS +UNIT + +II +Part II +Figure 22-18. +A. +Ascending aortic rupture and cardiac tam- +ponade. +B. +Disruption of coronary blood flow. +C. +Injury to the aortic valve causing regurgita- +tion. +D, E, and F. +Compromised blood flow to +branch vessels, causing ischemic complications. +(Images adapted from Creager MA, Dzau VS, +Loscalzo J, eds. +Vascular Medicine. +Philadelphia: +WB Saunders; 2006. +Copyright © Saunders/ +Elsevier, 2006. +Fig. +Figure 22-20 provides an algorithm +for the management of acute aortic dissection. +The subacute period +encompasses days 15 through 60 after the initial tear. +22-17). +Eventually, the ulcer can penetrate the aortic +wall, which leads to dissection or rupture. +Ultimately, +any condition that weakens the aortic wall increases the risk of +aortic dissection. +The location of the pain often indicates which aortic +segments are involved. +22-18 and +Table 22-5). +Ascending aortic dissection can directly injure the aortic +valve, causing regurgitation. +Patients with acute aortic +valve regurgitation may report worsening dyspnea. +The sudden disruption of +coronary blood flow can cause a myocardial infarction. +(Repro- +duced with permission from Creager +MA, Dzau VS, Loscalzo J, eds. +Vascu- +lar Medicine. +Philadelphia: WB Saun- +ders; 2006. +Copyright © Saunders/ +Elsevier, 2006, Fig. +35-2). +Free rupture into the pericardial space produces rapid tampon- +ade and is generally fatal. +Ascending aortic +dissection (Stanford A or +DeBakey I or II)? +Anti-impulse therapy +(beta blockers), +blood pressure control +Aortic dissection? +Complicated descending +aortic dissection +(malperfusion, rupture)? +Management of acute aortic dissection +Ascending aortic +dissection (Stanford A or +DeBakey I or II)? +Figure 22-20. +Algorithm used to facilitate decisions regarding treatment of acute aortic dissection. +For classification purposes (acute vs. +subacute +vs. +Unfortunately, laboratory studies are of little help in diag- +nosing acute aortic dissection. +22-21). +Treatment +Initial Assessment and Management. +22-20). +The goals of pharmacologic treatment are to stabi- +lize the dissection and prevent rupture. +Patients are monitored closely in an intensive care unit. +Central +venous catheters ensure reliable IV access for delivering vaso- +active medications. +Pulmonary artery catheters are reserved for +patients with severe cardiopulmonary dysfunction. +Particular attention is paid to changes in +neurologic status, peripheral pulses, and urine output. +Reductions in dP/dT are achieved by lowering both car- +diac contractility and blood pressure. +A. +An acute DeBakey type I aortic dissection. +The dissecting membrane appears +wavy (arrows) in the early phase of dissection. +Here, the true lumen of the proximal aorta can be seen to be extensively compressed. +This may +lead to malperfusion of the heart. +B. +A chronic DeBakey type III aortic dissection. +Doses of beta antag- +onists are titrated to achieve a heart rate of 60 to 80 bpm. +Nitro- +prusside, a direct vasodilator, can be administered once beta +blockade is adequate. +These drugs inhibit renin release, which +may improve renal blood flow. +22-22). +Also, it allows the surgeon to carefully +inspect the aortic arch for intimal tears. +A polyester tube graft +is sutured to the distal aortic cuff. +This is probably due to the +extensive coverage of the intercostal vessels by the stent-graft. +Illustration of proximal aortic repair for acute ascending aortic dissection. +A. +This repair requires a median sternotomy and +cardiopulmonary bypass. +22-8). +B. +The dissecting membrane is removed to expose the true lumen. +C. +D. +E. +F. +G. +(Reproduced with permission +from Creager MA, Dzau VS, Loscalzo J, eds. +Vascular Medicine. +Philadelphia: WB Saunders; 2006. +Copyright © Saunders/Elsevier, 2006, +Fig. +In most +respects, the operation is similar to that for acute dissection +repair. +Therefore, patients are continually reassessed for new +complications. +Long-term pharmacologic therapy is important for patients +with chronic aortic dissection. +The +first surveillance scan is obtained approximately 6 weeks after the +onset of dissection. +Acute malperfusion syndromes also warrant intervention. +In the recent past, visceral and renal malperfusion were consid- +ered indications for operation. +When the endovascular approach is unavailable +or unsuccessful, surgical options can be used. +However, in +acute cases, open surgery is associated with poor outcomes. +Therefore, endovascular intervention is the preferred initial +approach in such cases. +Placement of a stent graft in the true lumen of the aorta +can resolve a “dynamic” malperfusion. +However, these patients remain at risk of further complication or +future reintervention. +An aortogram is taken, and the intimal tear is +identified. +A stent graft approximately 10% wider in diameter than the +true lumen is selected for these cases. +The + distal half also may be replaced if it exceeds 4 cm in diameter. +When an endovascular approach +is unavailable or unsuccessful, open surgery is necessary. +22-23). +Asymmet- +ric expansion of the false lumen can create wide separation of +the renal arteries. +Illustration of distal aortic repair of a chronic dissection. +A. +Thoracoabdominal incision. +B. +Extent II thoracoabdominal aortic +aneurysm resulting from chronic aortic dissection. +C. +The isolated +segment of aorta is opened by using electrocautery. +D. +The dissecting membrane is excised, and bleeding intercostal arteries are oversewn. +E. +F. +G. +H. +Cold +crystalloid is delivered to the renal arteries. +The critical intercostal arteries are reattached to an opening cut in the graft. +I. +A second oval opening is fashioned in the graft +adjacent to the visceral vessels. +Selective perfusion of the visceral arteries continues during their reattachment to the graft. +A separate anas- +tomosis is often required to reattach the left renal artery. +J. +The final anastomosis +is created between the graft and the distal aorta. +(Reproduced with permission from Creager MA, Dzau VS, Loscalzo J, eds. +Vascular Medicine. +Philadelphia: WB Saunders; 2006. +Copyright © Saunders/Elsevier, 2006, Fig. +35-8A–J.) +rates and acceptable morbidity rates. +A meta- +analysis conducted by Koullias and Wheatley82 of data from +Figure 22-23. +Open Repair of Descending Thoracic and Thoracoabdomi- +nal Aortic Aneurysms. +For malperfusion of the visceral or +renal arteries, an endovascular approach is ideal. +Malperfusion was +present in one patient; this patient had an open fenestration pro- +cedure. +A substantial number of patients (n = 7, 22%) had con- +nective tissue disorders. +Green, MPH, and Stephen +N. +Palmer, PhD, ELS, for editorial assistance; Scott A. +Weldon, +MA, CMI, and Carol P. 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+Approximately +30% of vascular patients will be diabetic. +A history of prior and +current smoking status should be noted. +Only 5% of patients with claudication will need +intervention because of disabling extremity pain. +The +5-year mortality of a patient with claudication approaches +30%. +Symptoms persisting longer than 24 hours constitute +a stroke. +The patient fears eating because of the pain, avoids +food, and loses weight. +It should also be examined for +the presence of bruits. +The differential diagnosis is a transmitted +murmur from a sclerotic or stenotic aortic valve. +The carotid is +palpable deep to the sternocleidomastoid muscle in the neck. +Palpation, however, should be gentle and rarely yields clinically +useful information. +It is usually easily palpable in the axilla and medial upper arm. +The radial artery is +palpable at the wrist anterior to the radius. +Palpation of the popliteal artery is a bimanual tech- +nique. +The posterior tibial pulse is detected +by palpation 2 cm posterior to the medial malleolus. +Note should also be made +of nail changes and loss of hair. +A change in pulse +quality, aneurysmal enlargement, or a new bruit should be care- +fully noted. +Noninvasive Diagnostic Evaluation of the +Vascular Patient +Ankle-Brachial Index. +The ABI is determined in the following ways. +23-1). +Normal is more than 1. +Those with gangrene +have an ABI of less than 0.3. +These ranges can vary depending +on the degree of compressibility of the vessel. +The test is less +reliable in patients with heavily calcified vessels. +Segmental Limb Pressures. +This data can then be used to infer the level of the occlu- +sion. +The low thigh pressure should be +equivalent to brachial pressures. +Subsequent pressures should +fall by no more than 10 mmHg at each level. +Noncompressible arter- +ies yield ankle systolic pressures ≥250 mmHg and ABIs >1.40. +False-positive results with the TBI are +unusual. +Figure 23-1. +Calculating the ankle-brachial index (ABI). +23-2). +Radiologic Evaluation of the Vascular Patient +Ultrasound. +B-mode ultrasonography provides black and white, +real-time images. +Calci- +fication in atherosclerotic plaques will cause acoustic shadow- +ing. +B-mode ultrasound probes cannot be sterilized. +Experience is needed to +obtain and interpret images accurately. +Computed Tomography Angiography. +It depends on intrave- +nous infusion of iodine-based contrast agents. +femoral +0.75 +0.50 +0.25 +0.25 +0.00 +149 Brachial +0.66 U. +thigh +L. +832 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +slices. +23-3). +This technology has been advanced as a consequence of aortic +endografting. +23-4). +23-5). +Patients with +claustrophobia may require sedation to be able to complete the +test. +Diagnostic Angiography. +Diagnostic angiography is consid- +ered the gold standard in vascular imaging. +Nevertheless, contrast angiography still remains in +A B +Figure 23-3. +A. +B. +A 53-year-old male with occluded right common iliac artery (double arrows). +Figure 23-4. +833 +Arterial Disease +CHAPTER 23 +widespread use. +The imaging system and the contrast agent are used +to opacify the target vessel. +There are several considerations +when relying on angiography for imaging. +DSA also allows for real-time video replay (Fig. +23-6). +Magnetic resonance angiogram of aortic arch and +carotid arteries. +Figure 23-6. +Needles and Access +Needles are used to achieve percutaneous vascular access. +The +size of the needle will be dictated by the diameter of the guide- +wire used. +Most often, an 18-gauge needle is used, as it will +accept a 0.035-inch guidewire. +A 21-gauge micropuncture nee- +dle will accept a 0.018-inch guidewire. +Femoral arterial puncture is the most common site for +access. +The single-wall puncture technique requires a sharp, +beveled needle tip and no central stylet. +Retrograde femoral access is the most common arterial +access technique (Fig. +23-7). +The artery is accessed with a micropuncture needle just +proximal to the antecubital crease. +Guidewires +Guidewires are used to introduce, position, and exchange cath- +eters. +A guidewire generally has a flexible and stiff end. +In +general, only the flexible end of the guidewire is placed in the +vessel. +Guidewires come in different maximum transverse diam- +eters, ranging from 0.011 to 0.038 inches. +The stiffness of the guidewire is also an important charac- +teristic. +Stiff wires allow for passage of large aortic stent graft +devices without kinking. +They are also useful when trying to +perform sheath or catheter exchanges around a tortuous artery. +An example of a stiff guidewire is the Amplatz wire. +The +coating is primed by bathing the guidewire in saline solution. +Figure 23-7. +A. +Antegrade femoral artery access. +B. +Brachial artery approach. +Guidewires also come in various tip configurations. +The Rosen wire has a soft curled end, which makes it +ideal for renal artery stenting. +The soft curl of this wire prevents +it from perforating small renal branch vessels. +The sheath acts to protect the vessel +from injury as wires and catheters are introduced (Fig. +23-8). +Sheaths are sized by their inner diameter. +The multiple shapes permit access to ves- +sels of varying dimensions and angulations. +23-9). +Besides length and diameter, +Figure 23-8. +Low-compliance balloons are the +mainstay for peripheral intervention. +Fre- +quently, several inflations are required to achieve a full profile +of the balloon. +They serve to buttress collapsible vessels and help prevent +atherosclerotic restenosis. +Self-expanding stents (Fig. +The self-expanding stent is mounted on a central shaft and is +placed inside an outer sheath. +It relies on a mechanical spring- +like action to achieve expansion. +In this way, self-expanding stents are more difficult to place +with absolute precision. +There are several advantages related +to self-expanding stents. +This makes these stents ideal +for placement in the internal carotid artery. +23-11). +The most exciting area of development in stents is the +evolution of drug-eluting stents (DES). +Covered stents have been designed +Figure 23-9. +A. +An artery with luminal +narrowing caused by plaque. +B. +C. +The plaque is com- +pressed with widened flow lumen as the result +of balloon angioplasty. +837 +Arterial Disease +CHAPTER 23 +Figure 23-10. +Figure 23-11. +In a balloon-expandable stent, the stent is pre- +mounted on a balloon catheter. +The balloon stretches the stent +members beyond their elastic limit. +The stent is deployed by full +balloon expansion. +23-12). +Stroke due to carotid bifurcation occlusive disease is usu- +ally caused by atheroemboli (Fig. +23-13). +The carotid bifurca- +tion is an area of low flow velocity and low shear stress. +23-14). +Crescendo TIAs refer to a syndrome comprising +Figure 23-12. +A stent graft is a metal +stent covered with fabric that is com- +monly used for aneurysm exclusion. +It is implied that these are due to severe +Figure 23-13. +839 +Arterial Disease +CHAPTER 23 +extracranial disease and poor intracranial collateral recruitment. +When a neurologic deficit lasts longer than +3 weeks, it is considered a completed stroke. +This partial blindness usually lasts for a few minutes and then +resolves. +Monocular blindness progressing over a 20-minute period sug- +gests a migrainous etiology. +In +BA +Sectional view +Low +shear +region +High shear +region +Figure 23-14. +A. +The carotid bifurcation is an +area of low flow velocity and low shear stress. +B. +contrast, they represent loss or diminution of neurologic func- +tion. +Characteristically, the peak systolic velocity is +increased at the site of the vessel stenosis. +The end-diastolic +velocity is increased with greater degree of stenosis. +A ratio greater than 4 is a great predictor of angiographic ste- +nosis of 70% to 99%. +MRA is noninvasive and does not require iodinated contrast +agents. +23-15). +The advantages of CTA over MRA include faster +data acquisition time and better spatial resolution. +23-16). +A. +A carotid +artery occlusion is noted in the internal +carotid artery B. +Figure 23-16. +(symptomatic). +It is estimated that 15% of all strokes are pre- +ceded by a TIA. +The main conclusions of the tri- +als remain validated and widely acknowledged. +The dismal outcome reported in the early experience was likely +related to poor patient selection. +Carotid endarterectomy produced a relative +risk reduction of 53% over medical management alone. +2.3%) and a higher rate of myocardial infarction +in the endarterectomy group (2.3% vs. +1.1%). +All available randomized studies have provided some +answers and raised some questions. +Carotid artery +stenting is not recommended for asymptomatic patients at this +time. +Stump pressures have +been used to determine the need for intra-arterial carotid shunt- +ing. +23-17). +The platysma is divided completely. +Typically tributaries of the anterior jugular vein are ligated and +Figure 23-17. +844 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +divided. +The dissection is carried medial to the sternocleido- +mastoid. +This +muscle can be divided. +The carotid fascia is incised, and the +common carotid artery is exposed. +The common carotid artery +is mobilized cephalad toward the bifurcation. +A useful landmark in the +dissection of the carotid bifurcation is the common facial vein. +This vein can be ligated and divided. +The external carotid artery is +mobilized just enough to get a clamp across. +Intravenous heparin sulfate (1 mg/kg) is routinely admin- +istered just prior to carotid clamping. +The external and common carotid +arteries are clamped subsequently. +Endarterectomy is carried out to +remove the occlusive plaque (Fig. +23-18). +23-19). +Typically, a plane is teased +Figure 23-18. +A. +Carotid plaque is elevated from the carotid lumen. +B. +Figure 23-19. +out from the vessel wall, and the entire plaque is elevated and +removed. +23-20). +The endarterectomized surface is then irrigated +and any debris removed. +23-21). +845 +Arterial Disease +CHAPTER 23 +off the vessel wall. +The wound +is closed in layers. +Complications of Carotid Endarterectomy. +Acute ipsilateral stroke is a dreaded +complication following carotid endarterectomy. +Cerebral isch- +emia can be due to either intraoperative or postoperative events. +The most +common cause of postoperative stroke is due to embolization. +Less frequently, acute carotid artery occlusion can cause acute +postoperative stroke. +Re-exploration is mandated for acute +carotid artery occlusion. +Cerebral angiography can be useful if +intracranial revascularization is considered. +Local complications related to surgery include excessive +bleeding and cranial nerve palsies. +Any expanding hematoma should be evac- +uated and active bleeding stopped. +Often these are traction injuries but can +also be due to severance of the respective nerves. +BA +Figure 23-21. +A. +B. +A completion closure of carotid endarterectomy incision using a synthetic patch. +23-22). +The patient is placed in the supine position. +The patient’s blood +pressure and cardiac rhythm are closely monitored. +Using the Seldinger technique, we insert a +diagnostic 5- or 6-French sheath in the CFA. +A diagnostic arch +aortogram is obtained. +It is critical not to advance the sheath beyond the occlu- +sive plaque in the carotid bulb. +Several distal EPDs are available (Table 23-6). +The EPD device is carefully deployed beyond the target lesion. +All current +carotid stents use the rapid-exchange monorail 0.014-inch plat- +form. +The size selection is typically based on the size of com- +mon carotid artery. +The puncture +site is closed using available closure device or with manual +compression. +Throughout the procedure, the patient’s neuro- +logic function is closely monitored. +Complications of Carotid Stenting. +BA +Figure 23-22. +A. +Carotid angiogram +demonstrating a high-grade stenosis of +the left internal carotid artery. +B. +Com- +pletion angiogram demonstrating a sat- +isfactory result following a carotid stent +placement. +Acute carotid stent thrombosis is rare. +The incidence of in-stent +carotid restenosis is not well known but is estimated at 10% to +30%. +NA = not applicable. +Nonatherosclerotic Disease of +the Carotid Artery +Carotid Coil and Kink. +23-23). +In children, carotid coils appear to be congenital in +origin. +Kinking is more common in women +than men. +Most carotid kinks and coils are found incidentally +on carotid duplex scan. +Fibromuscular Dysplasia. +23-24). +Women in the fourth or fifth decade +of life are more commonly affected than men. +Hormonal effects  +on the vessel wall are thought to play a role in the pathogenesis +of FMD. +Four histologic types of FMD have been described +in the literature. +Commonly, mural dilations and microaneurysms +can be seen with this type of FMD. +Intimal fibroplasia accounts for 5% of all +cases and occurs equally in both sexes. +FMD can also involve the +renal and external iliac arteries. +The string of beads +can also be shown noninvasively by CTA or MRA. +Antiplatelet medication is the gener- +ally accepted therapy for asymptomatic lesions. +Endovascular +treatment is recommended for patients with documented lateral- +izing symptoms. +Surgical correction is rarely indicated. +Carotid Artery Dissection. +Subintimal dissections +can lead to intramural clot or thrombosis. +Iatrogenic dissections can +also occur due to catheter manipulation or balloon angioplasty. +Figure 23-24. +The ischemia may cause TIAs or infarctions, +or both. +23-25). +The dissection typically starts in the internal carotid artery distal +to the bulb. +The recurrence rate is low. +Carotid Artery Aneurysms. +Carotid artery aneurysms are +rare, encountered in less than 1% of all carotid operations +(Fig. +23-26). +The true carotid artery aneurysm is generally due +to atherosclerosis or medial degeneration. +Patients typically present with a pul- +satile neck mass. +Thrombosis and rupture of the carotid aneurysm are rare. +Pseudoaneurysms of the carotid artery can result from injury +or infection. +849 +Arterial Disease +CHAPTER 23 +Carotid Body Tumor. +23-27). +The gland is innervated by the glos- +sopharyngeal nerve. +Carotid body tumor is a rare lesion of the neuroen- +docrine system. +A. +An anteroposterior angiogram of the neck revealing a carotid artery aneurysm. +B. +A lateral projection of the carotid artery +aneurysm. +C. +Following endovascular placement, the carotid artery aneurysm is successfully excluded. +and adrenal medulla. +Approximately 5% to 7% of carotid body tumors are +malignant. +The risk of malignancy is +greatest in young patients with familial tumors. +Symptoms related to the endocrine products of the carotid +body tumor are rare. +A. +A carotid body +tumor (arrow) located adjacent to the +carotid bulb. +B. +Following periad- +ventitial dissection, the carotid body +tumor is removed. +850 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +mass. +The diagnosis of carotid body tumor requires confir- +mation on imaging studies. +Classically, a carotid body tumor will widen +the carotid bifurcation. +Surgical resection is the rec- +ommended treatment for suspected carotid body tumor. +Carotid Trauma. +Blunt or penetrating trauma to the neck can +cause injury to the carotid artery. +Spiral CTA has become the modality of choice to detect +extracranial carotid artery injury. +The most common location of aortic aneurysms is the +infrarenal aorta. +Advantages and potential complications of these treatments will +also be addressed. +Rupture risk appears to be directly related to aneurysm +size as predicted by Laplace’s Law. +In the past, AAA rupture risk has been +overestimated. +The rupture risk is quite low below 5.5 cm and +begins to rise exponentially thereafter. +Physical examination is neither sensitive nor specific except +in thin patients. +Rarely patients present with back pain and/or +abdominal pain with a tender pulsatile mass. +Patients with these +symptoms must be treated as a rupture until proven otherwise. +23-28). +Male aortas tend to be larger +Figure 23-28. +An operative view of an infrarenal aortic aneurysm. +Ninety percent of AAAs are +infrarenal in location and have a fusiform morphology. +There +is a higher predilection for juxtarenal and suprarenal AAAs in +women compared with men. +Distally, the iliac arteries can have severe tortu- +osity with multiple compound turns. +Cross-sectional imaging is required for definitive evalu- +ation of AAA. +Extremely high-resolution images are obtained with submilli- +meter spatial resolution (Fig. +23-29). +The spiral technique further affords the ability for three- +dimensional reconstruction. +Conventional angiography has a minimal role +in the current management of AAA. +Angiography is invasive +with an increased risk of complications. +The aneurysm sac is open next, and a prosthetic graft is +used to reconstruct the aorta. +23-30). +23-31). +Advantages and Risks of Open Abdominal Aortic Aneu- +rysm Repair. +The risk of aneurysm +Figure 23-29. +853 +Arterial Disease +CHAPTER 23 +recurrence or delayed rupture no longer exists. +As a result, long- +term imaging surveillance is not needed with these patients. +In +contrast, the long-term efficacy of endovascular repair remains +unclear. +A. +Schematic depiction of an aortic tube graft used to repair an aortic aneurysm. +B. +Intraoperative image of an aortic tube +graft reconstruction. +23-32). +Unlike open surgical repair, the aneurysm sac is not +Figure 23-31. +Intraoperative view of a bifurcated graft used to +repair an aortic aneurysm. +resected, which is subjected for potential aneurysm expansion or +even rupture. +Several techniques have been proposed to overcome +this limitation. +A. +An aortogram dem- +onstrating a large infrarenal abdominal +aortic aneurysm. +B. +Following endovas- +cular stent graft implantation, the aortic +aneurysm is successfully excluded. +All diameter measurements are mid-wall to +mid-wall of the vessel. +The usual distal landing zone is the common +iliac artery. +The next step in the preoperative planning is device selec- +tion. +Advantages and Risks of Endovascular Repair. +The obvi- +ous advantage of an endovascular AAA repair is its minimally +invasive nature. +Despite its many advantages, endovascular repair does +have potential complications. +Technical Considerations of Endovascular Aortic Aneu- +rysm Repair. +The patient is prepped and draped just as in open AAA repair. +A variety +of anesthetic options may be used. +Regional anesthesia may +be appropriate for patients with pulmonary disease. +Special attention is paid to avoid +the groin crease to decrease the risk of wound complications. +Transfemoral access is obtained using standard Seldinger +technique. +An angiographic catheter is advanced from +the contralateral femoral artery to the same level. +A road-mapping aortogram is obtained to localize the +renal arteries. +23-33). +The patients recover in the recovery room for 2 to 4 hours and +admitted to the general care floor. +Although in the past, patients +A +DC +B +Figure 23-33. +A. +B. +The device is deployed in the aorta just below the +renal arteries. +C. +D. +857 +Arterial Disease +CHAPTER 23 +were admitted to the intensive care unit, this is rarely needed. +Most patients can be started on a regular diet that evening and +discharged the next morning. +Surveillance Following Endovascular Aortic Aneurysm +Repair. +Life-long follow-up is essential to the long-term suc- +cess after endovascular AAA repair. +The abdominal +x-ray gives a “birds-eye” view of the overall morphology of the +stent graft. +Early reports on results with endovascular repair were +often flawed due to selection biases. +There was a +higher incidence of graft-related complications in the endolu- +minal group. +There was no difference in the nonvascular local +complication rate among the two groups. +Short-term mortality at 30 days was +4.7% in the open group and 1.7% in the endoluminal group. +2.1%). +As expected, the secondary intervention rate was higher in the +endoluminal group (9.8% vs. +5.8%). +Complication rates were +not reported in the EVAR-1 trial. +Criticisms can be applied to +both of these trials. +Patients had to be eligible for either type of +repair in order to be included in the study. +There was no difference in pri- +mary outcome of all-cause mortality. +Endovascular repair and +open repair resulted in similar long-term survival. +Rupture after endovascular +repair remains a concern. +A significant interaction was observed +between age and type of treatment. +Device-Specific Outcome. +There were no deployment failures or early conversions. +There +was an annual 7% reintervention rate. +Aneurysm growth was +demonstrated in 14% of patients at 2 years. +The endoleak rates were 7.4% and 5.4% at +1- and 2-year intervals, respectively. +There was a 5.3% migra- +tion of 5 mm at 1 year. +Freedom from rupture was noted to be 98.4% at 4 years. +Endoleak rate was 10%. +Three deploy- +ment failures were noted, and freedom from rupture was 100%. +Patients with a wide neck (>26 mm) +had a 3% growth and migration rate. +Narrow-neck patients +(<26 mm) had a 1% growth rate and a 2% migration neck. +Interestingly, short-neck patients (<15 mm) had no aneurysm +growths and a 2% migration rate. +Cost Analysis. +23-34). +Figure 23-35. +beyond the first year of follow-up. +Endoleaks can be detected +using conventional angiography, contrast CT (Fig. +23-35), +MRA, and color-flow duplex ultrasound. +Four types of endoleaks have been described (Table 23-10). +Persistent type I +endoleaks, on the other hand, require prompt treatment. +On angi- +ography, they are seen as a late filling of the aneurysm sac from +a branch vessel(s). +Regardless of the etiology or timing, these +should be promptly repaired. +Endotension Following Endovascular Aortic Aneurysm +Repair. +Secondary Interventions Following Endovascular Aortic +Aneurysm Repair. +The most common cause of mesenteric ischemia is +atherosclerotic vascular disease. +On the other hand, mesenteric isch- +emia can occur suddenly, as in the case of thromboembolism. +23-36). +In addition, the mesenteric cir- +culation responds to the gastrointestinal contents. +Certain +intrinsic vasoconstrictors, such as vasopressin, can diminish the +mesenteric blood flow. +On the other hand, neural regulation is +provided by the extensive visceral autonomic innervation. +This leads to transient anaerobic +metabolism and acidosis. +This vessel network provides +collateral flow between the superior mesenteric artery and IMA. +the splanchnic and systemic circulation. +23-37 and 23-38). +Figure 23-37. +Figure 23-38. +Fever, +nausea, vomiting, and abdominal distention are some common +but nonspecific manifestations. +The classical symptoms include postprandial abdominal pain, +food fear, and weight loss. +Persistent nausea and occasionally +diarrhea may coexist. +Abdominal pain is only +present in approximately 70% of these patients. +When present, +the pain is usually severe but may vary in location, character, +and intensity. +23-39). +Most patients +are young females between 20 and 40 years of age. +Metabolic acidosis +develops as a result of anaerobic metabolism. +Diagnosis of chronic mesenteric ischemia can be more +challenging. +Rarely, the vascular surgeon is the first to encounter a patient +with the above symptoms. +In this situation, it is advisable to +Figure 23-39. +Finally, +spiral CT with three-dimensional reconstruction (Fig. +23-40) +and MRA (Fig. +23-41) have been promising in providing clear +radiographic assessment of the mesenteric vessels. +In most +Figure 23-40. +23-42). +Figure 23-41. +Figure 23-42. +Mesenteric arteriography can also play a therapeutic role. +Surgical Repair +Acute Embolic Mesenteric Ischemia. +Appropriate antibiotics are given prior +to surgical exploration. +The operative management of acute +mesenteric ischemia is dictated by the cause of the occlusion. +Acute Thrombotic Mesenteric Ischemia. +The bypass graft may originate +from either the aorta or iliac artery. +Patency rates are similar regardless of inflow vessel +choice.101 +Chronic Mesenteric Ischemia. +Transaortic endarterectomy is indicated for +ostial lesions of patent CA and SMA. +A left medial rota- +tion is performed, and the aorta and the mesenteric branches +are exposed. +A lateral aortotomy is performed encompassing +both the CA and SMA orifices. +Otherwise, an intimal flap may develop, +which can lead to early thrombosis or distal embolization. +Restenosis after PTA is also an indication for stent +placement.107 +Acute Mesenteric Ischemia. +There are two main +drawbacks with regard to thrombolytic therapy in mesenteric +ischemia. +Nonocclusive Mesenteric Ischemia. +Once the diagnosis is made on the mesenteric arteriography (see +Fig. +23-42), intra-arterial papaverine is given at a dose of 30 to +60 mg/h. +This must be coupled with the cessation of other vaso- +constricting agents. +Techniques of Endovascular Interventions. +These stents can be placed over a low-profile 0.014- +or 0.018-inch guidewire system. +The balloon is then deflated and carefully +withdrawn through the guiding sheath. +Complications of Endovascular Treatment. +Complica- +tions are not common and rarely become life threatening. +These +include access site thrombosis, hematomas, and infection. +Dis- +section can occur during PTA and is managed with placement +of a stent. +Moreover, both groups had similar 3-year cumu- +lative recurrent stenosis and mortality rates. +Long-term patency rates appear to also +be superior with the open technique. +The study showed that covered +stents are associated with less restenosis (18% vs. +47%), symp- +tom recurrence (18% vs. +50%), and reintervention (9% vs. +44%) +at 24 months and better primary patency at 3 years (92% vs. +23-43).114 Atheroscle- +rotic lesions are bilateral in two thirds of patients. +Individuals +with this disease commonly present during the sixth decade of +life. +Men are affected twice as frequently as women. +23-44 and 23-45). +The cause of medial +fibroplasia remains unclear. +Figure 23-45. +Captopril inhibits the +secretion of angiotensin II. +Significant parenchymal +disease limits the reliability of this study. +This value represents the contribution of each kidney +to renin production. +The RSRI of the affected kidney in patients with +renovascular hypertension is greater than 0.24. +while using a minimally nephrotoxic agent. +Flow void may be +inaccurately interpreted as occlusion or stenosis in MRA. +Figure 23-46. +Magnetic resonance angiography of the abdominal +aorta reveals bilateral normal renal arteries. +Figure 23-47. +Types of Surgical Reconstruction. +Autologous vein is the preferred conduit. +If the vein is not suit- +able, then prosthetic material can be used. +After plaque removal, the arteri- +otomy is closed with a prosthetic patch. +Adequate mobilization of the +renal arteries is essential for a safe and complete endarterectomy. +Greater +saphenous vein is the conduit of choice. +A +redundant renal artery is a prerequisite for the procedure. +Completion angiog- +raphy is usually performed to assess the immediate results. +The +technical aspect of an endovascular renal artery revasculariza- +tion is discussed below. +Techniques of Renal Artery Angioplasty and Stenting. +Choosing a balloon with diameter 4 mm is a reasonable first +choice. +43%, respectively). +14%, respectively). +However,  transient  hemodialysis  may  become  necessary  in  +approximately 1% of patients. +Clinical Results of Endovascular Interventions +Percutaneous Transluminal Balloon Angioplasty. +The technical success +rate of balloon angioplasty for FMD was 95%. +Primary patency +rates were 81%, 69%, 69%, and 69% at 2, 4, 6, and 8 years, +respectively. +Assisted primary patency rates were 87%, 87%, +87%, and 87% at 2, 4, 6, and 8 years, respectively. +The resteno- +sis rate was 25% at 8 years. +Renal Artery Stenting. +Five-year patency +was 84.5% (mean follow-up, 27 months). +Hypertension was cured or  +improved in 78% of patients. +The authors concluded that primary +BA +Figure 23-48. +Renal artery stent- +ing. +A. +Focal lesion in the renal artery +(arrow). +B. +The overall cure rate for hypertension was 20%, +whereas hypertension was improved in 49%. +Renal function +improved in 30% of patients and stabilized in 38% of patients. +The restenosis rate at follow-up of 6 to 29 months was 17%. +Various risk factors exist that can lead to the devel- +opment of aortoiliac occlusive disease. +In addition, complaints that are +experienced upon standing suggest nonvascular causes. +23-49). +23-50). +23-51). +Due to the localized nature of this type of aortic +Figure 23-49. +23-52). +Aortoiliac disease can be classified into three types. +Type I represents focal disease affecting the distal aorta and proxi- +mal common iliac artery. +Type II represents diffuse aortoiliac dis- +ease above the inguinal ligament. +Figure 23-51. +Symptoms typically consist +of bilateral thigh or buttock claudication and fatigue. +Men report +diminished penile tumescence and may have complete loss of +erectile function. +These symptoms in the absence of femoral +pulses constitute Leriche’s syndrome. +Rest pain is unusual with +isolated aortoiliac disease unless distal disease coexists. +23-53). +A. +B. +This is consistent with +type I aortoiliac occlusive disease. +dominately the abdominal aorta with disease extension into the +common iliac artery. +This disease pattern affects approximately +25% patients with aortoiliac occlusive disease. +23-54). +875 +Arterial Disease +CHAPTER 23 +limb salvage rather than for claudication. +Patients should have hypertension, +hyperlipidemia, and diabetes mellitus controlled. +They should +be advised to stop smoking. +Most patients are empirically +placed on antiplatelet therapy. +A graduated exercise program +Figure 23-54. +Type A lesions +Type B lesions Type D lesions +Type C lesions +Figure 23-55. +Surgical Reconstruction of Aortoiliac +Occlusive Disease +Aortobifemoral Bypass. +A retro- +peritoneal approach may be selected as an alternative in certain +situations. +There are randomized reports, however, that support +and refute the superiority of this approach. +23-56). +23-57). +Furthermore, the distal aorta often pro- +ceeds to total occlusion after an end-to-side anastomosis. +The limbs of the +Figure 23-56. +In an end-to-end proximal aortic anastomosis, the +aorta is divided in half. +Figure 23-57. +Endarterectomy or patch angioplasty of the profunda femo- +ris may be required concurrently. +During this period, the +patient must be carefully monitored for hypotension. +As a rule, if the profunda femoris can accept a 4-mm probe and +if a No. +Aortic Endarterectomy. +Axillofemoral Bypass. +It may be performed under +local anesthesia and is used for limb salvage. +It +is anastomosed ipsilaterally at the CFA bifurcation into the SFA +and PFA. +23-58). +BA +Figure 23-58. +A. +Skin markings showing the incisions of an ilio- +femoral bypass. +B. +878 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Obturator Bypass. +Thoracofemoral bypass has long-term patency +comparable to aortofemoral bypass. +Focal Aortic Stenosis. +Bilateral CFA access is established followed by +insertion of a 10-French sheath. +Balloon size +will range from 12 to 18 mm in most cases. +A single stent is +generally sufficient in most cases. +Newer self-expanding stents have also been +used. +Occlusive Lesions of the Aortic Bifurcation. +PTA is most use- +ful in the treatment of isolated iliac stenoses of less than 4 cm in +length. +Technical Considerations for Iliac Interventions. +Crossing a +high-grade stenosis or occlusion can be challenging in the iliac +arteries. +Guidewire traversal must be achieved +for performance of endovascular iliac intervention. +Over 90% +of iliac occlusions can be passed with simple guidewire tech- +niques. +There are several approaches that can +be used to achieve re-entry of total chronic occlusions. +Intravascular ultrasound can +be used for true lumen re-entry under fluoroscopic guidance. +A 4-French Berenstein catheter (Cordis Corp., +Miami Lakes, FL) is used to probe the occlusion. +The approach to aortoiliac stenting is intui- +tive. +Stent Graft Placement for Aortoiliac Interventions. +The role of stent grafts in aortoiliac occlusive disease +has not been fully elucidated yet. +Many of these minor complications are related to the arterial +puncture site. +The most frequent complications relate to access +site cannulation. +The incidence of +pseudoaneurysm formation at the puncture site is 0.5%. +Arterial rupture may complicate the procedure in 0.3% of cases. +In +case of failure, surgical treatment is required. +24.6%). +The open bypass group experienced more complica- +tions (18.0% vs. +13.4%) and greater 30-day mortality (2.6% vs. +0.7%). +86.0%, 86.0% vs. +80.0%, and 82.7% vs. +71.4%, respectively); the same was true +for secondary patency (95.7% vs. +90.0%, 91.5 vs. +86.5%, and +91.0% vs. +82.5%, respectively). +Ideal +iliac angioplasty lesions are nonocclusive and short. +Likewise as vessel diameter and flow rates change, so do suc- +cess rates after angioplasty. +Ninety percent of acute ischemia +cases are either thrombotic or embolic. +In +addition, multiple comorbid conditions increase risks of surgical +procedures. +However, among patients with an ABI ratio  +<0.75, 42% were unknown to the primary physicians. +The bedside +ABIs using blood pressure cuff also aid in diagnosis. +Noninvasive studies are important in documenting the +severity of occlusive disease objectively. +Normal ABI is greater than 1.0. +Decrease in segmental pressure between two segments +indicates significant disease. +23-59 and 23-60). +Contrast angiography remains the gold standard imaging +study. +Symptom severity varies from mild to severe. +Nocturnal calf muscle spasms or night +cramps are not indicative of arterial disease. +They are common +but are difficult to diagnose with certainty. +Foot ulceration is not +always the result of arterial insufficiency. +Ischemic ulcers occur +on the toes or lateral side of the foot and are painful. +Ulcers may be the result of more than +one etiology. +Spinal stenosis causes pain +that is exacerbated with standing and back extension. +There are two major +classifications developed based on the clinical presentations. +Asymptomatic patients are classified +Figure 23-59. +Distal occlusive disease is noted in the left tibial arteries +(arrow). +Based on the guide- +line, femoropopliteal lesions are divided into four types: A, B, +C, and D. +23-61). +Type A lesions are single lesions less than 1 cm in length not +involving the trifurcation. +Most cases of lower extremity +ALI are the result of thrombosis of a prosthetic conduit. +This +stems from increased use of prosthetic conduits to address CLI. +Presenting symptoms in ALI are pain and loss of sensory +or motor function. +Atrial fibrillation is the most common +source. +Mural thrombi can also develop within a ventricle dilated by +cardiomyopathy. +Diseased valves are another source of distal +embolization. +Historically, this occurred as a result of rheumatic  +heart disease. +Currently, subacute endocarditis and acute bacte- +rial endocarditis are the more common causes. +Infected emboli +can seed the recipient vessel wall, creating mycotic aneurysms. +Type A lesions +Type B lesions +Type C lesions +Type D lesions +Figure 23-61. +The presence of mobile +plaque on transesophageal echocardiography is suggestive of +this source. +Arterial Thrombosis. +Thrombosis can occur in native arteries +and in arterial reconstructions. +The most common location for an embolus to +lodge in the leg is at the common femoral bifurcation. +Typically +a patient will complain of foot and calf pain. +Pulses are absent, +and there may be diminution of sensation. +This will prevent propagation of the clot into unaf- +fected vascular beds. +Intravenous fluid should be started and a +Foley catheter inserted to monitor urine output. +Baseline labs +should be obtained and creatinine levels noted. +Skeletal +muscle tissue appears to be most vulnerable to ischemia. +The more +severe the cellular damage, the greater are the microvascu- +lar changes. +The groin +is opened through a vertical incision, exposing the CFA and +its bifurcation. +The +artery is clamped and opened transversely over the bifurcation. +Good back-bleeding and antegrade bleeding +suggest that the entire clot has been removed. +Completion angiography is advisable to +ascertain the adequacy of clot removal. +The artery is then closed +and the patient fully anticoagulated. +Use of fluoroscopic imaging and an over-the-wire +thrombectomy catheter can overcome this problem. +Bypass Graft Thrombectomy. +Bypass thrombectomy is more +likely to succeed with prosthetic bypasses. +Gastrointestinal bleeding is reported in 5% +to 10% of cases. +Hematuria following thrombolysis is uncom- +mon and should prompt a search for urinary tumors. +The most feared complication that patients can sustain is +intracerebral hemorrhage. +Compartment syndrome occurs after prolonged ischemia +is followed by reperfusion. +23-62). +The most commonly affected compartment is the ante- +rior compartment in the leg. +Although controversial, pressures greater than 20 +mmHg are an indication for fasciotomy. +Compartment pressures  +are relieved in the leg by medial and lateral incisions. +Through +the lateral incision, the anterior and peroneal compartments are +opened. +Laboratory +evidence of rhabdomyolysis is seen in 20% of cases. +Schematic illustration of fascial compartments of +the lower extremity. +ulceration or gangrene (Table 23-24). +23-63). +Stenoses, which develop here, progress to occlusion of the dis- +tal third of the SFA (Fig. +23-64). +Pain +from isolated SFA and popliteal occlusion typically manifests as +calf claudication. +Activities such as climbing stairs or going uphill also exacerbate +the pain. +It is important to evaluate whether the symptoms are +progressive or static. +bGrades II and III, categories 4, 5, and 6, are encompassed by the term chronic critical ischemia. +AP = ankle pressure; PVR = pulse volume recording; TM = transmetatarsal; TP = toe pressure. +Patients may report +that they either sleep in a chair or hang the foot off the side of +the bed. +The pain is severe and relentless, even with narcot- +ics. +Ischemic ulceration most commonly involves the toes. +Any +toe can be affected. +Occasionally ulcers develop on the dor- +sum of the foot. +The +initial development of gangrene commonly involves the digits. +Endovas- +cular intervention provides an attractive alternative. +Proper selection of patients and techniques is critical in +achieving good long-term outcome. +BA +Figure 23-63. +A. +The foot +may be warm to touch, and pulses may be present in the distal pedal arteries. +B. +An ischemic ulcer is characterized by a gangrenous skin +change in the foot or toes. +The foot is usually cold to touch with absent pedal pulses. +The foot is painful to touch with decreased distal capil- +lary refills. +Figure 23-64. +Endovascular intervention for lower extremity occlusive +disease is continuously evolving. +Endovascular Treatment +Technical Considerations. +The most common and safest access site is CFA +via either a retrograde or an antegrade approach. +For diagnos- +tic angiography, arterial access should be contralateral to the +symptomatic sides. +The antegrade approach may be challenging, particularly in +obese patients. +Traversing the lesion with a wire is the most critical part +of the procedure. +After the procedure, all patients +are placed on antiplatelet therapy, such as aspirin. +Percutaneous Transluminal Balloon Angioplasty. +The balloon tends to be approximately +10% to 20% oversized. +The radiopaque markers of the balloon +catheter are placed so that they will straddle the lesion. +23-65). +The patient may experience mild pain, which is +not uncommon. +However, severe pain can be indicative of ves- +sel rupture, dissection, or other complications. +Frequently, several inflations +are required to achieve a full profile of the balloon (Fig. +23-66). +Low- +compliant balloons are the mainstay for peripheral intervention. +Furthermore, trackability, pushability, and +Figure 23-65. +A. +Angiogram demonstrating a focal stenosis in the superficial femoral artery (arrow). +B. +C. +Completion angiogram demonstrating satisfactory +radiographic result. +Figure 23-66. +A. +B. +C. +Completion angiogram demonstrated satisfactory result with no evidence of vessel dissection. +crossability of the balloon should be considered when choosing +a particular type of balloon. +After PTA, a completion angiogram +is performed while the wire is still in place. +Subintimal Angioplasty. +The occluded lumen is recanalized through the subintimal plan. +When the wire is advanced, a loop is naturally +formed at the tip of the guidewire. +Once the subintimal plan is +entered, the wire tends to move freely in dissection space. +This is followed by a balloon +angioplasty. +If flow is impaired, repeat balloon +dilatation may be necessary. +Multiple studies have demonstrated the efficacy of subin- +timal angioplasty. +Limb salvage +rates reached over 80% at 12 months. +Stent Placement. +There are sev- +eral situations where stent placement is appealing. +The primary +indication is the potential salvage of an unacceptable angio- +plasty result. +Stent placement is typically used when residual +stenosis after PTA is 30% or greater. +An endoluminal stent is +also used for dissection, perforation, and other PTA complica- +tions. +In addition, an endoluminal stent is potentially +beneficial for early restenosis after PTA. +Additionally, stent +characteristics may contribute to the patency rate. +The average +length treated was 60 mm. +Only 12% of patients who +died had a preceding major amputation. +Target limb revascularization occurred in 15% +of patients. +Stent Graft. +Stent grafts can be divided into two categories: +unsupported and fully supported. +The unsupported grafts are flexible +with a low profile, but prone to external compression. +The sup- +ported stent grafts consist of a metallic skeleton covered with +graft fabric. +There is no FDA-approved stent graft for peripheral +intervention. +Fifty limbs were randomized into each group. +Atherectomy. +The basic principle of atherectomy is to remove +the atheroma from obstructed arterial vessels. +Paul, MN), and +Rotablator system (Boston Scientific Corporation, Natick, MA). +These devices either cut and remove or pulverize the atheroma +plaques. +The atheroma protruding into the window is +excised and pushed into the collection chamber. +The rotating +cam tip pulverizes the atheromatous lesion into minute particles. +The work- +ing end consists of a hinged housing unit containing a carbide +cutting blade. +The Rotablator system high-speed rotational +device uses calcium ablation to achieve larger lumens. +It has +been used for more than 20 years to treat challenging, calcified +coronary artery disease. +The diamond-coated burr is designed +to preferentially engage calcium and modify lesion compliance. +Laser Atherectomy. +This lumen is further dilated by an angioplasty balloon. +Patency rates were 59% and 54% at 6 and 12 months, +respectively. +Complications of Endovascular Interventions +Angioplasty-Related Complications. +The adductor canal has nonlami- +nar flow dynamics, especially with walking. +The forces exerted +on the SFA include torsion, compression, extension, and flex- +ion. +These forces exert significant stress on the SFA and stents. +23-67). +Surgical Treatment for Chronic Limb Ischemia +due to Femoropopliteal Disease +Endarterectomy. +Endarterectomy has a limited, albeit impor- +tant role in lower extremity occlusive disease. +It is most fre- +quently used when there is disease in the CFA or involving the +PFA. +This permits the inner +layer containing the atheroma to be excised. +The +high incidence of restenosis is what limits utility of endarterec- +tomy in this location. +Short-segment stenoses are more appro- +priately treated with balloon angioplasty. +Bypass Grafting. +Bypass grafting remains the primary interven- +tion for lower extremity occlusive disease. +The type of bypass and +the type of conduit are important variables to consider. +Patients +with occlusive disease limited to the SFA, who have at least 4 cm +Figure 23-67. +In patients +with diabetes, it is frequently the peroneal artery that is spared. +Five-year +assisted patency rate for infrapopliteal venous bypasses is 60%. +Venous conduits have also been shown to be suitable for bypasses +to plantar arteries. +End- +to-side anastomoses are then created. +Amputation. +It is rarely necessary in patients who, as +a result of neglect, present with class III ALI. +Complications of Surgical Reconstruction +Vein Graft Stenoses. +Secondary patency is mark- +edly inferior to primary assisted patency. +Limb swelling tends to worsen with repeat revascularization +(see Table 23-22). +Wound Infection. +When +a prosthetic graft has been used, management of graft infection +is a major undertaking. +Choice of Conduit for Infrainguinal +Bypass Grafting +Autogenous Vein. +This preference is applicable not only +for the initial bypass but also for reoperative cases. +The small saphenous vein is of +particular utility when a posterior approach is used. +Cryopreserved vein grafts are more expensive +than prosthetic grafts and are more prone to failure. +Cryopreserved grafts are also +prone to aneurysmal degeneration. +If a +vein is truly unavailable, PTFE or Dacron is the best option for +above-knee bypass. +29% for PTFE with no cuff) and also improve limb salvage +(84% vs. +Distal runoff is +another powerful predictor of long-term success. +Additionally, +stent characteristics may contribute to the patency rate. +Patients were treated with Cordis SMART +self-expanding nitinol stents. +The mean lesion length was +12.2 cm (range, 4–28 cm). +The technical success was 98%. +Mean +follow-up was 302 days. +Mean recanalization +length was 19 cm (range, 3–53 cm). +Mean follow-up time was +2.4 years (range, 3 days–4.8 years). +The his- +tologic and pathologic changes and laboratory findings are simi- +lar. +Cerebral symptoms occur when the disease process +extends to the carotid arteries. +Jaw claudication and temporal +artery tenderness may be experienced. +Symptoms are related to end-organ ischemia. +The acute inflammation can destroy the arterial media and lead +to aneurysm formation. +However, these associa- +tions have not been seen in North America. +The pathologic changes pro- +duce stenosis, dilation, aneurysm formation, and/or occlusion. +These include fever, anorexia, weight +loss, general malaise, arthralgias, and malnutrition. +Repair is problematic because the +vessel wall is soft and sutures pull through the fragile tissue. +Ligation may be the only option in many circumstances. +Ocular manifestations are flattened corneas, +lens subluxation, and myopia. +Skin, central nervous system, and +pulmonary features may be present as well. +Aortic root dilata- +tion will generally occur in all patients. +An +infectious agent may be causative; however, no specific agent +has been identified. +A classification system of systemic vasculitis by +vessel size is shown in Table 23-28. +An HLA linkage has been  +found, indicating a genetic component to the etiology. +This disease +predominantly affects men over women by a 2:1 ratio. +PAN +develops subacutely, with constitutional symptoms that last +for weeks to months. +Intermittent, low-grade fevers, malaise, +weight loss, and myalgias are common presenting symptoms. +Patients may succumb to renal failure, +intestinal hemorrhage, or perforation. +The mainstay of treatment +is steroid and cytotoxic agent therapy. +Radiation-induced damage to blood vessels has been well +studied. +The digital vessels then +relax, eventually leading to reactive hyperemia. +The majority +of patients are young women less than 40 years of age. +Different changes +in digital blood pressure will occur in patients with Raynaud’s +syndrome. +The majority (90%) of patients will +respond to avoidance of cold and other stimuli. +Calcium channel–blocking agents +such as diltiazem and nifedipine are the drugs of choice. +FMD occurs most frequently in women +(90%) and is recognized at approximately 55 years of age. +Clinically, symptoms are due to encroachment on the ves- +sel lumen and a reduction in flow. +Surgical treatment has been favored +for symptomatic patients with angiographically proven disease. +PTA has been used effectively in +patients with FMD-induced hypertension. +Adventitial Cystic Disease of the Popliteal Artery. +Noninvasive studies may suggest arterial stenosis with ele- +vated velocities. +Various therapeutic methods have been described for the +treatment of adventitial cystic disease. +Popliteal Artery Entrapment Syndrome. +Concomitant popliteal vein impinge- +ment occurs in up to 30% of cases. +Twenty-five percent of cases +are bilateral. +Although +CT and MRI have been employed, angiography remains the +most widely used test. +Lysis will improve distal runoff and may improve +limb-salvage and bypass patency rates. +End-stage lesions demonstrate organized thrombus and +blood vessel fibrosis. +Even if symptoms are not yet +present in a limb, angiographic findings may be demonstrated. +35%). +REFERENCES +Entries highlighted in 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D. +The Ehlers-Danlos +specter revisited. +Vasc Endovasc Surg. +2002;36:213-217. +240. +Ho  NC,  Tran  JR,  Bektas  A. +Marfan’s  syndrome. +Lancet. +2005;366:1978-1981. +241. +Davies JE, Sundt TM. +Surgery insight: the dilated ascending +aorta—indications for surgical intervention. +Nat Clin Pract +Cardiovasc Med. +2007;4:330-339. +242. +Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A. +J Med Genet. +2005;42:881-892. +243. +Yeung RS. +Pathogenesis and treatment of Kawasaki’s disease. +Curr Opin Rheumatol. +2005;17:617-623. +244. +Krause I, Weinberger A. +Behcet’s disease. +Curr Opin Rheu- +matol. +2008;20:82-87. +245. +Pettigrew HD, Teuber SS, Gershwin ME. +Polyarteritis nodosa. +Compr Ther. +2007;33:144-149. +246. +Herrick AL. +Pathogenesis of Raynaud’s phenomenon. +Rheu- +matology (Oxford). +2005;44:587-596. +247. +Stoyneva Z, Lyapina M, Tzvetkov D, Vodenicharov E. +Cur- +rent pathophysiological views on vibration-induced Rayn- +aud’s phenomenon. +Cardiovasc Res. +2003;57:615-624. +913 +Arterial Disease +CHAPTER 23 +248. +Das CJ, Neyaz Z, Thapa P, Sharma S, Vashist S. +Fibromus- +cular dysplasia of the renal arteries: a radiological review. +Int +Urol Nephrol. +2007;39:233-238. +249. +Gray BH. +Intervention for renal artery stenosis: endovascular  +and surgical roles. +J Hypertens Suppl. +2005;23:S23-S29. +250. +Pannone A, Di Cesare F, Bartolucci R, Maritati G, Luc- +chetti G, Rabitti G. +Cystic adventitial disease of the popliteal +artery. +A case report and review of the literature. +Chir Ital. +2008;60:153-158. +251. +di Marzo L, Cavallaro A. +Popliteal vascular entrapment. +World J +Surg. +2005;29(Suppl 1):S43-S45. +252. +Paraskevas KI, Liapis CD, Briana DD, Mikhailidis DP. +Thromboangiitis obliterans (Buerger’s disease): searching for +a therapeutic strategy. +Angiology. +2007;58:75-84. +This page intentionally left blank +Venous and Lymphatic Disease +Jason P. +Jundt, Timothy K. +Liem, +and Gregory L. +Alterations in the intricate balance of these +factors can result in venous pathology. +Structure of Veins +Veins are thin-walled, highly distensible, and collapsible. +In the axial veins, unidirectional blood flow is achieved +with multiple venous valves. +In the axial veins, valves are more numerous +distally in the extremities than proximally. +The deep veins follow the course of major arteries in the +extremities. +Venous bridges +connect the paired veins in the lower leg. +The popliteal vein +continues through the adductor hiatus to become the femoral +vein. +Potentially +clinically important perforator veins are the Cockett and Boyd +perforators. +They connect the poste- +rior arch vein (a tributary to the GSV) and the posterior tibial +vein. +They may become varicose or incompetent in venous +insufficiency states. +These +sinuses are valveless and are linked by valved, small venous +channels that prevent reflux. +A large amount of blood can be +stored in the venous sinuses. +Deep veins of the upper extremity are +paired and follow the named arteries in the arm. +It then joins with the deep brachial +veins to become the axillary vein. +The axillary vein becomes the subclavian vein at the lat- +eral border of the first rib. +The risk is further increased in patients with +malignancy and a history of venous thromboembolism. +However, prophylaxis should be stratified based on the +patient's level of risk. +5 The mainstay of treatment for chronic venous insufficiency +is compression therapy. +6 Lymphedema is categorized as primary (with early or +delayed onset) or secondary. +The goals of treatment are to +minimize edema and prevent infection. +Risk factors for acute and chronic +venous disease are identified. +24-1). +The superficial veins of a +Figure 24-1. +Varicose vein demonstrating evidence of chronic +venous insufficiency. +Possible signs of superficial venous abnormal- +ities are listed in Table 24-1. +CVI results from incompetence of venous valves, venous +obstruction, or both. +The leg may also be indurated and pigmented with eczema +and dermatitis. +24-2). +24-3). +There +are two components to this test. +Characteristic hyperpigmentation of chronic venous +insufficiency. +Figure 24-3. +Venous ulceration located proximal to the medial +malleolus. +Identifiable risk factors for VTE generally +relate to one of the conditions described by Virchow. +Often +more than one risk factor is present. +Specific risk factors for +VTE are listed in Table 24-2. +Heritable risk factors include male sex, factor V Leiden +and deep veins. +The GSV valves are incompetent if the second +component of the test yields a positive result. +Noninvasive Evaluation. +Invasive Evaluation. +Complications of venography include pain, thrombosis, +or hematoma at the puncture site. +External compression of major veins +by masses of various types can also lead to venous thrombosis. +Many cases of VTE are potentially preventable. +Diagnosis +Clinical Evaluation. +Isolated +proximal DVT without tibial vein thrombosis is unusual. +Early +in the course of a DVT, there may be no or few clinical findings +such as pain or swelling. +Even extensive DVT may sometimes +be present without signs or symptoms. +History and physical +examination are therefore unreliable in the diagnosis of DVT. +Clinical symptoms may worsen as DVT propagates and +involves the major proximal deep veins. +24-4). +This condition is char- +acterized by pain and pitting edema with associated cyanosis. +Source: Summary of recommendations from Gould MK, Garcia DA, Wren SM, et al. +Chest. +2012;141:227S. +Reproduced with permission from the American College of Chest Physicians. +Normally, in transverse section, +the vein walls should coapt with pressure. +Lack of coaptation +indicates thrombus. +Calf vein thrombi are often best detected +by abnormalities in color flow imaging. +The examination begins at the ankle and continues +proximally to the groin. +Each vein is visualized, and the +flow signal is assessed with distal and proximal compres- +sion. +24-6), inability to compress the vein (Fig. +Again, lack of +venous compression on B-mode imaging is the primary diag- +nostic variable. +In the supine patient, normal lower extremity venous flow +is phasic (Fig. +Figure 24-4. +Phlegmasia cerulea dolens of the left leg. +Note the +bluish discoloration. +Figure 24-5. +Duplex ultrasound scan of a normal femoral vein +with phasic flow signals. +Figure 24-6. +No compressionC ompression +R FVP R FVP +Figure 24-7. +B-mode ultrasound of the femoral vein in cross-section. +The femoral vein does not collapse with external compression +(arrows). +It is still, however, frequently used in research +studies evaluating DVT prophylaxis. +Antithrombotic Therapy. +A minimum of 5 days of heparin or fondaparinux therapy is rec- +ommended.27 Recently, the U.S. +Unfractionated heparin (UFH) binds to antithrombin via +a specific 18-saccharide sequence. +This increases antithrombin +activity over 1000-fold. +UFH therapy is most commonly administered with an ini- +tial IV bolus of 80 units/kg. +The +half-life of IV UFH ranges from 45 to 90 minutes and is dose +dependent. +This should correspond with plasma heparin anti-Xa +activity levels of 0.3 to 0.7 IU/mL. +An increase of 20% or more in one area +of a limb indicates an area of thrombus. +Venography Venography is the gold standard to which other +diagnostic modalities are compared. +A small catheter is placed +in a dorsal foot vein with injection of a radiopaque contrast +agent. +Radiographs are obtained in at least two projections. +24-8). +A normal +1 +Figure 24-8. +Venogram showing a filling defect in the popliteal +vein (arrows). +Protamine sulfate binds to +UFH and forms an inactive salt compound. +Side effects of protamine sulfate include hypotension, pul- +monary edema, and anaphylaxis. +Protamine adminis- +tration should be terminated if any side effects occur. +In addition to hemorrhage, heparin also has unique com- +plications. +Low molecular weight heparins (LMWHs) are derived +from the depolymerization of porcine UFH. +However, LMWHs have fewer additional saccharide +units. +This results in less inactivation of thrombin (factor IIa). +Moni- +toring may be performed using anti-Xa activity assays. +The ther- +apeutic anti-Xa goal range depends on the type of LMWH and +the frequency of dosing. +Treatment dosing for one LMWH therefore +cannot be extrapolated for use with another. +6.9% for LMWH) or major bleeding complications (2.0% for +UFH vs. +0.5% for LMWH). +There was, however, a 67% reduc- +tion in mean days in the hospital for the LMWH group. +The half-life of fondaparinux is approximately +17 hours in patients with normal renal function. +These +actions are independent of antithrombin. +Commercially available hirudin is manufactured using +recombinant DNA technology. +It is indicated for the prophy- +laxis and treatment of patients with HIT. +The half-life ranges from 30 to +60 minutes. +The less commonly used ecarin clotting time is an alter- +native method of monitoring. +Argatroban is indicated for the prophylaxis and treatment +of thrombosis in HIT. +In these patients, therapy is monitored +using the activated clotting time. +There is no reversal agent +for argatroban. +Factors X and II have the longest half-lives, in the +range of 36 and 72 hours, respectively. +A steady-state concen- +tration of warfarin is usually not reached for 4 to 5 days. +Current ACCP recommendations +for duration of warfarin therapy are summarized in Table 24-4. +Source: Summary of recommendations from Kearon C, Akl EA, Com- +erota AJ, et al. +Chest. +2012;141:e495S. +Reproduced with permission from the American +College of Chest Physicians. +warfarin (0.7 events per 100 person-years vs. +secondary) than by the actual presence +or absence of the more common thrombophilic conditions. +Fevers and shivering occur in 1% to 4% +of patients. +Urokinase is derived from human neonatal kidney cells +grown in tissue culture. +However, it often is used for CDT +of DVT. +Reteplase and tenecteplase are indicated only for the +treatment of acute myocardial infarction. +However, +venous function was not significantly improved. +In addition, +more bleeding complications occurred (RR 1.73). +At 6 months, iliac +vein patency was significantly improved in the thrombolysis +group (65.9% vs. +47.4%). +Early filters +were placed surgically through the femoral vein. +When possible, therapy should be continued in patients +with vena cava filters. +IVC filters are associated with acute and late complica- +tions. +24-9). +Such patients can be treated with so-called removable +IVC filters. +Operative Venous Thrombectomy. +More +than 90% of patients had minimal or no symptoms of PTS. +There were 12 (16%) early thrombectomy failures. +Emergency pulmonary embolectomy for +acute PE is rarely indicated. +Patients with preterminal massive +PE (Fig. +Mechanical clot frag- +mentation is followed by CDT. +Results of catheter-based +fragmentation are based on small case series. +The first manifestation of VTE may be a +life-threatening PE (Fig. +24-11), and as indicated earlier, clinical +evaluation to detect DVT before PE is unreliable. +The distal thrombus in the +leg is removed by manual pressure beginning in the foot. +If the thrombus +in the femoral vein is old and cannot be extracted, the vein may +be ligated. +The IVC is opened and the thrombus is removed by gentle mas- +sage. +An intraoperative completion venogram determines if any +residual thrombus or stenosis is present. +Heparin is administered postoperatively for several days. +Warfarin anticoagulation is maintained for at least 6 months +after thrombectomy. +In limbs with success- +ful thrombectomy, valvular competence in the thrombectomized +Figure 24-9. +A +B +Figure 24-10. +Autopsy specimen showing a massive pulmonary +embolism. +Venous Thromboembolism Prophylaxis in Nonorthopedic +Surgery. +A composite score is created using +assigned values for each risk factor. +The risks +for bleeding differ, depending on the dosage. +Lower dosages +of LMWH appear to be associated with less bleeding risk than +Figure 24-11. +Source: Adapted with permission from Rogers SO Jr, Kilaru RK, +Hosokawa P, et al. +J Am Coll Surg. +2007;204:1211. +Copyright © American College of Surgeons. +A validation study of retrospective ve- +nous thromboembolism risk scoring method. +Ann Surg. +2010;251:344. +Copyright Wolters Kluwer Health. +0.2%). +DVT occurred at the insertion site in 3.1% of the +patients. +IVC patency was 97.1% at 3 years. +Fatal and nonfatal PE can still occur in patients with vena +cava interruption. +Careful follow-up is required +to assure all potentially removable filters are in fact removed. +Upper extremity vein +928 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +of all patients with ASVT. +24-13). +A guide- +wire is traversed through the thrombus, and a catheter is placed +within the thrombus. +Various catheter-based mechanical techniques may also be +employed to speed thrombus removal. +Heparin is administered +concurrently with the thrombolytic infusion. +Patients with suppurative SVT may have +fever and leukocytosis. +Topical medications appear to improve local symptoms. +Primary ASVT occurs in only a small minority +Figure 24-12. +Figure 24-13. +Upper extremity venogram showing stenosis of the +right subclavian vein (arrow). +Correctable anatomic abnormalities may then be considered for +treatment. +MVT is more common in patients with a +hypercoagulable states, malignancy, and cirrhosis. +Patients with MVT are treated with fluid resuscitation, +heparin anticoagulation, and bowel rest. +Once the patient’s + clinical status improves, oral intake can be carefully started. +Broad-spectrum antibiotics are admin- +istered perioperatively. +Operative findings consist of edema +and cyanotic discoloration of the mesentery and bowel wall. +In +more advanced cases, thrombus involves the distal mesenteric +veins. +The arterial supply to the involved bowel is usually intact. +Nonviable bowel is resected, and primary anastomosis can be +performed. +A mild amount of edema is often present. +Elastic compres- +sion provides sufficient relief of symptoms in many symptom- +atic patients. +Cosmetic concerns may lead to intervention. +Sclerotherapy acts by +destroying the venous endothelium. +Sclerosing agents include +hypertonic saline, sodium tetradecyl sulfate, and polidocanol. +The GSV is removed using a blunt tip catheter or an +invagination pin stripper. +Larger varicose veins are best treated by surgical excision +using the “stab avulsion” technique. +24-14). +In most cases the vein +is simply avulsed with no attempt at ligation. +Importantly, severe CVI is not necessarily associ- +ated with varicose veins. +Venous reflux results from abnormalities of the venous valve. +Secondary valvular reflux is diagnosed when an identifiable +cause is present. +The most frequent secondary cause is DVT. +The patient is asked to perform 10 tiptoe exercises. +The pressure at this point +Figure 24-14. +Removal of varicose veins via stab avulsions. +is the AVP, which is measured in millimeters of mercury. +Elevations of AVP +indicate venous hypertension. +The magnitude of AVP reflects +the severity of CVI. +Noninvasive plethysmography has been +used to evaluate CVI. +Pho- +toplethysmography provides a measurement of VRT. +In limbs +with CVI, VRT is shortened compared with that in a normal +limb. +AVP and VRT are only measures of the overall venous +function of a lower extremity venous system. +They cannot local- +ize the site of reflux or evaluate the function of the calf pump. +The patient is +then asked to assume an upright position with the examined leg +non-weight bearing. +The venous volume of the examined leg +is determined when the volume curve flattens. +Next, the patient performs a single +tiptoe maneuver, and the ejection fraction (EF) is determined. +At this point, the veins of the leg are allowed to +refill. +The residual volume fraction is +a reflection of overall venous function. +Venous Duplex Ultrasound. +Pneumatic pressure cuffs +of appropriate size are placed around the thigh, calf, and fore- +foot. +24-15). +The cuff is then inflated to a standard pressure for +3 seconds and then rapidly deflated. +Compression therapy is the mainstay +of CVI management. +24-16), and pneumatic compression devices. +The exact mechanism by which compression +therapy can improve CVI remains uncertain. +Increases in subcutaneous tissue +Figure 24-15. +Evaluation of a patient with chronic venous insuf- +ficiency with duplex ultrasonography. +Figure 24-16. +Multilayered dressing for treatment of chronic +venous insufficiency. +A definitive diagnosis of venous ulceration must be made before +treatment is initiated. +Arterial insufficiency +is assessed by physical examination or noninvasive studies. +Compression therapy is most commonly achieved with +graduated elastic compression stockings. +6 of 11 patients (55%) who were noncompliant +(P < .0001). +The mean time to ulcer healing was 5 months. +Patients +were treated with 30- to 40-mmHg elastic compression stock- +ings. +Further improve- +ments were noted at 16 months after treatment. +They may also have difficulty applying elastic stockings. +24-17), and metal fitting aids (Fig. +24-18), are available to +assist patients in applying elastic stockings. +Another method of compression was developed by the +German dermatologist Paul Gerson Unna. +Unna’s boot has +5 +932 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Figure 24-17. +Elastic compression device with Velcro to facilitate +treatment of chronic venous insufficiency. +Figure 24-18. +Metal fitting aid to assist in placement of elastic +compression stockings. +been used for many years to treat venous ulcers and is available +in many versions. +The bandage +becomes stiff after drying, and the rigidity may aid in prevent- +ing edema formation. +However, Unna’s boot has several disadvantages. +It +is bulky and can be uncomfortable, which may affect patient +compliance. +Occasionally, +patients may also develop contact dermatitis to the components +of Unna’s boot. +The efficacy of Unna’s dressing has been studied. +The median time to healing for +individual ulcers was 9 weeks. +Unna’s dressing has been com- +pared to other forms of treatment. +It +must be used within 5 days of release from the manufacturer111 +(Fig. +24-19). +The disk is easily handled and applied and con- +forms to irregularly contoured ulcer beds. +49%, P = .02). +181 days, P = .003). +No evidence of rejection or sensitization has +been reported in response to Apligraf application. +Surgical/Interventional Treatment of Chronic +Venous Insufficiency +Perforator Vein Ligation. +The patient is posi- +tioned on the operating table with the affected leg elevated at +45° to 60°. +An Esmarch bandage and a thigh tourniquet are used +to exsanguinate the limb. +Carbon dioxide is +then used to insufflate the subfascial space. +The thigh tourni- +quet is inflated to prevent air embolism. +The perforators are then +identified and doubly clipped and divided. +After completion of +Figure 24-19. +Apligraf skin graft material supplied as a disk on an +agarose gel nutrient medium. +the procedure, the leg is wrapped in a compression bandage for +5 days postoperatively. +In +a report from a large North American registry of 146 patients +undergoing SEPS113 (Fig. +24-20), healing was achieved in 88% +of ulcers (75 of 85) at 1 year. +Adjunctive procedures, primarily +superficial vein stripping, were performed in 72% of patients. +Ulcer recurrence was predicted to be 16% at 1 year and 28% at +2 years by life table analysis. +These results are similar to those +achieved in some studies with compression therapy alone. +Superficial Venous Surgery. +compression alone +in the treatment of venous ulcer. +Trocar placement for subfascial endoscopic perfo- +rator vein surgery. +(Used with permission of Dr. +The outcomes for venous +transposition are similar to those for valve transplantation. +Venous Stenting. +Currently there is great interest in the role +of venous stents in the treatment of CVI. +The original classification system, described by Allen, +is based on the cause of the lymphedema. +Lymphedema praecox is the most +common form of primary lymphedema, accounting for 94% of +cases. +Lymphedema praecox is far more common in women, +with the gender ratio favoring women 10:1. +The onset is during +childhood or the teenage years, and the swelling involves the +foot and calf. +Lymphedema tarda is uncommon, accounting for +<10% of cases of primary lymphedema. +The onset of edema is +after 35 years of age. +Secondary lymphedema is far more common than primary +lymphedema. +Secondary lymphedema develops as a result of +lymphatic obstruction or disruption. +Patients +commonly complain of heaviness and fatigue in the affected +extremity. +The limb, however, never completely nor- +malizes. +24-21). +Recurrent cellulitis is a common complication of lymph- +edema. +Repeated infection results in further lymphatic damage, +worsening existing disease. +Many medical conditions can cause edema. +Venous insufficiency is often confused +with lymphedema. +Bilateral pitting edema is +Figure 24-21. +Patient with severe longstanding lymphedema. +Radiologic Diagnosis +Duplex Ultrasound. +They are invasive and tedious and rarely +change the management of a patient with lymphedema. +Lymphoscintigraphy. +It has largely replaced lymphangiography. +24-22). +Within +3 hours, uptake should be present in the pelvic and abdominal +lymph nodes. +In patients with lymphedema, various patterns +may be seen on lymphoscintigraphy. +There may be delayed +or absent transport to the inguinal nodes. +Increased cutaneous +Figure 24-22. +Lymphoscintigraphy of the lower extremity. +collaterals may be seen with obstruction of the primary axial +channels. +Lymphangiography. +An oil-based dye is then injected slowly into the +lymphatics over several hours. +The lymphatic channels and nodes +are then visualized with traditional radiographs (Figs. +24-23 and +24-24). +The primary goals of treatment are to minimize swelling and +to prevent recurrent infections. +Graded compression stockings +are widely used in the treatment of lymphedema. +Normal lymphangiogram of the pelvis. +936 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +among patients. +The +stockings should be worn during waking hours. +The garments +should be replaced approximately every 6 months when they +lose elasticity. +Bedrest and Leg Elevation. +Elevation is an adjunct to lymphedema ther- +apy but is not the mainstay of treatment. +Intermittent Pneumatic Compression Therapy. +Staphylococcus and β-hemolytic +Figure 24-24. +Normal lymphangiogram of the thigh and lower leg. +Streptococcus are the most common organisms causing soft tis- +sue infection. +The drug of choice is penicillin or a cephalosporin +active against Streptococcus for 5 days. +A variety of surgical procedures have been devised +for the treatment of lymphedema. +This does not +improve lymphatic drainage but debulks redundant tissue. +Controlling the edema protects the skin and potentially +prevents cellulitis. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Moncada S, Radomski MW, Palmer RM. +Endothelium- +derived relaxing factor. +Identification as nitric oxide and role +in the control of vascular tone and platelet function. +Biochem +Pharmacol. +1988;37:2495. +2. +van Bemmelen PS, Beach K, Bedford G, et al. +The mecha- +nism of venous valve closure. +Its relationship to the velocity +of reverse flow. +Arch Surg. +1990;125:617. +3. +Moneta GL, Strandness DE Jr. +Basic data concerning nonin- +vasive vascular testing. +Ann Vasc Surg. +1989;3:190. +4. +Bettman MA, Robbins A, Braun SD, et al. +Radiology. +1987;165:113. +5. +White R. +The epidemiology of 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+eter at this point is 1.6 cm. +Laparoscopic hiatal hernia +repair with fundoplication is the most common approach to +repair. +5 Achalasia is the most common primary esophageal motor +disorder. +It +is best treated with laparoscopic Heller myotomy and par- +tial fundoplication. +a +b +c +d +e +A +B +sphincter mechanism. +Manometrically, the length of the esophagus between +Figure 25-1. +A. +B. +Lat- +eral radio-graphic appearance with +landmarks identified as labeled in +A. +The location of C6 is also included +(f). +25-4). +The opening of +the esophagus is collared by the cricopharyngeal muscle, which +A +B +Figure 25-2. +Barium esophagogram. +A. +Posterior-anterior view. +White arrow shows deviation to left. +Black arrow shows return to midline. +B. +Lateral view. +Black arrow shows anterior deviation. +Important clinical endoscopic measurements of the +esophagus in adults. +Philadelphia: Lea & +Febiger, 1989, p 78.) + Superior pharyngeal +constrictor m. +Middle pharyngeal + constrictor m. +Inferior pharyngeal + constrictor m. +Cricopharyngeus m. +Esophagus +BA +Figure 25-4. +External muscles of the pharynx. +A. +Posterolateral +view. +B. +Posterior view. +Dotted line represents usual site of myot- +omy. +Keith +in 1910 showed that these two parts of the same muscle serve +totally different functions. +The thoracic portion of the esophagus is approximately +20 cm long. +It starts at the thoracic inlet. +Just above the tracheal +bifurcation, the esophagus passes to the right of the aorta. +25-5). +25-6). +25-7). +This portion of the +esophagus is subjected to the positive-pressure environment of +the abdomen. +The upper 2 to 6 cm +of the esophagus contains only striated muscle fibers. +From +then on, smooth muscle fibers gradually become more abun- +dant. +When a surgical esophageal myotomy is indicated, +the incision needs to extend only this distance. +25-4). +Figure 25-5. +A. +Cross-section of the thorax at the level of the tracheal bifurcation. +B. +Contraction of +the longitudinal muscle fibers shortens the esophagus. +The cir- +cular muscle layer of the esophagus is thicker than the outer +longitudinal layer. +Two esophageal branches arise directly from the aorta. +A. +Cross-section of the thorax at the midleft atrial level. +B. +Attachments and structure of the phrenoesophageal +membrane. +Transversalis fascia lies just above the parietal perito- +neum. +25-8). +Arterial blood supply of the esophagus. +25-9). +25-10). +Venous drainage of the esophagus. +Innervation of the esophagus. +Philadelphia: Lea & Febiger, 1989, p 85.) +pathways. +25-11). +Lymphatic drainage of the esophagus. +Curr Probl Surg 25:498, 1988. +The three +valves in the pharyngeal cylinder are the soft palate, epiglottis, +and cricopharyngeus. +The valve of the esophageal pump is the +LES. +Once +initiated, swallowing is entirely a reflex act. +25-12). +25-12). +The backward tilt +of the epiglottis covers the opening of the larynx to prevent aspi- +ration. +The entire pharyngeal part of swallowing occurs within +1.5 seconds. +1. +Elevation of tongue +2. +Posterior movement of tongue +3. +Elevation of soft palate +4. +Elevation of hyoid +5. +Elevation of larynx +6. +Tilting of epiglottis +1 +2 +3 +4 +5 6 +Figure 25-12. +Sequence of events during the oropharyngeal phase +of swallowing. +I. +Philadelphia: W.B. +Saunders, 1991, p 95. +25-13). +Med Clin +North Am 65:1237, 1981. +The +postrelaxation contraction continues down the esophagus as a +peristaltic wave (Fig. +25-14). +Intraluminal esophageal pressures in response +to swallowing. +Med Clin North Am 65:1238, 1981. +In +more severe injury, swallowing can be grossly disrupted, lead- +ing to repetitive aspiration. +The pharyngeal activity in swallowing initiates the +esophageal phase. +25-13). +The peristaltic wave generates an occlusive pressure vary- +ing from 30 to 120 mmHg (see Fig. +25-14). +This allows a sleeve resection of the esophagus to be done +without destroying its normal function. +This secondary contraction occurs +without any movements of the mouth or pharynx. +Current studies suggest that secondary peri- +stalsis is not as common as once thought. +25-15). +25-14). +Wall thickness and orientation of fibers on micro- +dissection of the cardia. +Consequently, there are fewer opportunities for reflux to +occur in the supine position. +This gradient favors the flow of gastric +juice up into the thoracic esophagus when upright. +The gradi- +ent diminishes in the supine position. +The LES has intrinsic myogenic tone, which is modu- +lated by neural and hormonal mechanisms. +It is not clear +to what extent cholinergic nerve activity controls LES pressure. +The vagus nerve carries both excitatory and inhibitory fibers to +the esophagus and sphincter. +Tests to Detect Structural Abnormalities +Endoscopic Evaluation. +Many different grading systems have +been proposed. +25-16). +Grade IV esophagitis is the presence of a +stricture. +Its severity can be assessed by the ease of passing a +36F endoscope. +When a stricture is observed, the severity of the +esophagitis above it should be recorded. +25-16). +Histologically, it +appears as intestinal metaplasia (IM). +Its presence is confirmed by biopsy. +The earliest sign of the latter is high +grade dysplasia or intramucosal adenocarcinoma (Fig. +25-16). +Changes seen +in one biopsy are significant. +25-17). +When a submucosal mass is identified, +biopsy specimens are usually not performed. +This complicates the surgical dissec- +tion by increasing the risk of mucosal perforation. +Endoscopic +ultrasound provides a better method for evaluating these lesions. +Radiographic Evaluation. +Barium swallow evaluation is +undertaken selectively to assess anatomy and motility. +25-18), or the hernia is of the paraesopha- +geal variety. +These include small esophageal +A +CD +B +Figure 25-16. +Complications of reflux disease as seen on endoscopy. +A. +Linear erosions of grade II esophagitis. +B. +Uncomplicated Barrett’s +mucosa. +C. +High Grade dysplasia in Barrett’s mucosa, D. +Early adenocarcinoma arising in Barrett’s mucosa. +neoplasms, mild esophagitis, and esophageal varices. +952 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +B +A +C +Figure 25-17. +A. +Grade I flap valve appearance. +Note the ridge of tissue that is closely approximated to the shaft of the retroflexed endo- +scope. +It extends 3–4 cm along the lesser curve. +B. +Grade II flap valve appearance. +C. +Grade III flap valve appearance. +The ridge is barely present, and there is often failure +to close around the endoscope. +It is nearly always accompanied by a hiatal hernia. +D. +Grade IV flap valve appearance. +There is no muscular +ridge at all. +A +hiatal hernia is always present. +(Reproduced with permission from Hill LD, Kozarek RA, et al.: The gastroesophageal flap valve. +In vitro and +in vivo observations. +Gastrointest Endosc. +44:541, 1996. +In these situations, esophageal +function tests are necessary to identify a functional disorder. +Stationary Manometry. +Manometry is indicated whenever a motor +D +Figure 25-17. +(Continued ) +Figure 25-18. +Radiogram of an intrathoracic stomach. +This is the end +stage of a large hiatal hernia, regardless of its initial classification. +Other specially designed catheters can be used to assess +the upper sphincter. +25-19). +To +account for the asymmetry of the sphincter (Fig. +Overall length +Pressure +10 sec. +Esophageal +baseline +pressure Abdominal length +Gastric +baseline +pressure +Figure 25-19. +Manometric pressure profile of the lower esopha- +geal sphincter. +The distances are measured from the nares. +Am J Surg. +155:105, 1988. +Copyright Elsevier.) +LA +LP +L +P +A +RP +R +RA +25 +0 +50 +Figure 25-20. +Radial configuration of the lower esophageal +sphincter. +Dig Dis Sci 22:348, 1977. +(eds): Surgical +Treatment of Digestive Disease. +Chicago: Year Book Medical, 1990, +p 89. +Copyright Elsevier. +Ten +wet swallows (5 mL water each) are performed. +Ten wet swallows are recorded. +The data are used to identify motor +disorders of the esophagus. +High-Resolution Manometry. +25-21). +Powerful, computer- +based, and easy-to-use tools give unprecedented data analysis +capability. +Esophageal Impedance. +Air has a very low electrical con- +ductivity and, therefore, high impedance. +Saliva and food cause +an impedance decrease because of their increased conductivity. +25-22). +Until recently, this dif- +ferentiation could not be made. +Esophageal Transit Scintigraphy. +Normal high-resolution manometry motility study. +Pressure measurements are recorded with color coding (red = high; +blue = low). +LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter. +Note the +absence of lower esophageal sphincter tone. +Pressure measurements are recorded with color coding (red = high; blue = low). +LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter. +High-resolution manometry motility study in patient with deficient esophageal body peristalsis. +Note the very weak peri +- +stalsis in the lower two-thirds of the esophagus. +Pressure measurements are recorded with color coding (red = high; blue = low). +LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter. +High-resolution manometry motility study in patient with achalasia. +Pressure measurements are recorded with color coding (red = high; blue = low). +LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter. +High-resolution manometry motility study in patient with diffuse esophageal spasm. +LES = lower esophageal sphincter; PIP = pressure inversion point; UES = upper esophageal sphincter. +25-23). +Esophageal impedance probe measures electrical +resistance between evenly spaced electrodes. +LES = lower esopha- +geal sphincter. +abnormal motility of the esophageal body. +Tests to Detect Increased Exposure +to Gastric Juice +24-Hour Ambulatory pH Monitoring. +It passes spon- +taneously within 1 to 2 weeks. +Esophagograms from a patient with cricopharyngeal achalasia. +A. +B. +3. +Benign Esophageal Disease. +St. +Louis: Mosby, 1987, p 345. +25-24). +The upper limits of normal were established at the +ninety-fifth percentile. +Most centers use pH 4 as the threshold. +mp = meal period; sp = supine period. +I. +Philadelphia: +W.B. +Saunders, 1991, p 119. +of episodes 19.00 12.76 46.90 +No. +>5 min 0.84 1.18 3.45 +Longest episode 6.74 7.85 19.80 +SD = standard deviation. +(eds): Surgical +Treatment of Digestive Disease. +Chicago: Year Book Medical, 1990, +p 68. +Copyright Elsevier. +The latter is suggested by an +increased alkaline exposure time above pH 7 or 8. +(eds): Surgical +Treatment of Digestive Disease. +Chicago: Year Book Medical, 1990, +p 69. +Copyright Elsevier. +25-27). +Generally, 48 hours of pH data are measured with +this probe. +The capsule eventually detaches and passes +through the digestive tract in 5 to 7 days. +Radiographic Detection of Gastroesophageal Reflux. +Gastric Emptying. +Gastric emptying studies are performed +with radionuclide-labeled meals. +The resulting emptying +curve can be compared with data obtained in normal volunteers. +In general, normal subjects will empty 59% of a meal within +90 minutes. +24-Hour Gastric pH Monitoring. +The latter is +divided into the time spent upright and supine. +25-25). +A. +B. +The gastric tracing (lower) is taken +from a probe lying 5 cm below the upper esophageal sphincter. +I. +Philadelphia: W.B. +Saunders, +1991, p 123. +The most simplistic approach is to define the disease by +its symptoms. +Even when +excessive, these symptoms are not specific for gastroesophageal +reflux. +It is commonly, although not universally, relieved by +antacid or antisecretory medications. +When questioned, most patients can distinguish the two. +Esophageal dysphagia refers to the sensation of food sticking in +the lower chest or epigastrium. +esophageal origin. +One +person’s heartburn is another’s chest pain. +Considerable insight has been acquired, however. +The Lower Esophageal Sphincter. +25-26). +The most +common cause of a defective sphincter is an inadequate abdomi- +nal length. +LES = +lower esophageal sphincter. +be healed with antisecretory medication, reflux will continue +to occur. +Reflux may occur in the +face of a normal LES resting pressure. +Relationship Between Hiatal Hernia and Gastroesopha- +geal Reflux Disease. +25-27). +Yield pressure of the lower esophageal sphincter +decreases as hiatal hernia size increases. +Summary. +It is believed that GERD has its origins within the +stomach. +The increased swallow- +ing results in aerophagia, bloating, and belching. +The com- +ponent of duodenal juice thought to be most damaging is bile +acids. +Conjugation increases the sol- +ubility and ionization of bile acids by lowering their pKa. +Acidification of bile to below pH 2 results in an +irreversible bile acid precipitation. +(eds): Surgical +Treatment of Digestive Disease. +Chicago: Year Book Medical, 1990, +p 81. +Copyright Elsevier. +968 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +aspiration studies (Fig. +25-28). +25-29). +25-30). +umol/l +0 +Figure 25-28. +A. +Prevalence of reflux types in 53 patients with +gastroesophageal reflux disease. +B. +Esophageal luminal pH during +bilirubin exposure. +Ann Surg. +(*P<.03 vs all other +groups, **P <.03 vs. +Ann Surg. +222:525, 1995.) +969 +Esophagus and Diaphragmatic Hernia +CHAPTER 25 +eventually intramural fibrosis. +Second, the tubular esophagus +may become replaced with columnar epithelium. +This specialized IM is currently +required for the diagnosis of BE. +This continued injury is pH +dependent and may be modified by medical therapy. +An esophageal stricture can be associated with severe +esophagitis or BE. +In such patients, dila- +tion usually corrects the problem of dysphagia. +Heartburn, which +may have occurred only because of the chemical injury, need not +be treated. +These strictures are often resistant +to dilation. +He incorrectly +believed it to be congenital in origin. +The definition of BE has evolved considerably over the +past decade. +The hallmark of IM is the presence of intestinal goblet +cells. +Most patients with BE are symptomatic. +Gastric hypersecretion occurs +in 44% of patients. +Fortunately +this complication occurs very rarely. +Adenocarcinoma developing in Barrett’s +mucosa was considered a rare tumor before 1975. +Most, if not all, cases of adenocarcinoma of the esophagus +arise in Barrett’s epithelium (Fig. +25-31). +About one-third of all +patients with BE present with malignancy. +Etiology of Reflux-Induced Respiratory Symptoms. +Next, with ambulatory pH testing, acid +AB +Figure 25-31. +Photomicrographs. +A. +Barrett’s epithelium with severe dysplasia. +(×200.) Note nuclear irregularity, stratification, and loss of +polarity. +B. +Barrett’s epithelium with intramucosal carcinoma. +I. +Philadelphia: W.B. +Saunders, 1991, +p 113. +Treatment. +Improvements in pulmonary function can be +demonstrated in around 30% of patients. +Medical Therapy for Gastroesophageal Reflux Disease. +This approach may successfully and completely resolve +the symptoms. +In patients with persistent symptoms, the mainstay of +medical therapy is acid suppression. +This usu- +ally heals mild esophagitis. +In severe esophagitis, healing may +occur in only one-half of the patients. +This can allow persistent mucosal damage in an +asymptomatic patient. +However, this hypothesis +remains controversial. +Suggested Therapeutic Approach. +Traditionally a stepwise +approach is used for the treatment of GERD. +First-line therapy +entails antisecretory medication, usually PPIs, in most patients. +Treatment options for these patients entails either long +term PPI use vs. +antireflux surgery. +These studies will serve to establish the diagnosis +and assess esophageal body dysfunction. +Surgical Therapy for Gastroesophageal +Reflux Disease +Selection of Patients for Surgery. +These patients are prone to breakthrough of +their symptoms while receiving medical therapy. +Patients with BE are at risk of the development of +an adenocarcinoma. +Preoperative Evaluation. +Before proceeding with an antire- +flux operation, several factors should be evaluated. +The clinical +symptoms should be consistent with the diagnosis of gastro- +esophageal reflux. +973 +Esophagus and Diaphragmatic Hernia +CHAPTER 25 +Hiatal anatomy should also be assessed. +When identified these surgeons usually undertake +add a gastroplasty to the antireflux procedure. +Principles of Surgical Therapy. +This will result in an increase in +the pressure of the distal esophageal sphincter region. +25-32). +25-33). +However, the aim of any fundoplication +Distention +Figure 25-32. +Am J +Surg. +143:43, 1982. +Third, the operation should allow the reconstructed car- +dia to relax on deglutition. +A 360° gastric wrap should be no longer than 2 cm and +constructed over a large (50 to 60F) bougie. +A bougie is not necessary when construct- +ing a partial wrap. +Procedure Selection. +Primary Antireflux Repairs +Nissen Fundoplication. +The most common antireflux proce- +dure is the Nissen fundoplication. +Hiatal dissection and preservation of both vagi along their +entire length +2. +Circumferential esophageal mobilization +3. +Hiatal closure, usually posterior to the esophagus +4. +Patient positioning and trocar placement for lap- +aroscopic antireflux surgery. +The patient is placed with the head +elevated approximately 30° in the modified lithotomy position. +Five ports are usually used (Fig. +A tension-free fundopli- +cation should be constructed. +A. +Laparoscopic Nissen fundoplication is performed with a five-trocar technique. +B. +The liver retractor is affixed to a mechani- +cal arm to hold it in place throughout the operation. +C. +D. +The grasper is withdrawn, pulling the posterior aspect of +the gastric fundus behind the esophagus. +E. +F. +Final position of the fundoplication. +The fundic lips are manipulated to +allow the fundus to envelop the esophagus without twisting. +Some surgeons +use a single U-stitch of 2-0 polypropylene buttressed with felt +pledgets (Fig. +25-35), and others use 2-4 interrupted sutures. +Posterior Partial Fundoplication. +The commonest approach has been a posterior partial or Toupet +fundoplication. +25-36). +It is usually stabilized by anchoring the +wrap posteriorly to the hiatal rim. +Anterior Partial Fundoplication. +(Continued ) +Figure 25-36. +Completed laparoscopic posterior partial (Toupet) +fundoplication. +rim and the esophageal wall. +Various degrees of anterior partial fundoplication have +been described—90°, 120°, 180°. +The anterior 180° partial fun- +doplication (Fig. +Figure 25-37. +Completed laparoscopic anterior 1800 partial fundo- +plication. +Unlike the Nissen +procedure, the fundus is not pulled behind the esophagus. +977 +Esophagus and Diaphragmatic Hernia +CHAPTER 25 +Collis Gastroplasty. +The commonest +approach to this is the Collis gastroplasty. +Laparoscopic techniques for +Collis gastroplasty have been described (Fig. +25-38). +A. +The interior end of the staple line is marked 2/5 cm below the angle of His. +B. +C. +D. +Outcome after Fundoplication. +national trends in use and +outcomes. +Postoperative pH studies indicate that more than +90% of patients will normalize their pH tracings. +The challenge is to accomplish this without inducing +dysphagia or other untoward side effects. +Dysphagia, existing +before surgery, usually improves following laparoscopic fun- +doplication. +Most patients cannot vomit through an intact wrap, +though this is rarely clinically relevant. +without division of the +short gastric vessels. +Nissen vs. +Posterior Partial Fundoplication Eleven ran- +domized trials have compared Nissen vs. +posterior partial +fundoplication. +Lundell et al reported the outcomes of Nissen vs. +Strate et al reported 2 year follow-up in +a trial that enrolled 200 patients. +8 patients). +Only Booth et al. +demonstrated less dysphagia following posterior fundoplication. +without poor preoperative +oesophageal motility. +Nissen vs. +Anterior Fundoplication Six trials have evaluated +Nissen vs. +anterior partial fundoplication variants. +Four have +assessed Nissen vs. +Two trials compared laparoscopic anterior 90° partial +fundoplication vs. +Nissen fundoplication (Watson et al–112 +patients, Spence et al–79). +Satisfaction with the overall outcome +was similar for both fundoplication variants. +Anterior vs. +posterior partial fundoplication Two random- +ized trials have directly compared anterior vs. +posterior par- +tial fundoplication. +Hagedorn et al randomized 95 patients to +undergo either Toupet vs. +anterior 120° partial fundoplication, +and Khan et al enrolled 103 patients to anterior 180° vs. +979 +Esophagus and Diaphragmatic Hernia +CHAPTER 25 +posterior partial fundoplication. +Outcome of Antireflux Surgery in Patients with Barrett’s +Esophagus. +Parrilla and colleagues reported the only randomized trial +to evaluate this issue. +They enrolled 101 patients over 18 years +(1982 to 2000), and median follow-up was 6 years. +About 15 % of patients had abnormal +acid exposure after surgery. +Within the +control arm of a randomized trial of ablation vs. +surveillance. +Biopsy specimens should be reviewed by +a pathologist with expertise in the field. +Reoperation for Failed Antireflux Repairs. +Table 25-7 +Symptomatic outcome of surgical therapy for Barrett's esophagus +AUTHOR yEAR NO. +When dysphagia is the cause of failure, the situation can +be more difficult to manage. +25-39C). +In this situation the +abnormality is usually referred to as an intrathoracic stomach +(Fig. +25-39D). +When radiographic +Figure 25-39. +A. +Radiogram of a type I (sliding) hiatal hernia. +B. +Radiogram of a type II (rolling or paraesophageal) hernia. +C. +Radiogram +of a type III (combined sliding-rolling or mixed) hernia. +D. +Radiogram of an intrathoracic stomach. +This is the end stage of a large hiatal +hernia regardless of its initial classification. +The PEH is also known as the giant hiatal hernia. +Over time the +pressure gradient between the abdomen and chest enlarges +the hiatal hernia. +In many cases the type 1 sliding hernia will +evolve into a type III mixed hernia. +Type II hernias are quite rare. +The median age +of the former is 61 years old; of the latter, 48 years old. +PEHs are +more likely to occur in women by a ratio of 4:1. +There is usually a +C +D +Figure 25-39. +Repair of the hernia without addressing the reflux can cre- +ate extremely bothersome heartburn. +The association of anemia and PEH is best proven by fixing +the hernia. +Anemia is corrected in >90% of patients with this +condition. +In contrast, many patients with PEH +are asymptomatic or complain of minor symptoms. +Mano- +metrically, this is reflected by a double-humped high-pressure +zone at the GEJ. +Consequently, this abnormality is +often confused with typical GERD. +Surgical reduction of the +hernia results in relief of the dysphagia in 91% of patients. +This is usually caused by a PEH or an intrathoracic +stomach. +25-39B and C). +25-40). +Surprisingly, +esophageal peristalsis in patients with PEH is normal in 88%. +Treatment +The treatment of paraesophageal hiatal hernia is largely surgi- +cal. +Indications and Surgical Approach. +This recommendation is largely +Figure 25-40. +Note the gastric rugal folds extending +above the impression caused by the crura of the diaphragm. +Second, emergency repair carries a high mortality. +For the most part, these catastrophes occurred +without warning. +Others have reported similar findings. +Recent studies suggest that catastrophic complications +may be somewhat less common. +Watchful waiting of asymptomatic PEHs +may be an acceptable option. +Each has its advantages and disadvantages. +Laparoscopic repair of PEH would appear to have become +the standard approach. +There are several reasons for this. +Techniques to reduce hernia recurrence +continue to evolve. +Role of Fundoplication in Giant Hiatal Hernia +Repair. +There are several reasons for this. +The presence of a short esophagus increases +the difficulty of laparoscopic PEH repair. +Hence, the diagnosis of this entity continues to be made +definitively only in the operating room. +The risk of +incarceration, strangulation, or obstruction is minimal. +Its significance and pathogenesis are +unclear (Fig. +25-41). +Below the ring is a hiatal hernia. +the esophagus. +They also have better LES function. +Little is known about the natural progres- +sion of Schatzki’s rings. +In most, the +disease follows a prolonged course. +Renal involvement occurs +in a small percentage of patients and signals a poor prognosis. +In the GI tract, +the predominant feature is smooth muscle atrophy. +25-42). +The LES pressure is progressively +weakened as the disease advances. +This combined defect can lead +to severe esophagitis and stricture formation. +25-43). +Only 50% of the patients have a good-to-excellent +result. +Med Clin North Am. +65:1252, +1981. +Copyright Elsevier.) +Figure 25-43. +Barium esophagogram of a patient with scleroderma +and stricture. +Note the markedly dilated esophagus and retained +food material. +Med Clin North Am. +65:1253, 1981. +Dysphagia may occur with liquids +or solids, but solid food dysphagia is most common. +Signs +A barium swallow should be the first test obtained in the patient +with dysphagia. +25-44). +25-45). +Pathology +Endoscopic biopsy specimens should be taken when eosino- +philic esophagus is suspected. +25-46). +If dysphagia is not +relieved with steroids, it may be necessary to dilate the esopha- +gus. +Great care must be +exercised, as the inflamed EE is quite friable. +Figure 25-44. +The esophagus on the left shows a +stacking of rings, demonstrating eosinophilic esopha- +gus. +The esophagus on the right is a normal barium +swallow. +Figure 25-45. +Diagnostic Assessment of the Cricopharyngeal Segment. +A cluster of eosinophils are visualized in the esophageal epithelium in a patient with EE. +segment, and the dynamics of airway protection during swal- +lowing. +It readily identifies a diverticulum (Fig. +A. +Zenker’s diverticulum, initially discovered 15 years +ago and left untreated. +B. +Note its marked enlargement and evi- +dence of laryngeal inlet aspiration on recent esophagogram. +Med Clin North +Am. +65:1257, 1981. +Copyright Elsevier.) +988 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +most situations (Fig. +25-48). +A. +Schematic drawing of a pharyngeal pressure +wave indicating the presence of the bolus pressure. +B. +UES = upper esophageal +sphincter. +Gastroenterology. +25-49). +This enlarges the pharyngoesophageal segment and reduces +outflow resistance. +Zenker’s Diverticulum. +Chronic aspiration and repetitive respiratory infec- +tion are common associated complaints. +Once suspected, the +diagnosis is established by a barium swallow. +Cricopharyngeal Myotomy. +This attitude has resulted in an overall success rate in the relief +of symptoms of only 64%. +Open Cricopharyngeal Myotomy, Diverticulopexy, and +Diverticulectomy. +25-50). +It can be difficult to identify the cricopha- +ryngeus muscle in the absence of a diverticulum. +Med Clin North Am. +65:1257, +1981. +Copyright Elsevier.) +pharyngoesophageal segment. +Oral alimentation is started the +day after surgery. +The patient is usually discharged on the first +or second postoperative day. +25-51). +Endoscopic Cricopharyngotomy. +Endoscopic stapled crico- +pharyngotomy and diverticulotomy recently has been described. +More than one stapler application may be needed, depending on +the size of the diverticulum (Fig. +25-52). +Consequently, after myotomy, there is protection against esoph- +agopharyngeal regurgitation. +body or the relaxation of the LES. +The manometric characteristics of these disorders are +shown in Table 25-9. +Achalasia. +The technique for transoral cricopharyngotomy and +Zenker’s diverticulotomy. +I. +Philadelphia: W.B. +Saunders, 1991, p 115. +Copyright Elsevier. +25-53). +25-54). +As the disease progresses, the esophagus becomes massively +dilated and tortuous. +Pressurization of esophagus: Ambulatory motility +tracing of a patient with achalasia. +A. +Before esophageal myotomy. +B. +After esophageal myotomy. +The tracings have been compressed +to exaggerate the motility spikes and baseline elevations. +No such rise occurs +postmyotomy (panel B). +992 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +are a common finding in these patients. +Diffuse and Segmental Esophageal Spasm. +DES is charac- +terized by substernal chest pain and/or dysphagia. +Nonetheless, it is impossible to differentiate achalasia +from DES on the basis of symptoms alone. +Esophagogram and +esophageal manometry are required to distinguish these two +entities. +The causation and neuromuscular pathophysiology of +DES are unclear. +Figure 25-54. +Med Clin North +Am. +65:1244, 1981. +However, this figure +is arbitrary and often debated. +The LES in patients with DES usually shows a normal +resting pressure and relaxation on swallowing. +A hypertensive +sphincter with poor relaxation may also be present. +25-55). +25-56). +Nutcracker Esophagus. +The disorder, termed nutcracker or +supersqueezeresophagus, was recognized in the late 1970s. +It is the most +common of the primary esophageal motility disorders. +Contraction amplitudes in these patients can easily be above +400 mmHg. +At the lower end of peak pressure, it is unclear +whether nutcracker esophagus causes any symptoms. +In fact, +Figure 25-55. +Barium esophagogram of patient with diffuse +spasm showing the corkscrew deformity. +Treatment in these patients should be aimed at the treatment +of GERD. +Hypertensive Lower Esophageal Sphincter. +In the remainder, the disorder exists as an isolated +abnormality. +Myotomy of the LES may be indicated in patients not respond- +ing to medical therapy or dilation. +Secondary Esophageal Motility Disorders. +Figure 25-56. +Symptoms of these disorders are heartburn and dysphagia. +The latter may be a result of a peptic stricture rather than the +esophageal dysmotility. +Nonspecific Esophageal Motor Disorders and Ineffec- +tive Esophageal Motility. +These motility +abnormalities have been termed nonspecific esophageal motility +disorders. +Their significance in the causation of chest pain or +dysphagia is still unclear. +Diverticula of the Esophageal Body. +Conse- +quently, earlier texts focused on them as specific entities based +upon their location. +When a large diverticulum is associated with +a hiatal hernia, then hiatal hernia repair is added. +All these pro- +cedures may be performed with traditional or minimally inva- +sive techniques. +Midesophageal or traction diverticula were first described +in the nineteenth century (Fig. +25-57). +It was theorized that adhesions formed +between the inflamed mediastinal nodes and the esophagus. +25-58). +In such patients, the radiologic abnormality may +be ignored. +The diverticulum in such patients is most +likely to have an inflammatory etiology. +Figure 25-57. +Barium esophagogram showing a midesophageal +diverticulum. +Despite the anatomic distortion, the patient was +asymptomatic. +Med Clin North Am. +65:1255, 1981. +Copyright Elsevier.) +Inflamed +nodes +Traction diverticulum +Figure 25-58. +The indication for surgical intervention is dictated by +the degree of symptomatic disability. +Usually, midesophageal +diverticula can be suspended due to their proximity to the spine. +The symptom of chest +pain alone is not an indication for a surgical procedure. +25-59). +Most surgeons extend the myotomy +distally across the LES to reduce outflow resistance. +25-60). +The procedure may be performed either open or via thora- +coscopy. +The open technique is performed through a left thora- +cotomy in the sixth intercostal space (Fig. +25-61). +The +esophagus is not circumferentially dissected unless necessary. +A tongue of gas- +tric fundus is pulled into the chest. +This exposes the GEJ and +its associated fat pad. +The latter is excised to give a clear view +of the junction. +The muscle layer is dissected from the +mucosa laterally for a distance of 1 cm. +Care is taken to divide +all minute muscle bands, particularly in the area of the GEJ. +This +maintains separation of the muscle and acts as a partial fundo- +plication to prevent reflux. +The +myotomy is then performed on the opposite esophageal wall. +100% +% Symptomatic +10 cm +5 cm +0 cm +80% +60% +40% +20% +0% +Pre Rx +17 N +Eso. +diameter +% Retention +0–24 +mo +17 +25–48 +mo +16 +49–72 +mo +14 +73–120 +mo +12 +Figure 25-60. +(Based +on Topart P, et al.: Long-term effect of total fundoplication on the +myotomized esophagus. +Ann Thorac Surg. +54:1046, 1992.) +996 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Figure 25-61. +Technique of long myotomy: A. +B. +C. +Retraction of tongue of gastric fundus into the chest through the previously made +incision. +D. +Removal of the gastroesophageal fat pad to expose the gastroesophageal junction. +E. +A myotomy down to the mucosa is started +on the esophageal body. +F. +Completed myotomy extending over the stomach for 1 cm. +G. +H. +Most patients gain or maintain rather than +lose weight after the operation. +The thoracoscopic technique may be performed through +the left or right chest. +Performing abdominal myotomy (and +diverticulectomy, if present) may be all that is required. +The POEM +Figure 25-61. +A long submu- +cosal plane is developed with the endoscope, down to and below +the LES. +The submucosal +entry site in the esophagus is then closed with endoscopic clips. +25-62). +The neck of the diverticulum is transected with a GIA +stapler after passage of a 48F dilator. +Closure of the muscle over the +staple line is preferable. +Solid +foods are withheld for 2 weeks to decrease the likelihood of +staple line leak. +Buttressing or sealing the staple line with fibrin +glue is also an attractive option. +This requires disrupting the LES mus- +cle. +25-63). +Botulinum toxin injection may achieve similar +Figure 25-62. +A. +B. +Stapler amputates +neck of diverticulum. +C. +Muscle reapproximated over staple line, and Heller myotomy is performed. +Responsiveness to botulinum toxin injection may predict a good +response to Heller myotomy. +25-64). +Close follow- +up is required, and if dilation fails, myotomy is indicated. +Dig Dis Sci 41:2138, 1996. +(Data reproduced +from: Ellis FH Jr.: Oesophagomyotomy for achalasia: A 22-year +experience. +Br J Surg. +80:882, 1993; Goulbourne IA, Walbaum PR: +Long-term results of Heller’s operation for achalasia. +J Royal Coll +Surg. +Ann Tho- +rac Surg. +Dig Dis Sci. +Gastroenterology. +Myotomy of the LES can be accomplished via either an +abdominal or thoracic approach. +The fourth issue centers on whether or not a cure of this +disease is achievable. +In fact, primary procedures can almost +always be successfully completed via laparoscopy. +The esophagus and a tongue of gastric fun- +dus are exposed as described for a long myotomy. +The tongue of gastric fundus is +allowed to retract into the abdomen. +After dilation, 13% of patients +regained some peristalsis, compared with 28% after surgery. +Failure to do this will result in continuing dysphagia and a dis- +satisfied patient. +A good therapeutic response improves esophageal emptying +toward normal. +When an antireflux procedure is +added to the myotomy, it should be a partial fundoplication. +25-65). +Exposure of the GEJ via removal of the +gastroesophageal fat pad follows. +The anterior vagus nerve is +swept right laterally along with the fat pad. +A distal esophageal myotomy is performed. +An antireflux procedure follows completion of +the myotomy. +Per Oral Endoscopic Myotomy (POEM) +The POEM procedure was developed in Japan. +It is the ultimate +minimally invasive myotomy as it requires no incisions through +the skin. +A long +submucosal plane is developed with the endoscope, down to +and below the LES. +The submucosal entry site in the esophagus is +then closed with endoscopic clips. +The use of +symptoms alone as an endpoint to evaluate therapy for achalasia +may be misleading. +Esophageal baseline +pressure is usually negative compared to gastric pressure. +A postdilatation sphincter pressure +<10 mmHg predicted a good response. +Overall, only 30% of patients dilated remained in symp- +tomatic remission at 5 years. +They concluded that there was a +Figure 25-65. +A. +Longitudinal muscle is divided. +B. +Mechanical disruption of lower esophageal sphincter muscle fibers. +C. +Myotomy must +be carried across gastroesophageal junction. +D. +Gastric extension should equal 2 to 3 cm. +E. +Anterior (Dor) fundoplication is sutured to the +diaphragmatic arch. +F. +Posterior (Toupet) fundoplication is sutured to cut edges of myotomy. +EG jct = esophagogastric junction. +Overall, 89% +of patients were improved at the 9-year mark. +The outcome of laparoscopic myotomy and hemifun- +doplication has been well documented. +Two reports of over +1002 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Figure 25-65. +Ann Thorac Surg 58:1343, 1994; Ellis FH Jr.: +Oesophagomyotomy for achalasia: A 22-year experience. +J R Coll Surg Edinb. +30:101, 1985. +Conversion to an open procedure occurs in 0% to +5% of patients. +Complications are uncommon, occurring in +<5% of patients. +The incidence of objective reflux dis- +ease as evidenced by abnormal acid exposure is <10%. +The best treatment for achalasia +is a laparoscopic Heller myotomy and partial fundoplication. +The role of POEM in the management of classic (nonspastic) +achalasia is yet to be established. +The presence of these abnormalities signals +end-stage motor disease. +In these situations esophageal replace- +ment is usually required to establish normal alimentation. +In Western societies, smoking and alcohol +consumption are strongly linked with squamous carcinoma. +25-66), and +now accounts for more than 50% of esophageal cancer in most +Western countries. +Furthermore, the clinical picture of esophageal adenocar- +cinoma is changing. +The potential for cure becomes of paramount importance. +The gross appearance resembles that of squamous cell car- +cinoma. +Either vocal cord may +6 +1004 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +U.S. +Incidence and mortality rate trends for esophageal +cancer. +NCI = National Cancer Institute. +(Reproduced with permis- +sion from the National Cancer Institute. +Systemic organ metastases are +usually manifested by jaundice or bone pain. +The situation is +different in high-incidence areas where screening is practiced. +In these communities, the most prominent early symptom is +pain on swallowing rough or dry food. +Consequently, the dis- +ease is usually advanced if symptoms herald its presence. +With tumors of the cardia, anorexia and +weight loss usually precede the onset of dysphagia. +When given before surgery, these treat- +ments are referred to as neoadjuvant or induction therapy. +For +disseminated cancer, treatment is aimed at palliation of symp- +toms. +Staging starts with the history and physical. +Studies also showed that +patients having five or fewer LN metastases have a better out- +come. +Most surgeons agreed that the 1983 tumor, nodes, and metas- +tasis system left much to be desired. +Clinical Approach to Carcinoma +of the Esophagus and Cardia +The selection of a curative vs. +Tumor Location. +25-68). +Except in advanced disease, it is unusual +for intrathoracic LNs to be involved. +Tumors of the lower esophagus and cardia are usually +adenocarcinomas. +No evidence of primary tumor. +High-grade dysplasia. +Tumor invades lamina propria, muscularis mucosae, or submucosa. +Tumor invades lamina propria or muscularis mucosae. +Tumor invades submucosa. +Tumor invades muscularis propria. +Tumor invades adventitia. +Tumor invades adjacent structures. +Resectable tumor invading pleura, pericardium, or diaphragm. +Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc. +Regional lymph nodes cannot be assessed. +No regional lymph node metastasis. +Metastases in 1–2 regional lymph nodes. +Metastases in 3–6 regional lymph nodes. +Metastases in ≥7 regional lymph nodes. +No distant metastasis. +Distant metastasis. +1007 +Esophagus and Diaphragmatic Hernia +CHAPTER 25 +Age. +CT = computed tomography; FEV1 = forced expiratory volume in 1 second. +(Reproduced with +permission from DeMeester TR: Esophageal carcinoma: Current controversies. +Sem Surg Oncol. +Incidence of carcinoma of the esophagus and cardia +based on tumor location. +established its success in highly selected patients. +Cardiopulmonary Reserve. +Clinical evaluation +and electrocardiogram are not sufficient indicators of cardiac +reserve. +Nutritional Status. +Clinical Staging. +Preoperative Staging with Advanced Imaging. +EUS provides the most reliable method of determining +depth of cancer invasion. +In the absence of enlarged LNs, the +degree of wall invasion dictates surgical therapy. +It is difficult to provide modern treatment of esophageal +cancer without access to this modality. +Aortic esophageal fistulas are +extremely rare and nearly 100% lethal. +In +a few patients, definitive chemoradiation will be successful in +all sites but the esophagus. +For individuals with dysphagia grades IV and higher, addi- +tional treatment generally is necessary. +The mainstay of therapy +is in-dwelling esophageal stents. +The major limitations to stenting exist in cancers at the GEJ. +J Surg Oncol 9:547, +1977. +In cancers at +this level, radiation therapy alone may be preferable. +If feeding +access is desirable, a laparoscopic jejunostomy is usually the +procedure of choice. +Mucosally Based Cancer. +Nodules should be resected in entirety, as +they often harbor adenocarcinoma. +In this clinical situation, EMR is typically combined with +EUS to rule out more invasive disease. +On the other hand, intramucosal cancers have +little risk of spreading to regional LNs. +This approach dictates the need for future +therapy such as esophagectomy. +This specimen is then +removed and sent to pathology. +A positive margin or involvement of the +submucosa warrants esophagectomy. +Minimally Invasive Transhiatal Esophagectomy. +Several variations of MIS +transhiatal esophagectomy have been developed. +25-69A). +The conduit +can be created through a mini-laparotomy or laparoscopically. +A Kocher maneuver releases the duodenum, and a pyloroplasty +may be performed (optional). +25-69B). +This technique +is reserved for patients with high-grade dysplasia. +25-69C). +A. +Laparoscopic retrograde inversion. +B. +Laparo- +scopic antegrade inversion. +A silk suture holds the tunnel after the +esophagus is removed. +C. +Open Transhiatal Esophagectomy. +Minimally Invasive Two- and Three-Field Esophagectomy. +Both proce- +dures will be described. +Double +lumen intubation is required. +Hilar, and posterior mediastinal nodes are all removed and sent +with the specimen or individually. +The thoracic duct is divided +at the level of the diaphragm and removed with the specimen. +A +feeding tube is placed and the pyloroplasty may be performed +laparoscopically. +Great care is made +to avoid stretching the recurrent laryngeal nerve. +Cervical anastomosis is then +performed. +The MIS transthoracic two-field esophagectomy is slightly +different. +Other complications of this approach relate to pulmonary and +cardiac status. +Ivor Lewis (En Bloc) Esophagectomy. +All LNs are removed en bloc with the lesser curvature of +the stomach. +In the majority of cases, colon interposition is +unnecessary, and a gastric conduit is used. +Chest tubes are placed, and the patient is +taken to the intensive care unit. +Three-Field Open Esophagectomy. +Salvage Esophagectomy. +Surprisingly, the cure rate of salvage esophagectomy is not +inconsequential. +Comparative Studies of Esophagectomy +Technique +Transthoracic vs. +Transhiatal Esophagectomy. +The mortality and morbidity after transhiatal esopha- +gectomy appeared to be less. +There was no difference in procedure-related +mortality between the approaches. +Alternative Therapies +Radiation Therapy. +Radiation is effective in patients who have hemorrhage from +the primary tumor. +Adjuvant Chemotherapy. +This is particularly beneficial in +the case of squamous cell tumors above the level of the carina. +Preoperative Chemotherapy. +Eight randomized prospec- +tive studies of neoadjuvant chemotherapy vs. +surgery alone +have demonstrated mixed results. +This +trial is one of the few to include enough patients (800) to detect +small differences. +The trial had a 10% absolute survival benefit +at 2 years for the neoadjuvant chemotherapy group. +Preoperative Combination Chemo- and Radiotherapy. +There have been 10 +randomized prospective studies (Table 25-13). +surgery, or neoadjuvant chemotherapy vs. +bUnpublished thesis. +cYear of activation not reported, but imputed. +dOnly available as an abstract. +SCC = squamous cell carcinoma. +Source: Reproduced with permission from Gebski V, et al. +Lancet Oncol 8:226, 2007. +Table 1, p 228. +Copyright Elsevier. +ARR = absolute risk reduction; NNT = number needed to treat to prevent one death. +Source: Reproduced with permission from Gebski V, et al. +Lancet Oncol 8:226, 2007. +Table 2, p 231. +Copyright Elsevier. +is detected in the specimen after esophagectomy. +After incomplete resection of +an esophageal cancer, the 5-year survival rates are 0% to 5%. +The importance of +early recognition and adequate surgical resection cannot be +overemphasized. +Figure 25-70 is a global algorithm for the +management of esophageal carcinoma. +25-71). +Table 25-15 +Results of neoadjuvant therapy in adenocarcinoma of the esophagus +INSTITUTION yEAR NO. +OF PATIENTS REGIMEN +COMPLETE PATHOLOGIC +RESPONSE (%) SURVIVAL +M. +D. +Louis +University Medical Center; VBL = vinblastine. +Ann Thorac Surg 58:1574, 1994. +Copyright Elsevier. +25-72). +Esophagoscopy commonly shows an intraluminal necrotic +mass. +When this is not done, the biopsy specimen will show only tis- +sue necrosis. +Suggested global algorithm for the management of carcinoma of the esophagus. +CT = computed tomography. +1016 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +A +B +Figure 25-71. +A. +B. +There was no evidence of lymph node metastasis at the time of operation. +AB +Figure 25-72. +A. +B. +Operative specimen showing 9-cm polypoid leiomyoblastoma. +1017 +Esophagus and Diaphragmatic Hernia +CHAPTER 25 +reported 5-year survivals. +Resection also provides an excellent +means of palliating the patient’s symptoms. +The other +five patients were reported to have survived more than 5 years. +BENIGN TUMORS AND CYSTS +Benign tumors and cysts of the esophagus are relatively uncom- +mon. +Intramural lesions are either solid tumors or cysts, and the +vast majority are leiomyomas. +They are made up of varying por- +tions of smooth muscle and fibrous tissue. +Fibromas, myomas, +fibromyomas, and lipomyomas are closely related and occur +rarely. +Pedunculated intraluminal tumors +should be removed. +If the lesion is not too large, endoscopic +removal with a snare is feasible. +Leiomyoma +Leiomyomas constitute more than 50% of benign esophageal +tumors. +Leiomyomas +are twice as common in males. +They are usually solitary, but multiple tumors have been +found on occasion. +They vary greatly in size and shape. +Actually +tumors as small as 1 cm in diameter and as large as 10 lb have +been removed. +Typically, leiomyomas are oval. +The overlying mucosa is +freely movable and normal in appearance. +A barium swallow is the most useful method to demon- +strate a leiomyoma of the esophagus (Fig. +25-73). +The majority can be removed by +simple enucleation. +If, during removal, the mucosa is inadver- +tently entered, the defect can be repaired primarily. +The location of the lesion and the +extent of surgery required will dictate the approach. +Videothoracoscopic and laparoscopic approaches are now fre- +quently used. +Figure 25-73. +Barium esophagogram showing a classical, smooth, +contoured, punched-out defect of a leiomyoma. +Esophageal Cyst +Cysts may be congenital or acquired. +In some, +epithelial lining cells may be absent. +Their symptoms are similar to those of a leiomyoma. +The +diagnosis similarly depends on radiographic, endoscopic, and +endosonographic findings. +Surgical excision by enucleation is +the preferred treatment. +ESOPHAGEAL PERFORATION +Perforation of the esophagus constitutes a true emergency. +It +most commonly occurs following diagnostic or therapeutic pro- +cedures. +If subcutaneous emphysema is present, the diagnosis is almost +certain. +Spontaneous rupture usually occurs into the left pleu- +ral cavity or just above the GEJ. +This is due to the stretching of the supra- +diaphragmatic portion of the gastric wall. +Mediastinal widening secondary to edema +may not occur for several hours. +The site of perforation also can +influence the radiographic findings. +25-74). +A pleural effusion sec- +ondary to inflammation of the mediastinum occurs late. +In 9% +of patients, the chest radiogram is normal. +The +use of a water-soluble medium such as Gastrografin is preferred. +Of concern is that there is a 10% false-negative rate. +This may +be due to obtaining the radiographic study with the patient in +the upright position. +The studies should be done with the patient +in the right lateral decubitus position (Fig. +25-75). +Management +The key to optimum management is early diagnosis. +A flap +of stomach is pulled up and the soiled fat pad at the GEJ is +removed. +The edges of the injury are trimmed and closed pri- +marily (Fig. +25-77). +Mortality associated with immediate closure varies +between 8% and 20%. +In some situations, the +retained esophagus may be so long that it loops down into the +chest. +The contaminated mediastinum is drained and a feeding +jejunostomy tube is inserted. +Nonoperative management of esophageal perforation has +been advocated in select situations. +25-78), (b) symptoms should be mild, +and (c) there should be minimal evidence of clinical sepsis. +If +these conditions are met, it is reasonable to treat the patient with +Figure 25-74. +Figure 25-75. +Figure 25-76. +Oral intake is resumed in +7 to 14 days, dependent on subsequent radiographic examinations. +Mallory-Weiss tears are characterized by arterial bleeding, +which may be massive. +In the majority of patients, the bleeding will stop sponta- +neously with nonoperative management. +Endoscopic injec- +tion of epinephrine may be therapeutic if bleeding does not +stop spontaneously. +Only occasionally will surgery be required +to stop blood loss. +The procedure consists of laparotomy and +high gastrotomy with oversewing of the linear tear. +Mortality is +uncommon, and recurrence is rare. +Pathology +The swallowing of caustic substances causes an acute and a +chronic injury. +During the chronic phase, the focus is on treatment +Figure 25-77. +The technique of closure of an esophageal perfora- +tion through a left thoracotomy. +A. +B. +Reinforcement of +the closure with a parietal pleural patch. +Figure 25-78. +Barium esophagogram showing a stricture and a +contained perforation following dilation. +Nonoperative management was +successful. +Acids and alkalis affect tissue in different ways. +Cleansing products can contain up to +90% sodium hydroxide. +The lesions caused by lye injury occur in three phases. +First is the acute necrotic phase, lasting 1 to 4 days after injury. +Second +is the ulceration and granulation phase, starting 3 to 5 days +after injury. +This +phase lasts 10 to 12 days, and it is during this period that the +esophagus is the weakest. +Third is the phase of cicatrization and +scarring, which begins the third week following injury. +Adhesions +between granulating areas occur, resulting in pockets and bands. +It is during this period that efforts must be made to reduce stric- +ture formation. +The presence of +fever is strongly correlated with the presence of an esophageal +lesion. +Bleeding can occur, and frequently, the patient vomits. +These initial complaints disappear during the quiescent period +of ulceration and granulation. +Of the patients who develop strictures, 60% do so within 1 +month, and 80% within 2 months. +If dysphagia does not develop +within 8 months, it is unlikely that a stricture will occur. +Conversely, esophageal burns can +be present without apparent oral injuries. +The degree of injury can be graded according +to the criteria listed in Table 25-16. +Even if the esophagoscopy +is normal, strictures may appear later. +The most common locations of caustic injuries are +shown in Table 25-17. +The immediate treatment consists of limiting the +burn by administering neutralizing agents. +To be effective, this +must be done within the first hour. +Lye or other alkali can be +neutralized with half-strength vinegar, lemon juice, or orange +juice. +Acid can be neutralized with milk, egg white, or antac- +ids. +If necessary, +a feeding jejunostomy tube is inserted to provide nutrition. +Oral +feeding can be started when the dysphagia of the initial phase +has regressed. +Management of acute injury is summarized in the algo- +rithm in Fig. +25-79. +Some authors have advocated the use of an +intraluminal esophageal stent (Fig. +Esophagoscopy should be +done, and, if strictures are present, dilations initiated. +During the treatment 55 patients died. +Algorithm summarizing the management of acute +caustic injury. +Figure 25-80. +The use of an esophageal stent to prevent stricture. +A Penrose drain is +placed over the distal end as a flap valve to prevent reflux. +Continuous suction removes saliva and +mucus trapped in the pharynx and upper esophagus. +Free jejunal grafts based on the supe- +rior thyroid artery have provided excellent results. +25-81). +25-82). +This allows excision of supraglottic strictures and elevation and +anterior tilting of the larynx. +In both of these situations, the +patient must relearn to swallow. +The management of a bypassed damaged esophagus after +injury is problematic. +Traumatic fistulas and +those associated with esophageal diverticula account for the +remainder. +To prevent recurrence, a pleural flap should +be interposed. +Treatment of malignant fistulas is difficult, par- +ticularly in the presence of prior irradiation. +Generally, only pal- +liative treatment is indicated. +This can best be done by using a +Figure 25-81. +Anastomosis of the bowel to a preserved pyri- +form sinus. +Analysis of 18 cases. +Ann +Surg. +207:439, 1988.) +Figure 25-82. +Anastomosis of the bowel to the posterior orophar- +ynx. +A triangle-shaped +piece of the upper half of the cartilage is resected. +Closure of the +oropharynx is done so that the larynx is pulled up (sagittal sec- +tion). +Analysis of 18 cases. +Ann Surg. +A salivary tube +is also a good option for proximal esophageal fistulas. +Rarely, combinations of these grafts +will be the only possible option. +Because +the anastomosis is within the chest, a thoracotomy is necessary. +A. +B. +Philadelphia: Lea & Febiger, 1989, p 419.] +esophagogastrostomy. +25-83). +Of the two, the colon +provides the longest graft. +Gastric interposition has the +advantage that only one anastomosis is required. +When it occurred, the most com- +mon cause was recurrent mediastinal tumor. +This is less likely in patients +who have had a colonic interposition for esophageal replace- +ment. +The stomach is divided with an Endo-GIA stapler just +below the GEJ. +The colon is prepared to provide an interposed +segment as previously described. +The left carotid sheath is +retracted laterally and the thyroid and trachea medially. +The left recurrent laryngeal nerve is +identified and protected. +A vein stripper is passed up the +esophagus into the neck wound. +An end-to-end anastomosis is performed to +the cervical esophagus using a single layer technique. +BIBLIOGRAPHY +entries highlighted in bright blue are key references. +General References +Balaji B, Peters JH: Minimally invasive surgery for esophageal +motor disorders. +Surg Clin North Am 82:763, 2002. +Bremner CG, DeMeester TR, Bremner RM: Esophageal Motility +Testing Made Easy. +St. +Louis: Quality Medical Publishing, 2001. +Castel DW, Richter J (eds): The Esophagus. +Boston: Little, +Brown & Co., 1999. +DeMeester SR, Peters JH, DeMeester TR: Barrett’s esophagus. +Curr Probl Surg 38:549, 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marginal +ulceration and/or gastric stasis (Roux syndrome) may become +problematic. +6 Most patients with primary gastric lymphoma can be +treated without gastric resection. +7 Gastric carcinoids should usually be removed either endo- +scopically or surgically. +Table 26-1 +Historic milestones in gastric surgery +DATE EVENT DATE EVENT +350 b.c. +– +201 a.d. +Guy de Chauliac describes closure of +gastric wound. +Marcellus Donatus of Mantua describes +gastric ulcer at autopsy. +Reports of surgeons cutting stomach to +remove foreign bodies. +Muralto describes duodenal ulcer at +autopsy. +Morgagni describes both gastric and +duodenal ulcer at autopsy. +William Beaumont reports data recorded +during his care of Alexis St. +Martin who +developed a gastric fistula from a left +upper quadrant musket wound. +Gross. +Sidney Jones in London publishes the first +successful gastrostomy for feeding. +Paen performed distal gastrectomy and +gastroduodenostomy. +The patient died +5 d later. +Rydygier resected a distal gastric cancer, +and the patient died 12 h later. +Billroth resects distal gastric cancer and +performs gastroduodenostomy (Billroth I). +Patient Therese Heller recovers and +survives 4 mo. +Anton Wolfler performs loop +gastrojejunostomy to palliate an +obstructing distal gastric cancer. +Rydygier reports an unsuccessful +gastrojejunostomy for benign gastric outlet +obstruction. +Mikulicz performs similar operation. +Jaboulay describes bypassing the intact pylorus with +gastroduodenostomy. +Finney from Baltimore describes pyloroplasty +technique. +Subtotal gastrectomy grows popular as an operation for +peptic ulcer. +Von Haberer and Finsterer proponents. +Dragstedt and Owen describe transthoracic truncal +vagotomy to treat peptic ulcer disease. +Edwards and Herrington (Nashville) describe truncal +vagotomy and antrectomy for peptic ulcer. +Zollinger and Ellison describe the eponymous +syndrome. +Evolving role of laparoscopic techniques in the +treatment of surgical gastric disease. +Dramatic increase in bariatric operations. +Development of natural orifice translumenal endoscopic +surgery. +26-2). +The left lateral segment of the liver usually covers a large part +of the anterior stomach. +Inferiorly, the stomach is attached to the +transverse colon by the gastrocolic omentum. +Posterior to +the stomach is the lesser omental bursa and the pancreas. +26-3). +The veins draining the stomach generally parallel the +arteries. +This is +Figure 26-1. +Anatomic regions of the stomach. +II. +Philadelphia: +Saunders, 2002, p 3. +Anatomic relationships of the +stomach. +II. +Philadelphia: Saunders, +2002, p 3. +The nodes along both the greater and lesser +curvature commonly drain into the celiac nodal basin. +pancreatic + duodenal a. +Abdominal + Aorta +Inferior pancreatic + duodenal a. +Hepatic a. +Left gastric a. +Branches +to greater +omentum +Splenic a. +& v. +L. +gastroepiploic a. +Sup. +mesenteric + a. +& v. +Inferior +mesenteric a. +Ileocolic a. +26-5). +In 50% of patients, +there are more than two vagal nerves at the esophageal hiatus. +The branch that the posterior vagus sends to the posterior fundus +Figure 26-3. +Arterial blood supply to the +stomach. +a. += artery; v. += vein. +II. +Philadelphia: Saunders, +2002, p 3. +Copyright Elsevier.] +1039 +Stomach +CHAPTER 26 +is termed the criminal nerve of Grassi. +They also play +a role in appetite control and perhaps even mucosal immunity +and inflammation. +Stations 3 to 6 are +commonly removed with D1 gastrectomy. +Stations 1, 2, and 7 to 12 are commonly removed with D2 gastrectomy. +Berlin: +Springer-Verlag, 1997, p 82–83. +The epithelium, lamina propria, and muscularis +mucosa constitute the mucosa (Fig. +26-7).14 The epithelium of +the gastric mucosa is columnar glandular. +26-8, Table 26-2).15,16 There are also +endocrine cells present in the gastric glands. +Hepatic br. +left vagus +Celiac br. +rt. +vagus +Nerve of Laterjet +Pyloric br. +Left vagus n. +Figure 26-5. +Vagal innervation of the stomach. +br. += branch; n. += +nerve; rt. += right. +Philadelphia: Saunders, 1976, p 8. +Layers of the gastric wall. +Philadelphia: Saunders, +1986, p 625. +Copyright Elsevier.] +Figure 26-7. +Gastric mucosa. +(Reproduced with permission from Bloom W, Fawcett DW: A Textbook of Histology, 10th ed. +Philadelphia: +Saunders, 1975, p 639.) +extend down into the gland pits for variable distances. +In the +fundus and body, the glands are more tubular and the pits are +deep. +Parietal and chief cells are common in these glands +(Fig. +26-9). +26-9). +Mammalian gastric gland from the body of the stom- +ach. +J Cell Biol 16:541, +1963. +Copyright © 1963 The Rockefeller University Press. +They tend to +be clustered toward the base of the gastric glands and have a low +columnar shape. +26-10). +These proenzymes are activated in +an acidic luminal environment. +The collagen-rich +submucosa gives strength to GI anastomoses. +Specialized pacemaker cells, the interstitial cells of +Cajal (ICC), also are present. +The outer layer of the stomach is the serosa, also known as +the visceral peritoneum. +This layer provides significant tensile +strength to gastric anastomoses. +In this way, the serosa may be thought of as an +outer envelope of the stomach. +In +an acidic environment, pepsin and acid facilitate proteolysis. +The parietal cell is stimulated to secrete acid +(Fig. +Source: From Antonioli et al,16 with permission. +SC +M +TV +Figure 26-9. +Ultrastructural features of the parietal (oxyntic) +cell. +SC = secretory canaliculus; M = mitochondria; TV = tubulo- +vesicle. +Baltimore: Williams & Wilkins, 1998, p 13.] +ZG +GA +GER +Figure 26-10. +Ultrastructural features of the chief (zymogenic) +cell. +GA = Golgi apparatus; GER = granular endoplasmic reticu- +lum; ZG = zymogen granule. +26-12). +Endocrine cells of the stomach—proportion by +site. +Philadelphia: Saunders, 2002, p 715. +Control of acid secre- +tion in the parietal cell. +II. +Philadelphia: Saunders, +2002, p 3. +Copyright Elsevier.] +protein kinases and activation of H+/K+-ATPase. +Physiologic Acid Secretion. +Food ingestion is the physi- +ologic stimulus for acid secretion (Fig. +26-13). +Acetylcholine is released, leading to +stimulation of ECL cells and parietal cells. +When food reaches the stomach, the gastric phase of +acid secretion begins. +The gastric phase of acid secretion has +several components. +Antral distention also stimulates +antral gastrin secretion. +Acetylcholine stimulates gastrin release +and gastrin stimulates histamine release from ECL cells. +The intestinal phase of gastric secretion is poorly under- +stood. +It accounts for about 10% of meal- +induced acid secretion. +Basal acid secretion is reduced 75% to 90% by vagotomy or H2 +receptor blockade. +26-13. +The mucosal D cell, which releases somatostatin, is also +an important regulator of acid secretion. +Somatostatin inhibits +histamine release from ECL cells and gastrin release from antral +G cells. +Physiologic control of acid secretion. +ECL = +enterochromaffin-like. +II. +Philadelphia: Saunders, 2002, +p 3. +Somatostatin inhibits pepsinogen secre- +tion. +Pepsin catalyzes the hydrolysis of proteins +and is denatured at alkaline pH. +A variety of factors are important in maintain- +ing an intact gastric mucosal layer. +“Back-diffused” hydrogen is +buffered and rapidly removed by the rich blood supply. +If this protective response is blocked, gross ulcer- +ation can occur. +Sucralfate acts +locally to enhance mucosal defenses. +Gastric Hormones13,26 +Gastrin. +The large majority of gastrin released by the human +antrum is G17. +26-13). +Gastrin is trophic to gastric parietal cells and +to other GI mucosal cells. +Somatostatin. +Somatostatin is produced by D cells located +throughout the gastric mucosa. +The predominant form in +humans is somatostatin 14, though somatostatin 28 is present +as well. +Somatostatin inhibits acid secretion from parietal cells +and gastrin release from G cells. +It also decreases histamine +release from ECL cells. +Gastrin-Releasing Peptide. +Leptin. +Leptin is a protein primarily synthesized in adipocytes. +Ghrelin levels are decreased after gastrectomy. +J Clin Endocrinol Metab. +10 a.m. +noon +2 p.m.4 p.m. +6 p.m.8 p.m. +10 p.m. +A and B. +Ghrelin +secretion after bariatric surgery. +B. +Top = +RYGBP; B bottom = SG. +(Fig. +N Engl J Med 346:1623, +2002. +Copyright ©2002 Massachusetts +Medical Society. +All rights reserved. +Fig. +When feeding begins, the stomach +relaxes to accommodate the meal. +Serotonin has been shown to modulate both contraction +and relaxation. +Enteric nervous system. +New York: McGraw-Hill, +2003, p 355. +Segmental Gastric Motility. +Rapid phasic contractions may be superimposed on the slower +tonic motor activity. +When food is ingested, intragastric pres- +sure falls as the proximal stomach relaxes. +NO and VIP are the principal mediators of proximal gas- +tric relaxation. +The distal stomach breaks up solid food and is the main +determinant of gastric emptying of solids. +These waves originate from +the proximal gastric pacemaker, high on the greater curvature. +26-17). +The relationship between intracellular electrical activity and muscle cell contraction. +During mechanical quiescence, there are regular depolarizations that do not reach +threshold. +Mayo Clin Proc. +Migrating motor complex, the +fasting pattern of GI activity. +Dig Dis Sci. +27(4):321, +1982. +26-18). +Phase I +(about half the length of the entire cycle) is a period of relative +motor inactivity. +High-amplitude muscular contractions do not +occur in phase I of the MMC. +Phase IV is a transi- +tion period. +This suggests that phase III is regulated by intrinsic +nerves and/or hormones. +There are clearly motilin receptors on antral smooth muscle +and nerves. +Feeding abolishes the MMC and leads to the fed motor +pattern. +Ileal perfusion with fat has the same effect. +The pylorus is readily apparent grossly as a thick ring of +muscle and connective tissue. +The motor activity +of the pylorus is both tonic and phasic. +During phase III of the +MMC, the pylorus is open as gastric contents are swept into the +duodenum. +During the fed phase, the pylorus is closed most +of the time. +Modulation of pyloric motor activity is complex. +There +is evidence of both inhibitory and excitatory vagal pathways. +Nitric oxide +is an important mediator of pyloric relaxation. +Gastric Emptying.13 The control of gastric emptying is com- +plex. +In general, liquid emptying is faster than solid emptying. +CCK has been consistently shown +to inhibit gastric emptying at physiologic doses (Fig. +26-19). +The orexigenic hormone +ghrelin has the opposite effect. +Liquid Emptying. +26-20). +Up to an osmolarity of +about 1 M, liquid emptying occurs at a rate of about 200 kcal +per hour. +Generally, liquid emptying is delayed in the supine position. +Cholecystokinin (CCK) inhibits gastric emptying. +Some observations suggest an active role for the distal +stomach in liquid emptying. +Solid Emptying. +Normally, the half-time of solid gastric +emptying is less than 2 hours. +It is during this phase that much of the +grinding and mixing occurs. +When liquids +and solids are ingested together, the liquids empty first. +The larger the solid component of +the meal, the slower the liquid emptying. +Nutrient composition and caloric density affect +liquid gastric emptying. +Glucose solution (purple circles), the least +calorically dense, emptied the fastest. +J Physiol. +Three prokinetic agents are commonly used to treat delayed +gastric emptying. +Typical doses and mechanism of action are +shown in Table 26-4. +Nausea, vomiting, bloating, and +anemia also are frequent complaints. +Diagnostic Tests +Esophagogastroduodenoscopy. +The fundus and GE junction are inspected by +retroflexing the scope. +pylori. +Radiologic Tests. +Computed Tomographic Scanning and Magnetic Resonance +Imaging. +Usually, significant gastric disease can be diagnosed +without these sophisticated imaging studies. +26-21). +Endoscopic Ultrasound. +EUS is the best way to +clinically stage these patients locoregionally. +Suspicious nodes +can be sampled with EUS-guided endoscopic needle biopsy. +EUS +also can be used to assess tumor response to chemotherapy. +Submucosal masses are commonly discovered during routine +EGD. +Submucosal varices also can be assessed by EUS. +Gastric Secretory Analysis. +Normal basal acid output (BAO) is greater than 5 mEq/h. +MAO is the average of the two final stimulated 15-minute peri- +ods and is usually 10 to 15 mEq/h. +Peak acid output is defined +as the highest of the four stimulated periods. +In patients with gastrinoma, the +ratio of BAO to MAO exceeds 0.6. +Scintigraphy. +A +curve for liquid and solid emptying is plotted, and the half-time +calculated. +Normal standards exist for each facility. +Tests for Helicobacter pylori. +A variety of tests can help the +clinician to determine whether the patient has active H. +pylori infection in the screened population. +A +positive test is quite accurate in predicting H. +pylori infection, +but a negative test is characteristically unreliable. +Thus, in the +appropriate clinical setting, treatment for H. +Because of the association between +H. +pylori. +Urease is an omnipresent +enzyme in H. +pylori strains that colonize the gastric mucosa. +The labeled carbon-13 urea breath test has become the standard +test to confirm eradication of H. +The labeled urea is acted upon by the urease +present in the H. +pylori and converted into ammonia and carbon +dioxide. +26-22). +It also +can be detected in a blood sample. +The fecal antigen test also +is quite sensitive and specific for active H. +pylori infection and +may prove more practical in confirming a cure. +1052 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +AB +CD +E +Figure 26-21. +Axial computed +tomographic scan (B) also shows a protruding polyp (arrow). +EGG consists of the transcutaneous recording of gastric myo- +electric activity. +There are pressure-recording sensors extending from the stom- +ach to the distal duodenum. +Labeled urea breath test to +detect Helicobacter infection. +N Engl J Med 333:984, 1995. +Copyright ©1995 Massachusetts Medical +Society. +All rights reserved.) +Acid +Pepsin +NSAIDs +H. +Balance of aggressive and defensive factors in +the gastric mucosa. +(Reproduced with permission from Mertz HR, +Walsh JH: Peptic ulcer pathophysiology. +Med Clin North Am +75:799, 1991. +pylori infection. +Pathophysiology and Etiology +A variety of factors may contribute to the development of PUD. +pylori infection and/or +NSAID use17,52 (Fig. +Thus, the adage “no acid, no ulcer” remains true. +Acid +suppression heals both duodenal and gastric ulcers and prevents +recurrence. +In general H. +NSAID use causes ulcers predominantly by com- +promise of mucosal defenses. +Elimination of H. +pylori infec- +tion, NSAID use, and/or cigarette smoking. +Helicobacter pylori Infection. +With specialized flagella +and a rich supply of urease, H. +pylori, a +major cause of chronic gastritis. +Helicobacter also clearly has an +etiologic role in the development of gastric lymphoma. +The ammonia is damaging to the surface epithelial +cells. +Mutant strains of H. +pylori that do not produce urease +are unable to colonize the stomach. +The organism lives in the +mucus layer atop the gastric SECs, and some attach to these +cells (Fig. +This is due, in part, to the inhibitory effect that H. +H. +pylori +infection +NSAID +use +None known +Z.E., other +H. +pylori +infection +Duodenal Gastric +Figure 26-24. +“Causes” of peptic ulcer +disease. +Z.E. += Zollinger-Ellison syn- +drome. +Philadelphia: +Saunders, 2002, p 747. +Copyright Elsevier.] +Figure 26-25. +Helicobacter pylori closely adherent to the cell mem- +brane (top), and spiral-shaped H. +pylori attached to epithelial surface +and surrounding microvilli (bottom). +(From Parsonnet J: Clinician-discoverers—Marshall, Warren, +and H. +pylori. +N Engl J Med 353:2421, 2005. +These effects are probably mediated +by H. +pylori–mediated increases in other local mediators +and cytokines. +The result is hypergastrinemia and acid hyper- +secretion (Fig. +This duodenal metaplasia allows H. +When H. +When H. +pylori infec- +tion is successfully treated, acid secretory physiology tends to +normalize. +Other mechanisms whereby H. +pylori in +the pathophysiology of PUD is strong. +Patients with H. +pylori infec- +tion. +pylori infection. +It +is clear from multiple randomized prospective studies that cur- +ing H. +pylori +infection in stomach +H. +pylori colonization in duodenum Figure 26-26. +Model of Helico- +bacter effects on duodenal ulcer +pathogenesis. +Am J Med 102:200, +1997. +pylori infection. +pylori is indubitably +an important factor in the development and recurrence of PUD. +H. +pylori infection. +In patients with gastric ulcer, acid secretion is variable. +Type IV gastric ulcers occur near the GE junction, and acid +cag+ +H. +Pathogen-host interactions in the pathogenesis of Helicobacter pylori infection. +(Reproduced with permission from Suerbaum +S, Michetti P: Helicobacter pylori infection. +N Engl J Med 347:1175, 2002. +Copyright ©2002 Massachusetts Medical Society. +All rights +reserved.) +secretion is normal or below normal. +Type V gastric ulcers are +medication induced and may occur anywhere in the stomach. +NSAIDs and aspirin have similar effects. +Helicobacter treatment dramatically decreases the +recurrence rate of duodenal and gastric ulcer. +A randomized controlled study. +Frequency of physiologic abnormalities +in patients with duodenal ulcer (DU). +HCO3 = bicarbon- +ate; MAO = maximal acid output. +Modified Johnson classification for gastric ulcer. +I. +Lesser curve, incisura. +II. +Body of stomach, incisura + duodenal +ulcer (active or healed). +III. +Prepyloric. +IV. +High on lesser curve, +near gastroesophageal junction. +V. +Medication-induced (NSAID/ +acetylsalicylic acid), anywhere in stomach. +Philadelphia: +Mosby Elsevier, 2008, p 81. +Copyright Elsevier.] +1058 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +taking NSAIDs. +This risk increases to five times in patients more +than age 60 years old. +Smoking, Stress, and Other Factors. +Smoking increases gastric acid secretion and +duodenogastric reflux. +e21% of patients in CLASS study were taking low-dose aspirin. +Gastroenterology +120:594, 2001. +Copyright Elsevier. +In 1842, Curling described duo- +denal ulcer and/or duodenitis in burn patients. +Even the ancients +recognized the undeniable links between PUD and stress. +Alco- +hol is commonly mentioned as a risk factor for PUD, but con- +firmatory data are lacking. +The pain is typically nonradiating, burning in quality, and +located in the epigastrium. +The mechanism of the pain is unclear. +Patients with duodenal ulcer often experience pain 2 to 3 hours +after a meal and at night. +Two thirds of patients with duodenal +ulcers will complain of pain that awakens them from sleep. +A double-contrast +upper GI X-ray study may be useful. +pylori, and for histologic evaluation. +Additional testing for +H. +pylori may be indicated. +It is not unreasonable to test all pep- +tic ulcer patients for H. +pylori (Table 26-8) 63A baseline serum +gastrin level is appropriate to rule out gastrinoma. +Chey +WD, Wong BCY.63 Practice Parameters Committee of the American +College of Gastroenterology. +Am J Gastroenterol. +2007;102:1808. +Copyright © 2007. +26-31).65 Patients with a bleeding peptic ulcer +typically present with melena and/or hematemesis. +Nasogas- +tric aspiration is usually confirmatory of the upper GI bleed- +ing. +Abdominal pain is quite uncommon. +Shock may be present, +necessitating aggressive resuscitation and blood transfusion. +Planned surgery under controlled circumstances often +yields better outcomes than emergent surgery. +Causes of upper GI bleeding. +BMJ 323:1115, 2001. +The complete Rockall score ranges from 0 to 11, with higher scores indicating higher +risk. +N Engl J Med. +359:928, 2008. +Copyright +©2008 Massachusetts Medical Society. +All rights reserved. +The patient can often give the exact time of onset of the +excruciating abdominal pain. +The patient is in +obvious distress, and the abdominal examination shows perito- +neal signs. +Usually, marked involuntary guarding and rebound +tenderness is evoked by a gentle examination. +Upright chest +X-ray shows free air in about 80% of patients (Fig. +26-32). +Gastric outlet obstruction occurs in no more than 5% of +patients with PUD. +Pain or discomfort is common. +Weight loss may be promi- +nent, depending on the duration of symptoms. +A succussion +splash may be audible with stethoscope placed in the epigas- +trium. +The diagnosis is +confirmed by endoscopy. +Patients hospital- +ized for ulcer complications should receive PPI by continuous +Figure 26-32. +Pneumoperitoneum on upright chest X-ray in +patient with perforated ulcer. +Peptic ulcer patients should +stop smoking and avoid alcohol and NSAIDs (including +aspirin). +If H. +If initial H. +pylori testing is negative +and ulcer symptoms persist, an empirical trial of anti-H. +pylori +therapy is reasonable since false-negative H. +pylori tests are +common. +Generally, acid suppression can be stopped after 3 +months if the ulcerogenic stimulus (usually H. +pylori, NSAIDs, +or aspirin) has been removed. +26-33). +Copyright +Elsevier. +6–8cm +7cm +Figure 26-33. +Highly selective vagotomy. +I. +Stamford, Connecticut: Appleton & Lange, +1997, p 987. +HSV may be substituted for truncal +vagotomy. +The advantage of V + D is that it can be performed +safely and quickly by the experienced surgeon. +During truncal vagotomy +(Fig. +26-34), care must be taken not to perforate the esophagus, +a potentially lethal complication. +Unlike HSV, V + D is widely +accepted as a successful definitive operation for complicated +PUD. +When applied to gastric ulcer, the ulcer +should be excised or biopsied. +26-35). +Marginal ulceration is a potential com- +plication. +26-36). +Other +occasionally useful techniques include the Finney (Fig. +26-37) +and the Jaboulay pyloroplasties (Fig. +26-38). +26-39) or a Billroth II +loop gastrojejunostomy (Fig. +26-40). +26-41). +Resected segment Resected segment +Celiac branch +Hepatic branch +Figure 26-34. +Truncal vagotomy. +[Reproduced with permission +from Zollinger RM Jr., Zollinger RM Sr. +(eds): Zollinger’s Atlas of +Surgical Operations, 8th ed. +New York: McGraw-Hill, 2003, p 45. +Copyright © The McGraw-Hill Companies, Inc.] +Figure 26-35. +Retrocolic gastrojejunostomy. +Note +mesocolon sutured to stomach (b, c, d). +Vol. +II. +Philadelphia: +Saunders, 2002, p 129. +Table 26-12 shows the surgical options for managing +various aspects of PUD. +Because ulcer recurrence often is related to H. +A through D. +Heineke-Mikulicz pyloroplasty. +[Reproduced with permission from Zinner MJ (ed): Atlas of Gastric Surgery. +New York: Churchill Livingstone, 1992, p 17. +Gastric ulcer requires biopsy if not resected. +The management of bleeding peptic ulcer is summarized +in the algorithm provided in Fig. +26-42. +tier) +Duod. +Cushing +seromuscular +suture (2nd ant. +tier) +Posterior +through & +through suture +Figure 26-37. +A through D. +Finney pyloroplasty. +ant. += anterior; Duod. += duodenum; Stom. += stomach. +Philadelphia: Saunders, +1996, p 150. +The mortality rate for surgery for +bleeding peptic ulcer is around 20%. +Angiography and emboli- +zation may be useful in some patients. +Operation for Bleeding Peptic Ulcer (Fig. +Patients +who are in shock or medically unstable should not have gastric +resection. +Multiple sutures are usually necessary. +Once the surgeon is + S t o m a ch + S t o m . +A +B +D +C +Pylorus +Inverted +incision +Gall +bladder +Duodenum +Connell +through & through +suture (1st ant. +tier) +Duod. +Cushing +seromuscular +suture (2nd ant. +tier) +Posterior +through & +through suture +Figure 26-38. +A through D. +Jaboulay pyloroplasty. +ant. += anterior; Duod. += duodenum; Stom. += stomach. +Philadelphia: +Saunders, 1996, p 150. +A though C. +Billroth I gastroduodenostomy. +[Reproduced with permission from Zinner MJ (ed): Atlas of Gastric Surgery. +New York: Churchill Livingstone, 1992, p 35. +Copyright Elsevier.] +Figure 26-40. +A through D. +Billroth II antecolic gastrojejunostomy. +I. +Stamford, Connecticut: +Appleton & Lange, 1997, p 1112. +Roux-en-Y gastrojejunostomy. +Oversewa +2. +Oversew, V + D +3. +V + A +1. +Oversew and biopsya +2. +Oversew, biopsy, V + D +3. +Distal gastrectomyb +Perforation 1. +Patcha +2. +Patch, HSV +3. +Patch, V + D +1. +Biopsy and patcha +2. +Wedge excision, V + D +3. +Distal gastrectomyb +Obstruction 1. +HSV + GJ +2. +V + A +1. +Biopsy; HSV + GJ +2. +Distal gastrectomyb +Intractability/ +nonhealing +1. +HSVb +2. +V + D +3. +V + A +1. +HSV and wedge +excision +2. +bOperation of choice in low-risk patient. +Right upper quadrant closed suction +peritoneal drainage is important. +Use of a feeding jejunostomy +is also considered. +A Billroth II anastomosis reestablishes gas- +trointestinal continuity. +Second best +is V + D with oversewing and biopsy of the ulcer to rule out +cancer. +Perforated Peptic Ulcer (Fig. +In stable patients without longstanding perforation, the addition +of HSV may be considered. +Vagotomy is usually added for type II and III gastric +ulcers. +However, +potentially curable gastric or duodenal cancers can be missed +with this approach. +pylori +Avoid NSAIDs/ASA if possible +Yes Shock? +No +YesT ransfusion? +No +Yes Active bleeding on EGD?N o +YesV isible vessel on EGD?N o +Yes Abnormal PT, PTT, or platelets? +No +Figure 26-42. +Algorithm for the treatment of bleeding peptic ulcer. +ASA = acetylsalicylic acid; EGD = esophagogastroduodenoscopy; +O.R. +Because +acid secretion can be totally blocked and H. +Or +High operative risk? +or +difficult duodenum? +Algorithm for operation for bleeding peptic ulcer. +Figure 26-44. +Algorithm for operation for perforated peptic ulcer. +Or +Perforation on RX? +Or +NSAIDs/ASA necessary? +Gastric ulcer* Duodenal ulcer* +Hemodynamically unstable? +Or +High operative risk? +Or +Perforation >24 hours + * In all patients, test and treat for H. +pylori, and if vagotomy not performed (most patients today) + consider lifelong PPI. +If surgery is necessary, a lesser operation may be preferable. +Otherwise, distal gastrectomy (to include the ulcer) is +recommended. +26-45). +Most cases (80%) are sporadic, but +20% are inherited. +Gastrinoma is the most common pancreatic +tumor in patients with MEN I. +Five-year survival in patients present- +ing with metastatic disease is approximately 40%. +The larger the +primary gastrinoma, the higher the likelihood of metastatic dis- +ease. +More than 90% of patients with sporadically, completely +resected gastrinoma will be cured. +The most common symptoms of ZES are epigastric pain, +GERD, and diarrhea. +More than 90% of patients with gastri- +noma have peptic ulcer. +Operations for gastric ulcer. +Philadelphia: Saunders, 1998, +p 702. +ZES is an important part of the differential diagnosis of +hypergastrinemia (Fig. +26-46). +26-46). +pylori +give B12 +Significant elevation in serum +gastrin in response to IV secretin? +Algorithm for diagnosis and management of hypergastrinemia. +the secretin stimulation test. +An increase in serum gastrin of 200 pg/mL or greater suggests +the presence of gastrinoma. +About 80% of primary tumors are found in the gastrinoma +triangle (Fig. +26-47), and many tumors are small (<1 cm), mak- +ing preoperative localization difficult. +Transabdominal ultra- +sound is quite specific, but not very sensitive. +CT will detect +most lesions >2 cm in size and MRI is comparable. +26-48). +Currently, angiographic localiza- +tion studies are infrequently performed for gastrinoma. +Secre- +tin is injected into the visceral artery and gastrin is sampled in +the hepatic vein. +This test should be performed if pancreaticoduodenectomy is +contemplated. +Probably the most important means of locating +gastrinomas is intraoperative exploration. +Intraoperative EGD +with transillumination may be considered. +If the tumor can +not be located, generous longitudinal duodenotomy with +Figure 26-47. +Gastrinoma triangle. +Philadelphia: Lippincott, 1995, p 128.] +Figure 26-48. +Positive octreotide scan in patient with gastrinoma. +Lymph nodes from the portal, peripancreatic, and celiac drain- +age basins should be sampled. +Ablation or resection of hepatic +metastases should be considered. +Acid hypersecretion in patients with gastrinoma can +always be managed with high-dose PPIs. +Gastrectomy for ZES is no longer +indicated. +GASTRITIS AND STRESS ULCER +Pathogenesis and Prevention +Gastritis is mucosal inflammation. +Additionally, there is poor correlation between symp- +toms and histologic gastritis. +The most common cause of gastritis +is H. +pylori. +These agents cause injury by a variety of different mecha- +nisms. +When blood flow is inadequate, these processes fail and muco- +sal breakdown occurs. +Angiographic +embolization and endoscopic hemostatic treatment should be +considered as well. +Other rare primary malignancies +Table 26-14 +Frequency of gastric tumors +TUMOR TyPE NO. +Washington DC: American Registry of Pathology, +1973, p 82, Table VI. +include carcinoid, angiosarcoma, carcinosarcoma, and squa- +mous cell carcinoma. +Adenocarcinoma +Epidemiology. +26-49). +In Asia and Eastern Europe, gas- +tric cancer remains a leading cause of cancer death. +Gastric cancer has a +higher incidence in groups of lower socioeconomic status. +Etiology. +This strongly +suggests an environmental influence on the development of gas- +tric cancer. +The commonly accepted risk factors +for gastric cancer are listed in Table 26-15. +Dietary nitrates have been impugned as a possible cause of +gastric cancer. +Regular aspirin use may be protective. +Helicobacter pylori 54,84 The risk of gastric cancer in patients +with chronic H. +pylori infection is increased about threefold. +As diagrammed in Fig. +Not all +patients with gastric cancer have H. +pylori, and there are some +geographic areas with a high prevalence of chronic H. +pylori infec- +tion and a low prevalence of gastric cancer (the “African enigma”). +Death rates for gastric +cancer in different countries. +Epstein-Barr Virus About 10% of gastric adenocarcinomas +carry the EBV virus. +Most gastric cancers +are aneuploid. +The most common genetic abnormalities in spo- +radic gastric cancer affect the p53 and COX-2 genes. +Additionally, approxi- +mately the same proportion have overexpression of COX-2. +Gastric tumors that overexpress COX-2 are more aggressive +tumors. +By far the most common precancerous lesion is +atrophic gastritis. +Hyperplastic pol- +yps usually occur in the setting of chronic inflammation. +Gastric adenomas are premalignant, similar to colon adenomas. +Helicobacter and gastritis, and the +pathogenesis of duodenal ulcer (DU) or gastric +cancer. +pylori Diet low in vitamin C, E +High-salt diet +Figure 26-51. +Gastric carcinogenesis. +Philadelphia: Saunders, 2002. +Copyright Elsevier. +Precancerous lesions of the stomach. +Atrophic Gastritis Chronic atrophic gastritis (Fig. +26-52). +In many patients, it is likely that H. +pylori is involved +in the pathogenesis of atrophic gastritis. +26-54). +There is evidence that eradication of H. +Therefore, treatment of +H. +pylori infection. +Figure 26-53. +Chronic atrophic gastritis. +The risk is controversial, +but the phenomenon is real. +Periodic surveillance +EGD is prudent in all the above conditions. +Figure 26-54. +Complete intestinal metaplasia of the stomach. +Note +intestinal type crypts lined with goblet cells and intestinal absorp- +tive cells. +Approximately 10% of patients with early +gastric cancer will have lymph node metastases. +There are sev- +eral types and subtypes of early gastric cancer (Table 26-17 and +Fig. +26-55). +The over- +all cure rate with adequate gastric resection and lymphad- +enectomy is 95%. +In some Japanese centers, 50% of the +gastric cancers treated are early gastric cancer. +In the United +States, less than 20% of resected gastric adenocarcinomas are +early gastric cancer. +In the first two, the bulk of the tumor mass is +intraluminal. +In the +latter two gross subtypes, the bulk of the tumor mass is in the +wall of the stomach. +Palliative chemo- +therapy may prolong median survival94A. +Type 0-IIa Slightly elevated tumors. +(superficial +elevated) + Type 0-IIb Tumors without elevation or depression. +(superficial flat) + Type 0-IIc Slightly depressed tumors. +Several decades ago, the large +majority of gastric cancers were in the distal stomach. +There are several histologic classifications of gastric can- +cer. +The World Health Organization recognizes several histologic +types (Table 26-18). +The Japanese classification is similar but +more detailed. +Pathologic types of early gastric cancer. +Semin Oncol. +23(3):292, +1996. +Baltimore: Williams & +Wilkins, 1998. +gastric cancer, HER2 overexpression has been reported in 13% +to 30% of patients. +Clinical Manifestations. +Abdominal pain (usually not severe and often +ignored) also is common. +Other symptoms include nausea, +vomiting, and bloating. +Dysphagia is +common if the tumor involves the cardia of the stomach. +Physical examination typically is normal. +Other than signs +of weight loss, specific physical findings usually indicate incur- +ability. +Diagnostic Evaluation. +In some patients with gastric tumors, upper GI series can be +helpful in planning treatment. +The image of virtual endoscopy is now quite +similar to that of upper endoscopy. +In the near future, this novel +technology may play a role in the screening of the stomach. +MRI is probably comparable. +However, there are limitations to tumor staging +with EUS. +EUS is most accurate in distinguishing +early gastric cancer (T1) from more advanced tumors. +Unfortunately, +it is also unclear how much these patients benefit from gastric +resection. +Treatment. +The goal of curative surgical treatment is resection of all +tumor (i.e., R0 resection). +Generally, the surgeon strives for a grossly +negative margin of at least 5 cm. +26-56). +Reconstruction +Gastroepiploic +vs. +A and B. +Radical subtotal gastrectomy. +vs. += vessels. +[Reproduced with permission from Daly JM, Cady B, Low DW +(eds): Atlas of Surgical Oncology. +St. +Louis: Mosby-Year Book, +1993, p 231. +The oper- +ative mortality is around 2% to 5%. +In the absence of involvement by direct extension, the +spleen and pancreatic tail are not removed. +Total gastrectomy with Roux-en-Y esophagojejunostomy +may be required for R0 resection (Fig. +26-57), and may be the +best operation for patients with proximal gastric adenocarcinoma. +26-4). +According to the type of gas- +trectomy, the definition of extent of lymphadectomy is different. +The standard opera- +tion for gastric cancer in Asia and specialized U.S. +centers is +60 cm +Figure 26-57. +Reconstruction after total gastrectomy. +Jejunal +pouch (not shown here) should be considered. +[Reproduced with +permission from Zinner MJ (ed): Atlas of Gastric Surgery. +New York: +Churchill Livingstone, 1992, p 167. +This stage shift suggests that many patients in the U.S. +Therefore, in the +U.S. +The Surgical Cooperative Group. +Lancet. +347:995, 1996. +cancer as well as several types of cancer, such as colon and lung. +In +Europe, triple therapy is more often epirubicin, cisplatin, and +5-FU. +EMR is indicated for patients in +whom the probability of lymph node metastasis is low. +New indications +for minimally invasive treatment will require evaluation before +implementation. +The addition of laparoscopic lymph node sampling may be +considered in selected patients. +Prognosis. +Survival is dependent on pathologic stage (TNM stage) +and degree of tumor differentiation. +Thus, screening is effective in a high-risk population. +Gastric Lymphoma +Gastric lymphomas generally account for about 4% of gastric +malignancies. +Over half of patients with non-Hodgkin’s lym- +phoma have involvement of the GI tract. +The stomach is the most +common site of primary GI lymphoma, and over 95% are non- +Hodgkin’s type. +Interest- +ingly, the normal stomach is relatively devoid of lymphoid tissue. +Again, H. +pylori is thought to be the culprit. +In populations with a high inci- +dence of gastric lymphoma, there is a high incidence of H. +pylori +infection; patients with gastric lymphoma also usually have H. +pylori. +Remarkably, +when the H. +pylori is eradicated and the gastritis improves, the +low-grade MALT lymphoma often disappears. +Thus, low-grade +MALT lymphoma is not a surgical lesion. +If low-grade lymphoma persists after H. +26-58). +The tumors may +bleed and/or obstruct. +Lymphadenopathy and/or organomegaly +suggest systemic disease. +Diagnosis is by endoscopy and biopsy. +Much of the tumor may be submucosal, and an assiduous attempt +at biopsy is necessary. +Primary lymphoma is usually nodular with +enlarged gastric folds. +This includes EUS; CT scanning of the chest, abdomen, +and pelvis; and bone marrow biopsy. +Treatment-related +perforation or bleeding is unusual but recognized. +Palliative gastrectomy for +tumor complications also has a role. +Any lesion >1 cm +can behave in a malignant fashion and may recur. +Thus, all GISTs +are best resected along with a margin of normal tissue. +Two-thirds of all GISTs occur in the stomach. +The glomus tumor type is seen only in the stomach. +GISTs are submucosal tumors that are slow growing. +An abdom- +inal mass may be palpable. +EUS may be help- +ful, but symptomatic tumors and tumors >1 cm in size should +be removed. +They are almost +always solitary. +Wedge resection with clear margins is adequate +surgical treatment. +True invasion of adjacent structures by the +primary tumor is evidence of malignancy. +Five-year survival +6 +1085 +Stomach +CHAPTER 26 +following resection for GIST is about 50%. +Interme- +diate risk was defined as <5 cm and 6 to 10/50 HPF or 5 to +10cm and >5/50 HPF. +It was known that the risk of recurrence differs by the +primary site of the tumor. +26-59. +They arise from gastric enterochromaffin-like +(ECL) cells and some have malignant potential. +pylori eradication therapy +and chemo** +/– XRT* +H. +pylori eradication therapy +Re-evaluate at 3–6 months +H. +pylori eradication therapy +Re-evaluate at 12 months +Figure 26-58. +Algorithm for the treatment of gastric lymphoma. +MALT = mucosa-associated lymphoid tissue. +Gastric carcinoids are classified into one of three differ- +ent types. +Type I is the most common type of gastric carcinoid, +accounting for about 75% of patients. +Type II gastric carcinoids are associated with MEN1 and +ZES. +Type III gastric carcinoids are sporadic tumors. +They are +most often solitary (usually >2 cm) and occur more commonly +in men. +They are not associated with hypergastrinemia and +biopsy shows a heterogeneous cell population. +Algorithm for the treatment of gastrointestinal stromal tumor. +Ann Surg 244:176, 2006.) +Gastric carcinoids are usually diagnosed with endoscopy and +biopsy. +Some tumors are submucosal and may be quite small. +They +are often confused with heterotopic pancreas or small leiomyomas. +Plasma chromogranin A levels are elevated in patients with gastric +carcinoid. +CT scan and octreotide scan are useful for staging. +Gastric carcinoids should be resected. +Careful follow-up +is necessary. +Larger lesions should be removed by D1 or D2 gastrec- +tomy. +Gastri- +noma should be resected if located in patients with type II carcinoid. +Surgical debulking may have a role in selected patients with meta- +static disease. +BENIGN GASTRIC NEOPLASMS +Leiomyoma +The typical leiomyoma is submucosal and firm. +If ulcerated, it has +an umbilicated appearance and may bleed. +Histologically, these +7 +1087 +Stomach +CHAPTER 26 +lesions appear to be of smooth muscle origin. +Lesions <2 cm are +usually asymptomatic and benign. +Excision is unnec- +essary unless the patient is symptomatic. +Eighty percent of these patients are women; some are +diabetic. +An upper GI +series may suggest slow gastric emptying and relative atony, +or it may be normal. +EGD may show bezoars or retained food +but is frequently normal. +Gastric emptying scintigraphy shows +delayed solid emptying, and often delayed liquid emptying. +Gastroparesis can be a manifestation of a variety of problems +(Table 26-22). +Risk stratification +is essentially accomplished by answering the following questions: +a. +What is the magnitude and acuity of the hemorrhage? +This is a high-risk situation. +b. +If yes, this is a high-risk situation. +c. +Is the patient anticoagulated, or immunosuppressed? +If yes, +this is a high-risk situation. +d. +Could the +patient be bleeding from an Arterio enteric fistula? +If yes, +this is a high-risk situation. +Park- +man HP et al. +Gastroduodenal motility and dysmotility: An update on +techniques available for evaluation. +Am J Gastroenterol. +1995;90:869. +Copyright © 1995. +Selected patients may +be discharged from the emergency room and managed on an +outpatient basis. +Type and cross-match for transfusion of blood products. +2. +Admit to ICU or monitored bed in specialized unit. +3. +Consult surgeon. +4. +Consult gastroenterologist. +5. +Start continuous infusion of PPI. +6. +Perform upper endoscopy within 12 hours, after resuscita- +tion and correction of coagulopathy. +Mucosal lesions can usually be controlled with endo- +scopic hemotherapy and medical management. +26-43). +The operative mor- +tality is 5%. +Liver transplantation should always be considered +in the cirrhotic patient. +The latter is characteristically associated with protein- +losing gastropathy and hypochlorhydria. +There are large rugal +folds in the proximal stomach, and the antrum is usually spared. +26-60). +This results in the selective expansion of surface +mucous cells in the gastric body and fundus. +There may be an increased risk of gastric +cancer. +Sometimes, the disease regresses spontaneously. +Gastric +resection may be indicated for bleeding, severe hypoprotein- +emia, or cancer. +Mucosal fibromuscular hyperplasia and hyalinization often are +present (Fig. +26-61). +Patients with GAVE +are usually elderly women with chronic GI blood loss requiring +transfusion. +Figure 26-60. +Mucosal biopsy in Ménétrier’s disease. +If this artery is eroded, impressive pulsatile bleeding may occur. +Treatment options include endoscopic +hemostatic therapy, angiographic embolization, or operation. +At +surgery, the lesion may be oversewn or resected. +Bezoars/Diverticula +Bezoars are concretions of indigestible matter that accumulate in +the stomach. +Trichobezoars, composed of hair, occur most com- +monly in young women who swallow their hair (Fig. +26-62). +They also are associated with persimmon inges- +tion. +Most commonly, bezoars produce obstructive symptoms, but +they may cause ulceration and bleeding. +Diagnosis is suggested by +upper GI series and confirmed by endoscopy. +Gastric diverticula are usually solitary and may be congeni- +tal or acquired. +Most gastric diverticula occur in the posterior cardia +or fundus (Fig. +26-63) and are usually asymptomatic. +However, +they can become inflamed and may produce pain or bleeding. +Perforation is rare. +Asymptomatic diverticula do not require treat- +ment, but symptomatic lesions should be removed. +This can often +be done laparoscopically. +Foreign Bodies +Ingested foreign bodies are usually asymptomatic. +Removal +of sharp or large objects should be considered. +This can usu- +ally be done endoscopically, with an overtube technique. +Figure 26-61. +Gastric antral vascular ectasia (watermelon stom- +ach). +Baltimore: +Williams & Wilkins, 1998, p 577.] +Figure 26-62. +Trichobezoar forming cast of stomach and duode- +num; removed from 15-year-old girl. +[Reproduced with permission +from DeBakey M, Ochsner A: Bezoars and concretions. +Surgery +4:934, 1938. +Copyright Elsevier.] +Figure 26-63. +Gastric diverticulum. +East Norwalk, +Connecticut: Appleton & Lange, 1989, p 577. +Surgical removal is +recommended in body packers, and in patients with large jag- +ged objects. +Corrosive objects (e.g., watch batteries) should be +removed promptly. +It presents +with upper GI bleeding, often with hematemesis. +Surgical treatment consists of oversewing +the bleeding lesion through a long gastrostomy. +It also can occur in patients +with an unusually mobile stomach without hiatal hernia. +26-64C). +If the +stomach twists around the transverse axis, it is called mesentero- +axial rotation (Fig. +26-64A and Fig. +26-64B). +Often, volvulus +is a chronic condition that can be surprisingly asymptomatic. +The risk of strangulation +and infarction has been overestimated in asymptomatic patients. +Symptoms are often relieved with +vomiting or passage of a nasogastric tube. +Gastric infarction is +a surgical emergency, and the patient can be moribund. +Gastric +necrosis may be extensive or focal. +The open techniques include the +Stamm method (Fig. +26-65), the Witzel method (Fig. +26-66), +and the Janeway method (Fig. +26-67). +A through C. +Gastric +volvulus. +[Reproduced with permis- +sion from Buchanan J: Volvulus of +the stomach. +Br J Surg. +18:99, 1930. +© British Journal of Surgery Soci- +ety, Ltd. +Permission is granted by +John Wiley & Sons, Ltd on behalf of +BJSS, Ltd.] A BC +Figure 26-65. +Stamm gastrostomy. +II. +These symp- +toms may be ameliorated by recumbence or saline infusion. +Crampy abdominal pain is not uncommon and diarrhea often +follows. +Late dumping is associated +with hypoglycemia and hyperinsulinemia. +Often, symptoms improve if the patient avoids liquids during +meals. +Hyperosmolar liquids (e.g., milk shakes) may be particu- +larly troublesome. +There is some evidence that adding dietary +fiber compounds at mealtime may improve the syndrome. +This can be increased +up to 500 μg twice daily if necessary. +The long-acting depot +octreotide preparation is useful. +Only a very small percentage of patients with dumping symp- +toms ultimately require surgery. +Most patients improve with time +(months and even years), dietary management, and medication. +Figure 26-66. +A through F. +Witzel gastrostomy. +II. +Multidisciplinary nonsurgi- +cal management must be optimized first. +The results of remedial operation for dumping are variable +and unpredictable. +There are a variety of surgical approaches, +none of which work consistently well. +Long-term follow-up is rare. +The reversed intesti- +nal segment is rarely used today—and rightly so. +This slows gastric emp- +tying, but often leads to obstruction, requiring reoperation. +26-68). +A through D. +Janeway gas- +trostomy. +II. +Philadelphia: +Saunders, 2002, p 46.] +Figure 26-68. +Duodenal switch operation. +Surg Clin North Am. +72:487, 1992. +Truncal vagotomy is +associated with clinically significant diarrhea in 5% to 10% of +patients. +The +symptoms tend to improve over the months and years after the +index operation. +The cause of postvagotomy diarrhea is unclear. +Octreotide should also be tried. +This can be confirmed with +a qualitative test for fecal fat and treated with acid suppression. +Postvagotomy diarrhea usually does not respond to treatment +with pancreatic enzymes. +Another option is the onlay antiperistaltic distal ileal +graft. +Endoscopy +shows gastritis and retained food or bezoar. +The anastomosis +and efferent limb should be evaluated for stricture or narrow- +ing. +This consists of dietary +modification and promotility agents. +The latter should be dealt with at reoperation. +Endoscopic dilation +is occasionally helpful. +If total gastrectomy +is performed, a jejunal reservoir should be fashioned. +Curiously, symptoms often +develop months or years after the index operation. +Excessively long limbs may be associated with +obstruction or malabsorption. +26-68). +The Achilles’ heel of this operation is, not sur- +prisingly, marginal ulceration. +These +patients present with vomiting, epigastric pain, and weight loss. +This clinical scenario has been labeled the Roux syndrome. +Anastomotic +inflammation and stricture from marginal ulceration is a con- +founding finding. +An upper GI series confirms these findings +and may show delayed gastric emptying. +Pre- +sumably, the disordered motility in the Roux limb occurs in all +patients with this operation. +Why only a subset develops the +Roux syndrome is unclear. +Perhaps those patients with disor- +dered gastric motility are at most risk. +The disorder seems to +be more common in patients with a generous gastric remnant. +Truncal vagotomy also has been implicated. +Medical treatment consists of promotility agents. +Surgi- +cal treatment consists of paring down the gastric remnant. +Care +should be taken to preserve adequate blood supply to the new +gastric pouch. +If gastric motility +is severely disordered, 95% gastrectomy or total gastrectomy +should be done. +Weight Loss +Weight loss is common in patients who have had a vagotomy +and/or gastric resection. +The degree of weight loss tends to +parallel the magnitude of the operation. +It may be insignificant +in the large person, or devastating in the asthenic female. +Consultation with +an experienced dietitian may prove invaluable. +Vitamin B12 bioavailability also +is facilitated by an acidic environment. +It also occurs +in up to one third of patients who have had a vagotomy and/or +gastric resection. +Marginal nutrient status should be +corrected with oral and/or parenteral supplementation. +Bone Disease +Gastric surgery 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RD: Helicobacter pylori and MALT +lymphoma. +Gastroenterology. +2005;128: 1579-1605. +108. +Gold JS, DeMatteo RP. +Combined surgical and molecular +therapy: The gastrointestinal stromal tumor model. +Ann +Surg. +2006;244:176-184. +109. +Rubin BP, Heinrich MC, Corless CL. +Gastrointestinal stromal +tumour. +Lancet. +2007;369:1731-1741. +110. +Stelow EB, Murad FM, Debol SM, et al. +Am J ClinPathol. +2008;129:219-225. +110A. +Fletcher CD, et al. +Diagnosis of gastrointestinal stromal +tumors: a consensus approach. +Hum Pathol. +2002;33: +459-464. +110B. +Miettinen M, et al: Gastrointestinal stromal tumors: Pathol- +ogy and prognosis at different sites. +Semin Diagn Pathol. +2006;23:70-83. +110C. +Lancet. +2009;373:1097-1104. +110D. +von Mehren M, et al: Soft tissue sarcoma, version 2: fea- +tured updates to the NCCN guidelines. +J Natl Compr Canc +Netw. +2012;10(8):951-960. +111. +Raut CP, Kulke MH, Glickman JN, et al. +Carcinoid tumors. +Curr Probl Surg. +2006;43:383-450. +112. +Modlin 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+2007;117:70. +120. +Sebastian S, O’Morain CA, Buckley MJ. +Current therapeutic +options for gastric antral vascular ectasia. +Aliment Pharmacol- +Ther. +2003; 18:157-165. +121. +Akhras J, Patel P, Tobi M. +Dig Dis Sci. +2007; 52:722-726. +122. +Harbison SP, Dempsey DT. +Mallory-Weiss syndrome, in +Cameron JL (ed): Current Surgical Therapy, 9th ed. +Philadel- +phia: Mosby, 2008. +123. +Schrag SP, Sharma R, Jaik NP, et al. +Complications related +to percutaneous endoscopic gastrostomy (PEG) tubes. +A +comprehensive clinical review. +J Gastrointestin Liver Dis. +2007;16:407-418. +124. +McClave SA. +Critical care nutrition: getting involved as a +gastrointestinal endoscopist. +J ClinGastroenterol. +2006;40: +870-890. +125. +Dempsey DT. +II. +Philadelphia: +Saunders, 2002, p 161. +126. +Meilahn JE, Dempsey DT. +Philadelphia: Elsevier Mosby, 2004. +127. +Ukleja A: Dumping syndrome: pathophysiology and treat- +ment. +NutrClinPract. +2005; 20:517-525. +127A. +Cuschieri A: Postvagotomy diarrhea: is there a place for +surgical management? +Gut. +1990; 31:245-246. +128. +Forster-Barthell AW, Murr MM, Nitecki S, et al. +J Gastrointest Surg. +1999;3:15-21. +129. +Jones MP, Maganti K. +A systematic review of surgical therapy +for gastroparesis. +Am J Gastroenterol. +2003;98:2122-2129. +130. +Van der Milje HC, Kleibeuker JH, Limburg AJ, et al. +Am J Surg. +1993;166:11-17. +131. +Farrell TM, Hunter JG. +II. +Philadelphia: +Saunders, 2002, p 202. +132. +Anderson C, Ellenhorn J, HellanM, Pigazzi A. +Surg Endosc. +2007;21:1662-1666. +133. +Lee J, Kim W. +Clinical experience of 528 laparoscopic gas- +trectomies on gastric cancer in a single institution. +Surgery. +2013;153(5):611-618. +133A. +Zeng YK, Yang ZL, Peng JS, et al. +Laparoscopy-Assisted +versus open distal gastrectomy for early gastric cancer. +Annals of Surgery. +2012;256: 39-52. +134. +Kaehler G, Schoenberg MB, Kienle P, Post S, Magdeburg R. +Transgastric appendicectomy. +Br J Surg. +2013;100(7):911. +135. +Bakker OJ, van Santvoort HC, van Brunschot S, et al. +Dutch +Pancreatitis Study Group. +JAMA 2012;307:1053-1061. +The Surgical Management of +Obesity +Philip R. +Outcomes, as reported for review by the +oversight committee, are better than ever. +Our patients have thus +been well served. +Obesity is a disease and is likely multifactorial in its ori- +gin. +The +components of the disease likely include a combination of envi- +ronmental and genetic factors. +Long-term +follow-up is essential before the merits of an operation can +be confirmed. +which to classify obesity. +The World Health Organization classifica- +tion of obesity is given in Table 27-1. +Source: Adapted from the World Health Organization (WHO) 2000205. +Data on obesity statistics have been updated annu- +ally since 1985. +The latest figures for obesity incidence in the +United States are that 35.7% of U.S. +The weight of adopted children correlates +strongly with the weight of their birth parents. +Other factors appear to contribute significantly to severe +obesity. +Intermittent or consistent excessive caloric intake +occurs. +As yet, the physiologic basis for +the explanation of such lack of satiety is not understood. +Weight gain results from increase in both +adipose cell size and number. +This preju- +dice against obesity remains the last unlegislated discrimina- +tion in existence. +Obese individuals are routinely discriminated +against in terms of employment. +Public facilities often do not +allow them to participate in activities. +They often endure +not only discrimination and prejudice, but outright ridicule and +disrespect. +Poor self-image is almost universal among obese +individuals. +1 +1102 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +There are two main reasons for this. +Medi- +cal comorbidities must be identified and treated. +Most patients also +have attempted commercially sponsored diets and diet plans. +Dietary +restriction and exercise can each independently create a +caloric deficit. +Longer follow-up shows recidivism. +Pharmacologic therapy is also an option for patients +attempting to lose weight. +Pharmacotherapy is normally used only after life- +style changes and dietary therapies have failed. +That number has now increased, but still is not over 2% of +individuals. +Part of this issue may be patient aversion to surgical therapy. +The +most common is restriction of intake. +Malabsorption of ingested +food is the second mechanism. +Restrictive operations may +include no or only a modest malabsorptive component. +Since the procedure was easily done, some surgeons performed +it in prolific numbers. +Staple breakdown predictably occurred +months to years later, with subsequent weight regain. +In 2001, LAGB was approved for use in +the United States. +Its popularity increased annually until 2009, +but since then, it has decreased in popularity. +The field then literally exploded in terms of growth +in the United States. +Operative procedures increased nearly +eight-fold. +Patients who +had or were contemplating surgery were able to communicate +via the Internet. +Many U.S. +Hospitals without programs +recruited surgeons so they could offer the service. +Bariatric +surgery presentations at national surgical meetings became +common instead of rare. +These were defined by the CMS in 2005 as +those listed in Table 27-2, with the exception of SG. +This factor, however, is normally beyond +surgeon control. +Number of Roux-en-Y gastric bypass operations per- +formed in the United States by year. +Body mass index ≥40 kg/m2 with or without comorbid +medical conditions associated with obesity + 2. +Has failed attempt at medically supervised diet + 4. +The NIH criteria do not set limits for age, and surgeon +opinion on this issue varies widely. +Surgeons have variable +practice patterns as to performance of surgery in the older +patient. +Known and documented drug +or alcohol addiction is a contraindication to surgery. +A poorly controlled eat- +ing disorder, especially bulimia, is also a contraindication to +surgery. +Table 27-4 summarizes potential contraindications for +surgery. +Table 27-4 +Potential contraindications for bariatric surgery +1. +Mentally incompetent to understand procedure +3. +Inability or unwillingness to change lifestyle +postoperatively +4. +Drug, alcohol, or other addiction +5. +Active problem of bulimia or other eating disorder +6. +Psychologically unstable +7. +Nonambulatory status +8. +An estimation of the patient’s motivation to change eating +habits is important. +The operation to be performed requires spe- +cific nutritional counseling and education. +Psychological assessment is required by most insurance +carriers. +Its treatment is felt to improve +postoperative outcomes. +Some will decide against the +procedure after thorough educational and counseling sessions. +Such sessions are imperative for improving outcomes. +Potentially undiag- +nosed medical problems are sought. +A diagnostic sleep study is indicated for these individuals. +Pulmonary consultation is indi- +cated for patients with hypoventilation syndrome. +Preoperative weight loss is not necessary to achieve good out- +comes from surgery. +Some sur- +geons make this an absolute requirement, while others do not. +Serum chemistries, liver function tests, and +usual screening blood tests are done. +However, the primary +reason to correct low vitamin D is improved long-term bone +disease health. +Jugular cannulation is often very difficult due to neck +adipose tissue. +However, ultrasound guidance can facilitate this +procedure. +Subclavian access is performed when other central +access routes are not feasible. +Experience is key in performing smooth intuba- +tion of this patient population. +Calculation of the dosage should be done by lean body +weight. +Benzodiazepines also exhibit a prolonged elimination +phase, causing persistence of their effects. +An +angled telescope is quite helpful. +Postoperative Follow-Up +Short-term follow-up is defined as follow-up of up to 2 years. +Failure to establish an adequate pneumoperitoneum +2. +Hemodynamic adverse reaction to pneumoperitoneum +3. +Intraoperative complications such as hemorrhage that are +best managed with an open approach +6. +Exceedingly thick body wall precluding adequate trocar +access or manipulation +7. +Medium-term follow-up is defined as that from 2 to 5 +years. +Few +publications have met these criteria. +open) have been performed. +Improvement +in study design and more complete data in future publications +are indicated. +Regular counseling sessions with the nutritionist are always +helpful. +Diligence to avoid +snacking and returning to other poor eating habits is also impor- +tant. +laparoscopic Adjustable gastric Banding +Background. +LAGB involves placement of an inflatable sili- +cone band around the proximal stomach. +Figure 27-2 shows +the LAGB apparatus in place. +Two major types of bands have been used for this pro- +cedure. +Technique. +Port placement for LAGB has varied among surgeons. +Figure 27-2 shows a common configuration used. +Laparoscopic adjustable band overall scheme. +(From +Schauer PR, et al, eds. +Minimally Invasive Bariatric Surgery, 1st ed. +New York: Springer; 2007. +Reprinted with permission, Cleveland +Clinic Center for Medical Art & Photography © 2005-2009. +All +rights reserved.) +1109 +T +HE + S +UR +g +ICA +l M +ANA +g +EMENT + +OF + O +BESITY +CHAPTER 27 +Figure 27-3. +Grasper being passed through under stomach to grasp +tubing during placement. +(From Schauer PR, et al, eds. +Minimally +Invasive Bariatric Surgery, 1st ed. +New York: Springer; 2007. +Reprinted with permission, Cleveland Clinic Center for Medical +Art & Photography © 2005-2009. +All rights reserved.) +His in the area of the divided peritoneum (Fig. +27-3). +27-4A,B). +27-5). +A +Figure 27-4. +A. +Lap-Band in place around stomach. +(From Schauer PR, et al, eds. +Minimally Invasive Bariatric Surgery, 1st ed. +New York: +Springer; 2007. +Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2005-2009. +All rights reserved. +B. +Realize (Swedish) Band around stomach. +The port is secured to the anterior abdominal +wall fascia. +The band is initially placed empty of +fluid in most circumstances. +Patient Selection and Preparation. +Most LAGB procedures +are done on an outpatient basis. +Technically the operation is +not as difficult as the other operations described later. +An orogastric +tube is inserted into the stomach. +These preoperative measures +are recommended in all the procedures described later as well. +Postoperative Care and Follow-Up. +The majority of LAGB +procedures are performed on an outpatient basis. +The first postoperative evaluation after LAGB generally +occurs 2 to 3 weeks after surgery. +Wounds are assessed, as are medical problems, oral intake, and +adherence to diet. +Recommendations for timing of band +adjustments vary from practice to practice. +Band fills usually are accomplished in the outpatient clinic +setting. +Stomach imbricated +over band. +A careful record should be maintained of the amount of +fluid in each patient’s band. +Some surgeons will withdraw all +the fluid at each fill, reinserting the desired amount. +Many will +just add additional fluid as indicated. +The amount of fluid added +is based on hunger, weight loss, and ability to eat meat or bread. +However, changing life and clinical circumstances +can require adjustments at any time thereafter. +Outcomes. +Overall mortal- +ity for LAGB was given as 0.1%. +Can still eat +chicken, +steak, or +bread? +Can still eat +chicken, +steak, or +bread? +Can eat +chicken, +steak, or +bread? +Weight +loss? +Weight +loss? +Weight +loss? +Adjustment +(How much?) +Adjustment +(How much?) +Adjustment +(How much?) +Adjustment +(How much?) +Hungry? +Hungry? +Hungry? +Hungry? +Algorithm for postoperative band adjustment. +RTC = return to clinic. +(Reproduced with permission from Ren CJ. +Laparoscopic +adjustable gastric banding: postoperative management and nutritional evaluation. +In: Schauer PR, et al, eds. +Minimally Invasive Bariatric +Surgery. +1st ed. +New York: Springer; 2007:200. +Prolapse is perhaps the most common emergent compli- +cation that requires reoperation after LAGB. +The incidence of +reoperation is generally around 3%. +Postoperative vomiting pre- +disposes to this problem. +The lower stomach is pushed upward +and trapped within the lumen of the band. +If the band is in a horizontal position, pro- +lapse must be strongly suspected. +Initial treatment for a prolapse is to remove all the fluid +from the system. +This often allows reduction of the prolapse and +resolution of symptoms. +If symptoms resolve, the necessity of +performing an upper gastrointestinal series is lessened. +Longer- +term follow-up rates may show higher rates of prolapse. +Band erosion is uncommon, reported in 1% to 2% of +most series. +Endoscopy can be +diagnostic. +Laparoscopic removal of the band is indicated, +with repair of any gastric perforation. +The true inci- +dence probably varies widely. +Angrisani et al77 reported a 40.9% +incidence of band removal after 10-year follow-up. +One of the positive outcomes of LAGB is the safety of +the procedure. +While complications are not rare, most of them +involve non–life-threatening events. +Nutritional complications +are uncommon and easily treated. +The Lap-Band also has its limitations, which may be the +cause of its reduced popularity. +It is often ineffective in pro- +ducing adequate weight loss. +Patients must have enough willpower to avoid such foods. +laparoscopic Roux-en-Y gastric Bypass +Background. +Currently over 90% of gastric +bypass operations nationally are performed laparoscopically. +Figure 27-7 depicts the configuration of the LRYGB. +A Roux limb of proximal jejunum is brought up and +anastomosed to the pouch. +Experience has resolved several controversies about gas- +tric bypass, but others are still debated. +Configuration of laparoscopic gastric bypass. +(From +Schauer PR, et al, eds. +Minimally Invasive Bariatric Surgery, 1st +ed. +New York: Springer; 2007. +Reprinted with permission, Cleve- +land Clinic Center for Medical Art & Photography © 2005-2009. +All rights reserved.) +(150 cm) Roux limb for patients with a BMI over 60 or even +50 kg/m2. +The gastrojejunal anastomosis can be constructed +in a variety of ways. +The operation generally is performed using five +ports plus a liver retractor. +The telescope requires a +port, usually in the supraumbilical region. +27-8). +Port scheme for laparoscopic gastric bypass. +(From +Schauer PR, et al, eds. +Minimally Invasive Bariatric Surgery, 1st ed. +New York: Springer; 2007. +Reprinted with permission, Cleveland +Clinic Center for Medical Art & Photography © 2005-2009. +A Penrose drain or suture is sutured to the proximal Roux limb +(Fig. +27-9) for identification and facilitation of advancement to +the gastric pouch. +The length of the Roux limb (usually 100–150 cm) to be +created is now measured. +A side-to-side stapled +anastomosis is performed (Fig. +27-10). +Passage of the Roux limb toward the stomach is now per- +formed. +27-11). +The left lobe of the liver is now retracted using any one +of several retractor types. +The patient is moved to a reverse +Trendelenburg position. +The harmonic scalpel divides the peri- +toneum in the area of the angle of His. +27-12). +Once the pouch is created, the Roux limb is brought up to +the proximal gastric pouch. +27-13). +Figure 27-9. +Creating Roux limb during +laparoscopic gastric bypass. +Figure 27-10. +Enteroenterostomy of lapa- +roscopic Roux-en-Y gastric bypass. +This is accomplished +by pulling the anvil transorally via an endoscopically placed +Figure 27-11. +Passage of Roux limb. +(From Schauer PR, et al, eds. +Minimally Invasive Bariatric Surgery, 1st ed. +New York: Springer; +2007. +Reprinted with permission, Cleveland Clinic Center for Med- +ical Art & Photography © 2005-2009. +All rights reserved.) +Figure 27-12. +Creation of gastric pouch for laparoscopic Roux-en- +Y gastric bypass. +(From Schauer PR, et al, eds. +Minimally Invasive +Bariatric Surgery, 1st ed. +New York: Springer; 2007. +Reprinted with +permission, Cleveland Clinic Center for Medical Art & Photogra- +phy © 2005-2009. +All rights reserved.) +3 +2 1 +Figure 27-13. +Gastrojejunostomy in laparoscopic Roux-en-Y +gastric bypass. +(From Schauer PR, et al, eds. +Minimally Invasive +Bariatric Surgery, 1st ed. +New York: Springer; 2007. +Reprinted with +permission, Cleveland Clinic Center for Medical Art & Photogra- +phy © 2005-2009. +All rights reserved.) +guidewire (Fig. +27-15). +Patient Selection and Preparation. +Postoperative Care and Follow-Up. +LRYGB patients are +usually hospitalized for 2 to 3 days. +Figure 27-14. +(From Schauer +PR, et al, eds. +Minimally Invasive +Bariatric Surgery, 1st ed. +New York: +Springer; 2007. +Reprinted with per- +mission, Cleveland Clinic Center +for Medical Art & Photography +© 2005-2009. +All rights reserved.) +Figure 27-15. +(Repro- +duced with permission from Schneider BE, et al. +Circular stapled +transabdominal technique. +In: Schauer PR, et al, eds. +Minimally +Invasive Bariatric Surgery. +1st ed. +New York: Springer; 2007:248. +Discharge on +a blenderized diet is standard for our practice. +Diet advancement occurs after the first clinic visit, usually +approximately 3 weeks after surgery. +At that time, an exercise +plan is initiated if not already started. +Outcomes. +Hyperlipidemias are almost always improved and resolve totally in +about 70% of cases. +Hypertension resolves in 50% to 65% of cases +(see Table 27-7). +Several complications that are specific to LRYGB must be +emphasized. +One of the most important is small bowel obstruc- +tion. +Thus, treatment +for these patients differs from most patients with small bowel +obstruction. +27-16). +If the bowel is viable, suturing the mesenteric defect is all that +is needed for treatment. +Marginal ulcers are another complication relatively spe- +cific to RYGB, either LRYGB or open RYGB. +The patient +presents with pain in the epigastric region that is not altered by +eating. +Diagnosis is by endoscopy. +Treatment is medical with +proton pump inhibitors, which are effective in 90% of cases. +Diagnosis is +by upper endoscopy. +Treatment is balloon dilatation. +Resolution +normally occurs with one or two treatments. +Open Roux-en-Y gastric Bypass +Background. +It has been the most +time-tested and proven of all bariatric operations. +Technique. +RYGB is performed essentially the same as +LRYGB. +Closure of the midline wound is per- +formed using a running monofilament suture. +Subcutaneous +tissues are thoroughly irrigated, and skin is closed with a skin +stapler. +Patient Selection and Preparation. +Patient selection is +essentially the same as for LRYGB, since the operation is the +same. +Preparation for open RYGB is identical to LRYGB. +Postoperative Care and Follow-Up. +Other visits, follow-up schedule, and +blood testing are identical to LRYGB. +Outcomes. +Christou and colleagues107 showed a lower incidence +of mortality (0.68% vs. +This was a reduc- +tion of 89% in the death rate. +Biliopancreatic Diversion and Duodenal Switch +Background. +However, +the procedure did develop a devoted following among a few +bariatric surgeons. +This +new procedure was originally called BPD with DS. +It is illustrated in Fig. +27-18. +Figure 27-17. +Diagram of biliopancreatic diversion. +(From +Schauer PR, et al, eds. +Minimally Invasive Bariatric Surgery, 1st +ed. +New York: Springer; 2007. +Reprinted with permission, Cleve- +land Clinic Center for Medical Art & Photography © 2005-2009. +All rights reserved.) +Figure 27-18. +Diagram of duodenal switch. +(From Schauer PR, +et al, eds. +Minimally Invasive Bariatric Surgery, 1st ed. +New York: +Springer; 2007. +Reprinted with permission, Cleveland Clinic Center +for Medical Art & Photography © 2005-2009. +Technique. +The terminal ileum is +identified and divided 250 cm proximal to the ileocecal valve. +The DS procedure differs from the BPD only in the proxi- +mal gut portion of the operation. +This end of the duodenum is +then anastomosed to the distal 250 cm of ileum. +This anastomo- +sis is often done in an end-to-end fashion with a circular stapler. +The distal +bowel configuration and cholecystectomy are similar to BPD. +Patient Selection and Preparation. +Frequent and large-quantity bowel +movement after any large amount of oral intake is common. +Patients who undergo either operation must +agree to close follow-up preferably by the surgeon. +Disastrous results may then +occur. +Postoperative Care and Follow-Up. +Postoperatively, BPD +and DS patients face the same potential complications as seen +after RYGB. +Distal anastomotic problems can occur with +either procedure as well. +Fat-soluble vitamins must be supplemented in +parenteral form. +Careful monitoring of protein intake and serum +albumin is necessary. +Outcomes. +Weight loss results with BPD or DS are both excel- +lent and comparable. +They also are very durable. +When it is diagnosed, the +treatment is parenteral nutrition. +SG had its origins in the early +days of laparoscopic bariatric surgery. +After patients had lost +weight, the malabsorptive component of the procedure was then +performed. +Until 2009, SG was considered an “experimental” proce- +dure by insurance carriers. +27-19. +National U.S. +Bariatric Volume Percent- +age by Procedure Type. +Obes Surg. +2013;23:427. +Whether a second stage is indicated +depends on the effectiveness of the SG. +The one exception is +GERD. +Technique. +The patient is positioned supine, with foot sup- +port to allow reverse Trendelenburg positioning. +27-21. +The other of +these ports is a 12-mm port. +A liver retractor is placed in the epigastric +region. +This can be a Nathanson or T-Boone retractor. +The harmonic scalpel works nicely to perform this tissue divi- +sion. +Asia/Pacific +Bariatric Volume Percentage by +Procedure Type. +Obes Surg. +2013;23:427. +With +kind permission of Springer +Science+Business Media.) +Figure 27-21. +Port scheme for Laparoscopic sleeve gastrectomy. +Stapled division of the stomach now follows. +This bougie +then serves as a guide for further gastric division. +It is most important not to narrow the stomach lumen at the +incisura. +27-22). +At +this point, changing staple loads to lower staple height is advis- +able. +Figure 27-23 shows the com- +pleted operation. +Controversy still exists as to the optimal size of the bougie +used during the procedure. +Performing sleeve gastrectomy. +(From Schauer +PR, et al, eds. +Minimally Invasive Bariatric Surgery, 1st ed. +New +York: Springer; 2007. +Reprinted with permission, Cleveland Clinic +Center for Medical Art & Photography © 2005-2009. +All rights +reserved.) +Figure 27-23. +Completed sleeve gastrectomy. +(From Schauer PR, +et al, eds. +Minimally Invasive Bariatric Surgery, 1st ed. +New York: +Springer; 2007. +Reprinted with permission, Cleveland Clinic Center +for Medical Art & Photography © 2005-2009. +All rights reserved.) +with staple buttressing material. +Some surgeons advocate rou- +tine staple line reinforcement, whereas others advocate none. +Postoperative Care and Follow-Up. +SG usually is performed +with an overnight stay of 2 nights after surgery. +Longer hos- +pitalizations are indicated for patients with more severe medi- +cal problems. +Follow- +up is similar to that after LRYGB. +Most surgeons advocate routine vitamin B12. +Outcomes and Complications. +Studies with 5-year follow-up for SG are +not yet common. +60.5%) at 1 year after surgery. +It is certain that appropriate stapling technique in dividing the +stomach is important. +Whether but- +tress materials do decrease the leak rate with SG is very con- +troversial. +This increased intraluminal pressure places the +staple line at risk for leakage. +Proximal staple line leaks may also present as +late leaks. +Late leaks are generally felt to be those that occur 6 +weeks or longer after surgery. +Late leaks are rare in other bar- +iatric procedures, but are seen with SG. +The increased pressure +of the system may be a reason SG is associated with late leaks. +Confirmation and treatment of stenosis symptoms early after SG +may prevent such leaks. +Endoscopic treatment can help straighten and +markedly alleviate the obstruction in such cases. +Such cases are now only recently being published +and discussed in the literature. +Reports of such leaks persisting for multiple months +postoperatively exist. +However, longer duration leaks are less likely to close. +Physiology of Weight loss. +SG is a fairly simple technical +operation, amenable to performance by many surgeons. +This will ensure optimal patient outcomes. +population has risen dramat- +ically during the past two decades. +This increase has included +children and adolescents as well. +Obese adolescents have a high likelihood of being obese +adults. +Clearly the younger the patient, the more rel- +evant the latter concern becomes. +How- +ever, it is still limited. +There were two late deaths at 2 and 6 years of +follow-up unrelated to surgery. +Most comor- +bidities resolved at 1 year after surgery. +Self-image was greatly +enhanced and social stigmatization greatly decreased. +After an average 5.5-year follow-up, aver- +age BMI for the group was 28 kg/m2. +No deaths occurred, but +two patients required revisional surgery. +No mortality or mor- +bidity was reported, and all comorbidities resolved. +Abu-Abeid +and colleagues137 treated 11 adolescents with LAGB. +The most common complication in the +meta-analysis was nutrient deficiencies. +The elderly patient population certainly suffers from +severe obesity. +There has been an increasing tendency to offer bariatric +surgery to patients over the age of 60. +Accumulation of data may also change these limits in +the future. +Macrosomia +is increased. +There is a two- to three-fold increase in the rate +of cesarean sections, with more complications. +However, iron replacement was cited as a criti- +cal need for these pregnant women. +The adjustability of the +band provides a potential advantage for the pregnant woman. +These prob- +lems were virtually eliminated after weight loss. +Type 2 Diabetes. +There has been a dramatic increase in the +potential application of surgical therapy to treat T2DM. +Reversal of the +operation led to return of the disease state. +Metabolic Syndrome. +These operations also are +effective in treating the other components of metabolic syndrome. +Cardiovascular Disease. +These +manifestations occur after all the various bariatric operations +that produce weight loss. +Heart failure also is increased in the setting of severe +obesity. +LAGB improves GERD but to a consider- +ably lesser extent than RYGB. +OSA is a disturbance of sleep associated with obesity. +It +is a measurable problem, quantitated by polysomnography. +It is estimated that 20% of +U.S. +adults have NAFLD, largely because of the high incidence +of obesity. +Biopsy reports showing +any degree of fibrosis should be further followed up by a hepa- +tologist. +Symptoms often resolve and usually improve in patients who +experience significant weight loss. +Excess skin can +be a limiting factor in exercise and sexual activity. +Many patients desire to be rid of the extra skin and its +associated problems. +Most insurance companies consider +this “cosmetic” surgery and will not authorize coverage. +A standard +abdominoplasty to remove this excessive tissue is performed. +The central abdominal fascia often +requires imbrication. +Medial thighplasty also may be needed for patients with +significant excess medial thigh skin. +This is done transversely. +Excess skin redundancy distal to the mid-thighs requires +long vertical medial excision of skin. +Frontal, right lateral, and left anterior oblique views 6 weeks after surgery for the woman in Fig. +27-24. +All redundant skin has been removed, leaving well-positioned scars and feminine features. +A mean excess weight loss of 23% was reported at +16-month follow-up for the second U.S. +Intragastric balloon placement has resurfaced on the bariat- +ric scene in the past few years. +It may have potential use +only as a preliminary procedure prior to a more definitive one. +Mean weight loss at 3 months was +19.0% in the study group and 6.9% in the control group. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Dimick JB, Nicholas LH, Ryan AM, et al. +Bariatric surgery +complications before vs. +after implementation of a national +policy restricting coverage to centers of excellence. +JAMA. +2013;309:792-799. +2. +Shimizu H, Timratana P, Schauer PR, Rogula T. +Review of +metabolic surgery for type 2 diabetes in patients with a 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surgery. +Plast Reconstr Surg. +2013;132: +826-833. +192. +Shikora SA. +Implantable gastric stimulation for weight loss. +J +Gastrointest Surg. +2004;8:408-412. +193. +Miller K, Hoeller E, Aigner F. +Treat Endocrinol. +2006;5:53-58. +194. +Toouli J, Kow L, Kulseng B, et al. +Presented at 25th Annual Meeting of the ASMBS, Washing- +ton, DC, June 19, 2008. +195. +Thompson CC, Slattery J, Bundga ME, Lautz DB. +Surg Endosc. +2006;20: +1744-1748. +196. +Garren L. +Garren gastric bubble. +Bariatr Surg. +1985;3:14-15. +197. +Genco A, Brui T, Doldi SB, et al. +BioEnterics intragastric bal- +loon: the Italian experience with 2515 patients. +Obes Surg. +2005;15:1161-1164. +198. +Schouten R, Rijs CS, Bouvy ND, et al. +Ann Surg. +2010;251:236-243. +199. +Familiari P, Costamagna G, Bléro D, et al. +Transoral gastro- +plasty for morbid obesity: a multicenter trial with a 1-year +outcome. +Gastrointest Endosc. +2011;74:1248-1258. +200. +Stimac D, Majanovic SK. +The position of endoscopic pro- +cedures in the treatment of obesity. +Curr Clin Pharmacol. +2013;8:238-246. +201. +Cohen R, Caravatto PP, Correa JL, et al. +Surg Obes Relat Dis. +2012;8:375-380. +202. +Gaitonde S, Kohli R, Seeley R. +The role of the gut hormone +GLP-1 in the metabolic improvements caused by ileal trans- +position. +J Surg Res. +2012;178:33-39. +203. +Niazi M, Maleki AR, Talebpour M. +Obes Surg. +2013;23:87-92. +204. +WHO. +Lancet +2004; 363: 157–163. +205. +WHO. +Obestiy: preventing and managing the global epidemic. +Report of a WHO consultation. +World Health Organ Tech Rep +Ser 2000; 894: 1–253. +Small Intestine +Ali Tavakkoli, Stanley W. +Ashley, and +Michael J. +The ileum is demarcated from the cecum by the ileocecal +valve. +These folds are more prominent in the proximal intestine than in +the distal small intestine. +28-1). +Gross examina- +tion of the small-intestinal mucosa also reveals aggregates of +lymphoid follicles. +Those follicles, located in the ileum, are the +most prominent and are designated Peyer’s patches. +Their venous +drainage occurs via the superior mesenteric vein. +Lymph drain- +age occurs through lymphatic vessels coursing parallel to corre- +sponding arteries. +28-2). +The mucosa is organized into villi and crypts (crypts of +Lieberkuhn). +Our understanding of these +crypt cells is rapidly expanding. +It appears that there are two +subgroups of intestinal stem cells, with specific cell markers. +2 Small bowel obstruction is one of the most common surgical +diagnoses. +4 Tumors and malignancies of the small bowel are rare and dif- +ficult to diagnose. +5 Small bowel may be the source of gastrointestinal bleeding, +which may be difficult to diagnose. +Jejunum +lleum +Figure 28-1. +Gross features of jejunum +contrasted with those of ileum. +Enterocytes are the predominant absorptive cell of the +intestinal epithelium. +Goblet cells produce mucin believed to play a role in mucosal +defense against pathogens. +In addition, the intestinal +epithelium contains M cells and intraepithelial lymphocytes. +These two components of the immune system are discussed +later. +The gut tube is divided into forgut, +midgut, and hindgut. +The yolk +sac and vitelline duct usually undergo obliteration by the end +of gestation. +Also during the fourth week of gestation, the mesoderm +of the embryo splits. +Subsequently, the duodenum becomes +a retroperitoneal structure. +28-3). +Errors in this recanaliza- +tion may account for defects such as intestinal webs and steno- +ses. +Organogenesis is complete by approximately the +twelfth week of gestation. +4. +Mucosa +Circular layer +Longitudinal +layer +2. +Muscularis propria +Subserous layer +1. +Submucosa +4 +3 +2 +1 +Opening of crypts (of Lieberkühn) +Figure 28-2. +Layers of wall of the +small intestine. +The individual layers +and their prominent features are repre- +sented schematically. +Solutes can traverse the epithelium by active or passive +transport. +Similarly, understanding of the paracellular pathway is evolving. +Water and Electrolyte Absorption and Secretion. +Eight +to nine L of fluid enters the small intestine daily. +28-4). +Figure 28-3. +Developmental rotation of the +intestine. +A. +B and C. +D. +Stomach +Duodenum +Proximal limb of prim. +intestinal loop +Vitelline +duct +Distal limb of prim. +Small intestinal fluid fluxes. +28-5. +Carbohydrate Digestion and Absorption. +Glycogen derived from meat contributes only a small +fraction of dietary carbohydrate. +Figure 28-5. +Model of transepithelial sodium (Na+) absorption. +28-6). +28-7). +Extruded monosaccharides diffuse into venules +and ultimately enter the portal venous system. +Ten to fifteen percent of +energy consumption in the average Western diet consists of pro- +teins. +Protein +digestion begins in the stomach with action of pepsins. +Digestion continues in the +duodenum with the actions of a variety of pancreatic peptidases. +Carbohydrate digestion. +Hexose transporters. +Fructose enters through facilitated diffusion via glu- +cose transporter 5 (GLUT5). +Fructose is extruded basolaterally via GLUT5. +These enzymes are secreted as inactive proenzymes. +This is in +contrast to pancreatic amylase and lipase, which are secreted +in their active forms. +28-8). +Absorbed amino acids and peptides then enter the portal venous +circulation. +Of all amino acids, glutamine appears to be a unique, +major source of energy for enterocytes. +Fat Digestion and Absorption. +Approximately 40% of the +average Western diet consists of fat. +Over 94% of the ingested fats are absorbed in +the proximal jejunum. +28-9). +Protein digestion. +Instead, +they are directly absorbed and enter the portal venous circulation +Figure 28-9. +Fat digestion. +These reactions are catalyzed by gastric +and pancreatic lipases. +Vitamin and Mineral Absorption. +Vitamin B12 (cobalamin) +malabsorption can result from a variety of surgical manipula- +tions. +The vitamin is initially bound by saliva-derived R pro- +tein. +Fat-soluble vitamins A, D, and E appear to be absorbed +through passive diffusion. +Vitamin K appears to be absorbed +through both passive diffusion and carrier-mediated uptake. +Calcium is absorbed through both transcellular transport +and paracellular diffusion. +Iron and magnesium are each absorbed through both tran- +scellular and paracellular routes. +28-10). +Overlying Peyer’s +patches are a specialized epithelium containing microfold (M) +cells. +Effector lymphocytes are distributed into distinct compart- +ments. +IgA-producing plasma cells are derived from B cells and +are located in the lamina propria. +CD4+ T cells are also located +in the lamina propria. +CD8+ T cells migrate preferentially to +the epithelium, but are also found in the lamina propria. +This configuration renders IgA resistant to proteolysis +by digestive enzymes. +Gut-associated lymphoid tis- +sue. +Select components of the gut-associated +lymphoid tissue (GALT) are schematically +represented. +Contractions +of the muscularis propria are responsible for small-intestinal +peristalsis. +28-11). +These two +EMN +SN +IMN +ProximalD istal +Figure 28-11. +Ascending excitation and descending inhibition. +It contributes to peristalsis. +Rhythmic segmentations or pressure waves traveling only short +distances also are observed. +The fasting +pattern or interdigestive motor cycle (IDMC) consists of three +phases. +This pattern is hypothesized to expel residual +debris and bacteria from the small intestine. +The median dura- +tion of the IDMC ranges from 90 to 120 minutes. +This intrinsic contractile mechanism is subject to neural +and hormonal regulation. +The enteric nervous system (ENS) +provides both inhibitory and excitatory stimuli. +Thus, they may act as true +blood-borne hormones as well as through local effects. +Some of these peptides, or their +analogues, are used in routine clinical practice. +Postresection intestinal adapta- +tion has been studied extensively using animal models. +The most commonly encountered etiologies of small +bowel obstruction are summarized in Table 28-3. +Jejunal resection +is generally better tolerated, as ileum shows better capacity to +compensate. +However, the magnitude of this response is limited. +This condition is +discussed in the Short Bowel Syndrome section at the end of +this chapter. +Intraluminal (e.g., foreign bodies, gallstones, or meconium) +2. +Intramural (e.g., tumors, Crohn’s disease–associated inflam- +matory strictures) +3. +These peptides +are also widely expressed in nonintestinal tissues. +The intestinal motility is eventually reduced with fewer +contractions. +This condition is termed strangulated +bowel obstruction. +Vomiting is a more +prominent symptom with proximal obstructions than distal. +Mild leukocytosis is common. +The diagnosis of small bowel obstruction is usually con- +firmed with radiographic examination. +The latter situation is associ- +ated with closed-loop obstruction. +28-12). +28-13 and 28-14). +28-15). +The water-soluble +contrast has been shown to have prognostic and therapeu- +tic value too. +In such cases, contrast +Figure 28-12. +Small bowel obstruction. +Figure 28-13. +Small bowel obstruction. +A computed tomography +scan of a patient presenting with signs and symptoms of bowel +obstruction. +At laparotomy, adhe- +sive bands from a previous surgery were identified and divided. +Figure 28-14. +Chronic partial small bowel obstruction. +Patient’s vomitus had characteristic fecu- +lent smell and quality. +At exploratory laparotomy, adhesive band +were identified and divided. +Abdomi- +nal radiographs are then taken serially as the contrast travels +distally in the intestine. +Therefore, fluid resuscitation is integral to treatment. +The stomach should be continuously evacuated of air and +fluid using a nasogastric (NG) tube. +Intestinal pneumatosis. +This computed tomography +scan shows intestinal pneumatosis (arrow). +The cause of this radio- +logic finding was intestinal ischemia. +Such patients need to be observed closely and +undergo serial exams. +Therefore, the goal is to operate before the onset of irreversible +ischemia. +28-16 for a proposed management algorithm). +Partial small bowel obstruction +2. +Obstruction occurring in the early postoperative period +3. +Intestinal obstruction due to Crohn’s disease +4. +In a recent study, using the National Inpatient Sample, this +principle was further highlighted. +CT scanning or a small bowel series is often +required to make the diagnosis. +Patients with obvious carcinomatosis +pose a difficult challenge, given their limited prognosis. +For example, adhesions are lysed, tumors are resected, +and hernias are reduced and repaired. +Criteria suggesting viability are normal color, +peristalsis, and marginal arterial pulsations. +Usually, visual +inspection alone is adequate in judging viability. +However, neither technique +has been found to be superior to clinical judgment. +At that time, definitive resection of nonviable +bowel is completed. +Develop signs or symptoms +of intestinal ischemia? +Yes +No +Yes Yes +Yes +Improving after 24 hours of +conservative management? +Figure 28-16. +Management algorithm of small bowel obstruction. +IVF = intravenous fluid; NG = nasogastric; NPO = nothing by mouth. +1151 +S +MALL + I +NTESTINE +CHAPTER 28 + adhesive band are best suited for this approach. +Mortality rates associated with surgery for stran- +gulating obstruction range from 8% to 25%. +These measures alone are often inadequate. +Ileus is a major +cause of morbidity in hospitalized patients. +Both sporadic and familial forms of +visceral myopathies and neuropathies exist. +Vomiting and abdominal distension may occur. +Diagnosis +Routine postoperative ileus should be expected and requires +no diagnostic evaluation. +Fluid and electrolytes should +be administered intravenously until ileus resolves. +If the dura- +tion of ileus is prolonged, TPN may be required. +Surgery should be +avoided if at all possible. +Prokinetic agents, such as +metoclopramide and erythromycin, are associated with poor +efficacy. +Incidence +rates have been stable since the 1980s. +The incidence +of Crohn’s disease varies among ethnic groups within the same +geographic region. +However, the +age at diagnosis can range from early childhood through the +entire lifespan. +Higher socioeconomic status is associated with an +increased risk of Crohn’s disease. +Crohn’s disease is more prevalent among +smokers. +Pathophysiology +Crohn’s disease is characterized by sustained inflammation. +Many infec- +tious agents have been suggested to be the causative organism +of Crohn’s disease. +There is no +conclusive evidence that any of these organisms is the causative +agent. +The IBD1 locus has +been identified as the NOD2 gene. +The earliest lesion character- +istic of Crohn’s disease is the aphthous ulcer. +In the small intestine, aphthous ulcers typically +arise over lymphoid aggregates. +As disease progresses, aphthae coalesce into larger, + stellate-shaped ulcers. +With transverse coalescence of ulcers, +a cobblestoned appearance of the mucosa may arise. +With advanced disease, inflammation can be transmural. +28-17). +This finding is virtually pathognomonic of Crohn’s +disease. +Figure 28-17. +Crohn’s disease. +There is substantial +overlap among these disease patterns in individual patients, + however. +The disease affects the small bowel in 80% of cases and +the colon alone in 20%. +In those with small bowel disease, +the majority have ileocecal disease. +The small bowel alone is +affected in 15% to 30% of patients. +Isolated perineal and ano- +rectal disease occurs in 5% to 10% of affected patients. +Uncom- +mon sites of involvement include the esophagus, stomach, and +duodenum. +One fourth of those affected will have more than one manifesta- +tion. +The most common extraintestinal manifesta- +tions are listed in Table 28-7. +No single symptom, sign, or diagnostic test establishes +the diagnosis of Crohn’s disease. +Pseudopolyps, as seen in +ulcerative colitis, are also often present. +Esophagogastro- +duodenoscopy (EGD) is done for disease of the proximal ali- +mentary tract. +Crohn’s disease. +It demonstrates a superficial ulceration in the small +bowel consistent with Crohn’s disease. +(Used with permission from +Dr. +Anne C. +Medical therapy is used to induce and maintain +disease remission. +Surgery is reserved for specific indications +described later. +Medical Therapy. +Their efficacy in the maintenance +of remission is less clear. +Patients with severe active disease +usually require intravenous administration of glucocorticoids. +Therefore, they +should be tapered once remission is achieved. +Such patients are said to have +steroid dependence. +A response to these medications is usually observed in +3 to 6 months. +In cases +of relapse, azathioprine can be considered. +In patients with fis- +tulas, infliximab and azathioprine are drugs of choice. +Growth retardation constitutes an indica- +tion for surgery in 30% of children with Crohn’s disease. +One of the most common indications for surgical inter- +vention is intestinal obstruction. +Both conditions should be treated medically; +ileal resection is not generally indicated. +The length of uninvolved +small intestine should be noted. +28-19). +In this technique, the bowel +Figure 28-19. +Stricturoplasty. +The wall of the strictured bowel is +incised longitudinally. +A +B +is opened longitudinally to expose the lumen. +Any intralumi- +nal ulcerations should be biopsied to rule out the presence of +neoplasia. +Most patients whose disease is resected eventually develop +recurrence. +Pathophysiology +The manifestations of fistulas depend on which structures are +involved. +Enterovesicular fistulas often cause recurrent urinary tract infec- +tions. +Fistulas have the potential to close spontaneously. +These fistulas are often asso- +ciated with intra-abdominal abscesses. +Leakage of contrast material from +the intestinal lumen can be observed. +Occasionally, contrast administered into the intestine +does not demonstrate the fistula tract. +Stabilization. +Fluid and electrolyte resuscitation is begun. +Nutrition is provided, usually through the parenteral route +initially. +Sepsis is controlled with antibiotics and drainage of +abscesses. +The skin is protected from the fistula effluent with +ostomy appliances or fistula drains. +2. +Investigation. +The anatomy of the fistula is defined using the +studies described earlier. +3. +Decision. +4. +Definitive management. +5. +Rehabilitation. +The overall objective is to increase the probability of spon- +taneous closure. +Nutrition and time are the key components +of this approach. +Timing of Surgical Intervention. +Patients with intestinal fistulas typically have extensive +and dense intra-abdominal adhesions. +As a result, operations +performed for nonhealing fistulas can present formidable chal- +lenges. +The indications for their use remain to be defined. +Outcomes +Over 50% of intestinal fistulas close spontaneously. +Morbidity was over 80%. +Other benign tumors include fibromas, lipomas, hem- +angiomas, lymphangiomas, and neurofibromas. +This suggests that the majority of small +bowel tumors are asymptomatic. +28-20). +In a ret- +rospective review of a large U.S. +Figure 28-20. +Duodenal polyp. +This polyp was incidentally +encountered during esophagogastroduodenoscopy. +It was biopsied +and found to be an adenoma. +Melanoma, in particular, is associated with a propen- +sity for metastasis to the small intestine. +Most patients with small-intestinal cancers are in their +fifth or sixth decade of life. +Adenomas are histologi- +cally classified as tubular, villous, and tubulovillous. +Tubular +adenomas have the least aggressive features. +The risk of duodenal cancer in these patients +is over 100-fold that in the general population. +28-21). +Pathologic KIT signal transduction is believed to be a cen- +tral event in GIST pathogenesis. +The majority of GISTs have +Figure 28-21. +Small bowel polyp in Peutz-Jeghers syndrome. +(Used with permission from +Dr. +Anne C. +Clinical Presentation +Most small-intestinal neoplasms are asymptomatic until they +become large. +Hemorrhage, usually indolent, is the second most +common mode of presentation. +Physical examination may be unrevealing. +Findings of intestinal obstruction +are reported to be present in 25% of patients. +Fecal occult blood +test may be positive. +Jaundice secondary to biliary obstruction +or hepatic metastasis may be present. +Cachexia, hepatomegaly, +and ascites may be present with advanced disease. +Lesions in the periampullary location can cause obstruc- +tive jaundice or pancreatitis. +As a result, symptoms of carcinoid +syndrome are rare in the absence of liver metastases. +Sixty to seventy percent of GISTs are located in the stom- +ach. +The small intestine is the second most common site, con- +taining 25% to 35% of GISTs. +There appears to be no regional +variation in the prevalence of GISTs within the small intestine. +28-22). +Metastatic tumors involving the small intestine can induce +intestinal obstruction and bleeding. +Contrast radiography of the small intestine may demon- +strate benign and malignant lesions. +Tumors located in the duodenum can be visualized and +biopsied on EGD. +Occasionally, the dis- +tal ileum can be successfully visualized during colonoscopy. +Recently, capsule endoscopy and double-balloon +endoscopy have been used to evaluate small bowel. +In general, duodenal tumors less +than 1 cm in diameter are amenable to endoscopic polypectomy. +Surgical options include transduodenal polypectomy and +segmental duodenal resection. +Jejunal gastrointestinal (GI) stro- +mal tumor (GIST). +This patient presented with +overt obscure GI bleeding and was found to have a +7-cm jejunal GIST. +He underwent a successful laparoscopic resection. +with those limited to the mucosa being amenable to endoscopic + polypectomy. +Further, localized resections are complicated +by high recurrence rates. +The goal of surgical therapy for carcinoids is resection of +all visible disease. +In approximately +30% of cases, multiple small-intestinal carcinoid tumors are +present. +Therefore, the entire small intestine should be exam- +ined before planning extent of resection. +The value to adjuvant chemotherapy after +resection of localized lymphoma is controversial. +Small-intestinal GISTs should be treated with segmental +intestinal resection. +GISTs are resistant to +conventional chemotherapy agents. +Studies have +emphasized the potential for development of tumor resistance to +this agent. +Systemic therapy +may be offered if effective chemotherapy exists for the primary +cancer. +The recurrence rate after resection of GISTs averages +35%. +The 5-year survival rate after surgical resection has been +reported to range from 35% to 60%. +Both tumor size and mitotic +index are independently correlated with prognosis. +With severe cases, mucosal sloughing, +ulceration, and hemorrhage are observed. +Symptoms are generally transient and subside after the discon- +tinuation of radiation therapy. +The +terminal ileum is the most frequently affected segment. +28-23). +CT scan +findings are neither very sensitive nor specific for chronic radi- +ation enteritis. +Therapy +Most cases of acute radiation enteritis are self-limited. +Support- +ive therapy, including the administration of antiemetics, is usu- +ally sufficient. +Rarely are symptoms severe enough to necessitate reduction in +or cessation of radiation therapy. +In contrast, the treatment of chronic radiation enteritis +represents a formidable challenge. +Radiation enteritis. +This condition is discussed in detail +later in the Short Bowel Syndrome section. +28-24). +Meckel’s diverticulum. +This intraoperative photograph +shows Meckel’s diverticulum in ileum that has been eviscerated. +1164 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +gastric mucosa. +Volvulus of the intestine around the fibrous band attaching +the diverticulum to the umbilicus +2. +Entrapment of intestine by a mesodiverticular band (Fig. +28-25) +3. +Intussusception with the diverticulum acting as a lead point +4. +These hernias, when +incarcerated, can cause intestinal obstruction. +Bleeding associated with Meckel’s +diverticula is rare among patients older than 30 years of age. +Intestinal obstruction is the most common presentation in +adults with Meckel’s diverticula. +28-26). +Figure 28-25. +A. +Meckel’s diverticulum with +mesodiverticular band. +B. +No controlled data supporting +or refuting these recommendations exist. +Approximately 75% of juxtapapillary diverticula +arise on the medial wall of the duodenum. +Acquired diverticula +in the jejunum or ileum are known as jejunoileal diverticula. +The prevalence of duodenal diverticula, as detected on +upper GI examinations (Fig. +A 23% prevalence rate +has been reported in an autopsy series. +The mean age of diagnosis ranges +from 56 to 76 years. +The prevalence of jejunoileal diverticula (Fig. +Figure 28-26. +Meckel’s diverticulum with ectopic gastric tissue. +The diagnosis was made in this patient using 99mTc-pertechnetate scintig- +raphy. +Figure 28-27. +Duodenal diverticulum. +Figure 28-28. +Jejunoileal diverticula. +The diverticula are typically located on the mesenteric aspect of the jejunum. +Resection was not indicated because the diverticula were +asymptomatic. +The relationship between these symptoms and the +presence of diverticula is similarly unclear. +Enteroclysis is the most sensitive test for detecting jejunoileal +diverticula. +Therapy +Asymptomatic acquired diverticula should be left alone. +Bacte- +rial overgrowth associated with acquired diverticula is treated +with antibiotics. +Similarly, perforation +can be managed with wide drainage rather than complex sur- +gery. +Four distinct pathophysiologic mechanisms can lead to +acute mesenteric ischemia: +1. +Arterial embolus +2. +Arterial thrombosis +3. +Vasospasm (also known as nonocclusive mesenteric isch- +emia [NOMI]) +4. +Acute thrombosis is usually +superimposed on pre-existing atherosclerotic lesions at these +sites. +The pain +is typically perceived to be colicky and most severe in the mid- +abdomen. +Associated symptoms can include nausea, vomiting, and +diarrhea. +Physical findings are characteristically absent early in the +course of ischemia. +Chronic mesenteric ischemia presents insidiously. +Overt GI bleeding +refers to the presence of hematemesis, melena, or hematochezia. +Meckel’s diverticulum is the most com- +mon etiology of obscure GI bleeding in children. +Enteroscopy is playing +an increasingly important role. +This procedure can allow for visualization of approximately +60 cm of the proximal jejunum. +Diagnostic yield in patients +with obscure GI bleeding ranges from 3% to 65%. +In addition to +diagnosis, push enteroscopy allows for cauterization of bleeding +sites. +However, this instru- +ment lacks biopsy or therapeutic capability. +This technique has reported +success rates as high as 90% in identifying a small bowel +pathology. +In a randomized study +of patients with obscure GI bleeding, evaluation with capsule +endoscopy vs. +small bowel contrast study had a much higher +diagnostic yield (30% vs. +7%, respectively); however, this +did not translate into an improvement in outcomes. +For persistent mild bleeding from an obscure GI source, +push and capsule enteroscopy can be used. +Therapy can be tailored based on the source. +Intra- +operative enteroscopy can be done during either laparotomy or +laparoscopy. +Fig. +28-29 provides a diagnostic and management algo- +rithm for patients with obscure GI bleeding. +This complication occurs in 0.3% to 2.1% of cases. +If perforation is suspected but not clinically obvious, CT scan- +ning should be performed. +Jejunal and ileal perforations require +surgical repair or segmental resection. +Diagnostic and management algorithm for obscure gastrointestinal (GI) bleeding. +EGD = esophagogastroduodenoscopy; +RBC = red blood cell. +Patients with chylous ascites develop abdominal distention +over a period of weeks to months. +Postoperative chylous ascites +can present acutely during the first postoperative week. +Dyspnea may result if +abdominal distention is severe enough. +Paracentesis is the most important diagnostic test. +Fluid triglyceride concentrations above +110 mg/dL are diagnostic. +There are few data on optimal management of patients +with chylous ascites. +This regimen is designed to minimize chyle production and +flow. +Patients who do not respond to this approach should be +fasted and placed on TPN. +Octreotide can further decrease +lymph flow. +Paracentesis is indicated for respiratory difficul- +ties related to abdominal distention. +Overall, two thirds of +patients will respond to conservative therapy. +However, one +third of patients will require surgical therapy for chylous asci- +tes. +Lymphatic leaks are localized and repaired with +fine nonabsorbable sutures. +Because of the viscosity of chyle, these shunts +are associated with a high occlusion rate. +CT scan is the investigation of choice, +where a “target sign” may be seen (Fig. +28-30). +It may affect any region of the GI tract, but is most +Figure 28-30. +Small bowel intussusception. +Panel B demonstrates the distal bowel clearly within the lumen of the proximal bowel (arrow). +1171 +S +MALL + I +NTESTINE +CHAPTER 28 +commonly seen in the jejunum. +The pathogenesis of pneumatosis intestinalis is not +fully understood. +28-15). +The prevalence of short bowel syndrome is hard to esti- +mate. +The most recent available data on chronic home total TPN +administration were obtained in 1992. +At that time, approxi- +mately 40,000 patients were receiving TPN chronically at home. +The colon has the capacity to absorb large fluid and +electrolyte loads. +Second, an intact ileocecal valve is believed to +be associated with decreased malabsorption. +As this pro- +cess completes, some patients are successfully weaned off TPN. +Therapy +Medical Therapy. +Most patients will +require TPN, at least initially. +Enteral nutrition should be gradu- +ally introduced, once ileus has resolved. +Because of these problems, alternative therapies for short bowel +syndrome are under investigation. +Nontransplant Surgical Therapy. +Reported experience with these procedures is limited +to case reports or series of a few cases. +This proce- +dure has the potential to double the length of small intestine to +which it is applied. +This procedure has generally been used for +pediatric patients with dilated residual small bowel. +28-31). +Nearly 80% of survivors have full intestinal graft function +with no need for TPN. +Alternative Therapies. +This figure depicts the +serial transverse enteroplasty (STEP) +procedure. +Information 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JM, Persson M, Jakobsen NO, et al. +Scand J Gastroenterol. +1994;29:483. +54. +Jemal A, Murray T, Sammuels A, et al. +Cancer statistics, 2003. +CA Cancer J Clin. +2003;53:5. +55. +Qubaiah O, Devesa SS, Platz CE, Huycke MM, Dores GM. +Can- +cer Epidemiol Biomarkers Prev. +2010;19:1908. +56. +Ceppa EP, Burbridge RA, Rialon KL, et al. +Endoscopic versus +surgical ampullectomy: an algorithm to treat disease of the +ampulla of Vater. +Ann Surg. +2013;257:315. +57. +Judson I, Demetri G. +Advances in the treatment of gastrointes- +tinal stromal tumors. +Ann Oncol. +2007;18:S20. +58. +Agrawal S, McCarron EC, Gibbs JF, Nava HR, Wilding +GE, Rajput A. +Surgical management and outcome in pri- +mary adenocarcinoma of the small bowel. +Ann Surg Oncol. +2007;14:2263. +59. +Girvent M, Carlson GL, Anderson I, et al. +Intestinal failure +after surgery for complicated radiation enteritis. +Ann R Coll +Surg Engl. +2000;82:198. +60. +Kiliç D, Egehan I, Ozenirler S, Dursun A. +Radiother Oncol. +2000;57:125. +61. +Waddell BE, Lee RJ, Rodriguez-Bigas MA, Weber TK, +Petrelli NJ. +Arch Surg. +2000;135:1212. +62. +Yahchouchy EK, Marano AF, Etienne JC, et al. +Meckel’s +diverticulum. +J Am Coll Surg. +2001;192:654. +63. +Cullen JJ, Kelly KA, Moir CR, et al. +Surgical management of +Meckel’s diverticulum. +An epidemiologic, population-based +study. +Ann Surg. +1994;220:564. +64. +Lobo DN, Balfour TW, Iftikhar SY, et al. +Periampullary diver- +ticula and pancreaticobiliary disease. +Br J Surg. +1999;86:588. +65. +Chow DC, Babaian M, Taubin HL. +Jejunoileal diverticula. +Gastroenterologist. +1997;5:78. +66. +Kumar S, Sarr MG, Kamath PS. +Mesenteric venous thrombo- +sis. +N Engl J Med. +2001;345:1683. +67. +Gralnek IM. +Obscure-overt gastrointestinal bleeding. +Gastro- +enterology. +2005;128:1424. +68. +Szold A, Katz LB, Lewis BS. +Surgical approach to occult gas- +trointestinal bleeding. +Am J Surg. +1992;163:90. +69. +Laine L, Sahota A, Shah A. +Does capsule endoscopy improve +outcomes in obscure gastrointestinal bleeding? +Randomized +trial versus dedicated small bowel radiography. +Gastroenterol- +ogy. +2010;138:1673. +70. +Genzlinger JL, McPhee MS, Fisher JK, et al. +Am J Gastroenterol. +1999;94:1267. +71. +Varban O, Ardestani A, Azagury D, et al. +Contemporary +management of adult intussusception: who needs a resection? +World J Surg. +2013;37:1872. +72. +Varban O, Ardestani A, Azagury D, et al. +Resection or reduc- +tion? +The dilemma of managing retrograde intussuscep- +tion after Roux-en-Y gastric bypass. +Surg Obes Relat Dis. +2013;9:725. +73. +Buchman AL, Solapio J, Fryer J. +AGA technical review on +short bowel syndrome and intestinal transplantation. +Gastro- +enterology. +2003;124:1111. +74. +Thompson JS, Langnas AN. +Surgical approaches to improving +intestinal function in the short-bowel syndrome. +Arch Surg. +1999;134:706. +75. +Bianchi A. +Intestinal loop lengthening: a technique for increas- +ing small-intestinal length. +J Pediatr Surg. +1980;15:145. +76. +Jones BA, Hull MA, Potanos KM, et al. +J Am Coll Surg. +2013;216:438. +77. +Cai J. +Clin Transpl. +2009;83. +78. +Messing B, Crenn P, Beau P, et al. +Gastroenterology. +1999;117:1043. +Colon, Rectum, and Anus +Kelli M. +Bullard Dunn and David A. +Both midgut and hindgut contribute to the colon, +rectum, and anus. +The dentate +line divides the endodermal hindgut from the ectodermal distal +anal canal. +Anatomy +The large intestine extends from the ileocecal valve to the anus. +It is divided anatomically and functionally into the colon, rectum, +and anal canal. +Colon Landmarks. +As a result, the cecum is most +vulnerable to perforation and least vulnerable to obstruction. +The ascending colon is usually fixed to the retroperitoneum. +The hepatic flexure marks the transition to the transverse colon. +3 Ostomies: Preoperative marking for a planned stoma is critical +for a patient’s quality of life. +Risk depends on the amount of colon +involved and the duration of disease. +Surgery is reserved for patients +with persistent or recurrent disease. +8 Rectal prolapse: Rectal prolapse occurs most commonly in +elderly women. +They are thought to play a role in maintaining +continence. +Resection is only indicated for refractory +symptoms. +The greater omentum is attached to the anterior/superior edge +of the transverse colon. +The splenic flexure marks the transition +from the transverse colon to the descending colon. +The descending colon is +relatively fixed to the retroperitoneum. +The sigmoid colon is the +narrowest part of the large intestine and is extremely mobile. +Colon Vascular Supply. +The arterial supply to the colon is +highly variable (Fig. +29-1). +This arcade is complete +in only 15% to 20% of people. +29-2). +Colon Lymphatic Drainage. +Lymphatic vessels and lymph nodes follow the +Middle +colic a. +Right +colic a. +Left +colic a. +Ileocolic a. +Superior +mesenteric a. +Superior +rectal a. +Sigmoidal a. +Inferior +mesenteric a. +Figure 29-1. +Arterial blood supply to the colon. +a. += artery. +Inferior +mesenteric v. +Middle +colic v. +Right +colic v. +Superior +mesenteric v. +Portal v. +Left +colic v. +Sigmoidal v. +Superior +rectal v. +Ileocolic v. +Figure 29-2. +Venous drainage of the colon. +v. += vein. +(Reproduced +with permission from Bell RH, Rikkers LF, Mulholland M, eds. +Digestive Tract Surgery: A Text and Atlas. +Philadelphia: Lippincott +Williams & Wilkins; 1996:1459.) +regional arteries. +The utility of sentinel lymph node dissection and analy- +sis in colon cancer remains controversial. +Colon Nerve Supply. +Sympathetic nerves +arise from T6-T12 and L1-L3. +Anorectal Landmarks. +The rectum is approximately 12 to +15 cm in length. +Three distinct submucosal folds, the valves of +Houston, extend into the rectal lumen. +The lateral liga- +ments support the lower rectum. +The anatomic anal canal extends from the dentate or +pectinate line to the anal verge. +These crypts are the source of crypto- +glandular abscesses (Fig. +29-3). +It begins at the anorectal junction and terminates at +the anal verge. +The deep +external anal sphincter is an extension of the puborectalis muscle. +29-4). +Anorectal Vascular Supply. +The lining of the anal canal. +(From Goldberg SM, Gordon PH, Nivatvongs S, eds. +Essentials of Anorectal Surgery. +Philadelphia: +J.B. +Lippincott Company; 1980:4. +Reproduced with permission from Stanley M. +Goldberg, MD.) +supplies the upper rectum. +29-5). +The venous drainage of the rectum parallels the arterial +supply. +The superior rectal vein drains into the portal system via +the inferior mesenteric vein. +The middle rectal vein drains into +the internal iliac vein. +Anorectal Lymphatic Drainage. +Lymphatic drainage of the +rectum parallels the vascular supply. +Conjoined +longitudinal m. +Superficial external +sphincter m. +Subcutaneous external +sphincter m. +Valve of Houston +Internal rectal +plexus +Muscularis +submucosa ani m. +Transverse septum +of ischiorectal fossa +External rectal +plexus +Internal +sphincter m. +Figure 29-4. +The distal rectum and anal canal. +m. += muscle. +1179 +Colon, Rectum, and Anus +CHAPTER 29 +mesenteric lymph nodes. +The anal +canal has a more complex pattern of lymphatic drainage. +Anorectal Nerve Supply. +Both sympathetic and parasym- +pathetic nerves innervate the anorectum. +Sympathetic nerve +fibers are derived from L1-L3 and join the preaortic plexus. +Parasympathetic +nerve fibers are known as the nervi erigentes and originate from +S2-S4. +These fibers join the sympathetic fibers to form the pel- +vic plexus. +Sympathetic and parasympathetic fibers then supply +the anorectum and adjacent urogenital organs. +While the rectum +is relatively insensate, the anal canal below the dentate line is +sensate. +Failure of canalization of the primitive gut can result in colonic +duplication. +Arterial supply to the rectum and anal canal. +The colon is a major site for water absorption and +electrolyte exchange. +Sodium is absorbed actively via sodium- +potassium (Na+/K+) ATPase. +The colon can absorb up to 400 mEq +of sodium per day. +Water accompanies the transported sodium +and is absorbed passively along an osmotic gradient. +Potassium +is actively secreted into the colonic lumen and absorbed by +passive diffusion. +Chloride is absorbed actively via a chloride- +bicarbonate exchange. +Bacterial degradation of protein and urea produces +ammonia. +Ammonia is subsequently absorbed and transported +to the liver. +Absorption of ammonia depends in part on intra- +luminal pH. +Escherichia +coli are the most numerous aerobes (108–1010 organisms/mL). +Colonic bacteria also are necessary for production of vitamin +K. +Intestinal gas arises from swallowed air, diffusion from +the blood, and intraluminal production. +Nitrogen and oxygen are largely derived from +swallowed air. +Hydrogen and methane are produced by +colonic bacteria. +The production of methane is highly variable. +1180 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Motility, Defecation, and Continence +Motility. +Instead, the colon displays intermittent +contractions of either low or high amplitude. +In general, +cholinergic activation increases colonic motility. +Defecation. +Continence. +The maintenance of fecal continence is at least +as complex as the mechanism of defecation. +The internal and external sphincters are tonically active +at rest. +Branches of the pudendal nerve innervate +both the internal and external sphincter. +Medi- +cation use must be detailed as many drugs cause gastrointestinal +symptoms. +Before recommending operative intervention, the +adequacy of medical treatment must be ascertained. +Endoscopy +Anoscopy. +The anoscope is a useful instrument for examina- +tion of the anal canal. +Anoscopes are made in a variety of sizes +and measure approximately 8 cm in length. +It is rotated 90° and reinserted to +allow visualization of all four quadrants of the canal. +Proctoscopy. +The standard proctoscope is 25 cm in length +and available in various diameters. +Most often, a 15- or 19-mm +diameter proctoscope is used for diagnostic examinations. +Suc- +tion is necessary for an adequate proctoscopic examination. +Flexible Sigmoidoscopy and Colonoscopy. +Sigmoidoscopes +measure 60 cm in length. +Both sig- +moidoscopy and colonoscopy can be used diagnostically and +therapeutically. +Capsule Endoscopy. +Capsule endoscopy is an emerging tech- +nology that uses a small ingestible camera. +Capsule endoscopy largely has been used to detect small bowel +lesions. +Double-contrast barium enema has been used as a +back-up examination if colonoscopy is incomplete. +Computed Tomography. +Computed Tomography Colonography. +When the radial margin is threatened, neoadjuvant +chemoradiation is generally indicated. +MRI also can be helpful +in the detection and delineation of complex fistulas in ano. +The +use of an endorectal coil may increase sensitivity. +Positron Emission Tomography. +PET/CT +increasingly is used to diagnose recurrent and/or metastatic +colorectal cancer. +However, the efficacy and utility of this tech- +nology remains unproven. +Angiography. +Angiography is occasionally used for the detec- +tion of bleeding within the colon or small bowel. +CT and magnetic resonance angiography are also useful +for assessing patency of visceral vessels. +This technique uses +three-dimensional reconstruction to detect vascular lesions. +Endorectal and Endoanal Ultrasound. +The normal rectal wall appears +as a five-layer structure (Fig. +29-6). +Ultrasound can also dif- +ferentiate superficial T1-T2 from deeper T3-T4 tumors. +Ultrasound may also prove useful +for early detection of local recurrence after surgery. +Endoanal ultrasound is used to evaluate the layers of the +anal canal. +Internal anal sphincter, external anal sphincter, and +puborectalis muscle can be differentiated. +Manometry. +Anorectal manometry is performed by placing a +pressure-sensitive catheter in the lower rectum. +A balloon attached to the tip of the catheter also can be used +to test anorectal sensation. +The high-pressure +zone estimates the length of the anal canal (normal, 2.0–4.0 cm). +Neurophysiology. +A. +Schematic of the layers of the rectal wall observed +on endorectal ultrasonography. +B. +Normal endorectal ultrasonography. +(A. +Used with permission of Charles O. +However, this examination is painful +and poorly tolerated by most patients. +Rectal Evacuation Studies. +Rectal evacuation studies include +the balloon expulsion test and video defecography. +Balloon +expulsion assesses a patient’s ability to expel an intrarectal balloon. +Video defecography provides a more detailed assessment of +defecation. +Laboratory Studies +Fecal Occult Blood Testing. +Increased specificity is now possible by using immunochemical +FOBT. +Any positive FOBT mandates further investigation, +usually by colonoscopy. +Stool Studies. +Stool studies are often helpful in evaluating the +etiology of diarrhea. +coli or Shigella species. +Stool cultures can detect pathogenic +bacteria, ova, and/or parasites. +C. +Serum Tests. +Specific laboratory tests that should be per- +formed will be dictated by the clinical scenario. +Preoperative +studies generally include a complete blood count and electrolyte +panel. +Tumor Markers. +Carcinoembryonic antigen (CEA) may be +elevated in 60% to 90% of patients with colorectal cancer. +Despite this, CEA is not an effective screening tool for this +malignancy. +However, this tumor marker is nonspecific, +and no survival benefit has yet been proven. +It is also important +to note that CEA may be mildly elevated in patients who smoke +tobacco. +However, +in the absence of an identified mutation, a negative result is +uninformative. +Evaluation of Common Symptoms +Pain +Abdominal Pain. +Abdominal pain is a nonspecific symptom +with myriad causes. +Pelvic Pain. +Pelvic pain can originate from the distal colon and +rectum or from adjacent urogenital structures. +Tenesmus may +result from proctitis or from a rectal or retrorectal mass. +Pelvic +inflammatory disease also can produce significant abdominal +and pelvic pain. +CT +scan and/or MRI may be useful in differentiating these diseases. +Proctoscopy (if tolerated) also can be helpful. +Occasionally, +laparoscopy will yield a diagnosis. +Anorectal Pain. +Physical examination can usually differentiate these +conditions. +Proctalgia fugax results from levator spasm and may +present without any other anorectal findings. +Physical exam is +critical in evaluating patients with anorectal pain. +MRI or other imaging studies may be +helpful in select cases where the etiology of pain is elusive. +Lower Gastrointestinal Bleeding. +The second goal is to identify the source of hemorrhage. +Anoscopy and/or +limited proctoscopy can identify hemorrhoidal bleeding. +Colectomy may be required +if bleeding persists despite these interventions. +Intraoperative +colonoscopy and/or enteroscopy may assist in localizing bleed- +ing. +29-7). +Unexplained iron-deficiency +anemia is also an indication for colonoscopy. +Hematochezia is commonly caused by hemorrhoids or +a fissure. +Failure to diagnose a source in the distal anorectum should +prompt colonoscopy. +Constipation and Obstructed Defecation. +A careful his- +tory of these symptoms often clarifies the nature of the problem. +Constipation has many causes. +A stricture or mass +lesion should be excluded by colonoscopy, barium enema, or +CT colonography. +Defecography can identify rectal pro- +lapse, intussusception, rectocele, or enterocele. +Algorithm for treatment of colorectal hemorrhage. +NG = nasogastric; 99mTc = technetium-99; RBC = red blood cell. +(Reproduced with permission of Taylor & Francis, LLC from Gordon PH, Nivatvongs S, eds. +Principles and Practice of Surgery for the +Colon, Rectum, and Anus. +2nd ed. +New York: Marcel Dekker, Inc.; 1999:1279. +Bloody diarrhea and pain are characteristic of colitis; +etiology can be an infection (invasive E. +coli, Shigella, Salmo- +nella, Campylobacter, Entamoeba histolytica, or C. +difficile), +inflammatory bowel disease (ulcerative colitis or Crohn’s coli- +tis), or ischemia. +Stool wet-mount and culture can often diag- +nose infection. +Sigmoidoscopy or colonoscopy can be helpful in +diagnosing inflammatory bowel disease or ischemia. +Chronic diarrhea may present a more difficult diagnos- +tic dilemma. +Large villous lesions may cause secretory diarrhea. +Collag- +enous colitis can cause diarrhea without any obvious mucosal +abnormality. +Biopsies should be taken even if the +colonic mucosa appears grossly normal. +Workup reveals no +underlying anatomic or physiologic abnormality. +Antispasmodics and bulking agents may be helpful. +Incontinence. +The underlying cause of incontinence is often multifactorial, +and diarrhea is often contributory. +In general, causes of inconti- +nence can be classified as neurogenic or anatomic. +Other causes include anorectal surgery, impalement, +and pelvic fracture. +Pudendal nerve terminal motor latency testing may +detect neuropathy. +Anal manometry can detect low resting and +squeeze pressures. +Physical examination and defecography can +detect rectal prolapse. +Endoanal ultrasound is invaluable in +diagnosing sphincter defects (Fig. +29-8). +Therapy depends on the underlying abnormality. +Diarrhea +should be treated medically (fiber, antidiarrheal agents). +Even in the absence of frank diarrhea, the addition of dietary +fiber may improve continence. +Some patients may respond to +biofeedback. +Many patients with a sphincter defect are candi- +dates for an overlapping sphincteroplasty. +A +B +Figure 29-8. +A. +Endoanal ultrasonography showing the normal +layers of the anal canal. +B. +Endoanal ultrasonography with anterior +sphincter defect from birthing injury. +EAS = external anal sphincter; +IAS = internal anal sphincter. +(Both images used with permission +of Charles O. +29-9). +Resection of a benign process does not +require wide mesenteric clearance. +Emergency Resection. +Emergency resection may be required +because of obstruction, perforation, or hemorrhage. +For left-sided tumors, the traditional +BA +DC +FE +Figure 29-9. +Extent of resection for carcinoma of the colon. +A. +Cecal cancer. +B. +Hepatic flexure cancer. +C. +Transverse colon cancer. +D. +Splenic flexure cancer. +E. +Descending colon cancer. +F. +Sigmoid colon cancer. +Minimally Invasive Techniques of Resection. +Return of bowel function and length of +hospital stay are highly variable. +Colectomy. +A variety of terms are used to describe different +types of colectomy (Fig. +29-10). +Ileocolic Resection. +An ileocolic resection describes a lim- +ited resection of the terminal ileum, cecum, and appendix. +The ileocolic vessels are ligated and divided. +A +variable length of small intestine may be resected depending on +the disease process. +A primary anastomosis is created between +the distal small bowel and the ascending colon. +Right Colectomy. +Approximately 10 cm of terminal ileum are usually included in +the resection. +A primary ileal-transverse colon anastomosis is +almost always possible. +Extended Right Colectomy. +The right colon and proximal transverse colon are +A +BC +D +E +FG +H +I +J +K +L +Figure 29-10. +(Reproduced with +permission from Fielding LP, Goldberg SM, eds. +Rob & Smith’s +Operative: Surgery of the Colon, Rectum, and Anus. +Such an anastomosis relies +on the marginal artery of Drummond. +Transverse Colectomy. +Left Colectomy. +A colocolonic anastomosis can +usually be performed. +Extended Left Colectomy. +An extended left colectomy is an +option for removing lesions in the distal transverse colon. +Sigmoid Colectomy. +Full mobilization of the splenic flexure is often required to cre- +ate a tension-free anastomosis. +Total and Subtotal Colectomy. +The superior rectal +vessels are preserved. +Proctocolectomy +Total Proctocolectomy. +Restorative Proctocolectomy (Ileal Pouch–Anal +Anastomosis). +Bowel continuity is restored by +anastomosis of an ileal reservoir to the anal canal. +The original +technique included a transanal mucosectomy and hand-sewn +ileoanal anastomosis. +29-12). +Anterior Resection. +(Reproduced with permission from Bell RH, Rikkers +LF, Mulholland M, eds. +Digestive Tract Surgery: A Text and Atlas. +Philadelphia: Lippincott Williams & Wilkins; 1996:1527.) +other incision. +Three types of anterior resection have been +described. +High Anterior Resection. +Low Anterior Resection. +A low anterior resection is used to +remove lesions in the upper and mid rectum. +Extended Low Anterior Resection. +An end-to-end stapled or hand-sewn anastomosis +has traditionally been the procedure of choice. +Ileal S-pouch anal anastomosis with temporary loop +ileostomy. +(Reproduced with permission from Bell RH, Rikkers LF, +Mulholland M, eds. +Digestive Tract Surgery: A Text and Atlas. +Finally, a very low anastomosis may involve and compromise +the upper sphincter. +In such patients, an end colostomy may be a more satisfac- +tory option. +Hartmann’s Procedure and Mucus Fistula. +Abdominoperineal Resection. +Anastomoses +Anastomoses may be created between two segments of bowel in +a multitude of ways. +The geometry of the anastomosis may be +end-to-end, end-to-side, side-to-end, or side-to-side. +The anas- +tomotic technique may be hand-sewn or stapled (Fig. +29-13). +The choice of anastomosis depends on the opera- +tive anatomy and surgeon preference. +Although many surgeons +advocate one method over another, none has been proven to +be superior. +Anastomotic Configuration +End-to-End. +End-to-Side. +An end-to-side configuration is useful when one +limb of bowel is larger than the other. +This most commonly +occurs in the setting of chronic obstruction. +Side-to-End. +Ileo- +rectal anastomoses commonly make use of this configuration. +Figure 29-13. +A. +Sutured end-to-end colocolic anastomosis. +B. +Sutured end-to-side ileocolic anastomosis. +C. +Stapled side-to-side, functional +end-to-end ileocolic anastomosis. +(Reproduced with permission from Bell RH, Rikkers LF, Mulholland M, eds. +Digestive Tract Surgery: A +Text and Atlas. +Side-to-Side. +This technique is commonly used +in ileocolic and small bowel anastomoses. +Anastomotic Technique +Hand-Sutured Technique. +Suture material may be either permanent +1191 +Colon, Rectum, and Anus +CHAPTER 29 +or absorbable. +Stapled Techniques. +The anastomosis may be reinforced with interrupted sutures if +desired. +Circular cutting/stapling devices can create end-to-end, +end-to-side, or side-to-end anastomoses. +The sta- +pler is opened, and the distal purse-string is tied. +Technique of end-to-end colorectal anastomosis using a circular stapler. +A. +The patient is in modified lithotomy position. +B. +C. +D. +The stapler is closed and fired. +E. +The stapler is removed, leaving a circular stapled end-to-end anastomosis. +colon is placed over the anvil and the purse-string tightened. +The stapler is closed and fired (Fig. +29-14). +The anastomosis in then completed as described ear- +lier (see Fig. +29-11). +A temporary proximal ileostomy may be indicated as well. +It may be end-on or a loop. +Preoperative planning includes counseling, education, +and stoma siting. +Postoperatively, the ET nurse assists with local +skin care and pouching. +Preoperative stoma siting is crucial for a patient’s postoper- +ative function and quality of life. +A poorly placed stoma can result +in leakage and skin breakdown. +29-15). +In emergencies, placement high on the +abdominal wall is preferred to a low-lying site. +Marking of an ideal site for ileostomy. +(Repro- +duced with permission from Bell RH, Rikkers LF, Mulholland M, +eds. +Digestive Tract Surgery: A Text and Atlas. +Philadelphia: +Lippincott Williams & Wilkins; 1996:1273.) +Figure 29-16. +Brooke ileostomy. +A. +B. +(Reproduced with permission from Bell RH, Rikkers LF, Mulholland +M, eds. +Digestive Tract Surgery: A Text and Atlas. +Philadelphia: +Lippincott Williams & Wilkins; 1996:1278.) +vein. +The bowel is then brought through the +defect and secured with sutures. +In order to make appliance use easier, +a protruding nipple is fashioned by everting the bowel. +29-16). +Ileostomy +Temporary Ileostomy. +In this setting, the stoma is often constructed as +a loop ileostomy (see Fig. +29-12). +A segment of distal ileum +is brought through the defect in the abdominal wall as a loop. +An enterotomy is created and the stoma matured as described +earlier. +The loop may be secured with or without an underly- +ing rod. +This +avoids a long laparotomy incision and generally is well tolerated. +A patient’s nutritional status +should be optimized. +Permanent Ileostomy. +29-16). +The end of the small intestine is brought through +the abdominal wall defect and matured. +Stitches are often used +to secure the bowel to the posterior fascia. +Complications of Ileostomy. +Stoma retraction may occur early or +late and may be exacerbated by obesity. +Local revision may +be necessary. +Ideally, ileos- +tomy output should be maintained at less than 1500 mL/d to +avoid this problem. +Bulk agents and opioids (Lomotil, Imodium, +tincture of opium) are useful. +The somatostatin analogue, +octreotide, has been used with varying success in this setting. +Skin irritation can also occur, especially if the stoma appliance +fits poorly. +Skin-protecting agents and custom pouches can help +to solve this problem. +Obstruction may occur intra-abdominally +or at the site where the stoma exits the fascia. +In general, symptomatic parastomal hernias should be repaired. +Prolapse is a rare, late +complication and is often associated with a parastomal hernia. +Colostomy. +Most colostomies are created as end colostomies +rather than loop colostomies (Fig. +29-17). +Most colos- +tomies are created on the left side of the colon. +An abdominal +wall defect is created and the end of the colon mobilized through +it. +Tacking the distal end of the colon to the abdominal wall or +Figure 29-17. +Intraperitoneal end colostomy. +The stoma is dissected free of the abdominal wall and the distal +bowel identified. +An end-to-end anastomosis is then created. +Complications of Colostomy. +Obstruction +is unusual, but may also occur. +Prolapse occurs rarely, but is more com- +mon with a loop colostomy. +Interestingly, it is almost always +the efferent limb of the loop that prolapses. +Dehydration is rare +after colostomy, and skin irritation is less common than with +ileostomy. +Unfortunately, complications, +especially complications related to valve slippage, are common. +Up to 50% have some degree of nocturnal incontinence. +Pouch failure rate averages 5% to +10%. +The inci- +dence of pouchitis ranges from 30% to 55%. +Symptoms include +increased diarrhea, hematochezia, abdominal pain, fever, and +malaise. +Diagnosis is made endoscopically with biopsies. +Dif- +ferential diagnosis includes infection and undiagnosed Crohn’s +disease. +The etiology of pouchitis is unknown. +Salicylate and corticosteroid +enemas have also been used with some success. +Occasionally, pouch excision is necessary to control the +symptoms of chronic pouchitis. +Anesthesia Considerations +Local Anesthesia. +Many anorectal procedures can be per- +formed with local anesthetic alone. +Intravenous sedation is often +provided to calm the patient. +The addition of dilute epinephrine +decreases bleeding and prolongs the anesthetic effect. +Regional Anesthesia. +Postoperative epidural anesthesia provides excellent pain relief +and improves pulmonary function. +General Anesthesia. +General anesthesia is required for the +vast majority of intra-abdominal procedures. +Patients should +undergo a thorough preoperative cardiovascular evaluation. +In +patients with significant comorbid disease, an anesthesia con- +sultation may be appropriate. +Positioning. +Most abdominal colectomies can be performed +in the supine position. +Anorectal procedures may be performed in lithotomy +or in the prone jackknife position. +Operative Preliminaries +Bowel Preparation. +PEG solutions require patients to drink a large volume +of fluid and may cause bloating and nausea. +Both are equally +efficacious in bowel cleansing. +There is no proven benefit to using +antibiotics postoperatively after an uncomplicated colectomy. +European surgeons in particular have advo- +cated abandoning this practice. +Lighted stents may be helpful in laparoscopic +and robotic resections. +Patients often have transient hematuria +postoperatively, but major complications are rare. +Multidisciplinary Teams. +INFLAMMATORY BOWEL DISEASE +General Considerations +Epidemiology. +The incidence of Crohn’s disease is slightly lower, +1 to 5 people per 100,000. +Crohn’s disease also affects North- +ern European and white populations disproportionately. +Etiology. +Many different etiologies for inflammatory bowel +disease have been proposed, but none are proven. +Alcohol and oral contraceptive +use have also been implicated. +Smoking has been implicated in +the etiology and exacerbation of Crohn’s disease in particular. +Finally, as noted earlier, an autoimmune +mechanism has been postulated. +Pathology and Differential Diagnosis. +The mucosa may be atrophic, and crypt abscesses +are common. +Symptoms are related to the degree of mucosal inflammation +and the extent of colitis. +Patients typically complain of bloody +diarrhea and crampy abdominal pain. +Proctitis may produce +tenesmus. +Severe abdominal pain and fever raise the concern +of fulminant colitis or toxic megacolon. +In the nonemergent setting, the +diagnosis is typically made by colonoscopy and mucosal biopsy. +Skip lesions and rectal sparing are +common. +Strictures +may produce symptoms of obstruction. +Weight loss is common, +both because of obstruction and from protein loss. +Physical findings are also related to +the site and severity of disease. +These patients typically present with symptoms similar +to ulcerative colitis. +Endoscopic and pathologic findings usually +include features common to both diseases. +diffi- +cile, Neisseria gonorrhoeae, Salmonella, and Shigella species. +Extraintestinal Manifestations. +The liver is a common site +of extracolonic disease in inflammatory bowel disease. +Forty percent to 60% of patients with primary sclerosing +cholangitis have ulcerative colitis. +Bile +duct carcinoma is a rare complication of long-standing inflam- +matory bowel disease. +Arthritis usually +improves with treatment of the colonic disease. +Medical +and surgical treatment of the colonic disease does not impact +symptoms. +Women are affected three to four times more +frequently than men. +The characteristic lesions are raised, red, +and predominantly on the lower legs. +The lesions progress and ulcerate, leading to a painful, +necrotic wound. +Pyoderma gangrenosum may respond to resec- +tion of the affected bowel in some patients. +In others, this disor- +der is unaffected by treatment of the underlying bowel disease. +Up to 10% of patients with inflammatory bowel disease +will develop ocular lesions. +These include uveitis, iritis, episcle- +ritis, and conjunctivitis. +They usually develop during an acute +exacerbation of the inflammatory bowel disease. +The etiology +is unknown. +Principles of Nonoperative Management. +In +general, mild to moderate flares may be treated in the outpatient +setting. +More severe signs and symptoms mandate hospitalization. +Pancolitis generally requires more aggressive therapy than lim- +ited disease. +Systemic therapy is rarely required in +these patients. +Salicylates. +They +require direct contact with affected mucosa for efficacy. +Antibiotics. +Antibiotics are often used to decrease the intra- +luminal bacterial load in Crohn’s disease. +Fluoroquinolones may also be effec- +tive in some cases. +Corticosteroids. +Failure to wean +corticosteroids is a relative indication for surgery. +Budesonide is available as an oral preparation. +Immunomodulating Agents. +However, the majority of these patients will ulti- +mately require colectomy. +Improvement is generally apparent within 2 weeks of beginning +cyclosporine therapy. +Methotrexate is a folate antagonist that also has been used +to treat inflammatory bowel disease. +Intravenous infusion of these agents decreases +inflammation systemically. +Recurrence is common, however; and many +patients require infusions on a bimonthly basis. +Patients with inflammatory bowel disease are often +malnourished. +Abdominal pain and obstructive symptoms may +decrease oral intake. +Diarrhea can cause significant protein loss. +Ongoing inflammation produces a catabolic physiologic state. +The severity of symptoms depends on +the degree and extent of inflammation. +Although anemia is +common, massive hemorrhage is rare. +Physical findings are +often nonspecific. +The diagnosis of ulcerative colitis is almost always made +endoscopically. +Because the rectum is invariably involved, +proctoscopy may be adequate to establish the diagnosis. +In more advanced disease, char- +acteristic findings include mucosal friability and ulceration. +Pus +and mucus may also be present. +However, +this modality is less sensitive than colonoscopy and may not +detect early disease. +Because the inflammation in ulcerative colitis is purely +mucosal, strictures are highly uncommon. +Indications for Surgery. +Indications for surgery in ulcer- +ative colitis may be emergent or elective. +Colonoscopy and barium enema are contraindicated, and +antidiarrheal agents should be avoided. +Deterioration in clinical +condition or failure to improve within 24 to 48 hours mandates +surgery. +However, the adequacy +of this type of screening is controversial. +For this rea- +son, any patient with dysplasia should be advised to undergo +proctocolectomy. +Neither approach has been shown definitively to +decrease mortality from colorectal cancer. +1198 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Operative Management +Emergent Operation. +Definitive surgery may +then be undertaken at a later date once the patient has recovered. +Elective Operation. +Most patients function well physically and psychologically after +this operation. +Crohn’s disease, however, may +affect any portion of the intestinal tract, from mouth to anus. +Indications for Surgery. +Crohn’s disease may present as an acute inflammatory +process or as a chronic fibrotic process. +Parenteral +nutrition should be considered if the patient is malnourished. +Most intra-abdominal abscesses can be drained percutaneously +with the use of CT scan guidance. +Simple +closure of the secondary fistula site usually suffices. +Chronic fibrosis may result in strictures in any part of the +gastrointestinal tract. +Chronic strictures almost never improve with medical therapy. +Strictures may be treated with resection or stricturoplasty. +Distal ileal strictures are sometimes amenable to colonoscopic +balloon dilatation. +Laparoscopy is also increasingly used in this setting. +Ileocolic and Small Bowel Crohn’s Disease. +Psoas abscess may result from ileo- +colic Crohn’s disease. +Parenteral nutrition may be necessary in patients with chronic +obstruction. +The extent of resection depends on the amount of +involved intestine. +Isolated chronic strictures should +also be resected. +29-18). +Crohn’s Colitis. +Crohn’s disease of the large intestine may +present as fulminant colitis or toxic megacolon. +An +elective proctectomy may be required if the patient has refrac- +tory Crohn’s proctitis. +Unlike ulcerative colitis, Crohn’s +colitis may be segmental, and rectal sparing is often observed. +A segmental colectomy may be appropriate if the remaining +colon and/or rectum appear normal. +An isolated colonic stricture +may also be treated by segmental colectomy. +Although it was +long thought that Crohn’s disease did not increase the risk of +Figure 29-18. +Alternative stricturoplasty techniques. +A. +A short stricture is opened along the antimesenteric surface of the bowel wall. +B. +The +enterotomy is closed transversely. +C. +A long stricture is opened along the antimesenteric surface of the bowel wall. +D. +The bowel is folded +into an inverted “U.” E. +A side-to-side anastomosis is made. +(Reproduced with permission from Corman ML. +Colon & Rectal Surgery. +2nd ed. +As in ulcerative +colitis, dysplasia is an indication for total proctocolectomy. +Anal and Perianal Crohn’s Disease. +Isolated anal Crohn’s +disease is uncommon, affecting only 3% to 4% of patients. +The most common perianal lesions in Crohn’s disease +are skin tags that are minimally symptomatic. +Fissures are also +common. +Perianal abscess and fistulas are common and can be particu- +larly challenging. +Fistulas tend to be complex and often have +multiple tracts (Fig. +29-19). +Recurrent abscess(es) or complex anal fistulae should raise +the possibility of Crohn’s disease. +Endoanal ultrasound and pelvic +MRI are useful for mapping complex fistulous tracts. +Liberal +use of setons can control many fistulas and avoid division of +the sphincter. +Photograph of a patient with multiple perianal +fistulas secondary to Crohn’s disease. +(Reproduced with permis- +sion from Hamilton SR, Borson BC. +Crohn’s disease: Pathology. +In: Berk JE, ed. +Bockus Gastroenterology. +4th ed. +Philadelphia: +Saunders; 1985:2229, Fig. +127-5. +Copyright Elsevier.) +inflammation. +In 10% to 15% of cases, intractable perianal sep- +sis requires proctectomy. +Rectovaginal fistula can be a particularly difficult problem +in these patients. +Metronidazole has +been used with some success in this setting. +Proinflammatory +cytokines such as interleukin-12 and interferon-γ are potential +targets. +Pathologic examination of the entire colon may then +allow a more accurate diagnosis. +Diverticulosis refers to the +presence of diverticula without inflammation. +Diverticulitis +refers to inflammation and infection associated with diverticula. +They are thought to be pulsion diverticula resulting +from high intraluminal pressure. +Diverticular bleeding can be +massive but usually is self-limited. +Diverticulosis is extremely common in the United States +and Europe. +It is estimated that half of the population older than +age 50 years has colonic diverticula. +The sigmoid colon is the +most common site of diverticulosis (Fig. +29-20). +Diverticulosis +is thought to be an acquired disorder, but the etiology is poorly +understood. +The high radial pressures +directed against the bowel wall create pulsion diverticula. +Peridiverticular and pericolic +Figure 29-20. +Diverticulosis of sigmoid colon on barium enema. +(Reproduced with permission from Nivatvongs S, Becker ER. +Colon, rectum, and anal canal. +In: James EC, Corry RJ, Perry JCF +Jr, eds. +Basic Surgical Practice. +Philadelphia: Hanley & Belfus; +1987. +Most patients present with left- +sided abdominal pain, with or without fever, and leukocytosis. +A mass may be present. +Plain radiographs are useful for detect- +ing free intra-abdominal air. +CT scan is extremely useful for +defining pericolic inflammation, phlegmon, or abscess. +Uncomplicated Diverticulitis. +Uncomplicated diverticulitis is +characterized by left lower quadrant pain and tenderness. +CT +findings include pericolic soft tissue stranding, colonic wall +thickening, and/or phlegmon. +Antibi- +otics should be continued for 7 to 10 days. +Most patients improve within 48 to 72 hours. +Failure to improve may suggest abscess formation. +Colonoscopy is recommended +4 to 6 weeks after recovery. +Inability to exclude malignancy is +another indication for resection. +Increasingly, laparoscopy is being used for elec- +tive sigmoid colectomy for diverticular disease. +Complicated Diverticulitis. +Small abscesses (<2 cm +in diameter) may be treated with parenteral antibiotics. +Larger +abscesses are best treated with CT-guided percutaneous drain- +age (Fig. +29-21) and antibiotics. +In almost all +cases, an attempt should be made to resect the affected seg- +ment of bowel. +A. +Computed tomography scan demonstrating pelvic abscess from perforated diverticular disease. +B. +(Both images used with permission of Charles O. +Relief of obstruction allows +full bowel preparation and elective resection. +A high-volume +oral bowel preparation is contraindicated in the presence of +obstructive symptoms. +Obstruction that does not rapidly respond +to medical management mandates laparotomy. +Sigmoid colec- +tomy with end colostomy is the safest procedure to perform in this +setting. +Colovesical fistulas are most common, followed by colovagi- +nal and coloenteric fistulas. +Colocutaneous fistulas are a rare +complication of diverticulitis. +CT +scan can identify associated abscesses or masses. +The differ- +ential diagnosis includes malignancy, Crohn’s disease, and +radiation-induced fistulas. +Suspicion +of carcinoma may mandate a wider, en bloc resection. +Consequently, the exact bleeding source may be dif- +ficult to identify. +Fortunately, in 80% of patients, bleeding stops +spontaneously. +Angiography may be diagnos- +tic and therapeutic in this setting. +Giant Colonic Diverticulum +Giant colonic diverticula are extremely rare. +Most occur on +the antimesenteric side of the sigmoid colon. +Plain radiographs may +suggest the diagnosis. +Barium enema is usually diagnostic. +Complications of a giant diverticulum include perforation, +obstruction, and volvulus. +Resection of the involved colon and +diverticulum is recommended. +Most patients with right-sided diverticula are +asymptomatic. +However, diverticulitis does occur occasionally. +Aging. +More than 90% +of cases diagnosed are in people older than age 50 years. +Hereditary Risk Factors. +Environmental and Dietary Factors. +In contrast, a diet high in +vegetable fiber appears to be protective. +In general, the duration and extent of colitis +correlate with risk. +Other Risk Factors. +Pelvic irradiation may increase +the risk of developing rectal carcinoma. +29-22). +Defects in the APC gene were first described in patients +with FAP. +By investigating these families, characteristic muta- +tions in the APC gene were identified. +They are now known to +be present in 80% of sporadic colorectal cancers as well. +The APC gene is a tumor suppressor gene. +Mutations +in both alleles are necessary to initiate polyp formation. +The +majority of mutations are premature stop codons, which result in +a truncated APC protein. +In FAP, the site of mutation correlates +with the clinical severity of the disease. +Thus, knowledge of the specific +mutation in a family may help guide clinical decision making. +APC inactivation alone does not result in a carcinoma. +Additional mutations +may include activation or inactivation of a variety of genes. +One of the most commonly involved genes in colorectal +cancer is K-ras. +The K-ras gene product is a G-protein involved in +intracellular signal transduction. +It is thought that this +then leads to uncontrolled cell division. +The tumor suppressor gene p53 has been well character- +ized in a number of malignancies. +p53 Other changes +Figure 29-22. +Schematic showing progression from normal colonic epithelium to carcinoma of the colon. +Mutations in p53 are present in 75% of +colorectal cancers. +The Loss of Heterozygosity Pathway. +The LOH pathway +is characterized by chromosomal deletions and tumor aneu- +ploidy. +Eighty percent of colorectal carcinomas appear to arise +from mutations in the LOH pathway. +Another example of LOH occurs in the region of chromo- +some 18q. +This region has been found to be deleted in up to +70% of colorectal cancers. +DCC +is a tumor suppressor gene, and loss of both alleles is required +for malignant degeneration. +Loss of either of these genes +is thought to promote cancer progression. +The Microsatellite Instability Pathway. +These +mismatch repair genes include MSH2, MLH1, PMS1, PMS2, +and MSH6/GTBP. +Accumulation of these errors then +leads to genomic instability and ultimately to carcinogenesis. +CpG Island Methylation Pathway. +In normal cells, methylation is critical for regulation of +gene expression. +For example, a mismatch repair gene may be +inactivated by methylation. +Errors in mismatch repair may then +allow mutations to inactivate a tumor suppressor gene. +Neoplastic Polyps. +By definition, these lesions are dysplas- +tic. +The risk of malignant degeneration is related to both the +size and type of polyp. +Tubulovillous adenomas are at +intermediate risk (22%). +Invasive carcinomas are rare in polyps +smaller than 1 cm; the incidence increases with size. +The risk of +carcinoma in a polyp larger than 2 cm is 35% to 50%. +Polyps may be pedunculated or sessile. +Most pedun- +culated polyps are amenable to colonoscopic snare excision. +Removal of sessile polyps is often more challenging. +Complications of polypectomy include perforation and +bleeding. +Bleeding may occur immediately after +polypectomy or may be delayed. +Occasionally angiography +and infusion of vasopressin may be necessary. +Rarely, colec- +tomy is required. +Hyperplastic Polyps. +Hyperplastic polyps are extremely +common in the colon. +In contrast, large hyperplastic +polyps (>2 cm) may have a slight risk of malignant degenera- +tion. +Moreover, large polyps may harbor foci of adenomatous +tissue and dysplasia. +These patients are at slightly increased risk for the development +of colorectal cancer. +Serrated Polyps. +Serrated polyps are a recently recognized, +histologically distinct group of neoplastic polyps. +However, it has become clear that +some of these polyps will develop into invasive cancers. +In addi- +tion, a familial serrated polyposis syndrome has recently been +described. +These lesions are the +characteristic polyps of childhood but may occur at any age. +Bleeding is a common symptom, and intussusception and/or +obstruction may occur. +Annual +screening should begin between the ages of 10 and 12 years. +Treatment is surgical and depends in part on the degree of rectal +involvement. +If the +rectum is carpeted with polyps, total proctocolectomy is the +more appropriate operation. +These patients are candidates for +ileal pouch–anal reconstruction to avoid a permanent stoma. +Characteristic melanin spots are often noted +on the buccal mucosa and lips of these patients. +However, carcinoma may occasionally develop. +Patients should be screened +for cancers. +Treatment is otherwise based on symptoms. +Inflammatory Polyps (Pseudopolyps). +Polyposis may be extensive, especially in patients with severe +colitis, and may mimic FAP. +Familial Adenomatous Polyposis. +The genetic abnormality in FAP is +a mutation in the APC gene, located on chromosome 5q. +Of +patients with FAP, APC mutation testing is positive in 75% of +cases. +Clinically, patients develop hundreds to thou- +sands of adenomatous polyps shortly after puberty. +The lifetime +risk of colorectal cancer in FAP patients approaches 100% by +age 50 years. +Periampullary carcinoma is a particular concern. +Once the diagnosis of FAP has been made and polyps are +developing, treatment is surgical. +COX-2 inhibitors and nonsteroidal, +anti-inflammatory drugs may also be beneficial in this setting. +Attenuated Familial Adenomatous Polyposis. +AFAP is a +recognized variant of FAP. +Patients are also at risk for duo- +denal polyposis. +When present, these mutations are expressed in an autosomal +dominant pattern. +When positive, genetic counseling and testing may be +used to screen at-risk family members. +Hereditary Nonpolyposis Colon Cancer (Lynch’s +Syndrome). +Approximately 70% +of affected individuals will develop colorectal cancer. +The risk of synchronous or metachronous colorectal carcinoma +is 40%. +The diagnosis of HNPCC is made +based on family history. +The presence of other HNPCC-related carcinomas should +raise the suspicion of this syndrome. +MSH6 inactivation also appears to be associated +with a higher risk for endometrial cancer. +Further significance +of these specific mutations remains to be determined. +Annual proctos- +copy is necessary because the risk of developing rectal cancer +remains high. +Familial Colorectal Cancer. +The lifetime risk of developing colorectal cancer +increases with a family history of the disease. +Fecal Occult Blood Testing. +FOBT is known to reduce +colorectal cancer mortality by 33% and metastatic disease by +50%. +Its specificity +is low because 90% of patients with positive tests do not have +colorectal cancer. +Flexible Sigmoidoscopy. +Colonoscopy. +Colonoscopy is currently the most accurate and +most complete method for examining the large bowel. +Nevertheless, +deaths have been reported. +Air-Contrast Barium Enema. +Unfortunately, there are no studies proving its +efficacy for screening large populations. +Computed Tomography Colonography (Virtual Colonos- +copy). +A +present, patients require a mechanical bowel preparation. +Guidelines for Screening. +Routes of Spread and Natural History +Carcinoma of the colon and rectum arises in the mucosa. +The +tumor subsequently invades the bowel wall and eventually +adjacent tissues and other viscera. +Tumors may become bulky +and circumferential, leading to colon obstruction. +The T stage (depth of invasion) is the single most +significant predictor of lymph node spread. +Four or more involved lymph nodes +predict a poor prognosis. +Lymphatic spread from the rectum follows +two routes. +In the +lower rectum, lymphatic drainage may course along the middle +rectal vessels. +29-23). +The most common site of distant metastasis from colorec- +tal cancer is the liver. +These metastases arise from hematog- +enous spread via the portal venous system. +However, even small tumors may pro- +duce distant metastasis. +The lung is also a site of hematogenous +spread, but this rarely occurs in isolation. +Staging and Preoperative Evaluation +Clinical Presentation. +The classic first symptoms are a change in bowel +habits and rectal bleeding. +Rectal +tumors may cause bleeding, tenesmus, and pain. +Staging. +The preoperative evaluation usually identifies stage IV +disease. +Disease +stage correlates with 5-year survival. +Patients with stages I and +II disease can expect excellent survival rates. +The presence of +nodal metastases (stage III) decreases survival (Table 29-4). +The 5-year survival rate with stage IV disease is less than 16%. +Sources: Data adapted from Smith et al,6 Pignone et al,68 and Levin et al.67 +Inferior +mesenteric a. +Superior +rectal a. +Middle +rectal a. +Inferior +rectal a. +Common +iliac a. +Figure 29-23. +Lymphatic drainage of the rectum. +a. += artery. +Source: From Gunderson et al.76 Copyright Elsevier. +prognosis. +This circumferential or radial margin is probably +best assessed preoperatively by MRI. +Preoperative Evaluation. +Once a colon or rectal carcinoma +has been diagnosed, a staging evaluation should be undertaken. +The colon must be evaluated for synchronous tumors, usually +by colonoscopy. +Synchronous disease will be present in up to +5% of patients. +29-24). +A chest/abdominal/pelvic +Figure 29-24. +Endorectal ultrasonography showing a T3 rectal +carcinoma. +The dotted line is being used to measure the diameter +of the lesion. +(Used with permission of Charles O. +Preoperative +CEA is often obtained and may be useful for postoperative +follow-up. +Therapy for Colonic Carcinoma +Principles of Resection. +Stage-Specific Therapy +Stage 0 (Tis, N0, M0). +Polyps containing carcinoma in situ +(high-grade dysplasia) carry no risk of lymph node metastasis. +Most pedunculated +polyps and many sessile polyps may be completely removed +endoscopically. +In cases where the +polyp cannot be removed entirely, a segmental resection is rec- +ommended. +Stage I: The Malignant Polyp (T1, N0, M0). +Segmental colectomy is then indicated. +29-25). +Stages I and II: Localized Colon Carcinoma (T1-3, N0, +M0). +The majority of patients with stages I and II colon cancer +will be cured with surgical resection. +Levels of invasive carcinoma in pedunculated and +sessile polyps. +ca = carcinoma. +1213 +Colon, Rectum, and Anus +CHAPTER 29 +survival in these patients. +It remains +controversial as to whether chemotherapy improves survival +rates in these patients. +Molecular profiling holds promise for +improving patient selection in these early cancers. +Stage III: Lymph Node Metastasis (Tany, N1, M0). +MSI status +in particular predicts good prognosis. +Survival +is extremely limited in stage IV colon carcinoma. +The most common site of metastasis is the +liver. +Of patients with systemic disease, approximately 15% will +have metastases limited to the liver. +Of these, 20% are poten- +tially resectable for cure. +All patients require adjuvant +chemotherapy. +Hemorrhage in an unresectable tumor +can sometimes be controlled with angiographic embolization. +External beam radiation also has been used for palliation. +Therapy for Rectal Carcinoma +Principles of Resection. +Therefore, local recurrence is higher than +with similar stage colon cancers. +Local Therapy. +The distal 10 cm of the rectum are accessible +transanally. +For this reason, several local approaches have been +proposed for treating rectal neoplasms. +Ablative techniques, such as electrocautery or endocavi- +tary radiation, also have been used. +Radical Resection. +Radical resection is preferred to local +therapy for most rectal carcinomas. +TME both decreases local recurrence rates and +improves long-term survival rates. +The principles of +TME should be applied to all radical resections for rectal cancer. +Recurrence of rectal cancer generally has a poor prog- +nosis. +A permanent colostomy and an ileal conduit to drain the urinary +tract may be necessary. +The sacrum may also be resected if nec- +essary (sacrectomy) up to the level of the S2-S3 junction. +1214 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Stage-Specific Therapy (Fig. +29-26). +Ultrasound evaluation can +guide choice of therapy in most patients. +MRI is useful to assess +mesorectal involvement. +When the radial margin is threatened +or involved, neoadjuvant chemoradiation is recommended. +Stage 0 (Tis, N0, M0). +A 1-cm margin should be obtained. +Stage I: Localized Rectal Carcinoma (T1-2, N0, M0). +For this reason, radical resection +is strongly recommended in all good-risk patients. +Diagnostic algorithm for rectal cancer. +CT = computed tomography; MRI = magnetic resonance imaging; U/S = ultrasound. +tolerate radical surgery has been controversial. +There are two schools of thought, each +differing in their approach to control local recurrences. +Stage III: Lymph Node Metastasis (Tany, N1, M0). +Appropriate timing of chemoradiation for locally advanced +rectal cancer has been debated. +In addi- +tion, the absence of small bowel adhesions in the pelvis may +decrease toxicity. +In addition, postoperative pelvic radiation may +compromise function of the neorectum. +Postoperative chemoradiation, +however, doubled the risk of postoperative stricture formation. +In addition, preoperative chemoradiation halved the risk of local +recurrence (6% vs. +12%). +Occasionally, a proximal diverting +colostomy will be required to alleviate obstruction. +A mucus +fistula should be created if possible to vent the distal colon. +If that +study is normal, colonoscopy should be repeated every 3 to +5 years thereafter. +The optimal method of following patients for recurrent +cancer remains controversial. +Thus, only selected patients who +would tolerate such an approach should be followed intensively. +CEA is often followed every 3 to 6 months for 2 years. +Resection of other involved organs may be necessary. +Nevertheless, radical salvage surgery can +prolong survival in selected patients. +Sev- +eral trials have laid to rest many of these fears. +Most small rectal carcinoids are benign, and +overall survival is greater than 80%. +Small carcinoids can be locally resected transanally. +Larger +tumors or tumors with obvious invasion into the muscularis +require more radical surgery. +Carcinoid tumors in the proximal +colon are less common and are more likely to be malignant. +These tumors should usually be treated with +radical resection. +Tumor debulking can offer effective palliation in +selected patients. +Carcinoid Carcinomas. +Lipomas. +Lipomas occur most commonly in the submucosa +of the colon and rectum. +Small asymptomatic lesions +do not require resection. +Lymphoma. +The cecum is most often involved, probably as a result of +spread from the terminal ileum. +Bowel resection is the treatment of +choice for isolated colorectal lymphoma. +Adjuvant therapy may +be given based on the stage of disease. +Leiomyoma and Leiomyosarcoma. +Most patients are +asymptomatic, but large lesions can cause bleeding or obstruc- +tion. +Leiomyosarcoma is rare in the gastrointestinal tract. +When +this malignancy occurs in the large intestine, the rectum is the +most common site. +Symptoms include bleeding and obstruction. +A radical resection is indicated for these tumors. +Gastrointestinal Stromal Tumor. +They are often mistaken +for leiomyomas. +Thirty percent to 50% are malignant; thus all +lesions should be resected. +Tumors that develop in this +space are often heterogeneous. +Congenital lesions are most common, comprising almost +two thirds of retrorectal lesions. +The remainder are classified as +neurogenic, osseous, inflammatory, or miscellaneous lesions. +Dermoid +and epidermoid cysts are benign lesions that arise from the +ectoderm. +Enterogenous cysts arise from the primitive gut. +Solid lesions include teratomas, chordomas, neurologic +tumors, or osseous lesions. +Teratomas are true neoplasms and +contain tissue from each germ cell layer. +They often contain +both cystic and solid components. +Chordomas arise from the notochord and are the +most common malignant tumor in this region. +These are slow- +growing, invasive cancers that show characteristic bony destruc- +tion. +Most lesions are palpable on digital rectal examination. +Myelogram is occasionally necessary if there is central +nervous system involvement. +Treatment is almost always sur- +gical resection. +The approach depends in part on the nature of +the lesion and its location. +Intermediate lesions may require +a combined abdominal and sacral operation. +The role of biopsy in this setting has been controversial. +Lymph from the anal canal distal to the dentate line usually +drains to the inguinal nodes. +29-27). +In many cases, therapy depends on whether the tumor +is perianal or intra-anal. +Squamous Intraepithelial Lesions. +Anal canal and peri- +anal dysplasia have long had a potpourri of nomenclature. +Superior +rectal a. +Middle +rectal a. +Inferior +rectal a. +Common +iliac a. +Figure 29-27. +Lymphatic drainage of the anal canal. +a. += artery. +1218 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +disease, and carcinoma in situ. +Both HSIL and LSIL are associated with infection +with HPV, especially types 16 and 18. +Treatment of HSIL is +ablation. +Rarely, extensive disease +may require resection with flap closure. +Medical therapy for +HPV has also been proposed. +Epidermoid Carcinoma. +The clinical behav- +ior and natural history of these tumors are similar. +Pain and bleeding may be present. +More than 80% of these tumors can be cured by using this +regimen. +Recurrence usually requires radical resection (APR). +Metastasis to inguinal lymph nodes is a poor prognostic sign. +Verrucous Carcinoma (Buschke-Lowenstein Tumor, Giant +Condyloma Acuminata). +Verrucous carcinoma is a locally +aggressive form of condyloma acuminata. +Basal Cell Carcinoma. +This is a slow- +growing tumor that rarely metastasizes. +Wide local excision +is the treatment of choice, but recurrence occurs in up to 30% +of patients. +Radical resection and/or radiation therapy may be +required for large lesions. +Adenocarcinoma. +Adenocarcinoma may occasionally arise from the +anal glands or may develop in a chronic fistula. +Radical resection +with or without adjuvant chemoradiation is usually required. +The lesion is typically plaque-like and may be indistin- +guishable from HSIL. +Characteristic Paget’s cells are seen histo- +logically. +Wide local excision is +usually adequate treatment for perianal Paget’s disease. +Melanoma. +In adults, this condition is far more common among +women, with a female-to-male ratio of 6:1. +Prolapse becomes +more prevalent with age in women and peaks in the seventh +decade of life. +In men, prevalence is unrelated to age. +Mucus discharge and +leakage may accompany the protrusion. +Operations can be categorized as either abdomi- +nal or perineal. +29-28). +In some cases, resection is combined with rectal +fixation (resection rectopexy). +29-29). +Reefing the rectal mucosa is effective +for patients with limited prolapse. +Anal encirclement procedures +generally have been abandoned. +Solitary Rectal Ulcer Syndrome. +Patients may complain of pain, +bleeding, mucus discharge, or outlet obstruction. +In colitis cystica profunda, +nodules or a mass may be found in a similar location. +Biofeedback has also +been reported to be effective in some patients. +The symptoms of volvulus are those of acute bowel +obstruction. +Patients present with abdominal distention, nau- +sea, and vomiting. +Symptoms rapidly progress to generalized +abdominal pain and tenderness. +Fever and leukocytosis are her- +alds of gangrene and/or perforation. +Sigmoid Volvulus. +29-30). +A rec- +tal tube may be inserted to maintain decompression. +Figure 29-28. +Transabdominal proctopexy for rectal +prolapse. +The fully mobilized rectum is sutured to the +presacral fascia. +A. +Anterior view. +B. +Lateral view. +If +desired, a sigmoid colectomy can be performed con- +comitantly to resect the redundant colon. +Cecal Volvulus. +Cecal volvulus results from nonfixation of the +right colon. +Unlike sigmoid volvulus, cecal volvulus can almost never +be detorsed endoscopically. +Simple detor- +sion or detorsion and cecopexy are associated with a high rate +of recurrence. +Transverse Colon Volvulus. +Transverse colon volvulus is +extremely rare. +Megacolon +Megacolon describes a chronically dilated, elongated, hypertro- +phied large bowel. +In general, the degree of megacolon is related to +the duration of obstruction. +The proximal, healthy bowel becomes +progressively dilated. +Surgical resection of the aganglionic +segment is curative. +Perineal rectosigmoidec- +tomy shown in lithotomy position. +A. +A +circular incision is made 2 cm proximal to +the dentate line. +B. +The anterior peritoneal +reflection is opened. +C. +The mesentery is +divided and ligated. +D. +The peritoneum +may be sutured to the bowel wall. +E. +The +bowel is resected. +F. +A hand-sewn anasto- +mosis is performed. +Acquired megacolon may result from infection or chronic +constipation. +Pseudo- +obstruction is thought to result from autonomic dysfunction and +severe adynamic ileus. +Strict bowel rest and intravenous hydration are crucial. +Most patients will respond to these measures. +In patients who +fail to improve, colonoscopic decompression often is effective. +Up to 40% of +patients recur. +Ischemic Colitis +Intestinal ischemia occurs most commonly in the colon. +Instead, most colonic isch- +emia appears to result from low flow and/or small vessel occlu- +sion. +Occasionally, thrombosis or embolism may +cause ischemia. +The rectum is relatively spared because of its rich col- +lateral circulation. +AB +Figure 29-30. +Sigmoid volvulus: (A) Illustration and (B) Gastrografin enema showing “bird-beak” sign (arrow). +(B: Reproduced with per- +mission from Nivatvongs S, Becker ER. +Colon, rectum, and anal canal. +In: James EC, Corry RJ, Perry JCF Jr, eds. +Basic Surgical Practice. +Philadelphia: Hanley & Belfus; 1987. +In mild cases, patients may have diarrhea +(usually bloody) without abdominal pain. +Peritonitis and/or systemic toxicity are signs of full- +thickness necrosis and perforation. +The diagnosis of ischemic colitis is often based on the +clinical history and physical examination. +CT often shows nonspecific colonic +wall thickening and pericolic fat stranding. +Angiography is +usually not helpful because major arterial occlusion is rare. +Treatment of ischemic colitis depends on clinical sever- +ity. +Long-term sequelae +include stricture (10%–15%) and chronic segmental ischemia +(15%–20%). +In this setting, all necrotic bowel should +be resected. +Primary anastomosis should be avoided. +Occasion- +ally, repeated exploration (a second-look operation) may be +necessary. +Infectious Colitis +Pseudomembranous Colitis (Clostridium difficile Colitis). +Pseudomembranous colitis is caused by C. +difficile, a gram- +positive anaerobic bacillus. +C. +C. +difficile is carried in the +large intestine of many healthy adults. +Although +clindamycin was the first antimicrobial agent associated with +C. +difficile colitis, almost any antibiotic may cause this disease. +Moreover, although the risk of C. +The pathogenic changes associated with C. +Diagnosis of this disease was tradition- +ally made by culturing the organism from the stool. +Management should include immediate cessation of +the offending antimicrobial agent. +Proctosigmoiditis may +respond to vancomycin enemas. +A total abdomi- +nal colectomy with end ileostomy may be lifesaving. +Over the +past decade, C. +Common bacterial infections include enterotoxic +E. +coli, Campylobacter jejuni, Yersinia enterocolitica, Salmo- +nella typhi, Shigella, and N. +gonorrhoeae. +Serum immunoassays may also be useful (amebia- +sis, HIV, CMV). +Occasionally, endoscopy with biopsy may be +required. +Treatment is tailored to the infection. +29-4). +Bleeding, thrombosis, and symptomatic hemorrhoidal prolapse +may result. +External hemorrhoids are located distal to the dentate line +and are covered with anoderm. +Skin tags are often confused with symptomatic hem- +orrhoids. +Treatment of exter- +nal hemorrhoids and skin tags is only indicated for symptomatic +relief. +Internal hemor- +rhoids are graded according to the extent of prolapse. +Second-degree hemor- +rhoids prolapse through the anus but reduce spontaneously. +Third-degree hemorrhoids prolapse through the anal canal and +require manual reduction. +Fourth-degree hemorrhoids prolapse +but cannot be reduced and are at risk for strangulation. +Hemorrhoidectomy is often required for +large, symptomatic, combined hemorrhoids. +Rectal varices, however, may +occur and may cause hemorrhage in these patients. +In general, +rectal varices are best treated by lowering portal venous pressure. +Rarely, suture ligation may be necessary if massive bleeding +persists. +Treatment +Medical Therapy. +Associated pruritus often may improve with improved +hygiene. +Rubber Band Ligation. +29-31). +In general, only one or two quadrants are banded +per visit. +Other complications of rubber band ligation include urinary +retention, infection, and bleeding. +Necrotizing infection is an uncommon, but life-threatening +complication. +Infrared Photocoagulation. +The instrument is applied to the apex of each hem- +orrhoid to coagulate the underlying plexus. +All three quadrants +may be treated during the same visit. +Sclerotherapy. +Excision of Thrombosed External Hemorrhoids. +Because the clot is usually loculated, simple incision and +drainage is rarely effective. +After 72 hours, the clot begins to +resorb, and the pain resolves spontaneously. +Excision is unnec- +essary, but sitz baths and analgesics are often helpful. +Operative Hemorrhoidectomy. +Closed Submucosal Hemorrhoidectomy. +The anal canal is +examined and an anal speculum inserted. +The apex of the hemorrhoidal plexus is then ligated +and the hemorrhoid excised. +The wound is then closed with a +running absorbable suture. +29-32). +Open Hemorrhoidectomy. +Whitehead’s Hemorrhoidectomy. +After excision, the +rectal mucosa is then advanced and sutured to the dentate line. +Procedure for Prolapse and Hemorrhoids/Stapled Hemor- +rhoidectomy. +These vessels are then ligated. +Pain can also lead to fecal impaction. +Bleeding may occur +Elastic +bands +Elastic +bands +Elastic +bands +Figure 29-31. +Rubber band ligation of internal +hemorrhoids. +The mucosa just proximal to the inter- +nal hemorrhoids is banded. +Severe pain, +fever, and urinary retention may be early signs of infection. +Anal stenosis may result from +scarring after extensive resection of perianal skin. +Ectropion +may occur after Whitehead’s hemorrhoidectomy. +Anal Fissure +A fissure in ano is a tear in the anoderm distal to the dentate +line. +The vast major- +ity of anal fissures occur in the posterior midline. +Ten percent +to 15% occur in the anterior midline. +Less than 1% of fissures +occur off midline. +Symptoms and Findings. +Anal fissure is extremely common. +Patients +are often too tender to tolerate digital rectal examination, anos- +copy, or proctoscopy. +There often is an associated external skin tag +and/or a hypertrophied anal papilla internally. +These fissures +are more challenging to treat and may require surgery. +Technique of closed sub- +mucosal hemorrhoidectomy. +A. +The patient +is in prone jackknife position. +B. +A Fansler +anoscope is used for exposure. +C. +A narrow +ellipse of anoderm is excised. +D. +E. +F. +Additional quad- +rants are excised to complete the procedure. +1226 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +or leukemia. +Treatment. +Internal +sphincter m. +Fissure Fissure-in-ano +A +B +C +D +Figure 29-33. +A through D. +Open lateral internal sphincterotomy +for fissure in ano. +m = muscle. +Anal +fissure +Sentinel + pile +AB +DC +dividing a portion of the muscle. +29-33) or closed (Fig. +29-34) technique. +Healing +is achieved in more than 95% of patients using this technique, +Figure 29-34. +A through D. +Closed lateral internal +sphincterotomy for fissure in ano. +1227 +Colon, Rectum, and Anus +CHAPTER 29 +and most patients experience immediate pain relief. +Anorectal Sepsis and Cryptoglandular Abscess +Relevant Anatomy. +The intersphincteric space separates +the internal and external anal sphincters. +It is continuous with +the perianal space distally and extends cephalad into the rectal +wall. +The ischio- +rectal space contains the inferior rectal vessels and lymphatics. +The anatomy of these spaces influences the location +and spread of cryptoglandular infection (Fig. +29-35). +As an abscess enlarges, it spreads in one of several direc- +tions. +These abscesses may become +extremely large and may not be visible in the perianal region. +Digital rectal exam will reveal a painful swelling laterally in the +ischiorectal fossa. +29-36). +Levator ani m. +Internal sphincter m. +Puborectalis and +deep external sphincter m. +Superficial external +sphincter m. +Subcutaneous +external sphincter m. +Deep postanal space +Superficial +postanal space +A +B +Figure 29-35. +Anatomy of perianorectal spaces. +(A) Anterior view and (B) lateral view. +m = muscle. +1228 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Diagnosis. +Severe anal pain is the most common presenting +complaint. +Occasionally, +patients will present with fever, urinary retention, or life- +threatening sepsis. +Treatment. +Anorectal abscesses should be treated by drainage as +soon as the diagnosis is established. +Antibiot- +ics alone are ineffective at treating perianal or perirectal infection. +Larger, more complicated +abscesses may require drainage in the operating room. +A skin +incision is created, and a disk of skin excised to prevent prema- +ture closure. +No packing is necessary, and sitz baths are started +the next day (Fig. +29-37). +Simple ischiorectal abscesses are drained through an +incision in the overlying skin. +29-38). +Perianal space +abscess +Levator +ani m. +External +sphincter m. +Longitudinal m. +Pelvirectal space +abscess +Intersphincteric space +abscess +Ischiorectal fossa +abscess +Figure 29-36. +A and B. +Pathways of anorectal infection in perianal spaces. +m = muscle. +A +B +C +Figure 29-37. +A through C. +Technique of drainage of perianal abscess. +infection. +The pain is so intense that it usually precludes a digital +rectal examination. +Digital +rectal examination may reveal an indurated, bulging mass above +the anorectal ring. +It is essential to identify the origin of a supra- +levator abscess prior to treatment. +Drainage of this type of abscess through the rectum +may result in an extrasphincteric fistula. +An increase in pain or +fever and/or clinical deterioration mandates an exam under +anesthesia. +Most of these infections are polymicrobial and +synergistic. +Occasionally, these infections may be encountered +postoperatively (e.g., after hemorrhoidectomy). +Immunocom- +promised patients and diabetic patients are at increased risk. +Physical examination may reveal necrotic skin, bullae, +or crepitus. +Patients often have signs of systemic toxicity and +may be hemodynamically unstable. +Multiple operations +may be necessary to ensure that all necrotic tissue has been +resected. +Fistula In Ano +Drainage of an anorectal abscess results in cure for about 50% +of patients. +The remaining 50% develop a persistent fistula in +ano. +The course of the fistula can often be predicted +by the anatomy of the previous abscess. +A complex, recurrent, or nonhealing fis- +tula should raise the suspicion of one of these diagnoses. +Diagnosis. +Patients present with persistent drainage from the +internal and/or external openings. +An indurated tract is often pal- +pable. +Goodsall’s rule can be used as a guide in determining the loca- +tion of the internal opening (Fig. +29-39). +However, exceptions to this rule often occur if an anterior +Figure 29-38. +Drainage of horseshoe abscess. +The deep postanal +space is entered, incising the anococcygeal ligament. +Counter drain- +age incisions are made for each limb of the ischiorectal space. +Goodsall’s rule to identify the internal opening of +fistulas in ano. +Such fistulas usually track to the posterior midline. +29-40A). +29-40B). +29-40C). +29-40D). +Treatment. +The goal of treatment of fistula in ano is eradica- +tion of sepsis without sacrificing continence. +The internal +opening may be more difficult to identify. +Injection of hydrogen +peroxide or dilute methylene blue may be helpful. +29-40A). +Treatment of a transsphinc- +teric fistula depends on its location in the sphincter complex. +Figure 29-40. +A. +Intersphincteric fistula with simple low tract. +B. +Uncomplicated transsphincteric fistula. +C. +Uncomplicated suprasphinc- +teric fistula. +D. +Extrasphincteric fistula secondary to anal fistula. +(Data from Gordon PH, Nivatvongs S, eds. +Principles and Practice of Surgery +for the Colon, Rectum, and Anus. +2nd ed. +29-40B). +Simi- +larly, suprasphincteric fistulas are usually treated with seton +placement (see Fig. +29-40C). +In general, the portion of the fistula outside the +sphincter should be opened and drained. +A primary tract at the +level of the dentate line may also be opened if present. +Liberal use of drains and +setons is helpful. +Failure to heal may ultimately require fecal +diversion (see Fig. +29-40D). +Biopsies of the fistula tract should +be taken to rule out malignancy. +A seton is a drain placed through a fistula to maintain drain- +age and/or induce fibrosis. +Alternatively, the seton may be left in +place for chronic drainage. +Higher fistulas may be treated by an +endorectal advancement flap (see below). +High rectovaginal fistulas result from operative or +radiation injury. +Complicated diverticulitis may cause a colo- +vaginal fistula. +Diagnosis. +Most patients experience some degree of +fecal incontinence. +Contamination may result in vaginitis. +Occasionally, a barium enema or vaginogram may identify +these fistulas. +Endorectal ultrasound may also be useful. +Treatment. +Low and mid-rectovaginal fistulas are usually best treated +with an endorectal advancement flap. +29-41). +Fecal diversion is rarely +required. +Fistulas caused by +malignancy should be treated with resection of the tumor. +Perianal Dermatitis +Pruritus Ani. +Pruritus ani (severe perianal itching) is a com- +mon problem with a multitude of etiologies. +Perianal infection +may also present with pruritus ani. +pallidum [syphilis]), +or viruses (HPV [condyloma acuminata]). +Antibiotic use may +also cause itching, usually by precipitating fungal infection. +Noninfectious dermatologic causes include seborrhea, psoriasis, +and contact dermatitis. +Occa- +sionally, systemic diseases such as jaundice and diabetes may +present with pruritus ani. +Biopsy and/or culture may be required to rule out +an infectious or dermatologic cause. +Skin barriers such as Calmoseptine can also provide +relief. +Systemic antihistamines or tricyclic antidepressants have +also been used with some success. +Nonpruritic Lesions. +Several perianal skin conditions may +present with perianal skin changes. +Biopsy can usually distinguish +these diagnoses. +Endorectal advancement flap for rectovaginal fistula. +(Reproduced with permission of Taylor & Francis, LLC from Gordon +PH, Nivatvongs S, eds. +Principles and Practice of Surgery for the Colon, Rectum, and Anus. +2nd ed. +New York: Marcel Dekker, Inc.; 1999:412. +Proctitis is a common symptom of ano- +rectal bacterial infection. +N. +Chlamydia trachomatis infec- +tion may be asymptomatic or may produce similar symptoms. +T. +Condyloma lata +are characteristic of secondary syphilis. +Inguinal lymphadenopathy and fluctuant, +draining lymph nodes are characteristic. +Parasitic Infections. +Entamoeba histolytica is an increas- +ingly common sexually transmitted disease. +Amebas produce +ulcerations in the gastrointestinal mucosa and can infect any +part of the gut. +Symptoms include diarrhea, abdominal pain, +and tenesmus. +Giardia lamblia is also common and produces +diarrhea, abdominal pain, and malaise. +Viral Infections +Herpes Simplex Virus. +Herpes proctitis is extremely common. +Patients com- +plain of severe, intractable perianal pain and tenesmus. +Diagnosis is confirmed by viral culture of tissue or vesicular +fluid. +Human Papillomavirus. +Condylomas occur in the +perianal area or in the squamous epithelium of the anal canal. +Occasionally, the mucosa of the lower rectum may be affected. +There are approximately 30 serotypes of HPV. +Treatment of anal condyloma depends on the location and +extent of disease. +Larger and/ +or more numerous warts require excision and/or fulguration in +the operating room. +Excised warts should be sent for pathologic +examination to rule out dysplasia or malignancy. +Human Immunodeficiency Virus. +Once an +acute episode has resolved, recurrence is common. +An acute abscess should be incised and drained as soon +as the diagnosis is made. +A number of procedures have been proposed to treat a +chronic pilonidal sinus. +Alternatively, a small lateral incision can be created and +the pit excised. +This method is effective for most primary pilo- +nidal sinuses. +In general, extensive resection should be avoided. +Infected glands rupture and form subcutane- +ous sinus tracts. +Radical excision +and skin grafting are almost never necessary. +Intractable rectal bleeding may require angio- +graphic embolization. +Iatrogenic Injury +Intraoperative Injury. +The key to managing these injuries is early +recognition. +Injury from Barium Enema. +Colonoscopic Perforation. +Fortunately, this complication is rare and occurs +in less than 1% of procedures. +Biopsy or fulguration can also cause +perforation. +A large perforation recognized during the procedure requires +surgical exploration. +It is also important to +know the indication for and findings at the time of colonoscopy. +If the patient has an underlying neoplasm and is stable, defini- +tive resection is best. +Evidence of peritonitis or any deterioration in clinical condition +mandates exploration. +Principles and Practice of Surgery for the Colon, Rectum, and +Anus. +2nd ed. +New York: Marcel Dekker, Inc; 1999:1249. +Surgical exploration is indicated if any clinical deteriora- +tion occurs. +More severe incontinence may require surgical repair. +Isolated sphincter injuries that do not involve +the rectum may be repaired primarily. +Sig- +nificant perineal tissue loss may require extensive débridement +and a diverting colostomy. +Surgical Repairs. +The most common method of repair of the +anal sphincter is a wrap-around sphincteroplasty (Fig. +The internal and +external sphincters may be overlapped together or separately. +The approach is via the intersphincteric plane +posteriorly. +It may be performed concomitantly with a perineal +repair of rectal prolapse. +These elective pro- +cedures usually do not require a diverting colostomy. +Another alternative in patients who have +failed other repairs is the artificial anal sphincter. +Gen- +eralized abdominal pain suggests intraperitoneal perforation. +Plain films of the abdomen are mandatory to detect +free intra-abdominal air. +Objects impacted higher in the rectum may require +regional or general anesthesia for removal. +Only rarely will a +laparotomy be required to remove the object. +Proctoscopy and/or flexible sigmoidos- +copy should be performed. +A hematoma without evidence of +perforation requires no surgical treatment. +Diarrhea, in particular, is extremely +common. +Overlapping sphincteroplasty for incontinence from +sphincter disruption. +A. +The external sphincter muscle with scar at +site of injury is mobilized. +B. +The muscle edges are aligned in an +overlapping fashion. +C. +Mattress sutures are used to approximate +the muscle. +D. +The completed operation. +C. +Patients may be asymptomatic or may develop +bleeding or obstruction. +Gastrointestinal lymphoma (usually +non-Hodgkin’s lymphoma) is also common. +Perianal disease is extremely common in patients with +HIV infection. +In these patients, infection and medication +are the most common causes of diarrhea. +Immunosuppressant +medications, in particular, may cause diarrhea. +CMV infection +is common and may be severe. +C difficile colitis also occurs +commonly. +CT scan of the abdomen often shows a dilated cecum +with pericolic stranding. +However, a normal-appearing CT scan +does not exclude the diagnosis. +An increase in +pain or fever and/or clinical deterioration mandates an exam +under anesthesia. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Tran K. +Capsule colonoscopy: PillCam Colon. +Issues Emerg +Health Technol. +2007;106:1-4. +2. +de Franchis R, 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Med. +2002;137:132-141. +69. +Mandel JS, Church TR, Bond JH, et al. +The effect of fecal +occult-blood screening on the incidence of colorectal cancer. +N Engl J Med. +2000;343:1603-1607. +70. +Imperiale TF, Wagner DR, Lin CY, et al. +N Engl J Med. +2000;343:169-174. +71. +Hardcastle JD, Armitage NC, Chamberlain J, et al. +Fecal occult +blood screening for colorectal cancer in the general population. +Results of a controlled trial. +Cancer. +1986;58:397-403. +72. +Winawer SJ, Flehinger BJ, Schottenfeld D, et al. +Screen- +ing for colorectal cancer with fecal occult blood testing and +sigmoidoscopy. +J Natl Cancer Inst. +1993;85:1311-1318. +73. +Yee J, Akerkar GA, Hung RK, et al. +Radiology. +2001;219:685-692. +74. +Greene FL, Fleming PD, Fleming ID, et al. +AJCC Cancer +Staging Manual. +Springer: New York; 2002. +75. +O’Connell JB, Maggard MA, Clifford KY. +J Natl Cancer Inst. +2004;96(19): +1420-1425. +76. +Gunderson LL, Sargent DJ, Tepper JE, et al. +Int J Radiat Oncol Biol Phys. 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Y, et al. +Ann Surg Oncol. +2013;20:707-714. +85. +Garcia-Aguilar J, Shi Q, Thomas CR Jr, et al. +Ann Surg Oncol. +2012;19:384-391. +86. +Sauer R, Liersch T, Merkel S, et al. +Preoperative versus +postoperative chemoradiotherapy for rectal cancer. +N Engl +J Med. +2004;351:1731-1740. +87. +Berends FJ, Kazemier G, Bonjer HJ, et al. +Subcutaneous +metastases after laparoscopic colectomy. +Lancet. +1994;344:58. +88. +Jayne DG, Guillou PJ, Thorpe H, et al. +J Clin Oncol. +2007;25:3061-3068. +89. +A comparison of laparoscopically assisted and open colec- +tomy for colon cancer. +N Engl J Med. +2004;350:2050-2059. +90. +Hazebroek EJ. +COLOR: a randomized clinical trial compar- +ing laparoscopic and open resection for colon cancer. +Surg +Endosc. +2002;16:949-953. +91. +Collinson FJ, Jayne DG, Pigazzi A, et al. +Int +J Colorectal Dis. +2012;27:233-241. +92. +Merchea AL, Hubner M, Wenger D, Rose P, Dozois E. +The +value of preoperative biopsy in the management of solid +presacral tumors. +Dis Colon Rectum. +2013;56:756-760. +93. +Darragh TM, Colgan TJ, Cox JT, et al. +J Low Genit Tract Dis. +2012;16:205-242. +1239 +Colon, Rectum, and Anus +CHAPTER 29 +94. +Stanley MA. +Imiquimod and the imidazoquinolones: mecha- +nism of action and therapeutic potential. +Clin Exp Dermatol. +2002;27:571-577. +95. +Bullard KM, Tuttle TM, Rothenburger DA, et al. +Surgical +therapy for anorectal melanoma. +J Am Coll Surg. +2003;196: +206-211. +96. +Cecil JA. +Clostridium difficile: changing epidemiology, +treatment and infection prevention measures. +Curr Infect +Dis Rep. +2012;14:612-619. +97. +Jonas M, Speake W, Scholefield J. +Diltiazem heals glyceryl +trinitrate-resistant chronic anal fissures: a prospective study. +Dis Colon Rectum. +2002;45:1091-1095. +98. +Mentes BB, Irkörücü O, Akin M, et al. +Dis Colon Rectum. +2003;46:232-237. +99. +Manfredelli S, Montalto G, Leonetti G, et al. +Conventional +(CH) vs. +stapled hemorrhoidectomy (SH) in surgical treat- +ment of hemorrhoids. +Ten years experience. +Ann Ital Chir. +2012;83:129-134. +100. +Schuurman JP, Borel Rinkes IH, Go PM. +Ann Surg. +2012;255:840-845. +101. +Nelson RL, Thomas K, Morgan J, et al. +Nonsurgical therapy for +anal fissure. +Cochrane Database Syst Rev. +2012;2:CD003431. +102. +North JH Jr, Weber TK, Rodriguez-Bigas MA, et al. +The +management of infectious and noninfectious anorectal +complications in patients with leukemia. +J Am Coll Surg. +1996; 183:322-328. +103. +Jacob TJ, Perakath B, Keighley MR. +Surgical interven- +tion for anorectal fistula. +Cochrane Database Syst Rev. +2010;5:CD006319. +104. +Shanwani A, Nor AM, Amri N. +Dis Colon Rectum. +2010;53:39-42. +105. +Gunter J. +Genital and perianal warts: new treatment opportuni- +ties for human papillomavirus infection. +Am J Obstet Gynecol. +2003;189(3 Suppl):S3-S11. +106. +Buie WD, Lowry AC, Rothenberger DA, et al. +Clinical +rather than laboratory assessment predicts continence after +anterior sphincteroplasty. +Dis Colon Rectum. +2001;44: +1255-1260. +107. +Baeten CG, Bailey HR, Bakka A, et al. +Dynamic Graciloplasty Therapy +Study Group. +Dis Colon Rectum. +2000;43:743-751. +108. +Tan EK, Vaizey C, Cornish J, et al. +Colorectal Dis. +2008;10:577-586. +109. +Cooksley CD, Hwang LY, Waller DK, et al. +Int J STD AIDS. +1999;10: +795-802. +110. +Palefsky JM. +Anal squamous intraepithelial lesions: relation +to HIV and human papillomavirus infection. +J Acquir Immune +Defic Syndr. +1999;21(Suppl 1):S42-S48. +This page intentionally left blank +The Appendix +Mike K. +Liang, Roland E. +Andersson, +Bernard M. +Jaffe, and David H. +She developed abdom- +inal pain and died. +He operated on an 11-year-old +boy with a scrotal hernia and a fecal fistula. +Within the hernia +sac, Amyand found a perforated appendix surrounded by omen- +tum. +The appendix and omentum were amputated. +Only sporadic cases of right lower quadrant pain were +treated with appendectomy. +In 1886, Reginald H. +In this situation, the appendix will remain +in the left upper quadrant of the abdomen. +Lymphoid aggregates occur in the +submucosal layer and may extend into the muscularis mucosa. +Lymphatic channels are prominent in regions underlying these +lymphoid aggregates. +The mucosa is like that of the large intes- +tine, except for the density of the lymphoid follicles. +4 Computed tomography scan has improved diagnostic accu- +racy in individual studies. +However, in population-wide +studies, the rate of misdiagnosis of appendicitis remains con- +stant. +5 The role of nonoperative treatment for uncomplicated appen- +dicitis remains controversial. +Currently, appendectomy +remains the standard of care. +Laparoscopic appendectomy +has a slight benefit over open appendectomy. +The role of interval appendectomy in these +cases remains controversial. +Natural orifice transluminal endoscopic surgery remains +an investigational procedure. +Postoperative anti- +biotics are unnecessary following uncomplicated appen- +dicitis. +For complicated appendicitis, a treatment +duration of 4 to 7 days is recommended. +12 The prevalence of appendiceal malignancy remains at or +below 1% of appendectomies. +Carcinoid and mucinous +adenocarcinoma remain the most frequent histologic +diagnosis. +The appendix may function as a reservoir to recolonize +the colon with healthy bacteria. +The frequency of obstruction rises with the +severity of the inflammatory process. +This causes reflex nausea +and vomiting, and the visceral pain increases. +As pressure in +the organ increases, venous pressure is exceeded. +This produces the characteristic shift in +pain to the right lower quadrant. +Microbiology +Appendicitis may occur in clusters, suggesting an infectious +genesis. +But, when combined, they yield high discriminatory power. +68%; specificity, 36%). +Diarrhea may occur in +association with perforation, especially in children. +Signs. +Early in presentation, vital signs may be minimally +altered. +The body temperature and pulse rate may be normal +or slightly elevated. +On abdominal palpation, there +is tenderness with a maximum at or near McBurney’s point +(Fig. +Rebound +tenderness can be very sharp and uncomfortable for the patient. +Laboratory Findings. +Laboratory examinations are therefore an impor- +tant part of the diagnosis. +Counts above this level raise the possibility +of a perforated appendix with or without an abscess. +Therefore, all inflammatory variables +should be viewed together. +McBurney’s point (1 = anterior superior iliac spine; +2 = umbilicus; x = McBurney’s point). +all normal. +The inflammatory response in acute appendicitis +is a dynamic process. +Early in the process, the inflammatory +response can be weak. +CRP elevation, in particular, can have up +to a 12-hour delay. +A decreasing inflammatory response may +indicate spontaneous resolution. +Bacteri- +uria is generally not seen. +Clinical Scoring Systems. +The Alvarado score is the most widespread scoring system. +Imaging Studies. +A chest radiograph is helpful to rule out referred pain +from a right lower lobe pneumonic process. +Outpatient follow-up. +5–8: Indeterminate group. +Active observation or diagnostic laparoscopy. +9–12: High probability. +Surgical exploration. +Ultrasonography has its limitations, particularly the operator- +dependent nature of results. +In the adult population, ultrasonog- +raphy remains limited in its use. +Fecaliths can be often visualized; +however, their presence is not pathognomonic of appendicitis. +The additional use of rectal contrast does not improve the results +of CT scanning. +Despite the potential usefulness of CT, there are signifi- +cant disadvantages. +The role of CT scanning in patients who present with right +lower quadrant pain is unclear. +One rationale is universal CT +scanning. +9.3%).50,51 The negative appendectomy rate is highest in women +of reproductive age. +The accuracy of preoperative diagnosis should be higher +than 85%. +Acute mesenteric adenitis is the disease +most often confused with acute appendicitis in children. +Almost +invariably, an upper respiratory tract infection is present or has +recently subsided. +The pain usually is diffuse, and tenderness +is not as sharply localized as in appendicitis. +Voluntary guard- +ing is sometimes present, but true rigidity is rare. +Generalized +lymphadenopathy may be noted. +Elderly Patient. +These entities should be considered, particularly in older +patients. +Female Patient. +As a +result, the rate of misdiagnosis remains higher among female +patients. +of studies 22 21 57 25 6 +No. +1248 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +inflammatory disease. +Pain and tenderness are usually lower, +and motion of the cervix is exquisitely painful. +Intracellular dip- +lococci may be demonstrable on smear of the purulent vaginal +discharge. +Pain and tenderness may be rather diffuse, and leukocytosis and +fever minimal or absent. +Serous cysts of the ovary are common and generally remain +asymptomatic. +Patients develop right lower quadrant pain, tenderness, rebound, +fever, and leukocytosis. +Both transvaginal ultrasonography and +CT scanning can be diagnostic. +Torsion requires emergent operative treatment. +Blastocysts may implant in the fallopian tube (usually the +ampullary portion) and in the ovary. +Rupture of right tubal or +ovarian pregnancies can mimic appendicitis. +Unfortunately, patients +do not always realize they are pregnant. +The development of +right lower quadrant or pelvic pain may be the first symptom. +The diagnosis of ruptured ectopic pregnancy should be rela- +tively easy. +The presence of blood and particularly decidual tissue is +pathognomonic. +The treatment of ruptured ectopic pregnancy is +emergency surgery. +Immunosuppressed Patient. +Follow-up was not longer than 1 year in any study. +Certain +subgroups with uncomplicated appendicitis may do well with +nonoperative therapy. +bStandard deviation. +cStandard error of the mean. +eStudy did not report the meaning of these values. +gThese patients declined to be included in the study and opted for surgical management. +Once diagnosed, a patient was emergently +taken to the operating room for surgical treatment. +Complicated Appendicitis. +The proportion of perforation increases +with increasing duration of symptoms. +There is, however, +no association of in-hospital delay with perforation. +This suggests +that most perforations occur early, before the patient arrives to +hospital. +In many cases, +rupture is contained and patients display localized peritonitis. +In 2% to 6% of cases, a palpable mass is detected on physical +examination. +CT scan may +be beneficial in establishing a diagnosis and guiding therapy. +Two meta-analyses have been performed. +This sub- +group had an overall complication rate of 13.5%. +The recurrence +rate was 7.4%, which does not necessitate interval appendectomy. +St. +Peter +and colleagues72 demonstrated that 20% of patients failed con- +servative treatment. +Early surgical intervention had equivalent +results to interval appendectomy. +30%, P = .003), intra-abdominal abscesses (37% vs. +19%, +P = .02), small bowel obstruction (10.4% vs. +0%, P = .01), and +readmissions (31% vs. +8%, P = .06). +The incidence of complicated appen- +dicitis following recurrence was low (2.4%). +Malignancy was +noted in 1.3% of cases where pathology was reported. +Most patients +underwent interval appendectomy 2 to 4 months after their acute +presentation. +The entire abdomen should +be prepped and draped in case a larger incision is needed. +If the appendix is not easily identified, the +cecum should be located. +The appendix will often have attachments to the lateral +wall or pelvis that can be dissected free. +The appendiceal stump can be man- +aged by simple ligation or by ligation and inversion. +Inversion of the stump +with plication of the cecum has also been described. +If appendicitis is not found, a methodical search must be +made for an alternative diagnosis. +The cecum and mesentery +should be inspected. +The small bowel should be evaluated in a +retrograde fashion beginning at the ileocecal valve. +Concerns +for Crohn’s disease or Meckel’s diverticulum should be of +priority. +In female patients, the reproductive organs should be +closely inspected. +If purulent or bilious fluid is encountered, it +is imperative that the source be identified. +This may be due to +the small incision already commonly used with open appen- +dectomy. +Laparoscopic appendectomy is performed under general +anesthesia. +An oro- or nasogastric tube and urinary catheter are +placed. +Both +surgeon and assistant should be standing on the patient’s left +facing the appendix. +The laparoscopic screens should be posi- +tioned on the patient’s right or at the foot of the bed. +Standard +laparoscopic appendectomy typically uses three ports. +The patient should be placed in Trendelenburg and +tilted to the left (Fig. +30-2). +Typically the base of the appendix is stapled, +followed by stapling of the mesentery. +The appendix is +removed through the infraumbilical trocar in a retrieval bag. +There is less pain, shorter length of stay, and +Figure 30-2. +Operating room setup. +Patients +tend to have improved satisfaction scores with laparoscopic +appendectomy. +Instead of two or three incisions, a single inci- +sion is made, typically periumbilical. +Under general anesthesia, the patient is secured in a supine posi- +tion with the left arm tucked. +The surgeon and assistant stand on +the left side facing the appendix and the screen. +The appendix may be placed in a +retrieval bag or removed through the single incision. +In this meta-analysis, there was no difference in operative +time (57 ± 10 vs. +55 ± 13 minutes), complications (11% vs. +8.3%), incisional surgical site infections (5.6% vs. +4.9%), intra- +abdominal abscesses (1.8% vs. +1.4%), or length of stay (3 ± 2 +vs. +4 ± 1 days). +There was no difference in overall +cost. +Late outcomes and patient quality- +of-life outcomes remain to be investigated. +A and B. +Appendiceal critical view. +of studies 25 16 44 12 34 8 11 28 16 +No. +1256 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +and 11 transgastric). +The main concern with NOTES has been complications +with closure of the enterotomy. +Antibiotic coverage is lim- +ited to 24 to 48 hours in cases of nonperforated appendicitis. +A history +of periumbilical pain migrating to the right lower quadrant +is reported infrequently. +The use of laparoscopy in the elderly has significantly +increased in recent years. +The incidence is approxi- +mately 1 in 766 births. +The physiologic leukocytosis of pregnancy has been defined as +high as 16,000 cells/mm3. +Another option is magnetic resonance +imaging, which has no known deleterious effects on the fetus. +It is important to note that a negative appendectomy +is not a benign procedure. +Maternal mortality after appendectomy is extremely rare +(0.03%). +These patients are at increased risk for surgical site +infections. +Patients with cellulitis can be started on antibiotics. +Most +commonly, percutaneous drainage with CT or ultrasound guid- +ance is effective. +A review of literature +has revealed only 60 reports of this phenomenon. +Likely, incom- +plete appendectomy is underreported, and the true prevalence is +much higher. +There was no difference +in initial surgery between laparoscopic and open procedures. +However, there were more complicated appendectomies on +initial surgery. +The key to avoiding stump appendicitis is prevention. +Prior appendectomy should not be an absolute crite- +rion in ruling out acute appendicitis. +On an annual basis, $20,000,000 had to be spent to +save the $6,000,000 cost of appendicitis. +Appendiceal carcinoid and appendiceal adenomas are the +most common lesions identified. +There is no clear age +relationship associated with the identification of these +masses. +The mean age in this case +series was 69 years (range, 42 to 89 years). +Treatment for tumors ≤1 cm is appendectomy. +Recently, a more +aggressive approach to ruptured appendiceal neoplasms has +been advocated. +NR = not reported. +1259 +T +HE + A +PPENDI +x +CHAPTER 30 +implants on peritoneal surfaces and omentum. +Pseudomyxoma +is two to three times more common in females than in males. +Pseudomyxoma is invariably caused +by neoplastic mucus-secreting cells within the peritoneum. +Patients with pseudomyxoma usually +present with abdominal pain, distention, or a mass. +Primary +pseudomyxoma usually does not cause abdominal organ dys- +function. +The use of imaging before surgery is advantageous to plan +surgery. +CT scanning is the preferred imaging modality. +Peritoneal surfaces of the bowel are usu- +ally free of tumor. +Thorough surgical debulking is the main- +stay of treatment. +All gross disease and the omentum should be +removed. +If not done previously, appendectomy is routinely per- +formed. +Hysterectomy with bilateral salpingo-oophorectomy is +performed in women. +In addition, morbidity (38%) and mor- +tality (6%) are high. +Recur- +rences are usually treated by additional surgery. +The management of appendiceal lymphoma confined +to the appendix is appendectomy. +A postoperative staging workup is indicated before + initiating adjuvant therapy. +1. +Williams RG. +Presidential address: a history of appendicitis. +Ann Surg. +1983;197:495-506. +2. +Deaver JB. +Appendicitis. +3rd ed. +Philadelphia: P Blakiston’s +Son & Co; 1905. +3. +Fernal J. +Universal Medicina, 1554. +Classic Description of +Disease. +U.S.: Springfield; 1932:614-615. +4. +Ellis H. +Appendix. +In: Schwartz SI, ed. +Maingot’s Abdomi- +nal Operations. +8th ed., vol. +2. +Norwalk: Appleton-Century- +Crofts; 1985:1255. +5. +McBurney C. +Experience with early operative interference in +cases of disease of the vermiform appendix. +N Y State Med J. +1889;50:676. +6. +Power D. +The prognosis and modern treatment of appendicitis. +Br Med J. 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appendix in the gravid +patient: a re-evaluation of the established concept. +Int J Gyne- +col Obstet. +2003;81:245-247. +83. +Tander B, Pektas O, Bulut M. +The utility of peritoneal drains +in children with uncomplicated perforated appendicitis. +Pedi- +atr Surg Int. +2003;19:548-550. +84. +Narci A, Karaman I, Karaman A, et al. +Is peritoneal drainage +necessary in childhood perforated appendicitis? +A compara- +tive study. +J Pediatr Surg. +2007;42:1864-1868. +85. +Toki A, Ogura K, Horimi T, et al. +Peritoneal lavage versus +drainage for perforated appendicitis in children. +Surg Today. +1995;25:207-210. +86. +Dandapat MC, Panda C. +A perforated appendix: should we +drain? +J Indian Med Assoc. +1992;90:147-148. +87. +Greenall MJ, Evans M, Pollock AV. +Should you drain a perfo- +rated appendix? +Br J Surg. +1978;65:880-882. +88. +St Peter SD, Adibe OO, Iqbal CW, et al. +Ann Surg. +2012;256:581-585. +89. +Giri SK, Shaikh FM, Sil D, Drumm J, Naqvi SA. +Am J Surg. +2007;194:231-233. +90. 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Lefering R, Holthausen U, Neugebauer EA. +Laparoscopic vs conventional appendectomy—a meta-analy- +sis of randomised controlled trials. +Langenbecks Arch Surg. +1998;383:289-295. +99. +Golub R, Siddiqui F, Pohl D. +Laparoscopic versus open appen- +dectomy: a metaanalysis. +J Am Coll Surg. +1998;186:545-553. +100. +Gill RS, Shi X, Al-Adra DP, Birch DW, Karmali S. +Surg Laparosc Endosc Percutan Tech. +2012;22:319-327. +101. +Coomber RS, Sodergren MH, Clark J, Teare J, Yang GZ, +Darzi A. +Natural orifice translumenal endoscopic surgery +applications in clinical practice. +World J Gastrointest +Endosc. +2012;4:65-74. +102. +Strickland AD, Norwood MG, Behnia-Willison F, Olakkengil +SA, Hewett PJ. +Surg Endosc. +2010;24:2424-2431. +103. +Bundy DG, Byerley JS, Liles EA, et al. +Does this child have +appendicitis? +JAMA. +2007;298:438-451. +104. +Colvin JM, Bachur R, Kharbanda A. +The presentation of +appendicitis in preadolescent children. +Pediatr Emerg Care. +2007;23:849-855. +105. 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risk of fetal loss. +J Am Coll Surg. +2007;205:534-540. +112. +Bree RL, Ralls PW, Bafle DM, et al. +Evaluation of patients +with acute right upper quadrant pain. +American College +of Radiology. +ACR Appropriateness Criteria. +Radiology. +2000;215(Suppl):153. +113. +Bailey LE, Finley RK Jr., Miller SF, Jones LM. +Acute appen- +dicitis during pregnancy. +Am Surg. +1986;52:218-221. +114. +Masoomi H, Nguyen NT, Stamos MJ, Smith BR. +Overview of +outcomes of laparoscopic and open Roux-en-Y gastric bypass +in the United States. +Surg Technol Int. +2012;22:72-76. +115. +Cash C, Frazee R. +Improvements in laparoscopic treatment for +complicated appendicitis. +J Laparoendosc Adv Surg Tech A. +2012;22:581-583. +116. +Mui LM, Ng CS, Wong SK, et al. +Optimum duration of pro- +phylactic antibiotics in acute non-perforated appendicitis. +ANZ J Surg. +2005;75:425-428. +117. +Hoelzer DJ, Zabel DD, Zern JT. +Determining duration of anti- +biotic use in children with complicated appendicitis. +Pediatr 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Kim KK, Park YH, Baek JH. +Int J +Colorectal Dis. +2011;26:617-621. +126. +Sieren LM, Collins JN, Weireter LJ, et al. +The incidence of +benign and malignant neoplasia presenting as acute appendi- +citis. +Am Surg. +2010;76:808-811. +127. +Debnath D, Rees J, Myint F. +Are we missing diagnostic oppor- +tunities in cases of carcinoid tumours of the appendix? +Sur- +geon. +2008;6:266-272. +128. +In’t Hof KH, van der Wal HC, Kazemier G, Lange JF. +Carcinoid tumour of the appendix: an analysis of 1,485 con- +secutive emergency appendectomies. +J Gastrointest Surg. +2008;12:1436-1438. +129. +Smeenk RM, van Velthuysen ML, Verwaal VJ, Zoetmulder +FA. +Appendiceal neoplasms and pseudomyxoma peritonei: a +population based study. +Eur J Surg Oncol. +2008;34:196-201. +130. +O’Donnell M, Badger SA, Beattie GC, Carson J, Garstin +WIH. +Malignant neoplasms of the appendix. +Int J Colorectal +Dis. +2007;22:1239-1248. +131. +Marudanayagam R, Williams GT, Rees BI. +Review of the +pathological results of 2660 appendicectomy specimens. +J +Gastroenterol. +2006;41:745-749. +132. +Lai HW, Loong CC, Tai LC, Wu CW, Lui WY. +J Gastroenterol +Hepatol. +2006;21:1693-1696. +133. +McGory ML, Maggard MA, Kang H, O’Connell JB, Ko CY. +Malignancies of the appendix: beyond case series reports. +Dis +Colon Rectum. +2005;48:2264-2271. +134. +Dhage-Ivatury S, Sugarbaker PH. +Update on the surgi- +cal approach to mucocele of the appendix. +J Am Coll Surg. +2006;202:680-684. +135. +McCusker ME, Cote TR, Clegg LX, Sobin LH. +Cancer. +2002;94:3307-3312. +136. +Hinson FL, Ambrose NS. +Pseudomyxoma peritonei. +Br J +Surg. +1998;85:1332-1339. +137. +Gough DB, Donohue JH, Schutt AJ, et al. +Pseudomyxoma +peritonei. +Long-term patient survival with an aggressive +regional approach. +Ann Surg. +1994;219:112-119. +138. +Stewart JH IV, Shen P, Russell GB, et al. +Ann Surg Oncol. +2006;13:624-634. +139. +Sugarbaker PH. +New standard of care for appendiceal epithe- +lial neoplasms and pseudomyxoma peritonei syndrome? +Lan- +cet Oncol. +2006;7:69-76. +140. +McQuellon RP, Russell GB, Shen P, et al. +Ann Surg Oncol. +2008;15:125-133. +141. +Crump M, Gospodarowicz M, Shepherd FA. +Lymphoma of +the gastrointestinal tract. +Semin Oncol. +1999;26:324-337. +142. +Pickhardt PJ, Levy AD, Rohrmann CA Jr, Abbondanzo SL, +Kende AL. +Non-Hodgkin’s lymphoma of the appendix: clini- +cal and CT findings with pathologic correlation. +AJR Am J +Roentgenol. +2002;178:1123-1127. +143. +Muller G, Dargent JL, Duwel V, et al. +Leukaemia and lym- +phoma of the appendix presenting as acute appendicitis or +acute abdomen. +Four case reports with a review of the litera- +ture. +J Cancer Res Clin Oncol. +1997;123:560-564. +Liver +Elaine Y. +Cheng, Ali Zarrinpar, David A. +Geller, +John A. +Goss, and Ronald W. +2000 B.C.) con- +sidered the liver to be the seat of the soul. +2 The liver is the largest gland in the body and performs a +diverse spectrum of functions. +The only defini- +tive treatment is orthotopic liver transplantation. +9 Surgical resection is the treatment of choice for hilar +cholangiocarcinoma. +LIVER ANATOMY +The liver is the largest organ in the body, weighing approxi- +mately 1500 g. +It is +reddish brown and is surrounded by a fibrous sheath known as + Glisson’s capsule. +The liver is held in place by several ligaments +(Fig. +31-1). +The left and right triangular ligaments +secure the two sides of the liver to the diaphragm. +Extending +from the triangular ligaments anteriorly on the liver are the +coronary ligaments. +31-2). +31-2). +31-3). +Segment IV can be subdivided into segment +IVA and segment IVB. +Hepatic ligaments suspending the +liver to the diaphragm and anterior abdominal +wall. +In situ liver hilar anatomy with hepatoduodenal and +gastrohepatic ligaments. +Foramen of Winslow is depicted. +Liver in situ +Foramen of +winslow +Gastrohepatic +ligament +Open hepato- +duodenal ligament +Figure 31-3. +Couinaud’s liver segments (I through VIII) num- +bered in a clockwise manner. +IVC = inferior vena cava. +Segment IVB is caudad and adjacent +to the gallbladder fossa. +Many anatomy textbooks also refer to seg- +ment IV as the quadrate lobe. +Quadrate lobe is an outdated term, +and the preferred term is segment IV or left medial segment. +Most +surgeons still refer to segment I as the caudate lobe, rather than +segment I. +The main scissura +contains the middle hepatic vein and separates the right and left +livers. +a. += artery; LHA = +left hepatic artery; RHA = right hepatic artery. +25% of the blood supply, and the portal vein approximately +75%. +31-4). +The hepatic artery proper divides +into the right and left hepatic arteries. +The most common hepatic arterial variants are shown +(Fig. +31-5). +Common hepatic +artery anatomic variants. +SMA = +superior mesenteric artery. +31-5). +31-6). +31-7). +The left portal vein then +Figure 31-6. +Portal vein anatomy. +The portal vein is formed by +the confluence of the splenic and superior mesenteric veins. +The +inferior mesenteric vein drains into the splenic vein. +The coronary +(left gastric) vein drains into the portal vein in the vicinity of the +confluence. +v. += vein. +Coronary v. +Portal v. +Superior mesenteric v. +Inferior +mesenteric v. +Splenic v. +Figure 31-7. +Anatomy of the left portal vein (LPV). +Cadaver cast +shows the transverse and umbilical portions of the LPV. +The por- +tal vein pressure in an individual with normal physiology is low +at 3 to 5 mmHg. +31-8). +The caudate lobe is unique +because its venous drainage feeds directly into the IVC. +This can be a source +of torrential bleeding if control of it is lost during right hepatec- +tomy. +In general, the hepatic +ducts follow the arterial branching pattern inside the liver. +Anterior +segment +structures +Gall bladder +Portal v. +Hepatic a. +Confluence of the three hepatic veins (HVs) and the inferior vena cava (IVC). +Note that the middle and left HVs drain into +a common trunk before entering the IVC. +a. += artery; v. += vein. +(Adapted with permission from Cameron JL, ed. +Atlas of Surgery. +Vol. +I, +Gallbladder and Biliary Tract, the Liver, Portasystemic Shunts, the Pancreas. +31-9). +The cystic duct itself also has +a variable pattern of drainage into the common bile duct. +The gallbladder sits adherent to hepatic +segments IVB (left lobe) and V (right lobe). +The denervated liver after +hepatic transplantation seems to function with normal capacity. +These include processes such as +storage, metabolism, production, and secretion. +Main variations of hepatic duct confluence. +CHD = common hepatic duct; lh = left hepatic; R = right; ra = right anterior; rp = right posterior. +(Reproduced with permission from Blumgart LH, Fong Y, eds. +Surgery of the Liver and Biliary Tract. +3rd ed, Vol. +I. +London: Elsevier Science; +2000. +Bilirubin is bound to albumin in the circulation and sent to the +liver. +This glucuro- +nide is then excreted into the bile canaliculi. +A small amount +dissolves in the blood and is then excreted in the urine. +Bile is produced by hepatocytes and secreted through the +biliary system. +Upon entry of food into the duodenum, bile is released +from the gallbladder to aid in digestion. +The human liver can +produce about 1 L of bile daily. +Bile salts are sodium and potassium salts of bile +acids conjugated to amino acids. +The bile acids are deriva- +tives of cholesterol synthesized in hepatocytes. +Bacteria in +the intestine can remove glycine and taurine from bile salts. +Bile salts secreted into the intestine are efficiently reab- +sorbed and reused. +Those lost in the stool +are replaced by synthesis in the liver. +In most cases, a drug is rela- +tively lipophilic to ensure good absorption. +There are +two main reactions important for drug metabolism. +Phase I reac- +tions include oxidation, reduction, and hydrolysis of molecules. +These result in metabolites that are more hydrophilic than the +original chemicals. +These subgroups +include glucuronate, acetate, glutathione, glycine, sulfate, and +methyl groups. +These drug reactions occur mainly in the smooth +endoplasmic reticulum of hepatocytes. +Many factors can affect drug metabolism in the liver. +An example is acetaminophen when +taken in larger doses. +ALT is predominately found in the liver and thus is more +specific for liver disease. +Hepatocellular injury is the trigger for +release of these enzymes into the circulation. +In alcoholic liver disease, an AST:ALT ratio of >2:1 is +common. +Moderate increases in the levels of +these enzymes are common in acute viral hepatitis. +The +liver produces approximately 10 g of albumin per day. +PT measures the rate of conversion of prothrombin to throm- +bin. +To standardize the reporting of PT and avoid interlabora- +tory variability, the INR was developed. +The INR is the ratio +of the patient’s PT to the mean control PT. +Bilirubin is a +breakdown product of hemoglobin metabolism. +Unconjugated +bilirubin is insoluble and thus is transported to the liver bound +to albumin. +In the liver, it is conjugated to allow excretion +in bile. +Normally, +>90% of serum bilirubin is unconjugated. +AP is an enzyme with a wide tissue distribution but is +found primarily in the liver and bones. +In the liver, it is expressed +by the bile duct epithelium. +GGT is another enzyme found in hepatocytes and released +from the bile duct epithelium. +Elevation of GGT is an early +marker and also a sensitive test for hepatobiliary disease. +For example, a raised GGT level with +increased AP level supports a liver source. +Jaundice can be caused by a wide range +of benign and malignant disorders. +Dysfunction in any of these phases can lead to jaundice.10 +Prehepatic. +Insufficient conju- +gation is often seen in processes that result in excessive heme +metabolism. +Causes of hemolysis include inherited and acquired hemolytic +anemias. +In contrast, direct Coombs’ +test results are negative in nonimmune hemolytic anemias. +Intrahepatic. +It is a benign condition that affects +approximately 4% to 7% of the population. +These episodes are self-limited and usually do not require fur- +ther treatment. +Another inherited disorder of bilirubin conjuga- +tion is Crigler-Najjar syndrome. +Posthepatic. +There is a +wide spectrum of pathologies that may present with obstructive +jaundice. +Extrinsic compression of the +biliary tree is commonly due to pancreatic disorders. +Ultrasound tech- +nology is based on the pulse-echo principle. +This real- +time gray scale (B-mode) imaging is augmented by Doppler +flow imaging. +It is excellent for diagnosing biliary pathology and focal liver +lesions. +Moreover, obesity and overlying bowel gas also can interfere +with image quality. +In addition, biopsy of lesions and +ablation of tumors can be guided by intraoperative ultrasound. +A CT scan with a +Figure 31-10. +Upper panel +shows the portal vein bifurcation with echogenic Glissonian sheath. +An accessory LHV is present in +this patient. +Lower panel is a color Doppler image showing flow. +The +liver is unique in that it has a dual blood supply. +However, many +liver tumors receive the majority of their blood supply from the +hepatic artery. +31-11). +Computed tomographic (CT) images of hepatic +veins and Couinaud’s liver segments. +LHV = left hepatic vein; +MHV = middle hepatic vein; RHV = right hepatic vein. +CT cholangiography has emerged as a new imaging modal- +ity for biliary disease. +In this technique, a vibration device is used +to induce a shear wave in the liver. +One of the most common clinical +indications for MRCP is biliary obstruction. +Fluorodeoxyglucose (FDG) is +the most common metabolic molecule used in PET imaging. +For this reason, dual-tracer PET has been introduced to improve +sensitivity in detecting all HCC. +It +was initially described as a specific disease entity in the 1950s. +It also has been referred to as fulminant hepatic failure. +ALF is a +rare disorder affecting approximately 2000 patients annually in +the United States. +Even with current medical care, ALF +can progress rapidly to hepatic coma and death. +The U.S. +Hepatic coma grade at presentation +was approximately equally distributed across grades I to IV. +In addition, +44% of the patients acquired a culture-proven infection. +The possibility of previous liver disease +needs to be explored. +4 +safest to obtain the tissue via a transjugular approach. +Patients +with ALF should be admitted to the hospital and monitored fre- +quently. +Most instances of drug-induced hepatotoxicity occur in +the first 6 months after drug initiation. +Serum phosphorus levels need to +be monitored. +Sedation should be avoided, and the head of the +bed should be elevated at least 30°. +Neurologic examinations +1277 +L +IVER +CHAPTER 31 +should be performed frequently. +Several systems have +been tested without definitive evidence of efficacy. +Conversely, a single disease process can demonstrate several +morphologic patterns. +Liver biopsy will reveal the typical findings of alcoholic +Figure 31-13. +Histology of cirrhotic liver with regenerating mac- +ronodules. +Upper panel: Grossly cirrhotic liver. +Antimitochon- +drial antibodies will test positive in the vast majority of cases. +Hereditary hemochromatosis is the most common meta- +bolic disorder causing cirrhosis. +On physical examination, a number of findings have +been described in patients with cirrhosis. +Ascites and pleural effu- +sion can be seen with fluid accumulation. +Jaun- +dice usually does not appear until the bilirubin rises above +2 to 3 mg/dL. +Asterixis can be detected in patients with hepatic +encephalopathy. +Although fat stores and muscle mass are reduced, rest- +ing energy expenditure is increased. +Spontaneous bacterial peritonitis also is seen +in cases of cirrhosis with ascites. +The cirrhotic patient usually has a mild +normocytic normochromic anemia. +The white blood cell and +platelet counts are reduced, and the bone marrow is macro- +normoblastic. +Urobilinogen is present and urinary sodium excretion is dimin- +ished in the presence of ascites. +The serum levels of bilirubin, +transaminases, and alkaline phosphatase may all be elevated. +However, normal liver function test results do not eliminate the +possibility of cirrhosis. +Liver +biopsy can be performed via a percutaneous, transjugular, or +laparoscopic approach. +However, no currently available +marker is sufficiently accurate for clinical use. +A number of laboratory tests have been used to assess +hepatic reserve in patients with cirrhosis. +In the +average adult, 1000 to 1500 mL/min of portal venous blood is +supplied to the liver. +However, this amount can be significantly +increased in the cirrhotic patient. +31-14). +The simplest initial investigation is abdominal ultrasonography. +A large portal vein suggests portal hypertension but is not diag- +nostic. +Doppler +ultrasound also is useful in evaluating blood flow through sur- +gical shunts and TIPS. +The most accurate method of determining portal hyperten- +sion is hepatic venography. +Clinically significant portal hypertension is +evident when HVPG exceeds 10 mmHg. +Intra-abdominal venous flow pathways leading to +engorged veins (varices) from portal hypertension. +a 1 +a +F +G +E +1 +A +B +b +D +2 +4 +c +d e +3 C +5 +causing leukopenia, thrombocytopenia, and anemia. +One third of all patients with varices will +experience variceal bleeding. +Each episode of bleeding is asso- +ciated with a 20% to 30% risk of mortality. +The needle track is dilated until a portal pressure +gradient of ≤12 mmHg is achieved. +Patient survival +is determined by hepatic reserve. +The Eck fistula also makes subsequent hepatic trans- +plantation much more technically difficult. +The surgical shunt currently used most often is the distal spl- +enorenal or Warren shunt (Fig. +31-15). +This shunt is technically +6 +1283 +L +IVER +CHAPTER 31 +the most difficult to perform. +Surgical shunts for portal hypertension. +Types of portacaval anastomoses. +A. +Normal anatomy. +B. +Side-to-side portacaval shunt. +C. +End-to-side portacaval +shunt. +D. +Mesocaval shunt. +E. +Distal splenorenal (Warren) +shunt. +(Reproduced with permission from Doherty GM, +Way LW, eds. +Current Surgical Diagnosis and Treatment. +12th ed. +New York: McGraw-Hill; 2006). +Copyright © The +McGraw-Hill Companies, Inc. +of the hemodynamic and humoral changes associated with + cirrhosis. +BCS is defined as primary when the obstructive +process involves an endoluminal venous thrombosis. +All +known inherited thrombophilias also have been implicated in the +development of BCS. +The obstruction +results in hepatomegaly, liver congestion, and right upper quad- +rant pain. +This caudate lobe hypertrophy, in +turn, can result in further obstruction of the IVC. +Thrombolytic therapy alone +may be attempted for acute thrombosis. +Due to the high level of retic- +uloendothelial cells in the liver, nonviral infections are unusual. +Anaerobic organisms such as Bacteroides fragilis also are seen +frequently. +There appears +Figure 31-16. +Computed tomographic scan of pyogenic liver +abscesses. +Multiple hepatic abscesses are seen in a patient after an +episode of diverticulitis. +Note the loculated large central abscess as +well as the left lateral segment abscess. +Patients commonly present with right upper quadrant pain +and fever. +Jaundice occurs in up to one third of affected patients. +Significant abnor- +malities in the results of the remaining liver function tests are +unusual. +Blood cultures will only reveal the causative organism +in approximately 50% of cases. +31-16). +Ana- +tomic surgical resection can be performed in patients with +recalcitrant abscesses. +Amebi- +asis is most common in subtropical climates, especially in areas +with poor sanitation. +E. +They con- +tain a proteolytic enzyme that also destroys liver parenchyma. +The abscesses formed are variable in size and can be single or +multiple. +This material has been +likened to anchovy paste or chocolate sauce. +Amebic abscesses +are the most common type of liver abscesses worldwide. +The most common biochemical abnormality is a +mildly elevated AP level. +Most patients have a positive fluorescent antibody test +for E. +histolytica, and test results can remain positive for some +time after a clinical cure. +The central cavity may have septations as well as fluid +levels. +CT scanning is also useful in the detection of extrahe- +patic involvement. +Each worm sheds approximately +500 ova into the bowel. +The ova have chitinous envelopes that are dissolved by gastric +juice. +Hydatid disease is most common in sheep-raising areas, +where dogs have access to infected offal. +These include South +Australia, New Zealand, Africa, Greece, Spain, and the Middle +East. +The +uncomplicated cyst may be silent and found only incidentally +or at autopsy. +Eosinophilia is +seen in approximately 30% of infected patients. +The appearance of the cysts on +images depends on the stage of cyst development. +Typically, +hydatid cysts are well-defined hypodense lesions with a dis- +tinct wall. +Ring-like calcifications of the pericysts are present +in 20% to 30% of cases. +Medical treatment with albendazole relies on +drug diffusion through the cyst membrane. +If complete cystectomy is not possible, then formal +anatomic liver resection can be undertaken. +Infection +of the lung also is common (alveolar echinococcosis). +Ascariasis +Ascaris infection is particularly common in the Far East, India, +and South Africa. +The Ascaris may serve as +a nidus for the development of intrahepatic gallstones. +Occasionally, worms can be seen moving into and +out of the biliary tree from the duodenum. +Surgical intervention may become necessary if the Ascaris can- +not be removed via ERCP. +Schistosomiasis +Schistosomiasis affects >200 million people in 74 countries. +They then re-enter human skin during contact with infected +water. +Those entering the intrahepatic portal system grow rapidly, +resulting in a granulomatous reaction. +The degree of consequent +portal fibrosis is related to the adult worm load. +Active infection is detected by stool examination. +A negative serologic test +result excludes the presence of schistosomal infection. +Serum +levels of transaminases are usually normal, but the AP level may +be mildly elevated. +A decreased serum albumin level is usually +the result of frequent GI bleeds and malnutrition. +GI bleeding usually is controlled by endoscopic variceal ligation. +Viral Hepatitis +The role of the surgeon in the management of viral hepatitis is +somewhat limited. +The most com- +mon physical findings are jaundice and hepatomegaly. +Because +the disease is self-limited, the treatment is usually supportive. +Hepatitis B and C, on the other hand, can both lead to +chronic liver disease, cirrhosis, and HCC. +The prevalence of +chronic hepatitis B infection in the U.S. +On the other hand, +the nucleoside analogs are generally well-tolerated by patients. +Untreated, most of these patients will eventually +develop chronic infection. +31-17). +Angiogram +Occult primary eval. +Algorithm for diagnostic workup of +an incidental liver lesion. +In these patients, laparoscopic liver biopsy can +be considered. +Hepatic cysts +are usually identified incidentally and can occur at any time +throughout life. +The most common benign lesion found in the +liver is the congenital or simple cyst. +The exact prevalence of +simple hepatic cysts in the U.S. +The cyst +epithelium is cuboidal and secretes a clear nonbilious serous +fluid. +With the exception of large cysts, simple cysts are usually +asymptomatic. +Large simple cysts may cause abdominal pain, +epigastric fullness, and early satiety. +Occasionally the affected +patient presents with an abdominal mass. +Asymptomatic simple cysts are best managed conser- +vatively. +This approach is approximately 90% effective +in controlling symptoms and ablating the cyst cavity. +The +laparoscopic approach is being used more frequently and is 90% +effective. +Although these lesions are usually benign, they can +undergo malignant transformation. +Patients with biliary cystad- +enomas commonly present with abdominal pain. +An abdominal +mass occasionally can be identified on physical examination. +Surgical +resection is the preferred mode of treatment. +Patients with a small number of cysts or with small cysts (<2 cm) +usually remain asymptomatic. +Disease +progression often results in renal failure and the need for hemo- +dialysis. +The principal aim of treatment for PCLD is to ameliorate +symptoms by decreasing liver volume. +Medical therapy options +for PCLD remain experimental at this time. +Common agents used for sclerosis +include ethanol, minocycline, and tetracycline. +OLT represents the only definitive therapy for patients +with symptomatic PCLD. +Most patients present by the age of 30 years, +and males and females are affected equally. +Rarely, patients +can present later in life with complications secondary to portal +hypertension. +The +diagnosis of Caroli’s disease is made based on imaging stud- +ies. +If the +disease is limited to a single lobe of the liver, hepatic resec- +tion can be beneficial. +Many of these lesions have typical features in +imaging studies that help confirm the diagnosis. +They are predomi- +nantly seen in women and occur in 2% to 20% of the popula- +tion. +They can range from small (≤1 cm) to giant cavernous +hemangiomas (10 to 25 cm). +Most hemangiomas are discov- +ered incidentally with little clinical consequence. +The majority of hemangiomas can be diagnosed by liver +imaging studies. +31-18). +Adenoma +Hepatic adenomas are benign solid neoplasms of the liver. +On gross examination, they appear +soft and encapsulated and are tan to light brown. +31-18). +Computed tomographic scans showing classic appearance of benign liver lesions. +Adenoma is hypovascular (lower left +panel). +Hemangioma shows asymmetrical peripheral enhancement (lower right panel). +Hepatic adenomas carry a significant risk of spontaneous +rupture with intraperitoneal bleeding. +Hepatic adenomas also have a risk of malignant transformation to +a well-differentiated HCC. +31-18). +After gadolinium administration, lesions +are hyperintense but become isointense on delayed images. +The fibrous septa extending from the central scar are also more +readily seen with MRI. +Oral contraceptive or estrogen use +should be stopped when either FNH or adenoma is diagnosed. +They +are firm, smooth, and whitish yellow in appearance. +Hence, the most common tumor seen +in the liver is metastatic colorectal cancer. +This compares with +approximately 18,000 new cases of HCC diagnosed annually in +the United States. +HCCs are typically hypervascular with +blood supplied predominantly from the hepatic artery. +Thus, +the lesion often appears hypervascular during the arterial phase +of CT studies (Fig. +MRI imaging also is effective in character- +izing HCC. +HCC is variable on T1-weighted images and usu- +ally hyperintense on T2-weighted images. +The treatment of HCC is complex and is best managed +by a multidisciplinary liver transplant team. +A complete algo- +rithm for the evaluation and management of HCC is shown +(Fig. +31-20). +For patients without cirrhosis who develop +HCC, resection is the treatment of choice. +Extrahepatic bile duct cancer can be located dis- +tally or proximally. +When proximal, it is referred to as a hilar +cholangiocarcinoma (Klatskin’s tumor). +Therefore, a search for a primary site should +Figure 31-19. +CT +scans reveal a large (upper panel) and small (middle panel) hyper- +vascular HCC. +A hypovascular left lobe peripheral cholangiocarci- +noma (CholangioCA) is also shown (lower panel). +This led transplant centers to consider +OLT for patients with hilar cholangiocarcinoma. +Gallbladder Cancer +Gallbladder cancer is a rare aggressive tumor with a very poor +prognosis. +Over 90% of patients have associated cholelithia- +sis. +In another study, a German registry of incidental +gallbladder cancer identified 439 patients. +Algorithm for the management of hepatocellular carcinoma (HCC). += vascular. +invasion +No metastasis +Not Tx candidate +Co-morbid factors +≥4 lesions +Gross vasc. +invasion +LN (+) or metastasis +LDLT ? +> 3 mos) +Perc/lap. +Major hepatectomy was performed in 91 patients (54%), +and recurrence rate was 84% at 5 years. +The treatment plan is +individualized and modified according to the response of the +patient. +A partial solution has been the use of living +donor grafts. +The resistance of the tissue to the rapidly alternating cur- +rent produced heat. +This discovery contributed to the development +of the surgical application of electrocautery. +In 1908, Beer used +RF coagulation to destroy urinary bladder tumors. +Cushing and +Bovie later applied RF ablation to intracranial tumors. +He found that RF caused local +tissue destruction with uniform necrosis. +In +a multicenter phase II U.S. +The average tumor size was 3.6 cm (range, +0.5 to 9.0 cm). +At a mean follow-up of 19 months, 47% of the +patients were alive with no evidence of disease. +There were no procedure- +related deaths. +It is most commonly used for treatment of +unresectable HCC. +31-21). +IVC RHV +MHV +VII +VIII IVa +II +VI +V +IVb +III +Falciform lig. +Portal vein +IVC +LHV +I +Figure 31-21. +Hepatic anatomy. +Hepatic segments removed in +the formal major hepatic resections are indicated. +2. +Open and explore the abdomen, and place a fixed table +retractor (e.g., Thompson or Bookwalter). +3. +Examine the liver with bimanual palpation. +Perform liver +ultrasound, and confirm the operation to be performed. +4. +Take down the round and falciform ligaments, and expose +the anterior surface of the hepatic veins. +5. +6. +7. +Right Hepatic Lobectomy (Right Hepatectomy or + Hemihepatectomy) + 8. +9. +10. +Doubly ligate and divide a replaced or accessory RHA if +present. +11. +Expose the portal vein, identifying its right and left +branches. +Divide the RPV either with a vascular +stapler or between vascular clamps. +12. +Pass a +silastic tube of a Jackson-Pratt drain through this gap. +13. +14. +Hang the liver over the drain by pulling up as you divide +through the liver parenchyma. +15. +16. +17. +Continue parenchymal division until the RHV is encoun- +tered. +18. +Divide the RHV between vascular clamps and suture ligate +the RHV. +19. +20. +Ensure hemostasis of the transected liver edge with an +argon beam coagulator and suture ligation. +21. +Inspect the transection surface for bile leaks. +These should +be clipped or suture ligated. +Applying a dilute solution of +hydrogen peroxide can facilitate the visualization of bile +leaks. +22. +Inspect the IVC and right retroperitoneal space for + hemostasis. +23. +24. +Fix the proximal falciform ligament back to the diaphragm +side with figure-of-eight sutures. +25. +31-22). +As for the transection plane, the key is to perform +Figure 31-22. +The right hepatic vein is ligated and +divided. +Middle hepatic vein branches inside the liver are divided. +Weaving in and out or bisecting the +MHV can leading to torrential back bleeding. +9. +Doubly ligate and divide a replaced or accessory left hepatic +artery (LHA) if present. +10. +11. +Divide any existing parenchymal bridge between segments +III and IVB. +12. +13. +14. +15. +Expose the portal vein, identifying the right and left +branches. +Divide the LPV either with a vascular stapler or +between vascular clamps. +16. +Ligate and divide the ligamentum venosum caudally. +17. +Identify the long extrahepatic course of the left hepatic duct +(LHD) behind the portal vein. +Ligate and divide the LHD +at the umbilical fissure. +18. +19. +Do not force it or +perforate the IVC or MHV. +20. +Pass the silastic tube of a Jackson-Pratt drain through this +window. +21. +22. +Hang the liver over the drain by pulling up as you divide +through the liver parenchyma. +23. +Do +not bisect the MHV as it passes tangentially from the left +to the right lobe. +24. +25. +Continue parenchymal division until the left/middle hepatic +veins are encountered. +26. +Divide the LHV and MHV between vascular clamps and +suture the ligate the LHV/MHV. +27. +28. +Inspect the transection surface for bile leaks. +These should +be clipped or suture ligated. +Apply dilute solution of hydro- +gen peroxide to facilitate the visualization of bile leaks. +29. +Perform completion ultrasound to confirm RPV inflow and +RHV outflow. +30. +Apply tissue sealant to the transected surface of the liver. +Place a Jackson-Pratt drain in the left subphrenic space and +close the abdomen (Fig. +31-23). +Completed left hepatic lobectomy (left hepatectomy) +resecting segments II, III, and IV. +1300 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +of devascularized liver remaining. +Left Lateral Segmentectomy (Left Lateral Sectionectomy) + 8. +9. +Doubly ligate and divide a replaced or accessory LHA if +present. +10. +Clamp the round ligament and pull it anteriorly as a handle +to expose the left hilum. +11. +Divide any existing parenchymal bridge between segments +III and IVB. +12. +13. +This will +facilitate encircling the segment III and II pedicles, which +can be divided separately. +14. +15. +Divide the LHV as the parenchymal transection is complete. +16. +Therefore, all +efforts should be made to minimize blood loss during hepatic +resection. +A +larger remnant may also be needed when patients have received +preoperative chemotherapy. +The specimen +is then removed from the hand-port incision. +Results with laparoscopic liver resections have been +excellent. +There were no differences in operative time or postoperative +mortality. +There were no reported +cases of port site recurrences or peritoneal 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A, Rao G, Ahmed I. +Laparoscopic vs. +open liver resection +for malignant liver disease. +A systematic review. +Surgeon. +2012;10(4):194. +188. +Buell JF, Cherqui D, Geller DA, et al. +The international +position on laparoscopic liver surgery: The Louisville +Statement, 2008. +Ann Surg. +2009;250(5):825. +189. +Laurent A, Tayar C, Andreoletti M, Lauzet JY, Merle JC, Cher- +qui D. +J Hepatobiliary +Pancreat Surg. +2009;16(3):310. +190. +Zhou YM, Shao WY, Zhao YF, Xu DH, Li B. +Meta-analysis +of laparoscopic versus open resection for hepatocellular car- +cinoma. +Dig Dis Sci. +2011;56(7):1937. +191. +Castaing D, Vibert E, Ricca L, Azoulay D, Adam R, Gayet B. +Ann +Surg. +2009;250(5):849. +This page intentionally left blank +Gallbladder and the Extrahepatic +Biliary System +Thai H. +Pham and John G. +The fundus is the rounded, blind +end that normally extends 1 to 2 cm beyond the liver’s margin. +32-1). +The epithelial lining of the gallbladder is supported by +a lamina propria. +The muscle layer has circular longitudinal +and oblique fibers, but without well-developed layers. +It is covered by the serosa except +where the gallbladder is embedded in the liver. +Gallbladder lymphatics drain into nodes +at the neck of the gallbladder. +chapter +The preganglionic sympathetic level is T8 and T9. +2 In Western countries, the most common type of gallstones are +cholesterol stones. +4 Common bile duct injuries, although uncommon, can be +devastating to patients. +5 The main risk factor for gallbladder disease in Western +countries is cholelithiasis. +a +b +c +d +e +f +g +h +i +j +k +l +m +n +Figure 32-1. +Anterior aspect of the biliary anatomy. +The two ducts join to form a common hepatic duct, +close to their emergence from the liver. +The common hepatic +duct is 1 to 4 cm in length and has a diameter of approximately +4 mm. +It lies in front of the portal vein and to the right of the +hepatic artery. +The length of the cystic duct is quite variable. +32-2). +They do not have any valvular function but may make cannula- +tion of the cystic duct difficult. +The common bile duct is about 7 to 11 cm in length and +5 to 10 mm in diameter. +There, the pancreatic duct fre- +quently joins it. +In about 10%, they exit via separate openings into +the duodenum. +32-3). +It controls the flow of bile, and in some +cases pancreatic juice, into the duodenum. +A fibroareolar tissue containing scant smooth muscle cells sur- +rounds the mucosa. +A distinct muscle layer is not present in +the human common bile duct. +These arteries anastomose freely within the duct +walls. +Variations of the cystic duct anatomy. +A. +Low junction between the cystic duct and common hepatic duct. +B. +Cystic duct adher- +ent to the common hepatic duct. +C. +High junction between the cystic and the common hepatic duct. +D. +Cystic duct drains into right hepatic +duct. +E. +Long cystic duct that joins common hepatic duct behind the duodenum. +F. +Absence of cystic duct. +G. +Cystic duct crosses posterior +to common hepatic duct and joins it anteriorly. +H. +Cystic duct courses anterior to common hepatic duct and joins it posteriorly. +Pancreatic duct +Common +bile duct +Sphincter +of Oddi +Duodenum +Duodenal wall +Figure 32-3. +The sphincter of Oddi. +Iso- +lated congenital absence of the gallbladder is very rare, with a +reported incidence of 0.03%. +Small ducts (of Luschka) may drain directly from the liver +into the body of the gallbladder. +An accessory right +hepatic duct occurs in about 5% of cases. +In about 20% of patients, the right hepatic artery +comes off the superior mesenteric artery. +The right hepatic +artery may course anterior to the common duct. +32-4). +The secre- +tion of bile is responsive to neurogenic, humoral, and chemical +stimuli. +With an intact sphincter of Oddi, bile flow +is directed into the gallbladder. +Bile is mainly composed of water, electrolytes, bile salts, +proteins, lipids, and bile pigments. +Variations in the arterial supply to the gallbladder. +A. +Cystic artery from right hepatic artery, about 80% to 90%. +B. +C. +Two cystic arter- +ies, one from the right hepatic, the other from the common hepatic +artery, rare. +D. +Two cystic arteries, one from the right hepatic, the +other from the left hepatic artery, rare. +E. +F. +Two cystic arteries arising from the right +hepatic artery, rare. +or extracellular fluid. +The synthesis of phospholipids +and cholesterol by the liver is, in part, regulated by bile acids. +Absorption and Secretion. +During fasting, +the gallbladder does not simply fill passively. +This process is mediated at +least in part by the hormone motilin. +One of the +main stimuli to gallbladder emptying is the hormone cholecys- +tokinin (CCK). +Over the following 60 to 90 minutes, the gallbladder +gradually refills. +This is correlated with a reduced CCK level. +Parasympatho- +mimetic drugs contract the gallbladder, whereas atropine leads +to relaxation. +It also relaxes the terminal bile duct, +the sphincter of Oddi, and the duodenum. +Vasoactive intestinal polypeptide inhibits contraction and +causes gallbladder relaxation. +Somatostatin and its analogues +are potent inhibitors of gallbladder contraction. +32-5). +For decades, it was the mainstay of investigation for gallstones. +An elevated +white blood cell (WBC) count may indicate or raise suspicion of +cholecystitis. +Serum aminotransferases may +be normal or mildly elevated. +In patients with biliary colic or +chronic cholecystitis, blood tests will typically be normal. +Adjacent organs can frequently +be examined at the same time. +Obese patients, patients with +Figure 32-5. +The effect of cholecystokinin on the gallbladder and +the sphincter of Oddi. +A. +During fasting, with the sphincter of Oddi +contracted and the gallbladder filling. +B. +In response to a meal, the +sphincter of Oddi relaxed and the gallbladder emptying. +Ultrasound will show stones in the gallbladder with sensi- +tivity and specificity of >90%. +Stones are acoustically dense and +reflect the ultrasound waves back to the ultrasonic transducer. +32-6). +Stones move with changes in position. +Polyps may be calcified +and reflect shadows, but do not move with change in posture. +Some stones form a layer in the gallbladder; others a sediment +or sludge. +A thickened gallbladder wall and local tenderness +indicate cholecystitis. +A contracted, thick-walled gallbladder is indicative of chronic +cholecystitis. +Frequently, the site +and, sometimes, the cause of obstruction can be determined by +ultrasound. +Stones are noted on a film as filling defects +in a visualized, opacified gallbladder. +Figure 32-6. +An ultrasonography of the gallbladder. +Arrows indi- +cate the acoustic shadows from stones in the gallbladder. +The sensitivity and specificity for the diag- +nosis are about 95% each. +Use of CT scan is an integral part of the differential diagnosis +of obstructive jaundice (Fig. +32-7). +Spiral CT scanning provides +Figure 32-7. +The can- +cer obstructs the common bile duct as well as the pancreatic duct. +32-8). +As with any invasive procedure, there are potential risks. +32-9). +32-10). +The procedure requires intravenous (IV) sedation +for the patient. +It is of particular value in the evaluation of +tumors and their resectability. +A. +Dilated intrahepatic bile duct is +entered percutaneously with a fine needle. +B. +Small guidewire is passed through the +needle into the duct. +C. +A plastic catheter +has been passed over the wire, and the wire +is subsequently removed. +A cholangiogram is +performed through the catheter. +D. +An external +drainage catheter in place. +E. +Long wire placed +via the catheter and advanced past the tumor +and into the duodenum. +F. +Internal stent has +been placed through the tumor. +ultrasonic guidance. +Certain conditions predispose to the +development of gallstones. +Magnetic resonance cholangiopancreatography. +Figure 32-10. +Endoscopic retrograde cholangiography. +A. +B. +An endoscopic cholangiography showing stones in the common bile duct. +The catheter has been placed +in the ampulla of Vater (arrow). +Note the duodenal shadow indicated with arrowheads. +Rarely, complication +of gallstones is the presenting picture. +Once symptomatic, patients +tend to have recurring bouts of biliary colic. +Complicated gall- +stone disease develops in 3% to 5% of symptomatic patients per +year. +Gallstone Formation +Gallstones form as a result of solids settling out of solution. +The +major organic solutes in bile are bilirubin, bile salts, phospho- +lipids, and cholesterol. +Pigment stones can be further classified as either black or brown. +Both +types of pigment stones are more common in Asia. +Cholesterol Stones. +Pure cholesterol stones are uncommon +and account for <10% of all stones. +They usually occur as single +large stones with smooth surfaces. +32-11). +Colors range from +whitish yellow and green to black. +Most cholesterol stones are +radiolucent; <10% are radiopaque. +Cholesterol is highly nonpolar and +insoluble in water and bile. +Vesicular maturation occurs +when vesicular lipids are incorporated into micelles. +Vesicular +phospholipids are incorporated into micelles more readily than +vesicular cholesterol. +Therefore, vesicles may become enriched +Figure 32-12. +The three major components of bile plotted on trian- +gular coordinates. +A given point represents the relative molar ratios +of bile salts, lecithin, and cholesterol. +(Reproduced with permission from Holzbach RT. +Pathogenesis and medical treatment of gallstones. +In: Slesinger +MH, Fordtran JS, eds. +Gastrointestinal Diseases. +Philadelphia: WB +Saunders; 1989:1672.) +Figure 32-11. +Gallbladder with cholesterol stones. +Note the dif- +ferent shapes and sizes. +in cholesterol, become unstable, and then nucleate cholesterol +crystals. +In unsaturated bile, cholesterol enrichment of vesicles +is inconsequential. +32-12). +Pigment Stones. +Black pigment stones are usually small, brittle, black, +and sometimes spiculated. +Like +cholesterol stones, they almost always form in the gallbladder. +Unconjugated bilirubin is much less soluble than conjugated +bilirubin in bile. +Deconjugation of bilirubin occurs normally in +bile at a slow rate. +Cirrhosis may lead to increased secre- +tion of unconjugated bilirubin. +Brown stones are usually <1 cm in diameter, brownish- +yellow, soft, and often mushy. +Precipitated calcium bilirubinate +and bacterial cell bodies compose the major part of the stone. +Clinical Presentation The chief symptom associated with +symptomatic gallstones is pain. +32-13). +The pain is severe and +comes on abruptly, typically during the night or after a fatty +meal. +It often is associated with nausea and sometimes vomit- +ing. +The pain is episodic. +The patient suffers discrete attacks of +pain, between which they feel well. +Physical examination may +reveal mild right upper quadrant tenderness during an episode of +pain. +If the patient is pain free, the physical examination is usu- +ally unremarkable. +Atypical presentation of gallstone disease is common. +Asso- +ciation with meals is present in only about 50% of patients. +Some +patients report milder attacks of pain, but relate it to meals. +The pain may be located primarily in the back or the left upper +or lower right quadrant. +Bloating and belching may be present +and associated with the attacks of pain. +Many +patients with other conditions have gallstones. +An impacted stone without chole- +cystitis will result in what is called hydrops of the gallbladder. +A. +B. +Sites of pain radiation +(%) during an episode of biliary pain in the same group of patients. +(Reprinted from Gunn A, Keddie N. +Some clinical observations on +patients with gallstones. +Lancet. +1972;300(7771):239-241, Copy- +right 1972, with permission from Elsevier.) +is not tender. +In <1% of +acute cholecystitis, the cause is a tumor obstructing the cystic +duct. +Why inflammation develops +only occasionally with cystic duct obstruction is unknown. +It +is probably related to the duration of obstruction of the cystic +duct. +Increase in prostaglandin synthesis amplifies the inflammatory +response. +Pericholecystic fluid often is present. +The mucosa +may show hyperemia and patchy necrosis. +Rarely, perforation of ischemic areas occurs. +The perforation is usually contained in the subhepatic space +by the omentum and adjacent organs. +It is usu- +ally more severe than the pain associated with uncomplicated +biliary colic. +A mild to moderate leukocytosis (12,000–15,000 cells/mm3) +is usually present. +However, some patients may have a normal +WBC. +Diagnosis Ultrasonography is the most useful radiologic test +for diagnosing acute cholecystitis. +It has a sensitivity and speci- +ficity of 95%. +32-14). +Biliary radionuclide +scanning (HIDA scan) may be of help in the atypical case. +CT scan is frequently +performed on patients with acute abdominal pain. +The antibiotics should +cover gram-negative aerobes as well as anaerobes. +The procedure is more +tedious and takes longer than in the elective setting. +For those unfit for surgery, a percutaneous +Figure 32-14. +Ultrasonography from a patient with acute chole- +cystitis. +The arrowheads indicate the thickened gallbladder wall. +There are several stones in the gallbladder (arrows) throwing +acoustic shadows. +cholecystostomy or an open cholecystostomy under local +analgesia can be performed. +For these patients, surgery is unavoidable. +The incidence +increases with age. +Clinical Manifestations Choledochal stones may be silent and +often are discovered incidentally. +Nausea and vomiting are common. +A +small stone may pass through the ampulla spontaneously with +resolution of symptoms. +Finally, the stones may become com- +pletely impacted, causing severe progressive jaundice. +It has the distinct advan- +tage of providing a therapeutic option at the time of diagnosis. +32-15). +If a choledochotomy is performed, a T tube is left +in place. +In these cases the common +bile duct is usually quite dilated (about 2 cm in diameter). +32-16). +If the stones were +Figure 32-15. +An endoscopic +sphincterotomy. +A. +The sphinctero- +tome in place. +B. +Completed sphinc- +terotomy. +C. +Endoscopic picture of +completed sphincterotomy. +The T tube +is then removed and a catheter passed through the tract into +the common bile duct. +Under fluoroscopic guidance, the stones +are retrieved with baskets or balloons. +Recurrent stones may be +multiple and large. +Mechanical hindrance +to bile flow facilitates bacterial contamination. +The patient with gall- +stone-induced cholangitis is typically older and female. +The most +common presentation is fever, epigastric or right upper quad- +rant pain, and jaundice. +A +B +Figure 32-16. +Retained common bile duct stones. +The patient pre- +sented 3 weeks after laparoscopic cholecystectomy. +A. +An ultra- +sound shows a normal or mildly dilated common bile duct with a +stone. +B. +However, the presentation may be atypical, with little if any +fever, jaundice, or pain. +Patients with indwelling stents rarely +become jaundiced. +The definitive diagnostic test is ERC. +In cases +in which ERC is not available, PTC is indicated. +These patients may +require intensive care unit monitoring and vasopressor sup- +port. +Most patients will respond to these measures. +However, +the obstructed bile duct must be drained as soon as the patient +has been stabilized. +The selection of procedure should +be based on the level and the nature of the biliary obstruction. +Acute cholangitis is associated with an overall mortality +rate of approximately 5%. +Biliary Pancreatitis. +Gallstones in the common bile duct are +associated with acute pancreatitis. +An ultrasonogram of the biliary +tree in patients with pancreatitis is essential. +Once the pancreatitis has subsided, the gallbladder should be +removed during the same admission. +It affects both sexes equally and occurs +most frequently in the third and fourth decades of life. +Cholan- +giohepatitis is caused by bacterial contamination (commonly +E. +Bacterial enzymes cause deconjuga- +tion of bilirubin, which precipitates as bile sludge. +The sludge +and dead bacterial cell bodies form brown pigment stones. +The +nucleus of the stone may contain an adult Clonorchis worm, +an ovum, or an ascarid. +Recurrence +of symptoms is one of the most characteristic features of the +disease. +MRCP and PTC are the mainstays of biliary +imaging for cholangiohepatitis. +Hepatic abscesses may +be drained percutaneously. +The long-term goal of therapy is to +extract stones and debris and relieve strictures. +Occasionally, resection of +involved areas of the liver may offer the best form of treatment. +32-17). +The +gallbladder can be removed later, if indicated, usually by lapa- +roscopy. +Carl Langenbuch performed the +Figure 32-17. +Percutaneous cholecystostomy. +Open cholecystectomy was a safe and effective treatment for both +acute and chronic cholecystitis. +Today, +laparoscopic cholecystectomy is the treatment of choice for symp- +tomatic gallstones. +Serious complications are rare. +The mortality rate for lapa- +roscopic cholecystectomy is about 0.1%. +The patient should be instructed to empty their bladder before +coming to the operating room. +Urinary catheters are rarely +needed. +Laparoscopic Cholecystectomy. +Initially, a small incision is made in the upper edge of the umbi- +licus. +Three additional ports are +placed under direct vision (Fig. +32-18). +Through the lateral-most port, a grasper is used to grasp +the gallbladder fundus. +The dissection starts at the junction of the gallbladder +and the cystic duct. +A helpful anatomic landmark is the cys- +tic artery lymph node. +A hemoclip is placed on the proximal cystic duct. +The cystic artery is then clipped and divided. +The gallbladder is removed through the umbili- +cal incision. +The fascial defect and skin incision may need to +be enlarged if the stones are large. +Open Cholecystectomy. +The same surgical principles apply +for laparoscopic and open cholecystectomies. +Intraoperative Cholangiogram or Ultrasound. +32-19A). +32-19B). +32-20). +If +needed, a flexible choledochoscope is the next step. +The cystic +duct may have to be dilated to allow its passage. +Occasionally, a choledochotomy, +an incision into the common bile duct itself, is necessary. +The choledochotomy is sutured +Figure 32-18. +Laparoscopic cholecystectomy. +A. +The trocar placement. +B. +C. +A clip is being placed on the cystic duct–gallbladder +junction. +D. +A small opening has been made into the cystic duct, and a cholangiogram catheter is to be inserted. +E. +The cystic duct has been +divided, and the cystic artery is being divided. +F. +The cystic artery can be seen crossing the dissected area upward and to the left. +32-21). +The duodenum is incised trans- +versely. +The sphincter then is incised at the 11 o’clock position +to avoid injury to the pancreatic duct. +The impacted stones are +removed, as are large stones from the duct. +There is no need to +Figure 32-19. +A. +An intraoperative cholangiogram. +The bile ducts are of normal size, with no intraluminal filling defects. +B. +An intraoperative cholangiogram +showing common bile duct stone (arrow). +A small amount of contrast has passed into the duodenum. +AB +fully clear the duct of stones, as they can pass spontaneously +through the cut sphincter. +Acalculous cholecystitis typically develops in critically +ill patients in the intensive care unit. +Laparoscopic bile duct exploration. +I. +Transcystic basket retrieval using fluoroscopy. +A. +The basket has been advanced past +the stone and opened. +B. +The stone has been entrapped in the basket, and together, they are removed from the cystic duct. +II. +Transcystic +choledochoscopy and stone removal. +C. +D. +Entrapped stone. +E. +A view from the choledochoscope. +III. +Choledochotomy and stone removal. +F. +A small incision +is made in the common bile duct. +G. +The common bile duct is cleared of stones. +H. +AB C +D +FG H +E +1329 +Gallbladder and the Extrahepatic Biliary System +CHAPTER 32 +Figure 32-21. +Biliary enteric anastomoses. +There are three types. +I. +Choledochoduodenostomy. +A. +The distal common bile duct is opened +longitudinally, as is the duodenum. +B. +Interrupted sutures are placed between the common bile duct and the duodenum. +C. +Completed cho- +ledochoduodenostomy. +II. +Choledochojejunostomy. +D. +The common bile duct and small bowel are divided. +E. +A Roux-en-Y limb of jejunum +is anastomosed to the choledochus. +III. +Hepaticojejunostomy. +F. +G. +Percutaneous transhepatic stents are placed across hepaticojejunostomy. +32-17). +If the diagnosis +is uncertain, percutaneous cholecystostomy is both diagnostic +and therapeutic. +About 90% of patients will improve with the +percutaneous cholecystostomy. +Choledochal cysts affect females +three to eight times more often than males. +The cause is +unknown. +Classification of choledochal cysts. +Type II, saccular diverticulum of an extrahepatic bile duct. +Rare, <5% of choledochal cysts. +Types IVa and IVb, mul- +tiple cysts, make up 5% to 10% of choledochal cysts. +Type V, intrahepatic biliary cysts, is very rare and makes up 1% of choledochal cysts. +cyst formation. +Choledochal cysts are classified into five types (Fig. +32-22). +Adults commonly present with jaundice or cholangitis. +It is a progressive disease that eventually +results in secondary biliary cirrhosis. +It is associated with ulcerative colitis in about +two thirds of patients. +Patients with sclerosing cholangitis are at risk for +developing cholangiocarcinoma. +Eventually, 10% to 20% of the +patients will develop cancer. +The mean age of presentation is 30 to 45 years, and men +are affected twice as commonly as women. +Symptoms of acute cholangitis are rare, +without preceding biliary tract intervention or surgery. +More +than one half of patients are symptomatic when diagnosed. +Colectomy for the colitis makes no +difference to the course of primary sclerosing cholangitis. +The hepatic +duct bifurcation is often the most severely affected segment. +Sclerosing cholangitis is followed by ERC and liver biopsies to +provide appropriate management. +Biliary strictures can be +dilated and stented either endoscopically or percutaneously. +It offers excellent results, with overall 5-year survival +as high as 85%. +Episodic pain of the biliary +type with abnormal liver function tests is a common presenta- +tion. +However, recurrent jaundice or pancreatitis also may play +a role. +Ampullary manometry and special provocation tests +are available in specialized units. +Less commonly, they may pres- +ent with jaundice without evidence of infection. +Liver function +tests usually show evidence of cholestasis. +MRC will also provide good anatomic informa- +tion about the location and the degree of dilatation. +32-23). +An endoscopic cholangiogram will outline the distal bile duct. +Treatment depends on the location and the cause of the stricture. +INJURY TO THE BILIARY TRACT +Gallbladder +Injuries to the gallbladder are uncommon. +Nonpenetrat- +ing trauma is extremely rare. +These include +acute or chronic inflammation, obesity, anatomic variations, and +bleeding. +An endoscopic retrograde cholangiography show- +ing stricture of the common hepatic duct (arrow). +most common cause of significant biliary injury. +The bile ducts +may be narrow and can be mistaken for the cystic duct. +A number of intra- +operative technical factors have been implicated in biliary +injuries. +An angled scope also will aid in the proper +placement of clips. +Careless use of electrocautery may lead to +thermal injury. +Critical +to the successful use of cholangiography is accurate interpretation +of the imaging. +Diagnosis. +More than half of patients +with biliary injury will present within the first postoperative +month. +32-24). +Bilious drainage through +operatively placed drains or through the wounds is abnormal. +The site of the bile leak can be confirmed noninvasively with +a HIDA scan. +32-23). +Management. +This +injury usually requires a biliary enteric anastomosis with a jeju- +nal loop. +A. +Computed tomographic scan of a patient with bile leak after cholecystectomy. +The short arrows indicate the intraperitoneal +collections. +Both air and bile are seen in the gallbladder bed (long arrow) as well as a surgical clip. +B. +Note the filling of the pancreatic duct. +32-24). +When the acute inflammation has resolved 6 to 8 +weeks later, operative repair is performed. +An anastomosis is performed +between the duct proximal to the injury and a Roux loop +of jejunum. +Outcome. +Approximately two thirds of recurrent +strictures become symptomatic within 2 years after repair. +The +more proximal strictures are associated with a lower success +rate than are distal ones. +Patients with +deteriorating liver function are candidates for liver transplants. +The overall +reported 5-year survival rate is about 5%.79 +Incidence. +Gallbladder cancer is the fifth most common GI +malignancy in Western countries. +The +pathogenesis has not been defined but is probably related to +chronic inflammation. +These gallbladders should be +removed, even if the patients are asymptomatic. +Pathology. +Between 80% and 90% of the gallbladder tumors +are adenocarcinomas. +Squamous cell, adenosquamous, oat +cell, and other anaplastic lesions occur rarely. +The histologic +subtypes of gallbladder adenocarcinomas include papillary, +nodular, and tubular. +The gallbladder +veins drain directly into the adjacent liver, usually segments +Figure 32-25. +Computed tomography scan of a patient with gall- +bladder cancer. +The image shown is at the level of the liver hilum. +The portal vein is bifurcating into the left and right portal branch. +IV and V, where tumor invasion is common (Fig. +32-25). +Lymphatics are +present in the subserosal layer only. +These include abdominal discomfort, right upper quadrant pain, +nausea, and vomiting. +Jaundice, weight loss, anorexia, ascites, +and abdominal mass are less common presenting symptoms. +More than one half of gallbladder cancers are not diagnosed +before surgery. +The sensitivity of +ultrasonography in detecting gallbladder cancer ranges from +70% to 100%. +Treatment. +One half of patients with T2 +tumors are found to have nodal disease on pathologic examina- +tion. +Prognosis. +Most patients with gallbladder cancer have unre- +sectable disease at the time of diagnosis. +25% +to 40%, respectively. +The prognosis for recurrent disease is very poor. +Death +occurs most commonly secondary to biliary sepsis or liver fail- +ure. +The main goal of follow-up is to provide palliative care. +About +two thirds are located at the hepatic duct bifurcation. +Most patients with unresectable disease die +within 1 year of diagnosis.89 +Incidence. +The autopsy incidence of bile duct carcinoma is +about 0.3%. +Etiology. +Features common to most risk factors include biliary +stasis, bile duct stones, and infection. +Over 95% of bile duct cancers are adenocarcino- +mas. +Anatomically, they are divided into distal, proximal, or peri- +hilar tumors. +About two thirds of cholangiocarcinomas are +located in the perihilar location. +32-26). +Type I tumors are confined to the common +Figure 32-26. +Bismuth-Corlette classification of bile duct tumors. +Type IV tumors involve both the right and +left secondary intrahepatic ducts. +Clinical Manifestations and Diagnosis. +Painless jaundice +is the most common presentation. +Pruritus, mild right upper +quadrant pain, anorexia, fatigue, and weight loss also may be +present. +Except for jaundice, physical examination is +usually normal in patients with cholangiocarcinoma. +32-27). +It is usually difficult to visualize the tumor itself +on ultrasound or on a standard CT scan. +Either ultrasound or +spiral CT can be used to determine portal vein patency. +The +biliary anatomy is defined by cholangiography. +PTC defines +BA +Figure 32-27. +A. +The gallbladder is not visualized because +of tumor obstructing its neck. +B. +the proximal extent of the tumor, which is the most important +factor in determining resectability. +ERC is used, particularly in +the evaluation of distal bile duct tumors. +For the evaluation of +vascular involvement, celiac angiography may be necessary. +Surgical excision is the only potentially cura- +tive treatment for cholangiocarcinoma. +They +are treated with pylorus-preserving pancreatoduodenectomy +(Whipple procedure). +However, for distal bile duct tumors, endoscopic place- +ment is often the preferred approach (Fig. +32-28). +Patients with unresectable disease +Figure 32-28. +A through F. +Percutaneous transhepatic cholangiography and placement of a biliary drainage catheter. +External-beam radiation has not been shown to be an +effective treatment for unresected disease. +Most patients with perihilar cholangiocarcinoma +present with advanced, unresectable disease. +Patients with unre- +sectable disease have a median survival between 5 and 8 months. +The most common causes of death are hepatic failure and chol- +angitis. +Therapy for recurrent disease is palliation of symptoms. +1. +Clemente CD/ Gray’s Anatomy. +Philadelphia: Lea & Febiger; +1985:132. +2. +Klein AS, Lillemoe KD, Yeo CJ, et al. +Liver, biliary tract, and +pancreas. +In: O’Leary JP, ed. +Physiologic Basis of Surgery. +Baltimore: Williams & Wilkins; 1996:441. +3. +Scott-Conner CEH, Dawson DL. +Operative Anatomy. +Phila- +delphia: JB Lippincott; 1993:388. +4. +Molmenti EP, Pinto PA, Klein J, et al. +Normal and variant +arterial supply of the liver and gallbladder. +Pediatr Transplant. +2003;7:80. +5. +Chen TH, Shyu JF, Chen CH, et al. +Variations of the cys- +tic artery in Chinese adults. +Surg 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+Coll Surg. +2003;196:385. +77. +Lee CM, Stewart L, Way LW. +Postcholecystectomy abdomi- +nal bile collections. +Arch Surg. +2000;135:538. +78. +Melton GB, Lillemoe KD, Cameron JL, et al. +Ann Surg. +2002;235:888. +79. +Grobmyer SR, Lieberman MD, Daly JM. +Gallbladder cancer +in the twentieth century: single institution’s experience. +World +J Surg. +2004;28:47. +80. +Pandey M, Shukla VK. +Diet and gallbladder cancer: a case- +control study. +Eur J Cancer Prev. +2002;11:365. +81. +Serra I, Calvo A, Baez S, et al. +Risk factors for gallbladder +cancer. +An international collaborative case control study. +Cancer. +1996;78:1515. +82. +Lowenfels AB, Walker AM, Althaus DP, et al. +Gallstone +growth, size, and risk of gallbladder cancer: an interracial +study. +Int J Epidemiol. +1998;18:50. +83. +Csendes A, Burgos AM, Csendes P, et al. +Late follow-up of +polypoid lesions of the gallbladder smaller than 10 mm. +Ann +Surg. +2001;234:657. +84. +Wagholikar G, Behari A, Krishnani N, et al. +Early gallbladder +cancer. +J Am Coll Surg. +2002;194:137. +85. +Kim JH, Kim TK, Eun HW. +J Magn Reson Imaging. +2002;16:676. +86. +Bartlett DL, Fong Y, Fortner JG, et al. +Long-term results after +resection for gallbladder cancer. +Implications for staging and +management. +Ann Surg. +1996;224:639. +87. +Wakai T, Shirai Y, Hatakeyama K. +World J Surg. +2002;26:867. +88. +Noshiro H, Chijiiwa K, Yamaguchi K, et al. +Factors affecting +surgical outcome for gallbladder carcinoma. +Hepatogastroen- +terology. +2003;50:939. +1340 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +89. +Strasberg SM. +Resection of hilar cholangiocarcinoma. +HPB +Surg. +1998;10:415. +90. +Tocchi A, Mazzoni G, Liotta G, et al. +Ann Surg. +2001;234:210. +91. +Ahrendt SA, Rashid A, Chow JT, et al. +J Hepatobiliary Pancreat Surg. +2000;7:426. +92. +Nehls O, Gregor M, Klump B. +Serum and bile markers for +cholangiocarcinoma. +Semin Liver Dis. +2004;24:139. +93. +Siqueira E, Schoen RE, Silverman W, et al. +Detecting cholan- +giocarcinoma in patients with primary sclerosing cholangitis. +Gastrointest Endosc. +2005;56:40. +94. +Ahrendt SA, Nakeeb A, Pitt HA. +Cholangiocarcinoma. +Clin +Liver Dis. +2001;5:191. +95. +Lillemoe KD, Cameron JL. +Surgery for hilar cholangiocarci- +noma: the Johns Hopkins approach. +J Hepatobiliary Pancreat +Surg. +2000;7:115. +96. +Mulholland MW, Yahanda A, Yeo CJ. +Multidisciplinary +management of perihilar bile duct cancer. +J Am Coll Surg. +2001;193:440. +97. +Vollmer CM, Drebin JA, Middleton WD, et al. +Utility of stag- +ing laparoscopy in subsets of peripancreatic and biliary malig- +nancies [Comment]. +Ann Surg. +2002;235:1. +98. +Strasberg SM. +ERCP and surgical intervention in pancreatic +and biliary malignancies. +Gastrointest Endosc. +2002;56:S213. +99. +Ortner ME, Caca K, Berr F, et al. +Gastroenterology. +2003;125:1355. +Pancreas +William E. +Fisher, Dana K. +Andersen, +John A. +Windsor, Ashok K. +Saluja, +and F. +33-1). +In an adult, the pancreas weighs +75 to 100 g and is about 15 to 20 cm long. +The neck of the pancreas lies directly +anterior to the portal vein. +The inferior mesenteric vein often joins the splenic vein near its +junction with the portal vein. +33-2). +The body and tail of the pancreas lie +just anterior to the splenic artery and vein. +These +branches must be divided to perform a spleen-sparing distal +pancreatectomy. +The splenic artery often is tortuous. +The anterior surface of the body of the pancreas is covered by +peritoneum. +“Thin cut” multidetector com. +Aggressive fluid resuscitation and early enteral feeding +both reduce the risk of complications. +6 The nidus of inflammation in chronic pancreatitis due to +any cause is the head of the gland. +Pancreatic anatomy as seen on computed tomography. +IMV = inferior mesenteric vein; SMA = superior mesenteric +artery; SMV = superior mesenteric vein. +aorta at the origin of the superior mesenteric artery. +The neck divides the pancreas into approximately +two equal halves. +Figure 33-2. +Variations in portal venous anatomy. +The pancreas +is formed by the fusion of a ventral and dorsal bud (Fig. +33-3). +The length of the common channel is variable. +33-3). +33-4). +The right gastric artery branches off the gastroduodenal +artery just superior to the duodenum. +A posterior ulcer in the duodenal +bulb can erode into the gastroduodenal artery in this location. +Therefore, it is impossible to resect the head of the +Figure 33-3. +Embryology of pancreas and duct variations. +The duct of Santorini can persist as a blind accessory duct or drain +through the lesser papilla. +Variations in the arterial anatomy occur in one out of +five patients. +The +body and tail of the pancreas are supplied by multiple branches +of the splenic artery. +They are, +from medial to lateral, the dorsal, great, and caudal pancreatic +arteries. +33-5). +The veins are usually +Figure 33-4. +Arterial supply to the pan- +creas. +Multiple arcades in the head and +body of the pancreas provide a rich blood +supply. +Venous drainage from the pancreas. +There is an anterior and posterior venous arcade within the head +of the pancreas. +The superior veins drain directly into the portal +vein just above the neck of the pancreas. +These venous tribu- +taries must be divided during a Whipple procedure. +Venous return from the +body and tail of the pancreas drains into the splenic vein. +The lymphatic drainage from the pancreas is diffuse and +widespread (Fig. +33-6). +Neuroanatomy +The pancreas is innervated by the sympathetic and parasympa- +thetic nervous systems. +These somatic fibers travel superiorly to the celiac ganglia +(Fig. +33-7). +Interruption of these somatic fibers can stop trans- +mission of pain sensation. +Lymphatic supply to the +pancreas. +Pan- +creatic juice is a combination of acinar cell and duct cell secre- +tions. +The acinar cells are pyramid- +shaped, with their apices facing the lumen of the acinus. +33-8). +The proteolytic enzymes are secreted as proenzymes that +require activation. +Trypsin, in turn, activates the +other proteolytic enzymes. +Innervation of the pancreas. +Acinar cell. +(Reproduced with permission from Bloom W, +Fawcett DW: A Textbook of Histology, 10th ed. +This accounts for about two-thirds of cases of hereditary pan- +creatitis. +Chymotrypsinogen is activated to form chymotrypsin. +Pancreatic lipase hydrolyzes triglycerides to 2-monoglyceride +and fatty acid. +Pancreatic lipase is secreted in an active form. +Phospholipase A2 is secreted by the pancreas as a proenzyme +that becomes activated by trypsin. +About +40 acinar cells are arranged into a spherical unit called an aci- +nus. +These +cells contain the enzyme carbonic anhydrase, which is needed +for bicarbonate secretion. +33-9). +CCK also stimulates bicarbon- +ate secretion, but to a much lesser extent than secretin. +CCK +potentiates secretin-stimulated bicarbonate secretion. +The pancreatic juice then travels into small +intercalated ducts. +Several small intercalated ducts join to form an +interlobular duct. +Endocrine Pancreas +There are nearly 1 million islets of Langerhans in the normal +adult pancreas. +They vary greatly in size from 40 to 900 μm. +1349 +P +ANCREAS +CHAPTER 33 +Insulin is the best-studied pancreatic hormone. +Figure 33-9. +Composition of pancreatic exocrine secretions. +In contrast, sodium and potassium concentrations are +independent of the secretory rate. +Acta Phys Scandinav. +There are two phases of insulin +secretion. +In the first phase, stored insulin is released. +This phase +lasts about 5 minutes after a glucose challenge. +The diagnosis of diabetes is made +by using oral and intravenous (IV) glucose tolerance tests. +As a result, oral glucose is a more vigorous stimulus to +insulin secretion than IV glucose. +Forty g/m2or 75 g of glucose is given orally +over 10 minutes. +Blood samples are taken every 30 minutes for +2 hours. +There is a considerable +amount of functional reserve in insulin secretory capacity. +Glucagon release is stimulated by hypoglycemia, and by +the amino acids arginine and alanine. +The major stimulant is probably intraluminal fat. +Acetylcholine from the +cholinergic neurons inhibits somatostatin release. +[Reproduced with permission from Cui YF & Andersen DK. +Vagal stimulation of the pancreas is +the most important regulator of PP secretion. +In fact, vagotomy +eliminates the rise in PP levels usually seen after a meal. +The other +cell types are located predominantly in the periphery. +However, individual islet cells can secrete multiple +hormones. +There is diversity +among the islets depending on their location within the pancreas. +Its hall- +mark is acute pancreatic inflammation associated with little or +no fibrosis. +Philadelphia: Saunders, 2000, p 1117. +Copyright Elsevier. +consumed (typically 100 to 150 grams per day) and the pattern of +drinking. +There are several mechanisms by which +ethanol causes acute pancreatitis. +Poisoning with antiacetylcholin- +esterase insecticides has a similar effect. +33-10). +Precipitating Initial Events +Acinar Cell Events. +Pathophysiology of acute pancreatitis. +This initiates the apoptotic cascade and +results in the apoptotic death of the acinar cells (Fig. +Fluid may collect in +and around the pancreas. +33-12). +Schematic representation of the +acinar cell events in acute pancreatitis. +Increased cytosolic calcium is +required for colocalization. +The NFκB- dependent inflammatory pathway is one such key +pathway. +Pancreas surrounded +by fluid, inflammation, and possible peripancreatic fat necrosis. +Commentary. +Gut. +2013;62:4. +With permission from +the BMJ Publishing Group. +early, or later secondary to the development of infected local +complications. +The +three organ systems most frequently involved are cardiovascu- +lar, respiratory, and renal. +Management of the Patient +General Considerations. +The management of acute pancre- +atitis covers a wide spectrum of severity. +Patients with sus- +pected acute pancreatitis should be admitted to hospital. +The risk of mortality reflects this spectrum of severity. +Am J Gastroenterol 77:633, 1982, +and From Ranson JH, Rifkind KM, Roses DF, et al. +Prognostic signs +and the role of operative management in acute pancreatitis. +Surg Gyne- +col Obstet 139:69, 1974. +Epi = epineptvine. +Norepi = norepinephrine. +∗Adrenergic agents administered for at least 1 h (doses given in μg/kg per min). +A score of 2 or more in any two systems indicates the presence of multiple organ failure. +it is important to measure either the pancreatic isoenzyme of +amylase or lipase. +For these reasons, it is recommended that amylase +concentrations also be measured in the urine. +Hemoconcentration then +results in an elevated hematocrit. +However, there also may be +bleeding into the retroperitoneum or the peritoneal cavity. +There is a lack of high quality evidence +to guide the choice of analgesic. +Morphine is to be +avoided, due to its potential to cause sphincter of Oddi spasm. +Both use clinical and biochemical +parameters scored over the first 48 hours of admission. +It can also be used in retrospect for +audit purposes. +Gallstones should be inves- +tigated by ultrasonography. +Figure 33-13. +Corresponding CT (A) and MR (B) images of a patient with a symptomatic pseudocyst. +(Reproduced with permission from Bollen TL et al. +Imaging of acute pancreatitis: Update +of the revised Atlanta Classification. +Radiol Clin North Am. +2012;50:429. +MR is +superior to CT scanning in detecting any solid content within +collections (Fig. +33-13). +The decisions regarding how and when +Figure 33-14. +Operative view of infected acute pancreatitis. +to intervene are often difficult. +33-14). +33-15). +Two minimally invasive interventions for local complications of acute pancreatitis: A. +video-assisted retroperitoneal debride- +ment and B. +endoscopic transgastric necrosectomy 76. +(Reproduced with permission from Bakker OJ et al. +JAMA. +2012;307(10):1053. +Copyright © 2012 American Medical +Association. +33-15). +When symptoms of pain or inability to eat persist +or infection occurs, intervention is required. +The severity of organ failure can be scored (Table 33-6). +1. +Local + A. +Pancreatic phlegmon + B. +Pancreatic abscess + C. +Pancreatic pseudocyst + D. +Pancreatic ascites + E. +Systemic + A. +Pulmonary + 1. +Pneumonia, atelectasis + 2. +Acute respiratory distress syndrome + 3. +Pleural effusion + B. +Cardiovascular + 1. +Hypotension + 2. +Hypovolemia + 3. +Sudden death + 4. +Nonspecific ST-T wave changes + 5. +Pericardial effusion + C. +Hematologic + 1. +Hemoconcentration + 2. +Disseminated intravascular coagulopathy + D. +GI hemorrhage + 1. +Peptic ulcer + 2. +Erosive gastritis + 3. +Portal vein or splenic vein thrombosis with varices + E. +Renal + 1. +Oliguria + 2. +Azotemia + 3. +Renal artery/vein thrombosis + F. +Metabolic + 1. +Hyperglycemia + 2. +Hypocalcemia + 3. +Hypertriglyceridemia + 4. +Encephalopathy + 5. +Sudden blindness (Purtscher’s retinopathy) + G. +Central nervous system + 1. +Psychosis + 2. +Fat emboli + 3. +Alcohol withdrawal syndrome + H. +Fat necrosis + 1. +Intra-abdominal saponification + 2. +New York: McGraw- +Hill, 1994, p 1524. +Copyright © The McGraw-Hill Companies, Inc. +hepatis. +The incidence is equal in both sexes. +Subse- +quently, the region was sequenced and revealed eight trypsino- +gen genes. +Men, with only one X chromo- +some, have no protection if they inherit a CLDN2 mutation. +33-16). +33-17). +33-18). +Schematic model of genetic causes of chronic pan- +creatitis. +Cationic and +anionic trypsinogen are normally active in the duodenum by entero- +kinase (EK). +(Adapted with permission from Macmillan Publishers, Ltd. +Nat Genet. +2012;44:1349. +Etiologies of chronic pancreatitis. +(Reproduced +with permission from Whitcomb DC. +Acad Med. +“Multiple hit” theory of the etiology of chronic +pancreatitis. +33-19). +ETOH = +ethyl alcohol. +Multiple classification +systems have been proposed. +From Singer et al.116 +1366 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Wirsung’s duct (Fig. +33-20). +Increased levels of +serum β-globulin or immunoglobulin G4 are also present. +Pancreas divisum. +(Reproduced with permission of Wiley-Blackwell. +A variable percentage of +SPINK1 and CFTR mutations have been described in various +studies. +Pathology +Histology. +33-21). +33-22). +Histology of early chronic pancreatitis. +(Courtesy of Rhonda +Yantiss, Weill Cornell Medical College.) +Figure 33-22. +Gross appearance of chronic pancreatitis. +(Courtesy of Rhonda Yantiss, Weill Cornell Medical College.) +areas of necrosis. +33-23). +33-19. +Stone Formation. +The fibrillar center of most stones contains no +calcium but rather a mixture of other metals. +Histology of severe chronic pancreatitis. +OPD Controls +Figure 33-24. +(Reproduced with +permission of Wiley-Blackwell. +33-24). +Duct Distortion. +But some patients with complete duct obstruction have +prolonged periods of painlessness. +Radiology. +33-25). +EUS has heavily impacted the evaluation and manage- +ment of patients with chronic pancreatitis. +33-26). +33-27). +Source: Reproduced with permission from Wiley-Blackwell. +33-28). +Sonography in chronic pancreatitis. +(Reproduced with permission from Bolondi +et al. +Radiol Clin North Am. +27: 815, 1989.) +Figure 33-26. +Endoscopic ultrasound of chronic pancreatitis. +Computed tomographic imaging of chronic pancre- +atitis. +(Reproduced with permission +from Forsmark CE:201 Management of pancreatitis. +Gastroenterol. +2013;144:1282. +© 2013 AGA Institute. +Published by Elsevier, Inc. +33-29). +Severe pancre- +atitis and deaths have occurred after ERCP. +Figure 33-28. +Pancreatic duct stenting. +Pancreatic duct stents are left in place for only a limited time to +avoid further inflammation. +Figure 33-30. +Pain location in chronic pancreatitis. +(Reproduced +with permission from Murayama KM, Jochl RJ. +Pain is the most common +symptom of chronic pancreatitis. +33-30). +The pain is typically steady +and boring, but not colicky. +Unlike ureteral stone pain or biliary +colic, the pain causes the patient to be still. +Nausea or vomit- +ing may accompany the pain, but anorexia is the most common +associated symptom. +Pain from chronic pancreatitis has been ascribed to three +possible etiologies. +33-31). +80 +75 +70 +65 +60 MIF +Pe +r +cent S +ympt +om R +elief (%) +INF SEF +Figure 33-31. +P<0.05 for MIF vs. +SEF by chi- +square analysis. +J Gastrointest Surg. +2013;17:682. +Relationship of lipase output to fat malabsorption. +(Data from DiMagno +et al.151) +Malabsorption and Weight Loss. +33-32). +In severe steatorrhea, an orange, +oily stool is often reported. +As exocrine deficiency increases, +symptoms of steatorrhea are often accompanied by weight loss. +As a result, +many patients with severe chronic pancreatitis are below ideal +body weight. +With progressive destruction of the gland, +endocrine insufficiency commonly occurs. +33-33). +This form of +diabetes is referred to as brittle diabetes and requires special +attention. +Laboratory Studies. +Copyright Elsevier.) +Table 33-14 +Tests for chronic pancreatitis +I. +Measurement of pancreatic products in blood + A. +Enzymes + B. +Pancreatic polypeptide +II. +Measurement of pancreatic exocrine secretion + A. +Direct measurements + 1. +Enzymes + 2. +Bicarbonate + B. +Indirect measurement + 1. +Bentiromide test + 2. +Schilling test + 3. +Fecal fat, chymotrypsin, or elastase concentration + 4. +[14C]-olein absorption +III. +Imaging techniques + A. +Plain film radiography of abdomen + B. +Ultrasonography + C. +Computed tomography + D. +Endoscopic retrograde cholangiopancreatography + E. +Magnetic resonance cholangiopancreatography + F. +33-34). +Pancreatic polypeptide (PP) response to a test meal. +A test meal was adminis- +tered at 0 minutes. +Means ± standard error of the mean are shown. +Pancrea- +tography in chronic pancreatitis: International definitions. +Gut 25:1107, +1984. +With permission from the BMJ Publishing Group. +cystic disease is present, but is not accurate in the absence of +these findings. +Continued +alcohol abuse has a similar effect on the response to surgical +treatment (Fig. +33-36). +Effect of alcohol use on survival +after surgical procedures. +Cumulative risk of pancreatic cancer in patients +with chronic pancreatitis. +The number of patients evaluated at +different time intervals is shown in parentheses. +(Reproduced with +permission from Lowenfels AB et al. +Copyright © 1993 Massachusetts +Medical Society. +All rights reserved.177) +and elsewhere. +Complications +Pseudocyst. +This +is referred to as an acute pseudocyst. +Pseudocysts are multiple in 17% of patients,182 or may +be multilobulated. +33-37). +Pseudocysts may become secondarily infected, in which +case they become abscesses. +33-38). +They also can perforate and +cause peritonitis or intraperitoneal bleeding.185 +Figure 33-37. +Extensive pseudocyst disease. +Figure 33-38. +Pseudoaneurysm of the gastroduodenal artery. +(Reproduced with permission from Balthazar EJ: CT +diagnosis and staging of acute pancreatitis. +Radiol Clin North Am. +1989;27:19. +Pseudocysts usually cause symptoms of pain, fullness, +or early satiety. +The timing and method of treatment requires careful con- +sideration. +Surgical options include a cystogastrostomy (Fig. +33-39), a +Roux-en-Y cystojejunostomy, or a cystoduodenostomy. +Cystogastrostomy can be +performed endoscopically187 (Fig. +Cystogastrostomy drainage of a retrogastric pancre- +atic pseudocyst. +Suture +reinforcement of the communication is performed to avoid the com- +plication of bleeding. +Technique of endoluminal cystogastrostomy. +A. +Endoscopic ultrasound (EUS)-guided transgastric puncture of +pancreatic pseudocyst. +B. +Transgastric stents placed across fused +posterior wall of stomach and anterior wall of pseudocyst. +(Repro- +duced with permission from Chauhan SS, Forsmark CE. +Evidence- +based treatment of pancreatic pseudocysts. +Gastroenterol 2013; +145: 512 Copyright Elsevier.) +cystoenterostomy. +Pancreatic Ascites. +Transpapillary drainage of a pancreatic pseudocyst. +A. +B. +Placement of a stent over the wire into the pseudocyst with +transpapillary drainage. +Pain +and nausea are rarely present. +33-42). +Serum amylase may also +be elevated, presumably from reabsorption across the parietal +membrane. +Serum albumin may be low, and patients may have +coexisting liver disease. +Paracentesis is therefore critical to dif- +ferentiate pancreatic from hepatic ascites. +33-43). +Pancreatic-Enteric Fistula. +The most common site of communication is the +transverse colon or splenic flexure. +The fistula usually presents +with evidence of GI or colonic bleeding and sepsis. +When the fis- +tula involves the colon, operative correction is usually required.196 +Figure 33-42. +Pancreatic ascites. +(Reproduced with permission from Cameron JL, +Cameron AM (eds): Current Surgical Therapy, 11th ed. +Philadelphia: +Elsevier, 2014, p 458. +Copyright Elsevier.) +1379 +P +ANCREAS +CHAPTER 33 +Head-of-Pancreas Mass. +Splenic and Portal Vein Thrombosis. +Vascular complica- +tions of chronic pancreatitis are fortunately infrequent, because +Figure 33-43. +Internal drainage for leaking pancreatic duct. +From +Beger et al.197 +they are difficult to treat successfully. +Although bleeding complications +are infrequent, the mortality risk of bleeding is >20%. +Treatment +Medical Therapy. +Analgesia. +It is essential for patients to abstain from alcohol. +Enzyme Therapy. +If pain relief is +achieved, therapy is continued. +33-44). +Antisecretory Therapy. +Neurolytic Therapy. +Endoscopic Management. +An average meal requires roughly 90,000 +USP units of lipase for fat digestion. +(Reproduced with permission from Forsmark CE. +Management of chronic pancreatitis. +Gastroenterol 2013; 144: 1282. +© 2013 +AGA Institute. +Published by Elsevier, Inc. +Management algorithm for chronic pancreatitis. +(Reproduced with permission from Forsmark CE: Management of pancreatitis. +Gastroenterol. +2013;144:1282. +© 2013 AGA Institute. +Published +by Elsevier, Inc. +33-45). +Extracorporeal shock wave lithotripsy treatment of +pancreatic duct stones. +The choice of resection vs. +33-47). +33-48). +Head-of-pancreas mass after Puestow procedure. +33-49). +33-50). +33-51). +Schematic diagram of the +ampullary, biliary, and pancreatic duct sphinc- +ters. +Operative sphincteroplasty of the biliary and pancre- +atic duct. +(Data from Moody et al.223) +Figure 33-49. +Duval’s caudal pancreaticojejunostomy. +Norwalk: Appleton-Century-Crofts, 1983, p 289. +Copyright © The McGraw-Hill Companies, Inc.) +Figure 33-50. +Puestow and Gillesby’s longitudinal pancreaticoje- +junostomy. +Norwalk: Appleton-Century- +Crofts, 1983, p 290. +33-52). +Advocates of the +Figure 33-51. +Longitudinal dochotomy in obstructing calcific +pancreatitis. +(Data from Partington et al.228) +A +B +Splenic artery +Figure 33-52. +Distal (spleen-sparing) pancreatectomy. +In the presence of minimal inflammation, a spleen-sparing +version can be performed, as shown here. +33-56). +33-57). +33-59). +Figure 33-53. +The pylorus-sparing version of the procedure is used most commonly. +33-60). +33-61). +The duodenum-preserving pancreatic head resec- +tion described by Beger and colleagues. +A. +B. +Intraoperative view of the Beger procedure. +The +gastroduodenal artery is encircled by a vessel loop. +A rim of well-vascularized pancreatic +tissue remains in the duodenal C-loop. +Frey procedure. +Reconstruction is performed with a side-to-side Roux-en-Y pancreaticojeju- +nostomy. +(Reproduced with permission from Bell.188) +Figure 33-57. +Operative view of excavated head of the pancreas +during the Frey procedure. +J Gastrointest Surg. +9:400, 2005.With kind permission +from Springer Science + Business Media.) +Figure 33-58. +Complete excavation of the pancreatic head and +distal pancreatic dochotomy. +Reconstruction is performed with a single side-to-side +Roux-en-Y pancreaticojejunostomy. +Arch Surg. +139:375, 2004. +Copyright © 2004 American +Medical Association. +All rights reserved.) +1389 +P +ANCREAS +CHAPTER 33 +Figure 33-59. +New York: Saunders, 2007, p 1310. +Excavation of pancreatic head without longitudinal +pancreaticojejunostomy. +(Data from Ho HS, Frey CF.259) +Figure 33-61. +Dig Surg. +18:21, 2001. +Copyright © 2001, Karger Publishers.) +chronic pancreatitis. +Pain control was similar between the two procedures. +The degree of pain relief was equal +over a 1- to 3-year follow-up. +hybrid or +resectional procedures for patients with persistent symptoms. +The MEN1 syndrome involves pituitary tumors, +parathyroid hyperplasia, and pancreatic neoplasms. +Unresectable disease in the liver is +often addressed with chemoembolization. +Neuroendocrine tumors of the +1391 +P +ANCREAS +CHAPTER 33 +pancreas often enhance with contrast. +33-62). +Routine laboratory studies will uncover a low blood sugar, +the cause of all of these symptoms. +Serum insulin levels are +elevated. +insulin production leads to excess C-peptide. +However, this can be dangerous and +must be done with close supervision. +Insulinomas are usually localized with CT scanning and +EUS. +They are typically cured by simple enucleation. +Approximately 90% of insulinomas are sporadic, and 10% +are associated with the MEN1 syndrome. +However, in the era of effective antacid therapy, the + presentation can be less dramatic. +At the time of diagnosis, 21% of patients with gas- +trinoma have diarrhea . +The diagnosis of ZES is made by measuring the serum +gastrin level. +It is important that patients stop taking proton +pump inhibitors for this test. +In most patients with gastrinomas, +the level is >1000 pg/mL. +Gastrin levels can be elevated under- +conditions other than ZES. +33-63). +However, because gastrinomas +can be found almost anywhere, whole-body imaging is required. +The test of choice is SSTR (octreotide) scintigraphy in combi- +nation with CT. +EUS is another modality that assists in the +preoperative localization of gastrinomas. +A combination of +octreotide scan and EUS detects >90% of gastrinomas. +Only one fourth of gastrinomas occur in association with the +MEN1 syndrome. +Multiple tumors are more common in patients with +Figure 33-63. +Passaro’s triangle. +Passaro. +Am J Surg. +1984;147:25. +Copyright Elsevier.) +MEN1 syndrome. +Aggressive surgical treatment is justified +in patients with sporadic gastrinomas. +All lymph nodes in +Passaro’s triangle are excised for pathologic analysis. +Pancreatic resection is justified +for solitary gastrinomas with no metastases. +This may reduce the +amount of expensive proton pump inhibitors required. +In gas- +trinomas, liver metastases decrease survival rates, but lymph +node metastases do not. +Large amounts of potassium are lost in the stool. +The diabetes usually is mild. +Patients +also complain of an enlarged, sensitive tongue. +The diagnosis is +confirmed by measuring serum glucagon levels, which are usu- +ally >500 pg/mL. +Glucagon is a catabolic hormone, and most +patients present with malnutrition. +The rash associated with glu- +cagonoma is thought to be caused by low levels of amino acids. +Again, debulking operations are +recommended in good operative candidates to relieve symptoms. +The tumor frequently +enhances with arterial contrast.(Fig. +33-64) Sometimes a cystic +component is seen due to central necrosis. +Octreoscan (soma- +tostatin receptor scintigraphy) can be helpful to stage the dis- +ease. +Surgical resection is always recommended in fit patients +in the absence of metastatic disease. +Neoplasms of the Exocrine Pancreas +Epidemiology and Risk Factors. +However, epidemiologic studies link- +ing various environmental and host factors provide some clues. +Pancreatic cancer is more common in the elderly with most +patients being >60 years old. +Pancreatic cancer is more common +in African Americans and slightly more common in men than +women. +Another risk +factor that is consistently linked to pancreatic cancer is cigarette +smoking. +1394 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Figure 33-64. +Pancreatic neuroendocrine tumor (PNET) demonstrating enhancement during arterial phase of CT scan. +Diabetes has been known to be associated with pancreatic +cancer for many years. +The mechanisms involved in carcino- +genesis in patients with pre-existing pancreatitis are unknown. +Genetics of Pancreatic Cancer. +Pathology. +33-65). +Three stages of pancreatic intraepithelial neoplasia +have been defined. +Adeno- +squamous carcinoma is a variant that has both glandular and +squamous differentiation. +Diagnosis and Staging. +The +tumor-node-metastasis (TNM) staging of pancreatic cancer is +shown in Table 33-21 . +T1 lesions are ≤2 cm in diameter and are limited to the pan- +creas. +T2 lesions also are limited to the pancreas, but are >2 cm. +T4 lesions involve the +celiac axis or superior mesenteric artery and are not resectable. +T1 +and T2 tumors with no lymph node involvement are considered +stage I disease (stage IA and IB). +More extensive invasion, such +as that associated with T3 tumors, indicates stage IIA disease. +Any lymph node involvement indicates stage IIB disease. +Pancreatic intraepithelial neoplasia (PanIN). +Am J Surg Pathol. +Ultimately, the majority of patients pres- +ent with pain and jaundice. +from choledocholithiasis), this aphorism is not accurate. +Serum levels are elevated in about 75% of patients +with pancreatic cancer. +If bile duct +dilation is not seen, hepatocellular disease is likely. +33-66). +Computed tomography scan demonstrating resectable pancreatic cancer. +SMA = superior mesenteric artery. +ascites, and distant metastases (e.g., liver). +33-67). +A +general exploration of the peritoneal surfaces is carried out. +The +ligament of Treitz and the base of the transverse mesocolon are +examined for tumor. +The gastrocolic ligament is incised, and the +lesser sac is examined. +As the quality of CT scanning has improved, the value +Figure 33-67. +Liver metastases identified at diagnostic laparoscopy. +1399 +P +ANCREAS +CHAPTER 33 +of routine diagnostic laparoscopy has decreased. +Biliary obstruction can be relieved with an endoscopic +approach in almost all cases. +An +algorithm for the diagnosis, staging, and treatment of pancreatic +cancer is shown in Fig. +33-68. +Palliative Surgery and Endoscopy. +The mainstay of pain control is oral +narcotics. +Sustained-release preparations of morphine sulfate +are frequently used. +If an operative bypass is performed, choledochoje- +junostomy is the preferred approach. +Diagnostic and treatment algorithm for pancreatic cancer. +1400 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Figure 33-69. +Biliary-enteric bypass to palliate unresectable pan- +creatic cancer. +Philadelphia: +Lippincott-Raven, 1996, p 1074.) +Figure 33-70. +Expandable metallic +biliary stent. +33-69). +33-70). +Endoscopic stents are definitely not as durable as +a surgical bypass. +In such a patient, it is better to place an endoscopic stent. +Palliative Chemotherapy and Radiation. +Gemcitabine (Gemzar®) was approved by the U.S. +Food and +Drug Administration (FDA) for use in pancreatic cancer in +1996. +Ablation for Locally Advanced Unresectable Disease. +Persistent arterial vascular encasement after neoadjuvant ther- +apy contraindicates resection. +Randomized prospective trials are needed. +Surgical Resection: Pancreaticoduodenectomy. +Tumor seeding along the subcutaneous tract of the needle is +uncommon. +Likewise, FNA under EUS guidance is safe and +well tolerated. +The initial portion of the procedure is an assess- +ment of resectability. +The liver and visceral and parietal peritoneal +surfaces are thoroughly assessed. +A Kocher maneuver is performed by dissecting +behind the head of the pancreas. +The gastroepiploic vein and +artery are ligated to prevent any traction injury. +Mesenteric vascular involvement is best determined by a +high quality preoperative CT scan. +The porta hepatis is examined. +The hepatic artery is dis- +sected and traced toward the porta hepatis. +The gastroduodenal branch of the hepatic +artery is identified. +Dissection is performed only on the +anterior surface of the vein. +If there is no tumor involvement, the +neck of the pancreas will separate from the vein easily. +A large, +blunt-tipped clamp is a safe instrument to use for this dissection. +The common hepatic duct is circumferentially dissected. +The pancreatic neck is divided anterior to +the portal vein (Fig. +33-71). +33-72). +Division of the pancreatic neck. +The pancreatic +neck is separated from the anterior surface of the portal vein and +then divided. +If there is no tumor involvement, the neck of the pan- +creas will separate from the vein easily. +A large, blunt-tipped clamp +is a safe instrument to use for this dissection. +Philadelphia: Lippincott-Raven, 1996, p 1054.) +Figure 33-72. +Dissection of the pancreatic head and uncinate pro- +cess. +There are various techniques for the pancreatic anastomoses, and +all have equivalent outcomes. +This is usually performed in an end-to-side fashion with one +layer of interrupted sutures. +Pancreaticoduodenectomy with Vascular Resection. +Reconstruction can often be accomplished with a primary +anastomosis of the vein. +This approach +is associated with decreased blood loss and quicker recovery. +1403 +P +ANCREAS +CHAPTER 33 +Variations and Controversies. +Techniques for pancreaticojejunostomy. +A to D. +Duct-to-mucosa, end-to-side E. +Intraoperative photographs of end-to-side +pancreaticojejunostomy. +F to J. +End-to-end invagination. +K to O. +End-to-side invagination. +33-73). +Pancreaticogastrostomy has also been +investigated. +Therefore, the choice of techniques +depends more on the surgeon’s personal experience. +( +Continued +) +1405 +P +ANCREAS +CHAPTER 33 +Figure 33-73. +(Continued) +the pancreaticojejunostomy cannot be avoided in one out of +10 patients. +Impending catastrophe is often preceded by +a small herald bleed from the drain site. +Open packing may be necessary to control diffuse necro- +sis and infection. +Jejunostomy tubes are certainly not benign and can result +in leaks and intestinal obstruction. +Total pancreatec- +tomy has also been considered in the past. +Pancreatic cancer can recur locally after pancreaticoduo- +denectomy. +IORT may improve local con- +trol and palliate symptoms after pancreaticoduodenectomy. +In the +acute phase, IV erythromycin may help but the problem usually +improves with time. +Many technical modifications to the classic pancreatico- +duodenectomy have been described. +the invagination +techniques. +Intraoperative hemorrhage typically occurs during the +dissection of the portal vein. +Sometimes, +the vein can be sutured closed with minimal narrowing. +Other +times, a segmental resection and interposition graft (internal +jugular vein) may be needed. +Uncom- +monly, a stress ulcer, or later, a marginal ulcer, can result in GI +hemorrhage. +Outcome and Value of Pancreaticoduodenectomy for +Cancer. +The tumor tends to recur locally +with retroperitoneal and regional lymphatic disease. +In addition, +most patients also develop hematogenous metastases, usually +in the liver. +Malignant ascites, peritoneal implants, and malig- +nant pleural effusions are all common. +Median survival after +pancreaticoduodenectomy is about 22 months. +Adjuvant Chemotherapy and Radiation. +Neoadjuvant Treatment. +For example, it avoids the risk that adjuvant +treatment is delayed by complications of surgery. +It +may even decrease the incidence of pancreatic fistula. +349 +Postoperative Surveillance. +Recurrence after successful +resection usually manifests as hepatic metastases. +Future Therapy. +Clinical trials +for pancreatic cancer are ongoing and offer hope for more mean- +ingful treatment. +Ampullary and Periampullary Cancer. +Ampullary can- +cers need to be distinguished from periampullary cancers. +The +ampulla is the junction of the biliary and pancreatic ducts within +the duodenum. +The term ampullary cancer is more specific and is +reserved for tumors that arise at the ampulla. +Management of Periampullary Adenomas. +Benign tumors +such as ampullary adenomas can also originate at the ampulla. +However, benign villous adenomas of the ampullary region can +be excised locally. +EUS may help to accurately determine if +there is invasion into the duodenal wall. +In some centers, small periampullary adenomas +can also be removed endoscopically. +Cystic Neoplasms of the Pancreas. +33-74). +Mucinous cystic neoplasm in tail of pancreas. +1409 +P +ANCREAS +CHAPTER 33 +CT scanning has increased. +The dilemma for +the surgeon is an accurate assessment of the risk-benefit ratio +of resection vs. +observation of these lesions in individual +patients. +33-75). +Pseudocysts. +Although not usually necessary, analysis of +pseudocyst fluid would reveal a high amylase content. +Cystadenoma. +Serous cystadenomas are essentially con- +sidered benign tumors without malignant potential. +Serous +cystadenocarcinoma has been reported very rarely (<1%). +The average rate of growth is about +0.45 cm/year. +About 50% of cystadenomas are asymptom- +atic and detected as an incidental finding. +Algorithm for management of pancreatic cystic neoplasms. +1410 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +moderate weight loss. +33-76). +For symptomatic patients with serous +cystadenoma, surgical resection is indicated. +For lesions in the +tail, splenectomy is not necessary, given the benign nature of +the tumor. +If a conservative management is adopted, it is important to be +sure of the diagnosis. +Mucinous Cystadenoma and Cystadenocarcinoma. +33-74). +There may be nodules or calcifications +within the wall of the cyst. +The cysts are lined by tall columnar +epithelium that fills the cyst with viscous mucin. +Elevated +CEA levels in the fluid (>200 ng/mL) may suggest malig- +nant transformation. +Resection is the +treatment of choice for most mucin-producing cystic tumors. +Malignancy cannot be ruled out without removal and extensive +sampling of the tumor. +Malignancy has been reported in 6% +to 36% of MCNs. +Current thinking is that all of these tumors +will eventually evolve into cancer if left untreated. +Malignant +transformation is more common with larger tumors, and older +Figure 33-76. +Table 33-23. +World Health Organization classification of primary tu- +mors of the exocrine pancreas +A. +Benign + 1. +Serous cystadenoma (16%) + 2. +Mucinous cystadenoma (45%) + 3. +Intraductal papillary-mucinous adenoma (32%) + 4. +Mature cystic teratoma +B. +Borderline + 1. +Mucinous cystic tumor with moderate dysplasia + 2. +Intraductal papillary mucinous tumor with moderate +dysplasia + 3. +Solid pseudopapillary tumor +C. +Malignant + 1. +Ductal adenocarcinoma + 2. +Serous/mucinous cystadenocarcinoma (29%) + 3. +There- +fore, a laparoscopic approach may not be appropriate for larger +lesions. +Completely resected MCNs without atypia are usually +cured especially if small (<3 cm). +Intraductal Papillary Mucinous Neoplasm. +(Fig. +33-77). +33-78). +33-79). +Intraductal papillary mucinous neoplasm histology. +(From Asiyanbola B, Andersen +DK: IPMN. +Editorial Update. +Access Surgery, McGraw-Hill, 2008, +with permission. +Copyright © The McGraw-Hill Companies, Inc.) +be resected in fit surgical candidates. +Branch- +duct IPMNs >3cm should be resected353. +Mucus can dilate the duct proximal and distal to the lesion. +33-78). +Survival of patients with IPMN, even when malignant and +invasive, can be quite good. +As with MCN, patients with bor- +derline tumors or carcinoma in situ are usually cured. +Solid-Pseudopapillary Tumor. +Solid-pseudopapillary tumors +are rare and typically occur in young women. +They are typi- +cally well circumscribed on CT (Fig. +33-80). +Most are cured by resection but liver +and peritoneal metastasis has been reported. +Other Cystic Neoplasms. +It is more common, 5% to 10%, for neuroendocrine tumors of +the pancreas to contain cysts. +These cysts are filled with sero- +sanguineous fluid rather than necrotic debris. +Lymphoepithe- +lial cysts of the pancreas usually occur in men in their fifth to +sixth decade. +These benign lesions may be unilocular or mul- +tilocular and vary widely in size. +Intraductal papillary mucinous neoplasm (IPMN). +A. +Examples of “fish-eye deformity” of IPMN. +Mucin is seen extruding +from the ampulla. +B. +Intraoperative +pancreatic ductoscopy to assess the pancreatic tail (right).C. +Views of pancreatic duct during ductoscopy; normal (left) and IPMN (right). +1413 +P +ANCREAS +CHAPTER 33 +material if there is increased keratin formation. +There may 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fistula after pancreati- +coduodenectomy? +Results of a prospective randomized trial. +J Gastrointest Surg. +2004;8:766-772, discussion 772-774. +329. +Nakao A, Fujii T, Sugimoto H, et al. +Is pancreaticogastros- +tomy safer than pancreaticojejunostomy? +J Hepatobiliary +Pancreat Surg. +2006;13:202-206. +330. +Payne RF, Pain JA. +Duct-to-mucosa pancreaticogastrostomy +is a safe anastomosis following pancreaticoduodenectomy. +Br +J Surg. +2006;93:73-77. +331. +Peng S, Mou Y, Cai X, et al. +Binding pancreaticojejunos- +tomy is a new technique to minimize leakage. +Am J Surg. +2002;183:283-285. +332. +Rosso E, Bachellier P, Oussoultzoglou E, et al. +Toward zero +pancreatic fistula after pancreaticoduodenectomy with pancre- +aticogastrostomy. +Am J Surg. +2006;191:726-732, discussion +733-734. +333. +Sutton CD, Garcea G, White SA, et al. +J Gastrointest Surg. +2004;8:701-705. +334. +Suzuki Y, Kuroda Y, Morita A, et al. +Fibrin glue sealing for +the prevention of pancreatic fistulas 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pancreaticoduodenectomy. +World J Gastro- +enterol. +2005;11:2456-2461. +342. +Di Carlo V, Chiesa R, Pontiroli AE, et al. +Pancreatoduodenec- +tomy with occlusion of the residual stump by Neoprene injec- +tion. +World J Surg. +1989;13:105-110, discussion 110-111. +343. +Buchler MW, Friess H, Wagner M, et al. +Pancreatic fis- +tula after pancreatic head resection. +Br J Surg. +2000;87: +883-889. +1422 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +344. +Tran K, Van Eijck C, Di Carlo V, et al. +Occlusion of the pan- +creatic duct versus pancreaticojejunostomy: a prospective ran- +domized trial. +Ann Surg. +2002;236:422-428, discussion 428. +345. +Fisher WE, Chai C, Hodges SE, Wu MF, Hilsenbeck SG, +Brunicardi FC. +Effect of BioGlue on the incidence of pancre- +atic fistula following pancreas resection. +J Gastrointest Surg. +2008;12:882-890. +346. +Kazanjian KK, Hines OJ, Eibl G, Reber HA. +Arch Surg. +2005;140:849-854, discussion +854-856. +347. +Group GTS. +Cancer. +1997;59:2006-2010. +348. +Neoptolemos JP, Dunn JA, Stocken DD, et al. +Lancet. +2001;358:1576. +349. +Gillen S, Schuster T, Meyer zum Büschenfelde C, et al. +PLoS Med. +7(4): e1000267. +Doi:10:1371/journal. +pmed.1000267. +350. +Yazawa K, Fisher WE, Brunicardi FC. +Current progress +in suicide gene therapy for cancer. +World J Surg. +2002;26: +783-789. +351. +Kiely JM, Nakeeb A, Komorowski RA, Wilson SD, Pitt HA. +Cystic pancreatic neoplasms: enucleate or resect? +J Gastroin- +test Surg. +2003;7:890-897. +352. +Obermeyer R, Fisher W, Sweeney J, et al. +Laparoscopic distal +pancreatectomy for serous oligocystic adenoma. +Surg Rounds. +2003;423. +353. +Salvia R, Fernandez-del Castillo C, Bassi C, et al. +Ann Surg. +2004;239:678-685, discussion +685-687. +354. +Boni L, Benevento A, Dionigi G, Cabrini L, Dionigi R. +Primary pancreatic lymphoma. +Surg Endosc. +2002;16: +1107-1108. +Spleen +Adrian E. +Park, Eduardo M. +Hippocrates1-3 in the fourth century bc was one of the first to +write on the spleen. +He taught broadly on the need for balance +and equilibrium between the patient and his environment. +The +influence of Galen’s teaching endured for more than 1200 years. +The +patient apparently survived. +Most patients who underwent sple- +nectomy in the three centuries that followed fared badly. +The +vast majority of splenectomies performed were partial. +There soon followed an enthusiastic effort by surgeons to cure +leukemia by splenectomy. +Dr. +Thomas Bryant performed the +first splenectomy in 1866 in a patient with leukemia. +Unfortunately, it took several decades for his words to be +heeded. +It may be most suitable in +cases of enlarged spleen. +Conclusive evidence is lacking. +The laparoscopic approach has emerged +as the standard for elective, nontraumatic splenectomy. +8 Overwhelming postsplenectomy infection (OPSI) is an +uncommon but potentially grave disease. +Children and +those undergoing splenectomy for hematologic malig- +nancy are at elevated risk. +9 Antibiotic prophylactic strategies against OPSI vary +widely. +Data regarding their use are lacking. +Preop- +erative vaccination before elective splenectomy is most +prudent. +Over 80% of accessory spleens are +found in the region of the splenic hilum and vascular pedicle. +The average adult spleen is 7 to 11 cm in length and weighs 150 g +(range, 70 to 250 g). +34-2). +The +relationship of the pancreas to the spleen also has important +clinical implications. +The splenic artery can be characterized by +the pattern of its terminal branches. +Sites where accessory spleens are found in order of +importance. +A. +Hilar region, 54%; B. +pedicle, 25%; C. +tail of pan- +creas, 6%; D. +splenocolic ligament, 2%; E. +greater omentum, 12%; +F. +mesentery, 0.5%; G. +left ovary, 0.5%. +A +B +C +D +E +F +G Figure 34-2. +Suspensory ligaments of the spleen. +(Data from + Poulin EC, Thibault C. +The anatomical basis for laparoscopic + splenectomy. +Can J Surg. +This gross +observation reflects the spleen’s microstructure. +34-3). +At the interface between the red and +white pulp is the narrow marginal zone. +Unlike the +cords of the red pulp, the sinuses of the red pulp are lined +by endothelial cells. +The former +play an important role in the targeting and clearance of +certain bacterial pathogens. +In +humans, the capsule is rich in collagen and contains some elas- +tin fibers. +The human splenic capsule and trabecu- +lae, by contrast, contain few or no smooth muscle cells. +Total splenic inflow of blood is approximately 250 to 300 +mL/min. +Splenic architecture. +From that entry, the flow rate through +the spleen may vary greatly. +Most of the spleen’s filtration func- +tion occurs via the slower circulation. +The white pulp, +by contrast, is involved only in adaptive immunity. +A minimum of 2 days of the +erythrocyte’s 120-day life cycle is spent sequestered in the +spleen. +Daily, approximately 20 mL of aged red blood cells are +removed. +The spleen can also serve as an extra medullary site for +hematopoiesis, if required. +Another role played by the spleen is +in recycling iron. +Erythrocytes in large numbers are destroyed +intravascularly throughout the body. +This gives rise to the elaboration of immunoglobulins +(predominantly IgM). +Antigen clearance is then facili- +tated by the splenic and hepatic reticuloendothelial systems. +Splenomegaly +refers simply to abnormal enlargement of the spleen. +Hypersplenism often is found in association with splenomegaly +but is not synonymous with it. +The life cycles of cellular elements vary widely in human +blood. +A neutrophil in circulation has a normal half-life of +approximately 6 hours. +The spleen’s role in the normal clearance +of neutrophils is not well established. +Platelets, on +the other hand, generally survive in the circulation for 10 days. +A +B +C +Figure 34-4. +Splenomegaly. +A. +Computed tomography (CT) scan. +B. +Three-dimensional reconstruction of CT scan. +C. +Postoperative +specimen. +Splenomegaly may result in +sequestration of up to 80% of the platelet pool. +In addition, in response to some anemias, +elements of the red pulp may revert to hematopoiesis. +Ultrasound +Ultrasound is the least invasive mode of splenic imaging. +It is +rapid, easy to perform, and does not expose the patient to ioniz- +ing radiation. +Splenic artery and vein +patency may be assessed using Doppler imaging. +The frequency of these artifacts increases with advanc- +ing patient age. +Plain films may also demonstrate +1429 +Spleen +CHAPTER 34 +splenic calcifications. +The spleen will gener- +ally have a homogeneous MR signal on noncontrast images. +This becomes important in deciding whether or +not a patient will benefit from a splenectomy. +Subsequent scintigraphy +demonstrates the site(s) of platelet sequestration and clearance. +Man- +agement of splenic injury in the trauma patient is beyond the +scope of this chapter. +The most common indication for elective +splenectomy is ITP. +Benign Disorders +Red Blood Cell Disorders +Congenital +Hereditary Spherocytosis. +Splenomegaly usually is present on physical examination. +The mean corpuscular volume is typically low to nor- +mal or slightly decreased. +Spherocytes are readily apparent on +peripheral blood film. +Near total splenectomy is advocated in children. +Red Blood Cell Enzyme Deficiencies. +Transfusions are given in cases of symp- +tomatic anemia. +All underwent splenectomy. +However, +warm-antibody AIHA has clinical consequences with which the +surgeon should be familiar. +Warm-antibody AIHA, although occurring primarily +in midlife, can affect individuals at all ages. +Clinical presentation may be acute +or gradual. +Findings include mild jaundice and symptoms and +signs of anemia. +One-third to one-half of patients present with +splenomegaly. +Sometimes in such cases the spleen is palpable +on physical examination. +Treatment of AIHA depends on the severity of the disease +and whether it is primary or secondary. +Severe symptomatic +anemia demands prompt attention, often requiring red blood cell +transfusion. +Mutant β +chains included in the hemoglobin tetramer create HbS. +Deoxy- +genated HbS is insoluble and becomes polymerized and sickled. +The disorder is characterized by painful intermittent episodes. +Sequestration occurs in the spleen, with splenomegaly +resulting early in the disease course. +It is only +indicated in cases of massive splenomegaly or frequent seques- +tration crisis. +The patients often have a functional asplenia. +The clinical spectrum of the thalassemias is wide. +Het- +erozygous carriers of the disease are usually asymptomatic. +Careful assessment of the +risk-benefit ratio is essential. +The duration of the bleeding helps to distinguish acute +from chronic forms of ITP. +In contrast, adults experience a more chronic form of +disease with an insidious onset. +Up to +10% of children, however, have a palpable spleen tip. +Response rates range from 50% to 75%, +but relapses are common. +An immediate response is common, but a sustained remis- +sion is not. +Therapeutic recommendations are summarized in Table 34-2. +Mortality was very low (1%), +and morbidity was 10%. +Thrombotic Thrombocytopenic Purpura. +Hemolysis may also be due in part to sequestration +and destruction of erythrocytes in the spleen. +Petechial hemorrhages in the lower +extremities are the most common presenting sign. +Along with +fever, patients may experience flu-like symptoms, malaise, or +fatigue. +Plasma exchange is the first-line therapy for TTP. +The role of splenectomy +in patients with white blood cell disorders varies. +Many HCL +patients have few symptoms and require no specific therapy. +More than 90% of patients with HD present with lymph- +adenopathy above the diaphragm. +The spleen is often an occult +site of spread, but massive splenomegaly is not common. +The most fre- +quent finding is lymphadenopathy. +When the spleen is enlarged, +it may be massive or barely palpable below the costal margin. +Palliative splenectomy also is indi- +cated for symptomatic splenomegaly. +Bone Marrow Disorders (Myeloproliferative Disorders). +Hypersplenism, when +it occurs in these conditions, usually is associated with spleno- +megaly. +Enlargement of the spleen is found in roughly one- +half of patients with CML. +Current therapy includes imatinib or +allogeneic stem cell transplantation. +Unlike CML, AML has a presentation that is more rapid +and dramatic. +Death usually results within weeks to months if AML +goes untreated. +Splenomegaly occurs in one- +third to one-half of patients with ET. +AMM also can be referred to as myeloscle- +rosis, idiopathic myeloid metaplasia, and osteosclerosis. +In this +chapter, the term myelofibrosis is synonymous with AMM. +Marrow failure is common. +Teardrop +poikilocytosis is another frequent finding. +A thorough preoperative workup must precede sple- +nectomy in patients with AMM. +Primary infections of the spleen +are infrequently reported. +The true incidence may be underreported, however. +Percuta- +neous drainage is successful for patients with unilocular disease. +Cysts. +Splenic cysts (Fig. +Such cysts are more commonly found in areas where the +pathogen is endemic. +Symptomatic parasitic cysts are best treated with +splenectomy. +Cysts resulting from trauma are termed pseudocysts due +to their lack of cellular lining. +Both of +these operations may be performed laparoscopically.66 +Tumors and Metastasis. +The most common primary tumor +of the spleen is sarcoma. +In +some circumstances, colorectal, ovary, and melanoma metasta- +ses can be isolated to the spleen. +The underlying +abnormality is a deficiency in the activity of a lysosomal hydro- +lase. +A. +Computed tomography (CT) scan of giant splenic cyst. +B. +Three-dimensional CT reconstruction of splenic cyst. +C and D. +Macroscopic aspect of a multicystic spleen lesion. +1438 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +in the spleen. +Four +types of the disease (A, B, C, and D) exist, with unique clinical +presentations. +Amyloidosis Amyloidosis is a disorder of abnormal extracellu- +lar protein deposition. +Symptoms of splenomegaly are relieved by splenectomy. +Any +organ system may be involved. +The most commonly involved +organ is the lung, followed by the spleen. +Splenomegaly occurs +in approximately 25% of patients. +Women +are four times more likely to be affected than men. +An excellent prognosis follows elective treatment. +Portal hypertension secondary to splenic vein thrombosis +is potentially curable with splenectomy. +In Felty’s syndrome the spleen +is four times heavier than normal. +The wandering +spleen is not normally attached to adjacent viscera in the splenic +fossa. +This may lead to splenic torsion and infarction. +The mechanism by which +vaccination protects asplenic patients is not entirely understood. +Serum antibody titers do not necessarily correspond to clinical +immunity. +Moreover, antibody levels after pneumococcus vac- +cination decline steadily within 5 to 10 years. +Anemic patients should be transfused before sur- +gery to a hemoglobin level of 10 g/dL. +Thrombocytopenia may be transiently corrected with platelet +transfusions. +Bowel preparation is not routinely +performed for patients undergoing elective splenectomy. +All +splenectomy patients do receive DVT prophylaxis, as discussed +previously. +After endotracheal intubation, a nasogastric (NG) +tube is inserted for stomach decompression. +Traumatic rupture of the spleen continues as the most +common indication for OS. +A midline incision is optimal for exposure when the spleen is +ruptured or massively enlarged. +34-6). +Splenic hilar dissection then takes place. +Splenocolic ligament is divided at the beginning of +open splenectomy. +1440 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +them. +The splenic bed is not routinely drained. +At the completion +of surgery, the nasogastric tube is removed. +34-7). +The double-access +technique requires the placement of five or six trocars. +34-7. +Use of an angled (30° or 45°) +laparoscope (2, 5, or 10 mm) greatly facilitates the procedure. +Figure 34-7. +Patient positioning and trocar placement for laparoscopic splenectomy. +nificantly reduce the available operating space. +The splenic +artery and vein are divided separately when possible. +Good +long-term outcomes, however, are increasingly being achieved +with mass hilar stapling (Fig. +34-8). +6 +1441 +Spleen +CHAPTER 34 +Once excised, the spleen is placed in a durable ripstop +nylon sack (Fig. +34-9), the neck of which is drawn through one +of the 10-mm trocar sites. +Morcellation of the spleen takes place +A +B +Figure 34-9. +Spleen extraction. +A. +Spleen is placed into a ripstop +nylon bag before morcellation. +B. +Splenic morcellation. +34-10). +295 minutes). +34-11). +A 7- to 8-cm incision should be made 2 to 4 cm caudal +to the inferior pole of the enlarged spleen. +Figure 34-10. +(Illustration +is reproduced with permission from Park A et al. +Laparoscopic vs +open splenectomy. +Arch Surg. +1999;134:1263. +Copyright © 1999 +American Medical Association. +All rights reserved.) +1442 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +A +B +C +Figure 34-11. +A. +Patient table placement for hand-assisted laparoscopic splenectomy (HALS) in case of splenomegaly. +B and C. +Intraop- +erative images of HALS. +This approach for +solid organs poses several technical challenges. +Both the +laparoscopic and open approaches for partial splenectomy have +been well described. +The devascularized segment of spleen +is transected along an obvious line of demarcation. +The true incidence is unknown. +The +gravity of such injury is not to be underestimated. +There are also reports of splenic injuries +after endoscopic procedures, such as colonoscopy. +Incisions and approaches must be tailored to both +patient circumstances and surgeon experience. +As with all hemorrhage, prompt temporary control +of bleeding is required. +The spleen is mobilized from its peritoneal attachments +and the nature of the injury assessed. +After splenectomy, leukocytosis and increased platelet counts +are common as well. +Hem- +orrhage can occur intraoperatively or postoperatively, present- +ing as subphrenic hematoma. +Sub- +phrenic abscess and wound infection are among the periopera- +tive infectious complications. +Hematologic responses may be +divided into initial and long-term responses. +These results are consistent with the long-term +success rate associated with OS. +A meta-analysis of perioperative outcomes of laparoscopic splenectomy for hematological diseases. +World J +Surg. +2012;36:2349-2358. +With kind permission from Springer Science+Business Media. +due to spherocytosis, the success rate is usually higher, ranging +from 90% to 100%. +Results of few prospective, randomized trials comparing +LS and OS have been published. +Sepsis in splenectomized patients is a +medical emergency. +Reason for splenectomy is +the single most influential determinant of OPSI risk. +Finally, +time interval from spleen removal must be considered. +A +large number of OPSI cases occur many years to decades later. +Microbiology and Pathogenesis. +pneumoniae, H. +influenzae, +and N. +meningitidis are classic examples). +Other +potential infectious bacterial sources include group A streptococci, +C. +Source: Data from Park A, McKinlay R. +Spleen. +In: Brunicardi FC, Andersen DK, Billiar TR, et al, eds. +Schwartz’s Principles of Surgery. +8th ed. +New +York: McGraw-Hill; 2005:1312. +Antibiotics and the Asplenic Patient. +Optimal +duration of chemoprophylaxis in children is unclear. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Moynihan B. +The surgery of the spleen. +Br J Surg. +1920;8:307. +2. +McClusky DA III, Skandalakis LJ, Colborn GL, et al. +Tribute +to a triad: history of splenic anatomy, physiology, and surgery– +part 1. +World J 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Dar O, Walsh S, Varty K. +Splenic artery aneurysms +in pregnancy—a systematic review. +Int J Surg. +2008;6:261-265. +1448 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +90. +Rashba EJ, Rowe JM, Packman CH. +Treatment of the neutro- +penia of Felty syndrome. +Blood Rev. +1996;10:177-184. +91. +Montenovo MI, Ahad S, Oelschlager BK. +Laparoscopic +splenopexy for wandering spleen: case report and review of +the literature. +Surg Laparosc Endosc Percutan Tech. +2010; +20:e182-e184. +92. +Mourtzoukou EG, Pappas G, Peppas G, Falagas ME. +Vac- +cination of asplenic or hyposplenic adults. +Br J Surg. +2008; +95:273-280. +93. +Bai YN, Jiang H, Prasoon P. +World J Surg. +2012;36:2349-2358. +94. +Park AE, Gagner M, Pomp A. +The lateral approach to laparo- +scopic splenectomy. +Am J Surg. +1997;173:126-130. +95. +Patel AG, Parker JE, Wallwork B, et al. +Massive splenomeg- +aly is associated with significant morbidity after laparoscopic +splenectomy. +Ann Surg. +2003;238:235-240. +96. +Pietrabissa A, 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risks Br J +Surg. +1991;78(9):1031-1038 +111. +Waghorn DJ. +J Clin Pathol. +2001;54(3):214-218 +112. +Park A, Maraccio M, Sterbach M, et al. +Laparoscopic vs open +splenectomy. +Arch Surg. +1999;134(11):1263-1269 +113. +Winslow ER, Brunt LM. +Surgery. +2003;134(4):647-653; +DISCUSSION 654-655 +114. +Vantansev C, Ece I, Jr. +Single incision laparoscopic sple- +nectomy with double ports. +Surg Laparosc Endosc Percutan +Tech. +2009.19(6):e225-227 +115. +Barbaros U, Dinccag A. +Single Incision laparoscopic sple- +nectomy: the fist two cases. +J Gastrointest Surg. +2009:13(8): +1520-1523 +Abdominal Wall, Omentum, +Mesentery, and Retroperitoneum +Neal E. +Seymour and Robert L. +35-1). +35-1). +35-2). +These relationships are of critical signifi- +cance in the management of inguinal hernias. +35-3). +35-4). +Anterior abdominal wall innervation is segmental. +Anterior abdominal wall. +(Reproduced with +permission from Moore KL, Dalley AF, +eds. +Clinically Oriented Anatomy. +4th ed. +There is no aponeurotic posterior covering +on the lower portion of the rectus muscles. +A lower recurrence rate benefit +remains controversial. +levels. +35-5). +External oblique m. +All of the +truncal muscles are involved in raising intra-abdominal pres- +sure. +This begs practical questions +of where and how to make incisions. +Incisions for open surgery +Figure 35-2. +(Reproduced with permission from Moore KL, Dalley AF, eds. +Clinically Oriented Anatomy. +4th ed. +Philadelphia: +Lippincott Williams & Wilkins; 1999:181.) +Figure 35-3. +Cross-sectional anatomy of the abdominal wall above and below the arcuate line of Douglas. +(Reproduced with permission from Moore KL, Dalley AF, eds. +Clinically Oriented Anatomy. +4th ed. +35-6). +Dermatomal sensory innervation of the abdominal +wall. +(Reproduced with permission from Moore KL, Dalley AF, +eds. +Clinically Oriented Anatomy. +4th ed. +Philadelphia: Lippincott +Williams & Wilkins; 1999:86.) +Figure 35-6. +Various anterior abdominal wall incisions for expo- +sure of peritoneal structures. +A. +Midline incision; B. +paramedian +incision; C. +right subcostal incision and “saber slash” extension to +costal margin (dashed line); D. +Rocky-Davis incision and Weir extension (dashed +line); F. +McBurney incision; G. +transverse incision and extension +across midline (dashed line); and H. +Pfannenstiel incision. +Figure 35-4. +Lymphatic drainage is via axillary +or inguinal nodal basins. +(Reproduced with permission from Moore +KL, Dalley AF, eds. +Clinically Oriented Anatomy. +4th ed. +Philadel- +phia: Lippincott Williams & Wilkins; 1999:188.) +procedures on the gastrointestinal tract. +The posterior, deeper layer consists of internal +oblique and transversus abdominis muscle. +Abdominal incisions can lead to short- and long-term +complications and patient disability. +The question of how large +an incision ought to be has no simple answer. +35-7). +Examples include the Bookwalter™, +Omni-Tract, and Thompson retractors. +The vitelline duct connects the +embryonic and fetal midgut to the yolk sac. +At the end of +the twelfth week, it returns to the abdominal cavity. +Defects in +abdominal wall closure may lead to omphalocele or gastroschi- +sis. +During the third trimester, the vitelline duct regresses. +Per- +sistence of a vitelline duct remnant on the ileal border results in +a Meckel’s diverticulum. +Bookwalter™ retractor in use for exposure of peri- +toneal structures during abdominal surgery. +pelvic position. +These are treated by urachal excision +and closure of any bladder defect that may be present. +Acquired Abnormalities +Rectus Abdominis Diastasis. +Diastasis is usually easily identified +on physical examination (Fig. +35-8). +Rectus Sheath Hematoma. +Figure 35-8. +Diastasis recti visible in the midepigastrium with +Valsalva maneuver. +This should not be mistaken for a ventral hernia. +A +hemoglobin/hematocrit level and coagulation studies should be +obtained. +Both ultrasonography and CT (Fig. +35-9) can provide +confirmatory imaging information and exclude other disorders. +Specific treatment depends on the severity of the hemor- +rhage. +Small, unilateral, and stable hematomas may be observed +without hospitalization. +Trans- +fusion or coagulation factor replacement may be indicated in +some situations. +Desmoid Tumors. +As many as 10% to 15% of FAP patients develop +Figure 35-9. +Computed tomography scan showing a medium- +sized right rectus sheath hematoma. +This occurred in an elderly, +anticoagulated patient without a clear history of trauma. +Involvement of margins is associated +with recurrence rates as high as 80%. +Other Abdominal Wall Tumors. +Abdominal Wall Hernias. +Ventral hernias may be +congenital or acquired. +The most common finding is a +mass or bulge, which may increase in size with Valsalva. +Primary ventral hernias (nonincisional) are generally +named according to their anatomic location. +Epigastric hernias +are located in the midline between the xiphoid process and the +umbilicus. +Most congenital umbilical hernias close +spontaneously by 5 years. +If closure does not occur, elective sur- +gical repair is usually advised. +Adults with small, asymptomatic +umbilical hernias should be followed clinically. +Umbilical hernia repair should be deferred until after the ascites +is controlled. +Repair may be accomplished +with either open or laparoscopic procedures. +Incisional Hernias. +The etiology of any given case of incisional +hernia can be difficult to determine. +Primary repairs of incisional hernia include both simple +suture closure and components separation. +Mesh repair has become the standard in the elective man- +agement of most incisional hernias. +Laparo- +scopic repairs use an underlay technique. +Each mesh material +type has specific density, porosity, and strength characteristics. +Some of the commercially available meshes for incisional her- +nia repair are listed in Table 35-1. +Permanent mesh implants +are made of prosthetic materials that do not degrade over time. +Their principal advantages are ease of use, relatively low cost, +and durability. +These characteristics +may be useful in the setting of contaminated or infected fields. +This method isolates mesh from the peritoneal contents. +Laparoscopic incisional hernia repair was first described +by LeBlanc and Booth in 1993. +Since that time, numerous +studies have examined early and late results compared to open +repair. +35-10). +within the peritoneal cavity. +Abdominal examination may reveal a tender, palpable mass. +However, some cases may be indistinguishable +from more worrisome surgical conditions. +Omental cysts are far +less common than mesenteric cysts. +Physical +examination may reveal a freely mobile intra-abdominal mass. +Treatment +involves resection of all symptomatic omental cysts. +Resection +of these benign lesions is readily accomplished using laparo- +scopic techniques. +Omental Neoplasms +Primary tumors of the omentum are rare. +Benign tumors of the +omentum include lipomas, myxomas, and desmoid tumors. +35-11). +The +related anatomic anomalies of the mesentery include paraduo- +denal or mesocolic hernias (Fig. +35-12), which can present as +chronic or acute intestinal obstruction in children or adults. +(Reproduced with +permission from Healy JE, Hodge J (eds). +Surgical Anat- +omy, 2nd ed. +Toronto: BC Decker, 1990:151.) +Figure 35-12. +(Reproduced with permission from Healy JE, +Hodge J, eds. +Surgical Anatomy. +2nd ed. +Toronto: BC Decker; +1990:153.) +rise to the various terms used to describe this condition. +mesenteric artery +Aorta +Mesosigmoid, not fixed +Transv. +mesen- +teric art. +Mesentery +fixed +A' A' +A' +A'" +A" +B" +B' +B' B' +B'" +A +B +Inferior mesenteric v. +Left colic a. +35-13). +Operative findings range from a discrete mesenteric mass +(Fig. +35-14) to broad areas of mesenteric nodularity and thick- +ening. +Rarely, an ostomy of some type for fecal diversion in the face of +obstruction can be considered. +Clinical symptoms +Figure 35-13. +Computed tomography scan of sclerosing mes- +enteritis (mesenteric lipodystrophy). +Figure 35-14. +Mesenteric cysts may be asymptomatic or cause acute +or chronic symptoms of a mass lesion. +CT (Fig. +35-15), ultrasound, and MRI all have been used +to evaluate patients with mesenteric cysts. +Cysts generally +appear unilocular without solid component on imaging. +These can be difficult to +treat and almost invariably recur after excision. +In this case, segmental bowel resec- +tion inclusive of the adjacent mesentery is performed. +Mesenteric Tumors +Primary tumors of the mesentery are rare. +Benign tumors of the +mesentery include lipoma, cystic lymphangioma, and desmoid +tumors. +Primary malignant tumors of the mesentery are similar +to those described for omentum. +Treatment of mesenteric malignancies involves wide +resection of the mass. +35-16). +Accordingly, +Figure 35-15. +Computed tomography (CT) scan of a mesenteric cyst (left panel). +The site of pain may be +variable and can include the back, pelvis, or thighs. +Erythema +may be observed around the umbilicus or flank. +35-17). +The disease primarily affects individu- +als in the fourth to the sixth decades of life. +Anatomy of the retroperitoneum. +(Reproduced with permission from Healy JE, Hodge J, eds. +Surgical Anatomy. +2nd ed. +Toronto: BC Decker; 1990:201.) +Figure 35-17. +in defining an autoimmune cause of retroperitoneal fibrosis. +The relationship of +these finding to the occurrence of fibrosis remains uncertain. +The fibrotic process begins in the ret- +roperitoneum just below the level of the renal arteries. +Bilateral involvement +is noted in 67% of cases. +Psoas major m. +Common +iliac a. +The retroperitoneal fibrosis regresses upon +discontinuation of these medications. +Presenting symptoms depend on the structure or structures +affected by the fibrotic process. +Initially, patients complain of +the insidious onset of dull, poorly localized abdominal pain. +Sudden-onset or severe abdominal pain may signify acute mes- +enteric ischemia. +Laboratory evaluation may reveal elevated +blood urea nitrogen and/or creatinine levels. +It may be useful +if iliocaval compressive or renal symptoms predominate. +Corticosteroids, with or without surgery, are the +mainstay of medical therapy. +Laparoscopic ure- +terolysis has been shown to be as efficacious as open the open +procedure. +Therapeutic efficacy is assessed +based on patient symptoms and interval imaging studies. +Because +long-term recurrences have been described, lifelong follow-up +is warranted. +BIBLIOGRAPHY +Entries highlighted in bright blue are key references. +General References +Burt BM, Tavakkolizaden A, Ferzoco SJ. +Incisions, closures, and +management of the abdominal wound. +In: Zinner MJ, Ashley +SW, eds. +Maingot’s Abdominal Operations. +11th ed. +New York: +McGraw Hill; 2007:71-102. +Flament JB, Avisse C, Delattre JF. +Anatomy of the 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surgical complication. +Hosp Physician. +2001;56: +35-37. +Pierce RA, Spitler JA, Frisella MM, et al. +Pooled data analysis +of laparoscopic vs. +open ventral hernia repair: 14 years of +patient data accrual. +Surg Endosc. +2007;21:378-386. +Quintini C, Ward G, Shatnawei A, et al. +Ann Surg. +2012; +255:511-516. +Ramirez OM, Ruas E, Dellon AL. +Plast Reconstr Surg. +1990;86:519-526. +Rogmark P, Petersson U, Bringman S, et al. +Ann Surg. +2013;258:37-45. +Stojadinovic A, Hoos A, Karpoff HM, et al. +Soft tissue tumors of +the abdominal wall. +Analysis of disease patterns and treatment. +Arch Surg. +2001;136:70-79. +Stoppa R, Ralaimiaramanana F, Henry X, et al. +Hernia. +1999;3:1-3. +Zainea GG, Jordan F. +Rectus sheath hematomas: their pathogenesis, +diagnosis, and management. +Am Surg. +1988;54:630-633. +Omentum +Beelen RHJ. +The greater omentum: physiology and immunological +concepts. +Neth J Surg. +1991;43:145-149. +Fukatsu K, Saito H, Han I, et al. +The greater omentum is the pri- +mary site of neutrophil exudation in peritonitis. +J Am Coll Surg. +1996;183:450-456. +Goldsmith HS, ed. +The Omentum: Research and Clinical Applica- +tions. +New York: Springer-Verlag; 2000. +Liebermann-Meffert D. +The greater omentum. +Anatomy, embry- +ology, and surgical applications. +Surg Clin North Am. +2000; +80:275-293, xii. +Liebermann-Meffert D, White H, eds. +The Greater Omentum. +Anat- +omy, Physiology, Pathology, Surgery with an Historical Survey. +New York: Springer-Verlag; 1983. +Logmans A, Schoenmakers CH, Haensel SM, et al. +High tissue fac- +tor concentration in the omentum, a possible cause of its hemo- +static properties. +Eur J Clin Invest. +1996;26:82-83. +Morison R. +Remarks on some functions of the omentum. +Br Med +J. +1906;1:76. +Nakagawa M, Akasaka Y, Kanai T, et al. +Hepatogastroenterology. +2003;50:691-695. +O’Leary DP. +Use of the greater omentum in colorectal surgery. +Dis +Colon Rectum. +1999;42:533-539. +Powers JC, Fitzgerald JF, McAlvanah MJ. +Surg Gynecol Obstet. +1976;143:105-106. +Saborido BP, Romero CJ, Medina ME, et al. +Idiopathic segmental +infarction of the greater omentum as a cause of acute abdomen. +Report of two cases and review of the literature. +Hepatogastro- +enterology. +2001;48:737-740. +Schwartz RW, Reames M, McGrath PC, et al. +Primary solid neo- +plasms of the greater omentum. +Surgery. +2011;15:409-411. +Mesentery +Burkett JS, Pickleman J. +The rationale for surgical treatment of mesen- +teric and retroperitoneal cysts. +Am Surg. +1994;60:432-435. +Daskalogiannaki M, Voloudaki A, Prassopoulos P, et al. +CT evalu- +ation of mesenteric panniculitis: prevalence and associated dis- +eases. +Am J Roentgenol. +2000;174:427-431. +Egozi EI, Ricketts RR. +Mesenteric and omental cysts in children. +Am Surg. +1997;63:287-290. +Emory T, Monihan J, Carr NJ, et al. +Sclerosing mesenteritis, mesen- +teric panniculitis, and mesenteric lipodystrophy: a single entity? +Am J Surg Pathol. +1997;21:392-398. +Genereau T, Bellin MF, Wechsler B, et al. +Dig Dis Sci. +1996;41:684-688. +Hebra A, Brown MF, McGeehin KM, et al. +Mesenteric, omental +and retroperitoneal cysts in children: a clinical study of 22 +cases. +South Med J. +1993;86:173-176. +Issa I, Baydoun H. +Mesenteric panniculitis: various presentations +and treatment regimens. +World J Gastroenterol. +2009;15: +3827-3830. +Kelly JK, Hwang WS. +Idiopathic retractile (sclerosing) mesenteritis +and its differential diagnosis. +Am J Surg Pathol. +1989;13:513-521. +O’Brien MF, Winter DC, Lee G, et al. +Mesenteric cysts—a series +of six cases with a review of the literature. +Ir J Med Sci. +1999;168:233-236. +Ogden WW, Bradburn DM, Rives JD. +Panniculitis of the mes- +entery. +Ann Surg. +1960;151:659-668. +Ros PR, Olmsted WW, et al. +Mesenteric and omental cysts: his- +tologic classification with imaging correlation. +Radiology. +1987;164:327-332. +Shamiyeh A, Rieger R, Schrenk P, Wayand W. +Role of laparo- +scopic surgery in treatment of mesenteric cysts. 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Lindstedt E, et al. +Steroid therapy for idio- +pathic retroperitoneal fibrosis: dose and duration. +J Urol. +2002;168:550-555. +1464 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Kottra JJ, Dunnick NR. +Retroperitoneal fibrosis. +Radiol Clin North +Am. +1996;34:1259-1275. +Martorana D, Vaglio A, Greco P, et al. +Chronic periaortitis and +HLA-DRB1*03: another clue to an autoimmune origin. +Arthri- +tis Rheum. +2006;55:126-130. +Marzano A, Trapani A, Leone N, et al. +Treatment of idiopathic +retroperitoneal fibrosis using cyclosporine. +Ann Rheum Dis. +2001;60:427-428. +Ormond JK. +Bilateral ureteral obstruction due to envelop- +ment and compression by an inflammatory process. +J Urol. +1948;59:1072-1079. +Pryor JP, Piotrowski E, Seltzer CW, et al. +Early diagnosis of ret- +roperitoneal necrotizing fasciitis. +Crit Care Med. +2001;29: +1071-1073. +Rhee RY, Gloviczki P, Luthra HS, et al. +Iliocaval complications of +retroperitoneal fibrosis. +Am J Surg. +1994;168:179-183. +Srinivasan AK, Richstone L, Permpongkosol S, et al. +J Urol. +2008;179: +1875-1878. +Uchida K, Okazaki K, Asada M, et al. +Pancreas. +2003;26:92-94. +Woodburn KR, Ramsay G, Gillespie G, et al. +Retroperitoneal nec- +rotizing fasciitis. +Br J Surg. +1992;79:342-344. +Soft Tissue Sarcomas +Janice N. +Cormier, Alessandro Gronchi, and +Raphael E. +The primary focus of +this chapter is soft tissue sarcomas. +More often, a minor +injury calls attention to a pre-existing tumor. +4 Overall 5-year survival rate for patients with all stages of soft +tissue sarcoma is 50% to 60%. +6 The treatment algorithm for soft tissue sarcomas depends +on tumor stage, site, and histology. +The two genes +most relevant to soft tissue sarcoma are retinoblastoma (Rb) and +figure 36-1. +The +dominant pattern of metastasis is hematogenous, primarily to +the lungs. +Tumors often grow centrifugally and can compress surrounding +normal structures. +Ultrasonography. +Finally, ultrasonography can be +used for postoperative surveillance and to guide biopsies. +Computed Tomography. +CT is also the preferred imaging technique for +evaluating retroperitoneal sarcomas (Fig. +For extremity sarcomas, CT may be useful if MRI is +not available or cannot be used. +Sagittal and coronal views +allow evaluation of anatomic compartments in three dimensions +(Fig. +36-3). +Soft tissue sarcomas of the extremities usually pres- +ent on MRI as a heterogeneous mass. +Their signal intensity tends +figure 36-2. +A 69-year-old woman with a leiomyosarcoma involv- +ing the inferior vena cava. +Hemorrhagic, cystic, or necrotic changes +may also be observed in the tumor. +MRI is also valuable for assessing tumor recurrence after +surgery. +A baseline image is usually obtained 3 months after +surgery. +Positron Emission Tomography. +PET imaging allows evaluation of the entire body. +Core Needle Biopsy. +The reported complication rate for core needle biopsy is less +than 1%.45,46 +Incisional Biopsy. +A 62-year-old man presented with right thigh pain. +Magnetic resonance imaging demonstrated a 20-cm high-grade sar- +coma within the medial compartment. +Excisional Biopsy. +However, excisional biopsy rarely provides +benefits over other biopsy techniques. +Wide en bloc excision is seldom performed as a diagnostic +procedure. +Histologic Grade of Aggressiveness. +Histologic grade is the +most important prognostic factor for patients with soft tissue +sarcoma. +The number of grades varies according to the classifica- +tion system used. +Tumor Size and Location. +Tumor size is an important prog- +nostic variable in soft tissue sarcomas. +Nodal Metastasis. +Distant Metastasis. +Distant metastases occur most often in +the lungs (Fig. +36-4). +Other potential sites of metastasis include bone +(Fig. +36-5), brain (Fig. +36-6), and liver (Fig. +36-7). +Visceral and +figure 36-4. +figure 36-5. +figure 36-6. +figure 36-7. +Prognostic factors. +2. +3. +4. +5. +6. +1473 +S +O +f +T + T +ISSUE + S +ARCOMAS +CHAPTER 36 +radical or complete anatomic compartment resection. +Amputation. +However, survival rates did not differ between the groups. +The vessels are dissected, and all collateral vessels are ligated. +Chemothera- +peutic agents are then added to the perfusion circuit and circu- +lated for 90 minutes. +This report led to larger +studies geared specifically to patients with sarcoma. +Conventional fractionation is usually 1.8 to 2 Gy per day. +Doses of 60 to 70 Gy are usually +necessary for postoperative treatment. +No consensus exists on the optimal sequence of radia- +tion therapy and surgery. +The available data come largely from +single-institution, nonrandomized studies. +For most patients with sarcoma, +results of conventional chemotherapy regimens have been poor. +Targeted Therapies. +Several targeted agents are being investi- +gated for the treatment of soft tissue sarcomas. +The use of adjuvant and +neoadjuvant chemotherapy for soft tissue sarcomas remains +controversial. +Recurrence is common after surgery for abdominal soft tis- +sue sarcomas. +The most common initial site of distant metastasis of soft tis- +sue sarcomas is the lung. +36-9). +figure 36-9. +Adjuvant Therapy. +Unfortunately, +the study was closed prematurely in 2006 because of low patient +accrual. +Treatment of Recurrence. +Retroperitoneal sarcomas recur +more often than extremity and trunk wall ones. +Retroperitoneal sarcomas can also recur diffusely +throughout the peritoneal cavity (sarcomatosis). +Establishing the diagnosis of a gastrointestinal sarcoma +preoperatively is often difficult. +Patients +with localized disease frequently present with a large intra- +abdominal mass. +local) failure, is to resect the tumor with a 2- to 4-cm +margin of normal tissue. +For sarcomas of the small or large intestine, segmental +bowel resection is the standard treatment. +For small, low +rectal lesions, clear margins may be achievable with a transanal +excision. +Mammography is often nonspecific, and diagnosis +requires punch or incisional biopsy. +Local and distant recurrences +are more common in patients with high-grade lesions. +Complete +excision with negative margins is the primary therapy. +Uterine Sarcoma +Sarcomas account for less than 5% of uterine malignancies. +Bilateral salpingo-oophorectomy is mandatory only +in endometrial stromal sarcoma. +Pelvic post- +operative irradiation has been studied instead in a randomized +fashion. +Adjuvant pelvic radia- +tion therapy can be considered for selected high-risk patients. +Adjuvant chemotherapy is controversial. +Endometrial stromal sarcomas account for approximately +7% to 10% of uterine sarcomas. +Tamoxifen is not recommended because +it may be proestrogenic in this setting. +It is associated with a poor prognosis even in patients +presenting with localized disease. +Systemic agents for +other soft tissue sarcomas are used for recurrent and/or meta- +static disease. +In a phase II +trial, patients with KIT exon 11 mutations had better response +rates (83.5% vs. +GIST most frequently metastasizes to the liver +and/or abdominal cavity. +Extended anatomic +resection and lymphadenectomy are not required. +The primary endpoint of the trial was sur- +vival. +In February 2002, the U.S. +When feasible, imatinib should be +continued in the absence of disease progression. +Many patients with GIST develop resistance to imatinib. +Sunitinib has both antiangio- +genic and antiproliferative activity. +36-10A [before imatinib], +Fig. +36-10B [after imatinib]). +The mechanisms of imatinib +resistance are currently being investigated. +A. +Before imatinib. +B. +After imatinib. +determined. +Adjuvant treatment with imatinib for GIST +patients was then examined in two key trials. +Food and Drug Administration in 2008 +and by the European Medical Agency (EMA) in 2009. +Beside the risk of recurrence, the other important factor +to consider is the tumor genotype. +Patients with sporadic wild-type GIST could be treated on an +individual basis. +Fortunately. +If not, then mutation status should be +investigated before continuing the treatment. +Preoperative treatment may shrink the tumor and allow +a more conservative local excision. +This is why there is growing +evidence that the primary approach could be more conserva- +tive. +When used, a dose of 50 +to 54 Gy is usually recommended. +Systemic treatment is another +option, when surgery is not indicated. +3.9 per million per year). +Satellite lesions may be found in patients with larger tumors. +Two primary histologic sub- +types account for 90% of cases: embryonal (70%) and alveolar +(20%). +Extent of disease is the strongest predictor of long-term +outcome. +Several staging systems for rhabdomyosarcoma are +available. +The Intergroup Rhabdomyosarcoma Study Group +system is based on surgical-pathologic groupings. +Recent findings suggest that +chemotherapy alone can adequately control many such tumors. +Therefore, multiagent chemo- +therapy is 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+Flamant F, Rodary C, Rey A, et al. +Treatment of non- +metastatic rhabdomyosarcomas in childhood and adoles- +cence. +Results of the second study of the International Society +of Paediatric Oncology: MMT84. +Eur J Cancer. +1998;34: +1050-1062. +250. +Crist WM, Anderson JR, Meza JL, et al. +Intergroup rhabdo- +myosarcoma study-IV: results for patients with nonmetastatic +disease. +J Clin Oncol. +2001;19:3091-3102. +251. +Crist WM, Garnsey L, Beltangady MS, et al. +Intergroup Rhabdomyo- +sarcoma Committee. +J Clin Oncol. +1990;8:443-452. +252. +Loeb DM, Thornton K, Shokek O. +Pediatric soft tissue sarco- +mas. +Surg Clin North Am. +2008;88:615-627, vii. +This page intentionally left blank +Inguinal Hernias +Justin P. +Wagner, F. +Charles Brunicardi, Parviz K. +Amid, and David C. +Approximately 75% of abdominal wall hernias occur in +the groin. +Abramson demonstrated the age +dependence of inguinal hernias in 1978. +For those that survived +the operation, recurrence of the hernia was common. +Outcomes improved, but recurrence +rates remained high with prolonged follow-up. +Modifications of the Bassini repair were +manifest in the McVay and Shouldice repairs. +37-1). +It is enveloped in three lay- +ers of spermatic fascia. +Key Points +1 Conservative management of asymptomatic inguinal hernias +is acceptable. +3 Elective repair of inguinal hernias can be undertaken using an +laparoscopic or open approach. +5 Recurrence, pain, and quality of life are important outcome +factors. +2 +ligament, and the conjoined tendon (Fig. +37-2). +It +forms on the deep inferior margin of the transversus abdomi- +nis and transversalis fascia. +Direct +hernias protrude medial to the inferior epigastric vessels, within +Hesselbach’s triangle. +Femoral +hernias protrude through the small and inflexible femoral ring. +The +Nyhus classification categorizes hernia defects by location, size, +and type (Table 37-2). +37-3). +37-4). +Two potential spaces exist within the pre- +peritoneum. +This area contains preperitoneal fat and areolar tissue. +37-5). +The inferior epigastric artery supplies +the rectus abdominis. +37-6 and 37-7). +The ilioinguinal and iliohypogas- +tric nerves arise together from the first lumbar nerve (L1). +The +Internal ring +External ring +Aponeurotic arch of +transverse abdominus m. +Spermatic cord +Femoral vessels +Inguinal ligament +Inguinal canal +Figure 37-1. +Location and orientation of the inguinal canal within the pelvic basin. +m. += muscle. +Adductor brevis m. +Adductor magnus m. +Gracilis +Figure 37-2. +m. += muscle. +It supplies +somatic sensation to the skin of the upper and medial thigh. +In +males, it also innervates the base of the penis and upper scrotum. +In females, it innervates the mons pubis and labium majus. +The +iliohypogastric nerve arises from T12–L1. +It then divides into lateral +and anterior cutaneous branches. +It then divides into genital and +femoral branches. +Anatomy of the groin region from the posterior perspective. +Posterior view of intraperitoneal folds and associ- +ated fossa: A. +Umbilicus. +B. +Median umbilical ligament. +C. +Medial +umbilical ligament (obliterated umbilical vein). +D. +Lateral umbili- +cal ligament (inferior epigastric vessels). +E. +Lateral fossa (indirect +hernia). +F. +Medial fossa (direct hernia). +G. +Supravesical fossa. +(Modified with permission from Rowe JS Jr, Skandalakis JE, Gray +SW. +Multiple bilateral inguinal hernias. +Am Surg. +In females, it supplies the ipsilateral mons +pubis and labium majus. +37-8). +and v. +Vas deferens Obturator n. +Obturator vessels +Lacunar ligament +Cooper's ligament +Figure 37-5. +Posterior view of the myopectineal orifice of Fruchaud. +a. += artery; n. += nerve; v. += vein. +Ilioinguinal n. +Iliohypogastric n. +Iliac m. +Lateral femoral +cutaneous n. +Femoral n. +Inguinal ligament +Genitofemoral n. +Retroperitoneal view of major inguinal nerves and their courses. +m. += muscle; n. += nerve. +37-10). +Anterior view of the five major nerves of the inguinal region. +Femoral branch of +genitofemoral n. +Ilioinguinal n. +Lateral femoral +cutaneous n. +Medial and intermediate +femoral cutaneous nn. +Saphenous n. +Iliohypogastric n. +Genital branch of +genitofemoral n. +Figure 37-8. +Sensory dermatomes of the major nerves in the groin +area. +n. += nerve. +Overall, there are +limited data regarding the etiology of inguinal hernia devel- +opment. +& v. +Lateral border: +reflected +peritoneum +Lat. +femoral cutaneous n. +Ant. +femoral cutaneous n. +or +other variable branches +Femoral br. +of genitofemoral n. +Femoral n. +Borders and contents of the (A) triangle of doom and (B) triangle of pain. +a. += artery; Ant. += anterior; br. += branch; Lat. += +lateral; n. += nerve; v. += vein. +(Modified with permission from Colborn GL, Skandalakis JE. +Laparoscopic cadaveric anatomy of the inguinal +area. +Probl Gen Surg. +DIAgNOsIs +History +Inguinal hernias present along a spectrum of scenarios. +Varying degrees of closure of the processus vagi- +nalis (PV). +A. +Closed PV. +B. +Minimally patent PV. +C. +Moderately +patent PV. +D. +Scrotal hernia. +Extrainguinal symptoms such as +a change in bowel habits or urinary symptoms are less com- +mon. +Neurogenic pain may be referred to the scrotum, +testicle, or inner thigh. +Questions should be directed to elicit and +characterize extrainguinal symptoms. +Important considerations of the patient’s history include +the duration and timing of symptoms. +Hernias will often increase +in size and content over a protracted time. +Questions should also be +directed to characterize whether the hernia is reducible. +Physical examination +Physical examination is essential to the diagnosis of inguinal +hernia. +37-11). +This allows the inguinal canal to be explored. +The patient is then asked to perform Valsalva’s maneuver to +protrude the hernia contents. +This is especially useful +in the case of a small hernia. +Digital examination of the inguinal canal. +A further challenge to the physical examination is +the identification of a femoral hernia. +Femoral hernias should +be palpable below the inguinal ligament, lateral to the pubic +tubercle. +Imaging in obvious cases is unnecessary and costly. +US is the least invasive technique and does not impart any +radiation to the patient. +Positive intra-abdominal pressure is used to elicit the +herniation of abdominal contents. +37-12). +Figure 37-12. +Computed tomography scan depicting a large +right inguinal hernia (arrow). +A smaller left inguinal hernia is also +visualized. +The indication for emergent inguinal hernia repair is +impending compromise of intestinal contents. +As such, stran- +gulation of hernia contents is a surgical emergency. +The option to administer locoregional anesthesia is an +advantage of the open approach. +In advance of the initial inci- +sion, a field block or ilioinguinal nerve block may be employed. +Exposure of the anterior inguinal region is common to +the open approaches. +An oblique or horizontal incision is per- +formed over the groin (Fig. +37-13). +The incision begins two +fingerbreadths inferior and medial to the anterior superior iliac +spine. +It is then extended medially for approximately 6 to 8 cm. +The  subcutaneous tissue is dissected using electrocautery. +Scarpa’s fascia is divided to expose the external oblique aponeu- +rosis. +The flaps of the external oblique aponeurosis are elevated +with Hemostat clamps. +The interior oblique fibers are dissected +bluntly from the overlying external oblique flaps. +Dissection of +the inferior flap reveals the shelving edge of the inguinal liga- +ment. +The iliohypogastric and ilioinguinal nerves are identified +and preserved. +37-14). +The floor of the ingui- +nal canal is fully assessed for direct hernias. +The sac +can then be grasped with a tissue forceps and bluntly dissected +from the cord. +The dissection is carried proximally toward the +deep inguinal ring. +The defect should be enlarged to +augment blood flow to the sac contents. +At this point, the inguinal canal is reconstructed, either +with native tissue or with prostheses. +Tissue Repairs. +Bassini Repair The Bassini repair was an historic advancement +in operative technique. +Its current use is limited, as modern tech- +niques reduce recurrence. +37-15). +A triple-layer repair is then +performed. +The +lateral aspect of the repair reinforces the medial border of the +internal inguinal ring. +A. +Layers of the abdominal wall in the anterior open approach to hernia repair. +B. +Ex. += external; SQ = subcutaneous. +Figure 37-14. +Anterior open exposure of the inguinal canal. +m. += +muscle; n. += nerve; v. += vein. +1507 +I +N +g +UINA +l He +RNIA +s +CHAPT +e +R 37 +tissue layers results in lower recurrence rates (Fig. +37-16). +At the pubic tubercle, this +suture is tied to the tail of the original stitch. +McVay Repair The McVay repair addresses both inguinal and +femoral ring defects. +37-17). +Bassini repair. +A. +The transversalis fascia is opened +B. +EO = external oblique aponeurosis. +A +B +Figure 37-16. +Shouldice repair. +A. +B. +Two +more suture lines affix the internal oblique and transversus muscles +medially. +Cooper’s ligament +Figure 37-17. +McVay Cooper’s ligament repair. +The upper flap is mobilized by +gentle blunt dissection of underlying tissue. +Cooper’s ligament +is bluntly dissected to expose its surface. +The +transversalis is then sutured to the inguinal ligament laterally to +the internal ring. +Prosthetic Repairs. +The techniques of the most commonly performed +prosthetic repairs are presented in this section. +37-18). +Initial exposure and mobiliza- +tion of cord structures is identical to other open approaches. +37-19). +In the case of an indirect +Figure 37-18. +Lichtenstein tension-free hernioplasty. +m. += muscle; +n. += nerve; v. += vein. +Slit +A +B +Figure 37-19. +Plug and patch repair. +A. +B. +Final view of the repair fol- +lowing placement of the plug and patch. +Exposure of the inguinal canal +is identical to that of other open approaches. +The mesh has an underlay flap and an onlay +flap, joined by a short cylindrical connector (Fig. +37-20). +The overlay flap reinforces the inguinal floor similar to a +tension-free repair. +The spermatic cord is placed through a slit +in the onlay portion of the mesh. +Wound Closure. +Scarpa’s fascia and skin are +appropriately closed. +giant Prosthetic Reinforcement of the Visceral sac. +The transversalis is incised, and the preperitoneal +space is dissected widely (Fig. +37-21). +Indirect her- +nias require directed dissection from the internal ring. +The middle por- +tion and lower corners of the mesh are clamped. +The mesh is +placed flat along the inferior margin of the preperitoneal space +(Fig. +37-22). +Splitting the mesh to accommodate +the cord may predispose to hernia recurrence. +The transversalis is reapproximated and the wound +is closed. +The indications for laparoscopic inguinal hernia repair are +similar to those for open repair. +The Prolene Hernia System prosthesis. +Peritoneum +Preperitonial +space +Abdominal +wall +Mesh +Figure 37-21. +Extensive dissection of the preperitoneal space on +both sides will accommodate a large prosthesis. +The operating room configuration is identical for TAPP, +TEP, and IPOM procedures. +The surgeon stands contralateral to the hernia, and +the assistant stands opposite the surgeon. +The patient’s arms are +tucked to the sides. +Fig. +37-23 demonstrates a typical operating +room setup for laparoscopic inguinal hernia repair. +Transabdominal Preperitoneal Procedure. +The abdominal cavity is accessed using a dissecting trocar or +open Hasson technique. +Pneumoperitoneum is instilled to a level +of 15 mmHg. +37-24). +The patient is then placed in the +Trendelenburg position, and the pelvis is inspected. +An indirect hernia sac will usually protrude anterior to +the spermatic cord. +The sac is dissected from +its adhesions, and the cord is skeletonized. +The mesh usually measures 10 × 15 cm to completely +cover the myopectineal orifice (Fig. +37-25). +It is rolled length- +wise and placed through the 12-mm trocar. +The mesh is then pulled +taut and fixed lateral to the anterior superior iliac spine. +The peritoneum should be closed completely to avoid contact +between the mesh and the intestine. +The abdomen is desufflated +and the trocars are removed. +The fascial defect of the 12-mm +port and the skin incisions are appropriately closed. +C +AB +D +A +A +B +B +C +C +D +D +H +H +E +E +F +F +G +G +Figure 37-22. +Giant prosthetic reinforcement of the visceral sac. +A. +Exposure of the preperitoneal space. +B. +Dissection of the hernia sac from +the spermatic cord. +C. +Reduction of the sac and elevation of the cord. +D. +Orientation and placement of the giant mesh. +1511 +I +N +g +UINA +l He +RNIA +s +CHAPT +e +R 37 +Totally extraperitoneal Procedure. +A small horizontal incision is made inferior to the umbi- +licus. +37-26). +37-24). +No modifications are necessary +to repair bilateral inguinal hernias with the TEP approach. +Figure 37-23. +Operating room setup for laparoscopic inguinal hernia repair. +1512 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +B A +Figure 37-24. +Figure 37-25. +View of mesh placement in posterior repairs. +A +large mesh overlaps the myopectineal orifice. +Figure 37-26. +Balloon dissection of the preperitoneal space in a +totally extraperitoneal inguinal hernia repair. +Trocars are removed, and the anterior rectus sheath is closed +with an interrupted suture. +Intraperitoneal Onlay Mesh Procedure. +Port placement and inguinal hernia identification are identical to +TAPP. +Instead, mesh is +placed directly over the defect and fixed in place with sutures +or spiral tacks. +synthetic Mesh Material. +A disadvantage of currently available commercial pros- +theses is their high cost. +Biologic Mesh. +While new prosthetic materials continue to be devel- +oped, no single biologic warrants routine use. +Fixation Technique. +Independent of prosthesis material, the +method of its fixation remains disputed. +In TEP repairs, fixation of mesh may not be compulsory. +A focused physical examination should be performed. +As with primary hernias, US, CT, or MRI can elucidate ambigu- +ous physical findings. +Con- +versely, failed preperitoneal repairs should be approached using +an open anterior repair. +Nociceptive pain is +the most common of the three. +Neuropathic pain occurs as a result of direct nerve +damage or entrapment. +Visceral pain refers to pain +conveyed through afferent autonomic pain fibers. +CT scan or +MRI excludes hernia recurrence, and bone scan is confirmatory +for the diagnosis. +Emergent orchiectomy is only +necessary in the case of necrosis. +Injury to the vas deferens within the cord may lead to +infertility. +In laparoscopic approach, +grasping the vas may result in a crush injury. +Injury to the +artery of the round ligament does not result in clinically signifi- +cant morbidity. +Urinary Retention. +Failure to void normally +requires reinsertion of the catheter for up to a week. +Ileus and Bowel Obstruction. +Abdominal imaging may be helpful to confirm the +diagnosis and to exclude bowel obstruction. +True +obstruction warrants reoperation. +Visceral Injury. +Small bowel, colon, and bladder are at risk +for injury in laparoscopic hernia repair. +Direct bowel injuries may also result from tro- +car placement. +Missed bowel injuries are associated +with increased mortality. +Vascular Injury. +In these cases, exsanguination may be swift. +Accordingly, the surgeon +should be aware of this intraoperative consideration. +Injury to spermatic cord vessels +may result in a scrotal hematoma. +Intermittent warm and cold compression aids in +resolution. +The latter three +sites are more frequently associated with laparoscopic repair. +Large +hernia sac remnants may fill with physiologic fluid and mimic +seromas. +Patients often mistake seromas for early recurrence. +Treatment consists of reassurance and warm compression to +accelerate resolution. +In +TAPP repair, the risk of intra-abdominal injury is higher than +in TEP repair. +Surgeons should tailor this experience to +optimize outcomes for each patient. +ReFeReNCes +Entries highlighted in bright blue are key references. +1. +Rutkow IM. +Demographic and socioeconomic aspects of her- +nia repair in the United States in 2003. +Surg Clin North Am. +2003;83:1045. +2. +Gould J. +Laparoscopic versus open inguinal hernia repair. +Surg Clin N Am. +2008;88:1073-1081. +3. +Abramson JH, Gofin J, Hopp C, et al. +The epidemiology of +inguinal hernia. +A survey in western Jerusalem. +J Epidemiol +Community Health. +1978;32:59. +4. +Rutkow IM. +Surg Clin +North Am. +1998;78:941. +5. +Johnson J, Roth JS, Hazey JW, et al. +The history of open +inguinal hernia repair. +Curr Surg. +2004;61:49. +6. +Desarda MP. +Physiological repair of inguinal hernia: a +new 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Hallen M, Leveau P, et al. +Surgery. +2003;133:464. +92. +Hallen M, Bergenfelz A, Westerdahl J. +Surgery. +2008;143:313. +93. +Lau H, Patil NG, Yuen WK. +Surg Endosc. +2006;20:76. +94. +Neumayer L, Giobbie-Hurder A, Jonasson O, et al. +Open +mesh versus laparoscopic mesh repair of inguinal hernia. +N Engl J Med. +2004;350:1819. +95. +Lal P, Kajla RK, Chander J, et al. +Laparoscopic total extraperi- +toneal (TEP) inguinal hernia repair: overcoming the learning +curve. +Surg Endosc. +2004;18:642. +96. +Katkhouda N, Campos GMR, Mavor E, et al. +Laparoscopic +extraperitoneal inguinal hernia repair. +A safe approach based +on the understanding of rectus sheath anatomy. +Surg Endosc. +1999;13:1243-1246. +97. +Wake BL, McCormack K, Fraser C, et al. +Cochrane Data- +base Syst Rev. +2005;1:CD004703. +This page intentionally left blank +Thyroid, Parathyroid, and Adrenal +Geeta Lal and Orlo H. +even +though the thyroid gland was not documented as such until the +Renaissance period. +Burnt seaweed was considered to +be the most effective treatment for goiters. +The open wound was treated with caustic powder and +left to heal. +The most notable thyroid surgeons were Emil Theodor Kocher +(1841��1917) and C.A. +However, as more patients survived thyroid operations, +new problems and issues became apparent. +It originates at the +base of the tongue at the foramen cecum. +38-1) that descends in the neck anterior +to structures that form the hyoid bone and larynx. +The +epithelial cells making up the anlage give rise to the thyroid fol- +licular cells. +Developmental Abnormalities +Thyroglossal Duct Cyst and Sinus. +Thyroglossal duct cysts +are the most commonly encountered congenital cervical anoma- +lies. +Rarely, the thyroglossal duct may persist in +whole or in part. +Medullary thyroid cancers (MTCs) are, however, not +found in thyroglossal duct cysts. +Lingual Thyroid. +Many of these patients develop +hypothyroidism. +Ectopic Thyroid. +Thyroid embryology—early development of the +median thyroid anlage as a pharyngeal pouch. +(Reproduced with +permission from Embryology and developmental abnormalities. +In: Cady B, Rossi R, eds. +Surgery of the Thyroid and Parathyroid +Glands. +2 Familial nonmedullary thyroid cancer is increasingly being +recognized as a separate entity. +Pyramidal Lobe. +Normally the thyroglossal duct atrophies, +although it may remain as a fibrous band. +38-2. +A pyrami- +dal lobe is present in about 50% of patients. +Blood Supply. +The inferior +Sup. +thyroid a. +and v. +Pyramidal +lobe +Common carotid a. +Common carotid a. +Thyroid +cartilage +Int. +jugular v. +Int. +jugular v. +Recurrent laryngeal n. +Recurrent +laryngeal n. +Vagus n. +Vagus n. +Vagus n. +Arch of aorta +Thyrocervical +trunk +Inf. +thyroid v. +Middle thyroid v. +Ext. +carotid a. +Thyroidea ima a. +(variable) +Trachea +Sternocleido- +mastoid m. +Inf. +thyroid a. +Vertebral +v. +and a. +Thyroid gland +Strap muscles +A +B +Figure 38-2. +a. += artery; +m. += muscle; n. += nerve; v. += vein. +The superior thyroid veins run with the superior +thyroid arteries bilaterally. +The middle vein or veins are the least +consistent. +The superior and middle veins drain directly into the +internal jugular veins. +The inferior veins often form a plexus, +which drains into the brachiocephalic veins. +nerves. +The right RLN arises from the vagus at its crossing with +the right subclavian artery. +38-3). +The RLNs terminate by entering the +larynx posterior to the cricothyroid muscle. +The superior laryngeal nerves also arise from the vagus +nerves. +The internal branch of +the superior laryngeal nerve is sensory to the supraglottic larynx. +Injury to this nerve is rare in thyroid surgery, but its occurrence +may result in aspiration. +38-4). +The fibers enter the gland with the blood vessels and +are vasomotor in action. +Parathyroid Glands. +38-5). +Lymphatic System. +The thyroid gland is endowed with an +extensive network of lymphatics. +These lymph nodes can +be classified into seven levels as depicted in Fig. +38-6. +38-7). +There are about 3 × 106 follicles +in the adult male thyroid gland. +The follicles are spherical and +average 30 μm in diameter. +Thyroid Physiology +Iodine Metabolism. +The remaining plasma iodine is cleared +via renal excretion. +Thyroid Hormone Synthesis, Secretion, and Transport. +The synthesis of thyroid hormone consists of several steps +(Fig. +38-8). +(Reproduced with permission from Bliss RD +et al. +Surgeon’s approach to the thyroid gland: Surgical anatomy +and the importance of technique. +World J Surg. +2000;24:893. +Both processes are catalyzed by +thyroid peroxidase (TPO). +The latter are deiodinated in the fifth step to +yield iodide, which is reused in the thyrocyte. +T3 is +less tightly bound to protein in the plasma than T4, and so it +enters tissues more readily. +The secretion of thyroid hormone is controlled by the +hypothalamic-pituitary-thyroid axis (Fig. +38-9). +TRH reaches the pituitary via the portovenous +circulation. +T3 also +inhibits the release of TRH. +Epinephrine +and human chorionic gonadotropin hormones stimulate thyroid +hormone production. +In contrast, glucocorticoids inhibit thyroid +Lower parathyroid +Upper parathyroid +Int. +jugular v. +Recurrent laryngeal n. +Thyroid +Inferior thyroid a. +Common carotid a. +Figure 38-5. +Relationship of the parathyroids to the recurrent laryngeal nerve. +a. += artery; v. += vein. +1527 +T +HYROID +, P +ARATHYROID +, +A +n +D + A +DRE +n +AL +CHAPTER 38 +hormone production. +Thyroid Hormone Function. +In humans, two types of T3 receptor genes (α and β) are +located on chromosomes 3 and 17. +Sternocleidomastoid m. +Spinal accessory n. +A and B. +Lymph nodes in the neck can be divided into six regions. +Upper mediastinal nodes constitute level VII. +m. += muscle; +n. += nerve. +Thyroid hormones affect almost every system in the body. +They are important for fetal brain development and skeletal mat- +uration. +Myocardial α recep- +tors are decreased, and actions of catecholamines are amplified. +Evaluation of Patients with Thyroid Disease +Tests of Thyroid Function. +A multitude of different tests are +available to evaluate thyroid function. +Figure 38-7. +Normal thyroid histology—follicular cells surround +colloid. +The protein kinase C (PKC) pathway is stimulated at higher +doses of TSH. +Mono- and diiodotyrosyl (MIT, DIT) residues are also coupled to form T4 and T3 by TPO. +Thyroglobulin carrying T4 and T3 is then +internalized by pinocytosis and digested in lysosomes. +Thyroid hormone is released into the circulation, while MIT and DIT are deiodinated +and recycled. +(Reproduced with permission from Kopp P. +Pendred’s syndrome and genetic defects in thyroid +hormone synthesis. +Rev Endocr Metab Disord. +2000;1:114. +Serum TSH levels reflect the ability of the anterior +pituitary to detect free T4 levels. +Individuals with these latter disorders may be euthyroid if their +free T4 levels are normal. +Free T4 estimates are not performed as a routine screening +tool in thyroid disease. +Free T4 levels may also +be measured indirectly using the T3-resin uptake test. +Therefore, more T3 binds with an ion-exchange resin, and +the T3-resin uptake is increased. +In a normal individual, TSH levels +should increase at least 6 μIU/mL from the baseline. +Serum Thyroglobulin Tg is only made by normal or abnormal +thyroid tissue. +It is also a sensitive marker of MTC. +In contrast, 131I has a half-life +of 8 to 10 days and leads to higher-dose radiation exposure. +Hypothalamic-pituitary-thyroid hormone axis. +T4 = thyroxine. +(Reproduced with permission from Greenspan FS. +The thyroid gland. +In: Greenspan FS, Gardner D, eds. +Basic and +Clinical Endocrinology. +6th ed. +New York: McGraw-Hill; 2001:217. +Areas that trap less radioactivity than the +surrounding gland are termed cold (Fig. +38-10), whereas areas +that demonstrate increased activity are termed hot. +This isotope is taken up by +the mitochondria, but is not organified. +It also has the advantage +of having a shorter half-life and minimizes radiation exposure. +It is particularly sensitive for nodal metastases. +There +are several recent reports of rates of malignancy in these lesions +ranging from 14% to 63%. +Ultrasound is also especially help- +ful for assessing cervical lymphadenopathy (Fig. +38-11) and to +guide FNAB. +An experienced ultrasonographer is necessary for +the best results. +If contrast is +necessary, therapy needs to be delayed by several months. +Com- +bined PET-CT scans are increasingly being used for Tg-positive, +RAI-negative tumors. +Benign Thyroid Disorders +Hyperthyroidism. +Hyperthyroidism may arise from a number of conditions that +are listed in Table 38-1. +Figure 38-11. +Thyroid ultrasound showing a lymph node (arrow) along the carotid artery. +Figure 38-10. +Etiology, Pathogenesis, and Pathology. +The exact etiology of +the initiation of the autoimmune process in Graves’ disease is +not known. +The nuclei exhibit mitosis, and papillary projections of +hyperplastic epithelium are common. +There may be aggregates +of lymphoid tissue, and vascularity is markedly increased. +Clinical Features. +The most common GI symptoms include increased frequency +of bowel movements and diarrhea. +On physical examination, weight loss and facial flush- +ing may be evident. +The skin is warm and moist, and African +American patients often note darkening of their skin. +38-12). +Gynecomastia is com- +mon in young men. +Onycholysis, or separation of fingernails from their +beds, is a commonly observed finding. +Diagnostic Tests. +If eye signs are present, other tests are generally not +needed. +However, in the absence of eye findings, an 123I uptake +and scan should be performed. +Anti-Tg and anti-TPO antibodies are elevated in +up to 75% of patients but are not specific. +MRI scans +of the orbits are useful in evaluating Graves’ ophthalmopathy. +Treatment. +The choice of treatment depends +on several factors, as discussed in the following sections. +Antithyroid Drugs. +Antithyroid medications generally are admin- +istered in preparation for RAI ablation or surgery. +Methimazole has a longer half-life and can be +dosed once daily. +Surgery should be +postponed until the granulocyte count reaches 1000 cells/mm3. +The dose of antithyroid medication is titrated as needed +in accordance with TSH and T4 levels. +Most patients have +improved symptoms in 2 weeks and become euthyroid in about +6 weeks. +The length of therapy is +debated. +These drugs have the added +effect of decreasing the peripheral conversion of T4 to T3. +Higher doses are some- +times required due to increased clearance of the medication. +Caution should be exercised in patients with asthma. +Radioactive Iodine Therapy (131I). +RAI forms the mainstay of +Graves’ disease treatment in North America. +Antithyroid drugs are given until the patient +A +B +Figure 38-12. +A. +Graves’ ophthalmopathy and (B) pretibial myx- +edema. +After standard treat- +ment with RAI, most patients become euthyroid within 2 months. +Lack of access to a high-volume thyroid surgeon +is also a consideration. +Surgical Treatment. +Surgery is best performed in +the second trimester. +The major action of iodine in this situation is to +inhibit release of thyroid hormone. +Steroids can be a useful adjunct in this situation. +euthyroidism) and surgeon experience. +A subtotal thyroidectomy, leaving a 4- +to 7-g remnant, was recommended for all remaining patients. +Over several years, enough +thyroid nodules become autonomous to cause hyperthyroidism. +Diagnostic Studies. +Treatment. +Hyperthyroidism must be adequately controlled. +Both RAI and surgical resection may be used for treatment. +RAI scanning shows a “hot” +nodule with suppression of the rest of the thyroid gland. +These +nodules are rarely malignant. +Smaller nodules may be man- +aged with antithyroid medications and RAI. +Larger nodules can +require higher doses, which can lead to hypothyroidism. +Oxygen supplementation and hemodynamic support +should be instituted. +Hypothyroidism. +Conditions that cause hypothyroidism are listed in Table 38-2. +Failure to thrive and severe mental retardation often are +present. +Hair becomes dry and brittle, and severe hair loss +may occur. +There is also a characteristic loss of the outer two +thirds of the eyebrows. +Patients may also have nonspecific abdomi- +nal pain accompanied by distention and constipation. +Libido +and fertility are impaired in both sexes. +Laboratory Findings Hypothyroidism is characterized by low +circulating levels of T4 and T3. +An electrocardiogram demonstrates +decreased voltage with flattening or inversion of T waves. +The dose can be slowly increased over weeks to months to +attain a euthyroid state. +Thyroiditis. +CT +scans may help to delineate the extent of infection and identify +abscesses. +Thyroidec- +tomy may be needed for persistent abscesses or failure of open +drainage. +Subacute Thyroiditis Subacute thyroiditis can occur in the +painful or painless forms. +History of a preceding upper respiratory tract infection +often can be elicited. +The gland is enlarged, exquisitely ten- +der, and firm. +The disorder classically progresses through four +stages. +A few patients develop recurrent disease. +The erythro- +cyte sedimentation rate is typically >100 mm/h. +Painful thyroiditis is self-limited, and therefore, +treatment is primarily symptomatic. +Short-term thyroid +replacement may be needed and may shorten the duration of +symptoms. +The clinical course also paral- +lels painful thyroiditis. +Patients with symptoms may require +β-blockers and thyroid hormone replacement. +Chronic Thyroiditis +Lymphocytic (Hashimoto’s) Thyroiditis. +Etiology, Pathogenesis, and Pathology. +Once activated, T cells can recruit cytotoxic +CD8+ T cells to the thyroid. +Clinical Presentation. +An enlarged pyramidal lobe often is palpable. +Diagnostic Studies. +The disease occurs predomi- +nantly in women between the ages of 30 and 60 years old. +Physical examination reveals a hard, “woody” thyroid +gland with fixation to surrounding tissues. +Surgery is the mainstay of the treatment. +Hypothyroid patients are treated with thyroid hormone +replacement. +Any enlargement of the thyroid gland is referred to as +a goiter. +The causes of nontoxic goiters are listed in Table 38-3. +Goiters may be diffuse, uninodular, or multinodular. +The TSH-dependent nodules progress +to become autonomous. +In the past, dietary +iodine deficiency was the most common cause of endemic goi- +ter. +In many sporadic goiters, no obvi- +ous cause can be identified. +As the goiters become very large, compres- +sive symptoms such as dyspnea and dysphagia ensue. +Patients +also describe having to clear their throats frequently (catarrh). +Dysphonia from RLN injury is rare, except when malignancy is +present. +38-13A). +Sudden enlargement of nodules +or cysts due to hemorrhage may cause acute pain. +Deviation or compression of the trachea +may be apparent. +If some nod- +ules develop autonomy, patients have suppressed TSH levels or +become hyperthyroid. +RAI uptake often shows patchy uptake +with areas of hot and cold nodules. +CT scans are helpful to evaluate the extent +of retrosternal extension and airway compression (Fig. +38-13B). +Treatment Most euthyroid patients with small, diffuse goi- +ters do not require treatment. +Endemic goiters are treated by iodine +administration. +History. +Patients with MTC may complain of a dull, aching +sensation. +A history of hoarseness is worrisome, as it may be +secondary to malignant involvement of the RLNs. +The risk is maximum 20 to 30 years +after exposure, but these patients require lifelong monitoring. +The thyroid gland is best palpated +from behind the patient and with the neck in mild extension. +The cricoid cartilage is an important landmark, as the isthmus +is situated just below it. +2 +1538 +SPECIFIC CONSIDERATIONS +UNIT II +part II +Diagnostic Investigations. +An algorithm for the workup of +a solitary thyroid nodule is shown in Fig. +38-14. +A. +This may become more prominent when patients raise their arms above the head—Pemberton’s sign. +B. +A sample of the aspirate is +also placed in a 90% alcohol solution for cytospin or cell pellet. +The slides are stained by Papanicolaou’s or Wright’s stains and +examined under the microscope. +A “benign” result is obtained in 60% to 70% of thyroid FNAs. +Other diagnoses include lymphocytic (Hashimoto’s) +thyroiditis and granulomatous thyroiditis. +Management of a solitary thyroid nodule based on Bethesda criteria. +Hürthle cell neo- +plasms are also included in this category. +Laboratory Studies Most patients with thyroid nodules are +euthyroid. +Determining the blood TSH level is helpful. +There is insufficient evidence to recom- +mend routine calcitonin testing for all nodules. +Ultrasound elastography is used +to evaluate tissue stiffness noninvasively. +PET scanning does not play a major role in the primary +evaluation of thyroid nodules. +Management. +When +FNAB is used in complex nodules, the solid portion should be +sampled. +If the nodule enlarges, repeat FNAB often is indicated. +In iodine-sufficient populations, the +data are less impressive. +Thyroid cancer is respon- +sible for six deaths per million persons annually. +Molecular Genetics of Thyroid Tumorigenesis. +The RET +proto-oncogene (Fig. +38-15) plays a significant role in the +pathogenesis of thyroid cancers. +The RET protein is expressed in tissues derived +from the embryonic nervous and excretory systems. +Structure of the RET tyrosine kinase receptor. +FMTC is associated with mutations at codons 768 and 804. +ATP = adenosine +triphosphate. +(Reproduced with permission from Wells S, Franz C. +Medullary carcinoma of the thyroid. +World J Surg. +2000;24:954. +The tyrosine +kinase domain of RET can fuse with other genes by rearrange- +ment. +These rearrangements +confer constitutive activation of the receptor tyrosine kinases. +Aberrant activation of the MAPK pathway leads to +tumorigenesis. +Aside from RET/PTC alterations, mutations in +the Ras genes can also activate the MAPK pathway. +There are three +Raf kinases, A-Raf, B-Raf (BRAF), and C-Raf. +Most patients are euthyroid and +present with a slow-growing painless mass in the neck. +Dys- +phagia, dyspnea, and dysphonia usually are associated with +locally advanced invasive disease. +Diagnosis is established by FNAB of the thyroid mass +or lymph node. +The most common sites are lungs, fol- +lowed by bone, liver, and brain. +Pathology. +Macroscopic calcification, necrosis, or cystic change may be +apparent. +Histologically, papillary carcinomas may exhibit pap- +illary projections (Fig. +The diagnosis is established by characteristic nuclear +cellular features. +38-16B]), which allow diagnosis +by FNAB. +These tumors +are also being identified more frequently due to the widespread +use of ultrasound. +About 25% of patients +with these tumors have associated occult lymph node metastases. +Prognostic Indicators. +In general, patients with PTC have an +excellent prognosis with a >95% 10-year survival rate. +The MACIS scale +is a postoperative system modified from the AGES scale. +Surgical Treatment. +38-17). +When final histology confirms carcinoma, +4 +Figure 38-16. +A. +Histomicrograph of a papillary thyroid cancer (hematoxylin-eosin stain). +B. +1544 +SPECIFIC CONSIDERATIONS +UNIT II +part II +completion thyroidectomy usually is performed. +Pain is uncommon, unless hemorrhage into the nodule has +occurred. +FNAB is unable to distinguish +benign follicular lesions from follicular carcinomas. +Large follicular tumors (>4 cm) in +older men are more likely to be malignant. +Many of these genetic changes can be identified using tis- +sue obtained during FNAB. +Additional studies are needed to assess its utility in the broader +clinical setting.41 +Pathology. +Follicular carcinomas usually are solitary lesions, +and the majority are surrounded by a capsule. +Histologically, +follicles are present, but the lumen may be devoid of colloid. +Architectural patterns depend on the degree of differentiation +demonstrated by the tumor. +Malignancy is defined by the pres- +ence of capsular and vascular invasion (Fig. +38-18). +They may, in fact, be unencapsulated. +Surgical Treatment and Prognosis. +(Reproduced with permission from Mazzaferri E, Jhiang S. +Am J Med. +1994;97:424. +Copyright Elsevier.) +Figure 38-18. +Hematoxylin-eosin–stained section from follicular +thyroid carcinoma showing capsular invasion. +1546 +SPECIFIC CONSIDERATIONS +UNIT II +part II +of thyroid cancer, or a history of radiation exposure. +Total thyroidectomy should be performed when thyroid cancer +is diagnosed. +Prophylactic central neck dissection may be con- +sidered in patients with large tumors. +Hence, they are considered to +be a separate class of tumors by some groups. +Early detection therefore +appears to be very important to improve prognosis. +Several features place patients at increased risk for local +recurrences or metastases. +Patients should receive +T3 during this time period to decrease the period of hypothyroid- +ism. +T3 has a shorter half-life than T4 (1 day vs. +1 week) and needs +to be discontinued for 2 weeks to allow TSH levels to rise before +treatment. +Levels >30 mU/L are considered optimal, based on non- +controlled studies. +A low-iodine diet also is recommended during +this 2-week period. +After a total thyroidectomy, this value should be <1%. +A 30-mCi dose is also effective +at ablating the remnant with recombinant TSH. +Tumor recurrence at a median of 16.7 years after thyroid surgery. +The P values are derived from log-rank statistical analysis of 40-year life- +table data. +(Reproduced with permission from Mazzaferri E, Kloos R. +Current approaches to primary therapy for +papillary and follicular thyroid cancer. +J Clin Endocrinol Metab. +2001;86:1453. +Up to 500 mCi can be +given with proper pretreatment dosimetry. +Other kinases target- +ing the VEGF and RET receptors have also shown promising +results. +TSH suppression reduces tumor recurrence rates. +Most MTCs occur sporadically. +All these +variants are known to result secondary to germline mutations in +the RET proto-oncogene. +The salient +clinical and genetic features of these syndromes are outlined +in Table 38-8. +Some clinical features of MEN2B patients are +shown in Fig. +38-20. +The female-to-male ratio is 1.5:1. +BA +Figure 38-20. +Features of MEN2B: thickened lips (A) and mucosal neuromas (A and B). +1550 +SPECIFIC CONSIDERATIONS +UNIT II +part II +Pathology. +Marked heterogeneity is present; cells may be polygo- +nal or spindle shaped. +These tumors also +stain positively for CEA and calcitonin gene–related peptide. +Diagnosis. +Calcitonin and CEA +are used to identify patients with persistent or recurrent MTC. +Calcitonin is a more sensitive tumor marker, but CEA is a better +predictor of prognosis. +Treatment. +Pheochromocytomas +need to be excluded. +If patients are found to have a pheochro- +mocytoma, this must be operated on first. +These tumors are gen- +erally (>50%) bilateral. +The role of prophylactic lateral neck +dissection is controversial. +However, chemoembolization may +be helpful in this setting. +There is no effective chemotherapy +regimen. +Patients with recurrent/metastatic disease +should be enrolled in well-designed clinical trials. +Postoperative Follow-Up and Prognosis. +Prognosis is related to dis- +ease stage. +Sur- +vival also is significantly influenced by disease type. +Prognosis is the +worst (survival of 35% at 10 years) in patients with MEN2B. +The +typical patient has a long-standing neck mass, which rapidly +enlarges and may be painful. +Associated symptoms such as +dysphonia, dysphagia, and dyspnea are common. +38-21). +Lymph nodes usually +are palpable at presentation. +Evidence of metastatic spread also +may be present. +Diagnosis is confirmed by FNAB revealing +characteristic giant and multinucleated cells. +Immunohistochemical markers can aid with excluding other +diagnoses. +Pathology. +On gross inspection, anaplastic tumors are firm and +whitish in appearance. +Microscopically, sheets of cells with +marked heterogeneity are seen. +The three main histologic growth +patterns are spindle cell, squamoid, and pleomorphic giant cell. +Tumors may show a predominance of one pattern or a mixture +of various patterns. +Treatment and Prognosis. +All forms of treatment have been disappoint- +ing. +All patients should have preoperative laryngoscopy to assess +the status of the vocal cords. +Tracheostomy should be avoided as long as +possible unless there is impending airway loss. +Patients may present with acute +respiratory distress. +Therefore, needle core or open biopsy may be necessary for +definitive diagnosis. +Combined treatment with +radiotherapy and chemotherapy often is recommended. +The patient is positioned supine, with a sandbag +between the scapulae. +The head is placed on a donut cushion, +and the neck is extended to provide maximal exposure. +38-22A), although longer incisions may be needed. +Magnetic resonance imaging scan of a patient +with anaplastic thyroid cancer. +Note heterogeneity consistent with +necrosis. +38-22B). +The strap muscles rarely need to be divided to +gain exposure to the thyroid gland. +C +Cricothyroid m. +External branch of +superior laryngeal n. +Superior +thyroid vessels +D +Figure 38-22. +Conduct of thyroidectomy. +A. +Correct placement of thyroidectomy incision. +B. +Raising subplatysmal flaps. +C. +Dissection of +middle thyroid vein. +D. +Dissection of the superior pole vessels, which should be individually ligated. +E. +Dissection at the ligament of Berry. +F. +Endoscopic thyroidectomy via axillary +incisions. +m. += muscle; n. += nerve; v. += vein. +The middle thyroid veins are ligated and +divided (Fig. +38-22C). +The +fascia just cephalad and caudad to the isthmus is divided. +38-22D). +The RLNs should then be identified. +The course of the right +RLN is more oblique than the left RLN. +The nerves can be most +consistently identified at the level of the cricoid cartilage. +Thyroid +E +F +Figure 38-22. +The RLN is most vulnerable to +injury in the vicinity of the ligament of Berry. +38-22E). +Use of the electrocautery should +be avoided in proximity to the RLN. +The procedure +is repeated on the opposite side for a total thyroidectomy. +The +sites should be marked with silk sutures and a clip. +The thyroid remnant +is suture ligated, taking care to avoid injury to the RLN. +Routine +drain placement rarely is necessary. +After adequate hemostasis +is obtained, the strap muscles are reapproximated in the midline. +The platysma is approximated in a similar fashion. +The skin can +be closed with subcuticular sutures or clips. +Video assis- +tance can be used to improve the visualization via the small inci- +sion. +The +endoscopic approaches can also be performed with the assistance +of robotic techniques. +38-22F). +An additional 5-mm +trocar is inserted adjacent to the incision. +The thyroid gland is exposed by split- +ting the sternothyroid muscle. +The lower pole is retracted upward +and dissected from the adipose tissue to identify the RLN. +The upper pole of the thyroid gland +then is dissected free. +Mediastinal goiters can be primary or second- +ary. +Virtually all intratho- +racic goiters can be removed via a cervical incision. +The goiter is approached via a neck incision. +The supe- +rior pole vessels and the middle thyroid veins are identified and +ligated first. +Placement of large 1-0 or 2-0 sutures deep into the goiter, when +necessary, helps deliver it. +38-23). +1 +2 +3 +Figure 38-23. +Conduct of thyroidectomy. +Incisions for a partial +sternotomy. +38-24A) to the anterior margin +of the trapezius muscle. +In contrast to +1 +2 +3 +McFee incision +A +B +Spinal +accessory n. +Phrenic n. +Vagus n. +Scalenus +anticus m. +Lymph +nodes +Carotid a. +Internal +jugular v. +Figure 38-24. +Conduct of neck dissection. +A. +Incisions for modified radical neck dissection. +B. +Anatomic relations of structures identified dur- +ing a modified radical neck dissection. +a. += artery; +m. += muscle; n. += nerve. +38-24B). +Seromas may need +aspiration to relieve patient discomfort. +Despite this, the technology has become widely adopted. +Not all experts agree with this recommendation. +In 1926, the first parathyroid operation was +performed at Massachusetts General Hospital. +Olch at the Barnes Hospital in St. +Louis, Missouri. +Postoperatively, the patient +developed tetany, requiring lifelong supplemental calcium. +The third branchial pouches give rise to the inferior para- +thyroid glands and the thymus (Fig. +38-25). +Approximately 15% of inferior glands are found in the +thymus. +The frequency of intrathyroidal glands +is about 2%. +Anatomy and Histology +Most patients have four parathyroid glands. +Parathyroid color depends on cellularity, fat content, and vas- +cularity. +Moreover, they often are embedded in and sometimes +difficult to discern from surrounding fat. +Normal parathyroid +glands are located in loose tissue or fat and are ovoid. +They +measure up to 7 mm in size and weigh approximately 40 to 50 +mg each. +The parathyroid glands drain ipsilaterally by the superior, mid- +dle, and inferior thyroid veins. +Super- +numerary glands were present in 13% of patients, most com- +monly in the thymus. +Only 3% of patients had less than four +glands. +38-26). +Parathyroid embryology. +(Reproduced +with permission from Henry J. +Applied embryology of the thyroid +and parathyroid glands. +In: Randolph G, ed. +Surgery of the Thyroid +and Parathyroid Glands. +Philadelphia: WB Saunders Company; +2003. +Copyright Elsevier.) +Figure 38-26. +Normal parathyroid histology showing chief cells +interspersed with adipose cells. +Calcium is absorbed from the small intestine in its +inorganic form. +Calcium fluxes in the steady state are depicted +in Fig. +38-27. +Approximately 50% of the serum cal- +cium is in the ionized form, which is the active component. +The +remainder is bound to albumin (40%) and organic anions such +as phosphate and citrate (10%). +Both concentrations are tightly regulated. +Total and, particularly, ionized calcium levels are influenced by +various hormone systems. +Parathyroid Hormone. +38-28). +The PTH gene is located on +chromosome 11. +Secreted PTH +has a half-life of 2 to 4 minutes. +The C-terminal component is excreted by +the kidneys and accumulates in chronic renal failure. +Calcitonin. +When administered intravenously to +experimental animals, it produces hypocalcemia. +At the kidney, +calcitonin increases phosphate excretion by inhibiting its reab- +sorption. +Calcitonin plays a minimal, if any, role in the regula- +tion of calcium levels in humans. +However, it is very useful as +a marker of MTC and in treating acute hypercalcemic crisis. +Vitamin D. +Vitamin D2 is available commercially in pharma- +PTH +PTH +VIT. +D PTH +Figure 38-27. +Calcium balance and fluxes +in a normal human. +Solid arrows depict a +direct effect, whereas dashed arrows depict +an indirect effect. +The thickness of the arrows +is representative of the magnitude of the flux. +ECF = extracellular fluid; PTH = parathyroid +hormone; VIT. += vitamin. +(Reproduced with +permission from Bruder J, et al. +Mineral +metabolism. +In: Felig P, Frohman L, eds. +Endocrinology and Metabolism. +New York: +McGraw-Hill Publishers, Inc; 2001:1081. +Vitamin D is metabolized in the +liver to its primary circulating form, 25-hydroxyvitamin D. +Primary Hyperparathyroidism. +PHPT is a common dis- +order, affecting 100,000 individuals annually in the United +States. +Etiology. +Various diets and inter- +mittent exposure to sunshine may also be related. +Regulation of calcium homeostasis. +PKC = +protein kinase C; PLC = phospholipase C. +(Reproduced with permission from Carling T. +Molecular pathology of parathyroid tumors. +Trends +Endocrinol Metab. +2001;12:54. +Genetics Most cases of PHPT are sporadic. +All of these syndromes are +inherited in an autosomal dominant fashion. +About 50% of patients develop gastri- +nomas, which often are multiple and metastatic at diagnosis. +This makes +presymptomatic screening for mutation carriers difficult. +HPT develops in about 20% +of patients with MEN2A and generally is less severe. +MEN2A +is caused by germline mutations of the RET proto-oncogene +located on chromosome 10. +This syndrome maps to a tumor suppressor locus +HRPT2 (CDC73 or parafibromin) on chromosome 1. +Patients +belonging to isolated HPT kindreds also appear to demonstrate +linkage to HRPT2. +RET mutations are rare in +sporadic parathyroid tumors. +These alterations are rare in benign para- +thyroid tumors and may have implications for diagnosis. +The +p53 tumor suppressor gene is also inactivated in a subset (30%) +of parathyroid carcinomas. +They are more likely to be mini- +mally symptomatic or asymptomatic. +Complications of +PHPT are described below. +Renal Disease. +Approximately 80% of patients with PHPT have +some degree of renal dysfunction or symptoms. +The calculi are typically composed of +calcium phosphate or oxalate. +Bone Disease. +Advanced PHPT +with osteitis fibrosa cystica now occurs in <5% of patients. +38-29). +Brown or osteoclastic tumors and bone cysts also +may be present. +Bone disease correlates +with serum PTH and vitamin D levels. +Gastrointestinal Complications. +PHPT has been associated with +peptic ulcer disease. +neuropsychiatric Complications. +The etiology of these symptoms +is not known. +Other Features. +PHPT and malig- +nancy account for >90% of all cases of hypercalcemia. +Figure 38-29. +Thiazide diuretics cause hypercalcemia by decreasing +renal clearance of calcium. +Patients +with FHH have lifelong hypercalcemia, which is not cor- +rected by parathyroidectomy. +Diagnostic Investigations +Biochemical Studies. +Furthermore, they do not cross- +react with PTHrP (Fig. +38-30). +Although extremely rare, +a patient with hypercalcemia may have a tumor that secretes +PTH. +In patients with FHH, 24-hour +urinary calcium excretion is characteristically low (<100 mg/d). +Other biochemical features of +PHPT are listed in Table 38-10. +(Reproduced with permission from Endres D, et al. +Measure- +ment of parathyroid hormone. +Endocrinol Metab Clin North Am. +1989;18:622. +These patients are prone to developing postoperative hypo- +calcemia due to bone hunger. +Serum and urine protein electro- +phoresis may be necessary to exclude multiple myeloma. +This can be accomplished by administering thiazide +diuretics. +Radiologic Tests. +Abdominal ultrasound examination is used +selectively to document renal stones. +Treatment +Indications for Parathyroidectomy and Role of Medical Management. +Average bone mass also remained relatively stable. +Unfortunately, bone density failed to improve in medi- +cally treated patients. +In addition, patients <50 years of age are advised +to undergo parathyroidectomy. +Similarly, uncertainty is also pres- +ent concerning the cardiovascular consequences of mild HPT. +Localization studies may be +classified into noninvasive or invasive modalities. +Some studies also show that +use of localization studies may be more cost-effective. +99mTc-labeled sestamibi (Fig. +Sestamibi scans generally are complemented by neck ultra- +sound (Fig. +More recently, four-dimensional CT (4D-CT) has shown +utility in parathyroid localization. +IOPTH mea- +surements, like localization studies, are less reliable in multiglan- +dular disease. +A. +B. +Endoscopic approaches include both video-assisted and +total endoscopic techniques. +The +procedure usually is performed under general anesthesia. +The +patient is positioned supine on the operating table with the neck +extended. +The +initial dissection and exposure is similar to that used for thy- +roidectomy. +Identification of Parathyroids. +A bloodless field is important to +allow identification of parathyroid glands. +(Repro- +duced with permission from Irvin G, et al. +Clinical usefulness of +an intraoperative “quick parathyroid hormone” assay. +Surgery. +1993;114:1020. +This maneuver often causes the parathyroid gland to “pop” out. +Normal parathyroids are light beige and only slightly darker or +brown compared to adjacent fat. +Hypercellular glands generally are darker, more firm, and more +vascular than normocellular glands. +Location of Parathyroid Glands. +The majority of lower parathy- +roid glands are found in proximity to the lower thyroid pole +(Fig. +38-33A). +If not found at this location, the thyrothymic +ligament and thymus should be mobilized. +One can then “walk down” the thymus with suc- +cessive right-angle clamps (Fig. +38-33B). +Applying light tension +along with a “twisting” motion helps to free the upper thymus. +38-33C). +The locations of ectopic upper and lower parathyroid glands are +shown in Fig. +38-34. +Every attempt must be made to identify +Upper parathyroid gland +Recurrent +laryngeal n. +Inf. +thyroid a. +Thymus +Lower +parathyroid +gland +Thyroid +A +B +C +Figure 38-33. +Conduct of parathyroidectomy. +A. +B. +C. +a. += artery; Inf. += inferior; +n. += nerve. +1569 +T +HYROID +, P +ARATHYROID +, +A +n +D + A +DRE +n +AL +CHAPTER 38 +all four glands. +Treatment depends on the number of abnormal +glands. +1. +The vascular pedicle is +clamped, divided, and ligated. +2. +If two abnormal and two normal glands are identified, the +patient has double adenomas. +Triple adenomas are present +if three glands are abnormal and one is normal. +3. +It often is difficult to distinguish multiple adenomas +from hyperplasia with variable gland size. +Hyperplasia may +be of the chief cell (more common), mixed, or clear cell +type. +However, autotransplanted tissue may fail to function in +about 5% of cases. +All four parathyroid glands are identified and carefully +mobilized. +The resected parathyroid tis- +sue is confirmed by frozen section or PTH assay. +If the rem- +nant appears to be viable, the remaining glands are resected. +Parathyroid tissue usually is transplanted into the +nondominant forearm. +A total of 12 to 14 pieces are +transplanted. +Autotransplanted tissue also has been reported to +function when transplanted into fat. +Intraoperative +PTH assay during the operation from large veins may be helpful. +A sternotomy is needed to deliver these tumors in approxi- +mately 5% of cases. +Location of ectopic upper and +lower parathyroid glands. +(Reproduced with +permission from Akerström G, et al. +Surgical +anatomy of human parathyroid glands. +Surgery. +1984;95:15. +The midline +sternotomy can be extended to the left or right side as required. +Upper glands tend to migrate to the posterior mediastinum in +the tracheoesophageal groove. +Special Situations +normocalcemic Hyperparathyroidism. +Data regarding the natural history of this +disorder are limited. +Limited studies show that parathyroidectomy is more +likely to be unsuccessful in these patients. +Parathyroid Carcinoma. +Parathyroid cancer accounts for approx- +imately 1% of PHPT cases. +Enlarged lymph nodes +also may be present. +Frozen sections are generally unreliable. +Accurate diagnosis necessitates histologic examination. +The recurrent nerve is not sacrificed unless it is directly +involved with tumor. +Adherent soft tissue structures (strap +muscles or other soft tissues) should also be resected. +Prophylactic neck dissection is +not advised. +If any question exists, +histologic review by another experienced pathologist can +be helpful. +Patients with equivocal pathologic findings and normo- +calcemia may be monitored closely. +Reoperation is indicated for +locally recurrent or metastatic disease to control hypercalcemia. +Chemotherapy is +not very effective. +Familial Hyperparathyroidism. +PHPT may occur as a component +of various inherited syndromes such as MEN1 and MEN2A. +Inherited PHPT also can occur as isolated familial HPT (non- +MEN) or familial HPT with jaw tumors. +Moreover, HPT is less aggressive in +these patients. +Hence, only abnormal parathyroid glands need +to be resected at neck exploration. +The other normal parathyroid +glands should be marked with a clip. +neonatal Hyperparathyroidism. +This disorder is associated with homozygous mutations in +the CASR gene. +Subtotal resection is associated with high recurrence rates. +Parathyromatosis. +The true etiology +of parathyromatosis is not known. +Aggressive local +resection of these deposits can result in normocalcemia but is +rarely curative. +Recurrences are rare (<1%), except in patients with famil- +ial HPT. +Recurrence rates of 15% at 2 years and 67% at 8 years +have been reported for MEN1 patients. +Persistent and Recurrent Hyperparathyroidism. +38-35). +In particular, a 24-hour urine collec- +tion should be performed to rule out FHH. +There are no published guidelines directly applicable +to this group of patients. +Preoperative localization studies +are routinely performed. +Anatomic location of ectopic parathyroid +glands. +Numbers represent number of glands found in each +location, with a total of 54. +(Reproduced with permission +from Shen W, et al. +Re-operation for persistent or recurrent +primary hyperparathyroidism. +Arch Surg. +1996;131:864. +Copyright © 1996 American Medical Association. +An algo- +rithm for the treatment of patients with recurrent and persistent +HPT is shown in Fig. +38-36. +Generally, these patients are approached with a focused +exploration. +The lateral approach is frequently used and can be +achieved via the previous incision. +Parathyroid tissue is cryopreserved +routinely. +Blind mediastinal +exploration is not recommended. +Hypercalcemic Crisis. +Calcium levels are markedly elevated and may be as high as 16 +to 20 mg/dL. +Parathyroid tumors tend to be large or multiple and +may be palpable. +Treatment consists of therapies to lower serum calcium +levels followed by surgery to correct HPT. +Occasionally, in life-threatening cases, hemodialysis may be +of benefit. +Secondary Hyperparathyroidism. +Patients generally are hypocalce- +mic or normocalcemic. +Studies also show +that calcimimetics may be less cost-effective in the long-term. +Follow-up +if mild +hypercalcemia +Parathyroidectomy Medical therapy +No Yes +Figure 38-36. +Management of recurrent and persistent hyperpara- +thyroidism (HPT). +FHH = familial hypocalciuric hypercalcemia; +PTH = parathyroid hormone. +Localization stud- +ies are not necessary but can identify ectopic parathyroid glands. +A bilateral neck exploration is indicated. +All parathyroid glands should be +identified. +Further studies are needed to define the best operative approach +for these patients. +Complications of Parathyroid Surgery. +Specific complications include transient and permanent vocal +cord palsy and hypoparathyroidism. +Acute hypocalcemia results in decreased ionized cal- +cium and increased neuromuscular excitability. +Patients +initially develop circumoral and fingertip numbness and +tingling. +Mental symptoms include anxiety, confusion, and +depression. +38-37). +Therefore, ectopic adrenocortical tissue may be +found in the ovaries, spermatic cord, and testes. +In contrast, the adrenal medulla is ectodermal in +origin and arises from the neural crest. +Most extra-adrenal +neural tissue regresses but may persist at several sites. +Adrenal medullary tissue also may be found in +neck, urinary bladder, and para-aortic regions. +The normal adrenal gland measures 5 × 3 × 1 cm and +weighs 4 to 5 g. +The left adrenal is closely associated +with the aorta, spleen, and tail of the pancreas. +Other vessels originating +from the intercostal and gonadal vessels may also supply the +adrenals. +The anatomic rela- +tionships of the adrenals and surrounding structures are depicted +in Fig. +38-38. +These latter zones are the +site of production of glucocorticoids and adrenal androgens. +It produces the catechol- +amine hormones epinephrine and norepinephrine. +The cells of +the adrenal medulla are arranged in cords and are polyhedral in +shape. +38-39). +Mineralocorticoids. +Cortisol has minimal effects on the kidney due to hor- +mone degradation. +Aldosterone secretion is regulated primarily +by the renin-angiotensin system. +Renin, in turn, leads to the production of angiotensin I from +its precursor angiotensinogen. +A small quantity of free aldosterone +also is excreted in the urine. +Mineralocorticoids cross the cell +membrane and bind to cytosolic receptors. +9 +1 +2 +3 +6 +7 +8 +C +A +4 +5 +B +Figure 38-37. +(Reproduced with permission from Avisse C, et al. +Surgical +anatomy and embryology of the adrenal glands. +Surg Clin North +Am. +2000;80:414. +Glucocorticoids. +and v. +Right phrenic a. +Celiac trunk +Superior +mesenteric a. +Left adrenal gland Right adrenal gland +Left superior adrenal aa. +Right superior adrenal aa. +Inferior adrenal a. +Renal +a. +and v. +Left adrenal v. +Inferior adrenal a. +Right +adrenal +v. +Middle +adrenal +a. +Figure 38-38. +Anatomy of the adrenals and surrounding structures. +a. += artery; v. += vein. +Synthesis of adrenal steroids. +DHEAS = dehydroepiandrosterone sulfate. +ACTH secretion may be +stimulated by pain, stress, hypoxia, hypothermia, trauma, and +hypoglycemia. +38-40). +Corti- +sol controls the secretion of both CRH and ACTH via a negative +feedback loop. +A similar mechanism leads to the inhibition of +CRH secretion by ACTH. +Approxi- +mately 10% of circulating cortisol is free and is the biologically +active component. +A small amount of unmetabolized cortisol is excreted +unchanged in the urine. +Glucocorticoid hormones enter the cell and bind cytosolic +steroid receptors. +Cortisol also binds the mineralocorticoid receptor with +an affinity similar to aldosterone. +Sex Steroids. +Adrenal androgens are weakly bound to plasma albumin. +Androgen metabolites are conju- +gated as glucuronides or sulfates and excreted in the urine. +Dur- +ing fetal development, adrenal androgens promote the formation +of male genitalia. +Catecholamines. +The substrate, tyrosine, is converted to catechol- +amines via a series of steps shown in Fig. +38-41A. +Diurnal variation in cortisol levels as determined by half-hourly sampling in a 16-year-old girl. +(Reproduced with permission +from Krieger DT, et al. +Characterization of the normal temporal pattern of corticosteroid levels. +J Clin Endocrinol Metab. +1971;32:269. +In the circulation, these pro- +teins are bound to albumin and other proteins. +38-41B). +Adrenergic receptors are transmembrane-spanning mol- +ecules that are coupled to G proteins. +Disorders of the Adrenal Cortex +Hyperaldosteronism. +Other symp- +toms include muscle weakness, polydipsia, polyuria, nocturia, +headaches, and fatigue. +Weakness and fatigue are related to the +presence of hypokalemia. +Diagnostic Studies +Laboratory Studies. +Once the diagnosis +is suspected, further tests are necessary to confirm the diagno- +sis. +Before testing, patients must receive adequate sodium and +potassium. +A. +Synthesis of catecholamines. +B. +Metabolism of catecholamine hormones. +Radiologic Studies. +If adrenal hyperplasia is suspected, the algorithm depicted +in Fig. +38-42 is useful. +This test, however, is not +widely available. +Rarely, acute +Addison’s disease may occur 2 to 3 days after adrenalectomy. +Cushing’s Syndrome. +38-43). +Cushing’s +syndrome (endogenous) is a rare disease, affecting 10 in 1 million +individuals. +It is more common in adults but may occur in children. +Women are more commonly affected (male:female ratio 1:8). +Management of an adrenal aldosteronoma. +CT = +computed tomography; MRI = magnetic resonance imaging. +Cushing’s syndrome may be classified as ACTH-dependent +or ACTH-independent (Table 38-17). +The most common cause +of hypercortisolism is exogenous administration of steroids. +Primary adrenal hyperplasia may be micronodular, mac- +ronodular, or massively macronodular. +Adrenal hyperplasia +resulting from ACTH stimulation usually is macronodular +(3-cm nodules). +Symptoms and Signs The classical features of Cushing’s syn- +drome are listed in Table 38-18. +Progressive truncal obesity is the +most common symptom, occurring in up to 95% of patients. +Figure 38-43. +Some characteristic features of Cushing’s +syndrome—moon facies, hirsutism, and acne. +ACTH = adrenocorticotropic hormone; CRH = corticotrophin-releasing +hormone. +Purple striae are often visible on the protuberant abdomen. +Rounding of the face leads to moon facies, and thinning of +subcutaneous tissues leads to plethora. +In children, +Cushing’s syndrome is characterized by obesity and stunted +growth. +38-44). +Laboratory Studies. +In this test, 1 mg of +a synthetic glucocorticoid (dexamethasone) is given at 11 p.m. +and plasma cortisol levels are measured at 8 a.m. +the following +morning. +Diagnosis of Cushing’s syndrome. +This is best accom- +plished by measurement of plasma ACTH levels (normal 10– +100 pg/mL). +ectopic). +The CRH test also is helpful in determining the etiology +of Cushing’s syndrome. +CRH stimulation also can enhance the usefulness of petrosal vein +sampling. +Radiologic Studies. +CT and MRI scans of the abdomen can iden- +tify adrenal tumors with 95% sensitivity. +MRI +scans have the added advantage of allowing assessment of vas- +cular anatomy. +Adrenal adenomas appear darker than the liver +on T2-weighted imaging. +In this study, +catheters are placed in both internal jugular veins and a periph- +eral vein. +Bilateral adrenalectomy is curative for +primary adrenal hyperplasia. +Duration of steroid therapy +is determined by the ACTH stimulation test. +This latter group of patients also may require mineralocorticoid +replacement therapy. +Adrenocortical Cancer. +Adrenal carcinomas are rare neo- +plasms with a worldwide incidence of two per 1 million. +Loci on 11p (Beckwith-Wiedemann syndrome), 2p (Car- +ney complex), and 9q also have been implicated. +Rarely, weight loss, anorexia, and nau- +sea may be present. +CT and MRI scans are useful to image these tumors +(Fig. +38-45). +Up to 70% of patients present with stage III or IV disease. +Pathology Most adrenocortical cancers are large, weighing +between 100 and 1000 g. +On gross examination, areas of hem- +orrhage and necrosis often are evident. +Capsular or vascular invasion is the most reliable sign of cancer. +Nodes (N): N0, no involvement of regional nodes; N1, positive regional +lymph nodes. +Metastasis (M): M0, no known distal metastases, M1, distant metastases +present. +Source: Used with permission of the American Joint Committee on +Cancer (AJCC), Chicago, Illinois. +Adrenocortical tumors commonly metasta- +size to the liver, lung, and bone. +However, this modality is used in the +palliation of bony metastases. +Sex Steroid Excess. +Adrenal adenomas or carcinomas +that secrete adrenal androgens lead to virilizing syndromes. +Feminizing adrenal tumors are less +common and occur in men in the third to fifth decades of life. +These tumors lead to gynecomastia, impotence, and testicular +atrophy. +Women with these tumors develop irregular menses +or dysfunctional uterine bleeding. +Vaginal bleeding may occur +in postmenopausal women. +Girls with these tumors experience +precocious puberty with breast enlargement and early menarche. +Treatment Virilizing and feminizing tumors are treated by adre- +nalectomy. +Congenital Adrenal Hyperplasia. +Partial enzyme deficiency may present at +birth or later with virilizing features. +These patients are less prone +to the salt wasting that characterizes complete enzyme deficiency. +Other enzyme deficiencies +include 3β-hydroxydehydrogenase and 17-hydroxylase defi- +ciency. +Urinary 17-hydroxyprogesterone, andro- +gens, and 17-ketosteroids also are elevated. +CT, MRI, and +iodocholesterol scans generally are used to localize the tumors. +Disorders of the Adrenal Medulla +Pheochromocytomas. +Pheochromocytomas occur in families with MEN2A and +MEN2B in approximately 50% of patients. +The incidence of pheochromocytomas +in the syndrome is approximately 14%. +The gene causing VHL +has been mapped to chromosome 3p and is a tumor suppres- +sor gene. +The most common clinical sign is hyperten- +sion. +Sudden death may occur in +patients with undiagnosed tumors who undergo other surgeries +or biopsy. +Diagnostic Tests +Biochemical Studies. +Many physiologic and pathologic states can alter the levels of +plasma catecholamines. +Hence, they often are thought to be +less accurate than urinary tests. +Radiologic Studies. +CT scans are 85% to 95% +sensitive and 70% to 100% specific for pheochromocytomas +(Fig. +38-46A). +CT scans do not provide functional information +and cannot definitively diagnose pheochromocytomas. +MRI +is also the study of choice in pregnant women as there is no +risk of radiation exposure. +Normal +adrenal medullary tissue does not take up appreciable MIBG. +131I-radiolabeled MIBG is, therefore, useful for localizing pheo- +chromocytomas (Fig. +38-46B), especially those in ectopic posi- +tions. +This test has a reported sensitivity of 77% to 89% and +specificity ranging from 88% to 100%. +Patients should be warned about orthostatic hypotension. +Adrenalectomy is the treatment of choice for patients with +pheochromocytoma. +Intraoperative arrhythmias are best managed +by short-acting β-blockers such as esmolol. +However, most pheochromocytomas <5 cm in diameter +can be safely resected laparoscopically. +Hereditary Pheochromocytomas. +Inherited pheochromo- +cytomas tend to be multiple and bilateral. +Malignant Pheochromocytomas. +There are no definitive +histologic criteria defining malignant pheochromocytomas. +In +fact, pleomorphism, nuclear atypia, and abundant mitotic fig- +ures are seen in benign tumors. +Capsular and vascular invasion +may be seen in benign lesions as well. +When pheochromocytomas develop in the MEN +syndromes, they rarely are malignant. +In general, soft tissue +lesions are treated with resection if feasible. +If the tumor is positive on somatostatin receptor +imaging, long-acting octreotide may be used. +The incidence of these lesions iden- +tified by CT scans ranges from 0.4% to 4.4%. +Differential Diagnosis. +The differential diagnosis of adrenal +incidentalomas is shown in Table 38-20. +Total cortisol produced and 24-hour urinary cortisol levels may +be normal. +Other less commonly encountered lesions include +adrenal cysts, ganglioneuromas, and hemorrhage. +Diagnostic Investigations. +Confirmatory tests can be per- +formed based on the results of the initial screening studies. +Determination of the malignant potential of an inciden- +taloma is more difficult. +The risk of malignancy in an adrenal +lesion is related to its size. +Carcinomas account for 2% of +lesions <4 cm and 6% of lesions 4.1 to 6 cm in size. +They also tend to be hypoattenuating lesions (<10 +Hounsfield units) on CT scanning. +Pheochromocytomas are +extremely bright, with mass-to-liver ratios >3. +Management. +An algorithm for the management of patients +with incidentalomas is shown in Fig. +38-47. +However, several important points must be considered in +the management of these patients. +Older patients are more likely to +have nonfunctioning adenomas. +2 +Is the tumor +metastatic? +3 +Is it at high +risk of being +malignant? +Figure 38-47. +Management algorithm for an adrenal incidentaloma. +CT = computed tomography; DST = dexamethasone suppression test; +VMA = vanillylmandelic acid. +Lesions that grow during follow-up also are treated by +adrenalectomy. +These tumors, even when large, can be +removed laparoscopically. +Suspected +adrenal metastases also may be resected for diagnosis. +There is no consensus regarding the follow up of patients +with adrenal incidentaloma. +Symptoms and Signs. +Symptoms +include fatigue, salt craving, weight loss, nausea, vomiting, and +abdominal pain. +Diagnostic Studies. +The peripheral blood +smear may demonstrate eosinophilia in approximately 20% +of patients. +Adrenal insufficiency is diagnosed by the ACTH +stimulation test. +ACTH (250 μg) is infused intravenously, and +cortisol levels are measured at 0, 30, and 60 minutes. +Peak cor- +tisol levels <20 μg/dL suggest adrenal insufficiency. +ACTH +levels also allow primary insufficiency to be distinguished from +secondary causes. +High ACTH levels with low plasma cortisol +levels are diagnostic of primary adrenal insufficiency. +Treatment. +Dexamethasone +(4 mg) should be administered intravenously. +The ACTH stimulation test +should be performed to confirm the diagnosis. +Adrenal Surgery +Choice of Procedure. +Adrenalectomy may be performed via a +laparoscopic or open approach. +The choice of approach depends on the size and +nature of the lesion and expertise of the surgeon. +There have been no ran- +domized trials directly comparing open vs. +laparoscopic adre- +nalectomy. +Laparoscopic Adrenalectomy. +The procedure is performed +under general anesthesia. +A nasogastric tube and Foley catheter are rec- +ommended. +Routine preoperative antibiotics are not needed, +except in patients with Cushing’s syndrome. +Patients, however, need to be repositioned for a bilateral +procedure. +The lateral transabdominal approach is widely used and +described in detail below. +38-48). +The surgeon and assistant both stand on the +same side, facing the front of the patient. +Pneumoperitoneum is +created using a Veress needle or insufflation via a Hasson port. +38-48), +although additional ports may be placed, if needed. +A 30° lapa- +roscope is inserted through the second or midclavicular port. +Most of the dissection is carried out via the two most lateral +ports. +However, the instruments and ports may be changed to +provide optimum exposure, as needed. +The right triangular ligament is divided +and the liver is rotated medially (Fig. +38-49A). +Rarely, the +hepatic flexure of the colon may need mobilization during a +right adrenalectomy. +The right kidney is identified visually and +by palpation with an atraumatic grasper. +The adrenal gland is +identified on the superomedial aspect of the kidney. +Gerota’s +fascia is incised with the hook cautery. +Alternatively, a vascular stapler may be +used to divide the vein endoscopically. +There may be a second +adrenal vein on the right. +Generally, two clips are left on the +vena cava side. +For a left adrenalectomy, the fan retractor is used to retract +the spleen. +Positioning of the patient and placement of trocars for a laparoscopic adrenalectomy. +Four trocars are placed from the mid- +clavicular to the anterior axillary line. +1592 +SPECIFIC CONSIDERATIONS +UNIT II +part II +divided using the electrocautery (Fig. +38-49B). +Gravity allows +the spleen and the pancreatic tail to fall medially. +The remain- +der of the dissection proceeds similarly to that described for the +right adrenal. +As with the right adrenal +vein, the left-sided veins also can be divided with a vascular +stapler. +Once the dissection is complete, the area of the adrenal +bed can be irrigated and suctioned. +A drain is rarely necessary. +Furthermore, bilateral adrenalectomy can be +performed without repositioning the patient. +This makes vascular control difficult and also renders it unsuit- +able for large (>5 cm) lesions. +This technique is being increas- +ingly used for small adenomas causing hyperaldosteronism. +Palpation +is used to identify the position of the twelfth rib. +The 0° laparoscope is replaced by a 45° laparoscope. +Two addi- +tional 5- or 10-mm trocars are placed, one each on either side +of the first port. +Laparoscopic ultrasound then is used to help +locate the adrenal gland and vessels. +Open Adrenalectomy. +Recovery time is +also quicker and hospitalization shorter. +However, it is associated +with significant morbidity and should be used selectively. +38-50). +38-51A). +The +lateral and superior surfaces usually are mobilized first. +38-51B). +An alter- +native approach is to enter the lesser sac by division of the +gastrocolic ligament. +Technique of laparoscopic adrenalectomy. +The gland is then mobilized as on +the right side. +The pleura also is mobilized cephalad, +and the adrenal and kidney are identified. +This prevents superior retraction of the adrenal +gland. +The remainder of the gland is then dissected and the adre- +nal gland and tumor removed. +The resulting space generally is +filled with perinephric fat and closed in layers. +A chest x-ray is +obtained postoperatively to rule out a pneumothorax. +The dissection then is performed +as indicated previously in Anterior Approach. +Complications of Adrenal Surgery. 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+Normocalcemic primary hyperparathyroidism: further +characterization of a new clinical phenotype. +J Clin Endocrinol +Metab. +2007;92:3001-3005. +72. +Silverberg SJ, Rubin MR, Faiman C, et al. +J Clin Endocrinol Metab. +2007;92:3803-3808. +73. +Carpenter JM, Michaelson PG, Lidner TK, Hinni ML. +Parathy- +romatosis. +Ear Nose Throat J. +2007;86:21. +74. +Udelsman R. +Approach to the patient with persistent or recur- +rent primary hyperparathyroidism. +J Clin Endocrinol Metab. +2011;96:2950-2958. +75. +Pitt SC, Sippel RS, Chen H. +Secondary and tertiary hyperpara- +thyroidism, state of the art surgical management. +Surg Clin +North Am. +2009;89:1227-1239. +76. +Yang RL, Freeman K, Reinke CE, et al. +Transplan- +tation. +2012;94:70-76. +77. +Schirpenbach C, Reincke M. +Primary aldosteronism: Current +knowledge and controversies in Conn’s syndrome. +Nat Clin +Pract Endocrinol Metab. +2007;3:220. +1596 +SPECIFIC CONSIDERATIONS +UNIT II +part II +78. +Rossi GP. +New concepts in adrenal vein sampling for aldoste- +rone in the diagnosis of primary aldosteronism. +Curr Hypertens +Rep. +2007;9:90. +79. +Pecori Giraldi F, Ambrogio AG, De Martin M, Fatti LM, Scac- +chi M, Cavagnini F. +J Clin +Endocrinol Metab. +2007;92:4123-4129. +80. +Bertherat J, Bertagna X. +Pathogenesis of adrenocortical cancer. +Best Pract Res Clin Endocrinol Metab. +2009;23:261-271. +81. +Rodgers SE, Evans DB, Lee JE, et al. +Adrenocortical carci- +noma. +Surg Oncol Clin N Am. +2006;15:535. +82. +Copeland PM. +The incidentally discovered adrenal mass. +Ann +Surg. +1984;199:116. +83. +Sturgeon C, Shen WT, Clark OH, Duh QY, Kebebew E. +J Am Coll +Surg. +2006;202:423-430. +84. +Aubert S, Wacrenier A, Leroy X, et al. +Am J Surg Pathol. +2002;26:1612-1619. +85. +Terzolo M, Angeli A, Fassnacht M, et al. +Adjuvant mito- +tane treatment for adrenocortical carcinoma. +N Engl J Med. +2007;356:2372-2380. +86. +Fassnacht M, Terzolo M, Allolio B, et al. +Combination che- +motherapy in advanced adrenocortical carcinoma. +N Engl +J Med. +2012;366:2189-2197. +87. +Fishbein L, Nathanson KL. +Pheochromocytoma and paragan- +glioma: understanding the complexities of the genetic back- +ground. +Cancer Genet. +2012;205:1-11. +88. +Sackett WR, Bambach CP. +Bilateral subtotal laparoscopic +adrenalectomy for phaeochromocytoma. +ANZ J Surg. +2003;73:664-666. +89. +Shen WT, Sturgeon C, Clark OH, et al. +Should pheochromo- +cytoma size influence surgical approach? +A comparison of +90 malignant and 60 benign pheochromocytomas. +Surgery. +2004;136:1129. +90. +McDermott S, O’Connor OJ, Cronin CG, Blake MA. +Radio- +logical evaluation of adrenal incidentalomas: current methods +and future prospects. +Best Pract Res Clin Endocrinol Metab. +2012;26:21-33. +91. +Zeiger MA, Thompson GB, Duh QY, et al. +Endocrine Pract. +2009;15(Suppl 1):3-20. +92. +Strong VE, D’Angelica M, Tang L, et al. +Laparoscopic adre- +nalectomy for isolated adrenal metastasis. +Ann Surg Oncol. +2007;14:3392. +Pediatric Surgery +David J. +Hackam, Tracy Grikscheit, Kasper Wang, +Jeffrey S. +Upperman, and Henri R. +Robert E. +1. +Children are not little adults, but they are little people. +2. +Sick children whisper before they shout. +Children with sur- +gical diseases can deteriorate very quickly. +But before they +deteriorate, they often manifest subtle physical findings. +3. +Always listen to the mother and the father. +Barotrauma and hypoxia should be avoided. +Timing and extent of surgery are dictated by the +stability of the patient. +Early sequelae of NEC include perforation, sepsis, and +death. +Later sequelae include short bowel syndrome +and stricture. +unfavorable). +Gross tumor rupture during surgery +automatically changes the stage to 3 (at a minimum). +10 Injury is the leading cause of death in children older than +1 year of age. +Blunt mechanisms account for the majority +of pediatric injuries. +1599 +P +EDIATRIC + S +URGER +y +CHAPTER 39 +have closely observed their child and know him or her best. +4. +Children suffer pain after surgery. +Timely and adequate pain +management must accompany surgical interventions. +5. +Pediatric tissue must be handled delicately and with pro- +found respect. +This is particu- +larly true in infants, who have little reserve when ill. +The infant’s +physiologic day is approximately 8 hours in duration. +At 12 weeks’ gestation, the total body water of a fetus +is approximately 94 cc/kg. +Parallel to the drop in total +body water is the reduction in extracellular fluid. +The capacity to concentrate urine +is very limited in preterm and term infants. +Potassium requirements are on +the order of 1 to 2 mEq/kg/d. +Respiratory acidosis implies hypoventilation, the cause +of which should be apparent. +The +last factor in the equation should be 0.4 for smaller children and +0.3 for older children. +One half of the corrective dose is given, and the +serum pH is measured again. +Respiratory alkalosis is usually caused by hyperventila- +tion, which is readily correctable. +To decrease the need for transfu- +sion, other strategies have been considered. +Plasma is given +in a dose of 10 to 20 mL/kg, and platelets are given in a dose +of 1 unit/5 kg. +Each unit of platelets consists of 40 to 60 mL of +fluid (plasma plus platelets). +The protein +and caloric requirements for the surgical neonate are shown in +Table 39-1. +Nutrition can be provided via either the enteral or paren- +teral route. +There are various enteral feeding preparations available; +these are outlined in Table 39-2. +The choice of formula is based +on the individual clinical state of the child. +Pediatric surgeons +are often faced with situations where oral feeding is not possi- +ble. +Prolonged parenteral +nutrition is delivered via a central venous catheter. +If the internal jugular +vein is used, care is taken to prevent venous occlusion. +The catheters are tunneled to an exit site separate from +the venotomy site. +Premature infants are particularly susceptible to changes in envi- +ronmental temperature. +Transport systems +incorporating heating units are necessary for premature infants. +During abdominal surgery, extreme +care is taken to avoid wet and cold drapes. +All fluids used to irri- +gate the chest or abdomen must be warmed to body temperature. +Pain Control +All children, including neonates, experience pain. +For situa- +tions where more pain is expected, IV narcotic agents should be +used. +Neck lesions are found either in the midline or lateral com- +partments. +Midline masses include thyroglossal duct remnants, +thyroid masses, thymic cysts, or dermoid cysts. +However, when +the involved nodes become fluctuant, incision and drainage are +indicated. +The lymphadenopathy associated +with infectious mononucleosis can be diagnosed based on serol- +ogy. +Accordingly, +such biopsies should be done under local anesthesia. +Thyroglossal Duct Remnants +Pathology and Clinical Manifestations. +The +“descent” of the thyroid is intimately connected with the devel- +opment of the hyoid bone. +Occasion- +ally it presents as an intrathyroidal mass. +Most thyroglossal duct +cysts are asymptomatic. +Submental lymphadenopathy and midline dermoid +cysts can be confused with a thyroglossal duct cyst. +Treatment. +If the cyst presents with an abscess, treatment +should first consist of drainage and antibiotics. +The first cleft and the first, second, third, and +fourth pouches give rise to adult organs. +In contrast, a third branchial cleft fistula passes posterior +to the carotid bifurcation. +Treatment. +Complete excision of the cyst and sinus tract is +necessary for cure. +Injection of a small amount of methylene blue dye into the tract +also may be useful. +Branchial cleft cysts can present as abscesses. +Lymphatic Malformation +Etiology and Pathology. +The cysts are lined by endothelium and filled with lymph. +Adjacent +connective tissue may show extensive lymphocytic infiltra- +tion. +39-1A). +Occasionally lymphatic malformations contain nests of +vascular tissue. +Infection within the cysts, usually caused by Streptococcus or +Staphylococcus, may occur. +In the neck, this can cause rapid +enlargement, which may result in airway compromise. +Occasionally, very +large lesions can cause obstruction of the fetal airway. +Treatment. +39-1B). +Radical ablative surgery is not indicated for this +lesion. +Postoperative wound drainage is important +and is best accomplished by closed-suction technique. +This lesion +results from fibrosis of the sternocleidomastoid muscle. +The +mass may be palpated in the affected muscle in approximately +two thirds of cases. +Rarely, surgical transection of the sternocleidomastoid may be +indicated. +RESPIRATORy SySTEM +Congenital Diaphragmatic Hernia (Bochdalek) +Pathology. +Diaphragmatic defects allow +abdominal viscera to fill the chest cavity. +The abdominal cavity +is small and underdeveloped and remains scaphoid after birth. +Both lungs are hypoplastic, with decreased bronchial and pul- +monary artery branching. +A. +Left cervical lymphatic malformation in a 2-day-old baby. +B. +Intraoperative photograph showing a vessel loop around the +spinal accessory nerve. +1604 +SPECIFIC CONSIDERATIONS +UNIT II +part II +on the ipsilateral side. +This anomaly is encountered more com- +monly on the left (80%–90%). +Amniocentesis with karyotype may identify chro- +mosomal defects, especially trisomy 18 and 21. +39-2). +Accurate prenatal +prediction of outcome for fetuses who have CDH is very diffi- +cult. +Following delivery, the diagnosis of CDH is made by +chest x-ray (Fig. +39-3). +Second, pulmonary hypertension develops. +Varying degrees of pulmonary hypo- +plasia on the opposite side may compound these effects. +The +second and third factors are thought to be the most important. +Treatment. +Many infants are symptomatic at birth due to hypoxia, hyper- +carbia, and metabolic acidosis. +Prompt cardiorespiratory stabi- +lization is mandatory. +Levels of PaCO2 in the range +1 +Figure 39-3. +Chest x-ray showing a left congenital diaphragmatic +hernia. +Figure 39-2. +Prenatal ultrasound of a fetus with a congenital dia- +phragmatic hernia. +Arrows point to the location of the diaphragm. +Arrow head points to the stomach, which is in the thoracic cavity. +The use of ECMO is associated with +significant risk. +They +may occur intracranially or at the site of cannula insertion +and can be life threatening. +Systemic sepsis is a significant +problem and may necessitate decannulation. +Upon decannulation, some centers repair the carotid artery. +Still others repair the diaphragm only after the infant is +off bypass. +The anterior +margin is often apparent, while the posterior muscular rim is +attenuated. +If the infant is heparinized on bypass, minimal dis- +section of the muscular margins is performed. +Electrocautery is +used liberally to minimize postoperative bleeding. +Anatomic closure of +the abdominal wall may be impossible after reduction of the +viscera. +Very slow weaning from the ventilator is necessary to +avoid recurrent pulmonary hypertension. +These symptoms may be stationary, or they may +progress rapidly or result in recurrent pneumonia. +A hyperexpanded hemithorax on the ipsilateral side is +pathognomonic for CLE. +39-4). +This should be done only in the +stable patient. +The prognosis is excellent. +Congenital Pulmonary Airway Malformations. +There +may be a single cyst with a wall of connective tissue contain- +ing smooth muscle. +CPAMs frequently occur +in the left lower lobe. +Clinical symptoms range from none +to severe respiratory failure at birth. +39-5). +Prenatal US may suggest the diagno- +sis. +As a result, resection of the affected lobe is usually performed +(Fig. +39-6). +Figure 39-5. +Figure 39-6. +39-5. +Figure 39-4. +Congenital lobar emphysema of the left upper lobe +in a 2-week-old boy. +Mediastinal shift is present. +1607 +P +EDIATRIC + S +URGER +y +CHAPTER 39 +Pulmonary Sequestration. +There are two kinds of sequestra- +tion. +It +is commonly found in cases of CDH. +39-7). +Venous drainage of both types can be systemic or +pulmonary. +Sequestrations +may, in some cases, exhibit mixed pathology with components +consistent with CPAMs. +Extralobar sequestration is asymptom- +atic and is usually discovered incidentally on chest x-ray. +If the +diagnosis can be confirmed (e.g., by CT scan), resection is not +necessary. +Diagnosis of intralobar sequestration may be made +prenatally and confirmed on postnatal CT scan. +Prognosis is gener- +ally excellent. +Bronchogenic Cyst. +In the lung parenchyma, they may become infected and +present with fever and cough. +Rarely, rupture of the +cyst can occur. +Chest CT delineates bron- +chiectasis with excellent resolution. +Figure 39-7. +1608 +SPECIFIC CONSIDERATIONS +UNIT II +part II +Airway Ingestion. +Aspiration of foreign bodies most com- +monly occurs in the toddler age group. +Oil from the peanut +is very irritating and may cause pneumonia. +Delay in diagnosis +can lead to atelectasis and infection. +The child usually will cough or choke +while eating but may then become asymptomatic. +A unilateral +wheeze is often heard on auscultation. +Bronchoscopy confirms +the diagnosis and allows removal of the foreign body. +Foreign Bodies and Esophageal Injury. +The most common +foreign body in the esophagus is a coin, followed by small toy +parts. +Toddlers are most commonly affected. +There is often a relatively asymptomatic +period after ingestion. +The initial symptoms are gastrointestinal +and include dysphagia, drooling, and dehydration. +These findings may be interpreted as signs of upper respiratory +infections. +The chest x-ray is diagnostic in +the case of a coin. +Rarely, esophagotomy is required for removal, particularly of +sharp objects. +In the not-so-distant past, nearly all infants born with EA and +TEF died. +Subsequently, Dr. +Anatomic Varieties. +The five major varieties of EA and TEF +are shown in Fig. +39-8. +The most commonly seen variety is EA +Figure 39-8. +The five varieties of esophageal atresia and tracheoesophageal fistula. +A. +Isolated esophageal atresia. +B. +C. +Esophageal atresia with tracheoesophageal fistula +between distal esophagus and trachea. +D. +Esophageal atresia with fistula between both proximal and distal ends of esophagus and trachea. +E. +Tracheoesophageal fistula without esophageal atresia (H-type fistula). +39-9). +Etiology and Pathologic Presentation. +The esophagus and +trachea share a common embryologic origin. +39-8. +Other congenital anomalies commonly occur in asso- +ciation with EA-TEF. +In nearly +20% of the infants born with EA, some variant of congenital +heart disease occurs. +Clinical Presentation of Infants with Esophageal Atresia +and Tracheoesophageal Fistula. +The anatomic variant of infants with EA-TEF predicts the clini- +cal presentation. +As the abdomen distends, it +becomes increasingly more difficult for the infant to breathe. +This leads to further atelectasis and respiratory compromise. +39-10). +The dilated +upper pouch may be occasionally seen on a plain chest radio- +graph. +This problem can occur in infants after +traumatic insertion of a nasogastric or orogastric tube. +Occasionally, a diagnosis of EA-TEF can be suspected +prenatally on US evaluation. +Typical features include failure +to visualize the stomach and the presence of polyhydramnios. +These findings reflect the absence of efficient swallowing +by the fetus. +In a child with EA, it is important to identify whether coex- +isting anomalies are present. +A patent anus should be confirmed clinically. +The kidneys in +Figure 39-10. +Type C esophageal atresia with tracheoesophageal +fistula. +Figure 39-9. +Barium esophagram showing H-type tracheoesopha- +geal fistula (arrow). +1610 +SPECIFIC CONSIDERATIONS +UNIT II +part II +a newborn may be assessed clinically by palpation. +Rib anomalies may also be pres- +ent. +These may include the presence of a thirteenth rib. +Initial Management. +A sump catheter is placed in the upper pouch on continuous suc- +tion. +IV antibiotic therapy is initiated, and warmed electrolyte solu- +tion is administered. +The timing of repair is influenced by the stability of the +patient. +Definitive repair of the EA-TEF is rarely a surgical +emergency. +Management of Esophageal Atresia and Tracheoesopha- +geal Fistula in the Preterm Infant. +This can be accom- +plished using HFOV. +If the gastric distention becomes severe, +a gastrostomy tube should be placed. +This procedure can be +performed at the bedside under local anesthetic, if necessary. +If these maneuvers are to +no avail, ligation of the fistula may be required. +Primary Surgical Correction. +There are two approaches to this operation: +open thoracotomy or thoracoscopy. +The operative technique for primary repair is as follows +(Fig. +39-11). +The anastomosis is performed +in a single layer. +2 +1611 +P +EDIATRIC + S +URGER +y +CHAPTER 39 +Postoperative Course. +When a transanastomotic tube is placed, feeds are begun slowly +in the postoperative period. +Some surgeons institute parenteral +nutrition for several days, using a central line. +If there is no leak, feedings +are started. +Complications of Surgery. +Revision of the +anastomosis may be possible. +Strictures are not infrequent (10%–20%), particularly +if a leak has occurred. +A contrast swallow or esophagoscopy +is confirmatory, and simple dilatation is usually corrective. +Occasionally, repeated dilatations are required. +A +B +CED +Azygos Vein +Esophagus +Esophagus Azygos Vein +Figure 39-11. +Primary repair of type C tracheosophageal fistula. +A. +Right thoracotomy incision. +B. +Azygos vein transected, proximal and +distal esophagus demonstrated, and fistula identified. +C. +Tracheoesophageal fistula transected and defect in trachea closed. +D. +End-to-end +anastomosis between proximal and distal esophagus (posterior row). +E. +Completed anastomosis. +Otherwise, reoperation may be required. +Special Circumstances. +Patients with type E TEFs (also +called H-type) most commonly present beyond the newborn +period. +Presenting symptoms include recurrent chest infections, +bronchospasm, and failure to thrive. +Outcome is usually excellent. +Definitive +repair can then be performed at a later point in time. +This occasionally allows for primary anastomosis to be +performed. +Outcome. +Spitz and +colleagues analyzed risk factors in infants who died with EA- +TEF. +There is no effective immediate antidote. +It is impor- +tant to endoscope only to the first level of the burn in order +to avoid perforation. +Early barium swallow may delineate the +extent of the mucosal injury. +Therefore, they are no longer part of the management +of caustic injuries. +Antibiotics are administered during the +acute period. +These patients should undergo +placement of a gastrostomy tube once clinically stable. +When estab- +lished strictures are present (usually 3–4 weeks), dilatation is +performed. +Pedicled or free grafts of the jejunum +are less commonly used. +In a recent review of +patients treated by gastric pull-up, long-term outcome was very +good. +GERD is particularly problematic in neurologically +impaired children. +Clinical Manifestations. +A barium swallow should be performed as +an initial test. +The frequency and severity of reflux should be assessed using a +24-hour pH probe study. +Treatment. +Most patients with GERD are treated initially by +conservative means. +In the infant, propping and thickening the +formula with rice cereal are generally recommended. +Some +authors prefer a prone, head-up position. +However, as a +long-term remedy, this therapy is associated with several prob- +lems. +These complications are more common in children +with neurologic impairment. +GASTROINTESTINAL TRACT +An Approach to the Vomiting Infant +The majority of infants vomit. +This may or may not be of concern, as +described earlier. +By contrast, vomit that has any +green color in it is always worrisome. +Hypertrophic Pyloric Stenosis +Clinical Presentation. +Male-to-female ratio +is nearly 5:1. +Wet diapers become less +frequent, and there may even be a perception of less passage +of flatus. +The cause of HPS has not been determined. +Infants with HPS develop a hypochloremic, hypokale- +mic metabolic alkalosis. +When the olive cannot be palpated, US can diagnose +the condition accurately in 95% of patients. +Criteria for US +diagnosis include a channel length of over 16 mm and pyloric +thickness over 4 mm. +Treatment. +After resuscitation, a Fredet-Ramstedt pyloromy- +otomy is performed (Fig. +39-12). +It may be performed using +an open or laparoscopic approach. +In recent years, the laparo- +scopic approach has gained great popularity. +Most infants can +be discharged home within 24–48 hours following surgery. +A nasogastric tube is left in place for 24 hours. +The +outcome is generally very good. +Prompt recognition and treatment of +neonatal intestinal obstruction can truly be life saving. +The incidence of neonatal intestinal obstruction is 1 in +2000 live births. +When a neonate develops bilious vomiting, one must +Pyloric “tumor” +Mucosa +A +B +C +Figure 39-12. +Fredet-Ramstedt pyloromyotomy. +A. +Pylorus deliv- +ered into wound and seromuscular layer incised. +B. +C. +3 +1615 +P +EDIATRIC + S +URGER +y +CHAPTER 39 +consider a surgical etiology. +Indeed, the majority of newborns +with bilious emesis have a surgical condition. +As such, contrast imaging may be necessary for diagno- +sis in some instances. +Distal obstructions typically presents with bilious emesis +and abdominal distention. +Passage of black-green meconium +should have occurred within the first 24 to 38 hours. +This topic +is covered in further detail later in this chapter. +Associ- +ated polyhydramnios is common and presents in the third tri- +mester. +Abdominal distention is typically not +present because of the proximal level of obstruction. +In infants +with obstruction proximal to the bile duct entry, the vomiting is +nonbilious. +39-13). +Treatment. +Typically, the abdomen is soft, and the infant is very +stable. +These patients should be evaluated for +associated cardiac anomalies. +Associated anomalies should be searched for at the +time of the operation. +These include malrotation, anterior portal +vein, a second distal web, and biliary atresia. +Gastrostomy tube placement is not routinely +performed. +Recently reported survival rates exceed 90%. +The incidence of intestinal atresia has been +4 +Figure 39-13. +Abdominal x-ray showing "double bubble" sign +in a newborn infant with duodenal atresia. +The two "bubbles" are +numbered. +39-14). +Surgical correction of the small intestinal atresia should +be performed urgently. +At laparotomy, one of several types of +atresia will be encountered. +In type 1, there is a mucosal atresia +with intact muscularis. +In type 2, the atretic ends are connected +by a fibrous band. +In type 3A, the two ends of the atresia are +separated by a V-shaped defect in the mesentery. +39-15). +The +proximal distended loop can be tapered as described earlier. +Malrotation and Midgut Volvulus +Embryology. +Genetic mutations likely disrupt the +signaling critical for normal intestinal rotation. +A volvulus +may therefore occur around the mesentery. +This twist not only +obstructs the proximal jejunum, but also cuts off the blood +Figure 39-14. +This child has +jejunal atresia. +Figure 39-15. +Operative photograph of newborn with “Christmas +tree” type of ileal atresia. +1617 +P +EDIATRIC + S +URGER +y +CHAPTER 39 +supply to the midgut. +Presentation and Management. +39-16). +In cases where the child is stable, laparoscopy +may be considered. +Under these con- +ditions, the patient may have malrotation without volvulus. +Volvulus occurs clockwise and is therefore untwisted coun- +terclockwise. +This procedure is performed as follows +(Fig. +39-17). +The appendix is removed to avoid diagnostic +errors in later life. +No attempt is made to suture the cecum +or duodenum in place. +Frankly necrotic bowel can then +be resected conservatively. +With early diagnosis and correc- +tion the prognosis is excellent. +A subset of patients with malrotation will demonstrate +chronic obstructive symptoms. +Meconium Ileus +Pathogenesis and Clinical Presentation. +This phenotype +is explained by the presence of mutations in the CFTR gene. +Abdominal radiographs show dilated +loops of intestine. +Figure 39-16. +Abdominal x-ray of a 10-day-old infant with bilious +emesis. +Note the dilated proximal bowel and the paucity of distal +bowel gas, characteristic of a volvulus. +Management. +Patients with uncomplicated meconium ileus can be +treated nonoperatively. +At this point, an end ileostomy may be created. +Figure 39-17. +Ladd procedure for malrotation. +A. +Lysis of cecal and duodenal bands. +B. +Broadening the mesentery. +C. +Appendectomy. +39-18). +Necrotizing Enterocolitis +Clinical Features. +Over 25,000 cases +of NEC are reported annually. +The overall mortality ranges +between 10% and 50%. +Multiple risk factors have been associated with the devel- +opment of NEC. +Techniques of intestinal anastomosis for infants with small bowel obstruction. +A. +End to back: distal limb has been incised, +creating “fish mouth” to enlarge the lumen. +B. +C. +D. +The common wall can be crushed with a special clamp to create a large stoma. +The stoma can be closed in an +extraperitoneal manner. +Clinical Manifestations. +Infants with NEC present with a +spectrum of disease. +In the earliest +stage (Bell stage I), infants present with feeding intolerance. +Infants with Bell stage II have established NEC that is not +immediately life threatening. +These findings indicate the development of +intestinal ileus and mucosal ischemia, respectively. +The diagnosis of NEC may be confirmed by abdomi- +nal radiography. +39-19). +Other findings include the presence of ileus or portal venous +gas. +Infants with Bell stage III have the most advanced form of +NEC. +Pathogenesis of Necrotizing Enterocolitis. +Several theo- +ries have been proposed to explain the development of NEC. +The infant is +resuscitated, and inotropes are administered to maintain perfu- +sion as needed. +Intubation and mechanical ventilation may be +required to maintain oxygenation. +TPN is started. +Subsequent +treatment may be influenced by the particular stage of NEC that +is present. +If the infant +fully recovers, feedings may be reinitiated. +Patients with Bell stage II disease merit close observation. +Serial physical examinations are performed looking for the +Figure 39-19. +Abdominal radiograph of infant with necrotizing +enterocolitis. +Arrows point to area of pneumatosis intestinalis. +Two schools of thought direct further +management. +One group favors exploratory laparotomy. +Necrotizing Enterocolitis in Older Infants. +Spontaneous Intestinal Perforation Versus Necrotizing +Enterocolitis. +The histopathology of +SIP is different from NEC. +In contrast to NEC, pneuma- +tosis intestinalis is absent in SIP. +However, both NEC and +SIP occur with similar frequency in low birth weight infants. +The outcome of patients in the two groups is slightly differ- +ent. +In short, the diagnosis of SIP versus NEC has impor- +tant prognostic significance. +The treatment strategies, however, +are essentially the same. +Outcome. +At the time of stoma closure, the entire +intestine should be examined to search for strictures. +As rates of prematurity are increasing, so are +the numbers of children with SBS. +Rarely, an intussusception may prolapse +through the rectum. +Clinical Manifestations. +Typically, the infant develops paroxysms +of crampy abdominal pain and intermittent vomiting. +Bloody mucus (“currant jelly” +stool) may be passed per rectum. +Treatment. +In the absence of peritonitis, +the child should undergo radiographic reduction. +Under most instances, this should not exceed 120 mmHg. +This strategy has +improved the success rate of nonoperative reduction in many +centers. +Failure to reduce +the intussusception mandates surgery. +Two approaches are used. +39-20). +Care should be taken not to +pull the bowel out, as this can cause damage to the bowel wall. +The blood supply to the appendix is often compromised, and +appendectomy is performed. +If the bowel is frankly gangrenous, +resection and primary anastomosis are performed. +In experi- +enced hands, laparoscopic reduction may be performed, even in +very young infants. +Atraumatic bowel +graspers allow the bowel to be handled without injuring it. +IV fluids are continued until the postoperative ileus +subsides. +Patients are started on clear liquids, and their diet +is advanced as tolerated. +Patients pres- +ent with recurrent symptoms in the immediate postoperative +period. +Treatment involves repeat air enema, which is success- +ful in most cases. +Appendicitis +Presentation. +When children present in this +manner, there should be little diagnostic delay. +Figure 39-20. +1623 +P +EDIATRIC + S +URGER +y +CHAPTER 39 +However, children often do not present in this manner. +Diagnosis of Appendicitis in Children. +In girls, +ovarian or uterine pathology must also be considered. +When +there is diagnostic uncertainty, the child may be observed, rehy- +drated, and reassessed. +Surgical Treatment of Appendicitis. +The definitive treat- +ment for acute appendicitis is appendectomy. +Patients should also +be started on antibiotics (such as a second-generation cepha- +losporin). +In general, the same steps are taken +when appendectomy is performed through an open approach. +The most common complication after appendectomy is a +surgical site infection. +Recovery from surgery is dependent on the individual patient. +During the recovery period, over-the-counter +pain medication may be required. +Older patients tend to require +a longer time for full recovery. +Management of the Child with Perforated Appendicitis. +Alternatively, the child may present +with symptoms of intestinal obstruction. +An abdominal mass +may be present in the lower abdomen. +39-21). +An individualized approach is necessary for the child who +presents with perforated appendicitis. +The operation can be performed through an open or +laparoscopic approach. +Drains are seldom used, and the +skin incisions can be closed primarily. +Thus, these +patients are more likely to require early surgical intervention. +Patients who have had symptoms of appendicitis for no more +Figure 39-21. +Other Causes of Abdominal Pain That Mimic Appendicitis +in Children. +Patients with urinary tract infection +can present very similar to those with appendicitis. +Constipation may be commonly confused with appendicitis in its +earliest stages. +Finally, children and young adults are always +at risk for the development of gastroenteritis. +Duplications may be long and tubular, but usually, they +are cystic masses. +In all cases, they share a common wall with +the intestine. +On exami- +nation, a palpable mass is often identified. +Children may also +develop intestinal obstruction. +Torsion may produce gangrene +and perforation. +CT, US, +and technetium pertechnetate scanning can be very helpful. +Occasionally, a duplication can be seen on small bowel follow- +through or barium enema. +39-22). +Pancreatic mucosa may also be present. +Diagnosis may be made +by technetium pertechnetate scans when the patient presents +with bleeding. +Treatment is surgical. +A linear stapler is especially useful +in this circumstance. +However, they do not contain any mucosa +or muscular wall. +Chylous cysts may result from congenital +lymphatic obstruction. +Mesenteric cysts can cause intestinal +obstruction or may present as an abdominal mass. +The diagno- +sis may be made by abdominal US or CT. +Treatment involves +surgical excision. +Hirschsprung’s Disease +Pathogenesis. +In his classic textbook entitled Pediatric +Surgery, Dr. +Operative photograph showing the presence of a +Meckel’s diverticulum (arrow). +This may explain why most cases of aganglionosis involve the +rectum and rectosigmoid. +In rare instances, total +colonic aganglionosis may occur. +Recent studies have shed light on the molecular basis for +Hirschsprung’s disease. +Clinical Presentation. +The incidence of sporadic Hirschsprung’s +disease is 1 in 5000 live births. +Occasionally such families have mutations in +the genes described earlier, including the Ret gene. +In children who do not respond to +nonoperative management, a decompressive stoma is required. +These children have severe constipation, which has usually been +treated with laxatives and enemas. +Abdominal distention and +failure to thrive may also be present at diagnosis. +Diagnosis. +The definitive diagnosis of Hirschsprung’s disease +is made by rectal biopsy. +Samples of mucosa and submucosa +are obtained at 1, 2, and 3 cm from the dentate line. +In older children, +the procedure should be performed using IV sedation. +The barium enema in total colonic aganglionosis may show +a markedly shortened colon. +Treatment. +The diagnosis of Hirschsprung’s disease requires +surgery in all cases. +The classic surgical approach consisted of +a multiple-stage procedure. +There are three viable +options for the definitive pull-through procedure that +are currently used. +39-23). +Many surgeons perform the intra-abdominal dissection +using the laparoscope. +In this operation, the aganglionic rectum is dissected in +the pelvis and removed down to the anus. +The ganglionic colon +is then anastomosed to the anus via a perineal approach. +This operation may be performed completely from +below. +In all cases, it is critical that the level at which ganglion- +ated bowel exists be determined. +Up to one third of patients who undergo +a transition zone pull-through will require a reoperation. +Anorectal Malformations +Anatomic Description. +The embryologic basis includes failure of +descent of the urorectal septum. +Instead, the +rectal pouch ends “blindly” in the pelvis, above or below the +levator ani muscle. +39-24). +The three operations for surgical correction of +Hirschsprung’s disease. +A. +B. +C. +Figure 39-24. +Low imperforate anus in a male. +Note the well- +developed buttocks. +The perineal fistula was found at the midline +raphe. +1627 +P +EDIATRIC + S +URGER +y +CHAPTER 39 +ends as a fistula into the membranous urethra. +In females, high +imperforate anus often occurs in the context of a persistent clo- +aca. +In both males and females, low lesions are associated with +a fistula to the perineum. +In males, the fistula connects with the +median raphe of the scrotum or penis. +39-25). +The third most common defect in +females is the persistent cloaca. +Typi- +cally, the external genitalia are hypoplastic. +Associated Malformations. +Approximately 60% of patients +have an associated malformation. +The most common is a urinary +tract defect, which occurs in approximately 50% of patients. +Skeletal defects are also seen, and the sacrum is most com- +monly involved. +Gastrointestinal anomalies occur, most commonly EA. +Management of Patients with Imperforate Anus. +Patients +with imperforate anus are usually stable, and the diagnosis is +readily apparent. +The principles of management center around diagnosing +the type of defect that is present (high vs. +low) and evaluating +the presence of associated anomalies. +Other tests +should include an echocardiogram and spinal radiographs. +A +US of the spine should be performed to look for the presence of +a tethered cord. +To further classify the location of the fistula as +either “high” vs. +“low,” a lateral abdominal radiograph can be +obtained with a radiopaque marker on the perineum. +This study is imprecise, however, and may add little +to the overall management of these patients. +The surgical management of infants with imperforate anus +is determined by the anatomic defect. +The muscles are +then reconstructed and sutured to the rectum. +The outcome +of 1192 patients who had undergone this procedure has been +reviewed by Peña and Hong. +Dilators are then placed over +Figure 39-25. +Imperforate anus in a female. +A catheter has been +placed into the fistula, which is in the vestibule of the vagina. +During fetal life, the placenta is the principal +route of elimination of unconjugated bilirubin. +In the newborn +infant, bilirubin is conjugated through the activity of glucoronyl +transferase. +By +definition, jaundice that persists beyond 2 weeks is considered +pathologic. +Biliary Atresia +Pathogenesis. +Biliary atresia is a rare disease associated with +significant morbidity and mortality. +The incidence of this disease is approximately 1 in 8000 +to 1 in 18,000. +The etiology of biliary atresia is likely multi- +factorial. +Recent ani- +mal studies strongly implicate perinatal exposure to reovirus or +rotavirus. +Clinical Presentation. +Infants with biliary atresia present +with jaundice at birth or shortly thereafter. +As such, it is not unusual for there +to be a delay in diagnosis. +Diagnosis. +Workup commonly includes +the analysis of TORCH infection titers as well as viral hepati- +tis. +The absence of a gallbladder is highly suggestive of the diag- +nosis of biliary atresia. +This may be performed using a laparoscope. +The cholangiogram may demonstrate hypoplasia of the extra- +hepatic biliary system. +Inspissated Bile Syndrome. +In some +instances, no etiologic factors can be defined. +Neonatal hepatitis +may present in a similar fashion to biliary atresia. +There may +be a viral etiology, and the disease is usually self-limited. +In this +case, cholangiography is both diagnostic and therapeutic. +Treatment. +The purpose +of this procedure is to promote bile flow into the intestine. +39-26). +39-27). +A com- +mon postoperative complication is cholangitis. +Two of these four biliary atresia studies are therapeutic trials. +Figure 39-26. +Operative photograph showing Kasai portoenteros- +tomy. +Arrows denote site of the anastomosis. +Note the engorged liver. +Figure 39-27. +Schematic illustration of the Kasai portoenteros- +tomy for biliary atresia. +The effect of hospital volume was not the focus +of this publication. +Recently, Bondoc and colleagues reported on their experience +with revision of portoenterostomies. +Choledochal Cyst +Classification. +Type I cyst is char- +acterized by fusiform dilatation of the bile duct. +This is the most +common type and is found in 80% to 90% of cases. +The cyst may be joined +to the common bile duct by a narrow stalk. +Type IVA cysts +consist of multiple dilatations of the intrahepatic and extra- +hepatic bile ducts. +Type IVB choledochal cysts are multiple +dilatations involving only the extrahepatic bile ducts. +The etiology of choledochal +cyst is controversial. +Clinical Presentation. +Choledochal cyst is more common in +females than in males (4:1). +Typically these present in children +beyond the toddler age group. +The classic symptom triad con- +sists of abdominal pain, mass, and jaundice. +However, this com- +plex is actually encountered in fewer than half of the patients. +If left undiagnosed, patients may develop cholangitis or +pancreatitis. +Cholangitis may lead to the development of cir- +rhosis and portal hypertension. +Often neonates will have an abdominal +mass at presentation. +Diagnosis. +Choledochal cyst is frequently diagnosed in the +fetus at a screening prenatal US. +CT will confirm the diagnosis. +Treatment. +The cyst wall is composed of fibrous tissue and +is devoid of mucosal lining. +Rarely, choledochal cyst +can lead to the development of a biliary tract malignancy. +This +provides a further rationale for complete cyst excision. +Resection of the cyst requires circumferential dissection. +More recently, laparoscopic- +assisted resections of choledochal cysts have been described. +The prognosis for children who have undergone complete +excision of choledochal cyst is excellent. +Complications include +anastomotic stricture, cholangitis, and intrahepatic stone forma- +tion. +These complications may develop a long time after surgery +has been completed. +As development is +completed, the intestine gradually returns to the abdominal cav- +ity. +Contraction of the umbilical ring completes the process of +abdominal wall formation. +Interruption of +central migration of the lateral folds results in omphalocele. +In such circumstances, early repair may be +advisable (Fig. +39-28). +Umbilical hernias are generally asymptomatic protrusions +of the abdominal wall. +They are generally noted by parents +or physicians shortly after birth. +The skin is closed using subcuticular sutures. +Persistence of this tract results in a communi- +cation between the bladder and the umbilicus. +The first sign of +a patent urachus is moisture or urine flow from the umbilicus. +Recurrent urinary tract infections can result. +A urachal cyst usually presents as an inflam- +matory mass inferior to the umbilicus. +Figure 39-28. +Umbilical hernia in a 1-year-old female. +The diagnosis of +patent urachus is confirmed by umbilical exploration. +The ura- +chal tract is excised and the bladder is closed with an absorbable +suture. +A patent vitelline duct may also present with umbilical +drainage. +Treatment includes umbilical exploration with resection of the +duct remnant (Fig. +39-29). +Omphalocele +Presentation. +39-30). +The umbilical cord inserts into the sac. +Chromosomal anomalies are more +common in children with smaller defects. +Treatment. +A blood glucose should be evaluated +because of the association with Beckwith-Wiedemann. +Prophylactic broad-spectrum antibiotics should be +administered in case of rupture. +The subsequent treatment and +outcome are determined by the size of the omphalocele. +This involves resec- +tion of the omphalocele membrane and closure of the fascia. +A layer of prosthetic material may be required to achieve clo- +sure. +39-30). +If repair is contraindicated, a nonoperative approach +can be used. +The omphalocele sac can be treated with topi- +cal treatments. +It typi- +cally takes 2 to 3 months before re-epithelialization occurs. +In cases of giant omphalocele, prolonged +hospitalization is typical. +Figure 39-29. +Patent vitelline duct. +8 +Figure 39-30. +Giant omphalocele in a newborn male. +1633 +P +EDIATRIC + S +URGER +y +CHAPTER 39 +Gastroschisis +Presentation. +Unlike omphalo- +cele, there is no overlying sac and the size of the defect is usu- +ally <4 cm. +39-31). +The umbilicus becomes +partly detached, allowing free communication with the abdomi- +nal cavity. +This defect can readily be diag- +nosed on prenatal US (Fig. +39-32). +There is no advantage +to performing a cesarean section instead of a vaginal deliv- +ery. +Treatment. +All infants born with gastroschisis require urgent +surgical treatment. +39-33). +In this case, +the fascial opening must be enlarged. +Surgical closure can usu- +ally be accomplished within approximately 1 to 2 weeks. +A +prosthetic piece of material may be required to bring the edges +of the fascia together. +If an atresia is noted at the time of closure, +Figure 39-31. +Gastroschisis in a newborn. +Note the location of the +umbilical cord and the edematous, thickened bowel. +Figure 39-32. +Prenatal ultrasound of a 30-week gestation fetus +with a gastroschisis. +Arrows point to the bowel outside within the +amniotic fluid. +8 +Figure 39-33. +Intestinal function does not typically return for +several weeks in patients with gastroschisis. +This is especially +true if the bowel is thickened and edematous. +Prune-Belly Syndrome +Clinical Presentation. +39-34). +The incidence is significantly higher in males. +Patients +manifest a variety of comorbidities. +The most significant is pul- +monary hypoplasia, which is not survivable in the most severe +cases. +Skeletal abnormalities include dislocation or dysplasia of +the hip and pectus excavatum. +The major genitourinary manifestation in prune-belly syn- +drome is ureteral dilation. +The ureters are typically long and +tortuous and become more dilated distally. +Treatment. +Inguinal hernia repair represents one of the most common +operations performed in children. +The presence of an inguinal +hernia in a child is an indication for surgical repair. +Embryology. +Closure of the processus vaginalis +normally occurs a few months prior to birth. +This explains the +high incidence of inguinal hernias in premature infants. +Partial closure can result in entrapped fluid, +which is known as a hydrocele. +Clinical Manifestation. +39-35). +Older children may notice the bulge themselves. +On examina- +tion, the cord on the affected side will be thicker, and pressure +Figure 39-34. +Eagle-Barrett (prune-belly) syndrome. +Notice the +lax, flaccid abdomen. +Figure 39-35. +Right inguinal hernia in a 4-month-old male. +The +arrows point to the bulge in the right groin. +The child will eventually develop intestinal +obstruction, peritonitis, and systemic toxicity. +Usually an incarcerated hernia can be reduced. +Occasion- +ally this may require light sedation. +Gentle pressure is applied +on the sac from below in the direction of the internal inguinal +ring. +Alternatively, the child may be scheduled for surgery at +the next available time slot. +This may require a laparotomy and bowel resection. +Transillumination as a method to distinguish between hydrocele +and hernia is nonspecific. +Surgical Repair. +A small incision is made in a skin crease +in the groin directly over the internal inguinal ring. +Scarpa’s +fascia is seen and divided. +The undersurface of the external oblique is +then cleared from surrounding tissue. +Care is taken not to grasp the vas +deferens. +The hernia sac is then dissected up to the internal ring +and doubly suture ligated. +The distal part of the hernia sac is +opened widely to drain any hydrocele fluid. +The opposite side may readily be explored laparoscopically. +To do so, a blunt 3-mm trocar is placed into the hernia sac of +the affected side. +The status of the processes vaginalis +on the opposite side can be visualized. +The long-term results of this technique remain +to be established. +GENITALIA +Undescended Testis +Embryology. +At birth, approximately 95% of infants have the +testicle normally positioned in the scrotum. +A distinction should be made between an undescended +testicle and an ectopic testicle. +1636 +SPECIFIC CONSIDERATIONS +UNIT II +part II +Clinical Presentation. +In addition, +fertility is decreased when the testicle is not in the scrotum. +For +these reasons, surgical placement of the testicle in the scrotum +(orchidopexy) is indicated. +Treatment. +Males with bilateral undescended testicles are often +infertile. +A child with unilateral cryptorchidism should +have surgical correction of the problem. +The operation is typi- +cally performed through a combined groin and scrotal incision. +An inguinal hernia often +accompanies a cryptorchid testis. +This should be repaired at the +time of orchidopexy. +Patients with a nonpalpable testicle present a challenge +in management. +The current approach involves laparoscopy to +identify the location of the testicle. +In the first stage, the testicular vessels can be +clipped via laparotomy or laparoscopically. +This promotes neo- +vasculogenesis along the vas deferens. +This may be done laparo- +scopically as well. +Other surgeons feel +that the staged approach to orchidopexy is superior. +To date, +no large-scale trial has been performed to answer this question. +Vaginal Anomalies +Surgical diseases of the vagina in children are either congeni- +tal or acquired. +These defects are pro- +duced by abnormal development of müllerian ducts and/or +urogenital sinus. +The diagnosis is made most often by physical +examination. +The anatomy may be defined using US. +Pelvic MRI +provides the most thorough and accurate assessment of the +pelvic structures. +Treatment is dependent on the extent of the +defect. +For an imperforate hymen, division of the hymen is +curative. +The most common acquired disorder of the vagina is the +straddle injury. +Typical +manifestations include vaginal bleeding and inability to void. +Prior to hospital discharge, it +is important that girls are able to void spontaneously. +Ovarian Cysts and Tumors +Pathologic Classification. +Ovarian cysts and tumors may +be classified as nonneoplastic or neoplastic. +The most +common variety is germ cell tumors. +Although these are malignant tumors, they are +extremely sensitive to radiation and chemotherapy. +The most +common lesions are the teratomas, which may be mature, imma- +ture, or malignant. +The +sex cord stromal tumors arise from the mesenchymal compo- +nents of the urogenital ridge. +These include the granulosa-theca +cell tumors and the Sertoli-Leydig cell tumors. +Although rare, epithelial tumors do occur +in children. +These include serous and mucinous cystadenomas. +Clinical Presentation. +Children with ovarian lesions usu- +ally present with abdominal pain. +Resection may +be performed laparoscopically; ovarian tissue should be spared +in all cases. +Surgical Management. +When a malignancy is suspected, the patient should +undergo a formal cancer operation. +This procedure is performed +through either a midline incision or a Pfannenstiel approach. +Ascites and peritoneal washings should be collected for cyto- +logic study. +The liver and diaphragm are inspected carefully +for metastatic disease. +An omentectomy is performed if there +is any evidence of tumor present. +Pelvic and para-aortic lymph +nodes are biopsied, and the primary tumor is resected com- +pletely. +Dysgerminomas +and epithelial tumors may be bilateral in up to 15% of cases. +It +is occasionally possible to preserve the ipsilateral fallopian tube. +More radical procedures are not indicated. +Ovarian Cysts in the Newborn. +An increasing number of +ovarian cysts are being detected by prenatal US. +Typically, resolution occurs +by approximately 6 months of age. +A laparoscopic approach is +preferable in these cases. +By contrast, complex cysts of any size +require surgical intervention at presentation. +Ambiguous Genitalia +Embryology. +Normal sexual differentiation occurs in the +sixth fetal week. +Normal sexual differentiation is directed by the +sex-determining region of the Y chromosome (SRY). +This is +located on the distal end of the short arm of the Y chromo- +some. +Therefore, the result of MIS secretion is a phenotypic male. +Thus, +the female phenotype prevails. +Ovotesticular DSD or 46,XX Testicular DSD. +This represents +the rarest form of ambiguous genitalia. +Occasionally, an ovotestis is present on +one or both sides. +The majority of these patients have a 46,XX +karyotype. +Both the testis and the testicular portion of the +ovotestis should be removed. +46,XY DSD. +Bilateral testes are present, but the duct structures differenti- +ate partly as phenotypic females. +The latter dis- +order is termed testicular feminization syndrome. +46,XX DSD. +The most common cause of this disorder is con- +genital adrenal hyperplasia. +These children have a 46,XX +karyotype but have been exposed to excessive androgens in +utero. +These patients are unable to synthesize +cortisol. +39-36). +These infants are prone to +salt loss and require cortisol replacement. +Those with mineralo- +corticoid deficiency also require fludrocortisone replacement. +Mixed Gonadal Dysgenesis. +This syndrome is associated with +dysgenetic gonads and retained müllerian structures. +The typical +karyotype is mosaic, usually 45,XO/46,XY. +Therefore, they should be removed. +Management. +Surgical assignment +of gender should never be determined at the first operation. +Discussion with the family also plays an important role. +Wilms’ Tumor +Clinical Presentation. +Wilms’ tumor is the most common +primary malignant tumor of the kidney in children. +Frequently, the mass is discovered by a par- +ent while bathing or dressing the child. +Other symptoms include +hypertension, hematuria, obstipation, and weight loss. +Occasion- +ally the mass is discovered following blunt abdominal trauma. +Genetics of Wilms’ Tumor. +Most of these tumors are associ- +ated with germline mutations. +It arises from mutations at +the 11p15.5 locus. +Impor- +tantly, most patients with Wilms’ tumor do not have mutations +at these genetic loci. +Surgical Treatment. +39-37). +There are +instances were preoperative chemotherapy is supported by both +Figure 39-36. +However, the overall survival rates are not different +between the NWTSG and SIOP approaches. +The goal of surgery is complete removal of the tumor. +It +is crucial to avoid tumor rupture or injury to contiguous organs. +A sampling of regional lymph nodes should be included, and +all suspicious nodes should be sampled. +Typically a transverse +abdominal incision is made, and a transperitoneal approach is +used. +The opposite side is carefully inspected to ensure that there +is no disease present. +If there is +spread above the hepatic veins, an intrathoracic approach may +be required. +Chemotherapy. +Even in stage IV, cure rates of 80% are achieved. +Neuroblastoma +Clinical Presentation. +Over 80% of cases present before the age +of 4 years, and the peak incidence is 2 years of age. +Neuro- +blastomas arise from the neural crest cells and show different +levels of differentiation. +The clinical presen- +tation depends on the site of the primary and the presence of +metastases. +Two thirds of these tumors are first noted as an asymp- +tomatic abdominal mass. +Occasionally, children may experience pain from the +tumor mass or from bony metastases. +Proptosis and perior- +bital ecchymosis may occur due to the presence of retrobulbar +metastasis. +Diagnostic Evaluation. +Wilms’ tumor of the right kidney (arrow) in a +3-year-old girl. +Table 39-3 +Staging of Wilms’ tumor +Stage I: Tumor limited to the kidney and completely +excised. +Stage II: Tumor that extends beyond the kidney but is +completely excised. +No residual tumor is apparent at or +beyond the margins of excision. +The tumor was biopsied, or +there was local spillage of tumor confined to the flank. +Stage III: Residual tumor confined to the abdomen. +Lymph +nodes in the renal hilus, the periaortic chains, or beyond +contain tumor. +Implants are found on the +peritoneal surfaces. +Tumor extends beyond the surgical +margins either microscopically or grossly. +Tumor is not +completely resectable because of local infiltration into vital +structures. +Treatment of +Wilms’ tumor. +Results of the Third National Wilms’ Tumor Study. +Cancer. +1989;64:349-360. +39-38). +Prior to the institution +of therapy, a complete staging workup should be performed. +Any abnormality on +chest x-ray should be followed up with CT of the chest. +Prognostic Indicators. +A number of biologic variables have +been studied in children with neuroblastoma. +An open biopsy is +required in order to provide tissue for this analysis. +Surgery. +The goal of surgery is complete resection. +After neoadjuvant treatment has been administered, surgical +resection is performed. +Abdominal tumors are approached through a transverse inci- +sion. +These +may have an intraspinal component. +This typically resolves, +although it may take many months to do so. +Neuroblastoma in Infants. +These patients may be observed +safely without surgical intervention or tissue diagnosis. +The clinical presentation of the tumor +depends on the site of origin. +It is +shown in Table 39-4. +If this is not possible, the lesion is biopsied, and intensive +chemotherapy is administered. +It is important to plan the biopsy +so that it does not interfere with subsequent resection. +After the +tumor has decreased in size, resection of gross residual disease +should be performed. +Abdominal neuroblastoma arising from the right +retroperitoneum (arrow). +Stage 3: Localized disease of any other primary site. +Stage 4: Metastatic disease at diagnosis. +Sources: Lawrence W Jr, Gehan EA, Hays DM, et al. +J Clin Oncol. +1987;5:46-54. +Lawrence W Jr, Anderson JR, Gehan EA, et al. +Children’s Cancer Study Group. +Pediatric +Oncology Group. +Cancer. +1997;80:1165-1170. +1641 +P +EDIATRIC + S +URGER +y +CHAPTER 39 +following initial treatment. +Prognosis. +Tumor histology influences +prognosis. +The embryonal variant is favorable, whereas the +alveolar subtype has an unfavorable prognosis. +Teratoma +Teratomas are tumors composed of tissue from all three embry- +onic germ layers. +Thoracic teratomas usually present as an anterior medi- +astinal mass. +Retroperi- +toneal teratomas may present as a flank or abdominal mass. +Tumors of higher grade are +more likely to have foci of yolk sac tumor. +Sacrococcygeal Teratoma. +Diagnosis may be established by prenatal US. +39-39). +The tumor has been classified based on the +location and degree of intrapelvic extension. +Lesions that grow +predominantly into the presacral space often present later in +childhood. +The differential diagnosis consists of neural tumors, +lipoma, and myelomeningoceles. +Most tumors are identified at birth and are benign. +Malig- +nant yolk sac tumor histology occurs in a minority of these +tumors. +Complete resection of the tumor as early as possible +is essential. +This is of particular concern in small, preterm infants +with large tumors. +The cure rate is excellent if the tumor is +excised completely. +Liver Tumors +More than two thirds of all liver tumors in children are malig- +nant. +There are two major histologic subgroups: hepatoblastoma +and hepatocellular carcinoma. +The age of onset of liver cancer +in children is related to the histology of the tumor. +The finding of a liver mass does +not necessarily imply that a malignancy is present. +Nearly 50% +of all masses are benign, and hemangiomas are the most com- +mon lesion. +The +patients are rarely jaundiced but may complain of anorexia and +weight loss. +Most liver function tests are normal. +39-40). +For malignant-appearing lesions, a +Figure 39-39. +Sacrococcygeal teratoma in a 2-day-old boy. +Figure 39-40. +Computed tomography of the abdomen showing a +hepatocellular carcinoma in a 12-year-old boy. +The fibrolamellar variant of +hepatocellular carcinoma may have a better prognosis. +Surgery. +Complete surgical +resection of the tumor is the primary goal and is essential for +cure. +Chemotherapy +is more successful for hepatoblastoma than for hepatocellular +carcinoma. +For unre- +sectable tumors, liver transplantation may be offered in select +patients. +TRAUMA IN CHILDREN +Injury is the leading cause of death among children older than +1 year. +Specific considerations apply to trauma in children that +influence management and outcome. +Mechanisms of Injury +Most pediatric trauma is blunt. +Age and +gender significantly influence the patterns of injury. +In the infant and toddler age group, falls +are a common cause of severe injury. +Injuries in the home are +extremely common. +These include falls, near-drownings, caus- +tic ingestion, and nonaccidental injuries. +Airway control is the first priority. +In a +child, respiratory arrest can proceed quickly to cardiac arrest. +The size of the endotracheal tube can +be estimated by the formula (age + 16)/4. +After evaluation of the airway, +breathing is assessed. +Pneumothorax +or hemothorax should be treated promptly. +IV access should be rapidly obtained once the patient arrives in +the trauma bay. +The first approach should be to use the antecubi- +tal fossa. +Percutaneous neck lines should +generally be avoided. +If the patient does not respond to two boluses, blood should +be transfused (10 mL/kg). +The source of bleeding should be +established. +Common sites include the chest, abdomen, pelvis, +extremity fractures, or large scalp wounds. +These should be +carefully sought. +Care is taken to avoid hypothermia by infus- +ing warmed fluids and using external warming devices. +Proc Am Soc Clin Oncol. +1994;13:A-1439. +All extremities that are suspicious +for fracture should also be evaluated by x-ray. +Significant elevation in these tests +requires further evaluation by CT scanning. +There is a +limited role for diagnostic peritoneal lavage (DPL) in children as +a screening test. +In the toddler age group, nonaccidental trauma +is the most common cause of serious head injury. +The initial head CT +can often underestimate the extent of injury in children. +Any change in the neurologic status warrants neurosurgical +evaluation and repeat CT scanning. +In patients with severe head +injury (GCS ≤8), urgent neurosurgical consultation is required. +Children who have sustained massive blunt thoracic injury may +develop traumatic asphyxia. +Man- +agement includes ventilation and treatment of coexisting CNS +or abdominal injuries. +Duodenal hematomas usually resolve without surgery. +These injuries are usually caused +by rapid deceleration in the setting of a lap belt. +39-41A). +This should alert the +caregiver to the possibility of an underlying small bowel injury +(Fig. +39-41B), as well as to a potential lumbar spine injury +(Chance fracture). +BA +Figure 39-41. +Abdominal computed tomography of patient who sustained a lap belt injury. +A. +Bruising is noted across the abdomen from +the lap belt. +B. +At laparotomy, a perforation of the small bowel is identified. +This approach avoids +surgery in most cases. +This optimizes the chance for healing and minimizes +the likelihood of reinjury. +At surgery, the spleen can often be salvaged. +The liver is also commonly injured +after blunt abdominal trauma. +39-42). +Renal contusions may occur after significant blunt abdomi- +nal trauma. +It is +important 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+2003;38:1480. +Wood JH, Partrick DA, Johnston RB Jr. +The inflammatory response +to injury in children. +Curr Opin Pediatr. +2010;22:315-320. +Yang EY, Allmendinger N, Johnson SM, Chen C, Wilson JM, +Fishman SJ. +J Pediatr Surg. +2005;40:1369-1375. +Anteriorly, they are confined by the posterior layer of +the peritoneum. +The renal veins, which course anteriorly to the renal +arteries, drain directly into the vena cava. +The left renal vein +passes anterior to the aorta and is much longer than the right +renal vein. +This explains why most surgeons prefer to take the +left kidney for living donor transplantation. +The right renal vein has no such collateral venous +drainage. +The renal pelvis can have either a mainly intrarenal or extrarenal +position. +The renal pelvis tapers into the ureteropelvic junction +(UPJ) where it joins with the ureter. +The adrenal glands lie superomedially to the kidneys +within Gerota’s fascia. +There is a layer of Gerota’s fascia +between the adrenal and the kidney. +On the right, the adrenal is drained +by a very short (<1 cm) vein to the vena cava. +It can be +avulsed by moderate traction and can be the source of trou- +blesome bleeding. +The blood supply has implica- +tions for managing ureteral injuries. +They enter the bladder at the lateral aspect of the +base. +The anatomic relations of the +bladder are dependent on the degree of filling. +A very distended +bladder can project above the umbilicus. +At physiologic volumes +(200–400 mL), the bladder projects modestly into the abdomen. +In males, the prostate is in continuity with the bladder +neck, and the urethra courses through it. +Proximally, they lie along the medial +aspects of the inferior pubic rami in the perineum. +Distally, +they fuse along their medial aspects and form the pendulous +penis. +Injury or excess traction of these nerves may cause erectile +dysfunction. +On the underside of the penis lies the corpus +spongiosum, which surrounds the urethra. +The tip of the penis, called the glans, is in continuity with the +corpus spongiosum. +Scrotum and Testes +The scrotum is a capacious structure that contains the testes +and epididymes. +These layers are not always distinct. +The visceral layer +of the tunica vaginalis is adherent to the testis. +The noncompli- +ant outer testis layer is the tunica albuginea. +Inside the tunica +are the seminiferous tubules. +The blood supply enters the testis +at the superior pole by way of the spermatic cord. +Some children are born with an undescended abdominal testicle. +Often, it is difficult to derive enough length to place the testicles +in the scrotum. +Most of these testicles remain viable as a result of +collaterals. +Bladder cancer can be categorized into invasive and non- +invasive types. +Management of urothelial carcinoma varies +greatly, depending on the depth of invasion. +Detubularization decreases +intrapouch filling pressure, which improves urinary storage +capacity. +Each segment of bowel that +is used offers its own advantages and inherent complications. +Tumor grade is extremely important in +assessing the risk of disease progression. +Surgical Approaches and Complications. +This allows +adequate exposure of the pelvic contents, iliac vessels, and +lower abdominal cavity. +In men, the prostate is removed with the bladder. +40-1). +A major risk for the develop- +ment of testicular cancer is cryptorchidism. +The non–germ cell +tumors are rare and generally follow a more benign course. +Germ +Figure 40-1. +Testicular cancer. +Patients often present with +advanced disease despite scrotal enlargement for several months. +Chest and abdominal imaging must +be performed to evaluate for evidence of metastasis. +Lymphoma +(especially among the elderly) may involve one or both testes. +Postchemotherapy RPLND for residual +masses can be challenging. +Surgical Approach and Complications. +Complex renal cyst. +A right kidney with a Bosniak +type 3 renal cyst. +Note the enhancing septum (arrow). +This cyst +was removed and found to be a high-grade papillary renal cell +carcinoma. +40-2). +Renal tumors are usually solid, but they +also can be cystic. +Simple cysts are very common and are not +malignant, but more complex cysts may be malignant. +These syndromes frequently involve +Table 40-1. +Also includes homogeneously hyperdense cysts <3 cm. +May contain nodular calcification. +Also includes hyperdense cysts >3 cm. +∼50%/surgical +IV Same as III, but with enhancing solid components. +∼100%/surgical +Source: Adapted with permission from Israel GM, Bosniak MA. +An update of the Bosniak renal cyst classification system. +Urology. +2005;66:484. +Copyright Elsevier. +1656 +SPECIFIC CONSIDERATIONS +UNIT II +PART + +II +a germline mutation in a tumor suppressor gene. +von Hippel- +Lindau disease is associated with multiple tumors including +clear cell RCC (Fig. +40-3). +Patients with heredi- +tary papillary RCC and hereditary leiomyomatosis develop pap- +illary RCC. +Patients with localized disease may be cured with either +partial or radical nephrectomy (Fig. +40-4). +However, patients +Figure 40-4. +Partial nephrectomy. +A kidney after partial resection +for a small renal mass. +Note the visible collecting system in the base +of the defect (arrow). +Figure 40-3. +von Hippel-Lindau disease. +Note the numerous +cysts in the head of the pancreas (arrow). +Minimally invasive techniques for renal surgery have +greatly changed the field of kidney cancer. +Surgeons are now capable +of performing intracorporeal suturing with much greater +ease. +The degree of venous extension directly impacts the +surgical approach. +40-5A). +Usually, the thrombus is not adher- +ent to the vessel wall. +40-5B). +Nephrectomy, +either partial or radical, can be performed through a number +of surgical approaches. +However, entry into the pleura is not +uncommon. +If small, the pleurotomy usually can be closed +without need for a chest tube. +The anterior subcostal approach +also is used for nephrectomy. +A chest tube +is used postoperatively. +The adrenal gland is no longer rou- +tinely removed unless the tumor is adherent to it. +The benefit +of lymph node dissection when the nodes are not clinically +involved is uncertain. +Partial nephrectomy has the added risks of delayed +bleeding and urine leak. +Ileus is not common when the perito- +neal cavity is not entered. +The U.S. +Preventive Services Task Force has +advised against the routine use of prostate cancer screen- +ing. +The American Urological Association has advised for +screening for men 55 to 69 years of age. +Grades range from 1 for the most differentiated to 5 for the +least. +The grades are added to give the Gleason score. +In cur- +rent practice, scores below 6 are almost never assigned. +Gleason +score, preoperative PSA level, and digital rectal exam are used +Figure 40-5. +Inferior vena cava thrombus. +A. +B. +This patient is alive 6 years after surgery. +After +definitive treatment, an increasing PSA is indicative of recur- +rent cancer. +The most common site of spread of prostate cancer is the +pelvic lymph nodes and bone. +For low-risk disease, the efficacy of each +treatment modality is thought to be similar. +Radical prostatectomy is associated with +early incontinence and ED (depending on nerve sparing). +Likewise, ED improves with time. +Once prostate cancer has spread, it is no longer cur- +able. +Surgical Approach and Complications. +The peritoneum is not entered. +The cavernosal nerves lay +immediately posterolateral to the prostatic capsule. +Benefits over open +Table 40-2. +Organ injury scaling. +Surg Clin North Am. +1995;75:293. +Copyright Elsevier. +radical retropubic prostatectomy include lower blood loss and +faster convalescence. +Complications of prostatectomy depend on approach. +All approaches carry a small risk of urinary +incontinence and a more substantial risk of ED. +Renal injuries are classified by extent of damage +(Table 40-2). +Addi- +tionally, most grade IV injuries can be managed nonoperatively +(Fig. +40-6).21 Patients typically are placed on restricted activity +until hematuria resolves. +Table 40-3 lists indications for assess- +ing surgical intervention in renal trauma patients. +Indications for surgical intervention for renal trauma +Absolute indications + 1. +Persistent, life-threatening hemorrhage from probable +renal injury + 2. +Renal pedicle avulsion (grade 5 injury) + 3. +Expanding, pulsatile, or uncontained retroperitoneal +hematoma +Relative indications + 1. +Large laceration of the renal pelvis or avulsion of the +ureteropelvic junction + 2. +Coexisting bowel or pancreatic injuries + 3. +Abnormal intraoperative one-shot intravenous urogram + 5. +Devitalized parenchymal segment with associated urine +leak + 6. +Renal vascular injuries after failed angiographic +management + 8. +Renovascular hypertension +Source: Reproduced with permission of Wiley-Blackwell. +From San- +tucci RA, Wessells H, Bartsch G, et al. +Evaluation and management of +renal injuries: consensus statement of the renal trauma subcommittee. +BJU Int. +2004;93:937. +Figure 40-6. +Blunt renal trauma after a bicycle accident. +A. +Delayed images showed urinary extravasation. +This patient +was managed nonoperatively. +B. +extent of injury. +If the IVP is abnormal or the hematoma is pul- +satile, renal exploration should be performed. +Renal exploration should begin once the renal hilum is +controlled. +Complete expo- +sure is necessary to evaluate the extent of injury. +If +the collecting system is injured, it should be repaired at this +time. +A stent and percutaneous drain should be considered to +prevent urinoma formation. +A +briefly misplaced suture may be removed usually without conse- +quence. +Ureteral stents should be placed in +this situation to facilitate healing without stricture. +Bladder +Bladder injury can occur from penetrating and blunt trauma. +The diagnosis should be entertained for any lower abdominal +or pelvic trauma. +Patients clinically present with fevers or a +prolonged ileus. +Radiographic evaluation begins with either a fluoroscopic +or CT cystogram. +It is vital to avoid underfilling, as it may lead +to a false-negative study. +The contrast +material should be allowed to fill to the natural capacity of the +bladder. +Extraperitoneal bladder injuries can typically be managed +with catheter drainage for 7 to 10 days. +Intraperitoneal bladder +injuries should be explored immediately and repaired. +Catheter placement can be attempted +in patients with partial urethral injuries. +Those with complete +disruptions should have placement of a suprapubic tube. +Anterior injuries often are related to blunt straddle inju- +ries and penetrating trauma. +If the patient is stable +with minimal hematoma formation, repair should be consid- +ered. +For most cases, catheter drainage is +recommended. +However, a single gentle passage performed by a +urologist is safe. +The patient’s other injuries dictate urologic +management. +They should be staged with either a retrograde +urethrography or voiding cystourethrogram (VCUG). +Patients +with short defects may be amenable to dilatation or cystoscopic +urethrotomy. +Depending on location, length, and severity, open +repairs may be required. +Long defects may require grafting to +avoid significant penile shortening. +For +penetrating trauma, immediate exploration is recommended for +accurate staging and repair. +Although salvage may be possible, an orchiec- +tomy usually is required. +40-7). +Men may notice an immediate audible “pop” and experience +rapid penile detumescence. +Immediate swelling develops. +Leakage should be visualized if there is +a urethral disruption. +If present, the urethra should be repaired, +taking care not to significantly narrow the lumen. +A Foley cath- +eter is left in place for several days after surgery. +Constipation, +a common side effect of those medications, can itself +worsen urinary retention. +Treatment should include placement of a +urethral catheter as quickly as possible. +However, BPH or ure- +thral strictures often make the placement of a catheter difficult. +40-8A). +40-8B). +A common mistake is +to use a smaller catheter to bypass the enlarged prostate. +Smaller catheters are useful for bypassing a urethral +stricture. +Using a 12F or 14F catheter often will allow the pas- +sage of the catheter into the bladder. +If catheter placement is +not successful, a urologic consultation should be requested. +The +urologist can either choose to (a) use a cystoscope, guidewire, +7 +Figure 40-7. +Penile fracture. +A. +A patient with a penile fracture that was suspected based on history and examination. +Note the lack of skin +discoloration that is often present. +B. +The +urethra, which is between the surgeon’s fingers, surprisingly escaped injury. +This is done through a large three-way +catheter that has an additional port for fluid inflow. +A urinalysis should be checked because a poorly empty- +ing bladder is prone to infection. +Renal function also should be +assessed for those in AUR by checking the creatinine level. +Once the bladder is adequately drained, the cause of AUR +should be addressed. +For men with suspected BPH, an α-blocker +such as tamsulosin should be started. +Narcotics should be tapered as tol- +erated, and constipation should be treated. +However, +most patients are resistant to this approach. +Testicular Torsion +The differential diagnosis of acute scrotal pain includes testicu- +lar torsion. +This usually occurs in neonates or adolescent males +but may be observed in other age groups. +Clinical history is vital for diagnosis. +Patients describe a +sudden onset of pain at a distinct point in time, with subsequent +swelling. +Children +normally have a brisk cremasteric reflex that usually is lost in +the setting of torsion. +Immediate surgical exploration can salvage an isch- +emic testis. +Coude catheter. +A. +B. +The tip of a coude catheter. +Note the curved tip, which should +always point to 12 o’clock when inserted. +Midline +(along the median raphe) or bilateral transverse scrotal incisions +are made. +40-9A). +Clinical signs include fevers, perineal and scrotal pain, +and associated indurated tissue. +Cellulitis, eschars, necrosis, +flaking skin, and crepitus may all be observed. +Classically, the +patient describes pain out of proportion to the physical findings. +40-9B). +Patients frequently require return trips to the oper- +ating room for further débridement. +Tight glucose control and +adequate nutrition are necessary to facilitate wound healing. +The +large tissue defect should be initially treated with frequent +dressing changes. +Priapism is divided into two types, +based on the underlying pathophysiology. +The most common +type—low-flow/ischemic priapism—is a medical emergency. +For those with sickle cell disease, hydration and +9 +Figure 40-9. +Fournier’s gangrene. +A. +Necrotic scrotal skin from +Fournier’s gangrene. +B. +Débridement of gangrenous tissue. +Note +the extensive débridement, which is commonly required. +If this fails, an operative distal shunt can +be performed (Al-Ghorab). +This form is not painful because it +is not related to ischemia and can be managed conservatively. +Paraphi- +mosis is a common problem that represents a true medical +emergency. +When foreskin is retracted for prolonged periods, +constriction of the glans penis may ensue. +Edema often forms in the genitals +of supine patients due to the dependent position of that area. +It is useful to apply firm pressure to the edematous +distal penis for several minutes. +Although painful, this reduc- +tion in penile edema can be the key to success. +If the foreskin cannot be +manually reduced, surgical intervention is required. +Emphysematous pyelo- +nephritis can be subdivided based on extent of infection. +An uncomplicated episode of cystitis requires a 3-day +course of antibiotics. +Those with complicated cystitis require +7 days of antibiotics and possible imaging studies. +Patients +typically present with flank pain and fevers. +Other- +wise, they should be hospitalized for IV antibiotics. +Treatment consists of broad-spectrum IV antibi- +otics and percutaneous drainage. +Patients present with +fevers, dysuria, and perineal or back discomfort. +A digital rectal +examination may indicate an indurated and tender gland. +Patients require a 4- to 6-week course of antibiotic +therapy, typically a quinolone. +If present, large abscesses +can be managed with transurethral unroofing or percutaneous +drainage. +Chronic prostatitis presents with continued lower urinary +tract symptoms and pelvic pain. +Chronic +nonbacterial prostatitis does not respond to antibiotics or most +other medications. +However, most men will not +show evidence of urinary tract infection. +The scrotum may be erythematous on the side of +involvement. +The white blood cell (WBC) count often is ele- +vated. +The onset is fairly rapid, but not as sudden as torsion. +An +ultrasound may provide supporting evidence such as increased +blood flow to the epididymis. +A reactive hydrocele may be +present. +Intratesticular abscesses +may form and usually result in orchiectomy. +The symptoms of BPH are urinary +frequency, urgency, hesitancy, slow stream, and/or nocturia. +Medical treatment of BPH is usually the first step. +α-Blockers act on α receptors in the smooth muscle of the +prostate and decrease its tone. +Both are used either singly +or in combination as medical therapy for BPH. +Trans- +urethral resection of the prostate is the mainstay of endoscopic +surgical BPH treatment. +It is extremely effective at improving +flow and decreasing residual urine. +It is due to hyponatremia and +fluid overload, and although rare, can result in death. +There also is less bleeding. +Urethral Stricture +The voiding symptoms of urethral stricture are very similar to +BPH. +Diagnosis is by retrograde urethrogram or +cystoscopy. +40-10). +Hydronephrosis and ureteral calculus. +A. +Left hydronephrosis from distal obstruction (arrow). +B. +A 4-mm calculus at the +ureterovesical junction (arrow). +Stents allow flow both +through the lumen and around it. +Several underlying causes exist for the formation of uri- +nary calculi. +Urinary calculi may occur anywhere in the urinary tract. +The obstruction may be partial or complete. +Several methods for treating urinary calculi are available, +depending on location. +Fragments are extracted, although they +usually will pass spontaneously. +This approach is well +suited to staghorn calculi. +Complications of lithotripsy are specific to the technique +used. +Ureteroscopy may occasionally lead to strictures due to +scarring from trauma to the ureter. +Better hydration +is useful for all etiologies. +Additionally, most patients will +benefit from alkalization of the urine (e.g., potassium citrate). +They are brought into the peritoneum and wrapped +in omentum to prevent re-entrapment. +UPJ obstruction also is commonly +observed in children and young adults. +Intrinsic and extrinsic +causes of UPJ obstruction exist and can be determined by pre- +sentation. +Over time, +elevated renal pelvic pressures and recurrent infections can +injure renal parenchyma. +Delayed +clearance of contrast or radiotracer implies obstruction. +Inva- +sive pressure-flow examinations (Whitaker test) rarely are per- +formed. +Not every case of UPJ obstruction requires operative inter- +vention. +However, patients with infections or impaired renal +function require repair to improve drainage. +Open dismembered +pyeloplasty is considered the gold standard approach, especially +in infants. +An endoscopic approach, endopy- +elotomy, is also an option in older children and adults. +However, +it is not as effective as a dismembered pyeloplasty. +The incidence of VUR decreases with advancing age. +VUR is graded according to the 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Steele D, Hunt J. +Splenic rupture after extracorpo- +real shock wave lithotripsy. +J Urol. +1996;156:1756. +53. +Marcuzzi D, Gray R, Wesley-James T. +Symptomatic splenic +rupture following extracorporeal shock wave lithotripsy. +J +Urol. +1991;145:547. +54. +Curhan GC, Willett WC, Rimm EB, et al. +N Engl J Med. +1993;328:833. +55. +Koep L, Zuidema GD. +The clinical significance of retroperito- +neal fibrosis. +Surgery. +1977;81:250. +56. +Srinivas V, Dow D. +Retroperitoneal fibrosis. +Can J Surg. +1984;27:111. +57. +Smellie JM, Normand IC. +Clinical features and signifi- +cance of urinary tract infection in children. +Arch Dis Child. +1968;43:468. +58. +Duckett JW. +Vesicoureteral reflux: a “conservative” analysis. +Am J Kidney Dis. +1983;3:139. +59. +Arant BS. +A preliminary report of the Southwest Nephrology +Group. +J Urol. +1992;148:1683. +60. +Kousidis G, Thomas DF, Morgan H, et al. +BJU Int. +2008;102:1020. +This page intentionally left blank +Gynecology +Chad Hamilton, Michael Stany, W. +Thomas Gregory, +and Elise C. +The pelvis is a very complex area, with a multitude of +spatially and temporally varied functions. +ANATOMY +Clinical gynecologic anatomy centers on the pelvis (from Latin +meaning basin). +41-1). +41-2). +The first two of these muscles +contribute fibers to the fibromuscular perineal body. +The internal iliac, or hypogastric, arter- +ies divide into anterior and posterior branches. +The latter sup- +ply lumbar and gluteal branches. +Deeper muscles of the pelvic floor. +Trauma in +pregnancy must be managed with these changes in mind. +8 Radical hysterectomy has unique risks of ureteral fistula +and bowel dysfunction. +41-2). +The major nerves found in the pelvis are the sciatic, obtu- +rator, and femoral nerves. +41-3). +41-1 and 41-3). +41-4). +The muscles and vasculature of the pelvis. +The nerve supply of the female pelvis. +External genitalia. +(Reproduced with permission from Rock J, Jones HW. +TeLinde’s Operative Gynecology. +9th ed. +Philadelphia, +PA: Lippincott Williams & Wilkins; 2003, Fig. +5-1, p. +70.) +1674 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +skin in the adult. +They fuse anteriorly over the anterior promi- +nence of the symphysis pubis, the mons pubis. +Both the urethra and the vagina open into the vestibule. +Skene’s glands lie lateral and inferior to the urethral meatus. +Cysts, abscesses, and neoplasms may arise in these glands. +41-1). +The clitoris is formed by two crura and +is suspended from the pubis. +These terminate in the midline in the perineal +body, caudal and deep to the posterior fourchette. +These originate from the perineal +body and insert into the body of the clitoris. +The upper two thirds of the vagina are not are not invested by +muscles. +The cervix opens into the posterior vaginal wall bulging into +the vaginal lumen. +The cen- +tral uterus and uterine cervix are supported by the pelvic floor +muscles. +The latter is also called the pouch or cul-de-sac of +Douglas. +41-6). +Internal pelvic anatomy, from above. +The avascular spaces of the female pelvis. +It lies between the bladder anteriorly and the +rectosigmoid posteriorly. +Sustained estrogenic stimulation can lead to hyperplas- +tic changes or carcinoma. +The myometrium can +develop benign smooth muscle neoplasms known as leiomyoma +or fibroids. +Cervix +The cervix connects the uterus and vagina and projects into +the upper vagina. +The transformation zone develops as the columnar epithelium +is replaced by squamous metaplasia. +These changes can be detected by +microscopic assessment of a cervical cytologic (or Pap) smear. +The tubes can be divided into four parts. +The interstitial part forms a passage through the myometrium. +The isthmus is the narrow portion extending out about 3 cm +from the myometrium. +The ampulla is thin-walled and tortuous +with its lateral end free of the broad ligament. +The infundibulum +is the distal end fringed by a ring of delicate fronds or fimbriae. +The fallopian tubes receive the ovum after ovulation. +Peristal- +sis carries the ovum to the ampulla where fertilization occurs. +The zygote transits the tube over the course of 3 to 4 days to +the uterus. +Abnormal implantation in the fallopian tube is the +most common site of ectopic pregnancies. +The tubes may also +be infected by ascending organisms, resulting in tubo-ovarian +abscesses. +The ovarian veins ascend +at first with the ovarian arteries, and then track more laterally. +Lymphatic drainage follows the arteries to the para-aortic lymph +nodes. +Beneath +this is a fibrous stroma within which are embedded germ cells. +At ovulation, an ovarian follicle ruptures through the ovarian +epithelium. +The pelvic examination starts with a full abdominal +examination. +Abnormalities are +documented, and a map with measurements of abnormalities +is drawn. +41-7). +It is critical that presurgical assessments include a full gen- +eral examination. +Common Screening and Testing +Cervical Preinvasive and Invasive Disease Screening. +The most recent cervical cytology guidelines by the U.S. +If an HPV test +Figure 41-7. +Bimanual abdominovaginal palpation of the uterus. +Microscopy of Vaginal Discharge. +The +test is positive for vaginal candidiasis when pseudohyphae are +seen (Table 41-2). +Chlamydia/Gonorrhea Testing. +A vaginal +swab, endocervical swab, and/or urine sample can be used for +this test. +The test can be completed within hours and has been +found to be more sensitive than cultures. +β-Human Chorionic Gonadotropin (β-hCG) Testing. +Common Office Procedures for Diagnosis +Vulvar/Vaginal Biopsy. +The specimen is elevated with Adson forceps and cut +from its base with scissors. +The vaginal biopsy can sometimes +be difficult to perform because of the angle of the lesion. +Colposcopy and Cervical Biopsy. +A colposcope is used to achieve 2× to 15× magni- +fication of the cervix. +This application dehydrates cells and +causes dysplastic cells with dense nuclei to appear white. +The +entire squamocolumnar junction is visualized during an ade- +quate colposcopy. +Endometrial Biopsy. +A patient with the potential for +pregnancy should have a pregnancy test before the procedure. +Evaluation for Fistula. +A simple +office procedure can be performed when there is a concern for a +vesicovaginal fistula. +If the test is negative, one can evaluate for a ureterovaginal fis- +tula. +The patient is given phenazopyridine, which changes the +color of urine to orange. +If a tampon placed in the vagina stains +orange, the test is positive. +Alternatively, the patient can be +given an intravenous injection of indigo carmine. +Rectal fistula must be considered when a patient reports +stool evacuation per vagina. +Vulvar Contact Dermatitis. +Leukoplakias. +There are three types of leukoplakia, a flat +white abnormality. +Lichen sclerosis is the most common cause +of leukoplakia.4 It affects women 30 to 40 years of age. +Diagnosis is confirmed +with biopsy, and treatment consists of topical steroids. +Lichen +planus is a cause of leukoplakia with an onset in the fifth and +sixth decades of life. +Histology is not specific, and biopsy +is recommended. +Treatment is with steroid ointments. +Systemic +steroids are indicated for severe and/or unresponsive cases. +Bartholin’s Cyst or Abscess. +They are lined with cuboidal epithelium and secrete +mucoid material to keep the vulva moist. +They +occasionally result in discomfort and dyspareunia and require +treatment. +Cysts and ducts can become infected and form +abscesses. +Infections are often polymicrobial; however, sexually +transmitted N. +gonorrhoeae and C. +trachomatis are sometimes +implicated. +Appropriate antibiotic therapy should be +instituted. +Molluscum Contagiosum. +Molluscum contagiosum presents +with dome-shaped papules and is caused by the poxvirus. +The +papules are usually 2 to 5 mm in diameter and classically have +a central umbilication. +Genital Ulcer Syndromes. +The frequency of the infectious +etiologies of genital ulcers varies by geographic location. +Non- +infectious etiologies include Behçet’s disease, neoplasms, and +trauma. +Table 41-3 outlines a rational approach to their evalua- +tion and diagnosis. +Vulvar Condyloma. +Data from Stenchever M, Droegemueller W, Herbst A, et al. +Comprehensive Gynecology. +4th ed. +St. +Louis: Mosby; 2001. +1680 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +with invasive cancers. +Lesions may be single or multiple and extensive. +Paget’s Disease of the Vulva. +Vulvar Intraepithelial Neoplasia (VIN). +VIN can be unifocal or multifocal. +Lesions may be vague or raised and velvety +with sharply demarcated borders. +Diagnosis is made with a vul- +var skin biopsy, and multiple biopsies are sometimes necessary. +Normal vaginal discharge is white or transparent, thick, +and mostly odorless. +Complaints of foul odor and abnormal +vaginal discharge should be investigated. +Candidiasis, bacte- +rial vaginosis, and trichomoniasis account for 90% of vaginitis +cases. +A pH greater than or equal to 4.9 is indicative of a bacterial or +protozoal infection. +41-8). +Bacterial Vaginosis (BV). +BV accounts for 50% of vaginal +infections. +The discharge typi- +cally produces a fishy odor upon addition of KOH (amine or +Whiff test). +Initial treatment is usually a 7-day course of met- +ronidazole. +Vulvovaginal Candidiasis (VVC). +VVC is the most common +cause of vulvar pruritus. +It is generally caused by Candida albi- +cans and occasionally by other Candida species. +Trichomonas vaginalis. +Initial treatment is usually a 7-day course of met- +ronidazole. +Gartner’s Duct Cyst. +If symptomatic, these +cysts may be surgically excised or marsupialized. +Vaginal Condyloma. +4 +1681 +GYNECOLOGY +CHAPTER 41 +Vaginal Intraepithelial Neoplasia. +The majority of lesions are located in the upper one third of +the vagina. +Lesions are usually asymptomatic and found inci- +dentally on cytologic screening. +Diagnosis is made via guided +biopsy of acetowhite lesions at the time of colposcopy. +The presence of aber- +rant vessels with marked branching is suggestive of invasive +disease. +VaIN is treated with laser ablation, surgical excision, +or topical 5-fluorouracil therapy. +Cervical Lesions +Benign Cervical Lesions. +Use of loop electro-excisional procedure (LEEP) is appro- +priate for larger lesions. +Laser or other ablative procedures are +appropriate for condyloma proven by biopsy. +Cervical Intraepithelial Neoplasia (CIN). +Loops +range in a variety of shapes and sizes to accommodate different +sizes of cervix. +Optimally, one pass of the loop should excise the +entire SCJ. +Different from a LEEP, a cervical CKC does not use +energy to excise the specimen. +The advantage of this procedure +is that the margin status is not obscured by cauterized artifact. +During a CKC, a +#11 blade is used to circumferentially excise the conical biopsy. +Hemostasis is achieved with the ball electrode, Monsel’s solu- +tion, or suture. +HPV Vaccine. +Two HPV vaccines have been developed and +approved by the U.S. +Cervarix is a bivalent vaccine that targets HPV genotypes 16 +and 18. +Treatment algorithm for vulvovaginitis. +1682 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +vaccines. +Immunocompromised women may receive the quadri- +valent vaccine. +Abnormal Uterine Bleeding (AUB). +Abnormal uterine bleed- +ing is described based on the bleeding pattern. +Menometrorrhagia is the occur- +rence of both. +Endometrial Polyps. +Polyps are common in patients on tamoxifen therapy and in +peri- and postmenopausal women. +Adenomyosis. +Adenomyosis refers to ectopic endometrial +glands and stroma situated within the myometrium. +Uterine Leiomyomas. +Leiomyomas are described according +to their anatomic location (Fig. +Other manifestations include pain, pregnancy +complications, and infertility. +Diagnosis is +usually made by transvaginal ultrasonography. +Hysterectomy is the only curative therapy. +The latter may make the preferred vaginal surgical +approach more feasible. +Endometrial Hyperplasia. +It +can be asymptomatic or, more commonly, result in abnormal +vaginal bleeding. +Hyperplasia can be either simple or complex, +based on the architecture of the glands. +Close follow-up and repeated sampling +are necessary. +Procedures Performed for Structural Causes of Abnormal +Uterine Bleeding +Dilation and Curettage. +The cervix is grasped on +the anterior lip with a tenaculum. +Some traction on the cervix is +necessary to straighten the cervical canal and the uterine cavity. +A uterine sound is inserted into the uterine cavity, and the depth +of the uterus is noted. +The cervical canal is then systematically +dilated beginning with a small cervical dilator. +41-10). +The endometrial cavity is then systemically scraped with +a uterine curette. +Laparoscopy to identify any +damage to vessels or bowel may be required. +Hysteroscopy. +Scopes can have an objective lens that is offset +from the long axis from 0° to 30°. +The diagnostic hysteroscope +usually has an external diameter of 5 mm. +Some diagnostic +sheaths allow passage of flexible instruments for biopsy and +cutting. +The loop can be replaced with a roller ball for +endometrial ablation. +Several types of distention media exist and vary by elec- +trolyte composition and osmolarity. +Types of uterine myomas. +These patients +require close monitoring and diuretic administration. +Although excessive intravasation does not lead to +hyponatremia, it can lead to volume overload. +Hysteroscopic Polypectomy or Myomectomy. +Extremely large polyps may have to be removed +piecemeal. +Any residual base of the polyp may be removed +with biopsy forceps. +Pedunculated or submucosal leiomyoma +can be removed safely hysteroscopically. +Because myoma tis- +sue is relatively dense, a power cutting instrument is required. +The most common method is use of electrosurgery. +A mono- +polar device may be used with an electrolyte-poor distention +medium. +Only bipolar devices may be used with normal saline +or lactated Ringer’s solution. +Morcellation is much easier when the stalk +is still attached for stability. +Hysteroscopes with a morcellation +attachment have been recently developed.36 +Endometrial Ablation. +Myomectomy (Fig. +A through C. +Dilatation and curettage of the uterus. +1685 +GYNECOLOGY +CHAPTER 41 +side and clamped to form a tourniquet for uterine blood flow. +An incision is then made through the uterine serosa into the +myoma. +Vessels to the myoma are dessicated with the electro- +surgical unit. +Several myomas may be removed through a sin- +gle incision, depending on size. +The uterine serosa is closed with a 3-0 absorbable +suture, placed subserosally if possible. +This is usually performed percutaneously with a spinal needle. +Pedunculated leiomyomas can be excised at the base using scis- +sors or a power instrument. +Adhesion barriers are placed laparoscopically. +Total Abdominal Hysterectomy (Fig. +41-12). +The uterus is grasped at either cornu with +clamps and pulled up into the incision. +The round ligament is +identified and divided. +The fallopian tube and utero-ovarian ligament are clamped, cut, +and ligated. +The cardinal ligaments are +then serially clamped, cut, and ligated. +The cervix is amputated from the vagina with +scissors or a knife. +Sutures are placed at each lateral angle of the +Figure 41-11. +Myomectomy. +A. +Hemostatic “tourniquet’” in place before myomectomy. +B. +Uterine incision for myomectomy. +C. +Removal +of myoma. +D. +Several myomas may be removed through a single incision. +E. +The uterine wound is closed with an absorbable suture. +F. +The +uterine wound covered with mesh to retard adhesions. +Hysterectomy. +A. +The uterus grasped at the cornua. +B. +The round ligament is cut. +C. +The ovarian ligament and fallopian tube +are isolated. +D. +The bladder is mobilized. +E. +The uterine vessels are clamped. +F. +The cardinal ligaments are clamped. +G. +The vagina is entered. +H. +The cardinal ligaments are sutured to the vagina. +I. +Pelvic reperitonealization is not necessary. +Transvaginal Hysterectomy (Fig. +41-13). +A circumferential incision may be made +with a scalpel or scissors. +The posterior cul-de-sac is identified +and entered with scissors. +A long weighted speculum is then +placed through this opening into the peritoneal cavity. +The uterosacral ligaments are identified, +doubly clamped, cut, and ligated. +The procedure is carried out usually +concurrently on the opposite side, and the uterus is removed. +This exteriorizes those areas that might +tend to bleed. +The sutures attached to the ovarian pedicles are +cut. +41-14). +This +procedure will allow the vaginal delivery of even very large +uterine leiomyomas. +Laparoscopic Hysterectomy. +The techni- +cally simplest is the LAVH. +During a +Figure 41-13. +Vaginal hysterectomy. +A. +Traction is placed on the uterus. +B. +The posterior cul-de-sac is entered. +C. +The vaginal mucosa is +circumcised. +D. +The anterior cul-de-sac is entered. +E. +The uterosacral ligaments are clamped. +F. +The uterosacral ligaments are tied. +G. +The +fallopian tube, round ligament, and ovarian ligament are ligated. +H. +The peritoneum is closed. +I. +The vaginal mucosa is closed. +The endocervix is +either cauterized or cored out. +This approach avoids both a large abdominal inci- +sion and a vaginal incision. +These can +present with varying degrees or pelvic pain, or sometimes be +completely asymptomatic. +Ultrasound is the best initial imaging +modality for evaluating ovarian abnormalities. +Ovarian Cystectomy. +When a cystic lesion persists or causes +pelvic pain, surgical intervention is usually justified. +The cyst is shelled out carefully through the incision. +The peritoneal cavity is copiously rinsed with Ringer’s lactate +solution. +If malignancy is detected, immediate definitive +surgery is recommended. +Removal of Adnexa. +Tubal Sterilization. +As in diagnostic laparoscopy, a one- or +two-port technique can be used. +With +electrosurgery, approximately 2 cm of tube should be desic- +cated. +Pregnancy rates after any of these techniques have been +reported in the range of 3 per 1000 women. +Other Pelvic Pathology +Chronic Pelvic Pain. +Often, a surgical +evaluation is needed for diagnosis and/or intervention. +Endometriosis. +Endometriosis is the finding of ectopic endo- +metrial glands and stroma outside the uterus. +Involvement of the fallopian tubes may lead to scarring, +Figure 41-14. +Uterine morcellation through the vagina. +1690 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +blockage, and subsequent infertility. +The severity of +symptoms does not correlate with the degree of clinical disease +present. +Endometriosis can also cause increases in serum can- +cer antigen 125 (CA-125). +Biopsy is not routinely done +but should be obtained if the diagnosis is in doubt. +Severe symptoms are treated +with GnRH agonists to induce medical pseudo-menopause. +Pelvic Adhesive Disease. +Pelvic Inflammatory Disease. +gonor- +rhoeae and/or C. +trachomatis, but numerous other organisms +have been implicated, including normal vaginal flora. +Screening +for concomitant HIV infection is strongly recommended. +1691 +GYNECOLOGY +CHAPTER 41 +reveal thickened fluid-filled tubes with or without free pelvic +fluid. +Laparoscopic findings include swollen erythematous +tubes with exudates. +Surgical intervention becomes necessary if medical +therapy fails or if the abscess ruptures. +Gastric motility is decreased, increasing the risk +of aspiration. +Peritoneal signs may be attenuated by the stretch- +ing of the abdominal wall. +Conditions and Procedures Performed Before +Viability +Amniocentesis/Chorionic Villus Sampling. +Chorionic villus sampling (CVS) +is performed for prenatal genetic testing. +Pregnancy loss +attributable to genetic amniocentesis is 1 in 300 to 500. +1692 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +second-trimester dilation and extractions. +Cerclage. +Ectopic Pregnancies. +Extrauterine pregnancies are most +commonly located along the fallopian tubes and on the ovary. +Rarely, implantation can occur primarily on other abdominal +organs or surfaces. +The myelomeningocele is closed +in standard fashion under magnification. +The mean biparietal +diameter of a term infant approaches 10 cm. +The measured hia- +tus of the nulliparous vaginal introitus is approximately 2 cm. +Episiotomies and Perineal Laceration. +First-degree tears +involve only the perineal skin and may or may not need to be +reapproximated. +Cervical and Vaginal Lacerations. +Puerperal Hematoma. +Typical presentation is pain and mass +effect. +Small hematomas can be managed conservatively with +close observation and patient monitoring. +1693 +GYNECOLOGY +CHAPTER 41 +Cesarean Deliveries. +41-15). +Abdominal +access is obtained by a Pfannenstiel or Maylard incision. +The uterine inci- +sion is then made and extended laterally, avoiding the uterine +vessels. +After amniotomy, the baby is delivered, and the uterus +closed. +Approximately 1000 mL of blood is typically lost dur- +ing a cesarean delivery. +Bleeding +can only be controlled in some instances by performing a cesar- +ean hysterectomy. +Postpartum Hemorrhage. +In the absence of atony, the genital tract should be thoroughly +evaluated for trauma. +Atony is the most common cause of post- +partum hemorrhage. +Retained products of conception may result +in uterine atony. +It may be possible to remove retained products +via manual extraction or with ring forceps. +Bedside ultrasound may +be helpful in localization. +When clinical suspicion is high, uterine +curettage is indicated. +Procedures Short of Hysterectomy. +The B-Lynch compression suture may con- +trol bleeding of atony at the time of cesarean section. +Hysterectomy. +41-16). +A massive transfu- +sion protocol is often helpful. +Gestational Trophoblastic Disease. +Figure 41-15. +Uterine incisions for cesarean delivery. +A. +Low +transverse incision. +B. +Low vertical incision. +C. +Classical incision. +D. +J incision. +E. +T incision. +(Reproduced from Gabbe S, Niebyl J, +Simpson J. +Obstetrics: Normal and Problem Pregnancies. +5th ed. +Philadelphia: Churchill Livingstone; 2007, Fig. +19-3. +There +are two subtypes of hydatidiform moles. +Complete moles con- +tain no fetal tissue and have a diploid karyotype. +Partial moles +contain fetal tissue and have triploid karyotypes. +The chromo- +some pattern suggests paternal origin. +Chemo- +therapy is primary therapy, and the incidence of bleeding com- +plications is significant. +Primary surgery for diagnosis and initial therapy is a suc- +tion dilatation and curettage. +Oxytocin is started either prior to +anesthesia or immediately as the cervix is being dilated. +β-hCG is then followed weekly until normal for 3 weeks, then +monthly for at least 6 months. +Reconstructive surgeons aim to repair or compensate +for many of these losses. +The epithelium is dissected away from +the underlying vaginal muscularis. +Posterior colporrhaphy is performed for +a symptomatic rectocele. +Demonstration of location of distal ureter and blad- +der and their relationship to uterine vessels. +(Reproduced from Nich- +ols DH. +Gynecologic and Obstetric Surgery, Vol. +1, 1993, Fig. +68-5, +p. +1130. +After the stitches are placed, the free ends are sewn to +the undersurface of the vaginal cuff. +Colpocleisis. +The procedure can be performed +with or without a hysterectomy. +Sacrocolpopexy. +The best procedure for patient with prolapse of +the vaginal apex is an abdominal sacrocolpopexy. +Sacrocolpopexies can be performed via laparotomy +as well as via laparoscopy. +Like rectopexies and low anterior +resections, deep pelvic access is needed. +Significant suturing +at varied angles is required. +A strip of synthetic mesh is +fixed to the anterior and posterior vaginal walls. +The peritoneum +overlying the presacral area is opened, extending to the poste- +rior cul-de-sac. +The sigmoid colon is retracted medially, and +the anterior surface of the sacrum is skeletonized. +The +peritoneum is then closed with an absorbable running suture. +The most dangerous potential complication of sacrocolpopexy +is sacral hemorrhage. +This condition +is often recognized clinically as the low pressure or “drainpipe” +urethra. +Burch Procedure. +Overlying fat and blood vessels +in the area of the vesical neck are cleared away. +Each stitch is then +anchored to the ipsilateral Cooper’s (iliopectineal) ligament. +Tensionless Sling. +The tension-free vaginal tape (TVT) is a +modified sling that uses a strip of polypropylene mesh. +Urethral Bulking Injections. +Patients must dem- +onstrate a negative reaction to a collagen skin test prior to injec- +tion. +Vulvar carcinomas are squamous in 90% of +cases. +Spread of vulvar carcinoma is by direct local extension +and via lymphatic microembolization. +Hematogenous spread +is uncommon except for vulvar melanoma. +41-18). +Extent of modified radical hemivulvectomy for +stages I and II squamous cancer of the vulva. +Superficial inferior +epigastric v. +Superficial +external +pudendal v. +Superficial femoral +lymph nodes +Great saphenous v. +Fossa ovalis +Superficial +circumflex iliac v. +Lymphatic drainage of the vulva delineated by +Stanley Way. +Inguinofemoral lymphadenectomy is indicated beyond +clinical stage IA. +41-19 and 41-20). +Risk factors are similar to other +HPV-related cervical and vulvar cancers. +Cervical Cancer +General Principles. +Femoral n. +Sartorius m. +Iliopsoas m. +Femur +Epidermus +lateral +medial +Adductor +longus +Pectineus m. +Femoral v. +Camper’s +fascia +Figure 41-19. +Superficial inguinal lymphadenectomy. +a. += artery; +m. += muscle; n. += nerve. +Pubic tubercle +Femoral v. +Sapheno-femoral +junction +Figure 41-20. +Incision recommended for superficial inguinal +lymphadenectomy. +v. += vein. +Cervical cancer is staged clinically.78 Staging +and management options are outlined in Table 41-8. +Procedures for Cervical Cancer Treatment +Radical Hysterectomy. +The principle steps of an open proce- +dure are demonstrated in Fig. +41-21. +Radical Trachelectomy. +The lower uterine segment is closed with a cerclage +and attached directly to the vaginal cuff. +41-22). +Cervical +cancer recurrences after primary surgical management are +treated with radiation. +Attempted exenteration +procedures are aborted intraoperatively if metastatic disease is +found. +Uterine Cancer +Endometrial Cancer. +Tamoxifen +is a mixed agonist/antagonist ligand for the estrogen receptor. +It +is an agonistic in the uterus and an antagonistic to the breast and +ovary. +Adenocar- +cinomas are the most prevalent histologic type. +Radical hysterectomy. +A. +Exposure of the inferior epigastric vessels before transection of the rectus muscles. +B. +Ligation +of the inferior epigastric vessels before transection of the rectus muscles. +C. +Ligation and division of the round ligaments opens the pelvic +retroperitoneum. +D. +First peritoneal incision lateral to the ovarian vessels and across the vesicouterine fold. +E. +F. +Pelvic lymphadenectomy (external and internal iliac vessels). +G. +Pelvic lymphadenectomy (obturator fossa). +H. +Development +of the uterine and superior vesical arteries. +I. +The uterine artery has been clipped and divided near its origin. +J. +K. +The rectovaginal space is developed using blunt finger dissection. +L. +Transection +of the uterosacral ligaments. +M. +Clamps are placed on the lateral vagina, taking care to remove 3 to 4 cm of the upper vagina. +Trans- +vaginal ultrasonography (TVUS) often reveals a thickened +endometrial stripe. +M +Ureter +Vagina +J +K Ovary and ligament +Fallopian tube +Ureter +L +Uterosacral +ligament +Figure 41-21. +Lynch Syndrome. +The risk of colorectal carcinoma is +as high as 75% by age 75. +Uterine Sarcomas. +There are limited data to support cytoreduction when +extrauterine disease is present. +Benefits of adjuvant therapy +are unknown. +Symptoms for either benign or +malignant ovarian tumors are nonspecific but frequent. +Additionally, a his- +tory of tubal ligation or hysterectomy also decreases EOC risk. +The objectives of surgery in EOC are threefold. +The first +is to make the histologic diagnosis. +The third objective is (complete when feasible) sur- +gical cytoreduction or debulking. +Con- +servative, fertility-sparing surgery can be considered for likely +stage I, grade 1 EOC. +Early-stage EOC has an excellent outcome. +Hormone replacement therapy +HNPCC = hereditary nonpolyposis colorectal cancer. +study of this regi- +men is now maturing. +A randomized controlled trial is ongoing to validate that cur- +rent state of treatment. +Finally, surgery is used to palli- +ate disease complications. +The most common cause of palliative +surgery is bypass of bowel obstruction. +Chemotherapy is the mainstay of therapy for recurrent +EOC. +Treatment approaches are based on platinum sensitivity101 +(Table 41-14). +Ovarian Germ Cell Tumors. +Ovarian germ cell tumors occur +most commonly in women under age 30. +Malignant forms often +grow and disseminate rapidly and are symptomatic. +Because they are +derived from primordial germ cells, many produce characteristic +tumor markers. +Tumor markers are +useful to follow during definitive therapy. +Debulk- +ing surgery is recommended for more extensive disease. +The Sertoli-Leydig +cell tumors can present with virilization as a primary symptom. +Evaluation of the ovary when this symptom is found is always +of value. +In general, a +camera port is placed near the umbilicus. +Sometimes it must be +placed more cephalad if the patient has a larger fibroid uterus. +Complications Related to Gynecologic Surgery +Abdominal Wall Vessels. +41-23). +Location of anterior abdominal wall blood vessels. +Intestinal Injury. +Some +bowel injuries may not be seen during surgery because of the 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of emotions. +The parietal lobe lies between the central +sulcus anteriorly and the occipital lobe posteriorly. +The postcen- +tral gyrus is the sensory strip, also arranged along a homunculus. +The occipital lobes are +most posterior. +The visual cortex is arrayed along the apposing +medial surfaces of the occipital lobes. +A +left occipital lesion would therefore result in an inability to see +objects right of center. +The temporal lobes lie below the sylvian +fissures. +The hypothalamus regu- +lates homeostasis via the autonomic and neuroendocrine systems. +The nuclei of cranial nerves III through XII are also located +within the brain stem. +The cerebellum arises from the dorsal aspect of the brain +stem. +Midline, or +vermian, lesions lead to truncal ataxia. +Lateral, or hemispheric, +lesions lead to tremor and dyscoordination in the extremities. +CSF then drains through +the cerebral aqueduct to the fourth ventricle within the brain +stem. +Paired nerves exit the spinal cord at each level. +There are 31 +pairs: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. +The principal motor tract of the spinal cord is the corticospi- +nal tract. +It is a two-neuron path, including an upper motor neuron +and a lower motor neuron. +The upper motor neuron cell body is +located within the motor strip of the cerebral cortex. +The lower motor neuron axon then travels +via peripheral nerves to its target muscle. +The two major sensory tracts are three-neuron pathways. +5 Brain tumors can arise from primary or metastatic tissues. +7 Infection of the nervous system is a serious and prevalent +medical problem. +Gamma knife surgery can be used to treat tumors, vascular +malformations, and cranial neuralgias. +The second synapse occurs +in the thalamus, and the output axons ascend to the sensory cortex. +The aforementioned motor and sensory tracts together consti- +tute the somatic nervous system. +In addition to this system, the ANS +is the other constituent of the nervous system. +The ANS is divided into the sympathetic, +parasympathetic, and enteric systems. +It arises from the thoracolumbar spinal seg- +ments. +It can run autonomously but is +regulated by the sympathetic and parasympathetic systems. +First, one must +assess mental status. +Table 42-1 details scor- +ing for motor assessment tests. +Figure 42-1 +diagrams the clinical patterns of posturing. +Patterns of motor responses associated with various lesions. +A. +Left hemispheric lesion with right hemiplegia and left localiza- +tion. +B. +Deep cerebral/thalamic lesion with bilateral flexor posturing. +C. +Midbrain or pontine lesion with bilateral extensor posturing. +D. +Med- +ullary lesion with general flaccidity. +Edinburgh; New York: Elsevier Mosby, 2005. +It +is critical to document sensory patterns in spinal cord injury +(SCI) patients. +Muscle stretch reflexes should be examined. +Check for ankle-jerk clonus or up-going toes +(Babinski’s test). +Presence of either is pathologic and signifies +upper motor neuron disease. +Diagnostic Studies +Plain Films. +Spinal +deformities and osteolytic or osteoblastic pathologic processes +also will be apparent. +The shoulder girdle usually poses prob- +lems in visualizing the cervicothoracic junction clearly. +Computed Tomography. +It is rapid and almost universally available in hospi- +tals in the United States. +Its sensitivity allows for the detec- +tion of acute hemorrhage. +A contrast-enhanced CT scan will +help show neoplastic or infectious processes. +Newer, multislice scan- +ner technology is approaching the resolution of conventional +angiography. +Magnetic Resonance Imaging. +MRI provides excellent +imaging of soft tissue structures in the head and spine . +It is a +complex and evolving science. +Several of the most clinically +useful MRI sequences are worth describing. +Diffusion- +weighted images can detect ischemic stroke earlier than CT. +MRI venograms can assess the dural venous sinuses for +patency or thrombosis. +Angiography. +Digital subtraction technologies minimize bony inter- +ference in the resultant images. +Electromyography and Nerve Conduction Studies. +EMG records +muscle activity in response to a proximal stimulation of the motor +nerve. +NCS record the velocity and amplitude of the nerve action +potential. +Invasive Monitoring. +The most reliable monitor, always, is +an alert patient with a reliable neurologic examination. +There are several methods of monitoring intracranial physiol- +ogy. +All +three procedures involve making a small hole in the skull with +a hand-held drill. +Add “T” after the GCS if intubated and no verbal +score is possible. +For these patients, the GCS can range from 3T to 10T. +External Ventricular Drain. +An external ventricular drain is +also known as a ventriculostomy. +A perforated plastic catheter is +inserted into the frontal horn of the lateral ventricle. +CSF also can be drained to reduce +ICP or sampled for laboratory studies. +Intraparenchymal Fiber-Optic Pressure Transducer. +An +intraparenchymal fiber-optic pressure transducer is commonly +referred to as a bolt. +Brain Tissue Oxygen Sensors. +The oxygen sensor catheter has an electrochemical +oxygen–tension sensitive membrane. +Sustained ICP +levels above 20 mmHg can injure the brain. +The +three normal contents of the cranial vault are brain tissue, blood, +and CSF. +CSF volume increases in the setting of hydrocephalus. +Figure 42-2 demonstrates the classic CT findings of hydro- +cephalus. +The addition of a lesion, such as a tumor or abscess, +also will increase ICP. +The pressure-volume curve depicted +in Fig. +In the +compensated region, increased volume is offset by decreased +volume of CSF and blood. +Increased ICP can injure the brain in several ways. +Focal +mass lesions cause shift and herniation. +Temporal lesions push +the uncus medially and compress the midbrain. +This phenom- +enon is known as uncal herniation. +Masses higher +up in the hemisphere can push the cingulate gyrus under the +falx cerebri. +This process is known as subfalcine herniation. +Uncal, transtentorial, and tonsillar herniation can cause direct +damage to the brain stem. +Figure 42-4 diagrams patterns of +herniation. +The effect is delayed by about 20 minutes and +has a transient benefit. +A ventricu- +lostomy and/or craniectomy may be needed for definitive +decompression. +Figure 42-2. +Head computed tomography scan demonstrating +hydrocephalus. +This is known as transepen- +dymal flow of cerebrospinal fluid. +Emergent intubation and ventilation to reduce Paco2 to roughly +35 mmHg can reverse this process. +This mass effect can also lead directly to +brain stem compression (Fig. +42-5). +An emergent head CT scan should be done. +1 +3 +2 +4 +Figure 42-4. +Schematic drawing of brain herniation patterns. +1. +Subfal- +cine herniation. +The cingulate gyrus shifts across midline under the falx +cerebri. +2. +Uncal herniation. +3. +Central transtentorial herniation. +The diencephalon and midbrain shift +caudally through the tentorial incisura. +4. +Tonsillar herniation. +The cer- +ebellar tonsil shifts caudally through the foramen magnum. +Philadelphia: Elsevier Saunders, 2012, p 313. +42-6). +An emergent MRI is helpful but not always diagnostically +necessary. +Patients with traumatic intracranial hemorrhage are at risk +for seizure. +Head Trauma +Glasgow Coma Scale Score. +The motor +score ranges from 1 to 6, verbal from 1 to 5, and eyes from 1 +to 4. +The GCS therefore ranges from 3 to 15, as detailed in +Table 42-2. +Tracheal intubation or severe facial or eye swelling +can impede verbal and eye responses. +Scalp Injury. +Direct pressure initially controls the +bleeding, allowing close inspection of the injury. +If a simple +laceration is found, it should be copiously irrigated and closed +primarily. +If the laceration is short, a single-layer, percuta- +neous suture closure will suffice. +Careful +reapproximation of the galea will provide a more secure clo- +sure and better hemostasis. +Blunt trauma also can cause crush +injury with subsequent tissue necrosis. +These wounds require +debridement and consideration of advancement flaps to cover +the defect. +Skull Fractures. +The usual classification system for bony +fractures may be applied to the skull. +An open, or compound, fracture is asso- +ciated with disrupted overlying skin. +Closed skull fractures do not normally require specific treat- +ment. +Open fractures require repair of the scalp and operative +debridement. +Depressed skull fractures may result from a focal injury +of significant force. +42-7). +However, fractures overlying dural venous +sinuses require restraint. +Surgical exploration can lead to life- +threatening hemorrhage from the lacerated sinus. +They are gener- +ally apparent on routine head CT, but should be evaluated with +Figure 42-5. +Swelling of the infarcted +tissue causes posterior fossa mass effect. +The fourth ventricle is +obliterated and not visible, and the brain stem is being compressed. +If +asymptomatic, they require no treatment. +Extravasation +of blood results in ecchymosis behind the ear, known as +Battle’s sign. +Copious clear drainage from the nose or ear makes the +diagnosis of CSF leakage obvious. +The halo test can help differentiate. +Allow a drop of the fluid to fall on an absorbent surface such as +A +CB +Figure 42-6. +A. +The infarcted tissue is the hypodense (dark) area indicated by the arrowheads. +Note the right-to-left midline shift. +B. +Same patient status post decompressive right hemicraniectomy. +Note the free expansion of swollen brain outside the normal confines of the +skull. +C. +This patient also required hemicraniectomy for severe mass effect. +Note the lack of midline shift postoperatively. +1717 +N +EUROSURGERY +CHAPTER 42 +a facial tissue. +Many CSF leaks will heal with elevation of the head of the +bed for several days. +A lumbar drain can augment this method. +Patients also may present with delayed-onset +facial nerve palsy. +Again, steroids are used and surgery can be +considered, with mixed results. +Closed Head Injury. +There are two important factors +that affect the outcome of CHI in general. +Subsequent neuronal damage due to the sequelae of +trauma is referred to as secondary injury. +The guidelines standardize the care +of these patients with the hope of improving outcomes. +The fourth element, assessment of “D,” for disability, is +undertaken next. +Motor activity, speech, and eye opening can be +assessed in a few seconds and a GCS score assigned. +A. +CT demonstrates a depressed skull fracture in the left posterior temporoparietal area. +B. +Arrowhead indicates +traumatic subarachnoid hemorrhage in the sylvanian fissure. +1718 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +and enter his or her field of view. +Observe whether the patient +is visually attentive. +Watch for eye opening and movement of the extremities, +whether purposeful or reflexive. +Assess the verbal response. +The motor, verbal, and eye-opening scores may be correctly +assigned using this rapid examination. +Hyperglycemia +and hyperthermia are toxic to injured neurons and contribute +to secondary injury. +Head-injured patients have an increased +prevalence of peptic ulceration and GI bleeding. +Ulcer prophylaxis should be used. +Classification TBI can be classified as mild, moderate, or +severe. +Many patients present to +emergency rooms and trauma bays with a history of TBI. +The patient +should return to the emergency department for evaluation of +such symptoms. +Otherwise the patient must be admitted for a +24-hour observation period. +The head CT is +normal, and deficits resolve over minutes to hours. +Memory +difficulties, especially amnesia of the event, are very com- +mon. +Concussions may be graded. +Studies have shown that the brain +remains in a hypermetabolic state for up to a week after injury. +The contused +areas appear bright on CT scan, as seen in Fig. +42-8. +The frontal, +Figure 42-8. +1719 +N +EUROSURGERY +CHAPTER 42 +occipital, and temporal poles are most often involved. +The brain +sustains injury as it collides with rough, bony surfaces. +Edema may develop around a contu- +sion, causing mass effect. +Contusions may enlarge or progress +to frank hematoma, particularly during the first 24 hours. +Contu- +sions also may occur in brain tissue opposite the site of impact. +This is known as a contre-coup injury. +These contusions result +from deceleration of the brain against the skull. +Axons may be completely disrupted and +then retract, forming axon balls. +Small hemorrhages can be seen +in more severe cases, especially on MRI. +Hemorrhage is classi- +cally seen in the corpus callosum and the dorsolateral midbrain. +Penetrating Injury These injuries are complex and must be +evaluated individually. +Some general principles apply. +If avail- +able, skull X-rays and CT scans are useful in assessing the nature +of the injury. +Antibiotics are given to decrease the chances of +meningitis or abscess formation. +Traumatic Intracranial Hematomas. +Hematomas can expand rapidly and cause +brain shift and subsequent herniation. +Emergent neurosurgical +evaluation and intervention often are necessary. +Epidural Hematoma EDH is the accumulation of blood +between the skull and the dura. +EDH usually results from arte- +rial disruption, especially of the middle meningeal artery. +The +dura is adherent to bone, and some pressure is required to dis- +sect between the two. +EDH has a classic, three-stage clinical +presentation that is probably seen in only 20% of cases. +The +patient is initially unconscious from the concussive aspect of +the head trauma. +The patient then awakens and has a “lucid +interval,” while the hematoma subclinically expands. +EDHs are associ- +ated with lower-energy trauma with less resultant primary brain +injury. +Prompt recognition and intervention minimizes sec- +ondary injury. +A true +chronic SDH will be nearly as dark as CSF on CT. +Traces of +white are often seen due to small, recurrent hemorrhages into +the collection. +These small bleeds may expand the collection +enough to make it symptomatic. +This phenomenon is referred to +as an acute-on-chronic SDH. +Figure 42-9 demonstrates the CT +appearance of an acute-on-chronic SDH. +Vascularized mem- +branes form within the hematoma as it matures. +These mem- +branes may be the source of acute hemorrhage. +Patients may present with head- +ache, seizure, confusion, contralateral hemiparesis, or coma. +A chronic SDH >1 cm or any symptomatic SDH should +be surgically drained. +A simple burr hole can effectively drain most chronic +SDHs. +There are various strategies to prevent reaccumulation of +blood. +Subdural or subgaleal drains may be left in place for 1 to +2 days. +Mild hydration and bedrest with the head of the bed flat +may encourage brain expansion. +High levels of inspired oxy- +gen may help draw nitrogen out of the cavity. +Bleed- +ing may occur in a contused area of brain. +Mass effect from +developing hematomas may present as a delayed neurologic +deficit. +Delayed traumatic intracerebral hemorrhage is most +likely to occur within the first 24 hours. +Trauma to the head or neck may cause dam- +age to the carotid or vertebrobasilar systems. +Generally, dis- +section refers to violation of the vessel wall intima. +The newly created space within the vessel wall is referred to +as the false lumen. +Tissue or organs supplied by dissected ves- +sels may subsequently be injured in several ways. +Pieces of thrombus may then detach and cause distal embolic +arterial occlusion. +Also, the remaining partial-thickness vessel +wall may rupture, damaging adjacent structures. +Dissections may be extradural or intradural. +Intradural +dissection can present with subarachnoid hemorrhage (SAH). +Four-vessel cerebral angiography should be performed when +suspicion of dissection exists. +Surgical options include vessel ligation and bypass graft- +ing. +Interventional radiology techniques include stenting and +vessel occlusion. +The patient may complain of a bruit. +This creates a high-pressure, +high-flow pathophysiologic blood flow pattern. +History revealed that +the patient sustained a fall 4 weeks before presentation. +Arrowheads +outline the hematoma. +1721 +N +EUROSURGERY +CHAPTER 42 +III, IV, and VI as they pass through the cavernous sinus). +Symp- +tomatic CCFs should be treated to preserve eye function. +Fistulae +may be closed by balloon occlusion using interventional neuro- +radiology techniques. +Com- +mon symptoms are neck pain, headache, and brain stem stroke +or SAH. +Consultation +of a stroke neurologist is recommended in this situation. +Brain Death. +Hospital regulations and local laws regarding +documentation should be followed closely. +Establish the absence of complicating conditions before +beginning the examination. +The patient must be normotensive, +euthermic, and oxygenating well. +The patient may not be under +the effects of any sedating or paralytic drugs. +Pathologic responses such as +flexor or extensor posturing are not compatible with brain death. +Spine Trauma +The spine is a complex biomechanical structure. +Trauma may fracture bones or cause ligamentous +disruption. +Often, bone and ligament damage occur together. +Spine trauma may occur with or without +neurologic injury. +Neurologic injury from spine trauma is classified as either +incomplete or complete. +Neurologic injury from spine trauma may occur immedi- +ately or in delayed fashion. +The Mechanics of Spine Trauma. +Trauma causes a wide +variety of injury patterns in the spine due to its biomechanical +complexity. +Although these forces are +discussed individually, they often occur in combination. +Flexion/Extension Bending the head and body forward into a +fetal position flexes the spine. +Arching the neck and back +extends the spine. +Extension loads the spine posteriorly and +distracts the spine anteriorly. +Compression/Distraction Force applied along the spinal axis +(axial loading) compresses the spine. +Compression loads the +spine anteriorly and posteriorly. +A +pulling force in line with the spinal axis distracts the spine. +Dis- +traction unloads the spine anteriorly and posteriorly. +Rotation Force applied tangential to the spinal axis rotates the +spine. +Rotation depends on the range of motion of intervertebral +facet joints. +1722 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +Patterns of Injury. +Always completely evaluate the spine. +Cervical The cervical spine is more mobile than the thoraco- +lumbar spine. +Stability comes primarily from the multiple liga- +mentous connections of adjacent vertebral levels. +Disruption of +the cervical ligaments can lead to instability in the absence of +fracture. +There +are usually two or more fractures through the ring of C1. +The +open-mouth odontoid view may show lateral dislocation of the +lateral masses of C1. +The transverse ligament stabilizes C1 with +respect to C2. +Surgical interven- +tion is not indicated. +Sev- +eral strong ligaments connect the dens to C1 and to the base +of the skull. +Odontoid fractures usually result from flexion +forces. +Odontoid fractures are classified as type I, II, or III. +A +type I fracture involves the tip only. +A type II fracture passes +through the base of the odontoid process. +A type III fracture +passes through the body of C2. +Type I fractures usually fuse with external +immobilization only. +The injury is defined by bilateral C2 pars interarticularis +fractures. +The pars interarticularis is the bone between superior +and inferior facet joints. +Thus, the posterior bony connection +between C1 and C3 is lost. +Hangman’s fractures heal well with +external immobilization. +Jumped Facets—Hyperflexion Injury The facet joints of the +cervical spine slope forward. +Patients with unilateral +injury usually are neurologically intact. +42-10). +Thoracolumbar The thoracic spine is stabilized significantly +by the rib cage. +The lumbar spine has comparatively large ver- +tebrae. +Thus, the thoracolumbar spine has a higher threshold +for injury than the cervical spine. +42-11). +Typical injury is from a lap seat-belt +hyperflexion with associated abdominal injury. +It often is unsta- +ble and associated with neurologic deficit. +42-12). +Initial Assessment and Management. +The possibility of a +spine injury must be considered in all trauma patients. +The latter often is due to impaired sensorium or +significant pain. +A hard cervi- +cal collar is kept in place. +The patient is then moved +from the board to a flat stretcher. +The primary survey and +resuscitation are completed. +Physical examination and initial +X-rays follow. +Evaluation for spine or SCI is easier and more informa- +tive in awake patients. +Assess motor function by response to com- +mands or pain, as appropriate. +Assess pinprick, light touch, +and joint position, if possible. +A +B +C +D +Figure 42-10. +A. +Lateral cervical spine X-ray of an elderly +woman who struck her head during a backward fall. +Arrowhead +points to jumped facets at C5–C6. +Note the anterior displace- +ment of the C5 body with respect to the C6 body. +B. +C. +Note restoration of normal alignment. +D. +The classification indicates com- +pleteness and level of the injury and the associated deficit. +A +form similar to that shown in Fig. +42-13 should be available in +the trauma bay and completed for any spine injury patient. +Neurologic Syndromes. +42-14). +Four pat- +terns are discussed. +The typical mechanism is a stab or gunshot wound. +This syndrome occurs in patients with preex- +isting cervical stenosis. +Studies. +Anteroposterior and lateral plain films provide a +rapid survey of the bony spine. +Plain films detect fractures +A +B +Figure 42-11. +A. +Lateral lumbar spine X-ray showing a compres- +sion fracture of L2. +Arrowhead points to anterior wedge deformity. +Note the posterior wall of the vertebral body has retained normal +height and alignment. +B. +Axial computed tomography scan through +the same fracture. +Arrowhead demonstrates a transverse discontinu- +ity in the superior endplate of the L2 body. +Figure 42-12. +1725 +N +EUROSURGERY +CHAPTER 42 +and dislocations well. +MRI provides the best +soft tissue imaging. +Figure 42-14. +Spinal cord injury patterns. +a. += artery. +In addi- +tion to steroids, hypothermia for SCI has also received attention. +Commonly used rigid cervical +orthoses include Philadelphia and Miami-J collars. +Cervical +collars are inadequate for C1, C2, or cervicothoracic instabil- +ity. +Halo-vest assem- +blies provide the most external cervical stabilization. +Four pins +are driven into the skull to lock the halo ring in position. +Four +posts arising from a tight-fitting rigid plastic vest immobilize +the halo ring. +Lumbar stabilization may be provided by thora- +columbosacral orthoses. +A variety of companies manufacture +lines of spinal orthotics. +A physician familiar with the technique +should fit a halo-vest. +Surgery Neurosurgical intervention has two goals. +It +also can allow early mobilization, aggressive nursing care, and +physical therapy. +Continued Care. +Frequently encountered ICU +issues include hypotension and aspiration pneumonia. +Peripheral nerves +transmit motor and sensory information from the CNS to the body. +An individual nerve may have pure motor, pure sensory, or mixed +motor and sensory functions. +The key information-carrying struc- +ture of the nerve is the axon. +Groups of axons and their endoneurium form bundles known +as fascicles. +Fascicles run through a tubular collagenous tissue +known as perineurium. +Groups of fascicles are suspended in +mesoneurium. +The +epineurium and its contents form the nerve. +There are four major mechanisms of injury to peripheral +nerves. +Nerves may be lacerated, stretched, compressed, or con- +tused. +Knives, passing bullets, or jagged bone fractures may +lacerate nerves. +Adjacent expanding hematomas or dislocated +fractures may stretch nerves. +Shock waves from high- +velocity bullets may contuse nerves. +These mechanisms of injury +cause damage to the various anatomic components of the nerve. +The patterns of damage are categorized in Types of Injury section. +Certain nerve segments are particularly vulnerable to +injury. +Types of Injury. +The traditional classification system for periph- +eral nerve injury is the Seddon classification. +Axon degen- +eration does not occur. +Return of normal axonal function occurs +over hours to months, often in the 2- to 4-week range. +Axonotmesis Axonotmesis is the disruption of axons and +myelin. +The surrounding connective tissues, including endo- +neurium, are intact. +The axons degenerate proximally and dis- +tally from the area of injury. +Distal degeneration is known as +Wallerian degeneration. +Axons regenerate at a rate of 1 mm per day. +Significant +functional recovery may occur for up to 18 months. +Peripheral collagenous components, such as the +epineurium, may or may not be intact. +Proximal and distal axonal +degeneration occurs. +For instance, an injury may damage +axons, myelin, and endoneurium, but leave perineurium intact. +Management of Peripheral Nerve Injury. +The sensory and +motor deficits should be accurately documented. +Deficits are usu- +ally immediate. +Clean, sharp injuries may also benefit from early exploration and +reanastomosis. +Most other peripheral nerve injuries should be +observed. +EMG/NCS studies should be done 3- to weeks postin- +jury if deficits persist. +Continued observation is indicated if function improves. +If intraoperative electrical +testing reveals conduction across the injury, continue observa- +tion. +However, anastomoses under tension will not heal. +A nerve graft +may be needed to bridge the gap between the proximal and distal +nerve ends. +Patterns of Injury +Brachial Plexus The brachial plexus may be injured in a variety +of ways. +An api- +cal lung (Pancoast) tumor can cause compression injury to the +plexus. +Two well-known eponymous syndromes are Erb’s +palsy and Klumpke’s palsy. +The +arm hangs at the side, internally rotated. +Hand movements are not +affected. +There is weakness of the +intrinsic hand muscles, similar to that seen with ulnar nerve injury. +Improper crutch use can cause damage to the axillary portion. +Axillary (proximal) +injury causes triceps weakness in addition to wrist drop. +It receives contributions from L4, L5, S1, and +S2. +Surgical exploration of a common peroneal +crush lesion is typically a low yield endeavor. +It is far more com- +mon than seizures or tumors. +These processes +may coexist. +For instance, a vessel containing an atheromatous +plaque will have a decreased luminal diameter. +Aneurysms and dissection often occur +in atheromatous vessels. +Ischemic Diseases +Ischemic stroke accounts for approximately 85% of acute +cerebrovascular events. +However, the anatomy of the circle of Willis is highly variable. +Similarly, one vertebral artery is often dominant and +the other is hypoplastic. +Neurologic deficit from occlusive disease may be tempo- +rary or permanent. +A patient with permanent deficit has had a completed +stroke. +Disease occurs at +the carotid bifurcation. +As discussed previously, this can be asymptomatic. +The +more common concern is thromboembolus. +Management. +This +time restriction significantly reduces the number of candidates. +Surgery should not be performed on obtunded or comatose +patients. +This time restriction significantly reduces the number +of candidates. +Characteristic clinical +syndromes result from embolic occlusion of the various vessels. +ACA stroke results in contra- +lateral leg weakness. +MCA stroke +results in contralateral face and arm weakness. +Dominant-hemi- +sphere MCA stroke causes language deficits. +42-6). +Posterior Cerebral Artery Stroke The PCA supplies the occip- +ital lobe. +PCA stroke results in a contralateral homonymous +hemianopsia (see Fig. +42-6). +Management. +Patients not eligible for tPA require hemodynamic opti- +mization and neurologic monitoring. +Permissive hypertension allows for maximal +cerebral perfusion. +Significant swelling from an MCA or +cerebellar strokes may cause herniation and brain stem injury. +Hemorrhagic stroke typically occurs within the basal +ganglia or cerebellum. +42-15). +Most hypertensive hemorrhages should be medically man- +aged. +Intubate patients who cannot clearly follow +commands to prevent aspiration and hypercarbia. +A. +The blood clot is bright white. +Hypodensity around the clot represents cerebral edema. +There is blood within the +ventricular system. +B. +Another patient with intraventricular extension of a basal ganglia hemorrhage. +The patient developed right-sided weak- +ness and then lethargy. +Head computed tomography indicated hydrocephalus. +Amyloid Angiopathy. +Amy- +loid laden vessels may hemorrhage multiple times. +Cerebral Aneurysm. +Table 42-4 shows the percentage distribution of cerebral aneu- +rysms by location. +Aneurysms are thin walled and at risk for +rupture. +The major cerebral vessels, and therefore aneurysms, +lie in the subarachnoid space. +Rupture results in SAH. +The +aneurysmal tear may be small and seal quickly, or it may not. +The Hunt-Hess grading system cat- +egorizes patients clinically (Table 42-5). +Patients with symptoms suspicious for SAH should have +a head CT immediately. +42-16. +CT is rapid, noninvasive, and approxi- +mately 95% sensitive. +Negative CT and LP +essentially rules out SAH. +Head computed tomography scan of a patient +who experienced a sudden, severe headache. +This gives +the classic five-pointed-star appearance of a subarachnoid hem- +orrhage. +Visible temporal tips of the lateral ventricles indicate +hydrocephalus. +SAH patients should be admitted to the neurologic ICU. +Hunt-Hess grade 4 and 5 patients require intubation and hemo- +dynamic monitoring and stabilization. +The current standard of +care for ruptured aneurysms requires early aneurysmal occlu- +sion. +There are two options for occlusion. +The second option is to “coil” the aneurysm via an +endovascular approach. +The coils support thrombosis and +prevent blood flow into the aneurysm. +Factors favoring coiling include age, +medical comorbidities, and narrow aneurysm necks. +The decision to clip or coil +is complex and should be fully explored. +In addition to routine ICU concerns, SAH +patients are also at risk for cerebral vasospasm. +Aneurysmal SAH has an approximate mortality rate of +50% in the first month. +Most require rehabilitation +after hospitalization. +Arteriovenous Malformations. +AVMs are abnormal, dilated +arteries and veins without an intervening capillary bed. +The nidus +of the AVM contains a tangled mass of vessels but no neural tis- +sue. +AVMs may be asymptomatic or present with SAH, intrapa- +renchymal hemorrhage, or seizures. +Headache, bruit, or focal neurologic deficits are +less common symptoms. +AVMs hemorrhage at an average rate +of 2% to 4% a year. +Figure 42-18 demonstrates the angiographic +appearance of an AVM in arterial and venous phases. +There are several management differences for intracranial +hemorrhage due to AVM vs. +aneurysm. +There is less risk of devastating +early rebleeding from AVMs, and vasospasm is much less com- +mon. +A. +B. +Figure depicting the +anatomy of the circle of Willis and the common sites for aneurysms. +ICA = internal cerebral artery; MCA = middle cerebral artery. +(Reproduced with permission from Osborn AG: Handbook of Neu- +roradiology: Brain and Skull, 1st ed. +St. +Louis: Mosby-Year Book, +Inc., 1991, p 81. +Copyright Elsevier.) +1732 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +(SRS). +Embolization +reduces flow through the AVM. +TUMORS OF THE CENTRAL NERVOUS SYSTEM +A wide variety of tumors affect the brain and spine. +Tumors metas- +tasize to the CNS from many primary sources. +Presentation +varies widely depending on relevant neuroanatomy. +Prognosis depends on histology and anatomy. +Tumors affecting the peripheral nervous system are discussed in +the Peripheral Nerve section. +Infratentorial tumors rarely cause seizures. +Lung and breast cancers account for more than half of cerebral +metastases. +Other +common locations are the cerebellum and the meninges. +MRI pre- and +postcontrast administration is the study of choice for evalua- +tion. +Figure 42-19 demonstrates bilateral cerebellar metasta- +ses. +These lesions are typically well circumscribed, round, and +multiple. +The beliefs of the patient and family +regarding aggressive care must be considered. +A. +B. +Same view taken 4.10 seconds after dye injection, providing a venous phase image. +The arrow points to the arteriovenous +malformation nidus. +The arrowheads indicate two pathologically enlarged draining veins. +ACA = anterior cerebral artery; ICA = internal +carotid artery; MCA = middle cerebral artery. +The several types of +glial cells give rise to distinct primary CNS neoplasms. +Astrocytoma. +Astrocytoma is the most common primary +CNS neoplasm. +Astrocyto- +mas are graded from I to IV. +Prognosis +varies significantly between grades I/II, III, and IV, but not +between I and II. +Figure 42-20 demonstrates the typical +appearance of a GBM. +The great majority of astrocytomas infiltrate adjacent +brain. +Juvenile pilocytic astrocytomas and pleomorphic xantho- +astrocytomas are exceptions. +These tumors are circumscribed, +low grade, and associated with a good prognosis. +Necrosis is pres- +ent only with GBMs; it is required for the diagnosis. +Gross total resection should be attempted for suspected +astrocytomas. +Such +lesions may be limited to stereotactic needle biopsy specimen. +Chemotherapy +such as temozolomide is of limited efficacy and typically is +reserved for GBM. +Oligodendroglioma. +Oligodendroglioma accounts for +approximately 10% of gliomas. +They often present with sei- +zures. +Calcifications and hemorrhage on CT or MRI suggest +the diagnosis. +Oligodendrogliomas are also graded from I to +IV; grade portends prognosis. +Prognosis is better overall than +for astrocytomas. +Median survival ranges from 2 to 7 years +for highest and lowest grade tumors, respectively. +Aggressive +resection improves survival. +Radiation has not been clearly shown to +prolong survival. +Figure 42-19. +A. +Patient presented with ataxia and then lethargy progressing to deep coma. +This patient has total effacement of the fourth ventricle and severe +brain stem compression. +The fourth ventricle cerebrospinal fluid space should be at the tip of the arrowhead. +Patient recovered to normal +mental status after emergent posterior fossa craniotomy. +B. +1734 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +Ependymoma. +Supratentorial ependymomas arise from the lateral or +third ventricles. +The tumors may grow out +the foramina of Luschka to form a cerebellopontine angle +mass. +They may also spread through the CSF to form “drop +mets” in the spinal canal. +Gross total resection +often is impossible because the tumor arises from the brain +stem. +The goal of surgery is to achieve maximal resection +without injuring the very delicate brain stem. +Postoperative +radiation therapy significantly improves survival. +Choroid Plexus Papilloma. +The choroid plexus is com- +posed of many small vascular tufts covered with cuboidal epi- +thelium. +It represents part of the interface between blood and +brain. +The choroid cells create CSF from blood and release it +into the ventricular system. +Papillomas are +well circumscribed and vividly enhance due to extensive vas- +culature. +Like ependymomas, adult choroid plexus papillomas +usually present with symptoms of increased ICP. +Treatment is +surgical excision. +Total surgical excision is curative; recurrent +papillomas should be re-resected. +Radiation or chemotherapy +are not indicated for papillomas. +Medulloblastoma. +Primitive neuroectodermal tumor is the +most common type of medulloblastoma. +Most occur in the +first decade of life, but there is a second peak around age 30. +Medulloblastoma is the most common malignant pediatric brain +tumor. +They are usually midline. +Most occur in the cerebel- +lum and present with symptoms of increased ICP. +Figure 42-20. +A. +B. +1735 +N +EUROSURGERY +CHAPTER 42 +Ganglioglioma. +Ganglioglioma is a mixed tumor in which +both neurons and glial cells are neoplastic. +The presenting symptom is usually a seizure, due +to the medial temporal location. +Patients have a good prognosis +after complete surgical resection. +They migrate in early development from +the primitive neural tube throughout the body. +Miscellaneous Tumors +Meningioma. +Meningiomas are derived from arachnoid cap +cells of the arachnoidea mater. +The most common intracranial locations +are along the falx (Fig. +42-21), the convexities (i.e., over the +cerebral hemispheres), and the sphenoid wing. +Most are slow growing, encapsu- +lated, benign tumors. +Aggressive atypical or malignant menin- +giomas may invade adjacent bone or cerebral cortex. +Previous +cranial irradiation increases the incidence of meningiomas. +Approximately 10% of patients with a meningioma have multi- +ple meningiomas. +Atypical and malignant +meningiomas may require postoperative radiation. +Patients may +develop recurrences from the surgical bed or distant de novo +tumors. +Vestibular Schwannoma (Acoustic Neuroma). +42-22). +Commonly, patients present with progressive +hearing loss, tinnitus, or balance difficulty. +Large tumors may +cause brain stem compression and obstructive hydrocephalus. +NF2 patients have an increased incidence of +spinal and cranial meningiomas and gliomas. +Risk of facial +nerve dysfunction increases with increasing tumor diameter. +Pituitary Adenoma. +Pituitary adenomas arise from the ante- +rior pituitary gland (adenohypophysis). +Tumors <1 cm diameter +are considered microadenomas; larger tumors are macroad- +enomas. +Functional tumors are often diagnosed when quite small, due +to endocrine dysfunction. +Figure 42-23 demonstrates a large +pituitary adenoma. +This is known as +pituitary apoplexy. +Hemangioblastoma. +Other tumors associated with VHL are renal cell +Figure 42-21. +This is a falcine meningioma. +Note also the +small separate meningioma arising from the dura over the cerebral +convexity. +Many +appear as cystic tumors with an enhancing tumor on the cyst +wall known as the mural nodule. +Surgical resection is curative +for sporadic (non-VHL associated) tumors. +Pathology reveals +abundant thin-walled vascular channels; internal debulking may +be bloody. +En bloc resection of the mural nodule alone, leaving +the cyst wall, is sufficient. +Lymphoma. +CNS lymphoma may arise either primarily in the +CNS or secondarily from systemic disease. +Recent rising inci- +dence may be due to growing transplant and AIDS populations. +Surgical exci- +sion is not indicated. +A stereotactic needle biopsy specimen +usually confirms the diagnosis. +Subsequent treatment includes +steroids, whole-brain radiation, and chemotherapy. +Intrathecal +methotrexate is an option. +Craniopharyngioma. +Craniopharyngiomas are benign cystic +lesions that occur most frequently in children. +There is a second +peak of incidence around 50 years of age. +Calcification occurs +in all pediatric and roughly half of adult craniopharyngiomas. +Symptoms result from compression of adjacent structures, espe- +cially the optic chiasm. +Pituitary or hypothalamic dysfunction +or hydrocephalus may develop. +Treatment is primarily surgical. +Excision is somewhat easier in children, as the tumor is often +soft and easily suctioned. +Adult tumors are often firm and adher- +ent to adjacent vital structures. +Visual loss, pituitary endocrine +Figure 42-22. +A. +Pathology demonstrated vestibular schwannoma. +B. +Note small incidental meningioma at the top of the scan. +Figure 42-23. +The patient presented with +progressive visual field and acuity loss. +Pathology and lab work +revealed a nonfunctioning pituitary adenoma. +Epidermoid. +The cysts contain keratin, cholesterol, and cellular +debris (Fig. +42-24). +Treatment is surgical drainage +and removal of the cyst wall. +Dermoid. +Dermoids are less common than epidermoid tumors. +They contain hair follicles and sebaceous glands in addition to a +squamous epithelium. +Dermoids may be found anywhere along +the craniospinal axis. +Bacterial meningitis +may occur when dermoids are associated with a dermal sinus +tract. +Treatment of symptomatic lesions is surgical resection, +again with care to control cyst contents. +Teratoma. +They contain +elements from all three embryonal layers: ectoderm, meso- +derm, and endoderm. +Teratomas may contain skin, cartilage, GI +glands, and teeth. +Surgical excision may be attempted. +However, the +prognosis for malignant teratomas is very poor. +Spinal Tumors +A wide variety of tumors affect the spine. +Approximately 20% +of CNS tumors occur in the spine. +Unlike cranial tumors, the +majority of spinal tumors are histologically benign. +Classically, the pain is worse at night. +Anatomic categorization provides the most logical approach +to these tumors. +Certain tumors present in characteristic loca- +tions. +Extradural Tumors. +Extradural tumors account for approxi- +mately 55% of spinal tumors. +Destruction of the bone can lead to instability +and fractures, causing pain and/or deformity. +Metastatic Tumors Metastatic tumors are the most common +extradural tumors. +The most +common primary sources of spine metastasis are lymphoma, +lung, breast, and prostate. +Other sources include renal, colon, +thyroid, sarcoma, and melanoma. +Most spinal metastases create +osteolytic lesions. +Osteoblastic, sclerotic lesions suggest pros- +tate cancer in men and breast cancer in women. +Preoperative neurologic function correlates with postop- +erative function. +Patients may lose function over hours. +Most +cases with significant bone involvement require both decom- +pression and fusion. +Bony fusion usually takes 2 to 3 months. +Prognosis governs operative decisions. +Figure 42-24. +White arrowhead indi- +cates interface of tumor and brain stem. +Black arrowhead indicates +deformed fourth ventricle. +Pathology revealed epidermoid tumor. +They occur in the vertebral bodies +of the thoracolumbar spine and are frequently asymptomatic. +They are often vascular and may hemorrhage, causing pain or +neurologic deficit. +Large hemangiomas can destabilize the spine +and predispose to fracture. +Osteoblastic lesions include osteoid +osteoma and osteoblastoma. +The latter tends to be larger and +more destructive. +They may cause pain or sufficiently weaken +the bone to cause a fracture. +They may compress the spinal cord, causing myelopathy, +or the nerve roots, causing radiculopathy. +Rare benign epidural masses +include arachnoid cysts, dermoids, and epidermoids. +Meningioma Meningiomas arise from the arachnoidea mater. +They appear to be dural based and enhance on MRI. +An enhanc- +ing “dural tail” may be seen. +They occur most commonly in +the thoracic spine (Fig. +42-25) but also arise in the cervical and +lumbar regions. +Some spinal meningiomas grow into the epi- +dural space. +Surgical excision is the treatment of choice. +Schwannoma Schwannomas are derived from peripheral nerve +sheath Schwann cells. +They are benign, encapsulated tumors +that rarely undergo malignant degeneration. +Symptoms result from radiculopathy, often +presenting as pain or myelopathy. +Symptomatic lesions should +be surgically resected. +The parent nerve root usually can be pre- +served. +Patients with multiple schwannomas likely have NF2. +Neurofibromas are benign but not encapsulated. +They +present similarly to schwannomas, and the two may be difficult +to differentiate on imaging. +Salvage of the parent nerve is more +challenging with neurofibromas. +Resection for symptomatic lesions should +be offered. +Intramedullary Tumors. +Intramedullary tumors constitute +approximately 5% of spinal tumors. +They arise from within the +parenchyma of the spinal cord. +Patients with such symp- +toms should undergo MRI of the entire spine with and without +enhancement. +Ependymoma Ependymomas are the most common intramed- +ullary tumors in adults. +There are several histologic variants. +The cellular type occurs more frequently in +the cervical cord. +Many spinal ependymomas have cystic areas +and may contain hemorrhage. +Surgical removal can improve +function. +A distinct tumor margin often exists, allowing safer +excision. +Postoperative radiation therapy after subtotal resection +may prolong disease control. +They +may occur at all levels, although more often in the cervical cord. +Spinal astrocytomas are usually +Figure 42-25. +Arrowhead points to dorsal location of the mass. +The patient pre- +sented with worsening gait and lower extremity spasticity. +Pathol- +ogy demonstrated meningioma. +As a result, +patients with astrocytomas fare worse overall than patients with +ependymomas. +Other Tumors. +Patients usually present +with pain. +The intervertebral +discs have two components. +The spongy material inside the +ring of the annulus is known as the nucleus pulposus. +The ligaments +stabilize the spine by limiting the motion of adjacent vertebrae. +The cervical spine is the most mobile. +The thoracic spine is the least mobile, +due to the stabilizing effect of the rib cage. +The sacral spine is fused together and +has no intrinsic mobility. +An unstable spine will shift or sublux under these forces. +The +determinants of spinal stability vary throughout the cervical, +thoracic, and lumbar portions. +In the setting of a pars defect, there is no solid +bony connection between the adjacent vertebrae. +The spine is +unstable and anterior listhesis (slippage) may result. +Radiculopathy in this setting indicates neuroforaminal compres- +sion. +Figure 42-26 demonstrates an L4 and L5 spondylolisthesis. +Subluxation +Figure 42-26. +This is called spondylolisthesis. +42-10B). +Reduced central canal area can +lead to myelopathy. +Reduced neural foraminal area can lead to +radiculopathy. +Myelopathy. +Compression of the spinal cord can cause distur- +bance of function known as myelopathy. +Loss of proprioception +makes fine motor tasks and ambulation difficult. +Radiculopathy. +Compression of the nerve roots causes distur- +bance of root function, known as radiculopathy. +Patterns of Disease +Cervical Radiculopathy. +For example, the C6 nerve root passes above the C6 pedicle at +the level of the C5–C6 discs. +Table 42-6 summarizes the effects of various disc herniations. +Most patients with acute disc herniations will improve with- +out surgery. +NSAIDs or cervical traction may help alleviate +symptoms. +ACDF allows +more direct access to and removal of the pathology (anterior +to the nerve root). +Figure 42-27 demonstrates a +C6–C7 ACDF with the typical interposed graft and plating sys- +tem. +Cervical Spondylotic Myelopathy. +Figure 42-28 demonstrates typical findings. +Some patients com- +plain of difficulty buttoning shirts, using utensils, and ambu- +lating. +Thorough cervical +laminectomy decompresses the cord posteriorly. +Care must be taken to avoid offering cervical laminec- +tomy to a patient with undiagnosed ALS. +Thoracic Disc Herniation. +Thoracic disc herniation accounts +for <1% of herniated discs. +Handbook of Neurosurgery, 7th ed. +New York: Thieme, 2010. +Table 18–18, p 461. +1741 +N +EUROSURGERY +CHAPTER 42 +BA +Figure 42-27. +A. +Patient presented with right triceps weakness and dysesthesias in the right fifth digit. +B. +The allograft bone spacer placed in the drilled-out disc space is also apparent. +Figure 42-28. +Note the bright signal +within the cord at that level, consistent with myelopathy. +Figure 42-29. +Lateral cervical spine X-ray status post C5 corpec- +tomy for cervical spondylotic myelopathy. +A bone strut is visible bridging C4 to C6. +The plate and screws stabilize the segments. +42-30). +Lumbar discs may herniate +with or without a history of trauma or straining. +Normally they +cause lancinating (radicular) pain down the leg (Table 42-7). +Most acute herniated lumbar discs improve symptomatically +without surgery. +Free-floating disc fragments may +be found. +Neurogenic Claudication. +It +is normally caused by degenerative lumbar stenosis causing +compression of the cauda equina. +The +usual surgery is an L3 to L5 lumbar laminectomy to decom- +press the nerve roots. +Cauda Equina Syndrome. +Saddle anesthesia is numbness in the perineum, +genitals, buttocks, and upper inner thighs. +AB +Figure 42-30. +A. +B. +Arrowheads delineate the extent of the herniation. +The arrow indicates the right S1 nerve root passing through free of +compression. +The left S1 nerve root is under severe compression and is not seen. +Handbook of Neurosurgery, 7th ed. +New York: Thieme, 2010. +Table 18–13, p 445. +Fusion procedures lock adjacent vertebrae together. +Stabilization and immobilization +promote bony fusion. +Most +spinal instrumentation constructs have two elements. +The first element is a device that solidly attaches to the +vertebral bodies. +The second element is a device that tra- +verses vertebral segments. +42-31). +Arthrodesis must occur in any fused segment +to have long-term stability. +Failure of arthrodesis results in +failed fusion, often in the form of a fibrous nonunion. +The +rates of successful fusion are higher in the cervical spine +than the lumbar spine. +The term autograft refers to the patient’s own bone, +often harvested from the iliac crest. +Iliac crest bone graft is +a source of both cortical and cancellous bone. +The term allograft refers to ster- +ilized bone from human tissue banks. +Allografts also may +be cortical, cancellous, or both. +Dynamic stabilization refers to the creation of spi- +nal stability without achieving a bony fusion. +The con- +cept applies to both cervical and lumbar motion segments. +However, their use is limited to very +select cases. +A. +B. +The patient had previ- +ously sustained an L4 burst fracture. +Note the significant loss of height +of the L4 body compared to adjacent levels. +Peripheral Nerve Tumors +Most peripheral nerve tumors are benign and grow slowly. +Significant pain increases the likelihood that the patient has a +malignant tumor. +These tumors have various degrees of involvement +with the parent nerve. +Some can be resected with minimal or no +damage to the nerve. +Tumors that grow within the nerve often +contain functioning fascicles. +Total excision of these tumors +requires sacrifice of the parent nerve. +The choice of subtotal +resection, nerve preservation, and observation, vs. +Schwannoma. +Most occur in the third decade of life. +These benign +tumors arise from Schwann cells, which form myelin in +peripheral nerves. +Spontaneous or continuous pain suggests malig- +nancy. +Schwannomas tend to grow slowly and eccentrically +on parent nerves. +Neurofibroma. +Neurofibromas often present as a +mass that is tender to palpation. +They usually lack the shooting +pains characteristic of schwannomas. +Neurofibromas are often +difficult to resect completely without sacrifice of the parent +nerve. +Patients with NF1 often have mul- +tiple neurofibromas. +These patients should be offered resection +for symptomatic tumors. +Risk of malignant degeneration is up +to 10%. +Malignant neurofibromas have the histologic charac- +teristics of sarcoma. +Malignant Nerve Sheath Tumors. +Treat- +ment for these tumors is radical excision. +This often requires +sacrifice of the parent nerve. +Usually EMG/NCS demon- +strate slowing across the entrapped segment of nerve. +Ulnar Neuropathy. +It passes posteriorly to the medial +epicondyle at the elbow in the condylar groove. +This segment +is superficial and subject to external compression and repeti- +tive minor impacts. +Motor deficits include weakness +and wasting of the intrinsic hand muscles. +Carpal Tunnel Syndrome. +Patients +may notice wasting of the thenar eminence. +This often provides prompt relief of pain symptoms and +slow recovery of numbness and strength. +Their characteristic presentations help distinguish +them from weakness due to structural lesions. +Guillain-Barré Syndrome. +Symptoms usually progress over 2 to 4 weeks and then +resolve. +Care is supportive. +Respiratory weakness may require +ventilatory support. +Myasthenia Gravis. +Most patients +have either thymic hyperplasia or thymoma. +The most common +symptoms are diplopia, ptosis, dysarthria, and dysphagia. +More +severe cases have limb or respiratory involvement. +Weakness +worsens with repetitive movement. +Treatment is with acetylcho- +linesterase inhibitors and possible thymectomy. +Eaton-Lambert Syndrome. +This is a paraneoplastic syndrome most commonly +associated with oat cell carcinoma. +Patients have weakness of +proximal limb muscles that improves with repetitive movement. +This diagnosis must prompt oncologic evaluation. +Cranial +Osteomyelitis. +The skull is highly vascular and resistant +to infections. +Staphylococcus aureus +and S. +epidermidis are the most frequent causative organ- +isms. +Patients usually present with redness, swelling, and +pain. +These wounds must be débrided and the bone flaps removed +and discarded. +Subdural Empyema. +Subdural empyema is a rapidly progres- +sive pyogenic infection. +Subdural empyemas usually occur over +the cerebral convexities. +Potential infectious sources include +sinus disease, penetrating trauma, and otitis. +Streptococci and +staphylococci are the most frequent sources. +The +most common deficit is contralateral hemiparesis. +Patients with +suggestive symptoms should undergo rapid contrast CT scan. +LP frequently fails to yield the offending organism and risks +herniation due to mass effect. +Typical treatment is wide hemi- +craniectomy, dural opening, and lavage. +The pus may be thick +or septated, making burr hole drainage or small craniotomy +insufficient. +Patients then require 1 to 2 months of antibiotics. +However, many patients do make a +good recovery. +Brain Abscess. +Brain abscess is encapsulated infection +within the brain parenchyma. +Disorganized cerebritis +often precedes formation of the organized, walled-off abscess. +Patients require antibiotic therapy after needle +aspiration or surgical evacuation. +Blood +and CSF cultures rarely give definitive diagnosis. +Common +chronic sequelae after successful treatment include seizures or +focal neurologic deficit. +Spine +Pyogenic Vertebral Osteomyelitis. +S. +aureus and Enterobacter +spp. +are the most frequent etiologic organisms. +Patients usu- +ally present with fever and back pain. +Plain films and CT help assess +the extent of bony destruction or deformity such as kyphosis. +MRI shows adjacent soft tissue or epidural disease. +Blood cul- +tures may be positive. +Tuberculous Vertebral Osteomyelitis. +The infection is indolent and symptoms +often progress slowly over months. +Tuberculosis rarely involves +the intervertebral disc. +The involved bodies may have sclerotic +rather than lytic changes. +Multiple nonadjacent vertebrae may +be involved. +The upper lumbar and lower thoracic vertebrae are +most commonly affected. +Diagnosis requires documentation of +acid-fast bacilli. +Treatment involves long-term antimycobacterial +drugs. +Discitis. +Spontaneous discitis occurs more commonly in children. +S. +aureus and S. +epidermidis account for most cases. +The pri- +mary symptom is back pain. +Epidural Abscess. +S. +aureus and Streptococcus spp. +are the most common organisms. +Methicillin-resistant S. +MRI best demonstrates the epidural space and degree of +neural compromise. +Most epidural +abscesses can be accessed via laminectomy without fusion. +Seizures may involve a part of the brain (focal) or the +entire brain (generalized). +All generalized seizures cause loss of conscious- +ness. +Focal seizures may secondarily generalize. +Patients with +multiple unprovoked seizures over time are considered to have +epilepsy. +Lack of +seizure control or patient intolerance of the medications may +constitute failure. +Four types of epilepsy surgery are discussed in sections that fol- +low. +Anterior Temporal Lobectomy. +Medial temporal lobe struc- +tural abnormalities can lead to complex partial seizures (CPS). +Many patients with CPS have poor seizure control on medi- +cations. +The amygdala and the head of the hip- +pocampus are removed as part of the lobectomy. +Corpus Callosotomy. +The corpus cal- +losum is a large white matter tract that connects the cerebral +hemispheres. +Loss of consciousness requires simultaneous +seizure activity in both hemispheres. +Divi- +sion of the corpus callosum can interrupt this spread. +Patients +may have decreased numbers of seizures and/or fewer epi- +sodes of lost consciousness. +1747 +N +EUROSURGERY +CHAPTER 42 +Hemispherectomy. +Vagus Nerve Stimulation. +Additionally, the majority of side +effects are stimulation-dependent and thus, reversible. +Procedures with brain region-specificity are being investigated. +Proper lead placement is accomplished with stereo- +tactic guidance. +A frame is rigidly fixed to the patient’s head, +and an MRI is obtained with the frame in place. +42-32). +Essential Tremor. +43,44 +Parkinson’s Disease. +In this study, 299 subjects +8 +Figure 42-32. +The electrodes appear thick and wavy due +to magnetic susceptibility artifact. +The study found no sig- +nificant difference in motor improvement between target sites. +However, a significant difference was found in a secondary +outcome measuring depression. +In terms of +overall severe adverse events, there was no difference between +groups. +Dystonia. +Cognitive function is typi- +cally spared, and pharmacological therapy is frequently inadequate. +Obsessive-Compulsive Disorder. +Thus, DBS has promise as a therapy of +last resort for carefully selected cases of severe OCD. +Expanding Indications of Deep Brain Stimulation. +Recently, there have been reports of significant +improvements in refractory depression with DBS. +Complex partial and the “most severe” +seizures were significantly reduced in the DBS-on group. +The pain is excruciating and can be debilitating. +They +are found in most radiation oncology departments. +After upgrades +to the software and collimators, SRS can be performed with these +existing units, . +Most lesions can be treated equally well with +either technology. +Currently, there are very few +centers using this technology. +CyberKnife is another radiosurgery system that has neu- +rosurgical application. +The applica- +tion of this technology is rapidly growing. +However, SRS is not effective +for lesions >3 cm. +Effective obliteration and elimination of +the risk of hemorrhage takes 2 to 3 years. +In these patients, SRS +may be used as an effective adjunctive therapy in these +patients. +Some studies +show improved survival with up to seven intracranial masses. +Patients with intracranial metastases live 3 to 6 months on +average with medical care and WBRT. +Dysraphism +may occur in the spine or head. +Neural tube defects are among +the most common congenital abnormalities. +Prenatal vitamins, +especially folic acid, reduce the incidence of neural tube defects. +Spina Bifida Occulta +Spina bifida occulta is congenital absence of posterior vertebral +elements. +Most of these patients are neurologically +normal. +Herniation of meninges without brain tissue is referred to as +a meningocele. +Most occur over the convexity of the skull. +More rarely, the tissue protrudes through the skull base into the +sinuses. +Treatment involves excision of the herniated tissue and +closure of the defect. +Most patients with encephaloceles and +meningoceles have impaired cognitive development. +The contralat- +eral normal forehead appears to bulge by comparison. +Unilateral or bilateral lambdoid +synostosis results in flattening of the occiput. +CSF pathways may be +occluded by adjacent tumors (Fig. +42-33). +A +B +Figurve 42-33. +A. +Axial head computed tomography scan reveal- +ing dilated ventricular system. +Note dilated atria of the lateral ven- +tricles (arrowheads) and rounded third ventricle (arrow). +42-2). +B. +1751 +N +EUROSURGERY +CHAPTER 42 +Communicating Hydrocephalus. +Obstruction at the level of +the arachnoid granulations constitutes communicating hydro- +cephalus. +This usually causes dilation of the lateral, third, and +fourth ventricles equally. +The most common causes in adults are +meningitis and SAH. +Obstructive Hydrocephalus. +Obstruction of CSF pathways is +known as obstructive hydrocephalus. +It may be seen as an inciden- +tal finding on MRI scans in asymptomatic patients. +Figure 42-34 demonstrates typical +MRI appearance of a Chiari I malformation. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Kandel E, Schwartz J, Jessell T. +Principles of Neural Science, +4th ed. +New York: McGraw-Hill Professional;2000. +2. +Stiefel MF, Spiotta A, Gracias VH, et al. +J Neurosurg. +2005;103:805-811. +3. +Masters SJ, McClean PM, Arcarese JS, et al. +Skull x-ray +examinations after head trauma. +Recommendations by a +multidisciplinary panel and validation study. +N Engl J Med. +1987;316:84-91. +4. +Bullock MR, Chesnut R, Ghajar J, et al. +Surgical man- +agement of depressed cranial fractures. +Neurosurgery. +2006;58:S56-S60. +5. +Guidelines for the management of severe traumatic brain +injury. +J Neurotrauma. +2007;24:S91-S95. +6. +Temkin NR, Dikmen SS, Wilensky AJ, et al. +A randomized, +double-blind study 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Neuropathie, +3rd ed. +Baltimore: Lippincott Raven;1999. +37. +Darouiche RO. +Spinal epidural abscess. +N Engl J Med. +2006;355:2012-2020. +38. +Benbadis SR, Heriaud L, Tatum WO, et al. +Epilepsy surgery, +delays and referral patterns—are all your epilepsy patients +controlled? +Seizure. +2003;12:167-170. +39. +Rausch R, Kraemer S, Pietras CJ, et al. +Early and late cog- +nitive changes following temporal lobe surgery for epilepsy +(see comment). +Neurology. +2003;60:951-959. +40. +Ben-Menachem E, Manon-Espaillat R, Ristanovic R, et al. +Vagus nerve stimulation for treatment of partial seizures. +A +controlled study of effect on seizures. +First International Vagus +Nerve Stimulation Study Group. +Epilepsia. +1994;35:616–626. +41. +Handforth A, DeGiorgio CM, Schachter SC, et al. +Vagus nerve +stimulation therapy for partial-onset seizures: a randomized +active-control trial. +Neurology. +1998;51:48–55. +42. +Neurosurgery. +1998;1265-1276. +43. +J Neurol Neurosurg +Psychiatry. +2003;74:305. +44. +Mov Disord. +2003;18:163. +45. +Mov Disord. +2006;21:S290. +46. +J Neurol Sci. +2001;192:9. +47. +Weaver FM, Follett K, Stern M, et al. +Bilateral deep brain +stimulation vs. +best medical therapy for patients with advanced +Parkinson disease: a randomized controlled trial. +JAMA. +2009;301:63-73. +48. +Follett KA, Weaver FM, Stern M, et al. +Pallidal versus sub- +thalamic deep-brain stimulation for Parkinson’s disease. +N Engl J Med. +2010;362(22): 2077-2091. +49. +Vidailhet M, Vercueil L, Houeto JL, et al. +Bilateral deep-brain +stimulation of the globus pallidus in primary generalized dys- +tonia. +N Engl J Med. +2005;352(5): 459-467. +50. +Goodman WK, Foote KD, Greenberg BD, et al. +Biol Psychiatry. +2010;67:535-542. +51. +Lozano AM, Giacobbe P, Hamani C, et al. +J Neurosurg 2012;116:315-322. +52. +Bewernick BH, Kayser S, Sturm V, et al. +Neuropsychopharmacology 2012;37:1975-1985. +53. +Fisher R, Salanova V, Witt T, et al. +Electrical stimulation of +the anterior nucleus of thalamus for treatment of refractory +epilepsy. +Epilepsia. +2010;51:899-908. +54. +Vassoler FM, Schmidt HD, Gerard ME, et al. +J Neurosci. +2008;28:8735-8739. +55. +Halpern CH, Tekriwal A, Santollo J, et al. +J Neurosci, in +press. +56. +Barker FG II, Jannetta PJ, Bissonette DJ, et al. +The long-term +outcome of microvascular decompression for trigeminal neu- +ralgia. +N Engl J Med. +1996;334:1077-1083. +57. +Kondo A. +Microvascular decompression surgery for trigemi- +nal neuralgia. +Stereotact Funct Neurosurg. +2001;77:187-189. +58. +Bova FJ, Goetsch SJ. +Modern linac stereotactic radiosurgery +systems have rendered the gamma knife obsolete. +Medical +Physics. +2001;28:1839-1841. +59. +Konigsmaier H, de Pauli-Ferch B, et al. +The costs of radiosur- +gical treatment: comparison between gamma knife and linear +accelerator. +Acta Neurochirurgica. +1998;140:1110-1111. +1753 +N +EUROSURGERY +CHAPTER 42 +60. +Suh JH, Barnett GH, Miller DW, et al. +Stereot Funct Neurosurg. +1999;72:159-167. +61. +Chen CC, Chapman P, Petit J, et al. +Proton radiosurgery in +neurosurgery. +Neurosurg Focus. +2007;23:E5. +62. +Gerszten PC, Ozhasoglu C, Burton SA, et al. +Neurosurgery. +2004;55:89-98, discussion 98-99. +63. +Karlsson B, Lax I, Soderman M. +Int J Radiat Oncol Biol Phys. +2001;49:1045-1051. +64. +Maruyama K, Kawahara N, Shin M, et al. +The risk of hemor- +rhage after radiosurgery for cerebral arteriovenous malforma- +tions. +N Engl J Med. +2005;352:146-153. +65. +Pan DH, Guo WY, Chung WY, et al. +J Neurosurg. +2000;93:113-119. +66. +Regis J, Pellet W, Delsanti C, et al. +Functional outcome after +gamma knife surgery or microsurgery for vestibular schwan- +nomas. +J Neurosurg. +2002;97:1091-1100. +67. +Shin M, Ueki K, Kurita H, et al. +Malignant transformation +of a vestibular schwannoma after gamma knife radiosurgery. +Lancet. +2002;360:309-310. +68. +Elsmore AJ, Mendoza ND. +The operative learning curve +for vestibular schwannoma excision via the retrosigmoid +approach. +Br J Neurosurg. +2002;16:448-455. +69. +Gerosa M, Nicolato A, Foroni R, et al. +Gamma knife radio- +surgery for brain metastases: a primary therapeutic option. +J Neurosurg. +2002;97:515-524. +70. +Pollock BE, Brown PD, Foote RL, et al. +J Neurooncol. +2003;61:73-80. +This page intentionally left blank +Orthopedic Surgery +Bert J. +Thomas, Freddie H. +5 The shoulder is one of the most commonly dislocated joints +and most dislocations are anterior. +Posterior dislocations are +associated with seizures or electric shock. +7 Hemorrhage from pelvic trauma can be life threatening. +CT scan +is more reliable in assessing spine injury than plain +radiographs. +This number is projected to grow to an astounding 67 +million adults by 2030 (or 25% of the U.S. +population). +The only documented ben- +efit of minimally invasive techniques appears to be +improved cosmesis. +43-1). +Fractures frequently result from high energy trauma as +well as from falls onto an extremity (Fig. +Meth- +ods of immobilization can vary and depend on the fracture +being treated. +Fractures that are displaced or angulated require closed +reduction to properly realign the bone. +This is done using anal- +gesia, local or general anesthesia, and often muscle relaxation. +A splint is then applied and can be gently molded to +help hold the reduction in place. +Figure 43-1. +Types of fractures A. +normal femur, B. +transverse, +C. +oblique, D. +spiral, E. +segmental, F. +comminuted. +ABCD EF +Figure 43-2. +Transverse tibia fracture and segmental fibula fracture. +Intramedullary rods are commonly used for long +bone fractures, such as the femur and tibia (Fig. +43-3A). +Prior +to their placement, the marrow in the canal is usually removed +with a reamer. +The rod is then inserted into the canal. +43-3B). +Open Fractures +An open fracture occurs when the bone breaks through the skin. +43-4A). +43-4B). +They can also cause +injuries to surrounding vessels and nerves, which must +be addressed as well. +Since the bone is subcutaneous, +the fracture is often evident on inspection. +If there is displacement of the fracture, +surgical management is often recommended. +A step-off, or separation, of the +AC joint may be apparent on radiographs. +The majority of +Figure 43-3. +A. +Transverse femur fracture. +B. +Intra- +medullary rod stabilizes femur fracture. +AB +AB +Figure 43-4. +A. +Open grade 3 comminuted tibia-fibula fracture (motorcycle injury). +B. +External fixator temporarily stabilizes grade 3 open +tibia fracture. +Most scapula fractures are treated nonoperatively with the +exception of fractures to the glenoid. +Pos- +terior dislocations are associated with seizures or electric +shock. +Range of motion +should be started as soon as the patient can tolerate therapy. +If the fracture can be well reduced, it is fixed with +1 or 2 screws. +Olecranon Fractures +Olecranon fractures occur following a fall directly onto a flexed +elbow. +Comminuted fractures are treated with plate +and screw fixation. +Both bone +forearm fractures often require surgery with plate and screw fix- +ation. +A Monteggia fracture is an ulna shaft fracture +along with a radial head dislocation. +An external fixator may also +be placed in the operating room. +Because it is a ring, displacement can only +occur if the ring is disrupted in two places. +This may occur either +from fractures of the bones or tears of the ligaments. +There are +three main fracture patterns that occur from trauma to the pelvis. +Treatment of pelvic fractures depends on the fracture pat- +tern. +Since these are stable injuries, they +can be managed nonoperatively with protected weight bearing. +CT scans are important to visualize the +fracture pattern. +These are best treated in the hands of experienced orthopedic +trauma surgeons. +Femoral Neck Fractures Femoral neck fractures occur with +the capsule of the hip joint. +Patients can usually begin protected +weight bearing immediately after surgery. +43-5A). +43-5B). +Patients can +begin weight bearing immediately after surgery. +Intertrochanteric Hip Fractures. +There are two devices that can be +used. +Both devices form stable constructs (though the +Figure 43-5. +A. +Failed hip hemiarthro- +plasty (periprosthetic fracture). +B. +Peripros- +thetic fracture repaired with modular femoral + component. +Subtrochanteric Hip Fractures. +While they can occur in elderly patients after a fall, they are also +seen in high energy trauma. +In most cases, protected weight bearing can begin soon after +surgery. +They can also occur in elderly patients +with osteoporotic bone after a fall onto the knee. +With regard to the +ligamentous injuries, an MRI will identify what structures have +been torn. +Stiffness and instability of the knee +are common complications after this injury. +Dis- +placed or comminuted fractures require surgery with either ten- +sion band wiring or screws. +Acute osteochondral fractures can +be managed with internal fixation (Fig. +43-6A and B). +They typically +dislocate laterally and often relocate spontaneously. +There is a high risk for recurrent dislocations, +which may require surgical intervention. +43-7A and B). +A CT scan is impor- +tant to visualize the intra-articular involvement of the fracture. +They +are treated with plates and screws placed medially, laterally, or +both. +Repair of ligament or meniscus injuries may also +be indicated at the time of surgery. +Knee stiffness and osteoar- +thritis are common complications of these injuries. +1763 +O +RTHOPEDIC + S +UR +g +ER +y +CHAPTER 43 +Figure 43-6. +A. +Osteochondral Patella Fracture. +B. +Internal fixation of osteochondralpatellar fracture. +AB +Figure 43-7. +A. +Knee traumatic articular lesion (trochlear groove). +B. +Lesion repaired with Draenert technique (autologous osteochondral +transplant). +Pilon fractures are typically high energy injuries from +axial compression or a shear force. +Patients are kept nonweight bearing for many +weeks until the fracture heals. +Ankle Fractures +Ankle fractures are very common and result from a twisting +injury to the ankle. +Swelling can be a significant problem so elevation of the foot is +encouraged. +Bimalleolar Fractures Fractures to both the medial and lateral +malleoli often require surgery. +They are treated by reducing and fixing both malleoli during +surgery. +The syndesmosis can be disrupted at the time of +ankle fractures and requires special attention. +Patients are kept non-weight bearing for several +weeks. +CT scans are useful to better visualize the fracture pattern. +There is a high risk of +osteonecrosis, ranging from 30% to 100%, and a high risk of +arthritis. +Lisfranc injuries can be seen following +torsional forces to the foot or from crush injuries. +The base of the 5th metatarsal, however, warrants close +attention. +These injuries encompass +various areas in the musculoskeletal system. +The most frequently injured joints are the shoulder, +hip and knee. +Therefore, treatment of common injuries in these +joints will be the scope of this paragraph. +43-8), +single- vs. +double-row fixation and the treatment of massive +or large tears. +Immobilization and passive exercise usu- +ally start in the first 4 to 6 weeks after surgery. +After 4 to 6 weeks, active exercises can be +gradually introduced. +Most of the +shoulder’s stability is provided by the rotator cuff and shoulder +capsule. +Since most of the shoulder’s +stability is provided by soft tissue, usually this is also injured. +Some sedation is helpful as it relaxes the +patient’s musculature and relieves the pain. +After surgery, the shoul- +der is temporarily immobilized with a sling. +Strengthening exer- +cises will gradually be added to the rehabilitation plan. +Injuries to +the superior labrum can be caused by trauma or by repetitive +shoulder motion. +Radiographs are generally obtained to evaluate +for concomitant injuries or osteoarthritic changes. +43-9). +Usually a sling is used for 4 weeks after surgery. +Return to early interval throwing can +generally be allowed around 3 to 4 months after surgery. +The goal of treatment is to reduce pain and restore func- +tion. +Initial treatment is generally nonsurgical and based on rest, +NSAIDs, and physical therapy. +Imaging and treatment of rotator cuff tears. +A. +B. +C. +1767 +O +RTHOPEDIC + S +UR +g +ER +y +CHAPTER 43 +ligament, and the coracoclavicular ligament. +Controversy exists however regarding early or delayed surgical +reconstruction for type III tears. +43-10). +Research into the use of orthobiologics (e.g. +When healing is complete, ROM and strength will need +Figure 43-9. +Imaging and treatment of a shoulder glenoid labrum tear. +A. +MRI axial T1 image showing a tear of the posterior superior +labrum (arrow). +B. +C. +Often- +times, this is associated with (medial) meniscus injury and +sometimes with an ACL. +The +majority of MCL injuries occur in the mid-substance or at the +femoral insertion side. +Reconstruc- +tion is rare, since surgical repair is usually effective in restoring +the MCL. +A functional +brace during sports is advised. +ACL tears are a common sports injury, especially in sud- +den cutting and stopping sports (e.g. +soccer, basketball) or con- +tact sports (e.g. +football). +Radiographs are obtained to evaluate joint condition and +possible associated osseous injuries. +To visualize the ACL +and other soft tissue in the knee however, an MRI should be +obtained. +Imaging and treatment of a knee lateral and meniscus tear. +A. +MRI sagittal T2 image of the knee showing a displaced bucket- +handle lateral meniscus tear (arrow). +B. +C. +43-11). +Reconstruction is performed with use of a tendon-graft that +will replace the native ACL. +Commonly used graft sources are +the patellar tendon, the hamstrings and the quadriceps tendon. +These tendons can be harvested from the same knee (i.e., auto- +grafts), during the same procedure. +Alternatively a donor graft +(i.e., allograft) can be used. +Injuries of the PCL are less common than other knee liga- +ment injuries. +Most Grade I and II injuries are treated nonop- +eratively. +Indication +for surgery is influence by age, activity level, and presence of +concomitant injuries. +With more chronic PLC +injuries, reconstruction is recommended to restore knee stability. +Recognition of FAI can be clinically and +radiologically difficult. +Patients report +pain with flexion and internal rotation and after prolonged sit- +ting. +The imaging findings of FAI can be seen on plain radio- +graphs, CT scan, MRI, and MRA. +Figure 43 -11. +MR imaging of a torn ACL. +CT scan is more +reliable in assessing spine injury than plain radiographs. +When neurologic deficits are present a decompressive procedure +may be indicated. +In spinal cord compression, prompt decom- +pression should be performed. +Most patients with this injury +suffer cervical cord injury, and do not survive. +Traction on the +spine is contraindicated. +Fractures of C1 (Jefferson Fracture) +Fracture of the C1 ring was described by Jefferson in 1920. +The +thin anterior and posterior rings of the C1 vertebra fracture with +axial loads. +This injury is rarely associated with +neurologic injury. +Odontoid fractures are most often type I fractures (an avulsion +fracture off the tip of the dens). +Type I fractures are stable and managed nonoperatively. +A type II fracture, at the base of the odontoid, results from +lateral loading forces. +Transfixing the odontoid +fracture with a screw maintains rotational movement. +Type III fractures extend into the body of C2, below the +origin of the odontoid process. +Type III fractures are generally +treated with halo brace. +Treatment is simple immobilization in +a halo vest. +The diag- +nosis can be made on lateral radiographs. +The patient is kept awake for +safety concerns. +The fracture is treated nonoperatively +with analgesics and a soft collar. +Thoracolumbar compression fractures +are treated nonoperatively with braces and analgesics. +A laterally placed plate and screws +add stability to the construct. +seatbelt) restraint. +“Chance frac- +tures” are treated with bracing. +Reduction of the displaced bones is the best way to +improve the canal dimensions. +Patients with fracture dislocations of the spine and par- +tial nerve function can recover. +Fracture dislocations are treated +operatively with surgical stabilization. +In the cervical +spine, spinal cord compression can occur. +The bulk of the extruded nucleus pulposus resorbs over +time. +Dissection is carried between the trachea and the +carotid sheath. +The disc is then removed. +The disc space may be +bone grafted to fuse the vertebrae. +A locking screw low profile +titanium plate is then attached to the vertebrae. +Posterior decompression and laminectomy exposes the pos- +terior elements of the spine. +Osteophyte for- +mation on the facet joints can also cause nerve impingement. +The claudication +symptoms result from standing and walking which increases +lumbar lordosis. +The symptoms resolve with sitting and bend- +ing forward (decreasing lumbar lordosis). +Spinal stenosis is treated with epidural steroid injections +and physical therapy. +Resistant cases may require surgical +decompression and stabilization with plates and screws. +Spinal stenosis usually occurs in patients over 50 years +of age. +Intervertebral disc replacement prostheses are now used +to treat degenerative disc disease. +Scoliosis +Scoliosis is a lateral curvature of the spine. +Lateral bending of the +spine is always accompanied by rotational deformity (coupling). +Idiopathic +scoliosis is the most common form, and represents a spectrum +of genetic disease. +Adults with scoliosis may present with axial pain and imbal- +ance in posture. +Treatment for scoliosis may include medications, +therapy, and activity modification. +In severe cases with objective +deformity surgical correction of the deformity may be indicated. +Ini- +tial management consists of observation. +Rapidly progressing +curves are treated with braces. +Brace treatment is recommended +for curves between 20 and 40 degrees. +Each has the potential to lead to loss of articular +cartilage lining the joints. +population) have been diagnosed with some form of +arthritis. +This number is projected to grow to an astounding +67 million adults by 2030 (or 25% of the U.S. +population). +population, +as age and obesity are two major factors in the onset of arthritis. +These measures can successfully manage +a patient’s condition and avoid a surgical procedure. +If you listen carefully to your patient, they will +often tell you their diagnosis. +Location of “hip pain” can nar- +row a differential diagnosis. +These details document functional status +and help to formulate a differential diagnosis. +Once an appropriate physical examination is complete, weight- +bearing radiographs are needed. +Advanced imaging, including +CT and MRI are rarely indicated in initial work up of patients. +Injections +Joint injections are commonly performed into the knee and +shoulder. +Common injections into the knee include corticoste- +roids and Hyaluronic-acid gels. +Corticosteroid injections can +decrease inflammation within the joint. +At the same time any benefit +received is therapeutic for the patient. +The +injections do not lead to articular cartilage repair. +How- +ever, other nonarthroplasty options exist. +These are typically +performed for specific diagnoses under specific indications. +11 +10 +1773 +O +RTHOPEDIC + S +UR +g +ER +y +CHAPTER 43 +head and neck are replaced. +Hip resurfacing is a form of hip +arthroplasty, used in younger patients with end stage arthritis. +The +acetabulum is not addressed surgically. +Fracture of the interposed +material or loosening of components often led to failure. +Later attempts introduced stemmed components to +improve fixation. +One of the earliest femoral components was +designed by Austin-Moorem. +Pelvic and femoral osteotomy can be utilized in treat- +ment of developmental dysplasia of the hip. +An osteotomy commonly used in the knee is a proximal +tibia osteotomy. +Arthrodesis. +Joint Arthroplasty/Joint Replacement. +The surfaces of the bones are replaced +after removing the damaged articular cartilage. +43-12). +Osteoarthritis femoral head. +Note erosion of weight- +bearing cartilage and peripheral osteophytes. +Each approach contains a +unique set of advantages and disadvantages. +Below, a compari- +son of the anterior and posterior approaches is made. +In addition, there is no true interner- +vous plane. +Minimally invasive total hip arthroplasty has been advo- +cated in recent years. +A greater trochanteric osteotomy can be performed in +order to mobilize the abductors. +Failed ceramic on metal hip arthroplasty compo- +nents. +Note the metallic staining on the ceramic femoral head. +ceramic articulations. +43-13). +Metal ions pose a theoretic risk of +causing problems with pregnancy or a theoretic risk of cancer. +(Figs. +On occasion, a lateral parapatellar arthrot- +omy is warranted and this can be performed safely. +This has no effect +on patient outcome. +43-16 and 43-17). +The patella is resurfaced with +a polyethylene component. +Options exist for a mobile bearing +Figure 43-14. +Valgus deformity. +Osteoarthritis of lateral compart- +ment right knee. +Figure 43-15. +Osteoarthritis of both knees. +Note varus align- +ment of right knee, and valgus alignment of left knee (“windswept + deformity”). +Figure 43-16. +Standard total knee instruments. +1776 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +knee arthroplasty. +These two systems have equivalent results in knee +arthroplasty. +AB +Figure 43-17. +A. +Varus knee with osteoarthritis. +B. +Right total knee replacement. +43-18). +In theory this would lead to improved patient +outcomes (Fig. +43-19A and B). +Negatives include increased +costs of the technology and prolonged operative times. +Use of computer navigation will likely +increase in the future as technology continues to improve. +The cement most +commonly used is polymethylmethacrylate (PMMA). +PMMA +serves as a grout between the component and the bone sur- +face. +In knee arthroplasty, cement utilization is gen- +erally preferred. +Osteolysis and Aseptic loosening. +Osteolysis is a term +used to describe abnormal resorption of bone. +Even with appropriately positioned components, some wear +of the bearing surfaces is expected. +Figure 43-19. +A. +Valgus knee with osteoarthritis. +B. +Robotic assisted total knee. +AB +1778 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +Dislocation Following Hip Arthroplasty. +Rarely, open reduction may be nec- +essary. +Patients with multiple dislocations should be assessed +for improperly positioned components. +ORTHOPEDIC PATHOLOgy AND ONCOLOgy +Diagnosis of Malignant Bone Tumors +History. +Diagnosis of musculoskeletal tumors begins with a +thorough patient history. +Patient age can help in establishing a differen- +tial. +Laboratory Test. +Elevated Prostate-specific +antigen (PSA) suggests prostate cancer. +Imaging. +Radiographic studies are critical to the diagnosis +of bony tumors. +Radiographs can help assess the aggressive- +ness of the tumor. +(b) What is the tumor doing to the bone (clinical behavior)? +(c) What is the bone doing to the tumor (biologic response)? +(d) What is the matrix pattern? +Matrix is the acellular interstitial +substance produced by tumor cells. +Ewing’s sarcoma has a characteristic ‘onion skin’ peri- +osteal reaction pattern. +This reaction pattern also occurs in other +tumors and infections. +“Activated” macrophages +lead to an osteolytic process and bone resorption. +Particulate +methylmethacrylate cement debris can also play a role in oste- +olysis. +Complications in Joint Arthroplasty. +Figure 43-20 Failed total knee replacement. +Note subsided, loose, +tibial component. +43-21). +Most + osteosarcomas present in patients between 10 and 20 years of +age. +Osteosarcoma. +The +preferred treatment is wide surgical excision. +The lesion appears chondroblas- +tic on histology. +Radiographs show scalloping of the underlying +cortex with a ‘sunburst’ periosteal reaction. +Treatment is wide +surgical excision. +Paget’s Sarcoma +Paget’s sarcoma is a rare complication of Paget’s disease. +Imaging may demonstrate osteolytic +areas, and loss of normal fatty marrow and multifocal lesions. +Treatment of Paget’s sarcoma is surgical excision, but the +prognosis is poor. +Treatment is a combination of chemotherapy and + surgery. +EWINg’S SARCOMA +Ewing’s sarcoma is the second most common primary bone +tumor in patients under 30. +The typical presentation is a +tumor in the diaphysis of the femur in a young white male. +43-22). +Diagnosis is confirmed with bone marrow biopsy +specimen. +Bone scan can identify multiple lesions. +Treatment +is chemotherapy and surgery or radiation therapy for spine or +pelvic lesions. +Pelvis, shoulder, and ribs are +frequent locations. +Chondroid or “popcorn” calcifications are +typical on radiographs. +Clear cell chondrosarcomas are low-grade +lesions that often affect the epiphyses. +For high- +grade lesions, wide or radical resection is recommended. +Radiographs show +a metadiaphyseal “soap bubble” appearance and endosteal scal- +loping. +Histology resembles desmoid tumors or fibromatosis. +Recommended treatment is wide excision. +Radiographs +typically show destructive lesions with soft-tissue extension. +Figure 43-22. +Ewing’s sarcoma. +Treatment +is wide surgical excision. +Malignant Vascular Tumors +Hemangioendothelioma. +Hemangioendothelioma is a +malignant neoplasm arising from vascular endothelium in long +bones. +Radiographs show a metadiaphyseal lytic lesion with a +“soap bubble” appearance. +Histology reveals eosinophilic cells +in a basophilic stroma. +Lesions may be multifocal. +Treatment + consists of curettage for low-grade lesions and wide excision +for high-grade lesions. +Histology reveals branching +“staghorn” vascular spaces. +The tumor cells resemble cells nor- +mally seen adjacent to capillaries. +Treatment is wide excision. +Angiosarcoma of Bone +Angiosarcoma is a soft tissue malignancy usually seen in +elderly males. +Histology reveals vascular channels with ana- +plasia. +Treatment is wide excision, or if inaccessible surgically, + radiation. +Presenting +complaints include pain and pathologic fracture. +Imaging +reveals eccentric, epimetaphyseal lytic lesions eroding the sub- +chondral bone. +Histology reveals multinucleate giant cells and +mononuclear stromal cells (Fig. +43-23). +These tumors can occa- +sionally metastasize to the chest. +Primary malignant giant cell +tumor has a poor prognosis. +Treatment of giant cell tumors is +with curettage and high-speed burr. +After pathologic fractures, wide excision may +Figure 43-23. +Giant cell tumor. +1781 +O +RTHOPEDIC + S +UR +g +ER +y +CHAPTER 43 +be required. +In tumors that are inaccessible surgically, radiation +may be indicated. +Radiographs have a soap bubble +appearance. +Patients may present with pain but often the diag- +nosis is incidental on radiographs. +Histology resembles fibrous +dysplasia, but with osteoblastic rimming. +Ossifying fibroma +may be a precursor to adamantinoma. +Adamantinomas are low grade malignancies capable of +metastasis seen in the tibia. +Histology reveals a tubular, basa- +loid, squamoid, or spindled pattern (Fig. +43-24). +The treatment of +adamantinoma is with wide surgical excision. +Primary Lymphoma of Bone +Primary lymphoma accounts for about 5% of all neoplasms of +bone. +Long bone involvement is more frequent than spine. +Lym- +phoma of bone typically occurs in males in their forties. +Histol- +ogy reveals large B cell lymphomas. +Treatment is a combination +of chemotherapy and radiation. +Surgery may be required for +stabilization of pathologic fractures. +Chordoma +Chordoma arises from notochordal rests in the sacrum. +These +tumors are found in middle-aged to older men and presents with +bladder and bowel symptoms. +An MRI shows a destructive +lesion with a large soft-tissue mass. +Histology shows epitheli- +oid cells arranged in cords with vacuolated physaliferous cells. +Treatment is surgical excision and muscle flaps and a mesh for +reconstruction. +Urinary diversion and colostomy may be needed +for loss of bladder and bowel control. +A +solitary myeloma lesion in bone is known as a plasmacytoma +(Fig. +43-25). +Myeloma protein 1-alpha stimulates +Figure 43-24. +Adamantinoma. +osteoclast formation. +RANKL induces osteoclast differentiation and +activation. +Myeloma cells inhibit osteoblast differentiation and +activity. +Serum and urine electrophoresis detect the M protein. +Plasma- +cytoma is usually treated with radiation to the lesion. +Myeloma +is treated with chemotherapy, stem cell transplantation, and +radiation therapy. +Many patients with myeloma develop a ver- +tebral compression fracture. +Kyphoplasty can be useful in pro- +viding pain relief. +If there is instability or if there is neural compression, +surgical stabilization may be required. +METASTATIC BONE TUMORS +Metastatic bone tumors are more common than primary bone +tumors. +Metastatic tumors affect the lung, liver, and bone. +Can- +cers that commonly metastasize to bone are breast, prostate, lung, +thyroid, and kidney. +The +most common site of involvement is the axial skeleton and proxi- +mal ends of long bones. +Bronchogenic and renal cell carcinomas +can metastasize distal to the knee and elbow. +Malignant cells are +able to detach from one location and set up a focus at a distant +site. +Large birth weight, forceps delivery, breech pre- +sentation, and prolonged labor are risk factors. +Brachial plexus +Figure 43-25. +Plasmacytoma. +Surgical repair of injured nerve roots and trunks may +be required in severe cases. +The typical cerebral palsy patient is +hyperreflexic with increased muscle tone and spasm. +Treatment con- +sists of abductor tendon releases. +Knee contractures are +treated with hamstring lengthening. +Foot and ankle deformities are treated even in nonambu- +latory patients to facilitate shoe wear. +Tendon balancing is +usually necessary and bony reconstruction may also be needed +in severe cases. +The +epiphysis, generally containing an articular surface, is found at +the ends of the long bone. +The physis or growth plate is found +beneath the epiphysis. +Surrounding the +metaphyseal and diaphyseal bone, is the periosteum. +A Salter-Harris Type I injury is a simple transverse +fracture through the physis. +Salter-Harris +Type III fracture occurs through the physis and exits through the +growth plate. +A +Salter-Harris Type V fracture crushes the physis itself. +Treatment of growth plate fracture requires anatomic +reduction of the fragments. +When internal +fixation of a diaphyseal fracture is required, the physis is avoided. +Children 14 years of age are +treated with an adult style intramedullary reamed nail. +Extra- +articular fractures of the distal femur or proximal tibia are man- +aged in a long leg cast. +Pediatric Ankle Fractures +Salter-Harris I and II fractures are managed with casting. +Smooth pins +are used, and the physis is avoided unless necessary for stability. +Pediatric Elbow Fractures +Management of pediatric elbow fractures is complex. +A fracture +of the distal humeral epiphysis can be misdiagnosed as a dislo- +cation of the elbow. +Familiarity with the timing of the ossifica- +tion centers’ appearance aids in diagnosis. +Treatment is closed +reduction and percutaneous pinning. +Injury to the brachial artery, the radial, ulnar, and medial +nerves are possible. +Neurovascular exam is required before, dur- +ing, and after treatment. +Close follow-up for maintenance of +reduction and neurovascular status is needed. +Untreated hip dislocations can lead to a dysplastic acetab- +ulum. +Newborns are examined for hip instability within the first +72 hours. +Ultrasound can often demonstrate a dis- +located or dislocatable hip. +Early treatment with abduction and +flexion in a Pavlik harness can result in a normal hip joint. +Avoid severe abduction to +avoid avascular necrosis of the head. +For mild to moderate dys- +plasia, 6 to 12 weeks in a Pavlik harness is sufficient. +In severe +disease, adductor tenotomy may be needed. +If treatment is delayed, open reduction may be necessary. +Through an anterior approach the pulvinar can be removed +and the femoral head located. +Adductor tenotomy and femoral +shortening may be indicated. +Treatment includes traction, physical therapy, abduction +exercises, and crutches. +Femoral and pelvic osteotomies may +be needed in extreme cases. +One-quarter of cases are bilateral. +Patients +generally present with groin and anterior thigh or even knee +pain and decreased motion. +In pediatric patients with knee pain, +assess the ipsilateral hip as well. +One +screw is adequate to prevent further slip. +Remember that a mild degree of intoeing +is normal in young children 3 to 5 years of age. +Excessive internal rotation of the femur will usually correct +by age 8. +Metatarsus adductus in infants will also resolve spontane- +ously in most cases. +Talipes + equinovarus can be corrected by sequential corrective casting +of the foot. +A successful program of casting may be complete +in one to five months. +This disorder is thought to result from mechanical stress +on the tendinous insertion. +Radiographs show calcified ossicles +within the tendon at its insertion. +The disease presents with severe +local pain and tenderness in the area of the tibial tubercle. +Treatment for the disease is activity restriction. +If the +symptoms are improved, athletic participation can be resumed. +Symptoms regress after skeletal maturity or the discontinuance +of active athletic participation. 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however, they +are referred to by name: thumb, index, middle, ring, and small. +There are five metacarpals, comprising the visible palm of the +hand. +The thumb, in contrast, moves princi- +pally in the flexion-extension arc at the MP joint. +The proximal +interphalangeal joint (PIP) is the critical joint for finger mobil- +ity. +Normal motion is 0 to 95° (full extension to flexion). +The thumb interpha- +langeal joint (IP) also moves only in a flexion-extension plane. +Its normal motion is highly variable between individuals, but +averages 0 to 80°. +Each of the MP and IP joints has a radial and ulnar col- +lateral ligament to support it. +The IP joint collateral ligaments +are on tension with the joint fully extended. +For the fingers, +the MP joint collateral ligaments are on tension with the joint +bent 90°. +The wrist consists of eight carpal bones divided into two +rows (Fig. +44-2B).2 The proximal row consists of the scaph- +oid, lunate, and triquetrum. +The lunate is the principle axis of +motion of the hand onto the forearm. +It bears approximately +35% of the load of the wrist onto the forearm. +Both the scaphoid and the lunate articulate +with the radius. +The triquetrum resides ulnar to the lunate. +44-2B). +The trapezium +resides between the scaphoid and the thumb metacarpal. +44-1B). +The trapezoid rests between the scaphoid and the +index finger metacarpal. +The index and middle finger CMC +joints are highly stable and have minimal mobility. +The ring and small finger CMC joints are mobile, prin- +cipally in the flexion-extension direction. +The pisiform is a carpal bone only by geography. +It is +a sesamoid bone within the FCU tendon (see below). +It does +not bear load and can be excised, when necessary, without +consequence. +44-3). +Three muscles flex the wrist, all of which originate from +the medial epicondyle of the humerus. +The FCR also deviates the wrist radially, +whereas the FCU deviates the wrist ulnarly. +1789 +S +UR +g +ERY + +OF + +THE + H +AND + +AND + W +RIST +CHAPTER 44 +AB +CD +Figure 44-1. +Directions of finger, hand, and wrist motion. +A. +Finger abduction (white arrows) and adduction (black arrows). +B. +Thumb +radial (black arrow) and palmar (white arrow) abduction. +C. +Thumb and small finger opposition. +D. +Hand/wrist pronation (black arrow) and +supination (white arrow). +All three wrist extensors are innervated by the radial nerve +or its branches. +The ECRL deviates +the wrist radially, whereas the ECU deviates the wrist ulnarly. +The long flexors of the fingers all originate from the +medial epicondyle of the humerus. +It inserts on the base of +the distal phalanx of the thumb and primarily flexes the IP joint. +All of these tendons can also flex the more proximal joint(s) in +their respective rays. +Cross-section of the wrist at the midcarpal level. +The relative geography of the neurologic and tendinous structures can be seen. +Bones: C = capitate; H = hamate; P = pisiform; S = scaphoid. +The thumb has three separate extrinsic extensors. +All of +these originate from the dorsal ulna in the mid-forearm and +are innervated by the PIN. +The extensor pollicis +brevis (EPB) inserts on the base of the thumb proximal phalanx. +Figure 44-2. +Bony architecture of the hand and wrist. +A. +Bones of the hand and digits. +All rays have metacarpophalangeal (MP) joints. +B. +Bones of the +wrist. +The proximal row consists of the scaphoid, lunate, and capitate. +The pisiform bone is a sesamoid +within the flexor carpi ulnaris tendon. +It overlaps the triquetrum and hamate but does not contribute to a carpal row. +CMC = carpometacarpal; +TFCC = triangular fibrocartilage complex. +The intrinsic muscles of the hand are what allow humans +fine, subtle movements of the hand. +Microsurgery, typing, and +even video gaming would be difficult, if not impossible, without +them. +The lumbrical muscles are unique in the body in that they +originate from a tendon. +Each finger’s lumbrical originates from +the FDP tendon in the palm. +The abductor digiti quinti +(ADQ) abducts the small finger. +The flexor digiti quinti (FDQ) flexes the small +finger metacarpal. +All of these muscles are innervated by the +ulnar nerve. +The interosseous muscles occupy the space between the +metacarpal bones. +Their tendons insert on the bases of the proxi- +mal phalanges. +All act to flex the MP joints and extend the IP +joints. +The three palmar interosseous muscles adduct the fin- +gers. +The four dorsal interosseous muscles abduct the fingers. +It acts to adduct the thumb. +All of these muscles, as well as the +deep head of the FPB, are innervated by the ulnar nerve. +This area is also known as the carpal tunnel (see +Fig. +44-3). +On the dorsum of the wrist, the extensor retinaculum is +divided into six compartments. +The second holds the ECRL and ECRB tendons. +The +EPL passes through the third compartment. +The sixth compartment is located on the +A5 +C3 +A4 +C2 +A3 +C1 +A2 +A1 +Figure 44-4. +Drawing of anteroposterior and lateral view of the +pulley system. +ulnar aspect of the distal ulna. +44-3). +There are no extensor +pulleys within the hand. +Each finger has five annular and three +cruciate pulleys (Fig. +44-4). +Vascular +Two major arteries serve the hand. +The radial artery travels +under the brachioradialis muscle in the forearm. +At the wrist level, the artery splits into two branches. +The ulnar artery travels deep to the FCU muscle in the +forearm. +When the FCU becomes tendinous, the ulnar artery +resides deep and slightly radial to it. +The larger, superficial branch forms the superficial +palmar arch. +44-5A). +44-5B). +The most critical of these from +a sensory standpoint is the median nerve. +It receives fibers from C5–T1. +The ulnar nerve is a terminal branch of the medial cord +of the brachial plexus. +It receives innervation from C8 and +T1 roots. +The FCU and FDP (ring/small) receive motor fibers +from the ulnar nerve. +Once +in the hand, the nerve splits into the motor branch and sensory +branches. +The sensory nerves provide +distal dorsal sensation similar to the median nerve branches. +It receives fibers from +C5–T1 nerve roots. +There is no ulnar nerve contribution to exten- +sion of the wrist, thumb, or finger MP joints. +Arteries of the hand and + finger. +A. +B. +The +patient is evaluated by inspection, palpation, and provocative +testing. +On inspection, one should first note the position of the +hand. +44-6). +Disturbance of this suggests a tendon or skeletal +problem. +Observe +Figure 44-6. +Palpation typically begins with the radial and ulnar artery +pulses at the wrist level. +Pencil Doppler examination can sup- +plement this and evaluate distal vessels. +Discrepancies between digits +should be noted. +Sensation must be evaluated prior to any administration of +local anesthetic. +Beware of writing “sensation intact” at the conclu- +sion of this evaluation. +Ability to flex and extend the wrist and digital joints is +typically examined next. +At the wrist level, the FCR and FCU +tendons should be palpable during flexion. +The wrist extensors +are not as readily palpated due to the extensor retinaculum. +Ability to flex the DIP joint (FDP) is tested by blocking the +finger at the middle phalanx level. +44-7). +This +maneuver makes use of the fact that the FDP tendons share a +common muscle belly. +The epitrochlear and axillary nodes should be +palpated for enlargement and tenderness. +Findings for specific +infectious processes will be discussed in the Infections section. +Congruency of adjacent joints should also be noted. +The +MP and IP joints of the fingers should all be in the same plain +on any given view. +Incongruency of the joint(s) of one finger +implies fracture with rotation. +44-8A). +Disruption of these implies ligamentous injury or +possibly dislocation (Fig. +44-8B). +44-9). +Unfortunately, it is also highly operator dependent. +With contrast, MRI can demonstrate an occult +abscess. +44-10). +Angiography +Angiography of the upper extremity is rarely used. +AB +Figure 44-8. +1795 +S +UR +g +ERY + +OF + +THE + H +AND + +AND + W +RIST +CHAPTER 44 +AB +Figure 44-9. +A. +Preoperative images demonstrate a nonunion of a scaphoid fracture sustained 4 years earlier. +This can be difficult to +discern on plain X-rays due to overlap of bone fragments. +An arterial +catheter can be used to deliver thrombolytic drugs to treat a +thrombotic process. +All injured patients should receive +an appropriate trauma survey to look for additional injuries. +The patient with upper extremity trauma is evaluated as +described in the Hand Examination section. +Sensory examina- +tion should be performed early. +Keep in mind that +all local anesthetics are less effective in areas of inflammation. +Figure 44-10. +T1-weighted magnetic resonance imaging shows +perfused bone as white. +Also, primary vascular disease of the upper extremity is relatively +uncommon. +For pediatric patients, the tolerated +dose is 2.5 mg/kg. +A commonly held axiom is that epinephrine is unac- +ceptable to be used in the hand. +This is performed in +the standard fashion. +Fingertip injuries are +particularly well anesthetized by this technique. +A digit can be +anesthetized via a flexor sheath approach or via the dorsal web +space (Fig. +44-11A,B). +44-11C–E). +A fracture is described by its displace- +ment, rotation, and angulation. +To avoid confusion, it is +useful to describe which direction the angle of the fracture +points. +Their force is directed proximally and, +to a lesser extent, volarly. +Transverse fractures are +typically stable. +Oblique fractures typically shorten. +Spiral +fractures typically rotate as they shorten and thus require +surgical treatment. +Fractures of the tuft of the distal phalanx are common. +Catching of a finger in a closing door is a common causative +mechanism. +Displaced transverse fractures of the phalanges can usu- +ally be reduced with distraction. +Postreduction X-rays should routinely be performed +to document satisfactory reduction. +Oblique and spiral frac- +tures usually are unstable after reduction. +Articular fractures of the IP and MP joints are worri- +some because they may compromise motion. +Chip fractures +must be evaluated for instability of the collateral ligaments. +If the joint is stable, the patient should initially be splinted for +comfort. +Motion therapy should be instituted early (ideally +within the first week) to prevent stiffness. +For larger fractures, +the patient should be splinted until surgical treatment can be +performed. +In +general, the patient should not be sent home with a joint that +remains dislocated. +Once there, the relocated PIP joint is gently flexed, +confirming the joint is in fact reduced. +The joint is splinted in +slight flexion to prevent redislocation. +On occasion, the head +of the proximal phalanx may pass between the two slips of the +FDS tendon. +For these patients, the joint may not be reducible +in a closed fashion. +Typical history is that the patient struck another individual or +rigid object with a hook punch. +These are often stable after +reduction using the Jahss maneuver (Fig. +44-12). +Fractures of the thumb metacarpal base are often unstable. +The Bennett fracture displaces the volar-ulnar base of the bone. +These +fractures nearly always require open reduction and internal +fixation. +Most nondisplaced fractures do not require surgical treat- +ment. +The scaphoid bone of the wrist is a notable exception to +this rule. +Local anesthesia can be administered at the digital or the wrist level. +A. +B. +Alternatively, one can inject from a dorsal approach into the web space +on either side. +C. +The dorsal sensory branch of the ulnar nerve is blocked in similar fashion over the distal ulna. +D. +E. +Ligament injuries of the wrist can be difficult to recognize. +Patients often present late and may not be able to localize their +pain. +This keeps the collateral ligaments on tension +and helps prevent secondary contracture. +In general, one +of three splints should be used for the ER patient (Fig. +44-13). +The ulnar gutter splint uses places plaster around the ulnar +Figure 44-12. +The Jahss maneuver. +border of the hand. +It is generally appropriate for small finger +injuries only. +Dorsal plaster splints can be used for injuries of +any of the fingers. +On inspection, injury is nor- +mally suspected by loss of the normal cascade of the fingers. +This is referred to at +the tenodesis maneuver. +Flexor tendon injuries are described based on zones +(Fig. +44-14). +The work of Dr. +The laceration should be washed out and closed at the skin level +only using permanent sutures. +Extensor tendons do not pass through a sheath in the + fingers. +As such, bulkiness of repair is less of a concern. +For patients with open injuries, a dermatotenodesis +suture is performed. +The DIP joint is splinted in extension. +More proximal injuries are typically repaired with a 3-0 +braided permanent suture. +Horizontal mattress or figure-of-eight +sutures should be used, two per tendon if possible. +Great care +should be used to ensure matching the appropriate proximal +and distal tendon ends. +The patient is splinted with IP joints in +extension and the wrist in extension per usual. +MP joints should +be splinted in 45° flexion, sometimes less. +Nerve repairs require +3 +1799 +S +UR +g +ERY + +OF + +THE + H +AND + +AND + W +RIST +CHAPTER 44 +Figure 44-13. +Commons splints used for hand injuries/surgeries. +A. +Ulnar gutter splint. +The ring and small fingers are included. +B. +Dorsal four-finger splint. +C. +Thumb spica splint. +In this patient, the IP joint was not +included. +For injuries at, or distal to, the MP joint, the IP should be included in the splint. +appropriate microsurgical equipment and suture; they should not +be performed in the ER. +As with tendons, nerve injuries do not +require immediate exploration. +The nerve must be resected back to healthy nerve +fascicle prior to repair. +The injured hand should be splinted +with MPs at 90° and IPs at 0°, as described earlier. +Vascular Injuries +Vascular injuries have the potential to be limb or digit threatening. +Consultations for these inju- +ries must be evaluated urgently. +One +should keep this tourniquet time to less than 2 hours to avoid +tissue necrosis. +The finger or hand +with vascular compromise requires urgent operative exploration. +For the noncritical vascular injury, two treatment options +exist. +Simple ligation will control hemorrhage. +As with all guidelines, one should evaluate the par- +ticular needs of the injured patient. +The ampu- +tated part should be wrapped in moistened gauze and placed +in a sealed plastic bag. +This bag should then be placed in an +ice water bath. +Bony prominences should be smoothed off +with a rongeur and/or rasp. +The zones of flexor tendon injury. +I. +Flexor digi- +torum superficialis insertion to the flexor digitorum profundus + insertion. +II. +Start of the A1 pulley to the flexor digitorum super- +ficialis insertion. +III. +End of the carpal tunnel to the start of the A1 +pulley. +IV. +Within the carpal tunnel. +V. +Proximal to the carpal tunnel. +neuroma in the skin closure. +Prostheses can be made for amputated parts. +The more +proximal the amputation, the more important to function the +prosthesis is likely to be. +To properly +assess the nail bed, the nail plate (hard part of the nail) should +be removed. +A Freer periosteal elevator is well suited for this +purpose. +Lacerations are repaired with 6-0 fast gut suture. +In some situations, tissue may have been avulsed in the +injury and be unavailable for repair. +Choice of treatment options +depends on the amount and location of tissue loss (Fig. +44-15). +Treatment algorithm for management of fingertip +injuries. +See text for description of flaps. +If sufficient local tissue is present, homodigital flaps can be +considered. +A wide range of antegrade and retrograde homodig- +ital flaps can be mobilized to cover the defect. +This flap is not appropriate for +the fingers. +44-16A–C). +For wounds too large to cover with homodigital tis- +sue, regional flaps can be considered. +The skin from the distal +radial thenar eminence can be raised as a random pattern flap +(Fig. +44-16D–F). +44-16G–I). +The flap is inset at 14 to 21 days. +The surgeon +then matches the available options to the particular patient +needs. +These injuries are typically quite innocuous to inspection. +They are, however, digit-threatening emergencies. +Compartment Syndromes +Compartment syndromes can occur in the forearm and/or +the hand. +As in other locations, these are potentially limb- +threatening issues. +There are three compartments in the forearm and four +groups of compartments in the hand. +The volar forearm is one +compartment. +In the hand, the the- +nar and hypothenar eminences each represent a compartment. +The seven interosseous muscles each behave as a separate + compartment. +Compartment syndrome can be caused by intrinsic and +extrinsic causes. +Intrinsic causes include edema and hematoma +due to fracture. +Measurement of compartment pressures can be a useful +adjunct to assessment of the patient. +Release of the volar forearm +compartment includes release of the carpal tunnel. +One +dorsal forearm incision can release the dorsal compartment and +the mobile wad. +In the hand, the thenar and hypothenar com- +partments are released each with a single incision. +Any dead muscle is débrided. +Incisions are +left open and covered with a nonadherent dressing. +The wounds +are reexplored in 2 to 3 days to assess for muscle viability. +Often +the incisions can be closed primarily, but a skin graft may be +needed for the forearm. +COMPLICATIONS +Nonunion +Any fractured bone has the risk of failing to heal. +Fortunately, in +the fingers and hand, this is a rare problem. +Phalan- +geal and metacarpal nonunions are also quite rare. +Local flaps for digital tip coverage. +A–C. +Sensation to the advanced skin is maintained. +D–F. +An 8-year-old girl underwent fingertip +replantation that did not survive. +A thenar flap was transferred to cover the defect. +Some authors advise against its use in patients over 30 years +old. +G–I. +In this 45-year-old man, the entire skin of P3 of the long finger was avulsed and unrecoverable. +A cross-finger flap was transferred +and provides excellent, durable coverage. +The border of the flap and surrounding skin is still apparent 4.5 months after surgery. +44-9A). +Stiffness +The desired outcome of any hand injury is a painless, mobile, +functional hand. +The surgeon performing the initial eval- +uation can greatly impact this last factor. +Neuroma +Any lacerated nerve will form a neuroma. +The SRN is particularly notorious for this problem. +By provid- +ing proximal axon sprouts a target, nerve repair is an excellent +preventive technique. +In some circumstances, such as injuries +requiring amputation, this is not possible. +For the patient who develops a painful neuroma, nonsurgi- +cal treatments are initiated first. +The neuroma can be identified +by the presence of a Tinel’s sign. +Corticosteroid injection to the neuroma has also proven +useful in some hands. +When these techniques fail, surgery is contemplated. +The +neuroma can be resected, but a new one will form to replace it. +Both are inaccurate, as the sympathetic ner- +vous system is not always involved. +Current terminology for +this condition is complex regional pain syndrome (CRPS). +There is often associated edema and changes in hair +and/or sweat distribution. +Comparison to the unaffected side +is useful to better appreciate these findings. +Patients suspected +of CRPS should be referred for aggressive hand therapy. +Brief +trials of oral corticosteroids have been successful in some series. +NERVE COMPRESSION +Nerves conduct signals along their axonal membranes toward +their end organs. +Sensory axons carry signals from distal to +proximal; motor axons from proximal to distal. +Myelin from +Schwann cells allows faster conduction of signals. +When compression occurs to +a sufficient degree for a sufficient time, individual axons may +die. +On a nerve conduction study, this manifests as a decrease +in amplitude. +Knowledge of the anatomic distribution of the peripheral nerves +can aid in diagnosis. +Diseases that cause systemic neuropathy (e.g., +diabetes) can make diagnosis more difficult. +Nerve compression can theoretically occur anywhere +along a peripheral nerve’s course. +Other, less common locations of nerve +compression are described as well. +In addition, a nerve can +become compressed in scar due to a previous trauma. +44-3). +The transverse +carpal ligament, also called the flexor retinaculum, is its super- +ficial border. +Of these +10 structures, the median nerve is relatively superficial and +radial to the other nine. +An estimated 53 per 10,000 working adults have evidence +of CTS. +Physical examination should begin with inspection. +Look +for evidence of wasting of the thenar muscles. +Early treatment of CTS consists of conservative man- +agement. +The patient is given a splint to keep the wrist at 20° +extension worn at nighttime. +Many patients can have years +of symptom relief with this management. +Skin is divided followed by palmar +fascia. +The carpal tunnel contents are visualized as they exit the +carpal tunnel. +Endoscopic techniques have been devised to address CTS. +All involve avoidance of incising the skin directly over the +carpal tunnel. +It stabilizes the ulnar nerve in this +location during elbow motion. +Over time, or sometimes after +trauma, the ulnar nerve can become less stabilized in this area. +Physical examination for cubital tunnel syndrome begins +with inspection. +Look for wasting in the hypothenar eminence +and the interdigital web spaces. +Tinel’s sign is +often present at the cubital tunnel. +Elbow flexion test will often +be positive. +Grip strength and finger abduction strength should +be compared to the unaffected side. +Early treatment of cubital tunnel syndrome begins with +avoiding maximal flexion of the elbow. +Splints are often used +for this purpose. +When conservative management fails, surgery has been +contemplated. +The ulnar nerve can be +compressed as it passes through Guyon’s canal. +As mentioned previously, any nerve +can become compressed in scar at the site of a previous trauma. +Symptoms typically begin +in the fifth decade of life. +Any of the joints can become involved. +The patient should always be asked to what degree +symptoms are impeding activities. +Physical findings are documented in serial fashion from +the initial visit and subsequent visits. +Pain with axial loading of +the joint may be present. +Decreased range of motion may be a +late finding. +Plain X-rays are typically sufficient to demonstrate arthritis. +Initially, the affected joint has a narrower radiolucent space +between the bones. +As joint degeneration progresses, the joint +space further collapses. +X-ray findings do not always correlate with patient symptoms. +Patients with advanced x-ray findings may have minimal symp- +toms, and vice versa. +Initial management begins with rest of the painful joint. +Oral +nonsteroidal anti-inflammatory medications such as ibuprofen +and naproxen are also useful. +The surgeon and patient must +decide together as to whether conservative measures have failed. +Arthrodesis, fusion of +a joint, provides excellent relief of pain and is durable over time. +However, it comes at the price of total loss of motion. +This allows for motion without bony contact that +would produce pain. +Multiple +different materials have been used to fabricate such implants. +Conservative management is +used first, as described earlier. +Multiple surgical options exist for thumb CMC arthritis. +44-17A), patients can +usually be treated with a motion-sparing procedure. +If there is +truly no arthritic change present, the scapholunate ligament can +be reconstructed. +If arthritis is limited to the radiocarpal joint, two motion- +sparing options are available. +This maintains the full length of the wrist and the +lunate in the lunate facet of the radius. +The only activity of daily living that cannot be done +with a fused wrist is personal toileting. +Inflamed synovium causes articular +cartilage breakdown with pain and decreased range of motion. +Recent advances in +Figure 44-17. +Arthritis of the hand and wrist. +A. +This patient +injured her scapholunate ligament years prior to presentation. +B. +This patient has had rheumatoid arthritis for decades. +MP joints of the fingers are commonly affected. +In more advanced cases, the joint may not be sal- +vageable (Fig. +44-17B). +For these patients, implant arthroplasty +is the mainstay of surgical treatment. +Extensor tendon centralization is +then performed, as needed, at the end of the procedure. +For MP joint and PIP joint disease, fusion is an option. +EDQ rupture may go unnoticed if a +sufficiently robust EDC tendon to the small finger exists. +The DRUJ synovitis must also be resected. +For both pro- +cedures, the remaining distal ulna must be stabilized. +The ruptured extensor tendons are typically degenerated +over a significant length. +Strict compliance with postoperative therapy is essential to +maximizing the surgical result. +Prolonged nighttime splint- +ing, usually for months, helps prevent recurrence of extensor lag. +Finally, the disease may progress over time. +Reconstructions that +were initially adequate may stretch out or fail over time. +There are also connec- +tions from this layer to the deep structures below and the skin +above. +Increased collagen deposition leads to a palpable nodule +in the palm. +Over time, there is increased deposition distally +into the fingers. +This collagen becomes organized and linearly + oriented. +Splinting has similarly been shown +not to retard disease progression. +Skin is elevated off of the underly- +ing cords. +All nerves, tendons, and blood +vessels in the operative field should be identified. +44-18). +INFECTIONS +Trauma is the most common cause of hand infections. +Other +predisposing factors include diabetes, neuropathies, and +immunocompromised patients. +Staphylococcus and Streptococcus are the +offending pathogens in about 90% of hand infections. +Heavily +contaminated injuries require anaerobic coverage. +Skin breakdown is a frequent cause, +but often no inciting factor is identified. +S. +aureus is the +second most common offending pathogen and will cause a +more localized cellulitis. +The diagnosis of cellulitis is clini- +cal. +The defining difference is an area +of fluctuance. +Skin-puncturing trauma is the most common +cause. +S. +aureus is the most common pathogen, followed by +Streptococcus. +Most should be allowed to heal second- +arily. +5 +1810 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +Figure 44-18. +Dupuytren’s disease. +A. +This patient has cords affecting the thumb, middle, ring, and small fingers. +B. +The resected specimens +are shown. +C. +The adjacent fingers +will be held in abduction with pain on adduction (Fig. +44-19). +It will take 2 to 3 weeks for periosteal reaction and +osteopenia to be detected on radiographs. +Bone scans and MRI +are useful modalities to aid in diagnosis. +Treatment consists of antibiotics alone +in the early stage as long as there is favorable response. +All +necrotic bone and soft tissue, if present, must be débrided. +Initial +intravenous antibiotic therapy should cover S. +aureus, the most +common pathogen, and should then be adjusted according to +bone cultures. +If the hardware is unstable, it must be replaced. +An +external fixation device may be useful in this setting. +Direct trauma and +local spread of an infection are the most common causes. +Hema- +togenous spread occurs most commonly in patients who are +immunocompromised. +S. +aureus is the most common pathogen, +followed by Streptococcus species. +A. +B. +erythema, and tenderness. +Joint aspiration with cell count, Gram stain, and culture is +used to secure the diagnosis. +Gonococcal septic arthritis is usually treated nonoperatively. +Intravenous ceftriaxone is first-line therapy. +Necrotizing infections +can result in loss of limb or life, even with prompt medical care. +An inciting event is not always +identified. +aureus, and anaerobes. +Patients will present with pain out of proportion +with findings. +Crepitus may occur if a gas-forming organism is involved. +There may be no +appreciable leukocytosis. +Unlike necrotizing fasciitis, muscle is universally involved and +found to be necrotic. +Wet gangrene is most common in diabetics with renal +failure and an arteriovenous shunt. +It is usually polymicrobial. +A variety of etiologies are responsible for this process. +Most +acute cases of FTS are due to purulent infection. +The primary mechanism of infectious FTS usually is +penetrating trauma. +Most infections are caused by skin flora, +including both Staphylococcus and Streptococcus species. +Bacteria involved vary by etiology of the infection: bite wounds +(Pasteurella multocida—cat, E. +gonorrhoeae); or water-related punctures +(Vibrio vulnificus, Mycobacterium marinum). +Patients with infectious FTS present with pain, redness, +and fever (Fig. +44-20). +Prompt medical ther- +apy in early cases may prevent the need for surgical drainage. +For healthy individuals, empiric antibiotic therapy should cover +Staphylococcus and Streptococcus. +If medical treatment alone is attempted, then initial inpa- +tient observation is indicated. +Surgical intervention is necessary +if no obvious improvement has occurred within 12 to 24 hours. +Several surgical approaches can be used to drain infec- +tious FTS. +The method used is based on the extent of the +infection. +The sheath is copiously irrigated with normal saline. +The catheter is removed after irrigation. +The incisions +Figure 44-20. +Suppurative flexor tenosynovitis of the ring finger. +A. +The finger demonstrates fusiform swelling and flexed posture. +B. +Proximal exposure for drainage. +C. +Distal drainage incision. +1813 +S +UR +g +ERY + +OF + +THE + H +AND + +AND + W +RIST +CHAPTER 44 +are left open. +Some surgeons prefer a continuous irrigation tech- +nique for a period of 24 to 48 hours. +The catheter is sewn in +place, and a small drain is placed at the distal incision site. +The hand is reexamined the +following day. +Whirlpool therapy and range of motion are begun. +Drains are removed before discharge from the hospital. +The wounds +are left open to heal by secondary intention. +In severe cases, repeat +irrigation and operative débridement may be required. +Antibiotic therapy is guided by culture results as well as +clinical improvement. +S. +aureus is the most +common pathogen. +The fingertip contains multiple septa con- +necting the distal phalanx to the skin. +Patients will experience +erythema, swelling, and tenderness of the volar digital pad. +44-21). +Felon. +A. +B. +artificial nails, or nail biting. +An acute paronychia is usually +caused by S. +aureus or Streptococcal species. +Treatment consists of warm water +soaks and oral antibiotics if diagnosed early. +44-22). +If the infection involves the eponychial +Figure 44-22. +Paronychia. +A. +Fluctuance in the nail fold is the +hallmark of this infection. +B. +The nail +plate must be removed if the infection extends beneath the nail +plate. +Packing is kept in place for 24 to 48 hours, followed by +warm water soaks and local wound care. +All hand infections other than cellulitis will require surgi- +cal management. +44-23. +Initial investigation for any mass starts with a complete +history and physical exam. +The workup proceeds in an orderly fashion +until a diagnosis is obtained. +Most soft tissue tumors will +appear dark on T1-weighted images and bright on T2-weighted +images. +Diagnostic algorithm. +Diagnostic workup for a patient with hand inflammation to evaluate for infection. +See text for details +about particular infectious diagnoses. +Scintigraphy uses methylene +diphosphonate attached to technetium-99m. +This complex will +attach to hydroxyapatite. +The cyst transilluminates. +There is always a stalk +that communicates with the underlying joint or tendon sheath. +The etiology is unclear. +The +increased mucin production dissects superficially and coalesces +into a cyst. +The benefit of +injected steroids is inconclusive. +Dorsal wrist ganglion cyst. +amendable to aspiration. +Recurrence rate after surgical excision +ranges from 4% to 40%.62 +Mucous Cyst. +A mucous cyst is a ganglion cyst of the DIP joint. +X-rays will show signs of osteoar- +thritis within the DIP joint. +Heberden nodes (osteophytes within +the DIP joint) are often seen on X-ray. +Possible treatment includes observation, aspiration, or +excision. +Any osteophytes in the +DIP joint must be removed to reduce recurrence. +It is generally not performed. +giant Cell Tumor of the Tendon Sheath. +It is a +benign lesion with no clear pathogenesis. +The tumor is a growth +of polyclonal cells with no risk of metastases. +44-25A). +These tumors do not transilluminate. +Direct +extension into joints and ligaments can make complete exci- +sion difficult. +44-25B). +Approximately +20% will show extrinsic cortical erosion on X-ray. +This is a risk +factor for recurrence, and removal of the cortical shell should +be considered. +MRI is useful for delineating involvement with +tendons, ligaments, and joints. +The standard treatment is marginal excision. +Despite this being a benign lesion, local recurrence is +approximately 30% (range, 5%–50%). +Lipomas +do not transilluminate. +They resemble mature fat histologically. +X-rays typically reveal no abnormality. +If MRI findings are not consistent with a lipoma, incisional +biopsy is warranted. +Recurrence after marginal excision is rare. +Malignant degeneration to liposarcoma is exceedingly rare but +has been reported. +Schwannoma. +A schwannoma, also known as a neurilem- +moma, is a type of benign peripheral nerve sheath tumor. +These tumors arise from the Schwann +cell and occur most often in the middle decades of life. +Schwannomas grow from the peripheral nerve sheath and are +usually connected by a pedicled stalk. +The tumor is well demar- +cated and can be readily separated from the nerve fascicles +(Fig. +44-26). +Unlike neurofibromas, they do not grow within the +nerve. +Less +cellular regions appear as Antoni type B areas. +An +MRI should be obtained prior to surgery to confirm that the +A +B +Figure 44-25. +Giant cell tumor of tendon sheath. +A. +The mass pro- +duces lobulated enlargement of the external finger. +B. +The excised +giant cell tumor has a multilobulated, tan-brown appearance. +Operative treatment +involves excisional biopsy. +44-27). +They are locally invasive, with 2% to +5% lymph node involvement. +Metastasis rates of up to +20% have been reported in radiation or burn wounds. +Standard treatment is excision with 0.5- to 1.0-cm margins. +Figure 44-27. +Squamous cell carcinoma involving the nail fold +and nail bed. +Note the wart-like and ulcerated appearance. +overlying telangiectasias (Fig. +44-28). +Metastasis is very rare. +Standard treatment is excision with 5-mm margins. +Basal cell carcinoma of the dorsal hand with sur- +rounding telangiectasia. +1818 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +Melanoma. +Breslow thickness is the most important factor in +predicting survival for a primary melanoma. +Only 14% of all soft tissue sarcomas occur +in the entire upper extremity. +Fewer than 5% of +soft tissue sarcomas of the upper extremity will develop lymph +node metastasis. +Many muscles +of the upper extremity and their compartments cross joints +(e.g., forearm flexors). +An in-depth review of each type of soft tissue sarcoma +is beyond the scope of this chapter. +It has a propensity for the +forearm, palm, and digits. +Spread to lymph nodes has been +reported. +It is most common in the second to +fifth decades of life. +Tumor size (>5 cm) is positively corre- +lated with mortality. +They are often found incidentally on X-rays +taken for other reasons (e.g., hand trauma). +Enchondroma +has never been reported in the trapezoid. +The etiology is believed to be +from a fragment of cartilage from the central physis. +44-29A). +Further imaging is seldom needed, but a CT would be the study +of choice. +Symptomatic lesions and those +with impending fracture are treated surgically. +Curettage and high-speed burring are used to ablate the tumor. +Intraoperative fluoroscopy is used to confirm complete ablation +(Fig. +44-29B). +The defect is then packed with bone graft or bone +substitute. +Recurrence ranges from 2% to 15%. +X-rays reveal a subperiosteal lytic, +unilobular lesion with erosion into adjacent cortex. +There is +often a rim of sclerosis. +Treatment includes en-bloc resection of periosteum and corti- +cocancellous bone. +Recurrence is less than 4%. +Osteoid Osteoma. +This is a tumor of bone origin. +An in-depth +review is beyond the scope of this chapter. +X-ray reveals endosteal erosion, cortical expan- +sion, cortical destruction, and calcification. +Metastasis has never +been reported for chondrosarcomas of the hand. +Radiation exposure is believed to be a possible +risk factor. +X-ray findings vary widely, with 90% of tumors +occurring at a metaphyseal location. +Enchondroma. +A. +X-ray of the phalanx +demonstrates a well-defined central lucency. +Surrounding +cortex may thin or thicken. +Thinning of the cortex contrib- +utes to risk of pathologic fracture. +B. +Intraoperative fluo- +roscopy after curettage of the tumor. +The most common primary site is the lung (40%), +followed by the kidney (13%) and the breast (11%). +Patients will +present with pain, swelling, and erythema. +Differential diag- +nosis includes felon, gout, osteomyelitis, trauma, RA, or skin +cancer. +Treatment is usu- +ally palliative (simple excision or amputation). +Burns to the hand can cause seri- +ous short- and long-term disability. +These will heal without scarring. +Second- +degree burns are classified as superficial or deep. +Topical dressings are the mainstay +of treatment. +These have decreased +sensation and no cap refill and appear pale or white. +Blistering +may be present. +Excision with skin grafting is needed. +They appear dry, leathery, and even +charred. +Acute Management +Advanced Trauma Life Support guidelines should be fol- +lowed. +After primary survey, circulation to the hand should +be assessed. +A sensorimotor exam should +be performed. +Escharotomy should proceed as distally as +necessary into the wrist and hand to restore perfusion. +The burns should be dressed as soon as examination is +complete. +It is critical that no dressing +is wrapped in a circumferential manner around any body part. +Edema and swelling can lead to extremity ischemia if a circum- +ferential dressing is in place. +Any other web +space that is burned should have the adjacent fingers splinted +in abduction. +This will help prevent web space contracture. +After the primary and secondary surveys are complete, the +wound should be evaluated again. +Devitalized tissue should be +débrided. +Wounds should be cleansed twice daily, typically with +normal saline. +Second-degree superficial burns may be dressed +with Xeroform gauze and Bacitracin. +Silver sulfadiazine cream +is another option for any second- or third-degree wound. +It cov- +ers gram-positive and gram-negative microbes, but it does not +penetrate eschar. +It should be applied at least one-sixteenth of +an inch thick. +Sulfamylon can be used in conjunction with silver +sulfadiazine or alone. +It deeply penetrates eschar and tissues and +has good gram-positive coverage. +After débridement of necrotic skin, grafting will eventu- +ally be necessary. +It can remain in place for up to 14 days before the body +will reject it. +It typically is left in place for 7 days. +Surgical Management +Any burn wound will eventually heal with proper wound care. +Purely +cosmetic concerns are addressed after complete scar maturation +(∼12 months). +In other cases, surgical excision and skin graft- +ing are necessary. +Once there is an adequate bed, grafting is the next step. +Skin grafts to the dorsum of the hand are typically +split-thickness sheet grafts (not meshed). +It is important to bolster every skin graft. +A bolster may consist of a tie-over bolster and a splint or +a negative-pressure dressing. +The hand should be splinted in +intrinsic plus for 7 days after skin grafting. +This is especially true for tendons, where gliding capability is +paramount for function. +Flap coverage is required in these situ- +ations. +44-30). +The digits may also be buried subcutaneously in +the lower abdominal skin or groin crease. +It is applied much like +a skin graft. +Conceptually, it works by replacing the lost dermis and adds +durability to a wound bed. +It may be reapplied multiple times to +the same area if thicker neodermis is desired. +They are not widely used. +Web space contractures are the most common deformity +resulting after hand burns. +They may occur late despite the best +Figure 44-30. +Free anterolateral thigh flap reconstruction of a +large dorsal hand wound. +1822 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +efforts. +This is reversed +in web space contractures and limits digit abduction. +Local +modified Z-plasty (double-opposing Z-plasty) is the preferred +treatment (Fig. +44-31). +They must also be removed +from the patient or continued burn injury will occur. +A com- +plete discussion of all chemicals causing burns is beyond the +scope of this chapter. +It avidly binds tissue and circulating calcium and can lead to +hypocalcemia and cardiac arrest. +The wound should be irrigated +Figure 44-31. +Z-plasty release of web space contracture. +A. +First +web space burn contracture. +B. +Immediate postoperative result. +copiously with water followed by topical application of an aque- +ous mixture of calcium gluconate. +Calcium gluconate may also +be infiltrated intradermally throughout the wound. +Effectiveness +of treatment is assessed by relief of pain. +Phenol burns should be irri- +gated with water and treated topically with polyethylene glycol. +Phosphorus burns leave phosphorus particles within the wound. +Chronic vascular +disorders tend to develop slowly and are typically seen in older +patients. +Disorders unique +or common to the hand are discussed in the following sections. +The etiology is believed to be +chronic trauma to the ulnar artery as it exits Guyon’s canal. +If a thrombus forms, it may embo- +lize, producing digital ischemia. +A high index of +suspicion must be maintained. +It is strongly influenced by smoking and will +often resolve upon smoking cessation. +Typical onset is before +50 years of age. +It +can continue to cause more proximal ischemia and ultimately +lead to loss of the hands. +Failure to stop smoking will make any surgical inter- +vention unsuccessful. +Arteriography is useful to determine arte- +rial flow and whether bypass is possible. +Perfusion is diminished and fingers +often become cyanotic. +Raynaud’s disease +occurs without another associated disease. +This disease predom- +inately affects young women and is often bilateral. +The vascular +system is structurally intact without any obstructions. +There is +no ulceration, gangrene, or digit loss. +Many organs can be affected, with the skin most commonly and +noticeably involved. +In this disease, blood vessels are injured +by intimal fibrosis leading to microvascular disease. +The decrease in sympathetic tone allows for vasodila- +tion and increased blood flow. +Congenital hand differences have an incidence of 1:1500 births. +There is a famil- +ial tendency to develop this deformity. +This deformity often +involves both hands, and males are more often affected than +females. +44-32). +Surgery usu- +ally is performed at 6 to 12 months of age. +Duplication +Duplication of digits is also known as polydactyly. +Radial +polydactyly is usually manifests as thumb duplication. +Optimal reconstruction +requires merging of elements of both component digits. +Usually +the ulnar thumb is maintained. +Surgery is usually performed at 6 to 12 months of +age. +Ulnar-sided polydactyly may often be treated by simple +excision of the extra digit. +In this situation, the hand and +the forearm also may be involved. +This condition is +more commonly seen in males. +Surgical treatment of this condi- +tion is complex, and the outcomes may be less than desirable. +Sometimes, amputation of the enlarged digit provides the best +functional result. +Undergrowth +Underdeveloped fingers or thumbs are associated with many +congenital hand deformities. +Surgical treatment is not always +required to correct these deformities. +The cause of the +ring constrictions is unknown. +Figure 44-32. +Syndactyly. +Hand of a 1-year-old patient with +complex syndactyly between the long and ring fingers. +Note the skin grafts on the +ulnar and radial sides of the new web space. +REFERENCES +Entries highlighted in bright blue are key references. +1. +American Society for Surgery of the Hand. +The Hand: + Examination and Diagnosis. +3rd ed. +New York: Churchill +Livingstone; 1990:5-13. +2. +Moore KL. +The upper limb. +In: Moore KL, ed. +Clinically +Oriented Anatomy. +3rd ed. +Baltimore: Williams & Wilkins; +1992:501-635. +3. +Schuind F, Cooney WP, Linscheid RL, An KN, Chao EY. +Force and pressure transmission through the normal wrist. +A theoretical two-dimensional study in the posterioanterior +plane. +J Biomech. +1995;28:587-601. +4. +Gordon JA, 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+S +UR +g +ERY + +OF + +THE + H +AND + +AND + W +RIST +CHAPTER 44 +85. +Herndon DN, ed. +Total Burn Care. +2nd ed. +London: WB +Saunders; 2002. +86. +Haslik W, Kamolz LP, Nathschläger G, et al. +Burns. +2007;33: +364-368. +87. +Hatzifotis M, Williams A, Muller M, et al. +Hydrofluoric acid +burns. +Burns. +2004;30:156-159. +88. +Conn J Jr, Bergan JJ, Bell JL. +Hypothenar hammer syndrome: +posttraumatic digital ischemia. +Surgery. +1970;68:1122-1128. +89. +Lifchez SD, Higgins JP. +Long-term results of surgical treat- +ment for hypothenar hammer syndrome. +Plast Reconstr Surg. +2009;124:210-216. +90. +McClinton MA, Wilgis EFS. +Ischemic conditions of the hand. +In: Mathes SJ, Hentz VR, eds. +Plastic Surgery. +Philadelphia: +WB Saunders; 2006:791-822. +91. +Ruch DS, Holden M, Smith BP, et al. +Periarterial sympathec- +tomy in scleroderma patients: intermediate-term follow-up. +J Hand Surg Am. +2002;27:258-264. +92. +Jones NF. +Acute and chronic ischemia of the hand: +pathophysiology, treatment, and prognosis. +J Hand Surg. +1991;16A:1074-1083. +93. +Giele H, Giele C, Bower C, et al. +The incidence and epidemi- +ology of congenital upper limb anomalies: a total population +study. +J Hand Surg Am. +2001;26:628-634. +94. +Swanson AB. +A classification for congenital limb malfor- +mations. +J Hand Surg Am. +1976;1:8-22. +95. +Wassel HD. +The results of surgery for polydactyly of the +thumb. +A review. +Clin Orthop Relat Res. +1969; 64:175-193. +96. +Lee WP, Mathes DW. +Hand transplantation: pertinent data and +future outlook. +J Hand Surg Am. +1999;24:906-913. +97. +Malt RA, McKhann CF. +Replantation of severed arms. +JAMA. +1964;189:716. +98. +Starzl TE, Fung J, Jordan M, et al. +Kidney transplantation +under FK 506. +JAMA. +1990;264:63-67. +99. +Gorantla VS, Brandacher G, Schneeberger S, et al. +Favoring +the risk-benefit balance for upper extremity transplantation: +the Pittsburgh Protocol. +Hand Clin. +2011;27:511-520. +100. +Schneeberger S, Gorantla VS, Brandacher G, et al. +Upper- +extremity transplantation using a cell-based protocol to mini- +mize immunosuppression. +Ann Surg. +2013;257:345-351. +101. +Shores JT. +Recipient screening and selection: who is the +right candidate for hand transplantation. +Hand Clin. +2011;27: +539-543. +This page intentionally left blank +Plastic and Reconstructive Surgery +Joseph E. +Losee, Michael L. +Gimbel, J. +Peter Rubin, +Christopher G. +by the practitioner Sushruta. +This text describes the reconstruction of +the nose with a pedicled arm flap. +The techniques for +perfecting human skin grafting followed later in the nineteenth +century. +Great advances in plastic surgery occurred as a result of +the first and second world wars. +H. +Blair, from +St. +Army. +With the +onset of World War II, centers of excellence for hand recon- +struction appeared as well. +Externally, skin and underlying subcutane- +ous tissue are acted on by gravity and clothing. +As a result, when skin is incised linearly, +it gapes to variable degrees. +F. +45-1). +In general, incisions are placed perpen- +dicular to the action of the joint. +45-2; Table 45-1). +Wound Healing +The fundamentals of plastic surgery are based on wound heal- +ing physiology. +Disrupted blood vessels fill +the wound space with red blood cells and plasma. +Injured cells +1830 Figure 45-1. +Relaxed skin tension lines. +2 Plastic surgery has been a field of innovation. +Long-term follow-up during growth and devel- +opment is critical for optimal outcomes. +Patients undergoing aesthetic surgery +present a unique challenge. +These cells then dominate the wound region for +days to weeks. +Like neutrophils, activated macrophages +continue the task of wound débridement. +Macrophages lead the procession of new +tissue into the wound dead space. +Immature, replicating fibro- +blasts follow the macrophages. +Fibroblasts are the major producers of collagen in the +repair response. +Lack of these agents as well as steroid treatments decrease col- +lagen in wounds. +Macrophages also usher along angiogenesis, largely +through the release of VEGF. +Schematic of the Z-plasty technique. +Top: Simple +Z-plasty. +Middle: Four-flap Z-plasty. +Bottom: Five-flap Z-plasty. +(Modified with permission from Hudson DA: Some thoughts on +choosing a Z-plasty: The Z made simple. +Plast Reconstr Surg. +Some thoughts +on choosing a Z-plasty: the Z made simple. +Plast Reconstr Surg. +2000;106:665. +These measures +all draw on what we understand of the physiologic wound heal- +ing process. +Skin Grafts and Skin Substitutes +Skin is comprised of 5% epidermis and 95% dermis. +Each technique has advantages and dis- +advantages. +Split-Thickness Grafts. +Split grafts may be meshed to expand the +surface area that can be covered. +This technique is particularly +useful when a large area must be resurfaced, as in major burns. +•    Assess recent nutrition and provide treatment as  +appropriate. +•    Treat existing infection. +•    Assess wound risk using the SENIC index. +•    Start administration of vitamin A in patients taking  +glucocorticoids. +•    Maintain tight blood glucose control. +SENIC = Study on the Efficacy of Nosocomial Infection Control. +Source: Modified with permission from Hunt TK, Hopf HW. +Wound +healing and wound infection: what surgeons and anesthesiologists can +do. +Surg Clin North Am. +1997;77:587. +Copyright Elsevier. +Table 45-4 +Postoperative management +•    Keep patient warm. +•    Provide analgesia to keep patient comfortable, if not pain  +free. +•    Keep up with third-space losses. +Remember that fever  +increases fluid losses. +•    Assess perfusion and react to abnormalities. +•    Avoid diuresis until pain is gone and patient is warm. +•    Assess losses (including thermal losses) if wound is open. +•    Assess need for parenteral/enteral nutrition and respond. +•    Continue to control hypertension and hyperglycemia. +Source: Modified with permission from Hunt TK, Hopf HW. +Wound +healing and wound infection: what surgeons and anesthesiologists can +do. +Surg Clin North Am. +1997;77:587. +Copyright Elsevier. +Keep antibiotic levels high during long +operations. +•    Keep patient warm. +•    Maintain gentle surgical technique with minimal use of ties  +and cautery. +•    Keep wounds moist. +•    Perform irrigation in cases of contamination. +•    Elevate tissue oxygen tension by increasing the level of  +inspired oxygen. +•    Delay closure of heavily contaminated wounds. +•    Use appropriate sutures (and skin tapes). +•    Use appropriate dressings. +Source: Modified with permission from Hunt TK, Hopf HW. +Wound +healing and wound infection: what surgeons and anesthesiologists can +do. +Surg Clin North Am. +1997;77:587. +Copyright Elsevier. +Classification and pathophysiology of skin grafts. +Clin Dermatol. +2005;23:332. +Copyright Elsevier. +Full-Thickness Grafts. +By definition, full-thickness skin +grafts include the epidermis and the complete layer of dermis. +Graft Take. +Skin graft take occurs in three phases: imbibition, +inosculation, and revascularization. +After 48 hours, a fine +vascular network begins to form within the fibrin layer. +These phases are generally com- +plete by 4 to 5 days after graft placement. +Composite tissue grafts are donor tissue +containing more than just epidermis and dermis. +They com- +monly include subcutaneous fat, cartilage and perichondrium, +and muscle. +45-3). +Random Pattern Flaps. +Unlike axial pattern flaps, random +flaps are limited by their geometry. +The generally accepted reli- +able length-to-width ratio for a random flap is 3:1. +Exceptions +to this rule abound, however. +There are many different types of +random cutaneous flaps that differ in geometry and mobility. +A +transposition flap is rotated about a pivot point into an adjacent +defect (Fig. +45-5). +45-2). +Another +common transposition flap is the rhomboid (Limberg) flap +(Fig. +45-6). +Rotational flaps are similar to transposition flaps +but differ in that they are semicircular (Fig. +45-7). +Advancement +flaps slide forward or backward along the flap’s long axis. +Two +common variants include the rectangular advancement flap and +the V-Y advancement flap (Fig. +45-8). +Like transposition flaps, +interpolation flaps rotate about a pivot point. +An example of an interpolation flap is the thenar +flap for fingertip reconstruction (Fig. +45-9). +Fasciocutaneous and Myocutaneous Flaps. +The composi- +tion of a flap describes its tissue components. +For example, a +cutaneous flap contains skin accompanied by a variable amount +of subcutaneous fat. +The contiguity of a flap describes its position related to its +source. +Local flaps are transferred from a position adjacent to the +defect. +Distant flaps are transferred from a different +anatomic region to the defect. +Thus its current use is, in essence, vascular pedicle in +shortened form. +Composite graft reconstruction of nasal lobule. +A. +Scarred lobule from previous lesion excision. +B. +Scar excision markings. +C. +Insetting of composite ear lobe skin and subcutaneous fat graft. +D. +Postoperative day 3; note the pink hue of revascularization. +E. +Appear- +ance at 5 weeks postoperatively. +F. +Donor site at 5 weeks postoperatively. +Segmental a. +Muscle +Dermal-subdermal plexus +Perforating aa. +Figure 45-4. +Random pattern flap architecture. +a. += artery. +(Repro- +duced with permission from Aston et al.5) +Primary defect Secondary defect +Figure 45-5. +Random pattern transposition flap. +Random pattern rotational flap. +A and B. +Random pattern transposition flap, the rhom- +boid flap. +(Photographs reproduced with permission from M. +Gimbel.) +Burow’s triangle +A +B +Figure 45-8. +Random pattern advancement flap. +A. +Rectangular +advancement flap with Burow’s triangle excision. +B. +V-Y advance- +ment flap. +The circulation of bone- and muscle- +containing flaps also is mainly axial in pattern. +This can be clarified conceptually. +Neigh- +boring angiosomes overlap, just as the dermatomes of neighbor- +ing nerves overlap. +The vessels that pass +Figure 45-9. +Random pattern interpolation flap—the thenar flap. +A. +Middle fingertip injury with exposed bone and tendon. +B. +Elevation of +distally based random pattern thenar flap. +C. +Insetting. +D and E. +Function and form at 3 months, after skin grafting of donor site. +(Photographs +reproduced with permission from M. +Both the dynamic and +potential angiosomes extend beyond the anatomic angiosome +of an artery. +As a result, the flap becomes conditioned to rely on the +superior epigastric artery. +This +classification is also applied to the respective myocutaneous +flaps. +In addition, this knowledge has reduced the morbidity associ- +ated with flap harvest. +Flap circulation must be restored +within a tolerable ischemia time. +It is now ubiquitously used in appropriate patients by +reconstructive plastic surgeons worldwide. +The +patient’s hemodynamic status influences that of the free flap and +should be optimized. +Critical vessels con- +necting flap components must also be recognized and preserved. +Interrupted sutures or, less com- +monly, continuous sutures can accomplish the anastomosis. +Its monofilament microsuture +is usually between 9-0 and 11-0 caliber. +The dimensions of the +vessels to be anastomosed define the choice of microneedle and +microsuture. +Triangulating or bisecting suturing techniques can help +to achieve an even placement of sutures. +The configuration +of the anastomosis can be either end-to-end (Fig. +45-10), if the +distal circulation can be adequately preserved, or end-to-side +(Fig. +A through D. +End-to-end anastomosis. +This is one example of a situation in which a backup +plan may require execution. +A through E. +End-to-side anastomosis. +1840 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +also can be helpful. +Both leave donor site defects with cosmetic and/ +or functional sequelae. +The cause of orofacial clefting +is felt to be multifactorial. +The increased chance of +clefting when there is an affected parent is approximately 4%. +Clefting can involve +the lip and nose, with or without a palatal cleft. +45-12). +Complete clefts of the +lip affect the entire lip and extend up into the nose. +Treatment Protocol. +Today, this is widely accepted as +the standard of care. +Once adequate nutrition and a safe airway are ensured, +attention is turned to the cleft anomaly. +45-13). +Unilateral Cleft Lip. +The unilateral cleft lip is classically asso- +ciated with a cleft lip nasal deformity. +A. +Unilateral cleft lip and palate. +B. +Bilateral cleft +lip and palate. +C. +Incomplete unilateral cleft lip. +oris muscle abnormally inserted on the alar base (Fig. +45-14A). +A. +Complete left-sided cleft lip, nose, and palate. +B. +Nasoalveolar molding. +C. +After nasoalveolar molding, preoperative +appearance before cleft lip and nose repair. +D. +Frontal view after cleft lip and nose repair. +E. +Worm’s-eye view after cleft lip and nose repair. +1843 +P +LASTIC + +AND + R +ECONSTRUCTI +v +E + S +URGER +y +CHAPTER 45 +column as possible. +Bilateral Cleft Lip. +Often, +the premaxilla and prolabium are outwardly displaced. +This is +referred to as a flyaway premaxilla. +45-15). +A. +Unilateral cleft lip and nose deformity. +B. +The +rotation-advancement repair. +n +sn +sn +cphs +cphi +al +ls +c +prn +sto +Figure 45-15. +Mulliken bilateral cleft lip and nose repair. +A cleft palate results from the failure of fusion of +the two palatal processes. +Velo- +pharyngeal competence allows intraoral pressure to be built up +for speech sounds. +A cleft palate precludes this from occurring +and results in velopharyngeal incompetence (VPI). +The increased +incidence of otitis media can result in hearing loss if not treated +appropriately. +In addition, VPI and nasal air escape during +speech results in hypernasal speech. +Most +agree that palate repair should be performed before the devel- +opment of speech. +The cleft palate usually is repaired when the +infant is between 6 and 18 months of age. +An +epinephrine solution is injected into the palate. +Soft +palate or velar closure techniques are divided into straight-line +and Z-plasty procedures. +45-16). +The literature reports fistula rates ranging +from approximately 1% to 20%. +The literature reports postop- +erative VPI rates ranging from 10% to 40%. +Craniofacial Anomalies +History, Overview, and Classification System. +In 1967, Dr. +An American disciple of Dr. +Tessier, Dr. +A. +Markings for the Furlow double opposing Z-plasty palatoplasty. +B. +Raising the oral flaps in a Furlow palatoplasty. +C. +The +complete dissection of a Furlow palatoplasty. +Rigid fixation is obtained with +bioresorbable plates, screws, and sutures. +Craniofacial Clefts. +The rare craniofacial clefts have been +subclassified by Tessier (Fig. +45-17). +The Tessier classification +Table 45-10 +Classification of craniofacial anomalies + I. +Clefts + a. +Centric + b. +Acentric + II. +Synostoses + a. +Symmetric + b. +Asymmetric +III. +Atrophy, hypoplasia +IV. +Neoplasia, hypertrophy, hyperplasia + V. +Unclassified +14 +13 12 +11 10 +9 +8 +7 +6 +5 4 +3 +0 12 3 4 +3 2 1 +Figure 45-17. +Tessier’s classification of craniofacial clefts. +45-18). +Treacher +Collins syndrome (Fig. +45-20). +Ear deformities range +from complete absence of the ear to only preauricular skin tags. +The classical deformity of +hemifacial microsomia affects the mandible. +Hypoplasia of the +hemimandible, as well as the maxilla, results in dental maloc- +clusions (Fig. +45-20C). +Mandibular hypoplasia may range from +Figure 45-18. +Craniofacial cleft. +(Reproduced with permission +from Losee J, Kirschner R, eds. +Comprehensive Cleft Care. +1st +ed. +New York: McGraw-Hill Professional; 2008, Chap. +27, Fig. +3. +Child with Treacher Collins syndrome. +A. +Frontal view. +B. +Lateral view. +C. +Three-dimensional computed tomographic scan +of the craniofacial skeleton. +Ear deformities are reconstructed with tech- +niques using costal cartilage and local soft tissue. +Orbital hypertelorism is +yet another type of midline craniofacial (0-14) clefting. +Child  with  left-sided  craniofacial/hemifacial  + microsomia. +A. +Frontal view. +B. +Lateral view. +C. +Bite plane. +Craniosynostosis. +These abnormal head shapes provide a basis for the classifi- +cation of craniosynostoses. +The chances of intracranial hypertension increase with +the number of sutures affected. +Atrophy and Hypoplasia. +Pierre Robin sequence may or may not be associated with +a palatal cleft. +The tongue-lip adhesion is taken down at the time of pala- +toplasty. +45-21). +45-22). +Hyperplasia, Hypertrophy, and Neoplasia. +For deep lesions, radiographic +studies may help determine the diagnosis. +Hemangiomas. +A. +Lateral view of a child with Pierre Robin +sequence and mandibular microretrognathia. +B. +C. +Lateral view of the child after +mandibular distraction with slight overcorrection of retrognathia. +The involution phase continues until 5 to 10 years +of age. +Regression of the lesion is then complete. +The involuted +phase begins in 50% of children by 5 years of age and in 70% by +7 years. +In 50% +of children, near-normal skin is restored. +Laser therapy has been effective in lighten- +ing affected skin. +vascular Malformations. +Fast-flow lesions +include arterial malformations (AMs) and arteriovenous mal- +formations (AVMs). +In addition, there are combined malforma- +tions. +45-24A). +CMs are pink-red macular vascular stains that are present +at birth and persist throughout life. +These lesions tend to become +more verrucous and darker throughout life. +Laser therapy +often is repetitive and prolonged. +45-24B). +Figure 45-23. +Hemangioma of the ear and retroauricular region. +Figure 45-22. +Frontal view of a child with left-sided Romberg’s +progressive hemifacial atrophy. +preterm infants (23%) (Fig. +45-23). +Hemangiomas are solitary +in 80% of cases and multiple in 20%. +1851 +P +LASTIC + +AND + R +ECONSTRUCTI +v +E + S +URGER +y +CHAPTER 45 +Figure 45-24. +A. +B. +Sturge-Weber syndrome, with V1 and V2 capillary malformation of the left face. +C. +Lymphatic malformation of +the neck, previously referred to as cystic hygroma. +D. +Venous malformation of the forehead. +They have +historically been called lymphangiomas or cystic hygromas +(Fig. +45-24C). +LMs can be classified as microcystic, mac- +rocystic, or both. +LMs expand or contract with the flow of +lymph, infection, or intralesional hemorrhage. +VMs are frequently bluish, soft, and compressible, and +swell when dependent (Fig. +45-24D). +VMs grow with the child, +expand slowly, and may enlarge during puberty. +Patients often +complain about stiffness and pain with thrombosis. +VMs can +affect the skin, muscle, and bone. +MRI is the modality of choice +for imaging these lesions. +VMs have the +tendency to recanalize and re-expand. +Pure AMs are rare and more commonly present as AVMs. +AVMs appear as red violaceous skin with a palpable mass +beneath. +Local warmth, bruit, and thrill are frequently pres- +ent. +The most common location of CMNs +is the trunk, followed by the extremities and head and neck. +Frequently, larger lesions are associated with multiple smaller +satellite lesions. +Small CMNs are +<1.5 cm in diameter, and large ones are >10 cm. +45-25). +Treatment options have particular indications with +respect to the location of the nevus. +Scalp lesions are best +treated with tissue expansion. +Full-thickness skin grafting is best +used for ear and eyelid reconstruction. +RECONSTRUCTIvE SURGERy +Facial Reconstruction after Fracture +General Principles. +Con- +comitant injuries beyond the face are the rule rather than the +exception. +4 +1853 +P +LASTIC + +AND + R +ECONSTRUCTI +v +E + S +URGER +y +CHAPTER 45 +Mandible Fractures. +45-26). +45-27). +Operative repair involves seating of the +Figure 45-25. +A. +Congenital melanocytic nevus (CMN) of the posterior shoulder. +B. +Treatment of CMN of the posterior shoulder with tissue +expansion. +C. +Orbital Fractures. +Orbital fractures may +involve the orbital roof, floor, or lateral or medial walls. +Late complications include +persistent diplopia, enophthalmos, ectropion, and entropion. +Special mention should be made of two uncommon com- +plications after orbital fracture. +These include +cranial nerves III, IV, and VI, and the first sensory division of +cranial nerve V. +Zygoma and Zygomaticomaxillary Complex Fractures. +The zygoma forms the lateral and inferior borders of the orbit. +45-28). +Zygoma fractures +may involve the arch alone or many of its bony relationships. +Isolated arch fractures manifest as a flattened, wide face with +associated edema and ecchymosis. +Coronoid +process +Ramus +Angle +Body +Symphysis +Condyle +Figure 45-26. +Mandibular anatomy. +(Reproduced with permission +from Thornton J, Hollier L. +Facial fractures II: lower third. +Selected +Readings Plast Surg. +2002;9:1.) +I +IIIII +Figure 45-27. +Angle classification. +(Reproduced with permission from Thornton +J, Hollier L. +Facial fractures II: lower third. +Selected Readings +Plast Surg. +If comminution is severe, this may be achievable +using transnasal wiring of the ligaments. +Frontal Sinus Fractures. +The region of the frontal sinus is a +relatively weak structural point in the upper face. +For this rea- +son, it is a common location for fracture in facial trauma. +Treatment of a frontal sinus fracture +depends on the fracture characteristics (Fig. +45-29). +Nasal Fractures. +Closed reduction of nasal fractures may be performed under +local or general anesthesia. +Panfacial Fractures. +Fractures of multiple bones in various +locations fall into the category of panfacial fracture. +Next, the maxilla +may be reduced to this framework, followed by palatal fixation +if needed. +Reconstruc- +tive approach often is determined by the size and location of the +defect. +Small helical lesions may be simply excised as a wedge +and closed primarily. +Facial bone anatomy. +45-30). +45-31). +Healing by secondary intention is suc- +cessfully used in concavities such as the alar groove. +Composite grafts may be used +for the nasal tip or alar rim (see Fig. +45-3). +Axial pattern flaps are commonly used for +larger defects. +45-32). +Even larger defects may require +scalping flaps or free radial forearm flaps. +Split calvarial canti- +lever bone grafts may provide the nasal dorsum support. +Three layers of tissue form the upper and +lower lips: skin, muscle, and mucosa. +Lip defects can arise from trauma, burns, +neoplasms, congenital lesions, clefts, or infection. +CSF leak or +displaced +posterior wall? +Figure 45-29. +Algorithm for the treatment of frontal sinus fracture. +Cross-lip +flaps include the Abbé flap and the Estlander flap. +45-33). +The technique +requires a second-stage procedure for division of the pedicle. +45-34). +Figure 45-30. +Modified Antia-Buch ear reconstruction. +A. +Superior helix lesion. +B. +Excision pattern and reconstruction markings. +C. +Defect, +flap elevation, and cartilage reduction. +D. +V-Y advancement of the flap. +E. +Flap insetting. +F. +Appearance at 1 month after surgery. +(Photographs +reproduced with permission from M. +Nasal aesthetic subunits. +(Photograph reproduced +with permission from M. +Gimbel.) +Figure 45-32. +Nasal reconstruction with axial pattern flaps. +Top row: Nasolabial flap reconstruction of an alar defect. +Bottom row: Parame- +dian forehead flap reconstruction of the nasal lobule. +(Photographs reproduced with permission from M. +The eyelid blood supply is +robust, and ischemia is rarely a concern in reconstruction. +Upper Eyelid. +45-35). +45-36). +45-37). +Lower Eyelid. +Lower eyelid reconstruction considerations +parallel those for the upper eyelid. +Grafts may also +be used if the defect is partial thickness. +Eyelid ptosis is cre- +ated by derangement of this cooperative action. +Ptosis may be +congenital or acquired. +Other corrections of mild ptosis usually involve +variations on this procedure. +Severe ptosis with poor levator +Figure 45-33. +Abbé flap upper lip reconstruction. +A. +Defect and flap design. +B. +Rotation of the flap and primary closure of the donor site. +C. +Division of the pedicle (after 2 to 3 weeks) and final insetting. +Figure 45-34. +Webster-Bernard lip reconstruction technique. +(Reproduced with permission from Closmann JJ, Pogrel A, Schmidt +BL. +Reconstruction of perioral defects following resection for oral +squamous cell carcinoma. +J Oral Maxillofac Surg. +2006;64:367. +Copyright Elsevier.) +Figure 45-35. +Upper eyelid defect of <25%. +Primary closure. +(Reproduced with permission from Pham RT. +Reconstruction of the +upper eyelid. +Otolaryngol Clin North Am. +2005;38:1023. +Skull and Scalp Reconstruction +Scalp Reconstruction. +Upper eyelid defect of 25% to 50%. +A. +Lateral can- +thotomy. +B. +Semicircular flap. +(Reproduced with permission from +Pham RT. +Reconstruction of the upper eyelid. +Otolaryngol Clin +North Am. +2005;38:1023. +Copyright Elsevier.) + forehead and anterior scalp blood supply. +These vessels run +in the subcutaneous tissue layer, just superficial to the galea. +If a partial- +thickness defect is small enough, primary closure or skin graft +can be used. +Defects larger than 8 to +10 cm are best treated with microsurgical free tissue transfer. +45-38). +Calvarial Reconstruction. +Autogenous bone remains the +material of choice for reconstruction of skull defects. +Its advan- +tages include resistance to infection and ability to heal with +strength. +All autogenous bone sources have the disadvantage +of donor site morbidity. +Care must be taken during +harvest to avoid compromise of the inner table. +Rib bone may +also be used, either as a split-rib graft or as a microsurgical free +osseous flap. +Another disadvantage of bone grafts, although not flaps, is graft +resorption over time. +1861 +P +LASTIC + +AND + R +ECONSTRUCTI +v +E + S +URGER +y +CHAPTER 45 +Tumor-Ablative Surgery. +A +C +B +D +Figure 45-37. +Upper eyelid defect of >50%. +A and B. +Cutler-Beard full-thickness lower eyelid advancement flap. +C and D. +Hughes lower +eyelid tarsoconjunctival advancement flap. +(Reproduced with permission from Pham RT. +Reconstruction of the upper eyelid. +Otolaryngol Clin +North Am. +2005;38:1023. +The reconstructive surgeon +aims to restore lost anatomic components adequately. +Consequently, head and neck cancers that were +historically unresectable have become more operable. +Twenty-five-year-old woman with 70% scalp avulsion after a pedestrian-automobile accident. +Top row: Defect and specimen +intraoperatively. +Bottom row: Appearance 9 weeks after microsurgical scalp replantation. +(Photographs reproduced with permission from +M. +Gimbel.) +1863 +P +LASTIC + +AND + R +ECONSTRUCTI +v +E + S +URGER +y +CHAPTER 45 +respectively. +The primary goal is to protect the airway from aspiration. +Swal- +lowing and articulation are often suboptimal after total glos- +sectomy reconstructions. +However, for select patients, +osseointegrated dental implants offer a far superior alternative. +These can be secured into the neomandible, either at the time +of reconstruction (primarily; Fig. +For venous drainage, tributaries of the superficial and +deep jugular systems are convenient. +A. +Left parasymphyseal segmental mandibulectomy with contiguous +dentition and oral lining. +B. +C. +D. +E. +F. +G. +H and I. +(Photographs reproduced with permission from F. +Neural Techniques. +Grafting ideally is performed at the time of the injury rather than +in delayed fashion. +Donor nerves include the cervical plexus, +great auricular nerve, and sural nerve. +G +H +I +Figure 45-39. +This requires the availability of distal facial nerve or nerve +branch stumps. +The extent of +axonal regeneration through the graft is monitored using Tinel’s +test. +Ancillary Procedures. +Sling materials include tensor +fasciae latae, Gore-Tex, and human acellular dermal allograft. +Contralateral mimetic muscle hypertonicity is +tempered with botulinum toxin injections. +45-40). +One in eight women will develop breast cancer +sometime during their life. +Timing of Reconstruction. +In general, this allows +a more aesthetically pleasing and symmetric reconstruction. +Delayed breast reconstruction is initiated at least 3 to +6 months after mastectomy. +This approach avoids mastectomy +flap unreliability and radiation therapy unpredictability. +Partial Breast Reconstruction. +45-41). +The oncologic implications +of reusing the flap in this setting are unclear. +Implant-Based Reconstruction. +By necessity or patient +choice, many women undergo mastectomy for local control of +breast cancer. +45-42 and 45-43). +After +another few months, the nipple is reconstructed. +Implant breast +reconstructions tend to lack the natural breast feel and ptotic +appearance. +This is particularly noticeable in unilateral recon- +structions. +45-44). +No +No +No +Yes +Yes +Yes +Is direct nerve +repair possible? +Are proximal and distal +nerve stumps available? +No +Is a distal +stump available? +No +Is proximal +stump available? +No +No +Is patient healthy/young? +Is patient healthy/young? +Facial reanimation treatment algorithm. +1868 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +AB +CD +Figure 45-41. +(Photographs reproduced with permission from M. +Total Autologous Tissue Reconstruction. +The most commonly used donor site is the abdomen. +Bilateral tissue expander/implant–based breast reconstruction. +Appearance preoperatively (A) and 2 months after saline +implant exchange (B). +(Photographs reproduced with permission from M. +Gimbel.) +Figure 45-42. +Tissue expansion and implant-based breast recon- +struction. +(Illustrations reproduced with permission from M. +Gimbel.) +and deflation. +A. +Preoperative photo. +B. +(Photographs reproduced with permission from M. +Gimbel.) +1871 +P +LASTIC + +AND + R +ECONSTRUCTI +v +E + S +URGER +y +CHAPTER 45 +Figure 45-45. +Deep inferior epigastric perforator +flap breast reconstruction. +(Illustrations reproduced +with permission from M. +Gimbel.) +delivered into the mastectomy defect, where it is then shaped into +a breast mound. +The donor site is closed in a manner similar to +an abdominoplasty. +In addition, patients +are often pleased to have the incidental benefit of an abdomi- +noplasty. +The pedicled TRAM flap procedure is also relatively +quick for a total autologous reconstruction. +The ultimate muscle-sparing free TRAM +flap is the deep inferior epigastric perforator flap (Fig. +45-45). +45-46A,B). +Implant and Autologous Tissue Reconstruction. +It is often reserved for reconstructing breasts when other +methods have previously failed. +45-47). +45-48). +Accessory Procedures. +Scores of methods have been described for reconstructing the +nipple. +1872 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Radiation-Related Considerations. +To date, no prospective study has been performed +comparing the two approaches. +Thoracic Wall. +Furthermore, it protects the heart, lungs, +and great vessels from external trauma. +Reconstructions of chest +wall defects must emulate these functions. +Figure 45-46. +A. +Middle upper and lower panels: Muscle-sparing FTRAM flap and its donor site defect. +Right upper and lower panels: Deep inferior epigastric +perforator flap and its donor site defect. +B. +(Photographs reproduced with permission from M. +(Continued ) +turnover flap based on its internal mammary perforators. +Both +methods are useful in covering the sternum after dehiscence or +infection. +45-49). +The flap is based on the thoracodorsal vessels arising from the +subscapular system. +Use of this donor site is rela- +tively well tolerated, but shoulder weakness can be significant. +Figure 45-47. +(Photographs reproduced with permission from M. +Gimbel.) +Figure 45-48. +Latissimus dorsi flap/implant–based breast recon- +struction. +(Illustrations reproduced with permission from M. +Partial Defects of the Abdominal Wall. +Myofascial defects are more difficult to manage. +The ensuing +hernia is repaired later with prosthetics under cleaner conditions. +Figure 45-49. +(Photographs reproduced with permission from M. +Extremity Reconstruction +Posttraumatic Reconstruction. +Bony stabilization may be +critical to controlling fracture hemorrhage. +Doppler ultrasound +examination may help assess vascular integrity. +until definitive reconstruction is possible. +This applies also to +segmental bone losses within a soft tissue envelope of doubtful +viability. +Dead space is critical to obliterate, and this is more readily +achieved using muscle. +Coverage for +weight-bearing areas should be durable, stable (nonshearing), +and sensate. +Properly fitted footwear provides essential protec- +tion against pressure-related complications. +Split-thickness skin +grafts are reasonable for coverage of exposed healthy muscle or +soft tissue. +Local flaps may be used to cover smaller defects. +45-50). +Osteomyelitis often complicates inadequately débrided +compound leg fractures. +Delayed coverage also appears to +increase the risk of this dreaded complication. +Reconstruction after Oncologic Resection. +Diabetic Ulceration. +Altered foot +1878 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +FE +CD +AB +Figure 45-50. +A. +Soft tissue +defect with exposed tibial metaphysis after débridement. +Note the arterial handheld Doppler signal (red dot) around which the flap has been +designed. +B. +C. +Satisfactory flap perfusion following inset. +D. +F. +(Photographs +reproduced with permission from L. +Blunted pain allows cutaneous fissuring and ulcer- +ation to progress. +Multiflora infections are established amid +local immunodeficiency and microvasculopathy. +Frank neu- +roarthropathic Charcot’s foot deformities may ultimately +result. +Plain radiographs, MRI, nuclear bone scans, +and angiography or duplex imaging may be indicated. +Vacuum-assisted closure may be appropriate for +superficial defects. +Skin grafts should be used cautiously and +not in weight-bearing areas. +Lymphoscintigraphy reveals +the lymphatic anatomy and quantifies lymphatic flow. +MRI pro- +vides anatomic information regarding lymphatic trunks, nodes, +and obstructive lesions. +Identified genetic causes include the autosomal dominant + Milroy’s disease. +It is usually unilateral and limited to the +foot and calf. +Lymphedema tarda appears after the age of +35 years and is relatively rare. +This method +was later modified into multiple staged excisions of subcutaneous +tissues. +Prevention of pressure ulcers first requires identifica- +tion of susceptible patients. +Patients with stage III +or IV ulcers should be evaluated for surgery. +Unfortunately, these requirements remove most pressure ulcers +from skin graft candidacy. +The mainstay of deep pressure ulcer +reconstruction is coverage with well-vascularized local flaps. +Sacral decu- +biti are well treated with gluteus maximus myocutaneous flaps +(Fig. +45-51). +A common alternative is the gluteal fasciocu- +taneous advancement or rotational flap. +A good first-choice flap for +ischial wound reconstruction is the hamstring V-Y myocutaneous +flap. +The gluteus maximus flap may also be transposed inferiorly +to cover this wound. +It can be advanced superiorly or transposed +on its long arc of rotation (see Fig. +45-51). +Nutrition and muscle spasm control are +carefully maintained. +However, as with solid organ +transplantation, there remains the issue of allograft rejection. +The basic principles of immunosuppression for solid organ +Figure 45-51. +Flap reconstruction of pressure ulcers. +(Photographs reproduced with permission from M. +As with any surgical procedure, the benefits, success rate, +and complications must be understood. +Unlike solid organ trans- +plantation, CTA is not a lifesaving procedure. +45-52). +Optimally, a good cosmetic outcome will +be associated with a high level of patient satisfaction. +Depth of the nasolabial folds and the +presence of “marionette” lines on the chin should be noted. +Brow position should be evaluated, along with the distance +from brow to hairline. +Facial fat atrophy and +descent, a hallmark of facial aging, should be noted. +Figure 45-52. +Hemifacial composite tissue allotransplantation in a +rat model. +(Photographs reproduced with permission from K. +A strip of orbicularis muscle is often excised to +accentuate the supratarsal fold. +Fat deep to the orbital septum +is resected selectively. +In the lower lid, excess skin is removed +through a subciliary incision. +Lower eyelid fat may be either +excised or repositioned. +Complications can include hematoma, +lower lid retraction, and injury to ocular muscles. +If a hematoma +forms in the retro-orbital region, a true surgical emergency exists. +Permanent vision loss can occur if it is not immediately decom- +pressed. +The SMAS lies deep to the subcutaneous tis- +sue and contains the muscles of facial expression. +The facial +nerves are in a plane just deep to the SMAS. +The SMAS can +be simply plicated or a portion of it excised and closed. +45-54 and 45-55). +Injury to facial nerves, most often temporal +Figure 45-54. +Incisions for cervicofacial rhytidectomy. +A +B +C +D +E +F +Figure 45-53. +Incisions for browlift. +45-56) and the way in which altering +this framework will impact the appearance of the nose. +Nasal airway obstruction can occur from several +structural problems. +A deviated septum can severely impede air- +flow, as can problems with the internal nasal valve. +Airway obstruction +can be addressed surgically at the time of rhinoplasty. +Small tips can be augmented with cartilage grafts harvested +from septum or auricle (Fig. +45-57). +Assessment of skin tone is +1884 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +Figure 45-55. +Facelift. +A. +Preoperative appearance. +B. +Postoperative appearance. +Rhinoplasty anatomy. +If there is skin laxity in the +area to be treated, it may worsen after liposuction. +45-58). +Minimal tissue effects are seen when the can- +nula is stationary. +A major advance in the field of liposuction was the devel- +opment of tumescent local anesthesia. +Tumescent volumes may range from +one to three times the anticipated aspirate volume. +When general anesthesia is +used, the lidocaine dose may be reduced or even eliminated. +This can be done by centrifugation or filtering. +Figure 45-57. +Rhinoplasty. +A. +Preoperative appearance. +B. +Post- +operative appearance. +Figure 45-58. +A and B. +C. +Patient 3 +months after surgery. +1887 +P +LASTIC + +AND + R +ECONSTRUCTI +v +E + S +URGER +y +CHAPTER 45 +Abdominoplasty/Panniculectomy. +45-59). +Brachioplasty (Arm Lift). +Brachioplasty, or arm lift, leaves +a visible longitudinal scar on the upper arm. +Therefore, it is +reserved for patients with excessive skin in that region. +The +patient willing to accept the scar can be happy with the results. +Complications include distal seroma and wound separation. +Scar contracture in +the axilla may limit shoulder excursion in rare cases and require +revision. +Thigh and Buttock Lift. +The same scar can be continued all the +way around the back to lift the buttocks as well. +In cases of severe excess skin on the inner thighs, a long +vertical incision is necessary. +Blood loss during the procedure may necessitate +transfusion. +Nipple ptosis is graded by +the nipple position relative to the inframammary fold (IMF). +Grade 1 ptosis describes a nipple ≤1 cm below the IMF. +Grade 2 +ptosis describes a nipple 1 to 3 cm below the IMF. +Grade 3 +ptosis describes a nipple position >3 cm below the IMF. +In addition to classification of +Figure 45-59. +A. +Preoperative photo of 35-year-old woman after gastric bypass and massive weight loss. +B. +Patient 12 months after a fleur- +de-lis abdominoplasty. +The base width of the breast should also be considered. +Many +patients are found to have significant baseline asymmetries in +these measurements. +The planned new nipple position should be symmetrical +at the IMF along the breast meridian. +The pedicle is de-epithelialized to pre- +serve the subdermal vascular plexus. +Fig. +45-60 shows the classic +“keyhole” Wise pattern reduction technique. +Inferior pedicle reduction mammaplasty. +A. +Markings for Wise pattern reduction. +B. +Purple area is region to be de-epithelialized. +C. +Dark blue region is area to be resected. +A segment of the inferior pedicle is de-epithelialized. +Lateral and medial segments are resected. +After this is accomplished, the superior +flap is dissected to the clavicle. +Breast subcutaneous tissue and parenchyma are resected from the superior pole. +The vertical limbs are brought +together and to the meridian of the inframammary fold. +The nipple is then set in its new superior position. +D. +T-shaped incision on final closure. +1889 +P +LASTIC + +AND + R +ECONSTRUCTI +v +E + S +URGER +y +CHAPTER 45 +scar. +Fig. +45-61 shows a patient treated using this technique. +Fig. +Long-term +complications include inability to breastfeed and pseudopto- +sis, as mentioned earlier. +The principles are the same, how- +ever. +The skin envelope is contoured, and the nipple location +is optimized. +The Wise keyhole pattern can be used for larger skin +excisions. +Figure 45-61. +A and B. +C and D. +Patient 6 months after surgery. +Vertical reduction mammaplasty, Lejour technique. +A. +Markings for vertical reduction. +B. +Purple area is region to be + de-epithelialized. +C. +Dark blue region represents inferior pole to be resected. +The superior pedicle is de-epithelialized and dissected to the chest wall. +The tissue and +parenchyma from the inferior pole are resected. +The pillars from the lateral and medial segments are sewn together. +The nipple is transposed +on its pedicle to its new position. +D. +Closure of the vertical mammaplasty. +The implants may be placed in a subglandular or subpectoral +position (Fig. +45-64). +The next issue to consider is existing nipple position. +For more severe ptosis, +a concurrent mastopexy is necessary. +The implant compli- +cations are essentially all local. +At +that time, saline-filled implants were still allowed for general +cosmetic use. +For saline implants, this results in rapid deflation. +For +silicone gel implants, the rupture may be not be obvious and +can be confirmed by MRI. +Implant malpo- +sition can also distort the breast shape and require reoperation. +Displacement techniques can be used by the +mammographer to view the breast tissue. +Incisions for augmentation mammaplasty. +A, Infra- +mammary; B, axillary; C, periareolar. +Implant +BA +Pectoralis major +muscle +Figure 45-64. +Placement of breast implant. +A. +Subglandular. +B. +Subpectoral. +1. +Wilhelmi BJ, 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(discussion). +Plast Reconstr Surg. +1988;82:792-803. +38. +Wei FC, Chen HC, Chuang CC, et al. +Fibular osteosepto- +cutaneous flap: anatomic study and clinical application. +Plast Reconstr Surg. +1986;78:191-200. +39. +Wei FC, Santamaria E, Chang YM, et al. +J Craniofac Surg. +1997;8:512-521. +40. +Wei FC, Seah CS, Tsai YC, et al. +Fibula osteoseptocutaneous +flap for reconstruction of composite mandibular defects. +Plast +Reconstr Surg. +1994;93:294-304. +41. +Wei FC, Yazar S, Lin CH, et al. +Double free flaps in head and +neck reconstruction. +Clin Plast Surg. +2005;32:303-308. +42. +Wallace CG, Chang YM, Tsai CY, Wei FC. +Harnessing the +potential of the free fibula osteoseptocutaneous flap in man- +dible reconstruction. +Plast Reconstr Surg. +2010;125:305-314. +43. +Archibald S, Young JE, Thoma A. +Pharyngo-cervical esopha- +geal reconstruction. +Clin Plast Surg. +2005;32:339-346. +44. +Tate JR, Tollefson TT. +Advances in facial reanimation (review). +Curr Opin Otolaryngol Head 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+In: Mathes SJ, ed. +Plastic Surgery. +2nd ed. +Philadelphia: Elsevier; 2006:1403. +71. +Hinchliffe RJ, Andros G, Apelqvist J, et al. +Diabetes Metab Res Rev. +2012;28(Suppl 1):179-217. +72. +Fitzgerald O’Connor EJ, Vesely M, Holt PJ, et al. +Eur J Vasc Endovasc Surg. +2011;41:391-399. +73. +Szuba A, Rockson SG. +Lymphedema: anatomy, physiology, +and pathogenesis. +Vasc Med. +1997;2:321-326. +74. +Szuba A, Rockson SG. +Lymphedema: classification, diagnosis, +and therapy. +Vasc Med. +1998;3:145-156. +75. +Chung KC, Kim HJ, Jeffers LL. +Lymphangiosarcoma (Stewart- +Treves syndrome) in postmastectomy patients. +J Hand Surg +Am. +2000;25:1163-1168. +76. +Warren AG, Brorson H, Borud LJ, et al. +Lymphedema: a com- +prehensive review. +Ann Plast Surg. +2007;59:464-472. +77. +Beahm EK, Walton RL, Lohman RF. +Vascular insufficiency +of the lower extremity: lymphatic, venous, and arterial. +In: +Mathes SJ, ed. +Plastic Surgery. +2nd ed. +Philadelphia: Elsevier; +2006:1455. +78. +Brorson H, Svensson H, Norrgren K, et al. +Lymphology. +1998;31: +156-172. +79. +O’Brien BM, Mellow CG, Khazanchi RK, et al. +Plast Reconstr Surg. +1990;85:562-572. +80. +Salgado CJ, Mardini S, Spanio S, Tang WR, Sassu P, Chen +HC. +Radical reduction of lymphedema with preservation of +perforators. +Ann Plast Surg. +2007;59:173-179. +81. +Demirtas Y, Ozturk N, Yapici O, et al. +J Reconstr Microsurg. +2010;25:137-143. +82. +Black J, Baharestani MM, Cuddigan J, et al. +National Pressure +Ulcer Advisory Panel’s updated pressure ulcer staging system. +Adv Skin Wound Care. +2007;20:269-274. +83. +Sorensen JL, Jorgensen BJ, Gottrup F. +Surgical treatment of +pressure ulcers. +Am J Surg. +2004;188:42S. +84. +Hettiaratchy S, Randolph MA, Petit F, et al. +Composite tissue +allotransplantation—a new era in plastic surgery? +Br J Plast +Surg. +2004;57:381-391. +85. +American Medical Association. +H-475.992 Definitions of +“Cosmetic” and “Reconstructive” Surgery. +Chicago: American +Medical Association; 2002. +86. +Paul MD. +The evolution of the brow lift in aesthetic plastic +surgery. +Plast Reconstr Surg. +2001;108:1409-1424. +87. +Thorne CM, Aston SG. +Aesthetic surgery of the aging face. +In: +Aston SG, Beasley RW, Thorne CH, eds. +Grabb and Smith’s +Plastic Surgery. +5th ed. +Philadelphia: Lippincott–Raven +Publishers; 1997:633. +88. +Sheen JH. +Aesthetic Rhinoplasty. +St. +Louis: Mosby; 1987. +89. +Rubin JP, Bierman C, Rosow CE, et al. +Plast +Reconstr Surg. +1999;103:990-996. +1894 +SPECIFIC CONSIDERATIONS +UNIT II +PART II +90. +Iverson RE, Lynch DJ. +Practice advisory on liposuction. +Plast +Reconstr Surg 2004;113:1478-1490. +91. +Ramirez OM. +Abdominoplasty and abdominal wall reha- +bilitation: a comprehensive approach. +Plast Reconstr Surg. +2000;105:425-435. +92. +Courtiss EH, Goldwyn RM. +Reduction mammaplasty by the infe- +rior pedicle technique. +Plast Reconstr Surg. +1977;59:500-507. +93. +Lassus C. +A 30-year experience with vertical mammaplasty. +Plast Reconstr Surg 1996;97:373-380. +94. +Lejour M. +Vertical mammaplasty without inframammary +scar and with breast liposuction. +Perspect Plast Surg. +1990;4: +369-379. +95. +Tebbetts JB. +Plast Reconstr Surg. +2002;109:1396-1409. +96. +Hidalgo DA. +Breast augmentation: choosing the optimal +incision, implant, and pocket plane. +Plast Reconstr Surg. +2000;105:2202-2216. +97. +U.S. +Food and Drug Administration. +Breast implants home +page, 2006. +Available at: http://www.fda.gov/cdrh/breastim- +plants/index.html. +Accessed January 15, 2008. +98. +Allergan saline-filled breast implants (package insert). +Santa +Barbara: Allergan; 2007. +99. +Allergan silicone-filled breast implants (package insert). +Santa Barbara: Allergan; 2007. +100. +Miglioretti DL, Rutter CM, Geller BM, et al. +Effect of breast +augmentation on the accuracy of mammography and cancer +characteristics. +JAMA. +2004;291:442-450. +101. +Braunstein GD. +Gynecomastia. +N Engl J Med. +1993;328: +490-495. +Anesthesia for the Surgical Patient +Robert S. +Charles Darwin, who witnessed two such +operations, “rushed away before they were completed. +Wells never recovered from +his humiliating experience and eventually committed suicide. +Diethyl ether had been +known for over 800 years but was not used for analgesic pur- +poses. +The First Anesthesiologists +John Snow (1813–1858) made science out of the art of anesthesia. +2 The role of the anesthesiologist has expanded to become the +perioperative physician. +Lundy +directed the department of anesthesiology at the Mayo Clinic for +28 years. +He successfully produced halothane in 1953. +Curare, a nondepo- +larizing muscle relaxant, was popularized by Harold Griffith of +Montreal. +It is what the body does to the drug. +It +relates to absorption, distribution, metabolism, and elimination. +Administration, Distribution, Metabolism, and Elimination. +Distribution is the delivery of a drug from the systemic +circulation to the tissues. +• Plasma protein and tissue binding. +Many drugs bind to +circulating proteins like albumin, glycoproteins, and glob- +ulins. +Metabolism is the permanent breakdown of original +compounds into smaller metabolites. +This is why an oral dose of a drug often +must be much higher than an equally effective IV dose. +It is important to remember that the response to drugs var- +ies widely. +This will be +discussed later in the Future Direction of Anesthesia section +on proteomics. +It is what the drug does to the body. +An agonist is +a drug that causes a response. +The efficacy of any therapeutic +agent is its power to produce a desired effect. +Two drugs may +have the same efficacy but different potencies. +If the ED50b equals 4 and the +ED50a equals 0.4, then drug a is 10 times as potent as drug b. +For example, 10 mg of morphine produces analgesia equal to +that of 1 mg of hydromorphone. +They are equally effective, but +hydromorphone is 10 times as potent as morphine. +The term dose only applies to the amount +administered and not the actual concentration. +A basic dose-response curve is +shown in Fig. +46-1. +The lethal dose (LD50) of a drug produces death in 50% +of animals to which it is given. +Basic dose-response curve. +Response +Log (Dose) +effective dose, LD50/ED50, is the therapeutic index. +ANESTHETIC AgENTS +Anesthesia can be local, regional, or general (Table 46-1). +The science and art of anesthesia are dynamic processes. +They include barbiturates, benzodiaz- +epines, propofol, etomidate, and ketamine. +Barbiturates The most common barbiturates are thiopental, +thiamylal, and methohexital. +They produce a rapid, smooth +induction within 60 seconds, and wear off in about 5 minutes. +It can be used +as a continuous infusion for sedation in the intensive care unit +setting. +Propofol is an irritant and frequently causes pain on +injection. +Fre- +quently used IV benzodiazepines are diazepam, lorazepam, and +midazolam. +The +benzodiazepines are excellent anticonvulsants and only rarely +cause allergic reactions. +Etomidate Etomidate is an imidazole derivative used for IV +induction. +Its rapid and almost complete hydrolysis to inactive +metabolites results in rapid awakening. +Like the above IV agents, +etomidate acts on the GABA receptor. +It is a dissociative anesthetic, producing a cataleptic +gaze with nystagmus. +Patients may associate this with delirium +and hallucinations while regaining consciousness. +The addi- +tion of benzodiazepines has been shown to prevent these side +effects. +Analgesia. +Thus, there is no completely safe opi- +oid analgesic. +Recovery is within minutes, but there +is little residual postoperative analgesia. +Naloxone and the longer-acting naltrexone are pure opi- +oid antagonists. +Unlike the μ-receptor agonists, ketamine supports respiration. +Intraoperative use of ketoro- +lac reduces postoperative need for opioids. +COX-2 is induced by inflammatory reactions to +produce more prostaglandins. +Side effects are +hypotension and bradycardia. +Neuromuscular Blocking Agents. +There is one commonly used depolarizing neuromuscu- +lar blocker—succinylcholine. +Unlike other +neuromuscular blocking agents, the effects of succinylcholine +cannot be reversed. +First-degree family +members should also be tested. +There are several competitive nondepolarizing agents +available for clinical use. +The longest acting is pancuronium, +which is excreted almost completely unchanged by the kid- +ney. +Anesthesiology and pain management. +In: Mulholland MW et al, eds. +Greenfield’s Sur- +gery: Scientific Principles and Practice. +4th ed. +Philadelphia: Lippincott Williams & Wilkins; 2006:271. +1902 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +down acetylcholine. +Inhalational Agents. +Minimum alveolar concentration (MAC) is a measure of +anesthetic potency. +The higher the MAC, the less potent an agent is. +Sevoflurane and desflurane are the two most recently +introduced inhalational agents in common use. +Source: Adapted with permission from Rutter TW, Tremper KK. +Anesthesiology and pain management. +In: Mulholland MW et al, eds. +Greenfield’s Sur- +gery: Scientific Principles and Practice. +4th ed. +Philadelphia: Lippincott Williams & Wilkins; 2006:270. +depolarizing agent succinylcholine, are triggering agents for +malignant hyperthermia. +Table 46-3 lists the advantages and +disadvantages of each agent. +Amides. +Ropivacaine is the most recently introduced local anes- +thetic. +All amides are +95% metabolized in the liver, with 5% excreted unchanged by +the kidneys. +Esters. +Cocaine is a Schedule II drug. +Tetracaine has a long duration and is +useful as a spinal anesthetic for lengthy operations. +Benzocaine +is for topical use only. +The esters are hydrolyzed in the blood +by pseudocholinesterase. +Properties, absorption, and disposition of local anesthetic agents. +In: Cousins MJ, +Bridenbaugh PO, eds. +Cousins and Bridenbaugh’s Neural Blockade in Clinical Anesthesia and Pain Medicine. +4th ed. +Philadelphia: Lippincott Williams & +Wilkins; 2009:49. +Toxicity manifests first in the more sensitive CNS and then +the cardiovascular system. +Central Nervous System Toxicity. +Slurred speech, seizures, and uncon- +sciousness follow. +Cardiovascular System Toxicity. +Bupivacaine is more cardiotoxic than other local anes- +thetics. +Calculation of the toxic dose before injection is impera- +tive. +It is helpful to remember that for any drug or solution, +1% = 10 mg/mL. +For lidocaine in the +same patient, the calculation is 50 kg × 5 mg/mL = 250 mg toxic +dose. +If a 1% solution is used, the allowed amount would be 250 +mg/10 mg/mL = 25 mL. +Additives to Local Anesthetics. +Epinephrine has one physi- +ologic and several clinical effects when added to local anes- +thetics. +Central +Peripheral Nerve Blocks. +Risks of +peripheral regional nerve blocks are dependent on their location. +Central Nerve Blocks: Spinal and Epidural. +Spinal and epidural +anesthesia block the spinal nerves as they exit the spinal cord. +Spinal nerves are mixed nerves; they contain motor, sensory, +and sympathetic components. +The level of injec- +tion is usually below L1 to L2, where the spinal cord ends in +most adults. +Epinephrine as an additive to the +local anesthetic will significantly prolong the blockade. +Indwell- +ing spinal catheters are no longer used. +Complications are similar to those of spinal anesthesia. +A careful review of major organ systems and +their function also should be performed. +Specific areas +to investigate are shown in Table 46-5. +Textbook of Anesthesia. +4th ed. +New York: Churchill +Livingstone; 2001:288. +Copyright Elsevier. +this chapter). +The ASA scale remains useful and should be applied to all +patients during the preoperative visit. +Evaluation of the Airway. +Mallampati Classification. +The Mallampati classification (Fig. +Consideration of Patients with Comorbidities. +Optimal anesthesia extends beyond +pharmacology and technical procedures. +Ischemic Heart Disease. +Additionally, the prob- +lem may be an increase in myocardial O2 demand (tachycar- +dia). +Reduction achieved +via decreased dietary fat or pharmacotherapy reduces risk. +High-density lipoprotein cholesterol is +protective. +Although definitely a risk factor, hypertension alone prob- +ably does not cause plaques. +Smoking causes endothelial damage, and therefore promotes +plaque thrombosis. +Cessation greatly reduces the risk of CAD. +The Mallampati + classification. +Other Risk Factors. +Reduction of levels by folate therapy may be beneficial. +Pulmonary Disease. +Chronic pulmonary disease has developed +into a worldwide public health problem. +Infection, noxious particles, and gases can exacerbate +COPD. +Renal Disease. +Prehydration and the depth of anesthesia may influ- +ence the renal response to anesthesia. +Hepatobiliary Disease. +The coexisting presence of liver disease may influence +the selection of volatile anesthetics. +Halothane is the anesthetic +most studied regarding possible hepatotoxicity. +Sevoflurane does not yield any +trifluoroacetylated metabolites and is unlikely to cause hepatitis. +An estimated 15 to 20 million adults in the United States have +biliary tract disease. +High intra-abdominal pressure may +increase the risk of passive reflux of gastric contents. +Tracheal +intubation with a cuffed tube is advised to minimize the risk of +pulmonary aspiration. +1908 +SPECIFIC CONSIDERATIONS +UNIT II +UNIT II +PART + +II +Metabolic and Endocrine Disease. +Metabolic and endocrine +disorders encompass a wide range of diseases. +Patients +with a BMI >28 kg/m2 have increased perioperative morbidity +over the general population. +Obesity in anaesthesia and intensive care. +Br J Anaesth. +2000;85:91. +By permission of Oxford University Press. +The impact of obesity on the pharmacokinetics of anes- +thetic drugs is variable. +For intracranial tumors, the mass +effect of the tumor makes control of ICP and CBF critical. +Regardless of the drugs or technique selected, maintenance +of stable hemodynamics is optimal. +46-3). +• Preoxygenate the patient. +• Rapidly introduce an IV induction agent (e.g., propofol). +Figure 46-3. +Techniques for the induction +of general anesthesia. +46-4). +The LMA is a cuffed oral airway that sits in the orophar- +ynx. +Because it does not pass +through the vocal cords, it does not fully protect against aspi- +ration. +It should not be used in patients with a full stomach +(Fig. +46-5; lower left). +The accurate placement of an endotracheal +tube requires skill and proper equipment and conditions. +To obtain a direct line of sight, the patient is placed in the +sniffing position. +The neck is flexed at the lower cervical spine +and extended at the atlanto-occipital joint. +This flexion and exten- +sion are amplified during laryngoscopy. +46-5, top row). +Several devices have +been developed to assist in management of the difficult airway. +46-6). +From left to right: two +nasal airways and three oral airways. +NASAL AIRWAYS ORAL AIRWAYS +Figure 46-5. +(Top) Laryngoscopes with curved straight blades. +well as facilitate tracheal intubation with an endotracheal tube. +46-8). +The flexible fiberoptic intubation scope is the gold stan- +dard for difficult intubation. +The scope is constructed of +fiberoptic bundles and cables encased in a sheath. +There is a port for suction +and/or insufflation of O2. +It requires skill for proper use, is expensive, +and requires careful maintenance (Fig. +46-9). +The ASA has developed algorithms for management of the +difficult airway (Figs. +Figure 46-6. +The Bullard rigid fiber- +optic laryngoscope with endotracheal +tube. +Figure 46-7. +Video laryngoscope showing view of vocal cords. +The colloids contain a +complex sugar or protein suspended in an electrolyte solution. +A further distinction between IV fluid types may be based on +the nature of the solution. +Food +and Drug Administration are the 6% high molecular weight +(450 kDa) formulations. +HES 450/NS may +be associated with more bleeding than other fluids. +Intubating laryngeal +mask airway with endotracheal tube. +Figure 46-9. +Flexible fiberoptic +intubation scope with endotracheal +tube. +1913 +A +NESTHESIA + +FOR + +THE + S +UR +g +ICAL + P +ATIENT +CHAPTER 46 +Figure 46-10. +American Society of Anesthesiologists airway management algorithm, Part I. +CO2 = carbon dioxide. +Anesthesiology. +American Society of Anesthesiologists airway management algorithm, Part II. +CO2 = carbon dioxide. +Anesthesiology. +Transfusion of Red Blood Cells +ABO Blood groups. +ABO-Incompatible Red Cell Transfusion. +This activates the com- +plement pathways, which damages the red cell membranes and +lyses the RBCs. +The patient +suffers acute renal failure and disseminated intravascular +coagulation. +Basics of Red Blood Cell Compatibility. +Ensuring that +the right blood group is transfused is imperative. +It is essen- +tial to ensure that no ABO-incompatible RBC transfusion is +ever given. +This avoidable accident is likely to kill or harm +the patient. +Physiologic Response and Tolerance of Anemia. +Adult Hb consists of four protein chains, each carrying +one heme group. +One mole of Hb is able to bind to a maxi- +mum of 4 moles of O2. +O2-binding capacity per gram of Hb is +1.39 g/mL. +The relationship between Pao2 and Hb O2 satura- +tion is shown in Fig. +46-12. +Tissue Po2 values of different organs are also shown +in Fig. +46-12 and lie on this steep part of the curve, facilitating +O2 release from Hb. +Hemodilution and Critical Hematocrit. +Collected blood is reinfused after +major blood loss has ceased, or sooner, if indicated. +Blood units +are reinfused in the reverse order of collection. +The critical hematocrit has been a source of debate for many +years. +The most commonly +used agents are neostigmine, pyridostigmine, and edrophonium. +Figure 46-12. +Oxygen hemoglobin dissociation curve. +O2 = + oxygen; Po2 = partial pressure of oxygen. +The name “recov- +ery room” has been changed to postanesthetic care unit (PACU). +The culture of +acceptance of postoperative pain is changing. +This approach may improve the efficacy of pain treatment. +Many departments of anesthesiology support an active pain +Figure 46-13. +Algorithm for the management of postoperative +nausea and vomiting (PONV). +Anesth Analg. +Nerve blocks can be of the upper or lower +extremities, truncal, epidural, or paravertebral (Fig. +46-14). +46-19). +46-20–46-22). +Figure 46-14. +Use of ultrasound to identify the popliteal nerve for +analgesia of the ankle. +1917 +A +NESTHESIA + +FOR + +THE + S +UR +g +ICAL + P +ATIENT +CHAPTER 46 +Figure 46-15. +Kidney transplant recipient incisions. +Figure 46-16. +Inguinal hernia incisions. +Figure 46-17. +Laparoscopy incisions. +Figure 46-18. +Pain from these incisions is reduced by transversus +abdominal plane block. +Figure 46-19. +The use of ultrasound to perform a transversus +abdominal plane block. +External oblique +Internal oblique +Transversus abdominus +Figure 46-21. +Ultrasound view of external oblique, internal +oblique, and transversus abdominis muscles. +External oblique +Internal oblique +Local anesthestic +Transversus abdominus +Needle tip +Figure 46-22. +Ultrasound image of local anesthetic above the +transversus abdominis. +A genetic +predisposition and one or more triggering agents are necessary +to evoke MH. +MH can be diagnosed with the caffeine-contracture halo- +thane test (which requires muscle biopsy). +A rise +in temperature is often a late sign of MH. +Treatment must be +aggressive and begin as soon as a case of MH is suspected: +• Call for help. +• Stop all volatile anesthetics and give 100% O2. +• Hyperventilate the patient up to three times the calculated +minute volume. +• Give bicarbonate to treat acidosis if dantrolene is ineffective. +• Treat hyperkalemia with insulin, glucose, and calcium. +• Avoid calcium channel blockers +• Begin infusion of dantrolene sodium, 2.5 mg/kg IV. +Repeat +as necessary, titrating to clinical signs of MH. +• Call the MH hotline to report the case and get advice: 1-888- +274-7899. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Darwin F, Darwin C. +The Autobiography of Charles Darwin. +Kallista, Victoria, Australia: Totem Books; 2003:12. +2. +Calverly RK. +Anesthesia as a specialty: past, present, and +future. +In: Barash PG, Cullen BF, Stoelting RK, eds. +Clinical +Anesthesia. +Philadelphia: Lippincott-Raven; 1996:6. +3. +Bigelow HJ. +Insensibility during surgical operations produced +by inhalation. +Boston Med Surgical J. +1846;35:356. +4. +Vandam LD. +History of anesthetic practice. +In: Miller RD, +ed. +Anesthesia. +Philadelphia: Churchill Livingstone; 2000:7. +5. +Meade RH. +An Introduction to the History of General Surgery. +Philadelphia: WB Saunders Co; 1968:78. +6. +Rushman GB, Davies NJH, Atkinson RS. +A Short History of +Anaesthesia. +Oxford: 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Siemons AW, Baus D, et al. +Can J Anaesth. +2000;47:1207-1215. +58. +Cittanova ML, Leblanc I, Legendre C, et al. +Lancet. +1996;348:1620-1622. +59. +Schortgen F, Lacherade JC, Bruneel F, et al. +Lancet. +2001;357: +911-916. +60. +Elhakim M, el-Sebiae S, Kaschef N, et al. +Intravenous fluid +and postoperative nausea and vomiting after day-case termina- +tion of pregnancy. +Acta Anaesthesiol Scand. +1998;42:216-219. +61. +Gan TJ, Soppitt A, Maroof M, et al. +Anesthesiology. +2002;97:820-826. +62. +Yogendran S, Asokumar B, Cheng DC, et al. +Anesth Analg. +1995;80:682-686. +63. +Williams EL, Hildebrand KL, McCormick SA, et al. +Anesth Analg. +1999;88:999-1003. +64. +Vogt NH, Bothner U, Lerch G, et al. +Anesth Analg. +1996;83:262-268. +65. +Vogt N, Bothner U, Brinkmann A, et al. +Anaesthesia. +1999;54:121-127. +66. +Lang K, Boldt J, Suttner S, et al. +Anesth Analg. +2001;93:405-409. +67. +Marik PE, Iglesias J, Maini B. +J Crit Care. +1997;12:51-55. +68. +Virgilio RW, Rice CL, Smith DE, et al. +Crystalloid vs. +col- +loid resuscitation: is one better? +A randomized clinical study. +Surgery. +1979;85:129-139. +69. +Hoeft A, Wietasch JK, Sonntag H, et al. +Theoretical limits of +“permissive anemia.” Zentralbl Chir. +1995;120:604-613. +70. +Hines R, Barash PG, Watrous G, et al. +Complications occur- +ring in the postanesthesia care unit: a survey. +Anesth Analg. +1992;74:503-509. +71. +Watcha MF, White PF. +Postoperative nausea and vomit- +ing. +Its etiology, treatment, and prevention. +Anesthesiology. +1992;77:162-184. +72. +Camu F, Lauwers MH, Verbessem D. +Incidence and aetiol- +ogy of postoperative nausea and vomiting. +Eur J Anaesthesiol. +1992;9:25-31. +73. +Gan TJ, Meyer T, Apfel CC, et al. +Consensus guidelines for +managing postoperative nausea and vomiting. +Anesth Analg. +2003;97:62-71. +74. +Sun R, Klein KW, White PF. +Anesth Analg. +1997;84:331-336. +75. +Henzi I, Walder B, Tramer MR. +Br J Anaesth. +1999;83:761-771. +76. +Kehlet H, Dahl JB. +The value of “multimodal” or “balanced +analgesia” in postoperative pain treatment. +Anesth Analg. +1993;77:1048-1056. +77. +Gorocs TS, Lambert M, Rinne T, Krekler M, Modell S. +Int J Clin Pract. +2009;63:112-120. +78. +Sun T, Sacan O, Whit PF, et al. +Perioperative vs. +postopera- +tive celecoxib on patient outcome after major plastic surgery +procedures. +Anesth Analg. +2008;106:950-958. +79. +De Oliveira GS, Agarwal D, Benzon HT. +Anesth Analg. +2012;114:424-433. +80. +Coloma M, Duffy LL, White PF, Kendall Tongier W, Huber +PJ Jr. +Dexamethasone facilitates discharge after outpatient +anorectal surgery. +Anesh Analg. +2001;92:85-88. +81. +Clarke H, Pereira S, Kennedy D, et al. +Pain Res Manage. +2009;14:217-222. +82. +Agarwal A, Gautam S, Gupta D, et al. +Br J Anaesth. +2008;101:700-704. +83. +Buvanendran A, Kroin JS. +Multimodal analgesia for con- +trolling acute postoperative pain. +Curr Opin Anaesthesiol. +2009;22:588-593. +84. +Chetwood A, Agrawal S, Hrouda D, Doyle P. +Anaesthesia. +2011;66:317-318. +85. +Heil JW, Ilfeld BM, Loland VJ, Sandhu NS, Mariano ER. +Reg Anesthes Pain Med. +2010;35:556-558. +86. +McDonnell JG, Laffey JG. +Transversus abdominis plane +block. +Anesthes Analg. +2007;105:883. +87. +Bharti N, Kumar P, Bala I, Gupta V. +Anesthes Analg. +2011;112:1504-1508. +88. +Mukhtar K, Khattak I. +Transversus abdominis plane blocks for +renal transplant recipients. +Br J Anaesth. +2010;104:663-664. +89. +Rosenberg H, Davis M, James D, Pollock N, Stowell K. +Malignant hyperthermia. +Orphanet J Rare Dis. +2007;2:21 +90. +Atkins JH, Johansson JS. +Anesth Analg. +2006;102:1207-1216. +91. +Orser BA, Mazer CD, Baker AJ. +Awareness during anesthesia. +CMAJ. +2008;178:185-188. +92. +Tennant F. +Interpretations and actions following cytochrome +P450 testing. +Practical Pain Manage. +2013;47-50. +This page intentionally left blank +Surgical Considerations +in the Elderly +Rosemarie E. +Hardin and Michael E. +The U.S. +It is, therefore, an accurate predictor of postoperative +morbidity and mortality. +The “young old patient” may lead an active lifestyle with few, +if any, comorbid conditions. +An important criterion in the geriatric surgery patient is +the frailty score. +Prior to +surgery,frailpatients and their family members should be aware +of this possibility. +Therefore, the frailty score is a more accurate +representation of the patient’s physiologic age. +The physiologic changes of aging are summarized in Table 47-1. +The terms “frailty,” “disability” and “comorbidity” have +mistakenly been used interchangeably. +These terms have very +different connotations for the geriatric patient. +They include +identification of geriatric syndromes, frailty indicators. +•    Adjust drug dosages for volume of  +distribution. +•    Ensure effective pain relief to allow  +mobilization, deep breathing. +•  Minimize use of nasogastric tubes. +•    Fever may be absent despite serious  +infection, especially in frail elderly. +•    Use vigorous fluid resuscitation to  +achieve optimal ventricular filling. +•    Be aware of hypothermia in trauma  +resuscitation. +•    Adjust drug dosages as appropriate for  +altered pharmacokinetics. +Source: Reproduced with permission from Watters JM: Surgery in the elderly. +Can J Surg 45:106, 2002. +© 2002 Canadian Medical Association. +47-1. +Older individ- +uals fail to augment heart rate to the same extent as younger +individuals. +ASA = American Society of Anesthesiologists. +Is elderly patient an +acceptable surgical risk? +No +Is disease state immediately + life threatening? +No +Observe with symptom +management (i.e. +• Pulmonary reserve? +• Renal reserve? +Can quality of life +be maintained? +It is estimated +that humans lose 35 mL of their FEV1 per year over the age +of 35 years old. +Screen- +ing spirometry can be performed to determine forced vital +capacity and FEV1. +Renal complications are also increased in elderly surgi- +cal patients in the perioperative period. +Renal size and volume +decrease with age, accompanied by intrarenal vascular changes. +The +etiology of this postoperative cognitive dysfunction may be mul- +tifactorial. +Finally, dementia is a +known predictor of poor long-term survival. +47-2). +Screen the patient for depression. +Identify the patient’s risk factors for developing postoperative +delirium. +Screen for alcohol and other substance abuse/dependence. +Document functional status and history of falls. +Determine baseline frailty score. +Monitor for +polypharmacy. +Determine patient’s family and social support system. +Order appropriate preoperative diagnostic tests focused on +elderly patients. +Figure 47-2. +Checklist of questions to be used during assessment +of geriatric patient. +(From Chow WB et al1 with permission from Elsevier. +The average survival of these patients is approximately 1.5 to +2 years. +Elderly patients require surgery for mitral valve disease +when ischemic regurgitation is present. +This increases the +morbidity and mortality from surgical intervention. +Neurologic complications from valve +surgery are particularly common in elderly patients. +1. +2. +3. +Respect patient autonomy: right to accept and refuse +treatment despite consequences of decision. +•   Ensure mental competency before establishing  +autonomy. +•   May appoint surrogate decision maker in case of  +incapacitation. +Elderly patients are at increased risk from bleeding-associated +anticoagulation complications. +A useful treat- +ment algorithm is provided in Fig. +47-3. +(Reproduced with permission from Balducci L, Beghe C. +Cancer Control. +Journal of +the Moffitt Cancer Center. +curative) is appropriate. +People with <5 years of life expectancy are unlikely +to benefit from screening. +3.8%, respectively). +Bowel obstruction +can be relieved with intestinal bypass or a diverting colostomy. +This would limit the benefit of screening in aged +populations with limited life expectancy. +For example, +in healthy men and women aged 75 to 79 years old, the NNS +was 50. +This can increase to as high as +18 months with palliative chemotherapy and radiation. +The +same holds true for chemotherapy and radiation. +Falls currently account for 20% of +severe injuries in elderly patients. +First, physiologic reserve can be challenged by trauma. +For example, previously unknown disease such as cardiac impair- +ment may be acutely unmasked. +47-4. +Warfarin therapy may be used +Figure 47-4. +Massive intracranial hemorrhage resulting from +seemingly minor trauma. +She expired from her intracra- +nial wounds. +(Photo used with permission of Dany Westerband, +MD, Suburban Hospital, Bethesda, MD). +in patients with atrial fibrillation, DVT, and prosthetic heart +valves. +Pressures up to 20 mmHg are associated with +increased filling pressures and cardiac output. +47-5). +Figure 47-5. +Comorbidities included severe aortic +stenosis. +The rest of the small +intestine and colon were inspected, all of which were viable. +A local +resection was performed, and the patient recovered quickly. +The most com- +mon complication following EVAR in elderly patients is renal +impairment. +EVAR remains a +viable option in elderly patients. +THYROID SURGERY +The prevalence of thyroid disease increases with advancing +age. +Age is also a prognostic indicator for patients with fol- +licular carcinoma. +There often is a sig- +nificant improvement in mental status after parathyroidectomy. +One study demonstrated that preoperative +Figure 47-6. +The half-life of +intact PTH is approximately 3 to 4 minutes. +REFERENCES +Entries highlighted in bright blue are key references. +1. +J Am Coll +Surg. +2012 Oct;215(4)453-466, doi: 10.1016/j.jamcollsurg. +2012.06.017. +Epub 2012 Aug 21. +2. +Jaklitsch MT, Bueno R, Swanson SJ, et al. +New surgical options +for elderly lung cancer patients. +Chest. +1999;116:480S-485. +3. +Asmis TR, Ding K, Seymour L et al. +Age and comorbidity +as independent factors in the treatment of 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MR (eds). +Principles +and Practice of Geriatric Surgery. +2nd ed. +New York: +Springer-Verlag; 2011. +43. +Biebl M, Lau LL, Hakaim AG, et al. +J Vasc Surg. +2004;40:435-442. +44. +Morales JP, Irani FG, Junes KG, et al. +Endovascular repair of a +ruptured aortic aneurysm under local anesthesia. +Brit J Radiol. +2005;78:62-64. +45. +McConahey WM, Hay ID, Wodner LB, et al. +Mayo Clin Proc. +1986;61:978-996. +46. +Mueller-Gaertner H, Brzac HT, Rehpenning W. +Prognostic +indices for tumor relapse and tumor mortality in follicular +thyroid carcinoma. +Cancer. +1991;67:1903-1911. +47. +Irvin GL, Carneiro DM. +“Limited” parathyroidectomy in geri- +atric patients. +Ann Surg. +2001;233:612-616. +48. +Sheldon DG, Lee FT, Neil NJ, Ryan JA Jr. +Surgical treatment +of hyperparathyroidism improves health related quality of life. +Arch Surg. +2002;137:1022-1026. +49. +O’Connell JB, Maggard MA, Ko CY. +Cancer-directed surgery +for localized disease: decreased use in the elderly. +Ann Surg +Oncol. +2004;11(11):962-969. +50. +Sullivan DJ, Hansen-Flaschen J. +Termination of life support +after major trauma. +Surg Clin North Am. +2000;80:1055-1066. +51. +Hinshaw DB, Carnahan JM, Johnson DL. +Depression, anxiety, and +asthenia in advanced illness. +J Am Coll Surg. +2002;195:271-277. +52. +Dunn GP, Milch RA, Mosenthal AC, et al. +Palliative care by +the surgeon: how to do it. +J Am Coll Surg. +2002;194:509-537. +53. +Conner SR. +Hospice: Practice, Pitfalls, and Promise. +Washington: Taylor and Francis;1988. +54. +Sheehan DC, Forman WB:.Hospice and Palliative Care Con- +cepts and Practice. +Boston: Jones and Bartlett;1996. +55. +Breen CM, Abernethy AP, Abbott KM, et al. +Conflict associ- +ated with decisions to limit life-sustaining treatment in inten- +sive care units. +J Gen Intern Med. +16:283-289. +This page intentionally left blank +Ethics, Palliative Care, and Care +at the End of Life +Daniel E. +Hall, Peter Angelos, Geoffrey P. +Dunn, +Daniel B. +Hinshaw, and Timothy M. +Pawlik +48 + Dedicated to the advancement of surgery along its scientific and +moral side. +The capacity to choose wisely in such +circumstances is the challenge of surgical practice. +The history of medical ethics has its origins in antiquity. +However, the +principles themselves do not resolve ethical dilemmas. +Choosing wisely requires the virtue of practical wisdom first +described by Aristotle (Fig. +48-1). +Practical wisdom cannot be learned from books and is developed +only through experience. +More than teaching merely technical mastery, surgical +residency is also moral training. +Figure 48-1. +Bust of Aristotle. +Marble, Roman copy after a +Greek bronze original by Lysippos from 330 b.c. +8575, Palazzo Altemps, Loca- +tion Ground Floor, Branch of the National Roman Museum. +. +. +In the 1972 +landmark case, Canterbury vs. +48-2). +These goals are aimed at respecting each patient’s +prerogative for autonomous self-determination. +The process of consent can also be challenging in the pedi- +atric population. +Algorithm for navigating the process of informed consent. +(From Childers R, Lipsett A, Pawlik T. +Informed consent and the +surgeon. +J Am Coll Surg. +E-pub Jan. +21, 2009. +and legislators +have sought a more reliable solution. +This phe- +nomenon is called “affective forecasting” and applies to many +situations. +In fact, the 1991 Patient Self Determination Act +requires all U.S. +In 1975, Quinlan lapsed +into a persistent vegetative state requiring ventilator support. +The hospital refused, fearing prosecution for euthanasia. +“extraordinary” care, has +been an area of much contention. +The 1983 Nancy Cruzan case +highlighted this issue. +Cruzan’s family asked that her tube feeds be +withheld, but the hospital refused. +The case was appealed to the +U.S. +b) The person must intend only the good effect, even +though the bad effect may be foreseen. +c) The act itself must not +be intrinsically wrong, or needs to be at least neutral. +d) The good +effect is sufficiently desirable to compensate for allowing the bad +effect. +Constitution. +In deliberating the issue of withdrawing vs. +withholding +life-sustaining therapies, the principle of “double effect” is +often mentioned. +The classic formulation of double effect has four + elements (Fig. +48-3). +Therefore, surgeons have valuable contri- +butions to make to palliative care. +In fact, the term palliative +care was coined in 1975 by Canadian surgeon, Balfour Mount. +[Healing] is the +central purpose of medicine . +. +. +the purpose of medicine is both +control of disease processes and care for the illness experience. +Each of these contributes to, but +is not synonymous with, suffering. +There is a steady decrease in desire +and requests for food and fluids. +As circulatory instability develops near death, patients +may exhibit cool and mottled extremities. +A number of cognitive changes occur as death approaches. +Patients who are in the last days of life may demonstrate some +signs of confusion or delirium. +Agitated delirium is a promi- +nent feature of a difficult death. +Air movement across the face generated by a fan can some- +times be quite helpful. +Supplemental O2 should be humidified to avoid exac- +erbation of dry mouth. +Sit down close  +to the patient. +•    Listen: Clarify the patient’s and/or the family’s  +understanding of the situation. +•    Silence: Pause after giving bad news. +Allow patient/family  +to absorb/react to the news. +•    Modify pathologic process when possible and appropriate. +•    In terminally ill, avoid medications not directly linked to  +symptom control. +•  Use a multidisciplinary approach. +•    Consider nonpharmacologic approaches whenever  +possible. +•    Engage participation of clinical pharmacist in treatment  +plan. +•    Select drugs that can multitask (i.e., use haloperidol for  +agitated delirium and nausea). +•    For pain, use adjuvant medications when possible (see  +Table 48-7). +•  Avoid fixed combination drugs. +•  Avoid excessive cost. +•  Select agents with minimum side effects. +•  Anticipate and prophylax against side effects. +•  No IM injections. +•  Scheduled dosing, not prn, for persistent symptoms. +•    Stepwise approach. +(See the World Health Organization  +Analgesic Ladder for pain. +See Table 48-5.) +•  Reassess continuously and titrate to effect. +•    Use equianalgesic doses when changing opioids (see  +Table 48-5). +•    Assess patient/family’s comprehension of management  +plan. +Such situations may require continuous administration +of parenteral opioids. +In +some states, deaths at home may require a brief police investiga- +tion and report. +For deaths in the hospital, the family must be +notified (in person, if possible). +Survivors may also be approached, if appropriate, regarding +potential autopsy and organ donation. +Bereavement is the experience of +loss by death of a person to whom one is attached. +In the academic com- +munity, monetary gain may not be the primary factor. +Oxycodone 5 mg PO q4h Sold as single agent or compounded with aspirin or + acetaminophen. +Slow release PO form available (MS Contin). +Do not use on opioid-naive + patients. +Absorption unpredictable in cachectic patients. +Methadone use for drug + withdrawal treatment requires special licensure. +Dose reduction and hydration reduce risk. +Slow-release preparations of morphine and oxycodone may be given rectally. +Timed-release tablets or patches should never be crushed or cut. +Opioid analgesics are the agents of choice for severe cancer-related pain. +Sedation is a common side effect when initiating opioid therapy. +Tolerance to this +usually develops within a few days. +If sedation persists beyond a few days, a stimulant (methylphenidate 2.5–5 mg PO bid) can be given. +Coanalgesics can be initiated for persistent pain +at any visual analogue scale level. +Gabapentin is commonly used as an initial agent for neuropathic pain. +Note: These are not recommendations for specific patients. +Philadelphia: Elsevier, +2008. +Copyright Elsevier. +Side effects may precede benefit. +Avoid in the elderly due to + anticholinergic side effects. +Pain may respond to + alternative antidepressants if no + response to initial agent. +Titrate + up rapidly as needed. +Max: 1800 mg qd +Commonly used first-line agent. +Generally + well tolerated. +Does not require blood + level monitoring. +Carbamazepine 200 mg PO q12h Effective. +Well studied. +Requires blood + monitoring. +Valproic acid 250 mg PO tid +Local anesthetics + Systemic use requires monitoring. +Lidocaine transdermal patch 5%. +Apply + to painful areas. +Max: 3 simultaneous + patches over 12 h (each patch contains + 700 mg lidocaine). +Lidocaine/prilocaine topical. +Apply to + painful areas. +Effective for postherpetic + neuralgia. +Contraindicated in + renal failure. +4–6 wk delay in + benefit. +Requires adequate bone + marrow reserve. +For prognosis of + more than 3 mo. +Philadelphia: Elsevier, +2008. +Copyright Elsevier. +true novel research. +12). +Patients require information regarding medical +errors so that additional harm can be avoided. +REFERENCES +Entries highlighted in bright blue are key references. +1. +Aristotle. +Nichomachean Ethics, Book VI. +In Ackrill J, ed. +A New Aristotle Reader. +Princeton, NJ: Princeton University +Press; 1987, p 416. +2. +Beauchamp TL, Childress JF. +Principles of Biomedical +Ethics, 3rd ed. +New York: Oxford University Press; 1989. +3. +Bosk, C. +Forgive and Remember, 2nd ed. +Chicago, University +of Chicago Press, 2003 (1979). +4. +McCullough LB, Jones JW, Brody BA, (eds): Surgical Ethics. +New York: Oxford University Press, 1998. +5. +Faden RR, Beauchamp TL. +A History and Theory of Informed +Consent. +New York: Oxford University Press; 1986. +6. +Bernat JL, Peterson LM. +Patient-centered informed consent in +surgical practice. +Arch Surg. +2006;141:86-92. +7. +Schneider CE. +The Practice of Autonomy: 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+Buckman R. +How to Break Bad News. +A Guide for Health Care +Professionals. +Baltimore: Johns Hopkins University Press; +1992. +41. +Kubler-Ross E. +On Death and Dying. +London: Routledge; +1973. +42. +Twycross R, Lichter I. +The terminal phase. +In: Doyle D, Hanks +G, MacDonald N, eds. +Oxford Textbook of Palliative Medicine. +New York: Oxford University Press; 1998, p 977. +43. +Hinshaw DB. +Spiritual issues in surgical palliative care. +Surg Clin North Am. +2005;85:257-272. +44. +Jacox A, Carr D, Payne R, et al. +Management of cancer +pain. +AHCPR Publication No. +94-052: Clinical Practice +Guideline No. +9. +Rockville: US Department of Health and +Human Services, Public Health Service;1994. +45. +Storey P, Knight C. +UNIPAC Three: Assessment and Treat- +ment of Pain in the Terminally Ill, 2nd ed. +New York: Mary +Ann Liebert, Inc; 2003. +46. +Rubenfeld GD, Crawford SW. +Principles and practice of with- +drawing life-sustaining treatment in the ICU. +In: Curtis JR, +Rubenfeld GD, eds. +Managing Death in the Intensive Care +Unit. +New York: Oxford University Press; 2001. +47. +Rousseau P. +Existential distress and palliative sedation. +Anesth +Analg. +2005;101:611-612, +48. +Bethesda: +National Cancer Institute; 2007. +49. +Worden J. +Bereavement Care. +Philadelphia: Lippincott + Williams and Wilkins; 2002. +50. +Bishop JP, Rosemann PW, Schmidt FW. +Fides ancilla medici- +nae: on the ersatz liturgy of death in biopsychosociospiritual +medicine. +The Heythrop Journal. +2008;49:20. +51. +Schroeder-Sheker T. +Transitus: A Blessed Death in the + Modern World. +Mt. +Angel: St. +Dunstan’s Press; 2001. +52. +Emmanuel EJ, Wendler D, Grady C: What makes clinical +research ethical? +JAMA 2000;283:2701-2711. +53. +Freedman B. +Equipoise and the ethics of clinical research. +N Engl J Med. +1987;317:141-145. +54. +Meakins J. +Innovation in surgery. +The rules of evidence. +Am +J Surg. +2002;183:399-405. +55. +Lefering R, Neugebauer E. +Problems of randomized controlled +trials in surgery. +Paper presented at: Nonrandomized Compar- +ative Clinical Studies 1997, Heidelberg. +56. +Flum DR. +Interpreting surgical trials with subjective outcomes: +avoiding UnSPORTsmanlike conduct. +JAMA. +2006;296: +2483-2485. +57. +Moseley JB, O’Malley K, Petersen NJ, et al. +A controlled trial +of arthroscopic surgery for osteoarthritis of the knee. +N Engl +J Med. +2002;347:81. +Summary for patients in: J Fam Pract. +2002;51:813. +58. +Angelos PA. +Sham surgery in research: asurgeon’s view. +Am +J Bioeth. +2003;3:65-66. +59. +Miller FG. +Sham surgery: an ethical analysis. +Sci Eng Ethics. +2004;10:157-166. +60. +Angelos P. +Sham surgery in clinical trials. +JAMA. +2007;297: +1545-1546, author reply 1546. +61. +Riskin DJ, Longaker MT, Gertner M, et al. +Innovation in + surgery: a historical perspective. +Ann Surg. +2006;244:686-693. +62. +Biffl WL, Spain DA, Reitsma AM, et al. +63. +McKneally MF, Daar AS. +Introducing new technologies: pro- +tecting subjects of surgical innovation and research. +World +J Surg. +2003;27:930-934. +64. +Kohn LT, Corrigan JM, Donaldson MS. +To Err Is Human: +Building a Safer Health System. +Washington: National Acad- +emy Press; 2000. +65. +Brennan TA, Leape LL, Laird NM, et al. +Incidence of adverse +events and negligence in hospitalized patients. +Results +of the Harvard Medical Practice Study I. +N Engl J Med. +1991;324:370-376. +66. +Hebert PC, Levin AV, Robertson G. +Bioethics for clinicians: +23. +Disclosure of medical error. +CMAJ. +2001;164:509-513. +Global Surgery +Raymond R. +Price and Catherine R. +Yet, surgery is currently unavailable to most people world- +wide. +The vast majority—90%—of the world’s population +receives only 10% of the surgical care delivered. +$1000/ person (Fig. +49-1).2 +Examples of disparities abound. +Many factors contribute to the disparity in access to surgi- +cal care. +The epidemiologic transition of diseases from primarily +infectious to more chronic conditions; +2. +Considering that the annual economic loss from +road traffic injuries alone exceeds U.S. +The epidemiologic transition of diseases +b. +The mobile nature of the world’s populations +c. +Ubiquitous information access +d. +A revolution for equity and human rights +e. +8 Surgery is gaining an increasingly recognized role for +improving public health. +9 Surgery has a role in prevention as well as treatment. +Figure 49-1. +Worldwide distribution of surgical procedures. +(Data +from Weiser TG, Regenbogen SE, Thompson KD, et al. +An estima- +tion of the global volume of surgery: a modeling strategy based +on available data. +Lancet. +2008;372(9633):139-144. +Only part of these systems falls within the traditional training +of surgeons. +49-2). +Many of the inter- +related components of this surgical ecosystem originate outside +the hospital. +Disparities in surgical care have geographical, socioeco- +nomic, and cultural components. +Yet, a lack of +reliable energy sources is a major limiting factor. +49-3). +Electricity is necessary for all modern surgery. +Only in the last 50 years or so could +stable electricity be expected in most wealthy cities. +However, +in rural areas of even wealthy countries, electricity remains +unpredictable (Fig. +49-4). +Components of the Global Surgery Ecosystem. +However, global +Figure 49-2. +Global surgery priorities. +These +often unappreciated colleagues make possible the daily practice +of surgery. +Burden of Surgical Disease +Epidemiologic Transition of Disease. +Population characteristics are changing rapidly. +Many of these chronic diseases are best +approached by surgery. +Foundation for creating surgical infrastructure. +(Reproduced with permission from Catherine R. +Map of world elec- +trification. +(NASA, Visible Earth, +http://visibleearth.nasa.gov/view. +php?id=79765) +Figure 49-5. +Key components of the global surgery ecosystem. +They present for care with much later stages of +cancer. +49-8). +Trauma. +Shift in disease burden 1990–2010. +(Data from Murray CJ, Vos T, Lozano R, et al. +Lancet. +2012;380(9859):2197-2223. +Illustration reproduced with permission from Intermountain Healthcare.) +Figure 49-7. +Ratio of mortality to incidence by solid tumor type and country income (2008). +(Data from Farmer P, Frenk J, Knaul FM, +et al. +Expansion of cancer care and control in countries of low and middle income: a call to action. +Lancet. +2010;376(9747):1186-1193. +Underlying unmet cancer burden in Haiti (2010).(Photos reproduced with permission from R. +Injuries and violence: the scale of the problem. +(Injuries and violence: the facts. +Change in traffic fatal- +ity risk (deaths/10,000 persons), 1975- +1998). +(Data from Kopits E, Cropper M. +Traffic fatalities and economic growth. +Accid Anal Prev. +2005;37(1):169-178. +Burns. +Almost 11 million people worldwide sought medical or +surgical care related to burns in 2004. +However, the vast major- +ity of burned people never present for medical care. +49-11). +Contrast this with the United +States, where more burns and burn deaths affect men. +Domestic kitchen: risk factor for burns in +women and children in LMICs. +(Reproduced with permis- +sion from James H. +Kenney, Jr.) +Figure 49-12. +Distribution of healthcare workers by burden of disease in WHO regions. +(Redrawn from Fig 5.1, The Business of Health in +Africa (29) by permission. +96% +1. +96% - 3.45% +3.45% - 4.93% + +Population Growth Rate +2012 +–1.01% - –0.48% +Figure 49-13. +Number of physicians, world populations, and world population growth rates. +In a 2004 study, more than 23% of U.S. +Human resources for health (HRH) by WHO region, 2006. +(Redrawn from Fig 5.2, The Business of Health in Africa (29) by +permission. +49-15). +Some even use the promise of healthcare to advance political, +religious, or personal agendas. +A 2009 survey indicated that 25% of U.S. +medi- +cal students have traveled to LMICs for clinical and research +electives. +Millennium Development Goals (MDGs). +The initial UN Confer- +ence in 1945 voted to establish a new international health orga- +nization. +Global surgery initiatives. +Reduce by half the number of people who suffer from +hunger and whose income is < $ 1/ day +2. +Provide universal primary education +3. +Promote gender equality +4. +Reduce mortality rate for children < 5 years by two-thirds +5. +Reduce maternal mortality rate by three quarters +6. +Halt and reverse the spread of AIDS, malaria, +tuberculosis, and other major diseases +7. +Improve the environment +8. +Strengthen the global partnership for development. +Data adapted from Millennium Development Goals. +http://www.undp. +49-16).67 +The Global Initiative for Emergency and Essential Surgical +Care (GIEESC). +Emergency and essential surgery: an integral component of primary care. +(The World Health Report 2008, Primary Health +Care Report, Now More Than Ever, p. +55, Figure 3.5. +49-17). +49-19 and 49-20).70 More important, countrywide morbidity and mortality dropped significantly (Fig. +49-21). +A Mongolian +edition facilitated early expansion of GIEESC throughout the +country. +First Level (Soum) Hospital. +(Photos reproduced with permission from Raymond R. +Price MD. +EESC Project: Mongolia 2004–2010. +(Henry JA, Orgoi S, Govind S, Price RR, Lundeg G, Kehrer B. +World J +Surg. +2012;36(10):2367, Fig. +Surgical procedures performed 1-2 years Post-training (13 soum hospitals evaluated). +(Henry JA, Orgoi S, Govind S, Price RR, +Lundeg G, Kehrer B. +World J Surg. +2012;36(10):2367, Fig. +Pilot Soum hospitals’ evaluation 2 years post-training. +(Henry JA, Orgoi S, Govind S, Price RR, Lundeg G, Kehrer B. +World J Surg. +2012;36(10):2367, Fig. +2010 [cited 2011 November 2]; Available from: www.doh.gov.mn. +Operate on the correct patient at the correct site + 2. +Recognize and effectively prepare for life-threatening +loss of airway or respiratory function + 4. +Recognize and effectively prepare for risk of high blood +loss + 5. +Consistently use method known to minimize risk of +surgical site infection + 7. +Prevent inadvertent retention of instruments or sponges +in surgical wounds + 8. +Secure and accurately identify all surgical specimens + 9. +Data from WHO Guidelines for Safe Surgery 2009 http://whqlibdoc. +who.int/publications/2009/9789241598552_eng.pdf. +Violence and Injury Prevention (VIP). +WHO Safe Surgery Saves Lives Initiative. +Surgeons have +always sought ways to prevent peri-operative complications. +Yet in reality, surgery and public health +priorities overlap in many areas (Fig. +49-23). +An entire volume dedicated +to surgical care is planned for the 3rd edition. +Recognition that surgery has a primary, secondary, and ter- +tiary preventative role; and +3. +Documentation that surgical care can be cost-effective for +community-based healthcare. +Assigning Disease Priorities. +These +recommendations have been used as a planning guide and as +an advocacy statement. +Obstetrical and Other Acute Surgical Emergencies. +Surgical safety checklist. +(WHO surgical safety checklist. +2009, http://whqlibdoc.who.int/publications/2009/9789241598590_ +eng_Checklist.pdf. +Additions and modifications to fit local practice are encouraged. +Yes +Is the site marked? +Yes + Not applicable +Is the anaesthesia machine and medication +check complete? +Yes +Is the pulse oximeter on the patient and +functioning? +Yes +Does the patient have a: +Known allergy? +No + Yes +Difficult airway or aspiration risk? +No + Yes, and equipment/assistance available +Risk of >500ml blood loss (7ml/kg in children)? +Confirm the patient’s name, procedure, + and where the incision will be made. +Has antibiotic prophylaxis been given + within the last 60 minutes? +How long will the case take? +What is the anticipated blood loss? +To Anaesthetist: + Are there any patient-specific concerns? +To Nursing Team: + Has sterility (including indicator results) + been confirmed? +Are there equipment issues or any concerns? +Is essential imaging displayed? +Nonacute Surgical Conditions. +Even common nonacute +conditions can have significant impact on the quality of life. +Overlapping priorities of surgery and public health. +Obstructed airway appropriately maintained + 2. +Impaired breathing supported + 3. +Pneumothorax and hemothorax promptly diagnosed and +treated + 4. +Bleeding promptly stopped (internal or external) + 5. +Shock recognized and treated appropriately (I.V. +fluids) + 6. +Timely decompression of space occupying lesions to +prevent secondary brain injury + 7. +Abdominal injuries diagnosed and promptly repaired +(intestinal injuries and others) + 8. +Disabling extremity injuries corrected + 9. +Potentially unstable spine injuries identified and +managed (early immobilization) +10. +Minimize consequences of injuries by appropriate +rehabilitative services +11. +Overview +of the Essential Trauma Care Project. +World J Surg. +2006;30(6): +919–929. +The priority should be shifted to 2 or 3 if any of the conditions are moderate or low. +Data adapted from: Mock C, et al. +World J Surg. +2010;34(3): 381–385. +2nd ed. +1245–59. +49-24). +By redesigning the intraocular lens and mass producing it locally in Nepal for U.S. +*EsTC: Essential Trauma Care. +Data adapted from Mock C, Lormand JD, Goosen J, Joshipura M, Peden M. +Guidelines for essential trauma care, 2004, Geneva: World Health Organiza- +tion, p. +21. +Himalayan cataract +project priorities, public health prin- +ciples, and outcome measurements. +The Preventive Role of Surgery. +Surgery plays a significant +role at all levels of prevention of disease (Table 49-7). +Trying to disassociate treatment from prevention presents +challenges. +Treatments can also be a form of prevention. +Eye surgeries Tilganga eye +center and outreach. +Funders in healthcare +look for measurable return on their investments. +(DALY += YLL + YLD). +Primary Root causes of +disease +Eliminate or reduce risk +of developing illness +2. +Secondary Illness or disease +at earliest stages +Limit progression of +disease +3. +and R.R. +Price. +Global Surgery and +Public Health: A New Paradigm. +1st ed, 2012, Sudbury, MA: Jones & +Bartlett Learning, LLC, p. +43-45. +The World Bank arbitrarily defined U.S. +$100/DALY +averted per day in low-income countries as highly cost-effective. +The median cost per +DALY averted by Cesarean-section was $304. +Commentary: +Cancer Care and Control - the role of surgery. +Global Surgery and Anes- +thesia. +2010. +Ozgediz D, Riviello R. +The “other” neglected diseases in global public health: surgical conditions in sub-Saharan Africa. +PLoS Med. +2008. +5(6):e121; +b. +Shillcutt SD, Clarke MG, Kingsnorth AN. +Cost-effectiveness of groin hernia surgery in the Western Region of Ghana. +Arch Surg. +2010;145(10): +954–961; c. +Shillcutt SD, et al. +Cost-effectiveness of ingunial hernia surgery in northwestern Ecuador. +World J Surg. +2013;37(1):32–41; d. +Alkire BC, +et al. +Obstructed labor and caesarean delivery: the cost and benefit of surgical intervention. +PLoS One. +2012;7(4): e34595; e. +Baltussen R, Sylla M, Mari- +otti SP. +Cost-effectiveness analysis of cataract surgery: a global and regional analysis. +Bull WHO. +There are three major factors that severely limit utiliza- +tion of surgical services: +1. +socioeconomic and cultural +2. +accessibility of facilities and +3. +quality of care (Fig. +Cultural and religious traditions may define accept- +ability of various treatment options. +Understanding local customs and cultural +concerns can improve utilization of surgical services. +49-27). +Sergelen formulated a plan to expand access to laparo- +scopic surgery throughout Mongolia. +This plan targeted the +three main areas affecting utilization and outcome. +c) Quality of Care Improve the surgical infrastructure for +each facility. +f) Quality of Care Expand the surgical residency to +include laparoscopic training. +Figure 49-26. +Factors affecting utilization +and outcome of surgical care. +[cited 2013 +February 27]; Available from: http://www. +unfpa.org/public/mothers/pid/4385. +Rural Ger. +(Photo reproduced with permission from Michelle K. +Price.) +Figure 49-28. +Regional diagnostic treatment and referral centers of Mongolia (RDTRCs). +Cholecystectomy trends in Mongolia. +(Adapted +from: Unursaikhan C. +(2010). +Information of biliary track surgery +in Mongolia. +Health Sciences University of Mongolia, unpublished +data. +West African College of Surgeons: +most desired skills. +(Adapted from Trigen Sur- +vey WACS: Akporiaye L. +(2010). +Trigen Survey: +West African College of Surgeon. +Port-Harcourt: +Unpublished data. +Even +programs to develop peritoneal dialysis cannot fully ease the +demand. +The majority of kidney transplants in developing countries +are from living related donation. +Partnering academic programs +with NGOs provides another opportunity for collaboration. +Some problems are so episodic that they are not +anticipated, and few guidelines exist. +federally funded, collaborative program of the Rwanda +Ministry of Health (MOH) and 13 U.S. +academic medical +centers and universities. +faculty educators to join the National University of Rwanda +(NUR) training faculty. +HRH physician faculty, including 6 surgeons. +Many for- +mer scholars become mentors for other residents when they +complete their training. +49-31). +12 +Academic Global Surgery Partnerships +A. +What entity should oversee +the flow of volunteer practitioners? +Can a standard set of guide- +lines meet the needs of most countries? +While +many countries require at least temporary licensure, some do +not. +In many cases enforcement is inconsistent. +And values about pri- +vacy vary markedly from region to region. +Gaming technology +can potentially teach algorithms for decision making and +Figure 49-31. +Training outcomes from NGO/academic partner- +ship. +Elements of disruptive innovation. +(Redrawn with +permission from Christensen CM, Grossman 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+2002;95(6): 275-276. +137. +Kushner AL, Kyamanywa P, Adisa CA, et al. +Editorial policy +on co-authorship of articles from low- and middle-income +countries. +World J Surg, 2011;35:2367-2368. +138. +Cameron JS, Hoffenberg R. +Kidney Int.1999;55(2):724-732. +139. +Christensen CM, Grossman JH, Hwang J, The Innovator’s +Prescription 2009, New York McGraw-Hill. +441. +Index +Note: Page numbers followed by t indicate tables; those followed by f indicate figures. +See also Thoracic +aortic aneurysms +anatomy of, 785, 786f +aneurysms of, 785–806. +See Appendectomy +appendicitis of, 1243–1251. +See also Biliary +tract, atresia of +of esophagus, 1608–1612. +See Parasympathetic +nervous system +in shock response, 112 +sympathetic. +See also +Gastric banding +gastric bypass in, Roux-en-Y, 1103, +1112–1119. +See also +Cholangiocarcinoma +cholangiography of. +See +Cholangiography +common +anatomy of, 1310–1311 +choledocholithiasis in, 1322, +1325–1327. +See also +Cholangiocarcinoma +cholangitis of, 1331. +See Gallbladder +gallstones in, 1316–1327. +See also +Gallstones +hamartoma of, 1291 +Oddi sphincter in. +A. +See Hypertension +in hypotension. +See also +Cardiopulmonary bypass +coronary, 742–747. +See also +Hypercalcemia +in hyperparathyroidism, 1560–1563, +1563t +hypocalcemia, 72. +See Ductal carcinoma of +breast +inflammatory, 555–556, 556f, 556t +lobular. +See also +Hemorrhage, intracranial +ischemic, 838, 1727–1728. +See also +Incontinence, fecal +urinary, disorders of, 1695. +See also +Stent grafts +stent placement in, 836, 837f. +See also Fibrinogen +Factor II, 86, 87, 99t. +See +Cholecystectomy +cholecystitis of. +See Intussusception +large intestine in, 1175–1236. +See also +Small intestine +stomach in, 1035–1095. +See also +Stomach +stromal tumors of, 1480–1481. +See +Cardiomyopathy +catheterization. +See Diaphragmatic +hernia +femoral. +See Femoral hernia +hiatal. +See Hiatal hernia +inguinal. +See Children and infants +Infarction +myocardial. +See Myocardium, +infarction of +omental, 1457 +Infections, 135–157 +abdominal, 149–150. +See Bariatric +surgery, laparoscopic +in children, 435–436 +cholecystectomy in. +See Breast cancer, +metastasis of +of colorectal cancer. +See Laparoscopy +in natural orifice transluminal +endoscopic surgery. +See Esophagus, motility +of +of large intestine, 1180 +of small intestine. +See Small intestine, +motility of +of stomach. +See also Head and neck disorders +cervical lymph nodes in. +See Cervical +lymph nodes +cervical spine in. +See also Colostomy +ileostomy, 1192–1193. +See also Flaps +free tissue transfer in, 1838–1840 +of hand. +See Hand, reconstructive +surgery of +of head and neck, 1860–1865. +See Hyperkalemia +in hypokalemia. +See also Atrium, septal +defect of +ventricular, 726–727. +See also +Diverticulum, of small intestine +duodenum in. +See Ileum +ileus and motility disorders of, +1151–1153 +intussusception of, 1170 +jejunum in. +See Hypernatremia +in hyponatremia. +See Anal sphincters +esophageal. +See Esophagus, sphincter +muscles of +of Oddi. +See Cervical spine +fusion surgery of, 1743 +instrumentation in, 1743, 1743f +intervertebral discs in. +See Imatinib +St. +See also Gastric +banding +bezoars in, 1089 +blood supply of, 1037–1038, 1038f +bypass surgery. +See Gastrectomy +gastritis of. +See also Varices, +gastroesophageal +volvulus of, 1090, 1090f +watermelon, 1088 +Stoma procedures. +See Ostomy procedures +Stool +continence of, 1180 +disorders of, 1185. +See Video-assisted +thoracic surgery +Thoracic trauma. +See also +Hyperthyroidism +hypothyroidism, 1534–1535. +See +also Tracheoesophageal fistula +intubation of. +See also Donors, in +organ transplantation +of heart. +See +also Kidneys, transplantation of +of liver, 345–352, 1975. +See also Liver, +transplantation of +of lung, 332, 354–358, 663–664. +See also +Pancreas, transplantation of +in poor countries, 1976–1977 +rejection in, 324. +See also +Chest trauma +in children, 222–223, 1642–1644. +See also Hand, +trauma of +of head. +See also +Hand +shoulder in, 1765–1767. +See Cervix uteri +endometriosis of, 1689–1690 +endometrium of. +See Endometrium +hyperplasia of, 1683 +hysterectomy of, 1684. +See also Healing +process +infections of, 255–259, 265 +deep, 256 +in surgical site. +Some material may require a desktop +or laptop computer for full access. +This eBook’s ISBN is 978-0-07-180092-1. +Back + + +A great deal of knowledge and skill is required to practise +as a doctor. +But how doctors think, reason and make decisions +is arguably their most critical skill. +Knowledge is necessary, but +not sufcient on its own for good performance and safe care. +This chapter describes the principles of clinical decision-making, +or clinical reasoning. +For every diagnostic error there are +a number of root causes. +Figure 1.1 shows the different elements involved in clinical +reasoning. +Reducing diagnostic errors in +medicine: what’s the goal? +Acad Med 2002; 77:981–992. +1.1 Elements of clinical reasoning. +Similarly, an LR of less than 1 1 +decreases the probability of disease. +LRs are developed against +a diagnostic standard (e.g. +in the case of meningitis, lumbar +puncture results), so do not exist for all clinical ndings. +LRs +illustrate how an individual clinical nding changes the probability +of a disease. +Studies show that physicians make a diagnosis in +70–90% of cases from the history alone. +1.2). +Likelihood ratios (LR) are clinical diagnostic weights. +Test results +give us test probabilities, not real probabilities. +Normal values +Most tests provide quantitative results (i.e. +a value on a continuous +numerical scale). +Many +quantitative measurements in populations have a Gaussian or +‘normal’ distribution. +1.3). +In some diseases there is no overlap between results from +the abnormal and normal population. +A low ferritin in a +young menstruating woman is not considered to be a disease +at all. +Normal, to some extent, is therefore arbitrary. +Data from Thomas KE, Hasbun R, +Jekel J, Quagliarello VJ. +1.3 Normal distribution and reference range. +Box 1.3 gives some examples. +Operating characteristics +Tests are also subject to operating characteristics. +This refers +to the way the test is performed. +Patients need to be able to +comply fully with some tests, such as spirometry (p. +569), and if +they cannot, then the test result will be affected. +Some conditions are paroxysmal. +A normal EEG therefore does not +exclude epilepsy. +This is referred to as an ‘incidental nding’. +Even a very +good test, with 95% sensitivity, will miss 1 in 20 people with +the disease. +Every test therefore has ‘false positives’ and ‘false +negatives’ (Box 1.4). +A very sensitive test will detect most disease but generate +abnormal ndings in healthy people. +For example, +dening an exercise electrocardiogram (p. +This trade-off is +illustrated by the receiver operating characteristic curve of the +test (Fig. +1.4). +For example, imagine that +an elderly lady has fallen and hurt her left hip. +Take +a moment to work this out. +In this problem, we have removed +clinical probability and are only considering prevalence. +The +answer is at the end of the chapter. +Predictive values combine sensitivity, specicity and prevalence. +Sensitivity and specicity are characteristics of the test; the +population does not change this. +Post-test probability and predictive values are different. +Bayes’ Theorem can +be used to calculate post-test probability for a patient in any +population. +It is not possible to transfer this value to a different +population. +prevalence of disease in the subgroup to which the patient +However, her hip X-rays are normal. +Does she have a fracture? +belongs and then adjust to take the individual factors into account. +A small percentage of fractures are therefore missed. +This is known +as ‘conditional probability’. +This principle +is illustrated in Figure 1.5. +The closer the curve lies to the top +left-hand corner, the more useful the test. +It is important to recognise that clinicians frequently deal with +uncertainty. +However, subjective estimates of probability can +sometimes be unreliable. +Knowing the patient’s true state is often unnecessary in clinical +decision-making. +The requirement for +diagnostic certainty depends on the penalty for being wrong. +Different situations require different levels of certainty before +starting treatment. +How we communicate uncertainty to patients +will be discussed later in this chapter (p. +10). +The point at +which the factors are all evenly weighed is the threshold. +If a test +or treatment for a disease is effective and low-risk (e.g. +On the other hand, if a test or +treatment is less effective or high-risk (e.g. +Sometimes tests +shift the probability of disease by less than we realise. +Do not try +to solve it mathematically but listen to your intuition: +A bat and ball cost ÂŁ1.10. +The bat costs ÂŁ1 more than the ball. +How much does the ball cost? +The answer is at the end of the chapter. +Most people get +the answer to this puzzle wrong. +1.6 The interplay between type 1 and +type 2 thinking in the diagnostic process. +Adapted from Croskerry P. +A universal model of +diagnostic reasoning. +Acad Med 2009; +84:1022–1028. +This has been termed ‘dual process theory’. +Box 1.6 +explains this in more detail. +With experience, complex procedures +become automatic, fast and effortless. +The same applies to +medical practice. +There is evidence that expert decision-making +is well served by intuitive thinking. +Both types of thinking interplay – they are not mutually +exclusive in the diagnostic process. +Figure 1.6 illustrates the +interplay between type 1 and type 2 thinking in clinical practice. +For example, imagine being asked to see a young woman who +is drowsy. +Already your mind has reached a working diagnosis. +It ts a +pattern (type 1 thinking). +You think she has taken an overdose. +At this point you can stop to think about your thinking (rational +override in Fig. +1.6): ‘What is the evidence for this diagnosis? +However, you recently heard about a +case of syncope due to a leaking abdominal aortic aneurysm. +1.6). +However, this +leads to ‘geography is destiny’. +For +example, a diabetic ketoacidosis +patient with abdominal pain and +vomiting is sent to surgery. +1.7 Common cognitive biases in medicine. +Adapted from Croskerry P. +Achieving quality in clinical decision-making: cognitive strategies and +detection of bias. +Various experiments demonstrate that we focus our attention +to lter out distractions. +In a team context, what is obvious to one person +may be completely missed by someone else. +Some problems (e.g. +low serum potassium) +require action but not necessarily a differential diagnosis. +Other problems (e.g. +vomiting) require a differential diagnosis. +The process of generating a problem list ensures nothing is +missed. +1.7). +188). +Red flags +in back pain are listed in Box 24.19 (p. +996). +1.8 Factors that affect our judgement and +Error +decision-making. +Newer strategies to avoid cognitive biases and errors in decision- +making are emerging. +These involve explicit training in clinical +reasoning and human factors. +Since then her +oxygen requirements have been steadily +increasing. +Chest X-ray shows extensive right lower zone +consolidation. +Recommendation Please can you come and see her as soon as +possible? +I think she needs admission to Intensive +Care. +They help clinicians to +estimate probability more accurately. +187). +These include the GRACE score in acute coronary syndromes +(see Fig. +16.62, p. +494) and the CURB-65 score in community- +acquired pneumonia (see Fig. +17.32, p. +583). +The SBAR system of communication has been +recommended by the UK’s Patient Safety First campaign. +It is +a structured way to communicate about a patient with another +health-care professional (e.g. +It is illustrated in Box 1.7. +From Royal College of Physicians of London. +National Early Warning Score: +standardising the assessment of illness severity in the NHS. +Report of a working +party. +As this chapter has described, clinicians frequently deal with +uncertainty/probability. +Research evidence provides statistics but these can be +confusing. +Terms such as ‘common’ and ‘rare’ are nebulous. +Visual aids can be used to +present complex statistical information (Fig. +1.9). +How uncertainty is conveyed to patients is important. +the patient’s social circumstances, +values and wishes). +He is clinically well. +A normal chest X-ray is a common nding in 1 +pulmonary embolism. +A very sensitive test will +detect most disease but generate abnormal ndings in healthy +people. +On the other hand, a negative result virtually, but not +completely, excludes the disease. +What +kind of imaging depends on individual patient characteristics +and what is available. +620) may be +a more suitable alternative. +However, what if the scan cannot +be performed until the next day? +Feel better +No difference +Stroke +Dead +Fig. +1.9 Visual portrayal of benets and risks. +From Edwards A, Elwyn G, Mulley A. +Explaining risks: turning numerical data into meaningful pictures. +BMJ +2002; 324:827–830, reproduced with permission from the BMJ Publishing +Group. +respiratory tract infection a week ago and was almost back to +normal when the symptoms started. +You have been asked to assess her for the +possibility of a pulmonary embolism. +There is nothing in the history to suggest an alternative +diagnosis (e.g. +high fever, productive cough, recent chest trauma). +The patient’s vital signs are normal, as is the physical examination. +Deciding pre-test probability +The prevalence of pulmonary embolism in 25-year-old women +is low. +We anchor on this prevalence and then adjust for +individual patient factors. +This patient has no major risk factors +for pulmonary embolism. +Combined with the low pre-test probability, +this scan result reliably excludes pulmonary embolism. +chest wall tenderness) to support the +diagnosis of musculoskeletal chest pain. +You request blood tests +including a D-dimer on the wrong patient. +Luckily, this error is +intercepted. +Reducing cognitive error +The diagnosis of pulmonary embolism can be difcult. +Clinical +prediction rules (e.g. +modied Wells score), guidelines (e.g. +from +the UK’s National Institute for Health and Care Excellence, or +NICE) and decision aids (e.g. +She is advised to re-present to +hospital if her symptoms suddenly get worse. +Do the math, +and you will see.’ The correct answer is 5p. +Further information +Books and journal articles +Cooper N, Frain J (eds). +ABC of clinical reasoning. +Oxford: +Wiley–Blackwell; 2016. +Kahneman D. +Thinking, fast and slow. +Harmondsworth: Penguin; +2012. +McGee S. +Evidence-based physical diagnosis, 3rd edn. +Philadelphia: +Saunders; 2012. +Scott IA. +Errors in clinical reasoning: causes and remedial strategies. +BMJ 2009; 338:b186. +Sox H, Higgins MC, Owens DK. +Medical decision making, 2nd edn. +Chichester: Wiley–Blackwell; 2013. +Trowbridge RL, Rencic JJ, Durning SJ. +Teaching clinical reasoning. +Philadelphia: American College of Physicians; 2015. +Vincent C. +Patient safety. +Edinburgh: Churchill Livingstone; 2006. +Websites +chfg.org UK Clinical Human Factors Group. +clinical-reasoning.org Clinical reasoning resources. +creme.org.uk UK Clinical Reasoning in Medical Education group. +improvediagnosis.org Society to Improve Diagnosis in Medicine. +Answers to problems +Harvard problem (p. +5) +Almost half of doctors surveyed said 95%, but they neglected to +take prevalence into account. +The chance that a person found to have a positive result actually +has the disease is 1/51 or 2%. +Bat and ball problem (p. +He writes, +‘A number came to your mind. +2.1 Pharmacokinetics and pharmacodynamics. +strength of the chemical bond. +• Selectivity describes the propensity for a drug to bind to +one target rather than another. +Selectivity is a relative +term, not to be confused with absolute specicity. +by affecting post-receptor signalling). +2.2). +2.1). +65). +Other drugs have useful but +less selective chemical properties, such as chelators (e.g. +2.2 Dose–response curve. +The green curve represents the benecial effect of the drug. +Emax on the dose–response +curve). +• Potency describes the amount of drug required for a given +response. +More potent drugs produce biological effects at +lower doses, so they have a lower ED50. +A less potent +drug can still have an equivalent efcacy if it is given in +higher doses. +2.2). +digoxin, +warfarin, insulin, phenytoin, opioids). +a stored neurotransmitter released from a nerve terminal) +or receptor phosphorylation. +• Tolerance describes a more gradual loss of response to a +drug that occurs over days or weeks. +accumulation of salt and water in +response to vasodilator therapy). +116) or +cancer chemotherapy drug. +Withdrawal should be gradual after +prolonged therapy (p. +The rate and extent of drug absorption +depend on the route of administration (Fig. +2.3). +As a consequence, +absorption is frequently incomplete following oral +administration. +• Buccal, intranasal and sublingual (SL). +organic nitrates +for angina pectoris, triptans for migraine, opioid +analgesics). +• Rectal (PR). +diazepam in status epilepticus). +the dose is +100% bioavailable), and rapidly achieve a high plasma +concentration. +It is ideal for very ill patients when a rapid, +certain effect is critical to outcome (e.g. +benzathine +benzylpenicillin for meningococcal meningitis). +• Intramuscular (IM). +IM administration is easier to achieve +than the IV route (e.g. +• Subcutaneous (SC). +insulin, heparin). +• Transdermal. +oestrogens, nicotine, nitrates). +skin, eye, ear). +salbutamol, beclometasone). +17.23, p. +571). +Patients who nd these difcult may use a +‘spacer’ device to improve drug delivery. +A special mode +2 +Oral +Circulating +plasma +Mouth +Parenteral +Buccal +Fig. +2.3 Pharmacokinetics summary. +Drug that remains in circulating +plasma is subject to liver metabolism and renal +excretion. +Drugs excreted in bile may be +reabsorbed, creating an enterohepatic circulation. +by intravenous +injection). +2.4A). +Drugs that are highly bound to plasma +proteins may have a Vd below 10 L (e.g. +gentamicin, amoxicillin). +digoxin, amitriptyline). +349). +2.4 Drug concentrations in plasma following single and multiple +drug dosing. +Drugs +bound to plasma proteins are not ltered by the glomeruli. +The +pH of the urine is more acidic than that of plasma, so that +some drugs (e.g. +salicylates) become un-ionised and tend toPrinciples of clinical pharmacology • 19 +be reabsorbed. +Alkalination of the urine can hasten excretion +(e.g. +after a salicylate overdose; p. +138). +methotrexate, penicillin). +2.3). +the volume of plasma that is +completely cleared of drug per unit time. +2.4A). +This elimination can be described by +the drug’s half-life (t1/2), i.e. +For a few drugs in common use (e.g. +phenytoin, alcohol), +elimination capacity is exceeded (saturated) within the usual +dose range. +This is called ‘zero-order’ kinetics. +digoxin – 36 hours) may not be +known for a few days. +In contrast, drugs with a very short half-life +(e.g. +More frequent administration (e.g. +levodopa). +dose, route, frequency, duration) +for many conditions. +34). +Differences in pharmacokinetics +more commonly account for different drug responses, however. +2.2) over several days (e.g. +antibiotics) or even for months or years (e.g. +antihypertensives, +lipid-lowering drugs, thyroid hormone replacement therapy). +This involves choosing +the size of each individual dose and the frequency of dose +administration. +This applies when starting new drugs and when +adjusting doses of current drugs. +rash, anaphylaxis) +• Previous ADRs, their nature and time course (e.g. +ankle oedema +with amlodipine) +• Adherence to therapy (e.g. +• Adverse drug reaction (ADR). +An ADR +will usually require the drug to be discontinued or the dose +reduced. +• Side-effect. +vasodilator-induced +ankle oedema). +• Hypersensitivity reaction. +penicillin-related anaphylaxis). +75). +• Drug toxicity. +2.2 and p. +137). +• Drug abuse. +1184). +2.7 Risk factors for adverse drug reactions +Patient factors +• Elderly age (e.g. +low physiological reserve) +• Gender (e.g. +ACE inhibitor-induced cough in women) +• Polypharmacy (e.g. +drug interactions) +• Genetic predisposition (see Box 2.5) +• Hypersensitivity/allergy (e.g. +β-lactam antibiotics) +• Diseases altering pharmacokinetics (e.g. +hepatic or renal +impairment) or pharmacodynamic responses (e.g. +bladder instability) +• Adherence problems (e.g. +cognitive impairment) +Drug factors +• Steep dose–response curve (e.g. +insulin) +• Low therapeutic index (e.g. +In many cases, the patients are at increased risk due +to their age, interacting drugs (e.g. +aspirin, warfarin) or a past +history of peptic ulcer disease. +Drugs that commonly cause +ADRs are listed in Box 2.8. +• Type B (‘bizarre’) ADRs. +anaphylaxis caused by penicillin, peripheral neuropathy +caused by isoniazid in poor acetylators). +These occur only +after prolonged continuous exposure to a drug. +• Type D (‘delayed’) ADRs. +These are delayed until long +after drug exposure, making diagnosis difcult. +• Type E (‘end-of-treatment’) ADRs. +These occur after +abrupt drug withdrawal (see Box 2.3). +phenytoin, +warfarin). +lisinopril) +Antibiotics +Nausea +Diarrhoea +(e.g. +amoxicillin) +Anticoagulants +Bleeding +(e.g. +warfarin, heparin) +Antipsychotics +Falls +Sedation +(e.g. +diazepam) +Cold peripheries +β-blockers +Bradycardia +(e.g. +atenolol) +Calcium channel blockers +Ankle oedema +(e.g. +amlodipine) +Digoxin Nausea and anorexia +Bradycardia +Diuretics +(e.g. +Reports are +analysed to assess the likelihood that they represent a true +ADR (Box 2.10). +hospitalisation, operations, new clinical diagnoses) and +other clinical data (e.g. +haematology, biochemistry). +It is important that these are recognised early. +blood pressure, +temperature, pulse, blood glucose and weight) or +laboratory results (e.g. +omeprazole, allopurinol, naloxone) +• the presence of risk factors for ADRs (see Box 2.7). +receptor, enzyme) or physiological system (e.g. +electrolyte excretion, heart rate). +There are numerous potential mechanisms: +• Absorption interactions. +Drugs that either delay (e.g. +anticholinergic drugs) or enhance (e.g. +Drugs that bind to form insoluble +complexes or chelates (e.g. +aluminium-containing +antacids binding with ciprofloxacin) can reduce drug +absorption. +• Distribution interactions. +Co-administration of drugs that +compete for protein binding in plasma (e.g. +Many drugs rely on metabolism +by different isoenzymes of cytochrome P450 (CYP) in the +liver. +CYP enzyme inducers (e.g. +CYP +enzyme inhibitors (e.g. +clarithromycin, cimetidine, grapefruit +juice) have the opposite effect. +• Excretion interactions. +These primarily affect renal +excretion. +For example, drug-induced reduction in +glomerular ltration rate (e.g. +digoxin, lithium, aminoglycoside +antibiotics). +methotrexate excretion may be inhibited +by competition with NSAIDs). +warfarin). +coagulation tests for warfarin) or of plasma concentration +(e.g. +digoxin). +Errors +may occur in prescribing, dispensing, preparing solutions, +administration or monitoring. +Medication errors are very common. +2.5). +2.5 Human error theory. +When they do, their rst duty +is to protect the patient’s safety. +This will involve a clinical +review and the taking of any steps that will reduce harm (e.g. +remedial treatment, monitoring, recording the event in the notes, +informing colleagues). +Patients should be informed if they have +been exposed to potential harm. +Regulators are responsible for licensing medicines, monitoring +their safety (pharmacovigilance; p. +This process typically takes longer than +10 years and may cost up to US$1 billion. +Meanwhile, competitor companies will often produce +similar ‘me too’ drugs of the same class. +Newer ‘biological’ products are +based on large molecules (e.g. +The number of new drugs produced by the pharmaceutical +industry has declined in recent years. +• Pharmacy (P). +These are available only from a pharmacist +but can be supplied without a prescription. +• General sales list (GSL). +Common situations where this +might occur include prescribing outside the approved age group +(e.g. +prescribing for children) or using an alternative formulation +(e.g. +administering a medicine provided in a solid form as an oral +solution). +These activities usually involve +both national (e.g. +National Institute for Health and Care +Excellence (NICE) in the UK) and local organisations (e.g. +drug +and therapeutics committees). +Evaluating evidence +The principles of evidence-based medicine are described on +page 10. +2.6). +Other subtle bias may be introduced because +of the sources of funding (e.g. +2.6 Systematic review of the evidence from randomised +controlled clinical trials. +For each trial, the purple +box is proportionate to the number of participants. +The tick marks show +the mean odds ratio and the black lines indicate its 95% condence +intervals. +Note that not all the trials showed statistically signicant effects +(i.e. +the condence intervals cross 1.0). +The local +formulary contains a more limited list than any national formulary +(e.g. +individual patient. +Health-care budgets are limited in every country and so it is +impossible to fund all new medicines. +A major challenge is to compare the value of +interventions for different clinical outcomes. +These +principles are exemplied in Box 2.16. +proton pump inhibitors for post-prandial retrosternal discomfort). +pain, nausea, constipation). +ACE inhibitors to prevent hospitalisation and +extend life in chronic heart failure). +physiotherapy, psychotherapy, +surgery). +Choosing a drug +For most common clinical indications (e.g. +type 2 diabetes, +depression), more than one drug is available, often from more +than one drug class. +Distribution +Distribution of a drug to a particular tissue sometimes dictates +choice (e.g. +Metabolism +Drugs that are extensively metabolised should be avoided in +severe liver disease (e.g. +opioid analgesics). +Excretion +Drugs that depend on renal excretion for elimination (e.g. +proton pump inhibitors rather +than H2-receptor antagonists). +β-blockers as treatment for angina in patients +with asthma). +116). +Severity of disease +The choice of drug should be appropriate to disease severity +(e.g. +paracetamol for mild pain, morphine for severe pain). +Coexisting disease +This may be either an indication or a contraindication to therapy. +the ACE inhibitor lisinopril once daily +rather than captopril 3 times daily for hypertension). +Cost +Prescribers should choose the cheaper drug (e.g. +a generic +or biosimilar) if two drugs are of equal efficacy and safety. +Sometimes a +more costly drug may be appropriate (e.g. +if it yields improved +adherence). +There are some general principles that should be +followed, as described below. +delirium or postural +hypotension in the elderly) or have altered pharmacokinetic +handling (e.g. +renal or hepatic impairment), and when using +drugs with a low therapeutic index (e.g. +benzodiazepines, +lithium, digoxin). +There are some exceptions, however. +antibiotics, glucocorticoids, +carbimazole). +2.4). +It is +important to remember that the shape of the dose–response +curve (see Fig. +Route +There are many reasons for choosing a particular route of +administration (Box 2.18). +Frequency +Frequency of doses is usually dictated by a manufacturer’s +recommendation. +2.4). +This is relevant if the +peaks are associated with adverse effects (e.g. +anti-Parkinsonian drugs). +Timing +For many drugs the time of administration is unimportant. +Formulation +For some drugs there is a choice of formulation, some for use by +different routes. +Some are easier to ingest, particularly by children +(e.g. +elixirs). +lithium, phenytoin, theophylline). +antibiotics). +analgesics, +antidepressants). +For many, the treatment will be long-term (e.g. +insulin, antihypertensives, levothyroxine). +Very often, patients +may wish to defer to the professional expertise of the prescriber. +furosemide) Once in the morning Night-time diuresis undesirable +Statins (e.g. +simvastatin) Once at night HMG CoA reductase activity is greater at night +Antidepressants (e.g. +isosorbide +Eccentric dosing regimen (e.g. +inhaled salbutamol in asthma) and safety (e.g. +of wasted medicines and unnecessary health-care episodes. +An +important reason may be lack of concordance with the prescriber +about the goals of treatment. +386). +This group includes a large proportion of elderly patients. +• More drug interactions: largely as a result of polypharmacy. +Supplying medicines in pill organisers (e.g. +Antihypertensive drugs: reduced baroreceptor function → +increased risk of postural hypotension. +gentamicin) +Vancomycin +Digoxin +Lithium +Other antibiotics (e.g. +ciprofloxacin) +Atenolol +Allopurinol +Cephalosporins +Methotrexate +Opioids (e.g. +morphine) +Phenytoin +Rifampicin +Propranolol +Warfarin +Diazepam +Lidocaine +Opioids (e.g. +in hepatic cirrhosis). +Some drugs that require extra caution in patients with hepatic +disease are listed in Box 2.21. +Drug therapy in pregnancy +may, however, be required either for a pre-existing problem (e.g. +epilepsy, asthma, hypothyroidism) or for problems that arise +during pregnancy (e.g. +morning sickness, anaemia, prevention +of neural tube defects, gestational diabetes, hypertension). +Common teratogens include retinoids (e.g. +• Adverse fetal effects in late gestation: e.g. +• Altered maternal pharmacokinetics: extracellular fluid volume +and Vd increase. +Plasma albumin falls but other binding globulins +(e.g. +for thyroid and steroid hormones) increase. +Glomerular ltration +increases by approximately 70%, enhancing renal clearance. +Placental metabolism contributes to increased clearance, e.g. +of +levothyroxine and glucocorticoids. +The overall effect is a fall in +plasma levels of many drugs. +Use drugs for which there is some record of safety in humans. +Use the lowest dose for the shortest time possible. +Choose the least harmful drug if alternatives are available. +The most commonly used +drugs are simple analgesics, antibacterial drugs and antacids. +2.24 High-risk prescribing moments +• Trying to amend an active prescription (e.g. +It should +be precise, accurate, clear and legible. +2.7). +A variety of +charts are in use and prescribers must familiarise themselves +with the local version. +anticoagulants, insulin, +oxygen, fluids). +antiemetics, analgesics). +altered dosage, discontinuation +or substitution). +Great care is required to ensure +that this list is accurate. +Important additional issues more relevant to +GP prescribing are: +• Formulation. +tablets or oral suspension). +• Amount to be supplied. +In the hospital the pharmacist will +organise this. +Creams and ointments should be specied in grams and +lotions in mL. +• Controlled drugs. +Prescriptions for ‘controlled’ drugs (e.g. +opioid analgesics, with potential for drug abuse) are +subject to additional legal requirements. +Inform the responsible doctor of the appropriate timescale. +1. +Patient refuses +2. +Patient not present +3. +Medicines not available – CHECK ORDERED +4. +Asleep/drowsy +5. +Administration route not available – CHECK FOR ALTERNATIVE +6. +Vomiting/nausea +7. +Time varied on doctor’s instructions +8. +Once-only/as-required medicine given +9. +Dose withheld on doctor’s instructions +10. +2.7 Example of a hospital prescription and administration record (‘drug chart’). +A Front page. +The patient’s name and date of birth should be written on each page of the chart. +B ‘Once-only medicines’. +This area is used for prescribing medicines that are +unlikely to be repeated on a regular basis. +Note that the prescriber has written the names of all drugs legibly in block capitals. +write ‘SIMVASTATIN’, not ‘ZOCOR’). +Kliovance). +The only acceptable abbreviations for drug dose units +are ‘g’ and ‘mg’. +‘Units’ (e.g. +Gaviscon liquid) or if the strength is not expressed in weight +(e.g. +adrenaline (epinephrine) 1 in 1000). +Use numbers/gures (e.g. +‘ORAL’ is preferred to per oram – ‘PO’. +Care should be taken in specifying +‘RIGHT’ or ‘LEFT’ for eye and ear drops. +The +prescription should be dated and have an administration time. +• ‘Repeat prescriptions’. +A large proportion of GP +prescribing involves ‘repeat prescriptions’ for chronic +medication. +This area is used for prescribing medicines that are going to be given regularly. +The ‘notes’ box can be used +to communicate additional important information (e.g. +State here the times for peak/trough plasma levels for drugs requiring therapeutic monitoring. +This action should be signed and dated and a supplementary note written to explain it (e.g. +describing any +adverse effect). +In this example, amlodipine has been discontinued because of ankle oedema. +The administration boxes allow the nurse to sign to conrm that the +dose has been given. +D ‘As-required medicines’. +These +prescriptions leave the administration of the drug to the discretion of the nursing staff. +Fig. +2.7, cont’d +is a future event (e.g. +This may be an +intermediate step in the pathophysiological process (e.g. +control of ventricular rate in a patient with atrial brillation). +Samples should be taken 6 hrs post dose. +6.18 (p. +122) +Levothyroxine > 120 Steady state may take up to 6 weeks to achieve (p. +640) +Lithium 24 Steady state takes several days to achieve. +Samples should be taken 12 hrs post dose. +Good correlation between concentration and toxicity. +Samples should be taken 6 hrs post dose. +123) +*Half-lives vary considerably with different formulations and between patients. +serum C-reactive protein as a +surrogate for resolution of inflammation in chest infection). +Such +surrogates are sometimes termed ‘biomarkers’. +Inter-individual +variability means that these can be used only as a guide. +Another important consideration is that some +drugs are heavily protein-bound (e.g. +phenytoin) but only +the unbound drug is pharmacologically active. +• The relationship between plasma concentration and clinical +effects is predictable. +• The therapeutic index is low. +Some examples of drugs that full these criteria are listed in +Box 2.25. +2.4B). +Powerful new technologies +are driving forward transformational change in health care. +3.1). +The chromatin is nally packaged into the chromosomes. +Chromosomes 1 through +to 22 are known as the autosomes and consist of identical +chromosomal pairs. +A normal female karyotype is +therefore written as 46,XX and a normal male is 46,XY. +3.1 The packaging of DNA, genes and chromosomes. +via the production of messenger ribonucleic acid (mRNA) to +the production of proteins. +3.2). +In protein-coding genes +this is known as messenger RNA (mRNA). +3.2 The central dogma of protein production. +Each of these chains has +an orientation. +For DNA and RNA, this is 5′ to 3′. +For peptides, this is +N-terminus to C-terminus. +• The sugar residue within the nucleotide is ribose, rather +than deoxyribose. +• It contains uracil (U) in place of thymine (T). +The activity of RNA polymerase is regulated by transcription +factors. +The human genome encodes more +than 1200 different transcription factors. +Mutations within +transcription factors, promoters and enhancers can cause disease. +For example, the blood disorder alpha-thalassaemia is usually +caused by gene deletions (see p. +954 and Box 3.4). +DNA can be modied by the addition of a +methyl group to cytosine molecules (methylation). +This contrasts with heterochromatin, which is densely packed and +transcriptionally silent. +They also +afford therapeutic targets. +3.3 RNA synthesis and its translation into protein. +This protects the RNA from +degradation and facilitates transport into the cytoplasm. +In the cytoplasm, +the mRNA binds to ribosomes and forms a template for protein production. +into the cytoplasm or packaged into vesicles for secretion. +This is the subject of considerable research interest at present. +3.4). +• Anaphase: spindle bres attach to the chromosome +and pull the sister chromatids apart. +The progression from one phase to the next is tightly controlled +by cell-cycle checkpoints. +Different proteins from the same +gene can have entirely distinct functions. +772). +ORFs in humans most commonly start with the amino +acid methionine. +3.3). +3.3). +3.9, +p. +50) complexed with proteins. +During translation, a different RNA +molecule known as transfer RNA (tRNA) binds to the ribosome. +3.3). +This +reduction to the haploid number occurs at the end +of meiosis II. +The individual steps in meiotic cell division are similar in males +and females. +However, the timing of the cell divisions is very +different. +In females, meiosis begins in fetal life but does not +complete until after ovulation. +A single meiotic cell division can +thus take more than 40 years to complete. +As women become +older, the separation of chromosomes at meiosis II becomes +less efcient. +That is why the risk of trisomies (p. +44) due to +non-disjunction grows greater with increasing maternal age. +In males, meiotic division does not begin until puberty and +continues throughout life. +In the testes, both meiotic divisions +are completed in a matter of days. +This ‘biological +clock’ is of great interest in the study of the normal ageing +process. +1034). +A distinct +mechanism of cell death is seen in apoptosis, or programmed +cell death. +The signal that triggers apoptosis is +specic to each tissue or cell type. +A third mechanism of cell death is necrosis. +Hypoxia is probably +the most common cause of necrosis. +3.4 Meiosis and gametogenesis: the main chromosomal stages +of meiosis in both males and females. +A single homologous pair of +chromosomes is represented in different colours. +The nal step is the +production of haploid germ cells. +G2 and mitosis ensures that all damaged DNA is repaired prior +to segregation of the chromosomes. +• Meiosis is a special, gamete-specic, form of cell division +(Fig. +3.4). +Like mitosis, meiosis consists of four phases42 • CLINICAL GENETICS +mutation (Box 3.1 and Fig. +3.5). +If a multiple of three nucleotides +is involved, this is in-frame. +The effect on the gene is typically severe because the +amino acid sequence is totally disrupted. +3.5 Different types of mutation affecting coding exons. +A Normal sequence. +This usually results in a loss-of-function mutation. +3.6 Splice site mutations. +B In a splice site +mutation the donor site is mutated. +3.2 Diseases associated with triplet and other repeat expansions* +No. +The latter tend to be longer. +These repeats are unstable and can expand or contract +in different generations. +Rarely, +individuals may gain (trisomy) or lose (monosomy) a whole +chromosome. +40). +The rate of these breaks is dramatically +increased by exposure to ionising radiation. +If the joined fragments are from +different chromosomes, this results in a translocation. +3.7). +3.7 and Box 3.3). +Mutations can have +profound or subtle effects on gene and cell function. +• Neutral variants have no effect on quality or type of protein +produced. +• Loss-of-function mutations result in loss or reduction in the +normal protein function. +3.7 Chromosomal analysis and structural chromosomal disorders. +• Gain-of-function mutations result in a gain of protein +function. +as a common polymorphism. +There may be mutations that are advantageous for survival +in particular conditions (e.g. +About 1% of the human population carries constitutional mutations +that cause disease. +The basic symbols and nomenclature used in drawing a +pedigree are shown in Figure 3.8. +Both her maternal grandmother +and grandfather died of ‘old age’. +There is no family history of +note on her father’s side of the family. +He has one brother and +both his parents died of old age, in their eighties. +Anne has two +healthy daughters, aged 12 and 14 years, and a healthy full sister. +This family history is typical of an autosomal dominant condition +(Fig. +830 and Box 3.11, p. +57). +3.8 Drawing a pedigree and patterns of inheritance. +A The main symbols used to represent pedigrees in diagrammatic form. +for the rst time in an +affected individual). +Expressivity describes the level of severity of each aspect +of the disease phenotype. +There is a long list of autosomal dominant conditions, some +of which are shown in Box 3.4. +405 +Box 15.28, p. +415 +Tuberous sclerosis TSC1 +p. +1264 +TSC2 +p. +1264 +Marfan’s syndrome FBN1 p. +508 +Long QT syndrome KCNQ1 p. +476 +Brugada’s syndrome SCN5A p. +477 +Neurobromatosis type 1 NF1 p. +1131 +Box 25.77, p. +1132 +Neurobromatosis type 2 NF2 p. +1131 +Box 25.77, p. +1132 +Hereditary spherocytosis ANK1 p. +947 +Vascular Ehlers–Danlos syndrome (EDS type 4) COL3A1 p. +970 +Hereditary haemorrhagic telangiectasia ENG, ALK1, GDF2 p. +970 +Osteogenesis imperfecta COL1A1, COL1A2 p. +1055 +Charcot–Marie–Tooth disease PMP22, MPZ, GJB1 p. +81 +Mevalonic aciduria (mevalonate kinase deciency) MVK p. +81 +Autosomal recessive polycystic kidney disease (ARPKD) PKHD1 Box 15.28, p. +415 +Kartagener’s syndrome (primary ciliary dyskinesia) DNAI1 Box 17.30, p. +578 +Cystic brosis CFTR1 p. +580 +Box 17.30, p. +578 +p. +842 +Pendred’s syndrome SLC26A4 p. +650 +Congenital adrenal hyperplasia-21 hydroxylase deciency CYP21A p. +676 +Box 18.27, p. +658 +Haemochromatosis HFE p. +895 +Wilson’s disease ATP7B p. +896 +Alpha1 -antitrypsin deciency SERPINA1 p. +897 +Gilbert’s syndrome UGT1A1 p. +897 +Benign recurrent intrahepatic cholestasis ATP8B1 p. +902 +Alpha-thalassaemia HBA1, HBA2 p. +951 +p. +954 +Beta-thalassaemia HBB p. +951 +p. +953 +Sickle cell disease HBB p. +951 +Spinal muscular atrophy SMN1 p. +1117 +X-linked conditions +Alport’s syndrome COL4A5 Box 15.28, p. +415 +p. +403 +Primary agammaglobulinaemia BTK p. +78 +Haemophilia A (factor VIII deciency) F8 p. +971 +Haemophilia B (factor IX deciency) F9 p. +973 +Duchenne muscular dystrophy DMD p. +Jamie was shown to have the PiZZ phenotype. +Testing +confirmed both parents as carriers with PiMZ phenotypes. +In the family, Jamie has an older sister who has no medical +problems. +Mr Kent is one of four children with two brothers +and a sister and Mrs Kent has a younger brother. +Both sets +of grandparents are alive and well. +There is no family history of +Îą1 -antitrypsin deciency. +This family history is characteristic of an autosomal recessive +disorder (Fig. +• Parents are blood related; this is known as consanguinity. +Where there is consanguinity, the mutations are usually +homozygous, i.e. +the same mutant allele is inherited from +both parents. +X-linked inheritance +The following is an exemplar of an X-linked recessive pedigree +(Fig. +3.8): +Edward has a diagnosis of Duchenne muscular dystrophy +(DMD, Box 3.6). +Edward’s mother has +no additional siblings. +Edward’s +father has an older sister and an older brother who are both well. +3.1). +The risk of a female carrier having an affected child is 25% +or half of her male offspring. +Mitochondrial inheritance +The mitochondrion is the main site of energy production +within the cell. +Mitochondria arose during evolution via the +symbiotic association with an intracellular bacterium. +They +have a distinctive structure with functionally distinct inner and +outer membranes. +Mitochondria produce energy in the form +of adenosine triphosphate (ATP). +ATP is mostly derived from +the metabolism of glucose and fat (Fig. +3.9). +Glucose cannot +enter mitochondria directly but is rst metabolised to pyruvate +via glycolysis. +Both NADH and FADH2 then donate +electrons to the respiratory chain. +Dephosphorylation +of ATP is used to produce the energy required for many cellular +processes. +3.9). +The mutational +rate of mtDNA is relatively high due to the lack of protection by +chromatin. +Several mtDNA diseases characterised by defects +in ATP production have been described. +3.8). +3.9 Mitochondria. +A Mitochondrial structure. +B Mitochondrial DNA. +These are broken down by the β-oxidation cycle to +produce acetyl-co-enzyme A (acetyl-CoA). +these are called imprinted loci. +Examples of imprinting disorders +are given in Box 3.8. +Due +to loss-of-function mutations in the maternal UBE3A gene. +664). +1055). +The most important example of human disease caused by +somatic mutations is cancer (see Ch. +33). +33.3, p. +1318). +Cancer is thus a disease that affects the fundamental +processes of molecular and cell biology. +3.10). +Array CGH and other array-based approaches can detect +small chromosomal deletions and duplications. +3.10 Detection of chromosome abnormalities by comparative genomic hybridisation (CGH). +Ratios in excess of 1 indicate duplications, whereas ratios below 1 indicate +deletions. +3.11). +3.12). +3.13). +Each cluster will act as a single sequencing +reaction. +• Capture: if an entire genome is being sequenced, this step +will not be included. +ThisInterrogating the genome: the changing landscape of genomic technologies • 53 +DNA +sample +Fig. +3.11 The polymerase chain reaction (PCR). +The reaction is then cooled to +50–60°C, which allows the primers to bind to the target DNA. +The reaction +is then heated to 72°C, at which point the polymerase starts making new +DNA strands. +3.12). +Variants are identied as +differences between the read and the reference genome. +The number of reads that align at a given +point is called the ‘depth’ or ‘coverage’. +The higher the +read depth, the more accurate the variant call. +3.12 Sanger sequencing of DNA, which is very widely used in DNA diagnostics. +This is performed using PCR-amplied fragments of DNA +corresponding to the gene of interest. +The UK has so far advocated a +conservative approach to incidental ndings. +3.13 Sequencing by synthesis as used in the Illumina system. +Each bound fragment is hybridised. +(3) Sequencing. +initially problematic). +It is also cheaper than NGS, as fewer reagents are required. +The +accuracy of NIPT in detecting pregnancy-specic +aneuploidy approaches 98%. +Relevant +clinical information included the age of cancer diagnosis and +number/type of tumours. +50). +NGS has transformed the ability to diagnose individuals +affected by a rare disease. +This might be done through a gene panel, a +clinical exome or an exome (see Box 3.9 and p. +53), and has +increased the diagnostic yield in neurodevelopmental disorders +to approximately 30%. +In this situation, the +genetic contribution to disease is termed polygenic. +osteosarcoma, chondrosarcoma, +rhabdomyosarcoma) +Breast carcinoma +Brain cancer (esp. +In DNA +repair diseases, the inherited mutations increase the somatic +mutation rate. +BRCA1). +This is exemplied by BRCA1 and BRCA2 +(BRCA1/2)-related breast cancer. +PARP inhibitors block the single-strand break-repair pathway. +Genomics in infectious disease +NGS technologies are also transforming infectious disease. +79) has +been successful. +This therapeutic +approach could be applied to any genetic disease caused by +nonsense mutations. +Losartan is +an antihypertensive drug that is marketed as an angiotensin II +receptor antagonist. +As you read the scenario, try +to think what counselling/ethical issues might arise. +There is no signicant cancer family +history of note. +This needs to be fully explored +with the patient and her sister prior to testing. +There is +also the potential issue of predictive testing in the patient’s +rst child. +Essential cell biology, 4th edn. +New York: Garland Science; 2013. +Firth H, Hurst JA. +Oxford desk reference: clinical genetics. +Oxford: +Oxford University Press; 2005. +Read A, Donnai D. +New clinical genetics, 2nd edn. +Banbury: Scion; +2010. +Strachan T, Read A. +Human molecular genetics, 4th edn. +New York: +Garland Science; 2010. +decipher.sanger.ac.uk Excellent, comprehensive genomic database. +ensembl.org Annotated genome databases from multiple organisms. +genome.ucsc.edu Excellent source of genomic information. +ncbi.nlm.nih.gov Online Mendelian Inheritance in Man (OMIM). +4.1). +102). +Antibodies +generated by the adaptive immune system also act as opsonins. +4.2). +4.2 Phagocytosis and opsonisation. +This can immobilise or kill microorganisms without +requiring phagocytosis. +Monocytes and macrophages +Monocytes are the precursors of tissue macrophages. +They can also be found +in an immature state in the blood. +More than 100 have +been identied. +Two important signalling pathways are illustrated in Figure 4.3. +4.3 Cytokines signalling pathways and +the immune response. +4.2) signal through the +nuclear factor kappa B (NFÎşB) pathway. +985), and by the Toll-like receptors and NOD-like +receptors (see Fig. +4.2). +The +function and disease associations of several important cytokines +are shown in Box 4.2. +1026), and the tyrosine kinase +inhibitor imatinib, which is used in chronic myeloid leukaemia +(p. +959). +Their role in autoimmune disease has been extensively +studied. +1109). +Complement +proteins are produced in the liver and are present in inactive form +in the circulation. +918). +There are three mechanisms by which the complement cascade +can be activated (Fig. +Activation of complement by any of these pathways results in +activation of C3. +This can puncture the cell wall, +leading to osmotic lysis of target cells. +4.4 The complement pathway. +important in the defence against encapsulated bacteria such as +Neisseria spp. +and Haemophilus influenzae. +4.2). +408). +4.14). +The effects of inhibitory receptors normally +predominate. +This allows NK cells to remain tolerant +to healthy cells but not to damaged ones. +This is an important mechanism by which these cells then evade +adaptive T-lymphocyte responses. +The net result is NK attack on the abnormal target cell. +NK cells can also be activated by binding of antigen–antibody +complexes to surface receptors. +Activated NK cells can kill their targets in various ways. +4.1). +• It is highly adaptive and can respond to an almost +unlimited number of molecules. +There are two major arms of the adaptive immune response. +Lymphoid organs +The primary lymphoid organs are involved in lymphocyte +development. +914) +and where B lymphocytes also mature, and the thymus, the site +of T-cell maturation (see Fig. +4.1). +After maturation, lymphocytes +migrate to the secondary lymphoid organs. +These include the +spleen, lymph nodes and mucosa-associated lymphoid tissue. +The thymus +is most active in the fetal and neonatal period, and involutes +after puberty. +Failure of thymic development is associated with +profound T-cell immune deciency (p. +The spleen +The spleen is the largest of the secondary lymphoid organs. +influenzae infection (see Box 4.5). +When B cells +encounter antigen, they undergo intense proliferation, +forming germinal centres. +• The paracortex is rich in T lymphocytes and dendritic cells. +• The medulla is the major site of antibody-secreting plasma +cells. +• Within the medulla there are many sinuses, which contain +large numbers of macrophages. +It has a similar function to the more organised, encapsulated +lymph nodes. +They include the tonsils, adenoids and Peyer’s patches +in the small intestine. +14.13, p. +372). +They +eventually coalesce and drain into the thoracic duct and left +subclavian vein. +Lymphatics may be either deep or supercial, +and follow the distribution of major blood vessels. +4.5). +Encounters with antigen usually occur within lymph +nodes. +4.5). +Immunoglobulins +Immunoglobulins (Ig) play a central role in humoral immunity. +4.6). +The +heavy chain determines the antibody class or isotype, such +as IgG, IgA, IgM, IgE or IgD. +Subclasses of IgG and IgA also +occur. +Antibodies have several functions. +4.5 B-cell activation. +(CD = cluster of +differentiation; IL = interleukin) +Constant +region (Fc) +Heavy chain +Fig. +4.6 The structure of an immunoglobulin (antibody) molecule. +4.4). +In addition, antibodies can +directly neutralise the biological activity of their antigen target. +4.1). +4.7 T-cell activation. +Additional signals are required for T-cell activation, however. +Mature T lymphocytes leave the thymus +and expand to populate other organs of the immune system. +Unlike B cells, T cells cannot recognise intact protein antigens +in their native form. +4.7). +The structure of HLA molecules varies widely +between individuals. +83). +• Th2 cells typically produce IL-4, IL-5, IL-10 and IL-13, and +promote allergic responses (p. +84). +• Th17 cells are pro-inflammatory cells dened by their +production of IL-17. +This is used +to inhibit T-cell activation in rheumatoid arthritis and solid organ +transplantation. +The role of inflammation in specic +diseases is discussed in many other chapters of this book. +The classical external signs include heat, redness, pain +and swelling (Fig. +4.8). +The inflammatory process is initiated by +local tissue injury or infection. +These proteins have a wide range of activities. +941). +Immunoglobulins are not acute phase proteins +but are often increased in chronic inflammation. +Septic shock +Septic shock is the clinical manifestation of overwhelming +inflammation (p. +196). +4.8 Clinical features of acute inflammation. +In this example, the response is to a penetrating injury and infection of the foot. +Early recognition and appropriate early intervention can improve +patient outcome (p. +196). +Resolution of inflammation +Resolution of an inflammatory response is crucial for normal +healing. +If this is associated with local deposition of brous +tissue, a granuloma may form. +The platelet count may also be increased. +The most widely used +laboratory measure of acute inflammation is CRP. +Chronic inflammation is frequently associated with a normocytic +normochromic anaemia (p. +943). +by the composition of plasma proteins and the morphology of +circulating erythrocytes. +These factors govern the propensity +of red cells to aggregate, the major determinant of the ESR. +In addition, abnormal red cell +morphology can make rouleaux formation impossible. +For these +reasons, an inappropriately low ESR occurs in spherocytosis +and sickle-cell anaemia. +Sequential measurements +are useful in monitoring disease activity (Box 4.4). +Erythrocyte sedimentation rate +The ESR is an indirect measure of inflammation. +T-cell deciencies can involve pathogens from all groups. +Clinical assessment +Clinical features that may indicate immune deciency are listed in +Box 4.6. +Further management +depends on the underlying cause and details are provided later. +Š Jeffrey Modell Foundation. +Aspergillus spp. +–– Candida spp. +Aspergillus spp. +1040 and 1034), +but a familial fever syndrome is a potential cause. +Serum ferritin should be checked, as very high levels support the +diagnosis of Still’s disease. +Imaging may be required +to exclude occult infection. +81). +Negative genetic testing does not, however, +entirely exclude a periodic fever syndrome. +Common triggers are shown in Box 4.10. +Several +other conditions can mimic anaphylaxis and these are listed +in Box 4.11. +4.9 Clinical manifestations of anaphylaxis. +a guide. +Enquiry should be made about potential triggers. +If none +is immediately obvious, a detailed history of the previous 24 hours +may be helpful. +The most common triggers of anaphylaxis are +foods, latex, insect venom and drugs (see Box 4.10). +A history +of previous local allergic responses to the offending agent is +common. +Management +The principles of management of the acute event are summarised +in Box 4.12. +If the trigger factor cannot be identied or avoided, +recurrence is common. +The most important examples are illustrated +in Figure 4.10 and discussed below. +Intracellular killing of mycobacteria in macrophages +is also impaired. +Most cases +are X-linked (p. +48). +Specialised tests show +reduced or absent expression of adhesion molecules on neutrophils. +This section gives an overview of +primary immune deciencies. +4.10 Normal phagocyte function and mechanisms of primary phagocyte deciency. +4.4). +Clinical features +Patients with deciency in complement proteins can present in +different ways. +1034). +87). +If abnormal, haemolytic +tests are followed by measurement of individual complement +components. +influenzae B vaccines to +boost their adaptive immune responses. +Patients should also carry a MedicAlert or similar. +The management of C1 +esterase deciency is discussed elsewhere. +influenzae. +The most important causes +are discussed in more detail below. +X-linked agammaglobulinaemia +This rare X-linked disorder (p. +Affected males +present with severe bacterial infections during infancy. +There is +a marked reduction in B-cell numbers and immunoglobulin levels +are low or undetectable. +Management is with immunoglobulin +replacement therapy and antibiotics to treat infections. +4.11 B lymphocytes and primary antibody deciencies (green boxes). +patients, there is a compensatory increase in serum IgG levels. +Specic treatment is generally not required. +It is a heterogeneous adult-onset +primary immune deciency of unknown cause. +The presentation +is with recurrent infections, and bronchiectasis is a recognised +complication. +influenzae and S. +These functional tests have generally +superseded IgG subclass quantitation. +An exception is deciency of IgA, which usually does not +require treatment. +This +has been shown to minimise progression of end-organ damage +and improve clinical outcome. +Treatment may be self-administered +and is life-long. +These disorders generally present in childhood. +Several causes +of T-cell deciency are recognised. +These are summarised in +Figure 4.12 and discussed in more detail below. +4.12 T-lymphocyte function and dysfunction (green boxes). +(HLA = human leucocyte antigen) +B-cell-positive SCID. +Bone +marrow transplantation (BMT; p. +936) is the treatment option of +rst choice. +Serum immunoglobulins should also be measured. +Second-line, functional tests of T-cell activation and proliferation +may be indicated. +Patients in whom T-lymphocyte deciencies +are suspected should be tested for HIV infection (p. +310). +Immunoglobulin +replacement is indicated for associated defective antibody +production. +Stem cell transplantation (p. +936) or gene therapy +may be appropriate in some disorders. +Other features +include lymphadenopathy, splenomegaly and a variety of other +autoimmune diseases. +Susceptibility to infection is increased +because of the neutropenia. +The presentation is with +recurrent attacks of fever, arthralgia, myalgia, serositis and +rashes. +Attacks may be prolonged for 1 week or more. +As in FMF, the major +complication is amyloidosis, and regular screening for proteinuria +is advised. +Acute episodes respond to systemic glucocorticoids. +Therapy with IL-1 inhibitors, such as anakinra, can be effective +in preventing attacks. +• Antibody production: decreased for many exogenous antigens. +Although autoantibodies are frequently detected, autoimmune +disease is less common. +• Allergic disorders and transplant rejection: less common. +Latent infections, including tuberculosis and herpes zoster, may be +reactivated. +• Manifestations of inflammation: may be absent, with lack of +pyrexia or leucocytosis. +• Secondary immune deciency: common. +11), HIV (Ch. +12), haematological disorders +(Ch. +23) and oncology (Ch. +33). +Amyloid diseases are classied by the +aetiology and type of protein deposited (Box 4.18). +Clinical features +The clinical presentation may be with nephrotic syndrome +(p. +395), cardiomyopathy (p. +538) or peripheral neuropathy +(p. +1138). +Immunohistochemical staining can identify the +type of amyloid bril present. +When the latter +is possible, regression of existing amyloid deposits may occur. +74). +Symptoms +resolve completely between episodes. +Most individuals have +their rst attack before the age of 20. +The major complication +of FMF is AA amyloidosis (see below). +Most patients +are from Western Europe, particularly the Netherlands and +northern France. +It remains unclear why this causes an +inflammatory periodic fever. +However, if these responses cause signicant organ +damage, autoimmune diseases occur. +Autoimmune diseases develop when self- +reactive lymphocytes escape from these tolerance mechanisms. +Multiple genetic and environmental factors contribute to the +development of autoimmune disease. +Autoimmune diseases are +much more common in women than in men, for reasons that +remain unclear. +4.7) +and cell death. +Occasionally, autoimmune disease may +be an adverse effect of drug treatment. +Clinical features +The clinical presentation of autoimmune disease is highly variable. +• Type I hypersensitivity is relevant in allergy but is not +associated with autoimmune disease. +Generalised deposition of immune +complexes gives rise to systemic diseases such as SLE. +4.13A). +4.13B). +4.13 Autoantibody testing. +A Measurement of antibody levels by +enzyme-linked immunosorbent assay (ELISA). +The antigen of interest is +used to coat microtitre plates to which patient serum is added. +If +autoantibodies are present, these bind to the target antigen on the +microtitre plate. +B Qualitative analysis of autoantibodies by patterns of nuclear staining. +If antinuclear antibodies are present, they are detected as bright green +staining. +24). +Testing +for cryoglobulins requires the transport of a serum specimen to +the laboratory at 37°C. +950). +Not all conditions require immune suppression, however. +Allergy +They comprise a range of disorders from mild to life-threatening +and affect many organs. +4.14 and see Box 4.9). +4.14 Type I (immediate) hypersensitivity response. +C On re-encounter with allergen, +the allergen binds to the IgE antibody-coated mast cells. +Allergic IgE-mediated reactions vary from mild to +life-threatening. +Peanut allergy +Peanut allergy is the most common food-related allergy. +Cooked fruits and vegetables are tolerated without difculty. +Severe allergic reactions are unusual. +Potential +allergens in the home and workplace should be identied. +Genetic factors also contribute strongly to the +development of allergic diseases. +Clinical features +Common presentations of allergic disease are shown in Box +4.22. +These usually do not require specic treatment. +Toxic +reactions to venom after multiple (50–100) simultaneous stings +may mimic anaphylaxis. +Positive and negative control material must be included in the +assessment. +Results are unreliable in patients +with extensive skin disease. +These may be +particularly useful in the investigation of occupational asthma or +food allergy. +Tryptase is the most stable of these and is +easily measured in serum. +299 and +288), lymphoma (p. +1043). +Normal total IgE levels do not exclude allergic +disease. +Eosinophilia +Peripheral blood eosinophilia is common in atopic individuals but +lacks specicity. +928). +Long-acting, +non-sedating preparations are particularly useful for prophylaxis. +It is poorly absorbed and therefore ineffective +in the management of food allergies. +Sublingual +immunotherapy is also increasingly used. +572). +It is under investigation for allergic +rhinitis but not yet approved for this indication. +Management +Management depends on the underlying cause. +Pathophysiology +The causes of angioedema are summarised in Box 4.23. +4.15) but can also affect the +extremities and genitalia. +A clinical history +of allergy or drug exposure can give clues to the underlying +4 +A B +Fig. +4.15 Angioedema. +This young man has hereditary angioedema. +A Normal appearance. +B During an acute attack. +From Helbert M. +Flesh and bones of immunology. +Edinburgh: Churchill Livingstone, Elsevier +Ltd; 2006. +Management of angioedema associated with C1 +inhibitor deciency is discussed below. +4.4). +Episodes of angioedema are +self-limiting and usually resolve within 48 hours. +Patients with HAE +generally present in adolescence but may go undiagnosed for +many years. +A family history can be identied in 80% of cases. +HAE is not associated with allergic diseases and is specically +not associated with urticaria. +The diagnosis can be conrmed by measurement +of C1 inhibitor levels and function. +Tranexamic acid can be helpful as prophylaxis in some +patients. +It is associated with autoimmune +and lymphoproliferative diseases. +Some autoimmune diseases +may improve during pregnancy but flare immediately after delivery. +• Antiphospholipid syndrome (p. +977): an important cause of fetal +loss, intrauterine growth restriction and pre-eclampsia. +• HIV in pregnancy: see p. +326. +Treatment +of the underlying disorder may induce remission of angioedema. +As with HAE, a low C4 is seen during acute episodes. +Stem cell transplantation and its complications are +discussed on page 936. +67). +• Hyperacute rejection results in rapid and irreversible +destruction of the graft (Box 4.25). +• Acute cellular rejection is the most common form of graft +rejection. +It is mediated by activated T lymphocytes and +results in deterioration in graft function. +If allowed to +progress, it may cause fever, pain and tenderness over +the graft. +It is usually amenable to increased +immunosuppressive therapy. +• Acute vascular rejection is mediated by antibody formed +de novo after transplantation. +• Chronic allograft failure, also known as chronic rejection, +is a major cause of graft loss. +Potential transplant recipients +are also screened for the presence of anti-HLA antibodies. +The +recipient is excluded from receiving a transplant that carries +these alleles. +Post-transplant biopsy: C4d staining +C4d is a fragment of the complement protein C4 (see Fig. +4.4). +This is useful in the early diagnosis +of vascular rejection. +The major complications of long-term +immunosuppression are infection and malignancy. +Immunisation with killed vaccines is appropriate, +although the immune response may be curtailed. +Live vaccines +should not be given. +Organ donation +The major problem in transplantation is the shortage of organ +donors. +211), frequently +as a result of road trafc accidents or cerebrovascular events. +An alternative is the use of living donors. +Altruistic living donation, +usually from close relatives, is widely used in renal transplantation. +Tumour immunology +arise. +allergyuk.org UK site for patients and health-care professionals. +anaphylaxis.org.uk Provides information and support for patients with +severe allergies. +5.1 Global premature mortality: top 15 ranked +causes, 20151,2 +1. +Ischaemic heart disease (4) +2. +Cerebrovascular disease (5) +3. +Lower respiratory infections (1) +4. +Neonatal preterm birth complications (2) +5. +Diarrhoeal diseases (3) +6. +Neonatal encephalopathy (6) +7. +HIV/AIDS (29) +8. +Road injuries (10) +9. +Malaria (7) +10. +Chronic obstructive pulmonary disease (12) +11. +Congenital anomalies (9) +12. +Tuberculosis (11) +13. +Lung cancer3 (20) +14. +Self-harm (16) +15. +Diabetes (> 30) +1 By Years of Life Lost (YLL). +2 Rank in 1990 is shown in brackets. +3‘All cancers +combined’ would rank in the top three causes. +All estimates are presented by age and sex groups +and by regions of the world. +Many countries now also report +their own national burden of disease data. +The age-standardised +death rates for most diseases globally are falling. +Lower back and neck pain (1) +2. +Sense organ diseases (3) +3. +Depressive disorders (4) +4. +Iron deciency anaemia (2) +5. +Skin diseases (5) +6. +Diabetes (9) +7. +Migraine (6) +8. +Other musculoskeletal conditions3 (7) +9. +Anxiety disorders (8) +10. +Oral disorders (11) +11. +Asthma (10) +12. +Schizophrenia (13) +13. +Osteoarthritis (19) +14. +Chronic obstructive pulmonary disease (14) +15. +Falls (12) +1 By Years of Life lived with Disability (YLD). +2 Rank in 1990 is shown in brackets. +3 Not otherwise classied as specic conditions such as osteoarthritis. +the population to older ages, and this is placing an increasing +burden on health systems. +For a few conditions (e.g. +GBD also provides estimates of disability from disease (Box +5.2). +This, in turn, has resulted in greater health policy priority +being given to these conditions. +High blood pressure (3) +2. +Smoking/second-hand smoke exposure (5) +3. +High fasting blood glucose (10) +4. +High body mass index (13) +5. +Childhood underweight (1) +6. +Ambient particulate matter pollution (6) +7. +High total cholesterol (12) +8. +Household air pollution (4) +9. +Alcohol use (11) +10. +High sodium intake (14) +11. +Low wholegrain intake (15) +12. +Unsafe sex (20) +13. +Low fruit intake (16) +14. +Unsafe water (2) +15. +Low glomerular ltration rate (21) +1 By percentage of burden of disease they cause. +2 Rank in 1990 is shown in +brackets. +Low physical activity was ranked 21, iron +deciency 16 and suboptimal breastfeeding 22 in 2015. +5.1 Hierarchy of systems that influence population health. +Adapted from an original model by Whitehead M, Dahlgren G. +What can be +done about inequalities in health? +Lancet 1991; 338:1059–1063. +5.1). +The life course +The determinants of health operate over the whole lifespan. +Influences on +health can operate even before birth. +pp. +1184 and 880). +Smoking +Smoking is one of the top three risk factors underlying GBD (see +Box 5.3). +573 and 598), and most smokers die either from these or +from ischaemic heart disease. +Maternal smoking is an +important cause of fetal growth retardation. +However, smoking +rates remain high in many poorer areas and are increasing +among young women. +In many developing countries, tobacco +companies have found new markets and rates are rising. +A complex hierarchy of systems interacts to cause smokers +to initiate and maintain their habit. +Obesity +Obesity is an increasingly important risk factor underlying GBD (see +Box 5.3). +698). +Instead of infections, chronic conditions such as heart disease +dominate in an older population. +Adverse health consequences +of excessive affluence are also becoming apparent. +Many countries are now experiencing a ‘double burden’. +The essential criteria are: +• Is the disease an important public health problem? +• Is there a suitable screening test available? +• Is there a recognisable latent or early stage? +• Is there effective treatment for the disease at this stage +that improves prognosis? +4). +These are illustrated in Figure 5.2. +438). +If, in the example +above, the same 1000 people were observed for a year (i.e. +with no one joining or leaving the group), then the 1-year risk is +10% (100/1000). +The time period should always be specied. +Temporal variation may occur seasonally (e.g. +malaria occurs +in the wet season but not the dry) or as longer-term ‘secular’ +trends (e.g. +malaria may re-emerge due to drug resistance). +Place comparisons +include the local environment (e.g. +urban versus rural) and +international comparisons. +Of these, the +clinical trial is closest to the laboratory experiment. +Poorly designed or +executed trials can also limit comparability between groups. +Allocation may not be truly random (e.g. +Chronic diseases and risk factors (e.g. +smoking, obesity etc.) +are often described in terms of their prevalence. +A prevalence is +simply a proportion: e.g. +the prevalence of diabetes in people +aged 80 and older in developed countries is around 10%. +The reason person-time is less +than 1000 is that 100 people experienced the event. +5.2 UK NHS Pregnancy and Newborn Screening Programmes: optimum times for testing. +Smoking and carcinoma of the lung. +Epidemiologists therefore +seek to minimise bias and confounding by good study analysis +and design. +There is a long tradition of maintaining health information +systems. +5.4). +• Access to diagnostic skill and facilities is required. +5.3 An example of a clinical trial: streptomycin versus bed rest +in tuberculosis. +The reasons for doing so are +beyond the scope of this text. +These designs are also much more subject to the +problem of confounding than are randomised trials. +Here, smoking is said to confound the +association between coffee and lung cancer. +heart failure, respiratory failure. +It means the disease, injury, or complication that caused death. +Fig. +5.4 Completed death certicate. +International Classication of Diseases 10 (ICD-10) codes are appended in red. +WHO ICD-10, vol. +2; 1990. +As +such, deriving useful, unbiased information from such data is a +considerable challenge. +Much of the discipline of health informatics is concerned +with addressing this challenge. +Lancet 2016; 388:1545–1602. +GBD 2015 Mortality and Causes of Death Collaborators. +Lancet 2016; +388:1459–1544. +GBD 2015 Risk Factors Collaborators. +Lancet 2016; 388:1659–1724. +Kindig D, Stoddart G. +What is population health? +Am J Public Health +2003; 93:380–383. +Websites +fph.org.uk UK Faculty of Public Health: What is public +health? +The manifestations of disease +may aid pathogen dissemination (e.g. +diarrhoea). +transmissible +from person to person. +The chain of infection (Fig. +6.1) describes six essential +elements for communicable disease transmission. +Key challenges remain in +tackling infection in resource-poor countries. +Mycobacterium leprae, Tropheryma whipplei ) or members +of the normal human flora (e.g. +Escherichia coli, Candida spp.). +The following groups of infectious agents are now recognised. +Viruses +Viruses are incapable of independent replication. +Viruses’ genetic material (the genome) consists +of single- or double-stranded DNA or RNA. +Retroviruses transcribe +their RNA into DNA in the host cell by reverse transcription. +In many viruses, the +nucleocapsid is packaged within a lipid envelope. +A generic virus life +cycle is shown in Figure 6.2. +A virus that infects a bacterium is +a bacteriophage (phage). +The Gram-negative cell wall is surrounded by an outer +membrane containing lipopolysaccharide. +The same organism must be present in every case of the disease +2. +The organism must be isolated from the diseased host and grown +in pure culture +3. +The isolate must cause the disease, when inoculated into a healthy, +susceptible animal +4. +The organism must be re-isolated from the inoculated, diseased +animal +Fig. +6.1 Chain of infection. +The infectious agent is the organism that +causes the disease. +The reservoir is the place where the population of an +infectious agent is maintained. +The portal of exit is the point from which +the infectious agent leaves the reservoir. +The portal of entry is the body +site that is rst accessed by the infectious agent. +This takes place in nucleus +or cytoplasm, depending on the specific virus +Fig. +6.2 A generic virus life cycle. +Virus release is achieved either by budding, as illustrated, or by lysis of the cell membrane. +Life +cycles vary between viruses. +6.2 How bacteria are identied +Gram stain reaction (see Fig. +β-haemolysis of blood agar in +haemolytic streptococci; see Fig. +58) +and motile bacteria are equipped with flagella. +Although many +prokaryotes are capable of independent existence, some (e.g. +Chlamydia trachomatis, Coxiella burnetii) are obligate intracellular +organisms. +Pathogenic eukaryotes +are unicellular (e.g. +fungi, protozoa) or complex multicellular +organisms (e.g. +nematodes, trematodes and cestodes, p. +Corynebacterium diphtheriae +Lactobacillus spp. +Listeria monocytogenes +Nocardia spp. +Clostridium spp. +Enterobacter spp. +Serratia spp. +Salmonella spp. +Shigella spp. +Yersinia spp. +Vibrio spp. +Dimorphic fungi exist in either form, depending on environmental +conditions (see Fig. +11.59, p. +300). +Fungi have a cell wall made up of polysaccharides, +chitin and mannoproteins. +These differences from mammalian cells are important because +they offer useful therapeutic targets. +Protozoa and helminths are often referred to as parasites. +Prions are +covered on page 250. +These colonising +B +A +Fig. +This image is half life size. +×0.5. +Fusobacterium spp. +Candida spp. +Small bowel +Distally, progressively increasing +numbers of large bowel bacteria +Candida spp. +Large bowel +Enterobacteriaceae +Escherichia coli +Klebsiella spp. +Enterobacter spp. +Proteus spp. +Enterococci +E. +faecalis +E. +faecium +Streptococcus anginosus group +Strep. +anginosus +Strep. +intermedius +Strep. +constellatus +Anaerobic Gram-positive bacilli +Clostridium spp. +Anaerobic Gram-negative bacilli +Bacteroides spp. +Prevotella spp. +Candida spp. +Pharynx +Haemophilus spp. +Moraxella catarrhalis +Neisseria spp. +(including N. +meningitidis) +Staph. +aureus +Strep. +pneumoniae +Strep. +pyogenes (group A) +Oral streptococci (Îą-haemolytic) +6 +Skin +Coagulase-negative staphylococci +Staph. +aureus +Corynebacterium spp. +Propionibacterium spp. +Malassezia spp. +Hands +Resident: as for skin +Transient: skin flora (including +meticillin-resistant and other +Staph. +aureus), bowel flora +(including Clostridium difficile, +Candida spp. +and Enterobacteriaceae) +Vagina +Lactobacillus spp. +Staph. +aureus +Candida spp. +Enterobacteriaceae +Strep. +agalactiae (group B) +Perineum +As for skin +As for large bowel +Fig. +6.5 Human non-sterile sites and normal flora in health. +6.5). +Maintenance of the normal flora is beneficial to health. +For +example, lower gastrointestinal tract bacteria synthesise and +excrete vitamins (e.g. +lowering pH), producing antibacterial agents (e.g. +Conversely, normally sterile body sites must be kept sterile. +The urethral sphincter +prevents flow from the non-sterile urethra to the sterile bladder. +Overgrowth +is exemplied by dental caries, vaginal thrush and ‘blind loop’ +syndrome (p. +808). +Translocation results from spread along a +surface or penetration though a colonised surface, e.g. +Genetic diversity enhances the pathogenic capacity of bacteria. +This phenomenon accounts for influenza +pandemics (see Box 6.10). +Despite the obvious benets of an intact +host response, an excessive response is undesirable. +196). +Fever is mediated +mainly by ‘pyrogenic cytokines’ (e.g. +lipopolysaccharide) and factors released by injured cells. +Characteristics of successful pathogens +Successful pathogens have a number of attributes. +Many microorganisms, including viruses, use ‘adhesins’ to +attach to host cells initially. +Some pathogens can invade through +tissues. +Many bacterial and fungal infections form ‘biolms’. +Endotoxin is +the lipid component of Gram-negative bacterial outer membrane +lipopolysaccharide. +It is released when bacterial cells are damaged +and has generalised inflammatory effects. +Intracellular pathogens, including viruses, bacteria (e.g. +Salmonella spp., Listeria monocytogenes and Mycobacterium +tuberculosis), parasites (e.g. +Leishmania spp.) and fungi (e.g. +230) +pseudomembranous colitis +Botulism Clostridium botulinum (p. +1126) +Cholera Vibrio cholerae (p. +264) +Diphtheria Corynebacterium diphtheriae +(p. +265) +Haemolytic uraemic syndrome Enterohaemorrhagic Escherichia +coli (E. +coli O157 and other +strains) (p. +263) +Necrotising pneumonia Staphylococcus aureus (p. +250) +Tetanus Clostridium tetani (p. +1125) +Toxic shock syndrome Staphylococcus aureus (p. +252) +Streptococcus pyogenes (p. +253)Investigation of infection • 105 +Investigation of infection +organism and its background. +• Flow cytometry can be used to analyse liquid samples +(e.g. +urine) for the presence of particles based on +properties such as size, impedance and light scatter. +This +technique can detect bacteria but may misidentify other +particles as bacteria too. +70). +Pathogens may be detected +directly (e.g. +Careful sampling +increases the likelihood of diagnosis (Box 6.5). +6.5). +sensitivity, specicity, positive +and negative predictive value, p. +4). +Mycobacterium +tuberculosis. +collecting urine, or sputum for culture) +Use the correct container +• Certain tests (e.g. +contamination of blood culture samples) or +false-negative (e.g. +antigen, toxin) +• Nucleic acid amplication (e.g. +Other methods may +be used, such as tissue culture cytotoxicity assay for C. +difcile +toxin. +stool C. +difcile toxin). +The most +commonly used amplication method is the polymerase chain +reaction (PCR; see Fig. +3.11, p. +53). +Reverse transcription (RT) +PCR is used to detect RNA from RNA viruses (e.g. +hepatitis C +virus and HIV-1). +in hepatitis C +infection, p. +877). +NAATs are the most sensitive direct detection methods +and are also relatively rapid. +PCR is particularly +helpful for microorganisms that cannot be readily cultured, e.g. +Tropheryma whipplei, and is being used increasingly in mycology +and parasitology. +even in rapid-culture systems. +Chlamydia spp. +and viruses) grow only in culture systems, which are slow and +labour-intensive. +‘Blood-stream infection’ +(p. +225) is the association of bacteraemia/fungaemia with clinical +evidence of infection. +by +detecting products of microbial respiration using fluorescence; +Fig. +6.6). +If growth is detected, organisms are identied and +sensitivity testing is performed. +6.7). +It is rapid and accurate. +This can be clinically important in the +identication of the source of infection (p. +530). +Antibody detection +Organism-specic antibody detection is applied mainly to blood +(Fig. +6.8). +68). +tissue, swabs and body +fluids). +Microbial growth is usually detected +by constant automatic monitoring of +CO2. +6.6 An overview of the processing of blood cultures. +*In laboratories equipped with MALDI-TOF-MS (p. +106), rapid denitive organism +identication may be achieved at stage 6 and/or stage 8. +an antibody with an enzyme that generates a colour change on +exposure to a chromogenic substrate. +Various congurations allow +detection of antigens or specic subclasses of immunoglobulin +(e.g. +IgG, IgM, IgA). +in Lyme disease, p. +255). +Fluorescence is visualised +using a microscope. +Any +specic antibody in the serum will complex with the antigen. +Complement is then added to the reaction. +Sheep erythrocytes, coated with an anti-erythrocyte antibody, +are added. +Agglutination tests +When antigens are present on the surface of particles (e.g. +surface (O) antigens are +added because the antibodies cross-react with the +Proteus antigens. +The Widal test reaction uses a +suspension of Salmonella typhi and S. +paratyphi ‘A’ and +‘B’, treated to retain only ‘O’ and ‘H’ antigens. +The test is not specic but is still used in some parts of +the world. +The complexes +are seen on staining as ‘precipitin bands’. +Immunodiffusion is +used in the diagnosis of dimorphic fungi (p. +300) and some +forms of aspergillosis (p. +596). +Immunochromatography is used to detect antigen. +The system +consists of a porous test strip (e.g. +Test +material (e.g. +in +HIV 1 and malaria (p. +276). +Adapted from +Sobin K, Hameer D, Ruparel T. +Digital genotyping using molecular afnity +and mass spectrometry. +Nature Rev Genet 2003; 4:1001–1008. +6.8 Detection of antigen, nucleic acid and +antibody in infectious disease. +6.9 Antibody (Ab) and antigen (Ag) detection by enzyme-linked immunosorbent assay (ELISA). +This can be congured in various ways. +C Patient Ab and antibody–enzyme conjugate bind to immobilised specic Ag. +Magnitude of colour change reaction is inversely +proportional to concentration of patient Ab. +In A, the conjugate Ab is specic for human immunoglobulin. +In B–D, it is specic for Ag from the disease-causing organism. +The +principle behind IGRA is discussed on page 594. +Breakpoints are determined for each antimicrobial agent from +a combination of pharmacokinetic (p. +17) and clinical data. +Susceptibility testing is often carried out by disc diffusion +(Fig. +6.10). +The MIC is commonly measured +in diagnostic laboratories using ‘diffusion strips’. +12 +A B +F C +E D +34 +A B +F C +E D +Zone of +Zone of +inhibition +inhibition +5 +Fig. +1. +The test organism is spread over the surface of an agar plate. +2. +Antimicrobial-impregnated discs (A–F) are placed on the surface and +the plate is incubated (e.g. +overnight). +3–4. +After incubation, zones of +growth inhibition may be seen. +5. +This is exemplied +by HIV-1, which is believed to have originated in higher primates +in Africa. +The infectious agent is transmitted from this reservoir +to a susceptible host. +Human reservoirs +Both colonised individuals and those with infection can act as +reservoirs, e.g. +with Staph. +aureus (including MRSA), Strep. +pyogenes and C. +difficile. +tuberculosis, sexually transmitted infections). +Humans are +the only reservoir for some infections (e.g. +measles). +Infected animals may be asymptomatic. +Zoonotic agents may be transmitted via any of the routes +described below. +Q fever, brucellosis, Ebola). +Environmental reservoirs +Many infective pathogens are acquired from an environmental +source. +5). +temperature range, humidity). +Factors that alter geographical +restriction include: +• expansion of an animal reservoir (e.g. +Lyme disease from +reforestation) +• vector escape (e.g. +airport malaria) +• extension of host range (e.g. +schistosomiasis from dam +construction) +• human migration (e.g. +carbapenemase-producing +Klebsiella pneumoniae) +• public health service breakdown (e.g. +diphtheria in +unvaccinated areas) +• climate change (e.g. +dengue virus and Rift Valley fever). +Pediatr Infect Dis J 2001; +20:380–388. +2 Centers for Disease Control, USA; cdc.gov/measles/hcp/. +3 Bennett +JE, Dolin R, Blaser MJ. +Mandell, Douglas and Bennett’s Principles and practice +of infectious diseases, 8th edn. +Philadelphia: Elsevier; 2015. +7 Exclude for +3 weeks if untreated. +2 Longer incubation periods have been reported. +3 WHO. +4 Health +Protection Agency (now Health Protection England). +5 Richardson M, Elliman D, +Maguire H, et al. +Pediatr Infect Dis J 2001; 20:380–388. +6 Centers for Disease +Control, USA. +(SARS = severe acute respiratory syndrome) +6 +and humans in MRSA. +104) and host +susceptibility. +• Faecal–oral route: ingestion of material originating from +faeces. +• Sexually transmitted infections: direct contact between +mucous membranes. +• Blood-borne infections: direct inoculation of blood or body +fluids. +Most infection +by this route requires contact with damaged skin (e.g. +surgical wound). +6.1, p. +100). +MRSA) +Coliforms +Candida +Pseudomonas spp. +Enterococcus spp. +Other infections of particular concern in hospitals include +C. +difcile (p. +264) and norovirus (p. +249). +Some examples are +shown in Figure 6.12. +IPC measures are described in Box 6.8. +The most important +is maintenance of good hand hygiene (Fig. +6.13). +HandInfection prevention and control • 113 +Wash hands only when visibly soiled! +Otherwise use handrub! +Duration of the entire procedure: 40–60 sec. +6.13 Hand-washing. +All rights reserved. +difcile infection +Multidrug-resistant organisms (e.g. +MRSA, ESBL, +GRE, VRSA, penicillin-resistant Strep. +May differ from local or national recommendations. +2 Not a CDC recommendation. +3Subject to +local risk assessment. +4 Or in any immunocompromised patient until possibility of disseminated infection excluded. +aureus; VZV = varicella zoster virus) +decontamination (e.g. +using alcohol gel or washing) is mandatory +before and after every patient contact. +In situations where the prevalence of +C. +difcile is high (e.g. +difcile spores, and hands must be washed. +Some infections necessitate additional measures to prevent +cross-infection (Box 6.9). +If this is found not to be the case, the +term pseudo-outbreak is used. +When an outbreak of infection +is suspected, a case denition is agreed. +Surveillance ensures that disease outbreaks are either +prevented or identied early. +Reasons for +a disease to be classied as reportable are shown in Box 6.11. +Many +diseases are reportable for more than one reason. +Passive immunisation +is achieved by administering antibodies targeting a specic +pathogen. +Antibodies are obtained from blood, so confer some of +the risks associated with blood products (p. +933). +outbreak +water-cooling tower, medical staff member +shedding MRSA). +contaminated food at a +party). +May complicate point source or common source +person spread +outbreak +*Adapted from cdc.gov. +Types of vaccine +Whole-cell vaccines consist of live or inactivated (killed) +microorganisms. +Component vaccines contain only extracted or +synthesised components of microorganisms (e.g. +polysaccharides +or proteins). +68) and are therefore +more immunogenic than inactivated whole-cell vaccines. +vaccinated to curtail further spread. +Vaccination is aimed mainly +at preventing infectious disease. +Vaccination +guidelines for individuals are shown in Box 6.14. +Recommended vaccination +schedules vary between countries. +ward or clinic). +AMS aims to improve patient +outcomes and reduce antimicrobial resistance (AMR). +IPC and +AMS complement each other (Fig. +6.14). +Toxoids are +bacterial toxins that have been modied to reduce toxicity but +maintain antigenicity. +removal of an infected +medical device or necrotic tissue +• managing complications, e.g. +severe sepsis (systemic +inflammatory response syndrome, or SIRS, p. +196) and +acute kidney injury (p. +411). +Principles of antimicrobial therapy +In some situations (e.g. +The principles underlying the choice of antimicrobial agent(s) +are discussed below. +meningitis) before the microbiological cause is +known. +Targeted or ‘directed’ therapy can be prescribed when +the pathogen(s) is known. +‘Start Smart – Then Focus’ (Fig. +National or local guidelines +are often used to inform antimicrobial prescribing decisions. +biolm infections) +• when no single agent’s spectrum covers all potential +pathogens (e.g. +antituberculous chemotherapy, +p. +592; antiretroviral therapy (ART), p. +324). +6.16) to all classes of antimicrobial agent +(antibiotics and their derivatives). +via a plasmid, p. +100). +Plasmids +often encode resistance to multiple antibiotics. +Plasmid-encoded carbapenemases have +been detected in strains of Klebsiella pneumoniae (e.g. +New Delhi +metallo-β-lactamase 1, NDM-1). +Penicillin, metronidazole, clindamycin +Fusobacterium spp. +There are many appropriate +alternatives to those listed. +6.16 Examples of mechanisms of antimicrobial resistance. +aureus; NDM-1 = New Delhi metallo-β-lactamase 1). +Factors promoting antimicrobial resistance include the +inappropriate use of antibiotics (e.g. +Despite use of +combination therapy for M. +Knowledge of +anticipated antimicrobial drug concentrations at sites of infection +is critical. +The concentration of antimicrobial +achieved after a single dose is illustrated in Figure 6.17. +The efcacy +of antimicrobial agents whose killing is concentration-dependent +(e.g. +For this reason, it has become customary to administer +aminoglycosides (e.g. +gentamicin) infrequently at high doses +(e.g. +7 mg/kg) rather than frequently at low doses. +vancomycin) are +adequate. +530). +colonic +resection or prosthetic hip insertion), following exposure to +a specic pathogen (e.g. +Bordetella pertussis) or in specic +situations such as post-splenectomy (Box 6.18). +6.17 Antimicrobial pharmacodynamics. +The curve represents drug +concentrations after a single dose of an antimicrobial agent. +meningococcal meningitis), and may +be administered by continuous infusion. +278) +*These are based on current UK practice. +Recommendations may vary locally or +nationally. +In the case of exposure, +it may be combined with passive immunisation (see Box 6.12). +They are classied +in Box 6.21. +• CSF levels are low, except when meninges are inflamed. +• Activity is not inhibited in abscess (e.g. +by low pH and +PO2, high protein or neutrophils). +• Generally safe in pregnancy (except imipenem/cilastatin). +Adverse effects +Immediate (IgE-mediated) allergic reactions are rare but life- +threatening. +Other reactions, +such as rashes, fever and haematological effects (e.g. +low +white cell count), usually follow more prolonged therapy (more +than 2 weeks). +84). +The monobactam aztreonam (p. +121) is the β-lactam +least likely to cross-react in patients with penicillin allergy. +More +severe forms of hepatitis can be observed with flucloxacillin +and co-amoxiclav. +British National Formulary +(online). +London: BMJ Group and Pharmaceutical Press; (medicinescomplete. +com) [accessed on 16 March 2013]. +2Theoretical risk of teratogenicity, not +supported by available clinical evidence. +ciprofloxacin) especially so. +• Hypersensitivity reactions: rise in incidence due to increased +previous exposure. +• Renal impairment: may be signicant in old age, despite ‘normal’ +creatinine levels (p. +386). +• Nephrotoxicity: more likely, e.g. +rst-generation cephalosporins, +aminoglycosides. +• Accumulation of β-lactam antibiotics: may result in myoclonus, +seizures or coma. +• Reduced hepatic metabolism: results in a higher risk of +isoniazid-related hepatotoxicity. +• Quinolones: associated with delirium and may increase the risk of +seizures. +122). +Thrombophlebitis +occurs in up to 5% of patients receiving parenteral β-lactams. +Drug interactions +Synergism occurs in combination with aminoglycosides in vitro. +Strep. +pyogenes has +remained sensitive to natural penicillins worldwide. +pneumoniae in Europe in 2014 varied widely from 0% +(Cyprus) to 46.7% (Romania). +Penicillinase-resistant penicillins are the mainstay of treatment +for infections with Staph. +aureus, other than MRSA. +Amoxicillin has better oral absorption than +ampicillin. +Unfortunately, resistance to these agents is widespread +(57.1% of E. +Carboxypenicillins (e.g. +ticarcillin) and ureidopenicillins (e.g. +Beta-lactamase inhibitors may be added +to extend their spectrum of activity (e.g. +piperacillin–tazobactam). +Cephalosporins and cephamycins +Cephalosporins are broad-spectrum agents. +Unfortunately, +their use is associated with CDI (p. +264). +With the exception of +ceftobiprole, the group has no activity against enterococci. +Only +the cephamycins have anti-anaerobic activity. +All cephalosporins +are inactivated by ESBL. +Cephalosporins are arranged in +‘generations’ (Box 6.22). +• Second-generation drugs retain Gram-positive activity but +have extended Gram-negative activity. +Cephamycins (e.g. +cefoxitin), included in this group, are active against +anaerobic Gram-negative bacilli. +• Third-generation agents further improve anti-Gram- +negative cover. +For some (e.g. +ceftazidime), this is +extended to include Pseudomonas spp. +pneumoniae and +β-haemolytic streptococci. +• Fourth-generation agents, e.g. +aeruginosa. +aeruginosa. +The spectrum of cephalosporins has also been enhanced by +adding β-lactamase inhibitors. +Monobactams +Aztreonam is the only available monobactam. +imipenem, meropenem, +ertapenem). +Macrolide and lincosamide antibiotics +Macrolides (e.g. +erythromycin, clarithromycin and azithromycin) +and lincosamides (e.g. +clindamycin) are bacteriostatic agents. +Both classes bind to the same component of the ribosome, +so they are not administered together. +Macrolides are used for +Legionella, Mycoplasma, Chlamydia and Bordetella infections. +infections. +Clindamycin +is used primarily for skin, soft tissue, bone and joint infections. +• High protein binding. +• Excellent intracellular accumulation. +Lincosamides (e.g. +clindamycin) +• Good oral bioavailability. +• Food has no effect on absorption. +• Good bone/joint penetration; limited CSF penetration. +Adverse effects +• Gastrointestinal upset, especially in young adults +(erythromycin 30%). +• Cholestatic jaundice with erythromycin estolate. +• Prolongation of QT interval can cause torsades de pointes +(p. +476). +• Clindamycin predisposes to CDI. +Some aminoglycosides, e.g. +amikacin, are important components of therapy for MDR-TB. +They +cause very little local irritation at injection sites and negligible +allergic responses. +Aminoglycosides are not subject to +an inoculum effect (p. +120) and they all exhibit a post-antibiotic +effect (p. +119). +Pharmacokinetics +• Negligible oral absorption. +• Very poor intracellular penetration (except hair cells in +cochlea and renal cortical cells). +• Peak plasma levels 30 minutes after infusion. +• Monitoring of therapeutic levels required. +6.18). +6.18 Dosing of aminoglycosides using the Hartford nomogram. +are < 1 mg/L and 5–10 mg/L (7–10 mg/L with less +sensitive organisms, e.g. +P. +aeruginosa), respectively. +• For other aminoglycosides, consult local guidance. +Adverse effects +• Renal toxicity (usually reversible) accentuated by other +nephrotoxic agents. +Unfortunately, resistance to spectinomycin is very common. +Ciprofloxacin has anti-pseudomonal activity but resistance +emerges rapidly. +In 2014, European surveillance showed that +resistance to fluoroquinolones in E. +coli ranged between 7.8% +(Iceland) and 46.4% (Cyprus). +• Wide volume of distribution; tissue concentrations twice +those in serum. +• Nephrotoxicity is rare but may occur with concomitant +aminoglycoside use, as may ototoxicity. +• Teicoplanin can cause rash, bronchospasm, eosinophilia +and anaphylaxis. +aureus infective endocarditis. +Daptomycin +is not effective for community-acquired pneumonia. +Treatment +can be associated with increased levels of creatine kinase and +eosinophilic pneumonitis. +aeruginosa +and Acinetobacter baumannii. +It can be administered by oral, intravenous and +nebulised routes. +Signicant adverse effects include neurotoxicity, +including encephalopathy, and nephrotoxicity. +Folate antagonists +These are bacteriostatic antibacterials (p. +109). +aureus. +Pharmacokinetics +• Well absorbed orally. +• Sulphonamides are hydrophilic, distributing well to the +extracellular fluid. +• Trimethoprim is lipophilic with high tissue concentrations. +Adverse effects +• Trimethoprim is generally well tolerated, with few adverse +effects. +948). +• Dapsone causes methaemoglobinaemia (p. +135) and +peripheral neuropathy. +pneumoniae, ‘atypical’ respiratory +pathogens* +Moxifloxacin Oral Strep. +pneumoniae, Staph. +Fluoroquinolones have variable activity against M. +tuberculosis and other +mycobacteria. +Adverse effects +• Gastrointestinal side-effects in 1–5%. +• Rare skin reactions (phototoxicity). +• Tendinitis and Achilles tendon rupture, especially in older +people. +• Prolongation of QT interval on ECG, cardiac arrhythmias. +• Ciprofloxacin use is associated with the acquisition of +MRSA and emergence of C. +difcile ribotype 027 (p. +264). +Some staphylococci and +enterococci demonstrate intermediate sensitivity or resistance. +Vancomycin use should be restricted to limit emergence of +resistant strains. +Teicoplanin is not available in all countries. +Neither drug is absorbed after oral administration but vancomycin +is used orally to treat CDI. +Tetracyclines can also +be used for malaria prevention. +calcium or iron, which should not +be administered at the same time. +Adverse effects +• All tetracyclines except doxycycline are contraindicated in +renal failure. +• Dizziness with minocycline. +• Oesophagitis/oesophageal ulcers with doxycycline. +• Phototoxic skin reactions. +difcile and other Clostridium +spp. +They also have signicant antiprotozoal activity against +amoebae and Giardia lamblia. +• Well distributed, especially to brain and CSF. +• Safe in pregnancy. +Adverse effects +• Metallic taste (dose-dependent). +• Severe vomiting if taken with alcohol – ‘Antabuse effect’. +• Peripheral neuropathy with prolonged use. +Phenicols +Chloramphenicol is the only example in clinical use. +It is +bacteriostatic to most organisms but apparently bactericidal to +H. +influenzae, Strep. +pneumoniae and N. +meningitidis. +Administration can be intravenous or oral. +Common linezolid adverse effects include mild gastrointestinal +upset and tongue discoloration. +Myelodysplasia and peripheral +and optic neuropathy can occur with prolonged use. +1199). +It is lipid-soluble and +distributes well to tissues. +Its antibacterial activity is, however, +unpredictable. +It interacts with coumarin derivatives and oral +contraceptives. +Its effectiveness has not been assessed in +severe CDI. +Fosfomycin +Fosfomycin acts by inhibiting cell wall synthesis. +Mutations in KatG +or InhA result in isoniazid resistance, which was reported in 15% +of cases of M. +tuberculosis infection globally in 2013. +Isoniazid is +well absorbed orally and metabolised by acetylation in the liver. +Rifampicin +is well absorbed orally. +Common side-effects include +hepatitis, influenza-like symptoms and hypersensitivity reactions. +Orange discoloration of urine and body secretions is expected. +Pyrazinamide is well +absorbed orally and metabolised by the liver. +Side-effects include +nausea, hepatitis, asymptomatic elevation of uric acid and myalgia. +Ethambutol +Ethambutol is a bacteriostatic agent. +Resistance is usually +seen when resistance to other antimycobacterial agents is also +present, e.g. +in MDR-TB strains. +It can also cause hepatitis. +It is administered intramuscularly. +Other antituberculous agents +Second-line agents used in MDR or XDR strains (p. +Their co-administration with +other agents with a similar side-effect prole (e.g. +fluoroquinolones) +therefore requires careful risk assessment. +Clofazimine +Clofazimine is used against M. +leprae and resistant strains of M. +tuberculosis. +Its mode of action may involve induction of oxidative +stress and it is weakly bactericidal. +Oral absorption is variable +and it is excreted in the bile. +Antifungal agents +See Box 6.24. +300), +Aspergillus spp. +(no activity against +Cryptococcus spp. +Side-effects vary but +include gastrointestinal upset, hepatitis and rash. +24). +Clotrimazole +is used extensively to treat supercial fungal infections. +Triazoles +are used for systemic treatment because they are less toxic. +Itraconazole is lipophilic and distributes extensively, including to +toenails and ngernails. +CSF penetration is poor. +Because oral +absorption is erratic, therapeutic drug monitoring is required. +It is used mainly in aspergillosis +(p. +596). +Side-effects include photosensitivity, hepatitis and +transient retinal toxicity. +and some mucoraceous moulds. +Echinocandins +The echinocandins inhibit β-1,3-glucan synthesis in the fungal +cell wall. +They have few signicant adverse effects. +Its +use in resource-rich countries has been largely supplanted by less +toxic agents. +Its long half-life enables once-daily administration. +CSF penetration is poor. +It may be ameliorated by concomitant +infusion of normal saline. +Irreversible nephrotoxicity occurs with +large cumulative doses of AmB. +Nystatin has a similar spectrum of antifungal activity to +AmB. +Its toxicity limits it to topical use, e.g. +in oral and vaginal +candidiasis. +The drug becomes active on dissociating from its lipid +component. +1327), and also in visceral leishmaniasis (p. +282). +Adverse effects include myelosuppression, +gastrointestinal upset and hepatitis. +It +is deposited in keratin precursor cells, which become resistant +to fungal invasion. +It is used topically for +dermatophyte skin infections and orally for onychomycosis. +The +major adverse reaction is hepatic toxicity (approximately 1: 50 000 +cases). +Terbinane is not recommended for breastfeeding mothers. +Antiviral agents +Most viral infections in immunocompetent individuals resolve +without intervention. +Antiviral therapy is available for a limited +number of infections only (Box 6.25). +Antiretroviral agents +These agents, used predominantly against HIV, are discussed +on page 324. +Famciclovir is the prodrug of penciclovir. +Resistance is mediated by viral TK or polymerase mutations. +Ganciclovir is administered +intravenously or as a prodrug (valganciclovir) orally. +It has variable CSF penetration. +6.2, +p. +101). +They are used in the treatment and prophylaxis of influenza. +in intensive care units. +It is now approved for +use in adults in a number of countries. +An intravenous formulation of +zanamivir is also in development for critically ill patients. +Laninamivir +is approved as an intranasal formulation in Japan. +6.2). +ventilated +patients). +Lassa fever, although it has not been +useful against Ebola virus. +Its derivatives, artemether and artesunate, were developed +for use in malaria in the 1970s. +Their mechanism of action is +unknown. +that are resistant +to other antimalarials. +Artemether is lipid-soluble and may be +administered via the intramuscular and oral routes. +Artesunate is +water-soluble and is administered intravenously or orally. +Serious +adverse effects are uncommon. +Atovaquone +Atovaquone inhibits mitochondrial function. +Signicant adverse effects are uncommon. +Pyrimethamine–sulfadoxine may be used in the +treatment of malaria. +They are employed in the treatment and prophylaxis +of malaria. +Primaquine is used for radical cure of malaria due to +Plasmodium vivax and P. +ovale (destruction of liver hypnozoites). +Chloroquine may also be given for extra-intestinal amoebiasis. +Chloroquine can cause a pruritus sufcient to compromise +adherence to therapy. +If used in long-term, high-dose regimens, +it causes an irreversible retinopathy. +Overdosage leads to life- +threatening cardiotoxicity. +Quinine +may cause hypoglycaemia and cardiotoxicity, especially when +administered parenterally. +Primaquine causes haemolysis in +people with glucose-6-phosphate dehydrogenase deciency +(p. +948), which should be excluded before therapy. +Its mechanism of action is unknown. +Signicant adverse +effects are uncommon. +279). +brucei gambiense infection) of the central +nervous system. +brucei +rhodesiense and gambiense). +It is administered intravenously. +Gastrointestinal and +neurological adverse effects are common. +brucei gambiense) and, to a lesser extent, +in visceral and cutaneous leishmaniasis. +It is also prescribed +in Pneumocystis jirovecii pneumonia. +It is administered via +intravenous or intramuscular routes. +Suramin +Suramin is a naphthaline dye derivative, used to treat East +African trypanosomiasis (T. +brucei rhodesiense). +It is administered +intravenously. +They +are used parenterally (intravenous or intramuscular) to treat +leishmaniasis. +The drug is absorbed slowly (enabling luminal +persistence) and has no effect in hepatic amoebiasis. +It is a +relatively non-toxic drug, the most signicant adverse effect +being flatulence. +Iodoquinol (di-iodohydroxyquinoline) +Iodoquinol is a quinoline derivative (p. +128) with activity against +Entamoeba histolytica cysts and trophozoites. +metronidazole), to treat extra-intestinal amoebiasis. +Nitazoxanide also +has activity against some anaerobic bacteria and viruses. +It is +administered orally in giardiasis and cryptosporidiosis. +Adverse +effects are usually mild and involve the gastrointestinal tract (e.g. +nausea, diarrhoea and abdominal pain). +Paromomycin +Paromomycin is an aminoglycoside (p. +122) that is used to +treat visceral leishmaniasis and intestinal amoebiasis. +Mebendazole is used for hookworm, +ascariasis, threadworm and whipworm. +The drugs are administered +orally. +Absorption is relatively poor but is increased by a fatty +meal. +Signicant adverse effects are uncommon. +Bithionol +Bithionol is used to treat fluke infections with Fasciola +hepatica. +It is well absorbed orally. +Adverse effects are mild +(e.g. +nausea, vomiting, diarrhoea, rashes) but relatively common +(approximately 30%). +Diethylcarbamazine +Diethylcarbamazine (DEC) is an oral agent used to treat lariasis +and loiasis. +It is an oral agent, +used in Strongyloides infection, lariasis and onchocerciasis. +Signicant side-effects are uncommon. +Niclosamide +Niclosamide inhibits oxidative phosphorylation, causing paralysis +of helminths. +It is an oral agent, used in Taenia saginata and +intestinal T. +solium infection. +Systemic absorption is minimal and +it has few signicant side-effects. +Piperazine +Piperazine inhibits neurotransmitter function, causing helminth +muscle paralysis. +It is an oral agent, used in ascariasis and +threadworm (Enterobius vermicularis) infection. +It is the drug of choice +for schistosomiasis and is also used in T. +saginata, T. +solium +(cysticercosis) and fluke infections (Clonorchis, Paragonimus) +and in echinococcosis. +It is administered orally and is well +absorbed. +Adverse effects are usually mild and transient, and +include nausea and abdominal pain. +It is used orally in ascariasis and +threadworm infection. +Systemic absorption is poor and adverse +effects are uncommon. +It is used orally in Strongyloides +infection and topically to treat cutaneous larva migrans. +Signicant +adverse effects are uncommon. +Further information +6 +Websites +cdc.gov Centers for Disease Control and Prevention, Atlanta, USA. +Provides information on all aspects of communicable disease, +including prophylaxis against malaria. +dh.gov.uk UK Department of Health. +The publications section provides +current UK recommendations for immunisation. +ecdc.europa.eu European Centre for Disease Prevention and +Control. +Includes data on prevalence of antibiotic resistance in +Europe. +gov.uk/government/organisations/public-health-england Public Health +England. +idsociety.org Infectious Diseases Society of America. +Publishes +up-to-date, evidence-based guidelines. +who.int World Health Organization. +Macleod’s Clinical examination, 11th edn. +Churchill Livingstone, Elsevier Ltd; 2005. +(Chemical burn) www.rewiki.net. +(Needle tracks) www.deep6inc.com. +(Pinpoint pupil) http://drugrecognition.com/images. +(Injected conjunctiva) http:// +knol.google.com. +Taking a history in poisoning +• What toxin(s) have been taken and how much? +• What time were they taken and by what route? +• Obtain details from witnesses (e.g. +Common or otherwise important substances +involved are shown in Box 7.1. +Accidental poisoning is also common, especially +in children and the elderly (Box 7.2). +In developing countries, the frequency of self-harm is more +difcult to estimate. +In China and South-east Asia, +pesticides account for about 300 000 suicides each year. +General approach to the +poisoned patient +A general approach is shown on pages 132–133. +Information is also available online (p. +150). +133). +Critically ill patients must be resuscitated (p. +174). +The AVPU (alert/verbal/painful/unresponsive) scale +is also a rapid and simple method. +Clinical assessment and investigations +History and examination are described on page 132. +Toxic causes of abnormal physical signs are shown on +page 133. +opiates, benzodiazepines), +stimulants and entactogens (e.g. +amphetamines, MDMA, +mephedrone, cocaine), hallucinogens (e.g. +Toxic prescription +medicines are more likely to be available. +There is a +higher risk of subsequent suicide. +7.3 Substances of very low toxicity +• Writing/educational materials, e.g. +pencil lead, crayons, chalk +• Decorating products, e.g. +7.1 Methaemoglobinaemia. +1 All units should be in mmol/L, except osmolality, which should be in mOsmol/kg. +2 Box 14.19 +(p. +365) gives non-toxic causes. +in younger people, but it is important to exclude other potential +causes (p. +194). +Calculation of anion and osmolar +gaps may help to inform diagnosis and management (Box 7.5). +7.1). +1187). +These are described on +page 133. +Use is ineffective for some toxins +that do not bind to activated charcoal (Box 7.6). +It is contraindicated if strong acids, alkalis +or petroleum distillates have been ingested. +If the urine is alkalinised (pH > 7.5) by the administration +of sodium bicarbonate (e.g. +1.5 L of 1.26% sodium bicarbonate +over 2 hrs), weak acids (e.g. +salicylates, methotrexate) are highly +ionised, resulting in enhanced urinary excretion. +It is also sometimes +used for poisoning with methotrexate. +Complications include +alkalaemia, hypokalaemia and occasionally alkalotic tetany +(p. +367). +Hypocalcaemia may occur but is rare. +Haemodialysis can also correct +acid–base and metabolic disturbances associated with poisoning +(p. +135). +It +involves intravenous infusion of 20% lipid emulsion (e.g. +Antidotes +Antidotes are available for some poisons and work by a variety +of mechanisms (Box 7.9). +The use of some of these in the +management of specic poisons is described below. +This results in hepatic and occasionally renal +failure. +Management +Activated charcoal may be used in patients presenting within +1 hour. +7.2). +Common features are itching and urticaria, and in severe +cases, bronchospasm and hypotension. +856). +Direct stimulation of the respiratory centre +produces hyperventilation and respiratory alkalosis. +Agitation, delirium, coma and ts may occur, especially +in children. +Management +Activated charcoal should be administered if the patient presents +within 1 hour. +Multiple doses may enhance salicylate elimination +but are not routinely recommended. +Dehydration should be corrected carefully because of the risk +of pulmonary oedema. +Urinary alkalinisation is indicated for adults +with salicylate concentrations above 500 mg/L. +Activated charcoal +may be given if the patient presents within 1 hour. +Symptomatic +treatment for nausea and gastrointestinal irritation may be needed. +Clinical features +Anticholinergic effects are common (Box 7.10). +7.2 Paracetamol treatment nomogram (UK). +Above the treatment +line, benets of treatment outweigh risk. +Hypoxia and electrolyte abnormalities should also +be corrected. +Anti-arrhythmic drugs should only be given on +specialist advice. +Prolonged seizures should be treated initially +with intravenous benzodiazepines (see Box 7.8). +Agitation, drowsiness and +convulsions occur infrequently and may be delayed for several +hours. +Cardiac arrhythmias occur infrequently and most patients +require supportive care only. +Management +Activated charcoal is ineffective. +Whole bowel irrigation is often used after substantial +overdose but efcacy is unproven. +The usual therapeutic range +is 0.4–1.0 mmol/L. +Adequate hydration should be maintained +with intravenous fluids. +Seizures should be treated as in Box 7.8. +7.3 ECG in severe tricyclic antidepressant poisoning. +This rhythm +strip shows a broad QRS complex due to impaired conduction. +tachycardia, ventricular brillation and, less commonly, heart +block). +Hypotension results from inappropriate vasodilatation or +impaired myocardial contractility. +Serious complications appear +more common with dosulepin and amitriptyline. +Management +Activated charcoal should be administered if the patient presents +within 1 hour. +A 12-lead ECG should be taken and continuous +cardiac monitoring maintained for at least 6 hours. +7.3). +QT interval prolongation may also occur. +Arterial blood gases +should be measured in suspected severe poisoning. +Severe +poisoning is often associated with hyperkalaemia. +After chronic exposure, concentrations +> 5 mmol/L suggest serious poisoning. +Signicant bradycardias +may respond to atropine, although temporary pacing is sometimes +needed. +Ventricular arrhythmias may respond to intravenous +magnesium (see Box 7.8). +These are effective for +both digoxin and yellow oleander poisoning. +Those with additional sodium channel-blocking effects +(e.g. +476). +Calcium channel blockers +L-type calcium channel blockers are highly toxic in overdose. +Dihydropyridines (e.g. +Isoproterenol and glucagon +may also be useful. +Cardiac pacing may be needed for severe +unresponsive bradycardias or heart block. +Gastrointestinal strictures are late complications. +> 5 mg/L). +Desferrioxamine may cause hypotension, allergic reactions +and occasionally pulmonary oedema. +QT interval prolongation and +torsades de pointes can occur with some typical (e.g. +haloperidol) +and atypical (e.g. +quetiapine, amisulpride, ziprasidone) agents. +Management +Activated charcoal may be of benet if given early. +Cardiac +monitoring should be undertaken for at least 6 hours. +Management +is largely supportive, with treatment directed at complications +(see Box 7.8). +Antidiabetic agents +Overdose is uncommon but toxic effects can be severe. +Clinical features +Sulphonylureas, meglitinides (e.g. +738). +Permanent neurological damage +can occur if hypoglycaemia is prolonged. +Metformin is uncommonly associated with hypoglycaemia. +There is limited experience of overdose involving +thiazolidinediones (e.g. +pioglitazone) and dipeptidyl peptidase +4 (DPP-4) inhibitors (e.g. +sitagliptin) but signicant hypoglycaemia +is unlikely. +Management +Activated charcoal should be considered for recent substantial +overdose. +cerebral haemorrhage or oedema). +In severe cases, +haemodialysis or haemodialtration is used. +Drugs of misuse +Drugs of misuse are common causes of toxicity requiring hospital +admission. +2IV use. +(GHB = gamma hydroxybutyrate; MDMA = 3,4-methylene-dioxymethamphetamine) +(Box 7.12). +Other complications of coma include pressure blisters +or sores and rhabdomyolysis. +Effects are potentiated by other +CNS depressants, including alcohol. +Essential supportive care is detailed in Box 7.8. +Antidotes are +available for some depressants. +Benzodiazepines +Benzodiazepines (e.g. +diazepam) and related substances (e.g. +TCAs) and those with a history of epilepsy. +experience, often accompanied by heightened sexual arousal. +Physical dependence occurs within a few weeks of regular +high-dose use. +Examination reveals tachycardia, hypertension, mydriasis and +facial flushing. +Commonly encountered opioids and clinical features of +poisoning are shown in Box 7.12. +Needle tracks may be visible +in intravenous users and there may be drug-related paraphernalia. +Methadone may also cause QTc prolongation and torsades de +pointes. +Patients should be monitored for at +least 6 hours after the last naloxone dose. +Rare complications +of naloxone therapy include ts, ventricular arrhythmias and +pulmonary oedema. +Coma +usually resolves abruptly within a few hours but occasionally +persists for several days. +Management is largely supportive. +Withdrawal symptoms may require treatment +with very high doses of benzodiazepine. +include mephedrone and methylenedioxypyrovalerone. +Tolerance +is common, leading regular users to seek ever higher doses. +Sympathomimetic stimulant and serotonergic effects are common +(see Boxes 7.10 and 7.12). +Management is supportive and directed at complications +(see Box 7.8). +Effects occur 10–30 minutes after smoking or 1–3 hours +after ingestion, and last 4–8 hours. +High doses may produce +anxiety, delirium, hallucinations and psychosis. +Psychological +dependence is common, but tolerance and withdrawal symptoms +are unusual. +Long-term use is thought to increase the lifetime risk +of psychosis. +Serious acute toxicity is uncommon and supportive +treatment is all that is required. +These may contain more than one SCRA and content +may change with time. +Coma, respiratory acidosis, seizures, +hypokalaemia and renal dysfunction are also reported. +Treatment +of intoxication is supportive. +Synthetic tryptamines, such +as alpha-methyltryptamine (AMT), have been encountered +recently. +mephedrone), piperazines (e.g. +benzylpiperazine), piperadines +(e.g. +ethylphenidate), benzofurans (e.g. +5-aminopropylbenzofuran) +and NBOMe compounds (e.g. +25I-NBOMe). +Effects appear rapidly after inhalation and especially after +smoking. +Sympathomimetic stimulant effects predominate (see +Box 7.12). +Cocaine toxicity should be considered in younger adults presenting +with ischaemic chest pain. +A 12-lead ECG and ECG monitoring should be undertaken. +Acidosis should be corrected and physical +cooling measures used for hyperthermia. +Hallucinations may +be pleasurable or terrifying (‘bad trip’). +Psychosis may sometimes last several days. +Treatment of intoxication is supportive. +Volatile substances +Inhalation of volatile nitrites (e.g. +These potent vasodilators commonly provoke +headache, dizziness, hypotension and tachycardia. +Severe cases are treated +with methylthioninium chloride (‘methylene blue’, see Fig 7.1). +Both groups are at +risk of severe toxicity if the packages rupture. +The risk of poisoning depends on +the quality of the wrapping, and the amount and type of drug +Fig. +7.4 Abdominal X-ray of a body packer showing multiple +drug-lled condoms. +ingested. +Patients suspected of body packing or stufng should be +admitted for observation. +The mouth, rectum and vagina should +be examined as possible sites for concealed drugs. +Packages may be visible on plain abdominal lms (Fig. +7.4) but ultrasound and computed tomography (CT) are more +sensitive. +One of these (preferably CT) should be performed in +all suspected body packers. +It is also present in +vehicle exhaust fumes and sometimes in smoke from house res. +CO is +a common cause of death by poisoning and most patients die +before reaching hospital. +Clinical features +Early features include headache, nausea, irritability, weakness +and tachypnoea. +Myocardial ischaemia may +result in arrhythmias or myocardial infarction. +Cerebral oedema +is common and rhabdomyolysis may cause myoglobinuria and +renal failure. +Extrapyramidal +effects, urinary or faecal incontinence, and gait disturbance may +also occur. +Poisoning during pregnancy may cause fetal hypoxia +and intrauterine death. +Arterial blood gas analysis should be checked in those with +serious poisoning. +Convulsions should +be controlled with diazepam. +Hyperbaric oxygen therapy is controversial. +Case fatality +following deliberate ingestion is high (5–20%). +The toxicology and management of nerve agent and pesticide +poisoning are similar. +7.5). +Initially, spontaneous hydrolysis of the OP–enzyme +Fig. +7.5 Mechanism of toxicity of organophosphorus compounds and +treatment with oxime. +Oximes may +provoke hypotension, especially if administered rapidly. +Ventilatory support should be instituted before the patient +develops respiratory failure. +Plasma cholinesterase is reduced +more rapidly but is less specic than red cell cholinesterase. +Cholinergic features may be prolonged over several +weeks with some lipid-soluble agents. +Sensory loss may also be present but is variable. +Initially, tendon reflexes are reduced or lost but mild spasticity +may develop later. +There is no specic therapy for OPIDN. +Regular physiotherapy +may limit deformity caused by muscle-wasting. +The mechanism, clinical features and management +of toxicity are similar to those of OP compounds. +Also, +carbamates penetrate the CNS poorly. +Nicotinic features +occur in nicotine poisoning and black widow spider bites. +Cholinergic features +are sometimes seen with some mushrooms. +Vomiting and profuse diarrhoea are typical following ingestion. +Bronchoconstriction, bronchorrhoea and salivation may cause +severe respiratory compromise. +Ataxia, coma, convulsions, cardiac +repolarisation abnormalities and torsades de pointes may occur. +Appropriate external decontamination +is needed (p. +133). +Gastric lavage or activated charcoal may be +considered if the patient presents sufciently early. +Seizures +should be treated as described in Box 7.8. +Atropine reverses ACh-induced +bronchospasm, bronchorrhoea, bradycardia and hypotension. +Large doses may be needed, but excessive doses may cause +anticholinergic effects (see Box 7.10). +In spite of this, case fatality can be high for some carbamates, +depending on their formulation. +Atropine may be given intravenously as for OP poisoning +(p. +146). +Diazepam may be used to relieve anxiety. +The use of +oximes is unnecessary. +There +is no specific antidote but activated charcoal is commonly +administered. +Hypocalcaemia, hypomagnesaemia and +hyperkalaemia are common. +Methanol poisoning causes headache, delirium and vertigo. +Blindness +may be permanent, although some recovery may occur over +several months. +Pancreatitis and abnormal liver function have +also been reported. +The osmolar and anion gaps should be +calculated (see Box 7.5). +The antidote should be continued until ethylene glycol +or methanol concentrations are undetectable. +Metabolic acidosis +should be corrected with sodium bicarbonate (e.g. +250 mL of +1.26% solution, repeated as necessary). +Convulsions should be +treated with an intravenous benzodiazepine. +Corrosive substances +Products containing strong acids (e.g. +hydrochloric or sulphuric +acid) or alkalis (e.g. +External decontamination (p. +133), if needed, should be +performed after initial resuscitation. +Strong analgesics +should be administered for pain. +It may also be an adulterant of +illicitly produced alcohol. +Both are rapidly absorbed after ingestion. +7.6). +As toxic metabolites are formed, metabolic acidosis, tachypnoea, +coma and seizures may develop. +Delayed endoscopy (e.g. +after several days) may +carry a higher risk of perforation. +Ingestion of +a few tablets can be fatal. +Copper sulphate +This is used as a fungicide. +7.1). +Chelation therapy is +unlikely to be benecial after acute exposure. +kyphosis) +and joint ankylosis. +Changes in the bones of the thoracic cage +may lead to rigidity that causes dyspnoea on exertion. +Very high +doses of fluoride may cause abdominal pain, nausea, vomiting, +seizures and muscle spasm. +Dental fluorosis is +endemic in East Africa and some West African countries. +Use appropriate personal +protective equipment. +Chemical warfare agents +Some toxins have been developed for use as chemical warfare +agents. +These are summarised in Box 7.16. +Health effects associated with chronic exposure to arsenic in +drinking water are shown in Box 7.17. +In exposed individuals, +high concentrations of arsenic are present in bone, hair and +nails. +‘red tide’). +In severe cases, +paralysis and respiratory failure can develop. +There is no specic +antidote and treatment is supportive. +Most cases resolve over +a few days. +Human exposure occurs through eating +contaminated fish, even if well cooked. +Convulsions and coma can occur, although death is +uncommon. +Fatigue and peripheral neuropathy can be long-term +effects. +There is no specic treatment. +Scombrotoxic sh poisoning +Under poor storage conditions, histidine in scombroid fish +(e.g. +(eds). +Oxford +desk reference: toxicology. +Oxford: Oxford University Press; +2014. +Benson BE, Hoppu K, Troutman WG, et al. +Position paper update: +gastric lavage for gastrointestinal decontamination. +Clin Toxicol +2013; 51:140–146. +Chyka PA, Seger D, Krenzelok EP, et al. +Position paper: single-dose +activated charcoal. +Clin Toxicol 2005; 43:61–87. +Thompson JP, Watson ID, Thanacoody HK, et al. +Guidelines for +laboratory analyses for poisoned patients in the United Kingdom. +Ann Clin Biochem 2014; 51:312–325. +Free for UK health +professionals but registration is required. +Access for overseas +users by special arrangement. +Low-cost smartphone app +available. +Copyright Š +Julian White. +Haematuria may indicate +a coagulopathy. +Dark urine is suggestive of +myoglobinuria, which is a sign of extensive +rhabdomyolysis. +Copyright Š Julian White. +Twenty-minute whole-blood clotting test (20WBCT). +The presence of coagulopathy is a +key indicator of major envenoming for some species. +This is dened +as a venom-induced disease (VID). +153) and the types of +envenoming they may cause. +> 100 000 Close to zero +Stingrays ? +> 100 000 ? +< 10 +Arthropoda Scorpions > 1 million ? +< 5000 +Spiders ? +> 100 000 ? +< 100 +Paralysis ticks ? +> 1000 ? +< 10 +Insects ? +> 1 million ? +> 1000* +Mollusca Cone snails ? +< 1000 ? +< 10 +? +< 100 ? +> 1 million ? +Copyright Š Julian White. +bees, wasps, ants) +*All venom components have lethal potential. +Stings by social insects such as bees and wasps may also +cause lethal anaphylaxis. +Other venomous animals may commonly +envenom humans but cause mostly non-lethal effects. +A few +animals only rarely envenom humans but have a high potential +for severe or lethal envenoming. +Within any given group, particularly snakes, +there may be a wide range of clinical presentations. +152). +General systemic effects +By denition, these are non-specic (Box 8.3). +Specic systemic effects +These are important in both diagnosis and treatment. +152). +• Excitatory neurotoxins cause an ‘autonomic storm’, often +with profuse sweating (p. +153) and huge rises +in serum creatine kinase (CK). +Secondary renal failure +can precipitate potentially lethal hyperkalaemic +cardiotoxicity. +• Cardiotoxicity is often secondary but symptoms and signs +are non-specic in most cases. +• Haemostasis system toxins cause a variety of effects, +depending on the type of toxin (Fig. +8.1). +Coagulopathy +may present as bruising and bleeding from the bite site +(p. +152), gums and intravenous sites. +Surgical interventions +are high-risk in such cases. +The role of these toxins in causing late- +developing capillary leak syndrome (p. +Local effects +These vary from trivial to severe (Box 8.3). +plasminogen activators), or as inhibitors of coagulation +(e.g. +serpin inactivators, platelet aggregation inhibitors) +Fig. +8.1 Sites of action of venoms on the haemostasis system. +Copyright Š Julian White. +associated with some snakebites (notably Russell’s viper), +is uncertain. +In cases with +intravascular haemolysis, secondary renal damage is likely. +(E) Kraits Flaccid paralysis2,3, myolysis4, hyponatraemia5 Indian PV or specic +Naja spp. +(E) Kraits Flaccid paralysis2,3 Specic AV from country +Naja spp. +2 Pre-synaptic. +3 Post-synaptic. +4 Only reported so far for B. +candidus, B. +niger and +B. +caeruleus. +5 Only reported so far for B. +multicinctus and B. +candidus. +6 Genus is subject to major taxonomic change (split into at least eight genera). +(Vc) Eyelash pit vipers Shock, pain and swelling Specic AV from country +Lachesis spp. +Stonesh Severe local pain CSL stonesh AV +1 For family name, see Box 8.4. +2 Pre-synaptic. +3 Post-synaptic. +(PVAV = polyvalent antivenom) +Copyright Š Julian White. +Transporting patients +Where possible, transport should be brought to the patient. +(Vv) Puff adders etc. +Procoagulant coagulopathy, shock, cardiotoxicity, +local necrosis/blistering +Europe +Vipera spp. +2 Pre-synaptic. +3 Post-synaptic. +Copyright Š Julian White. +152) when, in fact, the patient is conscious. +circulatory shock, respiratory failure; see Ch. +16) +• determining whether envenoming is present and if that +requires urgent treatment. +Critically ill +patients must be resuscitated (p. +202) and this takes precedence +over administration of any antivenom. +a tourniquet) – though beware sudden envenoming +on removal of a tourniquet. +153). +Multiple bites +or stings are more likely to cause major envenoming. +• Was the organism causing it seen and what did it look like +(size, colour)? +• What were the circumstances (on land, in water etc.)? +• Was there more than one bite/sting? +• What rst aid was used, when and for how long? +• What symptoms has the patient had (local and systemic)? +• Is there a past exposure to antivenom/venom and +allergies? +It may range +from a matter of minutes post-bite/sting to 24 hours later in +some cases. +Evidence of envenomation may become apparent +only through laboratory testing. +They are not available for other +types of envenomation, where venom concentrations are low. +153). +8 +envenoming. +It is made by hyperimmunising an animal, usually +horses, to produce antibodies against venom. +Once rened, +these bind to venom toxins and render them inactive or allow +their rapid clearance. +It is critical that the correct +antivenom is used at the appropriate dose. +Doses vary widely +between antivenoms. +8.2). +Thrombocytopenia may persist for days, despite antivenom. +The +role of antivenom in reversing established rhabdomyolysis and +renal failure is uncertain. +Antivenom +may not be the only crucial treatment, however. +Listing all of these is +beyond the scope of this chapter (see ‘Further information’ below). +Of the 3000-plus snake species, more +than 1000 either are venomous or produce oral toxins. +A selection of important species is included in Boxes 8.4–8.6. +152). +The nature of the risks posed will depend on the specic +snake fauna in a given region (p. +153). +8.2 Principal snake venom neurotoxins acting at the +neuromuscular junction (NMJ). +Copyright Š Julian White. +Mechanical ventilation (p. +Non-spitters are +now known to spit in parts of their range (e.g. +Naja kaouthia +in West Bengal) and may cause local necrosis in addition to +paralysis. +lepturus, and with similar lethal potential. +For most of these spiders, antivenom remains the key treatment +and is life-saving in some cases. +There are no antivenoms for tick paralysis. +The paralysis usually resolves by +about 48 hours following removal of all ticks. +Treatment includes use of a Brazilian specic antivenom +and supportive care. +75). +Cardiac collapse +can occur, especially in children. +Other clinical features may +vary, depending on the scorpion species. +Clinical features and management +The approach to management varies with species and region. +In Iran, H. +The giant wasps +and hornets of Asia can similarly cause systemic envenoming +with multiple attacks. +149). +Further information +Books and journal articles +Meier J, White J. +Handbook of clinical toxicology of animal venoms +and poisons. +Boca Raton: CRC Press; 1995. +World Health Organisation, Regional Ofce for Africa. +Guidelines for the +prevention and clinical management of snakebite in Africa; 2010 +(afro.who.int). +World Health Organisation, Regional Ofce for South-East Asia. +Guidelines for the management of snake-bites; 2010 (searo +.who.int). +7) and Acute +Medicine and Critical Illness (Ch. +10). +Chapter 5 deals with more +general effects of environmental factors on population health. +Radiation exposure +representing 1 J/kg. +‘Background radiation’ refers to our exposure to naturally +occurring radioactivity (e.g. +radon gas and cosmic radiation). +The gonads are highly radiosensitive and radiation +may result in temporary or permanent sterility. +Eye exposure can +lead to cataracts and the skin is susceptible to radiation burns. +Carcinogenesis represents a +stochastic effect. +9.1) and non-ionising radiations +(ultraviolet (UV), visible light, laser, infrared and microwave). +9.1). +radium, +uranium +Beta particles +e.g. +14carbon, +90strontium +X-rays/gamma rays +e.g. +Thereafter the incidence rises with +time. +In a hot environment, sweating +is the main mechanism for increasing heat loss. +This usually +occurs when the ambient temperature rises above 32.5°C or +during exercise. +9.2). +Moderate +hypothermia occurs below 32°C and severe hypothermia +below 28°C. +Other systems dene hypothermia on the basis +of symptoms rather than absolute temperature. +The temperature set-point is increased +in response to infection (p. +218). +9.2 Clinical features of abnormal core temperature. +218), and may be lost +in hypothalamic disease (p. +679). +In these circumstances, the clinical +picture at a given core temperature may be different. +633), hypoglycaemia (p. +725) and the possibility +of drug intoxication (p. +134) should be performed. +Careful handling is essential to avoid +precipitating the latter. +Underlying conditions should be treated promptly +(e.g. +hypothyroidism with triiodothyronine 10 Îźg IV 3 times +daily; p. +640). +This +is best achieved by cardiopulmonary bypass or extracorporeal +membrane oxygenation (ECMO). +Monitoring of cardiac rhythm and arterial blood gases, +including H+ (pH), is essential. +Signicant acidosis may require +correction (p. +364). +pneumonia, stroke +or fracture. +Fig. +9.3 Electrocardiogram showing J waves (arrows) in a +hypothermic patient. +alcohol and other drugs (e.g. +phenothiazines) commonly impede +the thermoregulatory response in younger people. +This classication is important, as it +determines the method of rewarming. +Clinical features depend on the degree of hypothermia (Fig. +9.2). +In a cold patient, it is very difcult to diagnose death reliably +by clinical means. +211). +9.3). +Cardiac arrhythmias, including ventricular brillation, may +occur. +Risk factors include smoking, peripheral vascular disease, +dehydration and alcohol consumption. +Frostbitten tissue is initially pale and +doughy to the touch and insensitive to pain (Fig. +9.4). +Once +frozen, the tissue is hard. +Rewarming should not occur until it can be achieved rapidly +in a water bath. +Give oxygen and aspirin 300 mg as soon as +possible. +Frostbitten extremities should be rewarmed in warm +water at 37–39°C, with antiseptic added. +Adequate analgesia +is necessary, as rewarming is very painful. +139 and 1199) +• Malignant hyperpyrexia +• Thyroid storm (p. +357). +A spectrum of illnesses occurs in the heat (see Fig. +9.2). +The +cause is usually obvious but the differential diagnosis should be +considered (Box 9.3). +There is no +elevation of core temperature. +Symptoms usually respond rapidly to rehydration with oral +rehydration salts or intravenous saline. +Heat syncope +This is similar to a vasovagal faint (p. +181) and is related to +peripheral vasodilatation in hot weather. +Fluid losses are replaced with either +oral rehydration mixtures or intravenous isotonic saline. +Up to +5 L positive fluid balance may be required in the rst 24 hours. +Untreated, heat exhaustion may progress to heat stroke. +The symptoms +of heat exhaustion progress to include headache, nausea and +vomiting. +The patient should be resuscitated with evaporative or +convective cooling. +9.4 Frostbite in a female Everest sherpa. +pentoxifylline (a phosphodiesterase inhibitor) have been shown +to improve tissue survival. +As yet, the role of hyperbaric oxygen +in the treatment of frostbite requires further research. +On rewarming, the limb +appears mottled and thereafter becomes hyperaemic, swollen +and painful. +The +pathology remains uncertain but probably involves endothelial +injury. +Gradual rewarming is associated with less pain than +rapid rewarming. +The patient is +at risk of further damage on subsequent exposure to the cold. +Chilblains +Chilblains are tender, red or purplish skin lesions that occur in +the cold and wet. +They are often seen in horse riders, cyclists +and swimmers, and are more common in women than men. +They are short-lived and, although painful, not usually serious. +The risk of heat-related illness +falls as acclimatisation occurs. +Heat illness can be prevented to a168 • ENVIRONMENTAL MEDICINE +should be avoided. +Intravenous dextrose may be necessary, +as hypoglycaemia can occur. +Once +emergency treatment is established, heat stroke patients are +best managed in intensive care. +Heat stroke is an emergency with a significant mortality. +Clear advice +to avoid heat and heavy exercise during recovery is important. +High altitude +on the shape of the sigmoid oxygen–haemoglobin dissociation +curve (see Fig. +23.5, p. +917) and the ventilatory response. +This process takes several days, so travellers +need to plan accordingly. +However, most altitude illness occurs +in travellers and mountaineers. +Ataxia and peripheral +oedema may be present. +The incidence in travellers to 3000 m +may be 40–50%, depending on the rate of ascent. +Occasionally, there is +progression to cerebral oedema. +HACE is rare, +life-threatening and usually preceded by AMS. +Papilloedema and retinal haemorrhages are common and focal +neurological signs may be found. +Treatment is directed at improving oxygenation. +Descent is +essential and dexamethasone (8 mg immediately and 4 mg 4 +times daily) should be given. +If descent is impossible, oxygen +therapy in a portable pressurised bag may be helpful. +Unlike HACE, HAPE may occur de novo without +the preceding signs of AMS. +Presentation is with symptoms +of dry cough, exertional dyspnoea and extreme fatigue. +Later, +the cough becomes wet and sputum may be blood-stained. +Tachycardia and tachypnoea occur at rest and crepitations +may often be heard in both lung elds. +9.5). +9.5). +9.5 Change in inspired oxygen tension and blood oxygen +saturation at altitude. +(To convert kPa to mmHg, multiply by 7.5.)Under water • 169 +of diffuse alveolar oedema. +Reduced arterial +oxygen saturation is not diagnostic but is a marker for disease +progression. +Treatment is directed at reversal of hypoxia with immediate +descent and oxygen administration. +Patients present with headache, poor concentration and other +signs of polycythaemia. +The haemoglobin concentration is high +(> 200 g/L) and the haematocrit raised (> 65%). +Affected individuals +are cyanosed and often have nger clubbing. +High-altitude retinal haemorrhage +This occurs in over 30% of trekkers at 5000 m. +The haemorrhages +are usually asymptomatic and resolve spontaneously. +Visual +defects can occur with haemorrhage involving the macula but +there is no specic treatment. +Venous thrombosis +This has been reported at altitudes of > 6000 m. +Risk factors +include dehydration, inactivity and the cold. +Refractory cough +A cough at high altitude is common and usually benign. +This may be indistinguishable +from the early signs of HAPE. +Oxygen saturation is also reduced but to a lesser degree (see +Fig. +9.5). +Asthmatic patients should be advised to carry their inhalers in +their hand baggage. +These include cardiac +arrhythmia, sickle-cell disease and ischaemic heart disease. +Most +airlines decline to carry pregnant women after the 36th week +of gestation. +In complicated pregnancies it may be advisable +to avoid air travel at an earlier stage. +Divers should +not fly for 24 hours after a dive requiring decompression stops. +750). +Advice is +available from Diabetes UK and other websites. +Patients should +be able to provide documentary evidence of the need to carry +needles and insulin. +Deep venous thrombosis +Air travellers have an increased risk of venous thrombosis +(p. +165). +Absorption of large +amounts of hypotonic fluid can result in haemolysis. +Clinical features +Those rescued alive (near-drowning) are often unconscious and +not breathing. +Hypoxaemia and metabolic acidosis are inevitable +features. +Acute lung injury usually resolves rapidly over 48– +72 hours, unless infection occurs (Fig. +9.6). +198). +456). +It is important to clear the airway of foreign bodies +and protect the cervical spine. +Continuous positive airways +pressure (CPAP; p. +202) should be considered for spontaneously +breathing patients with oxygen saturations of < 94%. +Observation +is required for a minimum of 24 hours. +Prophylactic antibiotics are +only required if exposure was to obviously contaminated water. +Diving-related illness +The underwater environment is extremely hostile. +For this +reason, compressed air can be used only for shallow diving. +9.6 Near-drowning. +Humanitarian crisis +Humanitarian crises are common. +The response is broken down into four phases: +1. +recognition (rst week) +2. +emergency response (rst month) +3. +consolidation phase (to crisis resolution or crisis +containment) +4. +handover and withdrawal. +9 +*Information required by diving specialists to decide appropriate treatment. +See +contact details on page 172. +This must +all occur during the emergency phase and is followed by the +in 25–30% of adults; p. +531). +Although DCS and AGE can be +indistinguishable, their early treatment is the same. +Other air-lled +body cavities may be subject to barotrauma, including the ear and +sinuses. +Management +The patient is nursed horizontally and airway, breathing and +circulation are assessed. +• Recompression is the denitive therapy. +Assessment of population need +2. +Safe water and sanitation +3. +Food and nutrition +4. +Shelter and warmth +5. +Emergency health care +6. +Immunisation of risk groups +7. +Control of communicable diseases +8. +Ongoing health surveillance and reporting +9. +Training and deployment of indigenous health-care +workers +10. +Is the end-tidal CO2 trace +normal? +Are there any signs of airway +obstruction? +Breathing +Is the physiology normal +(SpO2, respiratory rate, tidal +volume)? +What is the level of support? +Are there any abnormal signs +on chest examination? +How much support is required +(inotrope,vasopressor)? +H +Haematology +What are the haemoglobin/ +platelet levels? +Are there any signs of +bleeding? +E +F +G +Glucose +What is the glucose level? +Is insulin being administered? +F Fluids, electrolytes and +renal system +What is the fluid balance? +Urine volume and colour? +Is there any oedema? +Patients who deteriorate while in hospital make up a small +but important cohort. +If they are well managed, in-hospital +cardiac arrest rates will be low. +In many cases, it is clear early in the assessment process that a +patient requires admission. +Some presentations, +such as a unilateral swollen leg (p. +186), lend themselves to +this type of management (Box 10.1). +780); community- +acquired pneumonia with low CURB-65 score +(p. +It typically varies in intensity with movement and the phase +of respiration. +A malignant tumour invading the chest wall or +ribs can cause gnawing, continuous local pain. +Patients often emphasise that it is a discomfort rather +than a pain. +In +crescendo or unstable angina, similar pain may be precipitated +by minimal exertion or at rest. +This may be +difcult to distinguish from myocardial ischaemia. +Bronchospasm +may be associated with wheeze, atopy and cough (p. +556). +Other causes of chest pain tend to develop more gradually, over +hours or even days. +Some patients describe a feeling of +impending death, referred to as ‘angor animi’. +Patients +with myocarditis or pericarditis may describe a prodromal viral +illness. +2 Can sometimes cause central chest pain. +It may radiate to the neck, jaw, and upper +or even lower arms. +Occasionally, it may be experienced only +at the sites of radiation or in the back. +The severe pain of +aortic dissection is typically central with radiation through to the +back. +Central chest pain may also occur with tumours affecting +the mediastinum, oesophageal disease (p. +791) or disease of the +thoracic aorta (p. +505). +10.1 Identifying ischaemic cardiac pain: the ‘balance’ of evidence. +Anxiety may amplify the effects of organic disease +and a confusing clinical picture may result. +A detailed and clear history is key to narrowing the differential +diagnosis of chest pain. +The legs should be examined for clinical evidence +of deep vein thrombosis. +Pericarditis may be accompanied by a pericardial friction +rub. +In aortic dissection, syncope or neurological decit may +occur. +Examination may reveal asymmetrical pulses, features of +undiagnosed Marfan’s syndrome (p. +508) or a new early diastolic +murmur representing aortic regurgitation. +Initial investigations +Chest X-ray, ECG and biomarkers (e.g. +troponin, D-dimer) play a +pivotal role in the evaluation of chest pain. +The choice of investigation(s) is intimately +linked to the history and examination ndings. +The chest X-ray may confirm the suspected diagnosis, +particularly in the case of pneumonia. +Patients with a history compatible with myocardial ischaemia +require an urgent 12-lead ECG. +10.1) +and either ECG evidence of ischaemia or an elevated serum +troponin. +Further management of acute coronary +syndromes is discussed on page 498. +619 and Fig. +17.67). +Presentation +A key feature of the history is the speed of onset of breathlessness. +Acute severe breathlessness (over minutes or hours) has a distinct +10 +Fig. +10.2 Inhaled foreign body. +A Chest X-ray showing a tooth lodged +in a main bronchus. +B Bronchoscopic appearance of inhaled foreign body +(tooth) with a covering mucous lm. +differential diagnosis list to chronic exertional breathlessness. +In the severely ill patient, it may be necessary to +obtain the history from accompanying witnesses. +In children, +the possibility of inhalation of a foreign body (Fig. +10.2) or acute +epiglottitis should always be considered. +Leg swelling may +suggest cardiac failure or, if asymmetrical, venous thrombosis. +The presence of wheeze is not always indicative of +bronchospasm. +The patient may be unable to speak +and is typically distressed, agitated, sweaty and pale. +Respiration +is rapid, with recruitment of accessory muscles, coughing and +wheezing. +Sputum may be profuse, frothy and blood-streaked +or pink. +Patients sometimes describe chest +tightness as ‘breathlessness’. +A history of chest tightness or close correlation with +exercise should be sought. +Renal compensation and a large rise in +HCO3− will take at least 12 hours. +In acute type II respiratory failure +(p. +565), the rate of rise of PaCO2 is a better indicator of severity +than the absolute value. +Dizziness and presyncope are particularly common +in old age (Box 10.5). +Presentation +The history from the patient and a witness is the key to establishing +a diagnosis. +The history should always be supplemented by a direct eye- +witness account if available. +Attention should be paid to potential triggers (e.g. +medication, +micturition, exertion, prolonged standing), the patient’s appearance +(e.g. +colour, seizure activity), the duration of the episode, and +the speed of recovery (Box 10.6). +The blackout is usually brief and +recovery rapid. +It is rare for syncope to cause injury or to +cause amnesia after regaining awareness. +Aspects of the history that can help to differentiate seizure from +syncope are shown in Box 10.7. +• Symptoms: most frequently described as a combination of +unsteadiness and lightheadedness. +• Most common causes: postural hypotension and cardiovascular +disease. +Many patients have more than one underlying cause. +• Arrhythmia: can present with lightheadedness either at rest or on +activity. +• Anxiety: frequently associated with dizziness but rarely the only +cause. +• Falls: multidisciplinary workup is required if dizziness is associated +with falls. +disorders of +cranio-vertebral junction) +Sensation of +movement? +• Hypoglycaemia (Ch. +10.3 The differential diagnosis of syncope and presyncope. +or vocalisation, or by very prolonged duration (hours). +A history +of rotational vertigo is suggestive of a labyrinthine or vestibular +disorder (p. +1086). +Lightheadedness may occur with many +arrhythmias, but blackouts (Stokes–Adams attacks, p. +477) are +usually due to profound bradycardia or malignant ventricular +tachyarrhythmias. +The ECG may show evidence of conducting +system disease (e.g. +Ambulatory ECG recordings +are helpful only if symptoms occur several times per week. +The recognised risk factors for delirium +are shown in Box 10.8. +darkness) or overload +(e.g. +noise) +• Medications (e.g. +Alertness +This includes patients who may be markedly drowsy (e.g. +difďŹ��cult to +rouse and/or obviously sleepy during assessment) or agitated/ +hyperactive. +Observe the patient. +If asleep, attempt to wake with +speech or gentle touch on shoulder. +Emotional disturbance (anxiety, irritability or depression) +is common. +Symptoms suggestive of a physical illness, such as an infection +or stroke, should be elicited. +10.4 for commonly +implicated drugs). +1181). +Sedatives may +worsen delirium and should be used as a last resort. +Resolution of +delirium, particularly in the elderly, may be slow and incomplete. +Many patients fail to recover to their pre-morbid level of cognition. +10.4 Common causes and investigation of delirium. +All investigations are performed routinely, except those in italics. +*Tend to present over +weeks to months rather than hours to days. +The chest X-ray shows right mid- and lower zone consolidation. +The CT scan shows a subdural haematoma. +Other ‘red flag’ symptoms are shown in Box 10.11. +The pain of a +subarachnoid haemorrhage frequently causes signicant distress. +1042) should be considered. +Clinical assessment +An assessment of conscious level (using the Glasgow Coma +Scale (GCS); Fig. +10.5) should be performed early and constantly +reassessed. +Can you open your +eyes, please? +after headache onset, to look for evidence of xanthochromia. +Many +headaches require prompt involvement of specialists. +1042 for management). +There are three explanatory +mechanisms for development of oedema that are described +in Box 10.13. +463) for other causes. +The remainder of this +section focuses on the causes of ‘unilateral’ oedema. +The pain and swelling of a DVT is often fairly gradual +in onset, over hours or even days. +Often, however, symptoms and signs +are minimal. +10.5 Assessment of the Glasgow Coma Scale (GCS) score in an +obtunded patient. +Avoid using a sternal rub, as it causes bruising. +will be immediately required. +leg +ulcer or insect bite). +The patient may be febrile and systemically +unwell. +Early lymphoedema is indistinguishable from other causes of +oedema. +See Box 10.14 for the +examination ndings associated with compartment syndrome. +Figure 10.6 gives an algorithm for investigation +of suspected DVT based on initial Wells score. +The investigative pathway for DVT, +therefore, differs according to the pre-test probability (p. +11) of +DVT. +10.6 Investigation of suspected deep vein thrombosis. +Pre-test +probability is calculated in Box 10.15. +See also page 11. +From Wells PS. +Evaluation of D-dimer in the diagnosis of suspected deep-vein +thrombosis. +N Engl J Med 2003; 349:1227; copyright Š 2003 Massachusetts +Medical Society. +are given. +Ruptured Baker’s cyst and calf muscle tear can both +be readily diagnosed on ultrasound. +• DVT: pregnancy is a signicant risk factor, however. +• D-dimer: should not be measured in pregnancy; it has not been +validated in this group. +These are referred to as ‘rapid response systems’. +One popular +example of a rapid response system is a medical emergency +team (MET). +The team is expected to make a rapid assessment and institute +immediate management. +10.7). +These are outlined in +Box 10.17. +A rapid history should be obtained +while the initial assessment is undertaken. +Breathing should +be assessed with a focused respiratory examination. +Oxygen +saturations and ABGs should be checked early (p. +190). +10.7 Identifying and responding to physiological deterioration. +A An example of an early warning score chart. +10.7, cont’d +B Responses to physiological deterioration. +A and B, From Royal College of Physicians. +Report of a working party. +London: RCP, 2012. +Probably picks up subclinical +Low specicity. +NEWS or MEWS score +May miss single parameter deterioration that is still signicant, +e.g. +May deskill the ward-based teams in acute +care. +D – Disability +Conscious level should be assessed using the GCS (see Fig. +10.5 +and Box 10.24, pp. +186 and 194). +A brief neurological examination +looking for focal signs should be performed. +inotropes and haemoltration) +Patients with chronic impairment of one or more organ systems (e.g. +Tachypnoea may be primary +(i.e. +a problem within the respiratory system) or secondary to +pathology elsewhere in the body. +Cardiopulmonary causes +of tachypnoea have been covered on page 179. +More detailed information on metabolic +acidosis can be found on page 364. +10.8). +Hypoxaemia +Pathophysiology +Low arterial partial pressure of oxygen (PaO2) is termed +hypoxaemia. +It is a common presenting feature of deterioration. +Over 97% of oxygen carried in the blood is bound to +haemoglobin. +A shift in the curve will influence +the uptake and release of oxygen by the haemoglobin +molecule. +This increases capillary PO2 and hence cellular +oxygen supply. +10.8 Using ultrasound to rule out an anterior pneumothorax. +A Probe position and orientation. +B and C Two-dimensional (2D) ultrasound +images. +D and E M-mode ultrasound images. +Key: (1) Intercostal muscle. +(2) Rib. +(3) Normal bright pleural line –‘shimmering appearance’ of sliding +pleura. +(4) Lung. +(5) Absent ‘shimmering’ in pneumothorax and lung not visible. +(6) Normal – ‘sea shore’ sign excludes pneumothorax at that location. +10.10). +A classication of common causes +of hypoxaemia in hospitalised patients is shown in Box 10.20. +Further management of respiratory failure is discussed on page 202. +10.9 The haemoglobin–oxygen dissociation curve and the effect +of CO2 on oxygen saturations. +In pulmonary embolism, compensatory +hyperventilation often occurs. +PaCO2 decreases, shifting the +oxyhaemoglobin saturation curve to the left (green line). +Therefore, despite +a low PaO2 (8 kPa/60 mmHg), the saturation reading is 93%. +Hyperoxia is theoretically harmful via a number +of mechanisms. +10.10 Theoretical mechanisms of hypoxaemia. +A Normal physiology. +B Shunt caused by alveolar lling, e.g. +in pneumonia or alveolar +haemorrhage. +The mixture of oxygenated and deoxygenated blood causes arterial desaturation. +C Shunt caused by interstitial pathology, e.g. +pulmonary +oedema or brosis. +Because minute volume is usually maintained, this causes type I respiratory failure. +D Ventilation–perfusion (V/Q) mismatch caused by alveolar +hypoventilation, e.g. +in chronic obstructive pulmonary disease (COPD)/asthma. +Alveoli are under-ventilated relative to perfusion. +Alveolar PO2 falls and PCO2 +rises, causing type II respiratory failure. +E V/Q mismatch caused by central hypoventilation, e.g. +in neuromuscular disease or narcotic use. +The alveoli are +relatively over-perfused, causing type II respiratory failure. +F V/Q mismatch caused by a perfusion defect, e.g. +a small pulmonary embolism. +Minute volume is increased, so PCO2 is +not elevated. +Concealed bleeding (e.g. +The recognition and management of primary cardiac +dysrhythmias are discussed on page 468. +There +are thromboembolic concerns regarding chemical cardioversion +of AF of unknown duration. +It is rarely successful in dysrhythmias +secondary to systemic illness. +204). +the patient is shocked). +Shock +Shock means ‘circulatory failure’. +Hypotension is a common presentation +of shock but the terms are not synonymous. +antihypertensive) +Acidosis (e.g. +If shock is suspected, resuscitation should be +commenced (p. +204). +Hypotension +should serve as a ‘red flag’ that there may be serious underlying +pathology. +However, it can be the presenting feature +of a number of serious disease processes. +Ischaemia of the brainstem (commonly +via a pressure effect) will cause acute increases in BP. +A +neurological examination and CT scan of the head should +be considered. +• Fluid overload. +• Underlying medical problems. +• Primary cardiac problems. +Myocardial ischaemia, acute +heart failure and aortic dissection can all present with +hypertension. +• Drug-related problems. +The management of hypertension is discussed further on +page 510. +10.5 for how to assess +GCS). +While disorders that affect language or limb function +(e.g. +Coma is dened as a persisting state of deep unconsciousness. +In practice, this means a sustained GCS of 8 or less. +type II respiratory failure) ones. +Failure to obtain an +adequate history for patients in coma is a common cause of +diagnostic delay. +It is vital to exclude non-neurological +causes of coma. +358) and hypoglycaemia (p. +738) are easily corrected and +can cause irreversible brain injury if missed. +When the patient is intubated, there can be no +verbal response. +In the majority of inpatients there is no role for high volumes (i.e. +> 30 mL/kg) of intravenous fluid if the MAP is normal. +735 and +738) and diabetes insipidus (p. +687), where fluid management +should be guided by local protocols. +Diagnosis and management +Further assessment and management of oliguria are explained +on page 391. +Values over 20 mmHg suggest abdominal compartment +syndrome is present. +If conservative measures +fail, a laparostomy should be considered. +It can also occur following trauma and crush injury or after +over-exertion of muscles. +B +10 +Fig. +10.11 Hyperacute changes in conscious state are commonly of +vascular origin. +A Non-contrast CT of the head showing +hyperdense thrombus in the basilar artery (arrow). +This is a specic, but +not sensitive, sign. +B CT angiogram of the circle of Willis demonstrating +thrombosis in the basilar artery (arrow). +This has better sensitivity for acute +vascular occlusion. +The decision regarding intubation for +airway protection is always difcult. +In severe sepsis, intravascular +coagulation can become widespread. +Specic aspects of the diagnosis +and management of DIC are discussed on page 978. +Organ damage from sepsis +Any and all organs may be injured by severe sepsis. +The +pathological mechanisms are shown in Figure 10.12. +Lactate physiology +Lactate is an excellent biomarker for the severity of sepsis. +Hyperlactataemia (serum lactate > 2.4 mmol/L or 22 mg/dL) +is used as a marker of severity. +Resuscitation in sepsis +General resuscitative measures are discussed on page 204. +However, if certain factors +are present, the infection may become systemic. +Persistent hypotension requiring vasopressors to maintain a MAP +> 65 mmHg +2. +Appropriate antibiotics should be administered as early as +possible (Box 10.29). +Information on likely organisms and appropriate +antibiotics can be found on pages 117 and 226. +A CT scan of the chest and +abdomen with contrast is a high-yield test in this context. +223). +Deliver high-flow oxygen +2. +Take blood cultures +3. +Administer intravenous antibiotics +4. +Measure serum lactate and send full blood count +5. +Start intravenous fluid replacement +6. +10.12 Pathophysiology of organ damage in sepsis. +Macrovascular. +Paradoxically, most patients with +sepsis have an increased cardiac output and oxygen delivery. +Microvascular. +Tissue injury can occur from hypoxia secondary to microvascular injury and +thrombosis. +Damaged epithelium permits neutrophils, proteins and fluid to +leak out. +Shunting. +Organs fail in sepsis despite supranormal blood flow. +Cellular. +Ischaemic +e.g. +Adrenaline +(epinephrine) +gut +Salbutamol +Excess muscle +activity +e.g. +Normal +mixed venous oxygen saturation is 70%. +Secondary effects include loss +of surfactant and impaired surfactant production. +Classic chest X-ray and CT appearances are shown in +Figures 10.14 and 10.15, respectively. +605). +204). +When +vasoplegia is suspected, it may be necessary to add vasopressin +(antidiuretic hormone, ADH). +Intravenous glucocorticoids are +also commonly used in refractory hypotension. +There is a small +increased risk of secondary infection following glucocorticoid use. +Objective assessment (e.g. +10.14 Chest X-ray in acute respiratory distress syndrome +(ARDS). +Fig. +10.15 CT scan of the thorax in a patient with severe ARDS. +Note +the pathology is mainly in the dorsal (dependent) parts of the lung. +For example, a patient with a PaO2 of 10 kPa (75 mmHg) on 50% +oxygen, i.e. +FiO2 of 0.5, would have a Pa/FiO2 ratio of 20 kPa +(150 mmHg). +All measurements +should be taken on a minimum of 5 cmH2 O of PEEP or CPAP. +This is further exacerbated by peripheral +vasoconstriction. +These factors combine to create the ‘downward +spiral’ of cardiogenic shock (Fig. +10.17). +206). +491). +While cardiogenic shock is the nal common +pathway of many disease processes (e.g. +10.16) are described here. +10.16 Some common causes of cardiogenic shock. +should be treated intensively because overall cardiac function +may subsequently improve. +The clinical features and +treatment are discussed on page 619. +CT +pulmonary angiography usually provides a denitive diagnosis. +The diagnosis and management of these +conditions is discussed on pages 514, 506 and 544. +Post cardiac arrest +The initial management of cardiac arrest is discussed on +page 456. +Acute management +A MAP of > 70 mmHg should be maintained to optimise cerebral +perfusion. +207) may be required. +Specic cardiac interventions and their +indications are described in Chapter 16. +Other physiological +targets are listed in Box 10.35. +Tools to assist prognostication following cardiac arrest are +shown in Box 10.36. +Where there is doubt, more time should +be given to allow assessment of neurological recovery. +195). +This +should be continued for 72 hrs. +Muscle relaxants may be required +to prevent shivering +• Blood pressure management. +Aim for a MAP of at least 70 mmHg +and a systolic blood pressure of > 120 mmHg +• Glucose control. +Selecting the appropriate level of intervention for an individual +patient can be very difficult. +Some suggested techniques +to aid decision-making are listed in Box 10.38. +subarachnoid +haemorrhage +Electrophysiology +• EEG patterns may suggest brain injury, e.g. +Decision-making can be difcult when the +adolescent has impaired decision-making capacity. +It helps to recruit collapsed alveoli and can enhance clearance +of alveolar fluid. +It uses a simpler device than NIV but otherwise offers no direct +benet over it. +Timed breaths are used for patients with central apnoea. +Critical incidents are common because the patient is +often deteriorating rapidly and is exhausted. +The determination +of what constitutes critical will depend on the status of each +patient. +204). +It is, therefore, important that a +patient is permitted to breathe in a planned and controlled way. +The threshold of injurious ventilation is unique to each patient. +Strategies that may reduce the incidence and severity of +VILI include: +• Permissive hypercapnia. +• ‘Open lung’ ventilation. +Use of low tidal volumes, higher levels of +PEEP (Fig. +• Paralysis. +When respiratory failure is severe, patient effort +may worsen VILI. +An infusion of muscle relaxant can be +used to moderate dyssynchrony with the ventilator. +This cycle continues +until there is evidence of resolving lung injury. +10.19). +Venous blood is then pumped +through a membrane oxygenator. +10.19 Principles of extracorporeal membrane oxygenation (ECMO). +A Basic ECMO circuit: venous–arterial (VA) and venous–venous (V V). +B Example of a V V ECMO circuit. +bee sting), often associated with endothelial +disruption and capillary leak (p. +Guillain–BarrĂŠ syndrome (p. +The actions of commonly +used vasoactive drugs are summarised in Box 10.41. +Pulmonary artery (PA) catheters, sometimes referred to as +Swan–Ganz catheters (Fig. +Wide-bore +cannulae are required for rapid fluid administration. +Intra-osseous +or central venous access can be established if there are no +visible peripheral veins. +Ultrasound can provide assistance for +rapid and safe venous cannulation. +The fluid challenge can +be repeated if shock persists, to a maximum total of 30 mL/ +kg of fluid. +10.20 A pulmonary artery (Swan–Ganz) catheter. +When the balloon is deflated, the pulmonary artery pressure can be recorded. +The +circuit and principles are very similar to those described in ‘V V +ECMO’ above (see p. +204 and Fig. +If the return cannula is peripherally sited (e.g. +Renal support +Renal replacement therapy (RRT) is explained in detail on +page 420. +However, many units +use intermittent dialysis without signicant problems. +• Haemodialysis and haemoltration are equally good. +• Anticoagulation is usually achieved using citrate or heparin. +15.18, p. +411). +• Shock appears to reverse more rapidly when renal support +is instituted. +• Provide respiratory support to correct hypoxaemia and +hypercapnia. +• Treat circulatory problems, e.g. +• Manage acute brain injury with control of ICP. +In +refractory cases an infusion of sodium thiopental or +ketamine may be required. +ICP +rises in acute brain injury as a result of haematoma, contusions, +oedema or ischaemic swelling. +Cerebral blood flow is dependent +on an adequate CPP. +Sustained pressures of > 30 mmHg are +associated with a poor prognosis. +No single technique has been +shown to improve outcome in severe intracranial hypertension. +Further focused clinical reviews are +usually incorporated into twice-daily ward rounds. +Other key aspects of the daily review are outlined on page 174. +Box 10.43 compares the various agents used for sedation in +intensive care. +Often a combination of drugs is used to achieve +the optimal balance of sedation and analgesia. +Regular use of a scoring system +to adjust sedation is associated with a shorter ICU stay. +Delirium in intensive care +Delirium is discussed on page 183. +A widely used bedside assessment is the CAM-ICU +score. +Delirium of any type is associated with poorer outcome. +Pharmacological interventions are +not useful as prophylaxis or in hypoactive delirium. +Additional +information on diagnosis and management of delirium can be +found on page 184. +The technique is particularly +effective when linked to a reduction in sedation. +Signs of failure include rapid +shallow breathing, hypoxaemia, rising PaCO2, sweating and +agitation. +A useful tool to guide the weaning process is the rapid shallow +breathing index (RSBI). +There are, however, some simple rules that can +aid decision-making. +Conscious level must +be adequate to protect the airway, comply with physiotherapy, +and cough. +The advantages and +disadvantages of tracheostomy insertion are listed in Box 10.45. +Occasionally, a patient +will have a tracheostomy in situ following a laryngectomy. +Calculation of exact +requirements is complex and requires the expertise of a dietitian. +It is, however, useful to make a rough estimation of requirements +(p. +705). +Caution must be taken to avoid the consequences +of refeeding syndrome (p. +706). +Peptic ulcer prophylaxis +Stress ulceration during critical illness is a serious complication. +264). +Hypothermia has been excluded – rectal temperature must +exceed 35°C +c. +The pupils are xed and unreactive to light +b. +The corneal reflexes are absent +c. +There are no motor responses to adequate stimulation within the +cranial nerve distribution +e. +If treatment is unsuccessful, patients will either die or be left +with a degree of disability. +Brain death is a state in which cortical +and brainstem function is irreversibly lost. +Brain death is, by denition, irreversible but other states may +offer hope for improvement. +ICU-acquired weakness +Weakness is common among survivors of critical illness. +It is +usually symmetrical, proximal and most marked in the lower +limbs. +some +response to verbal stimuli (e.g. +1076 and 1140). +There are +no specic treatments aside from resolution of the underlying +cause and rehabilitation. +Weakness may persist long into the +convalescence stage of illness. +In some cases, the clinical picture +may be more in keeping with individual nerve involvement. +This +may be due to local pressure effects or part of a generalised +picture. +Nerve palsies such as foot +drop can be permanent. +Specialist help is required in managing +these issues. +Long-term physical consequences are also common. +Organ damage often persists and iatrogenic complications +are common (e.g. +1306) +to inform admission decision-making. +These processes result in loss of actin +myobrils and muscle weakness. +Typically, the CK is normal or +only mildly elevated. +Like critical illness polyneuropathy, critical +illness myopathy is usually a clinical diagnosis. +1076). +It characteristically shows selective loss of the thick myobrils +and muscle necrosis. +The practice of organ +donation varies throughout the world but the principles remain +the same. +This is termed ‘donation after +cardiac death’ (DCD). +Nursing ratios change from 1 : 1 (one nurse +per patient) or 1 : 2 to much lower stafng levels. +Death +Whilst most patients prefer to die at home, many spend their +nal days in hospital. +1354). +Only interventions that will improve the quality of +a patient’s remaining life should be offered. +Organ donation +Donation after brain death +The diagnosis of brain death is discussed on page 211. +17.32, p. +583). +Further information +Websites +criticalcarereviews.com Reviews and appraisal of ICU topics. +emcrit.org Online podcasts and general information on emergency +medicine and critical care. +lifeinthefastlane.com Information on a range of intensive care and +emergency medicine topics. +Ian Rennie, Royal +Hallamshire Hospital, Shefeld. +to antimicrobials, noting allergic +manifestation (e.g. +likelihood of BCG vaccination in childhood) +Occupation +• e.g. +Anthrax in leather tannery workers +Recreational pursuits +• e.g. +Leptospirosis in canoeists and windsurfers +Animal exposures +• Include pets, e.g. +HIV-1, +HBV and HCV +Sexual history +• Explore in a condential manner (Ch. +13); +remember that the most common mode of +HIV-1 transmission is heterosexual (Ch. +A +• Migrating erythema, e.g. +enlarging rash of erythema +migrans in Lyme disease +(see Fig. +11.21, p. +256) +• Purpuric or petechial rashes, +e.g. +B +• Macular or papular rashes, +e.g. +primary infection with HIV +(see Box 12.8, p. +312) +• Vesicular or blistering rash, +e.g. +C +• Erythema multiforme (see +Fig. +29.53 and Box 29.32, +pp. +1264 and 1265) +• Nodules or plaques, e.g. +Kaposi’s sarcoma (p. +315) +• Erythema nodosum ( D and +Box 29.33, p. +1265) +D +Streptococcal toxic shock syndrome. +A Meningococcal sepsis. +B Shingles. +• other specimens, as indicated by history and examination, +e.g. +Subsequent investigations in patients with HIV-related (p. +313), +immune-decient (p. +223), nosocomial or travel-related (p. +Replacement +of salt and water is important in patients with drenching sweats. +Further management is focused on the underlying cause. +216), and the likelihood of infection is reinforced by +investigation results (e.g. +neutrophilia with raised ESR and CRP +in bacterial infections). +Careful interpretation of the clinical features is vital (e.g. +Common infections that present with fever are shown in Figure +11.1. +116) +pending conrmation of the microbiological diagnosis. +Subsets of PUO +are described as HIV-1 related, immune-decient or nosocomial. +Up to one-third of cases of PUO remain undiagnosed. +Clinical assessment +Major causes of PUO are outlined in Box 11.2. +Rare causes, +such as periodic fever syndromes (p. +81), should be considered +in those with a family history. +Older adults are more likely to have certain infectious +and non-infectious causes (see Box 11.1). +Many of these are described in other chapters or below. +Fever +‘Fever’ implies an elevated core body temperature of more than +38.0°C (p. +138). +Fever is a response to cytokines and acute +phase proteins (pp. +65 and 70), and occurs in infections and in +non-infectious conditions. +The systematic +approach described on page 216 should be followed. +Box 11.1 +describes the assessment of elderly patients. +Non-infective causes +include polymyalgia rheumatica/temporal arteritis and tumours. +A +smaller fraction of cases remain undiagnosed than in young people. +• Common infectious diseases in the very frail (e.g. +11.1 Common infectious syndromes presenting with fever and localised features. +(p. +527) or features of vasculitis). +In men, the prostate should +be considered as a potential source of infection. +Particularly in patients who have received +prior antimicrobials, 16S rRNA analysis (Box 6.2, p. +101) may +aid diagnosis if a microorganism is not cultured. +Aspergillus spp., Candida spp. +or dimorphic +fungi) +• Infections with fastidious organisms (e.g. +Antibiotic fever, drug hypersensitivity reactions etc. +Factitious fever +Idiopathic (~15%) +*Most common causes within each group. +Bone marrow should +be sent for culture, as well as microscopy. +Laparoscopy is +occasionally undertaken with biopsy of abnormal tissues. +microsporidia) and other fastidious organisms (e.g. +IAV +or RSV +• Urine, e.g. +for Legionella antigen +Nucleic acid detection +• Blood for Bartonella spp. +for respiratory viruses +• Tissue specimens, e.g. +for T. +whipplei +• Urine, e.g. +for Chlamydia trachomatis, Neisseria gonorrhoeae +• Stool, e.g. +dengue virus NS1 antigen, Histoplasma antigen (restricted +availability) and malaria antigen (e.g. +HRP-2 for Plasmodium +falciparum or parasite-specic LDH for P. +falciparum and P. +2 Addition of these tests should be guided by the location of +presentation or travel history. +The most common +causes of fever are soft tissue or respiratory infections. +Clinical assessment +The history should address the following risk factors: +• Site of injection. +Injection of the +jugular vein can be associated with cerebrovascular +complications. +1184). +Infective organisms are introduced +by non-sterile (often shared) injection equipment (Fig. +11.2). +11.2 Fever in the injection drug-user: key features of clinical examination. +Full examination (p. +216) is required but features most common +amongst injection drug-users are shown here. +Tetanus, wound +botulism, anthrax and gas gangrene also occur. +• Technical details of injection. +HIV-1, hepatitis B +or C virus). +anaerobic streptococci, Fusobacterium spp. +and Prevotella +spp.). +• Substances injected. +Injection of cocaine is associated +with a variety of vascular complications. +Certain +formulations of heroin have been linked with particular +infections, e.g. +wound botulism with black tar heroin. +Drugs are often mixed with other substances, e.g. +talc. +• Blood-borne virus status. +• Surreptitious use of antimicrobials. +Addicts may use +antimicrobials to self-treat infections, masking initial blood +culture results. +Key ndings on clinical examination are shown in Figure 11.2. +Non-infected venous thromboembolism is also +common in this group. +Since blood sampling may +be difcult, contamination is often a problem. +11.3A); thromboembolic phenomena; or a new or previously +undocumented murmur. +11.3B). +Any pathological +fluid collections should be sampled. +Urinary toxicology tests may suggest a non-infectious cause +of the presenting complaint. +Injection drug-users may have more than one infection. +Skin and soft tissue infections are most often due to Staph. +aureus or streptococci, and sometimes to Clostridium spp. +or anaerobes. +11.3C). +Endocarditis with +septic emboli commonly involves Staph. +aureus and viridans +streptococci, but Pseudomonas aeruginosa and Candida spp. +are also encountered. +flucloxacillin) or, if meticillin- +resistant Staph. +aureus (MRSA) is prevalent in the community, a +A +B A B +11 +C +Fig. +11.3 Causes of fever in injection drug-users. +A Endocarditis: +large vegetation on the tricuspid valve (arrow). +C Tricuspid valve endocarditis caused by Staphylococcus aureus. +Thoracic CT scan shows multiple embolic lesions with cavitation (arrows). +The patient presented with haemoptysis. +C, Courtesy of Dr Julia Greig, +Royal Hallamshire Hospital, Shefeld. +glycopeptide (e.g. +vancomycin) or lipopeptide (e.g.daptomycin). +In injection +drug-users, meticillin-sensitive Staph. +Specialist advice +should be sought. +flucloxacillin plus co-amoxiclav +or clindamycin). +Non-adherence to prescribed antimicrobial +regimens leads to a high rate of complications. +77), HIV infection (Ch. +12) and iatrogenic224 • INFECTIOUS DISEASE +immunosuppression induced by chemotherapy (p. +1330), +transplantation (p. +88) or immunosuppressant medicines, +including high-dose glucocorticoids. +Metabolic abnormalities, +such as under-nutrition or hyperglycaemia, may also contribute. +Multiple elements of the immune system are potentially +compromised. +• Any past infections and their treatment. +• Prophylactic medicines and vaccinations administered. +Disseminated +infections can manifest as cutaneous lesions. +The areas around +ngernails and toenails should also be inspected closely. +Investigations +Initial screening tests are as described above (p. +218). +Chest CT scan +should be considered in addition to chest X-ray when respiratory +symptoms occur. +Useful molecular techniques include PCR for cytomegalovirus +(CMV) and Aspergillus spp. +DNA, and antigen assays (e.g. +cryptococcal antigen (CrAg) for Cryptococcus neoformans, +galactomannan for Aspergillus spp. +in blood, and (1,3)-β-D-glucan +for Aspergillus spp. +Antibody detection is rarely useful +in immunocompromised patients. +Neutropenic fever +Neutropenic fever is dened as a neutrophil count of less than +0.5 × 109/L (p. +Patients with neutropenia are particularly +prone to bacterial and fungal infection. +The routine addition of aminoglycosides to these agents is +not supported by trial data. +If fever has not resolved after 3–5 +days, empirical antifungal therapy (e.g. +caspofungin) is added +(p. +125). +936). +Those in the rst +month are mostly related to the underlying condition or surgical +complications. +Those occurring 1–6 months after transplantation +are characteristic of impaired T-cell function. +Later infections are more common if an +allogeneic procedure is performed. +Positive blood culture +Blood-stream infection (BSI) is a frequent presentation of +infection. +This can be community-acquired or hospital-acquired +(‘nosocomial’). +The most common causes are shown in Box 11.7. +In immunocompromised hosts, a wider range of microorganisms +may be isolated, e.g. +fungi in neutropenic hosts. +pneumonia or urinary +tract infection), and is more common in Staph. +aureus BSI. +In +community-acquired Staph. +Peripheral and central venous +catheters are an important source of nosocomial BSI. +BSI has an associated mortality of 15–40%, depending on +the setting, host and microbial factors. +Clinical assessment +The history should determine the setting in which BSI has +occurred. +Physical examination should focus on signs of endocarditis +(p. +Central venous catheters should be examined for erythema or +purulence at the exit site. +Particularly in cases with Candida spp. +Investigations +Positive blood cultures may be caused by contaminants. +Bacillus spp. +(‘aerobic spore bearers’) and +Clostridium spp. +often represent incidental transient bacteraemia +or contamination, but certain species (e.g. +C. +septicum) are more +likely to be genuine pathogens. +Further investigations are influenced by the causative organism +and setting. +Initial screening tests are similar to those for fever +(p. +Imaging should also include any areas of bone or joint pain and +any prosthetic material, e.g. +a prosthetic joint or an aortic graft. +527), those whose cultures reveal an organism +that is a common cause of endocarditis (e.g. +Staph. +Therefore, if TTE is negative, TOE should +be performed. +Certain rare causes of BSI have specic associations that warrant +further investigation. +Endocarditis caused by Streptococcus +gallolyticus subsp. +gallolyticus (formerly Strep. +bovis biotype I) +and BSI with C. +Two weeks +of therapy may be sufcient for Staph. +Other Staph. +aureus BSIs are usually treated for 4–6 weeks. +Tunnelled catheters, e.g. +Hickman catheters, may also +develop tunnel site infections. +aureus. +Other causes include enterococci and Gram-negative +bacilli. +Candida spp. +are a +common cause of line infections, particularly in association with +total parenteral nutrition. +Non-tuberculous mycobacteria may +cause tunnel infections. +Local evidence of +erythema, purulence or thrombophlebitis supports the diagnosis. +However, microbiological conrmation is essential (p. +106). +For Staph. +Infection prevention is a key component of the management +of vascular catheters. +with visual infusion phlebitis (VIP) score; see Box 11.37, +p. +251), and daily consideration of the continuing requirement +for catheterisation. +Sepsis +Sepsis is discussed on page 196 and there are many causes (Box +11.8). +The results of blood cultures and pre-existing host factors +guide initial investigations. +In many +regions, malaria and dengue must also be excluded. +In some +cases, severe systemic features may be out of keeping with +mild local features. +The +infection spreads quickly along the fascial plane. +Subcutaneous gas may be +present. +Type 2 necrotising fasciitis is caused by group A or other +streptococci. +Approximately 60% of cases are associated with +streptococcal toxic shock syndrome (p. +253). +In anaerobic cellulitis, usually due to C. +perfringens. +Severe pain at the site of the +injury progresses rapidly over 18–24 hours. +Alternative agents include cephalosporins and metronidazole. +Hyperbaric oxygen has a putative but controversial role. +aureus or Gram-negatives). +When +this affects the genital/perineal area, it is known as ‘Fournier’s +gangrene’. +This infection causes soft tissue +necrosis and bullae, and may lead to necrotising fasciitis. +11.4 Excision following necrotising fasciitis in an injection +drug-user. +11.4). +Empirical +treatment is with broad-spectrum agents (e.g. +piperacillin– +tazobactam plus clindamycin; meropenem with clindamycin). +Hyperbaric oxygen therapy may be considered for +polymicrobial infection. +Gas gangrene +Although Clostridium spp. +783), sometimes with vomiting, is the +predominant symptom in infective gastroenteritis (Box 11.10). +Acute diarrhoea may also be a symptom of other infectious and +non-infectious diseases (Box 11.11). +Stress, whether psychological +or physical, can also produce loose stools. +The clinical features of food-borne gastroenteritis vary. +Some +organisms (Bacillus cereus, Staph. +Other organisms, such +as Shigella spp., Campylobacter spp. +The incubation period is longer and more systemic upset occurs, +with prolonged bloody diarrhoea. +Salmonella spp. +Fever and bloody diarrhoea suggest an invasive, +colitic, dysenteric process. +Person-to-person spread suggests certain infections, such as +shigellosis or cholera. +Examination includes assessment of the degree of dehydration. +The blood +pressure, pulse rate, urine output and ongoing stool losses +should be monitored closely. +11.10 Causes of infectious gastroenteritis +Toxin in food: < 6 hrs incubation +• Clostridium spp. +enterotoxin +• Bacillus cereus (p. +262) +• Staphylococcus aureus (p. +262) +(p. +262) +Bacterial: 12–72 hrs incubation +• Enterotoxigenic Escherichia +coli (ETEC, p. +263) +• Shiga toxin-producing E. +coli +(EHEC, p. +263)* +• Enteroinvasive E. +coli (EIEC, +p. +263)* +• Vibrio cholerae (p. +264) +• Salmonella (p. +262) +• Shigella * (p. +265) +• Campylobacter * (p. +262) +• Clostridium difcile * (p. +264) +Viral: short incubation +• Rotavirus (p. +249) • Norovirus (p. +249) +Protozoal: long incubation +• Giardiasis (p. +287) +• Cryptosporidiosis (pp. +287 +and 317) +• Microsporidiosis (p. +317) +• Amoebic dysentery (p. +286)* +• Cystoisosporiasis (p. +233) +*Associated with bloody diarrhoea. +264) +• Acute diverticulitis (p. +833) +• Sepsis (p. +196) +• Pelvic inflammatory disease +(p. +336) +• Meningococcaemia (p. +1119) +• Pneumonia (especially +‘atypical disease’, p. +582) +• Malaria (p. +273) +Non-infectious causes +Gastrointestinal +• Inflammatory bowel disease +(p. +813) +• Bowel malignancy (p. +827) +• Overflow from constipation +(p. +834) +• Enteral tube feeding +Metabolic +• Neuro-endocrine tumours +• Diabetic ketoacidosis (p. +735) +releasing (e.g.) VIP or 5-HT +• Thyrotoxicosis (p. +635) +• Uraemia (p. +149) +• Plant toxins (p. +150) +• Heavy metals +• Ciguatera sh poisoning +(p. +149) +• Scombrotoxic sh poisoning +(p. +• Campylobacter spp. +Most are presumed to be caused by +dehydration leading to organ failure. +114). +21.7, p. +769). +The fluid +lost in diarrhoea is isotonic, so both water and electrolytes need +to be replaced. +Absorption of electrolytes from the gut is an +active process requiring energy. +ORS can be just as effective as intravenous replacement +fluid, even in the management of cholera. +Associated vomiting will compound this. +11.5 Bristol stool chart. +The stool is given a ‘score’ of 1–7 by +reference to the verbal and visual description. +Adapted from Lewis SJ, Heaton KW. +Stool form scale as a +useful guide to intestinal transit time. +Scand J Gastroenterol 1997; +32:920–924. +11.5). +difcile. +Stool culture should be performed and +C. +difcile toxin sought. +FBC and serum electrolytes indicate +the degree of inflammation and dehydration. +In a malarious area, +a blood lm for malaria parasites should be obtained. +(WHO = World Health Organisation)230 • INFECTIOUS DISEASE +• Replacement of ongoing losses. +The average adult’s +diarrhoeal stool accounts for a loss of 200 mL of isotonic +fluid. +Stool losses should be carefully charted and an +estimate of ongoing replacement fluid calculated. +• Replacement of normal daily requirement. +This will be increased +substantially in fever or a hot environment. +408) more likely due to increased toxin +release. +Antibiotics should therefore not be used in this condition. +Adsorbents, such +as kaolin or charcoal, have little effect. +These are discussed +on page 149. +It is most common in the elderly but can +occur at all ages. +Although the specic mechanism is unknown +in most cases of AAD, C. +difcile (p. +C. +to eggs, vaccines, antibiotics) +• Past vaccinations: +Childhood schedule followed? +Most travel-associated infections can be prevented. +Pre- +travel advice is tailored to the destination and the traveller (Box +11.15). +Medicines purchased in some countries +may have reduced efcacy, e.g. +for malaria prophylaxis. +Oral and injectable typhoid vaccinations are +70–90% effective. +Falciparum malaria tends to present between 7 +and 28 days after exposure in an endemic area. +11.6 Approach to the patient with suspected viral haemorrhagic fever (VHF). +See page 245. +Box 11.19 +lists diagnoses and investigations to consider in unexplained +acute fever. +Management is directed at the underlying cause. +In patients +with suspected VHF (p. +The risk of VHF should be +determined using epidemiological risk factors and clinical signs +(Fig. +11.6), and further management undertaken as described +on page 246. +and Cryptosporidium spp. +infections prevalent worldwide (Box +11.20). +Shigella spp. +The approach to patients with acute diarrhoea is described +on page 227. +11.20 Most common causes of travellers’ diarrhoea +Clinical examination is summarised on page 216. +Patients may be unaware +of tick bites or eschars (p. +270). +Body temperature should be +measured at least twice daily. +• Enterotoxigenic E. +coli +(ETEC) +• Shigella spp. +The differential diagnosis of diarrhoea persisting for +more than 14 days is wide (see Box 21.18, p. +784). +Box 11.21 lists +causes encountered particularly in visitors to or residents of the +tropics. +Tropical sprue is a malabsorption syndrome (p. +807) with +no dened aetiology. +Giardia lamblia infection may progress to a +malabsorption syndrome that mimics tropical sprue. +HIV-1 has now emerged as a major cause of chronic diarrhoea. +Isospora +belli ) or microsporidia (p. +316). +CMV or disseminated +Mycobacterium avium complex infections. +It may also arise +in HIV-1 and human T-cell lymphotropic virus (HTLV)-1 infection. +926) and parasitic causes (Box 11.22). +Travellers often have recent and light infections associated with +eosinophilia. +mansoni, S. +japonicum Chronic infection +Filariases +Loiasis Loa loa Skin nodules +Wuchereria bancrofti W. +malayi Brugian elephantiasis similar but typically less severe than that caused by W. +bancrofti +Mansonella perstans M. +Schistosoma haematobium can cause +haematuria or haematospermia. +Toxocara spp. +can give rise +to choroidal lesions with visual eld defects. +stercoralis in +immunocompromised hosts induces meningitis due to Gram- +negative bacteria. +Radiological investigations may +provide circumstantial evidence of parasite infestation. +Box 11.23 +describes initial investigations for eosinophilia. +Management +A specic diagnosis guides therapy. +Scabies and eczema +are discussed on pages 1241 and 1244. +Cutaneous leishmaniasis +and onchocerciasis have dened geographical distributions +(pp. +284 and 292). +Examples of skin lesions in tropical disease +are shown in Figure 11.7. +• Life-threatening infections: meningococcal infection (sepsis and/ +or meningitis). +These may reflect either +voluntary sexual activity or sexual coercion/abuse. +• Travel-related infections: diarrhoea, malaria etc. +are relatively +common. +Outpatient antimicrobial +therapy is preferred to minimise hospitalisation. +• Vaccination: engagement with age-specic vaccine programmes +should be ensured, e.g. +HPV, childhood booster vaccines and +meningococcal vaccine. +C D +Fig. +11.7 Examples of skin lesions in patients with fever +in the tropics. +A Subcutaneous nodule due to botfly infection. +B Emerging larva after treatment with petroleum jelly. +C Eschar +of scrub typhus. +D Rat bite fever. +A, B and D, Courtesy of +Dr Ravi Gowda, Royal Hallamshire Hospital, Shefeld. +C, Courtesy of Dr Rattanaphone Phetsouvanh, Mahosot +Hospital, Vientiane, PDR Laos. +Death +may also result from complications of measles encephalitis. +Antibiotic +therapy is reserved for bacterial complications. +Rubella (German measles) +Rubella causes exanthem in the non-immunised. +The incubation +period is 15–20 days. +Complications +are rare but include thrombocytopenia and hepatitis. +Encephalitis +and haemorrhage are occasionally reported. +In adults, arthritis +involving hands or knees is relatively common, especially in +women. +diabetes mellitus. +This is achieved either by +detection of rubella IgM in serum or by IgG seroconversion. +Prevention +All children should be immunised with MMR vaccine. +Maternal antibody usually gives protection for the rst 6–12 +months of life. +However, vaccination of more +than 95% of the population is required to prevent outbreaks. +Natural illness produces life-long immunity. +Clinical features +Infection is by respiratory droplets with an incubation period of +6–19 days. +11.8A). +11.8B). +Generalised lymphadenopathy and diarrhoea are common. +Measles does +not cause congenital malformation but may be more severe in +pregnant women. +Death usually results from a bacterial superinfection, occurring +A B +Fig. +11.8 Measles. +A Koplik’s spots (arrows) seen on buccal mucosa in the early stages of clinical measles. +Mucosal involvement also occurs +Arthropathies +Symmetrical small-joint polyarthropathy. +Parvovirus B19 +Parvovirus B19 causes exanthem and other clinical syndromes. +Some 50% of children and 60–90% of adults are seropositive. +The virus has +particular tropism for red cell precursors. +Clinical features +Many infections are subclinical. +Clinical manifestations result +after an incubation period of 14–21 days (Box 11.28). +The +classic exanthem (erythema infectiosum) is preceded by a +prodromal fever and coryzal symptoms. +A ‘slapped cheek’ +rash is characteristic but the rash is very variable (Fig. +11.9). +In +adults, polyarthropathy is common. +These individuals develop an acute anaemia that may be severe +(transient aplastic crisis; p. +968). +Erythropoiesis usually recovers +spontaneously after 10–14 days. +Detection of parvovirus B19 DNA in blood +is particularly useful in immunocompromised patients. +Giant +pronormoblasts or haemophagocytosis may be demonstrable +in the bone marrow. +Management +Infection is usually self-limiting. +Symptomatic relief for arthritic +symptoms may be required. +Severe anaemia requires transfusion. +11.9 Slapped cheek syndrome. +The typical facial rash of parvovirus +B19 infection. +Transmission is via saliva. +Clinical features +Exanthem subitum is also known as roseola infantum or sixth +disease (Box 11.29). +A high fever is followed by a maculopapular +rash as the fever resolves. +Fever and/or febrile convulsions may +also occur without a rash. +The disease is +self-limiting. +Treatment with ganciclovir or foscarnet is used in +immunocompromised hosts infected with HHV-6. +VZV is spread by aerosol and direct +contact. +It is highly infectious to non-immune individuals. +Disease +in children is usually well tolerated. +Manifestations are more +severe in adults, pregnant women and the immunocompromised. +New lesions occur +every 2–4 days and each crop is associated with fever. +The rash +progresses from small pink macules to vesicles and pustules +within 24 hours. +Self-limiting cerebellar ataxia and encephalitis are +rare complications. +Pneumonitis can be fatal +and is more likely to occur in smokers. +248) +disease +A B +Fig. +11.10 Varicella zoster virus infection. +A Chickenpox. +Diagnosis +Diagnosis is primarily clinical, by recognition of the rash. +Serology is used to identify seronegative individuals at risk of +infection. +More severe disease, particularly +in immunocompromised hosts, requires initial parenteral therapy. +immunocompromised or pregnant) (Box 11.31). +The vaccine may also be used prior to planned iatrogenic +immunosuppression, e.g. +before transplant and for the elderly +aged over 70 to prevent shingles. +Occasionally, paraesthesia occurs +without rash (‘zoster sine herpete’). +Chickenpox +may be contracted from a case of shingles but not vice versa. +Although thoracic dermatomes are most commonly involved +(Fig. +This condition can lead to blindness and +urgent ophthalmology review is required. +This may be mistaken for Bell’s +palsy (p. +1082). +Bowel and bladder dysfunction occur with +sacral nerve root involvement. +The virus occasionally causes +cranial nerve palsy, myelitis or encephalitis. +Predisposition to severe chickenpox +• Immunocompromised due to disease (e.g. +11.11 Typical unilateral mumps. +A Note the loss of angle of the +jaw on the affected (right) side. +B Comparison showing normal (left) side. +time have led to outbreaks in young adults. +Infection is spread +by respiratory droplets. +Clinical features +The median incubation period is 19 days, with a range of 15–24 +days. +11.11). +Meningitis complicates up to 10% of cases. +The CSF +reveals a lymphocytic pleocytosis or, less commonly, neutrophils. +Oophoritis is less common. +Abortion may +occur if infection takes place in the rst trimester of pregnancy. +Complications may occur in the absence of parotitis. +Diagnosis +The diagnosis is usually clinical. +Management and prevention +Treatment is with analgesia. +There is no evidence that +glucocorticoids are of value for orchitis. +Mumps vaccine is one +of the components of the combined MMR vaccine. +It is +caused by influenza A virus or, in milder form, influenza B virus. +Nomenclature of influenza strains is based on +these glycoproteins, e.g. +H1N1, H3N2 etc. +Capsaicin cream (0.075%) may be +helpful. +Enteroviral +infections are discussed further under viral infections of the skin +(see below). +Mumps +Mumps is a systemic viral infection characterised by swelling of +the parotid glands. +Infection is endemic worldwide and peaks +at 5–9 years of age. +pneumoniae, Staph. +aureus or other +bacteria. +Mortality +is greatest in the elderly, those with medical comorbidities and +pregnant women. +The disease may also be diagnosed +retrospectively by serology. +These agents have superseded +routine use of amantadine and rimantadine. +Infections with H5N1 viruses have been severe, with +enteric features and respiratory failure. +Treatment depends on +the resistance pattern but often involves oseltamivir. +Vaccination +against seasonal ‘flu’ does not adequately protect against avian +influenza. +Cases were still occurring +in the Indian subcontinent in 2014–16. +EBV is a gamma herpesvirus. +In developing countries, +subclinical infection in childhood is virtually universal. +In developed +countries, primary infection may be delayed until adolescence +or early adult life. +Under these circumstances, about 50% of +infections result in typical IM. +EBV is not highly contagious and isolation +of cases is unnecessary. +Complications +are listed in Box 11.33. +In both groups, pharyngeal symptoms are often absent. +EBV +may present with jaundice, as a PUO or with a complication. +961). +11.12A). +Sometimes antibody production is delayed, so an +initially negative test should be repeated. +Specic EBV serology conrms the diagnosis. +CNS infections may be diagnosed by +detection of viral DNA in CSF. +Management +Treatment is largely symptomatic. +If a throat culture yields +a β-haemolytic streptococcus, penicillin should be given. +11.12B). +When pharyngeal oedema is severe, a short course +of glucocorticoids, e.g. +prednisolone 30 mg daily for 5 days, +may help. +Current antiviral drugs are not active against EBV. +Unfortunately, about 10% of patients with IM suffer a +chronic relapsing syndrome. +Cytomegalovirus +Cytomegalovirus (CMV), like EBV, circulates readily among +children. +11.12 Features of infectious mononucleosis. +A Atypical lymphocytes in peripheral blood. +Jaundice is uncommon and usually +mild. +Management +Only symptomatic treatment is required in the immunocompetent +patient. +They can be given intravitreally if required. +Dengue +Dengue is a febrile illness caused by a flavivirus transmitted by +mosquitoes. +It is endemic in Asia, the Pacic, Africa and the +Americas (Fig. +11.13). +Aedes albopictus is a vector in some South-east +Asian countries. +978). +Clinical features +Many cases of dengue infection are asymptomatic in children. +Clinical disease presents with undifferentiated fever termed +dengue-like illness. +A rash frequently follows the initial febrile phase as the +fever settles. +Warning signs justify intense medical +management and monitoring for progression to severe dengue. +198). +Cerebrovascular bleeding may be +a complication of severe dengue. +Diagnosis +In endemic areas, mild dengue must be distinguished from other +viral infections. +The diagnosis can be conrmed by seroconversion +of IgM or a fourfold rise in IgG antibody titres. +Isolation of dengue virus +or detection of dengue virus RNA by PCR (p. +106) in blood or +CSF is available in specialist laboratories. +With intensive +care support, mortality rates are 1% or less. +Aspirin should be +avoided due to bleeding risk. +Glucocorticoids have not been +shown to help. +No existing antivirals are effective. +Breeding places of Aedes mosquitoes should be abolished +and the adults destroyed by insecticides. +A recently licensed +vaccine is available. +11.13). +Transmission is by +tree-top mosquitoes, Aedes africanus (Africa) and Haemagogus +spp. +(America). +Overall mortality is around 15%, although this varies widely. +Shock, +hepatic failure, renal failure, seizures and coma may ensue. +Leucopenia is characteristic. +Liver biopsy should be avoided +in life due to the risk of fatal bleeding. +Immunohistochemistry for viral antigens improves specicity. +Blood +transfusions, plasma expanders and peritoneal dialysis may be +necessary. +Patients should be isolated, as their blood and body +products may contain virus particles. +Vaccination is not +recommended in people who are signicantly immunosuppressed. +2 Mortality of uncomplicated and haemorrhagic dengue fever, respectively. +The outbreak +resulted in over 28 000 cases by 2016. +Mortality +rates of Ebola and Marburg are high. +New outbreaks and new agents are identied sporadically. +The +viruses cause endothelial dysfunction with the development +of capillary leak. +Bleeding is due to endothelial damage and +platelet dysfunction. +Hypovolaemic shock and ARDS may +develop (p. +198). +Haemorrhage is a late feature of most VHFs and most patients +present with earlier features. +In Lassa fever, joint and abdominal +pain is prominent. +Encephalopathy may develop and deafness affects 30% +of survivors. +The clue to the viral aetiology comes from the travel and +exposure history. +In Lassa fever, an AST of > 150 U/L is associated +with a 50% mortality. +Most patients suspected of having a VHF in the UK turn out +to have malaria. +All further laboratory tests +should be performed at BSL 4. +Transport requires an ambulance +with BSL 3 facilities. +The +2014 outbreak involved the Zaire strain of Ebola virus. +Clinical features +The incubation period is 2–21 days but typically 8–10 days. +Fever +and non-specic signs are accompanied by abdominal pain, +diarrhoea, vomiting and hiccups. +A maculopapular rash occurs +after 5–7 days in some. +In contrast, fluid losses from +diarrhoea are more marked and reach 10 L a day. +Complications +include meningoencephalitis, uveitis and miscarriages in pregnant +women. +Serology +provides a retrospective diagnosis. +Management +Treatment is supportive and aimed at fluid replacement. +Bacterial +super-infections should be promptly treated. +Mortality +is approximately 40%. +It +also can be transmitted in semen. +Clinical features +The incubation period is 3–12 days. +Complications include increased reports of +Guillain–BarrĂŠ syndrome. +Zika +virus appears to infect neural progenitor cells. +PCR detects +virus in the first week of illness or in urine up to 14 days. +Serology provides a retrospective diagnosis but cross-reacts +with other flaviruses. +Prevention +Prevention focuses on avoiding mosquito bites. +As this is an evolving area, +updated guidance should be sought. +There is currently no vaccine. +11.14), while HSV-2 predominantly +involves the genital mucosa (pp. +333 and 336), although there +is overlap (see Box 11.29). +Primary infection +is followed by episodes of reactivation throughout life. +The primary attack may be associated with fever +and regional lymphadenopathy. +Prodromal hyperaesthesia is followed by rapid vesiculation, +pustulation and crusting. +Recurrent HSV genital disease is a +common cause of recurrent painful ulceration (pp. +333 and 336). +11.14B). +11 +AB C +Fig. +11.14 Cutaneous manifestations of herpes simplex virus 1 (HSV-1). +A Acute HSV-1. +There were also vesicles in the mouth – herpetic +stomatitis. +B Herpetic whitlow. +C Eczema herpeticum. +11.14C). +Primary HSV-2 can cause meningitis or transverse myelitis. +HSV is the leading cause of sporadic viral encephalitis (p. +1121); +this follows either primary or secondary disease, usually with +HSV-1. +Without treatment, mortality is 80%. +HSV encephalitis is diagnosed +by a positive PCR for HSV in CSF. +Serology is of limited value. +Oral lesions in an immunocompetent +individual may be treated with topical aciclovir. +Suspicion of HSV encephalopathy +requires immediate empirical antiviral therapy. +314). +HHV-8 is spread via saliva, and men who have sex +with men have an increased incidence of infection. +Seroprevalence +varies widely, being highest in sub-Saharan Africa. +Current antivirals +are not effective. +A papular erythematous rash may +appear on buttocks and thighs. +Antiviral treatment is not available +and management consists of symptom relief with analgesics. +The lesions are short-lived, rupturing after 2–3 days +and rarely persisting for more than 1 week. +Treatment is with +analgesics if required. +Culture of the virus from vesicles or DNA +detection by PCR differentiates herpangina from HSV. +Poxviruses +These DNA viruses are rare but potentially important pathogens. +The virus is spread by +the respiratory route or contact with lesions, and is highly +infectious. +The incubation period is 7–17 days. +Lesions in one area +are all at the same stage of development with no cropping +(unlike chickenpox). +Vaccination can lead to a modied course +of disease with milder rash and lower mortality. +If a case of smallpox is suspected, national public health +authorities must be contacted. +Electron micrography (like Fig. +11.15) and DNA detection tests (PCR) are used to conrm +diagnosis. +Little +person-to-person transmission occurs. +Outbreaks outside +Fig. +11.15 Electron micrograph of molluscum contagiosum, a +poxvirus. +Courtesy of Prof. +Diagnosis is by electron micrography or DNA +detection (PCR). +The reservoir is thought to be wild rodents. +Vaccinia virus +This laboratory strain is the basis of the existing vaccine to prevent +smallpox. +However, +vaccination may still be recommended for key medical staff. +Other poxviruses: orf and molluscum contagiosum +See page 1239 and Figure 11.15. +Respiratory viral infections +These infections are described on page 581. +582). +By 2016 there had been +over 1700 reported cases. +Initial symptoms are fever, chills, headache, myalgia, +dry cough and dyspnoea. +Abdominal pain and diarrhoea may be +prominent. +Mortality is 35%. +Diagnosis is conrmed by +PCR of serum, nasopharyngeal or other respiratory samples. +Serology may also be useful. +Treatment is supportive. +Food handlers may transmit this virus, +which is relatively resistant to decontamination procedures. +The incubation period is 24–48 hours. +High attack rates and +prominent vomiting are characteristic. +There are winter epidemics +in developed countries, particularly in nurseries. +Adults in close +contact with cases may develop disease. +Dehydration is prominent. +Immunity develops +to natural infection. +Hepatitis viruses (A–E) +See Chapter 22. +They have also +been linked to cases of intussusception. +See also page 1121. +There are 10 000–20 000 cases +reported to the WHO annually. +Exposure +to rice paddies is a recognised risk factor. +Clinical features +The incubation period is 4–21 days. +Most infections are subclinical +in childhood and 1% or less of infections lead to encephalitis. +Mortality with neurological disease +is 25%. +Most children die from respiratory failure. +Some 50% +of survivors have neurological sequelae. +1121). +There is neutrophilia and often hyponatraemia. +CSF +analysis reveals lymphocytosis and elevated protein. +Treatment is supportive. +Vaccination is recommended for +travellers to endemic areas during the monsoon. +Some endemic +countries include vaccination in their childhood schedules. +The +disease has an avian reservoir and a mosquito vector. +Older +people are at increased risk of neurological disease. +Clinical features +Most infections are asymptomatic. +After 2–6 days’ incubation, +a mild febrile illness and arthralgia may occur. +A prolonged +incubation may be seen in immunocompromised individuals. +Children may develop a maculopapular rash. +Diagnosis and management +Diagnosis is by serology or detection of viral RNA in blood or +CSF. +Serological tests may show cross-reactivity with other +flaviviruses, including vaccine strains. +Treatment is supportive. +248) +and aseptic meningitis. +Mortality is around 30%. +Diagnosis is by PCR or serology. +964). +It is +found mainly in Japan, the Caribbean, Central and South America, +and the Seychelles. +Myositis +and uveitis may also occur with HTLV-1 infection. +Serology, +sometimes confirmed with PCR, establishes the diagnosis. +Treatment is usually supportive. +237), to blood-borne viruses, such as HBV and HIV-1 +and the sequelae of EVD. +Chikungunya virus +Chikungunya is an alphavirus that causes fever, rash and +arthropathy. +It is found principally in Africa and Asia, including +India. +Cases occur +in epidemics on a background of sporadic cases. +In 2007, an +outbreak extended as far north as Italy. +The incubation period is 2–12 days. +A period of fever may +be followed by an afebrile phase and then recrudescence of +fever. +Children may develop a maculopapular rash. +Diagnosis is by serology but cross-reactivity between +alphaviruses occurs. +Treatment is symptomatic. +aureus or streptococci (mainly Strep. +pyogenes) +(see pp. +1019 and 1237). +Staphylococcal infections +Staphylococci are usually found colonising the anterior nares and +skin. +Staph. +aureus is coagulase-positive, and most other species are +coagulase-negative. +In modern laboratory practice, however, the +identication of Staph. +aureus rarely involves the coagulase test.Bacterial infections • 251 +Staph. +aureus is the main cause of staphylococcal infections. +Staph. +Among coagulase- +negative organisms, Staph. +Staph. +Others implicated in human infections include Staph. +lugdunensis, Staph. +schleiferi, Staph. +haemolyticus and Staph. +caprae. +Coagulase-negative staphylococci are not usually +identied to species level. +11.16). +527). +Growth of Staph. +In addition, Staph. +1235–1237). +They may also be involved in necrotising +infections of the skin and subcutaneous tissues (p. +226). +11.17A). +Cannula-related infection +Staphylococcal infection associated with cannula sepsis (Fig. +11.17B and p. +The +Visual Infusion Phlebitis (VIP) score aids cannula evaluation (Box +11.37). +Staphylococci have a predilection for plastic, rapidly +A B +11 +Fig. +11.17 Manifestations of skin infection with Staphylococcus +aureus. +A Wound infection. +B Cannula-related infection. +Nursing Times 1997; 94:68–71. +Fig. +Meticillin-resistant Staph. +aureus +Resistance to meticillin is due to a penicillin-binding protein +mutation in Staph. +aureus. +Resistance to vancomycin/teicoplanin +(glycopeptides) in either glycopeptide intermediate Staph. +Meticillin-resistant Staph. +Community-acquired MRSA (c-MRSA) currently accounts for +50% of all MRSA infections in the USA. +111). +Treatment options for MRSA are shown in Box 6.16 +(p. +117). +Milder MRSA infections may be treated with +clindamycin, tetracyclines or co-trimoxazole. +Glycopeptides, +linezolid and daptomycin are reserved for treatment of more +severe infections. +aureus, which produces a specic toxin (toxic shock syndrome +toxin 1, TSST1). +aureus infection involving a +relevant toxin-producing strain. +It rapidly progresses over a few hours to multi-organ +failure, leading to death in 10–20%. +Recovery is accompanied +at 7–10 days by desquamation (Fig. +11.18). +Subsequent culture and demonstration of toxin production +are conrmatory. +clindamycin) to inhibit toxin production. +Intravenous +immunoglobulin is occasionally added in the most severe cases. +Fig. +11.18 Full-thickness desquamation after staphylococcal toxic +shock syndrome. +6.3, p. +102). +They are classied by the pattern of haemolysis they produce +on blood agar (see Fig. +6.4, p. +Some streptococci (e.g. +Strep. +milleri group) defy +simple classication. +Group A streptococci (GAS) are the leading cause of bacterial +pharyngitis. +GAS are also the major cause of +cellulitis, erysipelas and impetigo (pp. +1237 and 1235). +Group B streptococci +(GBS) colonise the gut and vagina. +A diffuse erythematous rash occurs, which blanches +on pressure (Fig. +11.19A), classically with circumoral pallor. +The +tongue, initially coated, becomes red and swollen (‘strawberry +tongue’, Fig. +11.19B). +Residual petechial lesions in the antecubital fossa may be seen +(‘Pastia’s sign’, Fig. +11.19C). +Like +staphylococcal TSST1 (see above), these act as super-antigens. +A faint erythematous rash, mainly on the chest, rapidly +progresses to circulatory shock. +Without aggressive management, +multi-organ failure will develop. +Intravenous +immunoglobulin is often administered. +11.38 Streptococcal and related infections +β-haemolytic group A (Strep. +11 +Îą- or non-haemolytic group D (Strep. +gallolyticus subsp. +gallolyticus/S. +mitis, Strep. +sanguis, Strep. +mutans, Strep. +This primary lesion +is followed by secondary eruptions. +milleri group – Strep. +anginosus, +Strep. +intermedius, Strep. +All streptococci can cause sepsis. +A B C +Fig. +11.19 Clinical features of scarlet fever. +A Characteristic rash with blanching on pressure. +B ‘Strawberry tongue’. +Clumps of acid-fast +bacilli can be detected in the ulcer floor. +A combination of rifampicin and streptomycin can cure the +infection. +Infected tissue should be removed surgically. +Systemic bacterial infections +Brucellosis +Brucellosis is an enzootic infection (i.e. +endemic in animals) +caused by Gram-negative bacilli. +abortus (cattle, mainly in Africa, Asia and South America), +B. +suis (pigs in South Asia) and B. +canis (dogs). +B. +melitensis +causes the most severe disease; B. +suis is often associated +with abscess formation. +Infected animals may excrete Brucella spp. +Clinical features +Brucella spp. +are intracellular organisms that survive for long +periods within the reticulo-endothelial system. +This explains +the disease chronicity and tendency to relapse, even after +antimicrobial therapy. +Occasionally, there is delirium, abdominal pain and +constipation. +Physical signs are non-specic, e.g. +enlarged +lymph nodes. +Splenomegaly may cause thrombocytopenia. +Localised infection (Fig. +Diagnosis +Denitive diagnosis depends on culture of the organism. +Blood +cultures are positive in 75–80% of B. +melitensis and 50% of +B. +abortus infections. +CSF culture in neurobrucellosis is positive in +about 30% of cases. +Serology may also aid diagnosis. +Management +Aminoglycosides show synergistic activity with tetracyclines +against brucellae. +Treatment regimens for different forms of +brucellosis are outlined in Box 11.40. +Investigations and management are outlined in Box +11.39. +Their diagnosis and management are as +for yaws (Box 11.39). +• Pinta. +Pinta is found only in South and Central America, +where its incidence is declining. +The infection is conned +to the skin. +The early lesions are scaly papules or +dyschromic patches on the skin. +The late lesions are often +depigmented and disguring. +• Bejel. +It has been eradicated from Eastern Europe. +The early and late lesions resemble those of +secondary and tertiary syphilis (p. +337) but cardiovascular +and neurological disease is rare. +ulcerans, an anaerobe) and Treponema +vincentii. +It is common in hot, humid regions. +The base of the +ulcer has a foul slough. +The initial lesion is a small subcutaneous nodule on the arm or +leg. +11.20 Clinical features of brucellosis. +They cause a variety of human +infections worldwide (Box 11.41). +Lyme disease +Lyme disease (named after the town of Old Lyme in Connecticut, +USA) is caused by B. +burgdorferi, which occurs in the USA, +Europe, Russia, China, Japan and Australia. +In Europe, two +additional genospecies are also encountered, B. +afzelii and B. +garinii. +Birds may +spread ticks over a wide area. +Ehrlichiosis is a common co-infection with Lyme disease. +Clinical features +There are three stages of disease. +Progression may be arrested +at any stage. +• Early localised disease. +11.21). +Initially, a red ‘bull’s eye’ +macule or papule appears 2–30 days after the bite. +It then +enlarges peripherally with central clearing and may persist +for months. +Atypical forms are common. +The lesion is not +pathognomonic of Lyme disease since similar lesions can +occur after tick bites. +• Late disease. +Late manifestations include arthritis, +polyneuritis and encephalopathy. +Doughy, +patchy discoloration occurs on the peripheries, eventually +leading to shiny atrophic skin. +The lesions are easily +mistaken for those of peripheral vascular disease. +Diagnosis +The diagnosis of early Lyme borreliosis is often clinical. +339). +Disseminated disease and arthritis require therapy for a +minimum of 28 days. +Arthritis may respond poorly and prolonged +or repeated courses may be necessary. +Prevention +Protective clothing and insect repellents should be used in +tick-infested areas. +Unfortunately, larval and nymphal ticks +are tiny and may not be noticed. +11.41 Clinical diseases caused by Borrelia spp. +Species Vector Geographical distribution +Lyme disease +B. +burgdorferi +Northern and eastern USA +Tick: Ixodes +sensu stricto +scapularis +I. +pacicus Western USA +B. +afzelii I. +ricinus Europe +I. +persulcatus Asia +B. +garinii I. +ricinus Europe +I. +persulcatus Asia +Louse-borne relapsing fever +B. +recurrentis Human louse: +Pediculus humanus +corporis +Worldwide +Tick-borne relapsing fever +B. +hermsii Tick: Ornithodoros +Western North America +hermsii +B. +turicatae O. +turicatae South-western North +America and northern +Mexico +B. +venezuelensis O. +rudis Central America and +northern South America +B. +hispanica O. +erraticus Iberian peninsula and +north-western Africa +B. +crocidurae O. +erraticus North Africa and +Mediterranean region +B. +duttonii O. +moubata Central, eastern and +southern Africa +B. +persica O. +tholozani Western China, India, +Central Asia, Middle East +B. +latyschewii O. +tartakovskyi Tajikistan, Uzbekistan +Fig. +11.21 Rash of erythema migrans in Lyme disease with +metastatic secondary lesions. +Courtesy of Dr Ravi Gowda, Royal +Hallamshire Hospital, Shefeld. +• Early disseminated disease. +Dissemination occurs via the +blood stream and lymphatics. +11.21). +Neurological involvement may follow weeks or months +after infection. +Borreliae (B. +Clinical features +Onset is sudden with fever. +11.22) and herpes labialis. +Thrombocytopenia is associated with a petechial rash and +epistaxis. +There may be severe serosal and intestinal haemorrhage, delirium +and meningism. +The safest treatment is procaine +penicillin 300 mg IM, followed the next day by 0.5 g tetracycline. +Tetracycline alone is effective and prevents relapse, but may +give rise to a worse reaction. +JHR is best managed in a high-dependency unit with expert +nursing and medical care. +The patient, clothing and all contacts must be freed from lice, +as in epidemic typhus. +Tick-borne relapsing fever +Soft ticks (Ornithodoros spp.) transmit B. +duttonii (and other +Borrelia species) through saliva while feeding on their host. +Leptospira interrogans is pathogenic +for humans. +The genus can be separated into more than 200 +serovars (subtypes) belonging to 23 serogroups. +Leptospirosis appears to be ubiquitous in wildlife and in +many domestic animals. +The most frequent hosts are rodents, especially the common +rat (Rattus norvegicus). +Particular leptospiral serogroups are +associated with characteristic animal hosts; for example, L. +ictero-haemorrhagiae is the classical parasite of rats and L. +canicola of dogs. +There is nevertheless considerable overlap in +host–serogroup associations. +Leptospirosis is common in the tropics and also in +freshwater sports enthusiasts. +The incubation period averages 1–2 weeks. +11.23). +Conjunctival congestion +is the only notable physical sign. +Aseptic meningitis +Classically associated with L. +canicola infection, this illness is +very difcult to distinguish from viral meningitis. +The conjunctivae +may be congested but there are no other differentiating signs. +11 +Fig. +11.22 Louse-borne relapsing fever. +11.23 Clinical syndromes of leptospirosis. +Conjunctival hyperaemia is a frequent feature. +Weil’s disease may also be associated with myocarditis, +encephalitis and aseptic meningitis. +Uveitis and iritis may appear +months after apparent clinical recovery. +Total bilateral lung consolidation +and ARDS (p. +324) with multi-organ dysfunction may develop, +with a high mortality (over 50%). +In jaundiced patients, there is hepatitis and the +prothrombin time may be prolonged. +Acute kidney +injury due to interstitial nephritis is common. +In +general, however, it is probably under-diagnosed. +• Blood cultures are most likely to be positive if taken before +the 10th day of illness. +Special media are required and +cultures may have to be incubated for several weeks. +Management and prevention +The general care of the patient is critically important. +Acute kidney +injury is potentially reversible with adequate support, such as +dialysis. +Most infections are self-limiting. +Parenteral ceftriaxone +(1 g daily) is as effective as penicillin. +JHR may occur but is usuallyBacterial infections • 259 +mild. +Uveitis is treated with a combination of systemic antibiotics +and local glucocorticoids. +There is no role for the routine use of +glucocorticoids in the management of leptospirosis. +Trials in military personnel have shown that infection with L. +interrogans can be prevented by taking prophylactic doxycycline +200 mg weekly. +If +domestic rats become infected, infected fleas may bite humans. +Hunters and trappers can contract plague from handling +rodents. +In the late stages of human plague, Y. +pestis may be +expectorated and spread between humans by droplets, causing +‘pneumonic plague’. +Epidemics of plague, such as the ‘Black Death’, have occurred +since ancient times. +It is often said that the rst sign of plague is +the appearance of dead rats. +11.24). +Y. +Inhalation of Y. +pestis causes alveolitis. +The incubation period is 3–6 days but shorter in pneumonic +plague. +Soon, aching and swelling at the site of the affected lymph +nodes begin. +The spleen is usually palpable. +The elderly are more prone to this form of illness. +Hypotension, shock, renal failure +and ARDS may lead to further deterioration. +Meningitis, pneumonia +and expectoration of blood-stained sputum containing Y. +pestis +may complicate septicaemic, or occasionally bubonic, plague. +Investigations +The organism may be cultured from blood, sputum and bubo +aspirates. +Y. +Smears are also subjected to antigen detection +by immunofluorescence, using Y. +pestis F1 antigen-specic +antibodies. +DNA +detection by PCR is under evaluation. +Plague is a notifiable disease under international health +regulations (p. +114). +Streptomycin (1 g twice daily) or gentamicin (1 mg/kg 3 times +daily) is the drug of choice. +Treatment may +also be needed for acute circulatory failure, DIC and hypoxia. +Prevention and infection control +Rats and fleas should be controlled. +In endemic areas, people +should avoid handling and skinning wild animals. +The patient +should be isolated for the rst 48 hours or until clinical improvement +begins. +Attendants must wear gowns, masks and gloves. +A recombinant subunit vaccine (protein antigens F1 + V) is +in development. +11 +Frequent transmission Infrequent or suspected +transmission +Fig. +11.24 Foci of the transmission of plague. +1078). +Investigations and management +Diagnosis is made by blood and CSF culture. +The organism +grows readily in culture media. +A sulfamethoxazole/trimethoprim combination can be used in +those with penicillin allergy. +Proper treatment of foods before eating is the key to preventing +listeriosis. +Pregnant women are advised to avoid high-risk +products, including soft cheeses. +Elsewhere, +they are relatively rare. +Enteric fevers are caused by infection +with Salmonella Typhi and Salmonella Paratyphi A and B. +These swell at rst, then +ulcerate and usually heal. +After clinical recovery, about 5% of +patients become chronic carriers (i.e. +Clinical features +Typhoid fever +Clinical features are outlined in Box 11.42. +The pulse is often slower than would be expected from +the height of the temperature, i.e. +a relative bradycardia. +It is usually visible only on white +skin. +Cough and epistaxis occur. +Around the 7th–10th day, the +spleen becomes palpable. +Constipation is followed by diarrhoea +and abdominal distension with tenderness. +Bronchitis and delirium +may develop. +If untreated, by the end of the second week the +patient may be profoundly ill. +The rash may be more abundant and the intestinal complications +less frequent. +Complications +These are given in Box 11.43. +Bone and joint +infection is common in children with sickle-cell disease. +Typically, +there is a leucopenia. +Blood culture establishes the diagnosis +and multiple cultures increase the yield. +Stool cultures are often +positive in the second and third weeks. +The Widal test detects +antibodies to the O and H antigens but is not specic. +Management +Antibiotic therapy must be guided by in vitro sensitivity testing. +Fluoroquinolones +are the drugs of choice (e.g. +Treatment should be continued +for 14 days. +Pyrexia may persist for up to 5 days after the start +of specic therapy. +Cholecystectomy +may be necessary. +Prevention +Improved sanitation and living conditions reduce the incidence +of typhoid. +Tularaemia +Tularaemia is primarily a zoonotic disease of the northern +hemisphere. +It is caused by a highly infectious Gram-negative +bacillus, Francisella tularensis. +F. +It is a potential weapon for +bioterrorism. +There is also a purely ‘glandular’ +form. +Bacterial yield from the lesions is extremely poor. +DNA +detection methods to enable rapid diagnosis are in development. +Patients +with diabetes, renal stones, thalassaemia or severe burns are +particularly susceptible. +Disease may present years or decades after the initial exposure. +Diarrhoea and hepatosplenomegaly may be observed. +The chest X-ray can resemble cavitatory tuberculosis. +Investigations and management +Culture of blood, sputum or pus on selective media, e.g. +Ashdown +agar, may yield B. +pseudomallei. +In the acute illness, prompt initiation of empirical therapy is life- +saving. +Abscesses should be drained +surgically. +Nocardiosis can +result in localised cutaneous ulcers or nodules, most often +in the lower limbs. +Both conditions are discussed on page 301. +On microscopy, Nocardia spp. +appear as long, lamentous, +branching Gram-positive rods, which are also weakly acid- +fast. +They are easily grown in culture but require prolonged +incubation. +Abscesses are drained +surgically when this is feasible. +Localised cutaneous infection is +usually treated with a single agent for 1–3 months. +Treatment +of actinomycetoma is discussed on page 301. +Actinomyces spp. +Actinomyces are anaerobic Actinomycetes, which are +predominantly commensals of the oral cavity. +Early disease may respond to shorter antibiotic +courses. +Spores +contaminate +uncooked +cereals, +e.g. +Staphylococcal food poisoning +Staph. +Nausea and profuse vomiting develop within 1–6 hours. +Diarrhoea may not be marked. +Most +cases settle rapidly but severe dehydration can occasionally +be life-threatening. +Antiemetics and appropriate fluid replacement are the +mainstays of treatment. +Suspect food should be cultured +for staphylococci and demonstration of toxin production. +The +public health authorities should be notied if food vending is +involved. +Bacillus cereus food poisoning +Ingestion of the pre-formed heat-stable exotoxins of B. +11.25). +The disease is self-limiting but can be quite severe. +Clostridium perfringens food poisoning +Spores of C. +perfringens are widespread in the guts of large +animals and in soil. +If contaminated meat products are incompletely +cooked and stored in anaerobic conditions, C. +perfringens spores +germinate and viable organisms multiply. +Subsequent reheating +of the food causes release of enterotoxin. +Symptoms (diarrhoea +and cramps) occur some 6–12 hours following ingestion. +The +illness is usually self-limiting. +Clostridial enterotoxins are potent and most people who ingest +them will be symptomatic. +perfringens, +type C. +The toxin is normally inactivated by certain proteases or +by normal cooking. +roundworms. +11.25 Bacillus cereus food poisoning. +The most common sources of the infection +are chicken, beef and contaminated milk products. +Pet puppies +have also been sources. +The incubation period is 2–5 days. +Colicky abdominal +pain may be severe and mimic acute appendicitis or other +surgical pathology. +Nausea, vomiting and signicant diarrhoea, +frequently containing blood, are common features. +Approximately 1% of cases will develop bacteraemia and +possible distant foci of infection. +Campylobacter spp. +have been +linked to Guillain–BarrĂŠ syndrome and post-infectious reactive +arthritis (pp. +1140 and 1031). +Salmonella spp. +infection +Salmonella enterica serovars other than Salmonella Typhi and +Paratyphi (p. +260), of which there are more than 2000, can cause +gastroenteritis. +They are widely distributed throughout the animal +kingdom. +Some strains have a clear relationship to particular +animal species, e.g. +Salmonella Arizonae and pet reptiles. +Vomiting may be present at the outset. +Reactive (post-infective) arthritis occurs in +approximately 2%. +Mortality, as with +other forms of gastroenteritis, is higher in the elderly (see Box +11.12, p. +228). +Entero-aggregative E. +coli +Entero-aggregative E. +Enterohaemorrhagic E. +coli +A number of distinct ‘O’ serotypes of E. +E. +coli +O157:H7 is perhaps the best known of these verotoxin-producing +E. +coli (VTEC) but others, including types O126 and O11, are +also implicated. +coli +O104:H4, an EAEC strain that had acquired genes encoding +shiga toxin 2a. +Although the incidence of enterohaemorrhagic +E. +The reservoir of infection is in the gut of herbivores. +The +organism has an extremely low infecting dose (10–100 organisms). +11.26). +The incubation period is between 1 and 7 days. +coli constitute part of the human gut +microbiome. +Travel to unfamiliar areas +of the world allows contact with different strains of endemic E. +coli +and the development of travellers’ diarrhoea. +coli with characteristic +virulence factors. +Enterotoxigenic E. +coli +Enterotoxigenic E. +232). +The illness is usually mild +and self-limiting after 3–4 days. +Antibiotics are of questionable +value (p. +232). +Entero-invasive E. +coli +Illness caused by entero-invasive E. +coli (EIEC) is very similar +to Shigella dysentery (p. +265) and is caused by invasion and +destruction of colonic mucosal cells. +No enterotoxin is produced. +Acute watery diarrhoea, abdominal cramps and some scanty +blood-staining of the stool are common. +The symptoms are +rarely severe and are usually self-limiting. +Enteropathogenic E. +coli +Enteropathogenic E. +coli (EPEC) organisms are very important +in infant diarrhoea. +The symptoms vary from mild non-bloody +diarrhoea to quite severe illness, but without bacteraemia. +Fig. +11.26 Verocytotoxigenic Escherichia coli (VTEC) infections. +There is little systemic +upset, vomiting or fever. +The potentially life-threatening haemolytic uraemic +syndrome (HUS, p. +HUS is treated by dialysis if necessary and may be averted +by plasma exchange. +Antibiotics should be avoided since they +can stimulate toxin release. +Clostridium difcile infection +C. +difcile is the most commonly diagnosed cause of antibiotic- +associated diarrhoea (p. +230), and is an occasional constituent +of the gut microbiome. +C. +difcile can produce two toxins (A +and B). +C. +difcile, if +the patient is exposed to C. +difcile spores. +A hypervirulent strain of C. +difcile strains. +Ileus +is also seen in pseudomembranous colitis. +Investigations +C. +The +diagnosis of CDI therefore rests on detection of toxins A or B +in the stool. +difcile, or of C. +difcile nucleic acid (e.g. +by PCR); if screening is +positive, a C. +difcile toxin ELISA or a tissue culture cytotoxicity +assay is performed. +11.27), or may resemble ulcerative colitis. +In some cases, +the rectum is spared and abnormalities are observed in the +proximal colon. +CT may +be useful when the diagnosis is in doubt. +Management +The precipitating antibiotic should be stopped and the patient +should be isolated. +Supportive therapy includes intravenous +Fig. +11.27 Clostridium difcile infection. +Colonoscopic view showing +numerous adherent ‘pseudomembranes’ on the mucosa. +fluids and bowel rest. +Although vancomycin is more effective than metronidazole +against hypervirulent C. +difcile strains (e.g. +enterococci, Staph. +aureus). +Fidaxomicin is associated with a lower relapse rate than +vancomycin but is more expensive. +Surgical intervention +needs to be considered early in severe cases. +It predominantly +causes disease in children but adults may also be affected. +The +illness resolves slowly. +Complications include reactive arthritis +(p. +1031; 10–13% of cases), which may be persistent, and +anterior uveitis. +V. +An atypical serotype, O139, has been responsible +for localised outbreaks in Bangladesh. +Organisms +survive for up to 2 weeks in fresh water and 8 weeks in salt water. +Shock and oliguria develop but mental clarity +remains. +Death from acute circulatory failure may occur rapidly +unless fluid and electrolytes are replaced. +Improvement is rapid +with proper treatment. +The majority of infections, however, cause mild illness with +slight diarrhoea. +The +disease is more dangerous in children. +Diagnosis and management +Clinical diagnosis is easy during an epidemic. +Otherwise, the +diagnosis should be conrmed bacteriologically. +Stool dark- +eld microscopy shows the typical ‘shooting star’ motility of +V. +cholerae. +Rectal swab or stool cultures allow identication. +Cholera is notiable under international health regulations. +Maintenance of circulation by replacement of water and +electrolytes is paramount (p. +229). +Ringer-Lactate is the best +fluid for intravenous replacement. +Total +fluid requirements may exceed 50 L over a period of 2–5 days. +cholerae and the total +volume of fluid needed for replacement. +Flies must be denied +access to food. +Oral vaccines containing killed V. +cholerae with or +without the B subunit of cholera toxin are used in specic settings. +Mass single-dose vaccination and treatment with tetracycline +are valuable. +coli (see above). +It is very common where ingestion of raw +seafood is widespread (e.g. +Japan). +Rarely, a severe septic illness arises; in this case, V. +parahaemolyticus can be isolated using specific halophilic +culture. +Bacillary dysentery (shigellosis) +Shigellae are Gram-negative rods, closely related to E. +coli, that +invade the colonic mucosa. +There are four main groups: Sh. +dysenteriae, flexneri, boydii and sonnei. +In the tropics, bacillary +dysentery is usually caused by Sh. +flexneri, while in the UK most +cases are caused by Sh. +sonnei. +Shigellae are often resistant to +multiple antibiotics, especially in tropical countries. +Shigella infection may spread rapidly among men who +have sex with men. +Clinical features +Disease severity varies from mild Sh. +sonnei infections that may +escape detection to more severe Sh. +flexneri infections, while +those due to Sh. +dysenteriae may be fulminating and cause +death within 48 hours. +Fever, dehydration and weakness occur, +with tenderness over the colon. +Reactive arthritis or iritis may +occasionally complicate bacillary dysentery (p. +1031). +The use of antidiarrhoeal +medication should be avoided. +Hand-washing is very important. +Respiratory bacterial infections +Most of these infections are described in Chapter 17. +Infection may also complicate skin lesions, especially +in alcoholics. +An antihistamine is also given. +A dose of up to 100 000 IU of antitoxin +is injected intravenously if the test dose is tolerated. +diphtheriae. +Patients allergic to penicillin can be given erythromycin. +Prevention +Active immunisation should be given to all children. +All contacts should also be immunised or given a booster +dose of toxoid. +Booster doses are required every 10 years to +maintain immunity. +Pneumococcal infection +Strep. +pneumoniae (the pneumococcus) is the leading cause +of community-acquired pneumonia globally (p. +582) and one of +the leading causes of infection-related mortality. +Otitis media, +meningitis and sinusitis are also frequently caused by Strep. +pneumoniae. +Occasional patients present with bacteraemia +without obvious focus. +Asplenic individuals are at risk of fulminant +pneumococcal disease with purpuric rash. +Increasing rates of penicillin resistance have been reported +around the world for Strep. +pneumoniae, although they remain +low in the UK. +Macrolide resistance is also +increasing. +Newer quinolones are also used (e.g. +levofloxacin) +but rates of resistance are rising. +Vaccination of infants with the protein conjugate pneumococcal +vaccine decreases Strep. +pneumoniae infection in infants and in +their relatives. +The polysaccharide pneumococcal vaccine is used +in individuals predisposed to Strep. +All asplenic individuals should +receive vaccination against Strep. +pneumoniae. +B. +100). +It is a Gram-positive organism with a central spore. +The spores can survive for years in soil. +Infection is commonly +acquired from contact with animals, particularly herbivores. +The +ease of production of B. +anthracis spores makes this infection +a candidate for biological warfare or bioterrorism. +B. +anthracis +produces a number of toxins that mediate the clinical features +of disease. +in Russia and South-east Asia. +Clinical features +The average incubation period is 2–4 days. +The disease begins +insidiously with a sore throat (Box 11.44). +Despite modest fever, +there is usually marked tachycardia. +The diagnostic feature is +the ‘wash-leather’ elevated, greyish-green membrane on the +tonsils. +It has a well-dened edge, is rm and adherent, and is +surrounded by a zone of inflammation. +There may be swelling +of the neck (‘bull neck’) and tender enlargement of the lymph +nodes. +With anterior nasal infection there is nasal discharge, frequently +blood-stained. +If infection spreads to the uvula, fauces +and nasopharynx, the patient is gravely ill. +Death from acute circulatory failure may occur within the rst +10 days. +Late complications arise as a result of toxin action on +the heart or nervous system. +These are usually reversible, with no permanent +damage other than heart block in survivors. +Neurological involvement occurs in 75% of cases. +After tonsillar +or pharyngeal diphtheria, it usually starts after 10 days with +palatal palsy. +Paralysis of accommodation often follows, manifest +by difculty in reading small print. +Generalised polyneuritis with +weakness and paraesthesia may follow in the next 10–14 days. +Recovery from such neuritis is always ultimately complete. +Empirical treatment should commence +after collection of appropriate swabs. +Diphtheria antitoxin is produced from hyperimmune horse +serum. +It +accounts for the vast majority of clinical cases. +Animal infection is +a serious problem in Africa, India, Pakistan and the Middle East. +Spores are inoculated into exposed skin. +A single lesion +develops as an irritable papule on an oedematous haemorrhagic +base. +This progresses to a depressed black eschar. +Despite +extensive oedema, pain is infrequent. +Gastrointestinal anthrax +This is associated with the ingestion of contaminated meat. +Toxaemia and death can develop +rapidly thereafter. +Without rapid and aggressive therapy at the +onset of symptoms, the mortality is 50–90%. +Fever, dyspnoea, +cough, headache and sepsis develop 3–14 days following +exposure. +Meningitis may occur. +Management +B. +anthracis can be cultured from skin swabs from lesions. +Skin lesions are readily curable with early antibiotic therapy. +The addition of an aminoglycoside +may improve the outlook in severe disease. +Monoclonal antibodies against B. +anthracis protective antigen can be added for systemic infection. +69) towards M. +leprae +(Fig. +11.28). +Complications arise due to nerve damage, +immunological reactions and bacillary inltration. +People with +leprosy are frequently stigmatised and using the word ‘leper’ +is inappropriate. +Untreated lepromatous patients discharge bacilli from the nose. +Infection occurs through the nose, followed by haematogenous +spread to skin and nerve. +The incubation period is 2–5 years +for tuberculoid cases and 8–12 years for lepromatous cases. +Pathogenesis +M. +leprae has tropism for Schwann cells and skin macrophages. +In +lepromatous leprosy, there is abundant bacillary multiplication +(‘multibacillary’), e.g. +in Schwann cells and perineurium. +Fig. +11.28 Leprosy: mechanisms of damage and tissue affected. +They overlap in the centre where, in +addition, instability predisposes to type 1 lepra reactions. +At the peak in +the centre, neither bacillary growth nor cell-mediated immunity has the +upper hand. +Leprosy, 3rd edn. +Churchill +Livingstone, Elsevier Ltd; 1990. +Clinical features +Box 11.45 gives the cardinal features of leprosy. +Types of leprosy +are compared in Box 11.46. +• Skin. +The most common skin lesions are macules or +plaques. +Tuberculoid patients have few, hypopigmented +lesions (Fig. +11.29A). +In lepromatous leprosy, papules, +nodules or diffuse inltration of the skin occur. +The earliest +lesions are ill dened; gradually, the skin becomes +inltrated and thickened. +Facial skin thickening leads to the +characteristic leonine facies (Fig. +11.29B). +• Anaesthesia. +Anaesthesia can occur +in the distribution of a damaged large peripheral nerve. +A +‘glove and stocking’ sensory neuropathy is also common +in lepromatous leprosy. +• Nerve damage. +Peripheral nerve trunks are affected at +‘sites of predilection’. +11.29C). +The CNS is not affected. +• Eye involvement. +Blindness is a devastating complication +for a patient with anaesthetic hands and feet. +Eyelid +closure is impaired when the facial nerve is affected. +Damage to the trigeminal nerve causes anaesthesia of the +cornea and conjunctiva. +The cornea is then susceptible to +trauma and ulceration. +• Other features. +Many organs can be affected. +Nasal +collapse occurs secondary to bacillary destruction of the +nasal cartilage and bone. +This results in azoospermia +and hypogonadism. +• Type 1 (reversal) reactions. +2 Contraindicated in +women who may become pregnant. +31% hydrocortisone drops or ointment and +1% atropine drops. +Cell-mediated +Reactions Immune complexes +(type 2) +(type 1)Bacterial infections • 269 +A B +C D +Fig. +11.29 Clinical features of leprosy. +A Tuberculoid leprosy. +Single lesion with a +well-dened active edge and anaesthesia within +the lesion. +B Lepromatous leprosy. +Widespread +nodules and inltration, with loss of the eyebrows. +This man also has early collapse of the nose. +C Borderline tuberculoid leprosy with severe +nerve damage. +This boy has several well-dened, +hypopigmented, macular, anaesthetic lesions. +D Reversal (type 1) +reactions. +Erythematous, oedematous lesions. +11 +erythematous (Fig. +11.29D). +Peripheral nerves become +tender and painful, with sudden loss of nerve function. +• Type 2 (erythema nodosum leprosum, ENL) reactions. +They manifest with malaise, fever +and crops of small pink nodules on the face and limbs. +Iritis and episcleritis are common. +ENL may continue intermittently +for several years. +Pure neural leprosy (i.e. +without skin lesions) occurs principally +in India and accounts for 10% of patients. +There is asymmetrical +involvement of peripheral nerve trunks and no visible skin lesions. +On nerve biopsy, all types of leprosy have been found. +Smears are +useful for conrming the diagnosis and monitoring response to +treatment. +Neither serology nor PCR is sensitive or specic enough +for diagnosis. +Management +The principles of treatment are outlined in Box 11.48. +All +leprosy patients require MDT with an approved rst-line regimen +(Box 11.49). +Rifampicin is a potent bactericidal for M. +Dapsone is +bacteriostatic. +It commonly causes mild haemolysis and rarely +anaemia. +Clofazimine is a red, fat-soluble crystalline dye, weakly +bactericidal for M. +leprae. +New bactericidal drugs against M. +leprae have been +identied, notably fluoroquinolones (pefloxacin and ofloxacin). +Minocycline and clarithromycin may also be used. +These agents +are now established second-line drugs. +It is important to ask potentially infected patients about contact +with ticks, lice or fleas. +There are two main groups of rickettsial +fevers: spotted fevers and typhus (Box 11.50). +An eschar, a black necrotic crusted sore, +is often found in tick- and mite-borne typhus (see Fig. +11.7C, +p. +235). +This is due to vasculitis following immunological +recognition of the inoculated organism. +Regional lymph nodes +often enlarge. +The incubation +period is about 7 days. +Larger cutaneous and subcutaneous +haemorrhages may appear in severe cases. +The liver and spleen +become palpable. +At the extremes of life, the mortality is 2–12%. +Other spotted fevers +R. +conorii (boutonneuse fever) and R. +The incubation period is +approximately 7 days. +Infected ticks may be picked up by +walking on grasslands, or dogs may bring ticks into the house. +There +may be delirium and meningeal signs in severe infections but +recovery is usual. +R. +africae can be associated with multiple +eschars. +Some cases, particularly those with R. +africae, present +without rash (‘spotless spotted fever’). +Other spotted fevers are +shown in Box 11.50. +In many patients, one eschar or more develops, +surrounded by an area of cellulitis (see Fig. +11.7C, p. +Lepra reactions are treated as shown in Box 11.47. +Chloroquine +can also be used. +It should emphasise that gross deformities +are not inevitable. +Patients with anaesthetic hands or feet need to avoid and +treat burns or other minor injuries. +Good footwear is important. +Physiotherapy helps maintain range of movement of affected +muscles and neighbouring joints. +Lepromatous +leprosy (LL) is a progressive condition with high morbidity if +untreated. +typhi Rats Flea Worldwide Slight – – Rare3 +1 Eschar at bite site and local lymphadenopathy. +2 Highest in adult males. +3 Except in infants, older people and the debilitated. +enlargement of regional lymph nodes. +The incubation period is +about 9 days. +Mild or subclinical cases are common. +In severe illness, the general +symptoms increase, with apathy and prostration. +The rash fades +by the 14th day. +The temperature rises rapidly and continues +as a remittent fever (i.e. +In severe infection, +the patient is prostrate with cough, pneumonia, delirium and +deafness. +Cardiac failure, renal failure and haemorrhage may +develop. +Convalescence is often slow and tachycardia may +persist for some weeks. +Epidemic (louse-borne) typhus +Epidemic typhus is caused by R. +Patients suffering from epidemic typhus +infect lice, which leave when the patient is febrile. +In conditions +of overcrowding, the disease spreads rapidly. +Large epidemics have +occurred in Europe, usually as a sequel to war. +The incubation +period is usually 12–14 days. +The face is flushed +and cyanotic, the eyes are congested and the patient becomes +confused. +The rash appears on the 4th–6th day. +The neck and face are seldom affected. +During the second week, symptoms increase in severity. +Sores +develop on the lips. +The tongue becomes dry, brown, shrunken +and tremulous. +The spleen is palpable, the pulse feeble and the +patient stuporous and delirious. +The temperature falls rapidly at +the end of the second week and the patient recovers gradually. +Endemic (flea-borne) typhus +Flea-borne or ‘endemic’ typhus caused by R. +typhi is endemic +worldwide. +The incubation period is 8–14 days. +The symptoms +resemble those of a mild louse-borne typhus. +The rash may be +scanty and transient. +Investigation of rickettsial infection +Routine blood investigations are not diagnostic. +There is usually +hepatitis and thrombocytopenia. +Chloramphenicol- and doxycycline-resistant strains of O. +Nursing care is important, especially in epidemic typhus. +Sedation may be required for delirium and blood transfusion +for haemorrhage. +Convalescence +is usually protracted, especially in older people. +An important characteristic +of C. +When isolated +from animals or humans, C. +In culture, there is an antigenic shift to the phase II +form, which is not infectious. +Measurement of antigenic shift +helps differentiate acute and chronic Q fever. +Clinical features +The incubation period is 3–4 weeks. +Other presentations include +pneumonia and hepatitis. +Chronic Q fever may present with +osteomyelitis, encephalitis and endocarditis. +Phase I and II IgM titres peak at 4–6 weeks. +In chronic infections, +IgG titres to phase I and II antigens may be raised. +Prompt treatment of acute Q fever with doxycycline +reduces fever duration. +Valve surgery is often +required (p. +526). +The principal human pathogens +are Bartonella quintana, B. +henselae and B. +bacilliformis. +Bartonella +infections are associated with the following: +• Trench fever. +This is a relapsing fever with severe leg pain +and is caused by B. +quintana. +The disease is not fatal but +is very debilitating. +• Bacteraemia and endocarditis in the homeless. +Endocarditis due to B. +quintana or B. +henselae is +associated with severe damage to the heart valves. +11.51 Clinical diseases caused by Bartonella spp. +Reservoir Vector Organism Disease +Cats Flea B. +henselae Cat scratch disease, +bacillary angiomatosis, +endocarditis +Undened Lice B. +quintana Trench fever, bacillary +angiomatosis, +endocarditis +Undened Sandfly B. +bacilliformis Carrion’s disease: +Oroya fever and +verruga peruana +Undened Flea B. +rochalimae Fever, rash, anaemia, +splenomegaly +• Cat scratch disease. +B. +henselae causes this common +benign lymphadenopathy in children and young adults. +A vesicle or papule develops on the head, neck or arms +after a cat scratch. +Rare +complications include retinitis and encephalopathy. +• Bacillary angiomatosis. +This is an HIV-associated disease +caused by B. +quintana or B. +henselae (p. +316). +• Oroya fever and verruga peruana (Carrion’s disease). +This +is endemic in areas of Peru. +It is a biphasic disease +caused by B. +bacilliformis, transmitted by sandflies of the +genus Phlebotomus. +Fever, haemolytic anaemia and +microvascular thrombosis with end-organ ischaemia are +features. +It is frequently fatal if untreated. +Serum antibody detection +is possible but cross-reactions occur with Chlamydia and +Coxiella spp. +Bartonella spp. +are typically treated with macrolides or +tetracyclines. +Antibiotic use is guided by clinical need. +Chlamydial infections +These are listed in Box 11.52 and are also described on pages +340 and 582. +341) +Cervicitis, urethritis, proctitis +(p. +334) +Chlamydia psittaci Psittacosis (see Box 17.36, p. +582) +Chlamydophila (Chlamydia) +Atypical pneumonia (see Box 17.36, +pneumoniae +p. +Transmission +occurs through flies, on ngers and within families. +In endemic +areas, the disease is most common in children. +Pathology and clinical features +The onset is usually insidious. +Infection may be asymptomatic, +lasts for years, may be latent over long periods and may +recrudesce. +Early symptoms +include conjunctival irritation and blepharospasm. +The early +follicles are characteristic (Fig. +11.30) but clinical differentiation +from conjunctivitis due to other causes may be difcult. +The cornea becomes vascularised +and opaque. +The problem may not be detected until vision +begins to fail. +Diagnosis of trachoma is therefore based on +clinical and epidemiological features. +Prevention +Personal and family hygiene should be improved. +Proper care +of the eyes of newborn and young children is essential. +Family +contacts should be examined. +Protozoal infections +Protozoa are responsible for many important infectious diseases. +They can be categorised according to whether they cause +systemic or local infection. +Trichomoniasis is described on +page 335. +Systemic protozoal infections +Malaria +Malaria in humans is caused by Plasmodium falciparum, P. +vivax, +P. +ovale (subspecies curtisi and wallikeri), P. +malariae and the +predominantly simian parasite P. +knowlesi. +11.31). +Furthermore, +P. +Travellers are susceptible to malaria (p. +230). +Most cases are +due to P. +falciparum, usually from Africa, and of these 1% die +because of late diagnosis. +They have lost their partial immunity and frequently do +not take malaria prophylaxis. +Sporozoites disappear from human +blood within half an hour and enter the liver. +11 +Fig. +11.30 Trachoma. +Trachoma is characterised by hyperaemia and +numerous pale follicles. +Courtesy of Institute of Ophthalmology, Moorelds +Eye Hospital, London. +Fig. +11.31 Distribution of malaria. +P. +vivax and P. +P. +falciparum, P. +knowlesi and P. +Pathology +Red cells infected with malaria are prone to haemolysis. +This is +most severe with P. +falciparum, which invades red cells of all +ages but especially young cells; P. +vivax and P. +ovale invade +reticulocytes, and P. +ovale P. +malariae P. +11.33 Malarial parasites: life cycle. +Hypnozoites(*) are present only in Plasmodium vivax and P. +ovale infections. +(RBC = red blood cell)Protozoal infections • 275 +remain lighter. +In P. +They also form ‘rosettes’ and rouleaux with uninfected +red cells. +11.33). +P. +951), thalassaemia (p. +953), glucose-6-phosphate +dehydrogenase (G6PD) deciency (p. +948) and HLA-B53. +P. +falciparum does not grow well in red cells that contain haemoglobin +F, C or especially S. +Haemoglobin S heterozygotes (AS) are +protected against the lethal complications of malaria. +P. +P. +falciparum infection +This is the most dangerous of the malarias. +The onset is often +insidious, with malaise, headache and vomiting. +Cough and mild +diarrhoea are also common. +The fever has no particular pattern. +Jaundice is common due to haemolysis and hepatic dysfunction. +The liver and spleen enlarge and may become tender. +Anaemia +develops rapidly, as does thrombocytopenia. +11.34 and +Box 11.54). +Cerebral malaria is manifested by delirium, seizures +or coma, usually without localising signs. +Children die rapidly +without any specic symptoms other than fever. +Previous splenectomy increases +the risk of severe malaria. +P. +vivax and P. +Fever starts with a rigor. +The patient feels cold +and the temperature rises to about 40°C. +falciparum +Ring form in RBCs +Malaria retinopathy +with Roth’s spots +P. +11.34 Features of Plasmodium falciparum infection. +vivax and P. +Severe falciparum malaria. +In: Severe and complicated malaria, 3rd edn. +Trans Roy Soc Trop Med Hyg 2000; 94 (suppl. +1):S1–41. +an hour, the hot or flush phase begins. +It lasts several hours +and gives way to profuse perspiration and a gradual fall in +temperature. +The cycle is repeated 48 hours later. +Gradually, +the spleen and liver enlarge and may become tender. +Anaemia +develops slowly. +P. +malariae and P. +Chronic P. +malariae infection causes +glomerulonephritis and long-term nephrotic syndrome in children. +P. +knowlesi is usually mild but can deteriorate rapidly. +In the thick lm, erythrocytes +are lysed, releasing all blood stages of the parasite. +A thin lm is essential to +conrm the diagnosis, species and, in P. +P. +falciparum parasites may be very scanty, +especially in patients who have been partially treated. +With P. +falciparum, only ring forms are normally seen in the early stages +(Fig. +11.34); with the other species, all stages of the erythrocytic +cycle may be found. +falciparum and vivax) and Parasight-F (which detects +the P. +in the UK). +falciparum malaria +Since P. +co-artemether or artesunate–amodiaquine. +Unfortunately, +artemisinin resistance has now been reported in South-east Asia. +Complicated P. +The treatment of choice is intravenous artesunate. +Late +haemolysis is a treatment side-effect in some patients. +Quinine salt is the alternative. +Non-falciparum malaria +P. +vivax, P. +ovale, P. +knowlesi and P. +‘Radical cure’ is achieved +in patients with P. +vivax or P. +ovale malaria using a course of +primaquine, which destroys the hypnozoite phase in the liver. +Haemolysis may develop in those who are G6PD-decient. +7.1, p. +135). +All are sensitive to ACTs. +Box 11.56 gives the +recommended doses for protection of the non-immune. +Updated +recommendations are summarised at tfortravel.nhs.uk. +1224 and 1254). +Pregnant and lactating women may take proguanil +or chloroquine safely. +Research to produce a fully protective malaria vaccine is +ongoing. +vivax) or 15 mg orally daily +(for P. +vivax or +P. +ovale +• Chloroquine plus primaquine 0.75 mg/kg weekly orally for 8 weeks +Chloroquine-resistant P. +vivax +• Co-artemether as for P. +3 Causes photosensitisation and sunburn if high-protection sunblock is not used. +4 Avoid in pregnancy. +Babesiosis +Babesiosis is a tick-borne intra-erythrocytic protozoon parasite. +Most American cases of babesiosis are due to B. +microti and +most European cases to B. +divergens. +Patients present with +fever and malaise 1–4 weeks after a tick bite. +Illness may be +complicated by haemolytic anaemia. +Severe illness is seen in +splenectomised patients. +The diagnosis is made by blood-lm +examination. +Treatment is with quinine and clindamycin. +11.36). +T. +brucei rhodesiense trypanosomiasis +is found in parts of East and Central Africa. +gambiense. +T. +Rural populations employed in agriculture, +shing and animal husbandry are susceptible. +Within 2–3 weeks of +infection, the trypanosomes invade the blood stream. +11.35 Trypanosomiasis. +Scanning electron micrograph showing +trypanosomes swimming among erythrocytes. +No. +of cases +>1000 +501–1000 +101–500 +1–100 +None +Non-endemic +Fig. +11.36 Distribution of human African trypanosomiasis. +Data are +from 2009. +From Simarro PP, Diarra A, Ruiz Postigo JA, et al. +PLoS Negl Trop Dis +2011; 5(2):e1007. +There may be +a petechial rash. +The patient may die before there are signs of +involvement of the CNS. +The +spleen and liver may become palpable. +After some months without +treatment, the CNS is invaded. +Investigations +Trypanosomiasis should be considered in any febrile patient from +an endemic area. +In rhodesiense infections, thick and thin malaria +blood lms will reveal trypanosomes. +Concentration +methods include buffy coat microscopy and miniature anion +exchange chromatography. +No reliable serological test is available for +rhodesiense HAT. +A very high level of serum IgM or the presence of +IgM in the CSF is suggestive of trypanosomiasis. +Recognition +of CNS involvement is critical, as failure to treat it might +be fatal. +The +prognosis is good if treatment is begun early, before the brain +has been invaded. +Treatment-related mortality +with melarsoprol is 4–12% due to reactive encephalopathy. +Stage 2 +rhodesiense infection is treated with melarsoprol 2.2 mg/kg IV for +10 days. +In +rhodesiense endemic areas, control is difcult. +These bugs live in wild forests +in crevices, burrows and palm trees. +In some areas, +blood transfusion accounts for about 5% of cases. +Congenital +transmission occasionally occurs. +Young children +(1–5 years) are most commonly affected. +The entrance of T. +The acute infection may +be fatal to infants. +Dilatation +of the bile ducts and bronchi are also recognised sequelae. +Autoimmune processes may be responsible for much of the +damage. +There are geographical variations of the basic pattern +11280 • INFECTIOUS DISEASE +of disease. +Investigations +T. +cruzi is easily detectable in a blood lm in the acute illness. +Antibody detection is also highly sensitive. +Nifurtimox is given orally. +The paediatric dose is 15 mg/kg daily. +Cure rates of +80% in acute disease are obtained. +Both nifurtimox and +benznidazole are toxic, with adverse reaction rates of 30–55%. +Surgery may be needed. +Blood and organ donors should be screened. +11.37 Life cycle of Toxoplasma gondii. +The presenting feature is usually localised +or generalised painless lymphadenopathy. +The spleen is seldom palpable. +Retinochoroiditis (Fig. +Seropositive +females infected 6 months before conception have no risk of +fetal transmission. +235). +Toxoplasmosis +Toxoplasma gondii is an intracellular parasite. +The sexual phase of +the parasite’s life cycle (Fig. +11.37) occurs in the small intestinal +epithelium of the domestic cat. +OĂścysts may +survive in moist conditions for weeks or months. +Cats become infected or reinfected by ingesting tissue +cysts in prey such as rodents and birds. +Sheep, pigs and rabbits are the most +common meat sources. +Outbreaks of toxoplasmosis have been +linked to the consumption of unltered water. +241). +In India or Brazil, approximately 40–60% +of pregnant females are seropositive for T. +gondii. +In HIV-1 +infection (p. +infantum +L. +major +L. +mexicana complex +L. +(V.) brasiliensis complex +B +Fig. +11.38 Retinochoroiditis due to toxoplasmosis. +Anthroponotic VL, CL +L. +donovani +L. +gondii antiserum, or by the use of PCR to detect Toxoplasma- +specic DNA. +infantum +Fig. +11.39 Transmission of leishmaniasis. +A Zoonotic transmission. +B Anthroponotic transmission. +C Anthroponotic transmission in the +injection drug-user. +(CL = cutaneous leishmaniasis; VL = visceral +leishmaniasis) +plastidae). +11.39B and C). +The life cycle of Leishmania is shown in Figure 11.40. +Flagellar +promastigotes (10–20 Îźm) are introduced by the feeding female +sandfly. +chagasi L. +infantum L. +donovani +Bite +Fig. +11.41 World distribution of visceral leishmaniasis. +Amastigote +Amastigote +Macrophage +Dermis only +L. +tropica +L. +mexicana etc. +Dermis and +mucosae +(sometimes) +L. +brasiliensis +Viscera and +dermis +(sometimes) +L. +donovani +Fig. +11.40 Life cycle of Leishmania. +From Knight R. +Parasitic disease +in man. +Churchill Livingstone, Elsevier Ltd; 1982. +Fig. +11.42 Splenic smear showing numerous intracellular, and a few +extracellular, amastigotes. +Courtesy of Dr S. +Sundar and Dr H.W. +Murray. +lysis and infection of other cells. +Sandflies pick up amastigotes +when feeding on infected patients or animal reservoirs. +People living in such conditions are more prone to leishmaniasis. +donovani, L. +infantum and L. +chagasi). +India, +Sudan, Bangladesh and Brazil account for 90% of cases of VL. +11.41). +The majority of people infected remain asymptomatic. +In +visceral disease, the spleen, liver, bone marrow and lymph +nodes are primarily involved. +The incubation period +ranges from weeks to months (occasionally, several years). +The rst sign of infection is high fever, usually accompanied by +rigor and chills. +This is followed by a relapse of fever, often of lesser +intensity. +Moderate +hepatomegaly occurs later. +Pancytopenia is common. +Moderate to severe anaemia develops +rapidly and can cause cardiac failure. +Without adequate treatment, most patients with +clinical VL die. +Investigations +Pancytopenia is the dominant feature, with granulocytopenia and +monocytosis. +11.42); however, it carries a risk of serious +haemorrhage in inexperienced hands. +Parasites may be demonstrated in +buffy coat smears, especially in immunosuppressed patients. +Serodiagnosis, by ELISA or immunofluorescence antibody test, +is employed in developed countries. +The daily dose is 20 mg/ +kg body weight, intravenously or intramuscularly, for 28–30 +days. +The incidence +of cardiotoxicity and death is particularly high with improperly +manufactured Sb. +It has a cure rate of nearly +100%. +Lipid formulations of amphotericin B (p. +126) are less +toxic. +AmBisome is rst-line therapy in Europe for VL. +Dosing +recommendations vary according to geographical region. +No signicant +auditory or renal toxicity is seen. +The drug is approved in India +for VL treatment. +Pentamidine isethionate was used to treat Sb-refractory patients +with VL. +HIV–visceral leishmaniasis co-infection +HIV-induced immunosuppression (Ch. +12) increases the risk +of contracting VL 100–1000 times. +Most cases of HIV–VL +co-infection have been reported from Spain, France, Italy and +Portugal. +However, +numbers are increasing in Africa (mainly Ethiopia), Brazil and +the Indian subcontinent. +Diagnostic +principles remain the same as those in non-HIV patients. +Parasites +are numerous and easily demonstrable, even in buffy coat +preparations. +Serological tests have low sensitivity. +The face often appears erythematous +(Fig. +11.43A). +Hypopigmented macules can occur over all parts of +the body and are highly variable in extent. +There are no systemic +symptoms and little spontaneous healing occurs. +In addition to the dermatological features, a measles-like +micropapular rash (Fig. +11.43B) may be seen all over the body. +In Sudan, children are more frequently affected than in India. +Spontaneous healing occurs in about three-quarters of cases +within 1 year. +Immunofluorescence and immunohistochemistry may demonstrate +the parasite in skin tissues. +Treatment of PKDL is difcult. +In Sudan, Sb for 2 months is considered +adequate. +In the absence of a physical handicap, most patients +are reluctant to complete the treatment. +Prevention and control +Sandfly control through insecticide spray is very important. +Mosquito nets or curtains treated with insecticides will keep out +the tiny sandflies. +In endemic areas with zoonotic transmission, +infected or stray dogs should be destroyed. +Serology is +useful in diagnosis of suspected cases in the eld. +No vaccine +is currently available. +Transmission +is described on page 281. +In the Old World, CL is mild. +11.44). +The causative organisms for Old World zoonotic CL are L. +major, +L. +tropica and L. +aethiopica (Box 11.57). +Anthroponotic CL is +caused by L. +tropica, and is conned to urban or suburban areas +of the Old World. +A B +Fig. +11.43 Post-kala-azar dermal leishmaniasis. +A In India, with macules, papules, nodules and plaques. +B In Sudan, with micronodular rash. +A, From Sundar S, Kumar K, Chakravarty J, et al. +Cure of antimony-unresponsive Indian post-kala-azar dermal leishmaniasis with oral miltefosine. +Trans R +Soc Trop Med Hyg 2006; 100(7):698–700. +B, Courtesy of Dr E.E. +mexicana complex (comprising L. +mexicana, L. +amazonensis +and L. +venezuelensis) and by the Viannia subgenus L. +(V.) +brasiliensis complex (comprising L. +(V.) guyanensis, L. +(V.) +panamensis, L. +(V.) brasiliensis and L. +(V.) peruviana). +Clinical features +The incubation period is typically 2–3 months (range 2 weeks +to 5 years). +In all types of CL a papule develops at the site of +the vector bite. +A crust forms, overlying an ulcer with a granular base and +with raised borders (Fig. +11.45). +These ulcers develop a few +weeks or months after the bite. +There can be satellite lesions, +especially in L. +major and occasionally in L. +tropica infections. +Regional lymphadenopathy, pain, pruritus and secondary bacterial +infections may occur. +Lesions of L. +mexicana and L. +L. +mexicana is +responsible for chiclero ulcers, the self-healing sores of Mexico. +If immunity is effective, there is usually spontaneous healing +in L. +tropica, L. +major and L. +mexicana lesions. +In some patients +with anergy to Leishmania, the skin lesions of L. +aethiopica, +L. +mexicana and L. +Occasionally, +in L. +In L. +Later, ulceration develops. +Host Clinical features +L. +tropica Dogs Slow evolution, less severe +L. +major Gerbils, desert +Rapid necrosis, wet sores +rodents +L. +aethiopica Hyraxes Solitary facial lesions with +satellites +L. +mexicana +L. +brasiliensis +L. +infantum +L. +tropica +L. +major +L. +aethiopica +Fig. +11.44 World distribution of cutaneous leishmaniasis. +A B +Fig. +11.45 Cutaneous leishmaniasis. +A Papule. +B Ulcer. +brasiliensis, responsible +for the vast majority of cases in Brazil. +Touch preparations from +biopsies and histopathology usually have a low sensitivity. +Culture +of ne needle aspiration material has been reported to be the +most sensitive method. +ML is more difcult to diagnose parasitologically. +The leishmanin +skin test measures delayed-type hypersensitivity to killed +Leishmania organisms. +A positive test is dened as induration +of more than 5 mm, 48 hours after intradermal injection. +The +test is positive, except in diffuse CL and during active VL. +PCR +is used increasingly for diagnosis and speciation, which is useful +in selecting therapy. +There is no ideal antimicrobial therapy. +In CL, topical application of paromomycin 15% plus +methylbenzethonium chloride 12% is benecial. +brasiliensis strain. +Refractory +CL or ML should be treated with an amphotericin B preparation. +Other regimens may be effective. +guyanensis. +In ML, 8 +injections of pentamidine (4 mg/kg on alternate days) cure the +majority of patients. +Ketoconazole (600 mg daily for 4 weeks) +has shown some potential against L. +mexicana infection. +major. +In India, itraconazole (200 mg daily for 6 weeks) produced +good results in CL. +Prevention of CL and ML +Personal protection against sandfly bites is important. +No effective +vaccine is yet available. +Two non- +pathogenic Entamoeba species (E. +dispar and E. +moshkovskii) are +morphologically identical to E. +However, only E. +histolytica causes amoebic +dysentery or liver abscess. +The life cycle of the amoeba is shown +in Figure 11.46A. +Pathology +Cysts of E. +histolytica are ingested in water or uncooked foods +contaminated by human faeces. +Infection may also be acquired +through anal/oral sexual practices. +In the colon, trophozoite +forms emerge from the cysts. +11.46 Amoebiasis. +A The life cycle of Entamoeba histolytica. +B The chocolate-brown appearance of aspirated material from an amoebic liver +abscess. +A, From Knight R. +Parasitic disease in man. +Churchill Livingstone, Elsevier Ltd; 1982. +These are flask- +shaped ulcers, varying greatly in size and surrounded by healthy +mucosa. +Amoebic ulcers may cause severe haemorrhage +but rarely perforate the bowel wall. +They can multiply rapidly and destroy the liver parenchyma, +causing an abscess (see also p. +879). +Offensive diarrhoea, alternating +with constipation, and blood or mucus in the stool are common. +Amoebic liver abscess +The abscess is usually found in the right hepatic lobe. +There +may not be associated diarrhoea. +Movements cease rapidly as the stool preparation cools. +Several +stools may need to be examined in chronic amoebiasis before +cysts are found. +histolytica. +In endemic areas, one-third of the population are +symptomless passers of amoebic cysts. +Conrmation is by ultrasonic +scanning. +11.46B). +DNA detection by PCR has been shown to be useful in diagnosis +of E. +histolytica infections but is not generally available. +Nitazoxanide (500 mg twice +daily for 3 days) is an alternative drug. +Small serous effusions resolve +without drainage. +Giardiasis +Infection with Giardia lamblia is found worldwide and is +common in the tropics. +Its flagellar trophozoite form attaches to the +duodenal and jejunal mucosa, causing inflammation. +On +examination, there may be abdominal distension and tenderness. +Chronic diarrhoea and malabsorption may occur, with bulky +stools that float. +Stools obtained at 2–3-day intervals should be examined +for cysts. +Duodenal or jejunal aspiration by endoscopy gives a +higher diagnostic yield. +lamblia trophozoites. +A number of stool antigen detection tests are available. +Jejunal +biopsy specimens may show G. +lamblia on the epithelial surface. +Cryptosporidiosis +Cryptosporidium spp. +are coccidian protozoal parasites of humans +and domestic animals. +Infection is acquired by the faecal–oral +route through contaminated water supplies. +317). +Diagnosis is +by detection of oĂścysts on faecal microscopy or PCR of stool. +Treatment may be necessary in a few cases, using co-trimoxazole +960 mg twice daily for 7 days. +Eggs are passed in the faeces. +The worms attach +to the mucosa of the small intestine by their buccal capsule (Fig. +11.48) and withdraw blood. +The mean daily blood loss from one +A. +duodenale is 0.15 mL and that from N. +americanus 0.03 mL. +Hookworm infection is a leading cause of anaemia in the +tropics and subtropics. +A. +Intestinal human nematodes +Adult nematodes living in the human gut can cause disease. +The complex life cycle is shown in Figure 11.47. +mansoni, S. +japonicum, +S. +mekongi, S. +intercalatum +• Lung flukes: Paragonimus spp. +11.47 Ancylostomiasis. +Life cycle of Ancylostoma. +Fig. +11.48 Ancylostoma duodenale. +Electron micrograph showing the +ventral teeth. +From Gibbons LM. +SEM guide to the morphology of nematode +parasites of vertebrates. +Sometimes, frequent loose stools are +passed. +Anaemia with high-output cardiac failure may result. +The +mental and physical development of children may be delayed +in severe infection. +Investigations +There is eosinophilia. +The characteristic ovum can be recognised +in the stool. +Management +A single dose of albendazole (400 mg) is the treatment of choice. +Alternatively, mebendazole 100 mg twice daily for 3 days may +be used. +The eggs +hatch in the bowel but only larvae are passed in the faeces. +In +moist soil, they moult and become the infective lariform larvae. +Patients with Strongyloides +infection persisting for more than 35 years have been described. +Strongyloidiasis occurs in the tropics and subtropics, and is +especially prevalent in the Far East. +Clinical features +These are shown in Box 11.59. +The classic triad of symptoms +consists of abdominal pain, diarrhoea and urticaria. +Patients present with severe, +generalised abdominal pain, abdominal distension and shock. +Gram-negative sepsis +frequently complicates the picture. +Investigations +There is eosinophilia. +Serology (ELISA) is helpful but denitive +diagnosis depends on nding the larvae. +Larvae +may be found in jejunal aspirates or detected using the string test +(p. +287). +Larvae may also be cultured from faeces. +Alternatively, albendazole is +given orally (15 mg/kg twice daily for 3 days). +A second course +may be required. +For the Strongyloides hyperinfection syndrome, +ivermectin is given at 200 Îźg/kg for 5–7 days. +Ascaris lumbricoides (roundworm) +This pale yellow nematode is 20–35 cm long. +Humans are infected +by eating food contaminated with mature ova. +Investigations +The diagnosis is made microscopically by nding ova in the +faeces. +Adult worms are frequently expelled rectally or orally. +Occasionally, the worms are demonstrated radiographically by +a barium examination. +There is eosinophilia. +Patients should be warned that they +might expel numerous whole, large worms. +Complete intestinal obstruction and its +complications require urgent surgical intervention. +Prevention +Community chemotherapy programmes reduce Ascaris infection. +The whole community can be treated every 3 months for several +years. +Enterobius vermicularis (threadworm) +This helminth is common worldwide and affects mainly children. +11.49). +In females, the genitalia may be involved. +The adult +worms may be seen moving on the buttocks or in the stool. +This is then examined on a glass slide under the microscope. +A perianal swab, moistened with saline, also allows diagnosis. +If +infection recurs in a family, each member should be treated. +All nightclothes and bed linen are laundered during treatment. +Fingernails must be kept short and hands washed carefully before +meals. +Subsequent therapy is reserved for family members with +recurrent infection. +Trichuris trichiura (whipworm) +Whipworm infections are common worldwide with poor hygiene. +The adult worm is 3–5 cm long and has a +coiled anterior end resembling a whip. +Whipworms inhabit the +caecum, lower ileum, appendix, colon and anal canal. +The diagnosis is readily made by identifying ova in +faeces. +Tissue-dwelling human nematodes +Filarial worms are tissue-dwelling nematodes. +The +life cycle is completed when the vector takes up microlariae by +biting humans. +The worms are long-lived: microlariae survive 2–3 +years and adult worms 10–15 years. +The infections are chronic +and worst in individuals constantly reinfected. +W. +bancrofti is usually transmitted by night-biting culicine or +anopheline mosquitoes (Fig. +11.50). +11.49 Threadworm. +Silicates absorbed from volcanic soil +can also cause non-larial elephantiasis. +Patients present with +paroxysmal cough, wheeze and fever. +If untreated, this may +progress to debilitating chronic interstitial lung disease. +Filarial infections cause the highest +eosinophil counts of all helminthic infections. +They are usually +present in hydrocele fluid, which may occasionally yield an adult +laria. +By the time elephantiasis develops, microlariae become +difcult to nd. +Calcied lariae may sometimes be demonstrable +by radiography. +Movement of adult worms can be seen on scrotal +ultrasound. +PCR-based tests for detection of W. +bancrofti and +B. +malayi DNA from blood have been developed. +The test +becomes negative 1–2 years after cure. +Serological tests cannot +distinguish the different larial infections. +bancrofti antigen using ngerprick +blood samples taken at any time of the day. +The chest X-ray shows miliary changes or mottled +opacities. +Pulmonary function tests show a restrictive picture. +Management +Treatment is aimed at halting and reversing disease progression. +The main symptoms are +fever, headache, nausea, vomiting, arthralgia and prostration. +These usually occur within 24–36 hours of the rst dose of DEC. +Antihistamines or glucocorticoids treat these allergic phenomena. +For tropical pulmonary eosinophilia, +DEC for 14 days is the treatment of choice. +Plastic surgery +may be indicated in established elephantiasis. +11.50 Wuchereria bancrofti and Brugia malayi. +Life cycle of +organisms and pathogenesis of lymphatic lariasis. +B. +malayi usually causes less severe disease than W. +Pathology +Several factors contribute to the pathogenesis of lymphatic +lariasis. +Death of the adult worm +results in acute larial lymphangitis. +Lymphatic obstruction persists after death of the adult worm. +Secondary bacterial infections cause tissue destruction. +Inflammation of the spermatic cord, epididymis and testis is +common. +Episodes last a few days but may recur several times a +year. +Temporary oedema becomes more persistent and regional +lymph nodes enlarge. +The scrotum may reach an enormous size. +Chyluria and chylous effusions are milky and opalescent; on +standing, fat globules rise to the top. +Hydroceles and +chyluria can be repaired surgically. +Mass treatment should be combined with mosquito control +programmes. +Loiasis +Loiasis is caused by infection with the laria Loa loa. +The disease +is endemic in forested and swampy parts of Western and Central +Africa. +The vector is Chrysops, a +forest-dwelling, day-biting fly. +The host response to Loa loa is usually absent or mild, so +that the infection may be harmless. +Heavy infections, especially +when treated, may cause encephalitis. +Clinical features +The infection is often symptomless. +The incubation period is +commonly over a year but may be just 3 months. +It usually disappears after a +few days but may persist for 2–3 weeks. +Several swellings may +appear at irregular intervals, often in adjacent sites. +Sometimes, +there is urticaria and pruritus elsewhere. +Antilarial antibodies are positive in 95% +of patients and there is massive eosinophilia. +Occasionally, a +calcied worm may be seen on X-ray. +Management +DEC (see above) is curative, in a dose of 9–12 mg/kg daily, +continued for 21 days. +Prevention +Building houses away from trees and having dwellings wire- +screened reduce infections. +Protective clothing and insect +repellents are also useful. +DEC in a dose of 5 mg/kg daily for 3 +days each month is partially protective. +11.51 Onchocerca volvulus. +Life cycle of organism and +pathogenesis of onchocerciasis. +Humans are the only known hosts (Fig. +11.51). +Onchocerciasis is endemic in sub-Saharan Africa, Yemen and +a few foci in Central and South America. +Innumerable +microlariae, discharged by the female O. +volvulus, move actively +in these nodules and in the adjacent tissues. +The microlariae +are widely distributed in the skin and may invade the eye. +Death of microlariae in the eye causes +inflammation and may lead to blindness. +Clinical features +The infection may remain symptomless for months or years. +Hydrocele, femoral +hernias and scrotal elephantiasis can occur. +Firm subcutaneous +nodules of more than 1 cm in diameter (onchocercomas) occur +in chronic infection. +Adult flies inflict +painful bites during the day, both inside and outside houses. +Early manifestations include itching, lacrimation and +conjunctival injection. +Classically, ‘snowflake’ deposits are seen in the +edges of the cornea. +Microlariae are seen wriggling free in +all but the lightest infections. +A nodule may be removed and incised, showing +the coiled, thread-like adult worm. +Filarial antibodies are positive in up to 95% of patients. +Rapid strip tests to detect antibody or antigen are under clinical +evaluation. +It kills microlariae and has minimal toxicity. +Eradication of Wolbachia +with doxycycline (100 mg daily for 6 weeks) prevents worm +reproduction. +Simulium can be destroyed in its larval stage by +the application of insecticide to streams. +Long trousers, skirts +and sleeves discourage the fly from biting. +be broken. +Antibiotics for secondary infection and prophylaxis +of tetanus are also required. +grahami. +M. +M. +perstans is resistant to ivermectin and +DEC, and the infection may persist for many years. +Dirolaria immitis +This dog heartworm infects humans, causing skin and lung +lesions. +It is not uncommon in the USA, Japan and Australia. +Outbreaks have occurred in countries +where pork is eaten. +Clinical features +The clinical features of trichinosis are determined by the larval +numbers. +Larval migration may cause +acute myocarditis and encephalitis. +Eosinophilia is observed after +the second week. +An intense infection may prove fatal but those +who survive recover completely. +Serological tests are +also helpful. +The worm must never294 • INFECTIOUS DISEASE +muscles. +Glucocorticoids are necessary to control the serious +effects of acute inflammation. +11.52). +The track moves across the +skin at a rate of 2–3 cm/day. +This contrasts with the fast-moving +transient rash of Strongyloides (p. +289). +The most common site for CLM +is the foot but elbows, breasts and buttocks may be affected. +Most patients with CLM have recently visited a beach where the +affected part was exposed. +The diagnosis is clinical. +It causes eosinophilic +meningitis. +The role of combination therapy with glucocorticoids +and albendazole remains controversial. +It also +occurs in other parts of Asia, Central and South America, and +Africa. +Pruritic, +painful, migratory nodules appear 3–4 weeks after ingestion due to +larval migration. +Complications include cough, visual disturbance, +eosinophilic meningitis or encephalitis. +Trematodes (flukes) +These leaf-shaped worms are parasitic to humans and animals. +Their complex life cycles may involve one or more intermediate +hosts, often freshwater molluscs. +Schistosomiasis +Schistosomiasis is a major cause of morbidity in the tropics. +The +species commonly causing disease in humans are: Schistosoma +haematobium, S. +mansoni, S. +japonicum, S. +mekongi and S. +intercalatum. +S. +haematobium is sometimes called bilharzia or +bilharziasis. +Schistosome eggs have been found in Egyptian +mummies. +The life cycle is shown in Figure 11.53A. +Cercariae can penetrate the skin or the mucous membrane of +the mouth of humans. +11.53B). +The eggs of S. +S. +mansoni and S. +japonicum eggs +pass mainly through the wall of the lower bowel or are carried +to the liver. +The most serious, although rare, site of ectopic +egg deposition is the CNS. +Later, there is brosis and eggs calcify, which is often +visible radiologically. +Eggs of S. +haematobium may leave the +vesical plexus and be carried directly to the lung. +Those of S. +mansoni and S. +Fig. +11.52 Cutaneous larva migrans. +Miracidium +Ovum +Fig. +11.53 Schistosoma. +A Life cycle. +On examination, hepatomegaly, +splenomegaly, lymphadenopathy and pneumonia may be present. +These allergic phenomena may be severe in infections with S. +mansoni and S. +japonicum, but are rare with S. +haematobium. +The features subside after 1–2 weeks. +Chronic schistosomiasis is due to egg deposition and occurs +months to years after infection. +Schistosoma haematobium +Humans are the only natural hosts of S. +11.54). +Infection can be acquired +after a brief exposure, such as swimming in freshwater lakes +in Africa. +Painless terminal haematuria is usually the rst and most +common symptom. +Frequency of micturition follows, due to +bladder neck obstruction. +Pain is +often felt in the iliac fossa or in the loin, and radiates to the +groin. +mansoni and +Time Schistosoma haematobium +S. +japonicum +Cercarial penetration +Days Papular dermatitis at site of +As for S. +Immune complex +glomerulonephritis +As for S. +haematobium +pulmonary hypertension +association of S. +haematobium infection with squamous cell +carcinoma of the bladder. +Disease of the seminal vesicles may +lead to haematospermia. +Intestinal symptoms may follow296 • INFECTIOUS DISEASE +} +S. +mansoni +S. +intercalatum +Fig. +11.55 Ova of Schistosoma haematobium in urine. +Note the +terminal spike. +S. +haematobium S. +japonicum S. +mekongi +Fig. +11.54 Geographical distribution of schistosomiasis. +From Cook +GC, ed. +Manson’s tropical diseases, 20th edn. +Saunders, Elsevier Inc.; +1995. +brosis with splenic enlargement is usual. +Investigations +There is marked eosinophilia. +Serological tests (ELISA) are useful +as screening tests but remain positive after treatment. +In S. +haematobium infection, dipstick urine testing shows +blood and albumin. +11.55). +Cystoscopy reveals ‘sandy’ patches, bleeding +mucosa and later distortion. +In a heavy infection with S. +mansoni or S. +japonicum, the +characteristic egg with its lateral spine can usually be found in +the stool. +When the infection is light or of long duration, a rectal +biopsy can be examined. +Sigmoidoscopy may show inflammation +or bleeding. +Biopsies should be examined for ova. +Management +The object of therapy is to kill the adult schistosomes and stop +egg-laying. +japonicum and S. +mekongi, for which 60 mg/kg (20 mg for +3 doses) is recommended. +Side-effects are uncommon but +include nausea and abdominal pain. +Removal of rectal papillomas +by diathermy or by other means may provide symptomatic relief. +Prevention +No single means of controlling schistosomiasis has been +established to date. +Ectopic worms cause skin or +spinal cord lesions. +The severity of S. +haematobium infection varies greatly and +many with a light infection are asymptomatic. +Schistosoma mansoni +S. +mansoni is endemic throughout Africa, the Middle East, +Venezuela, Brazil and the Caribbean (Fig. +11.54). +Characteristic symptoms begin 2 months or more after +infection. +With severe advanced disease, increased +discomfort from rectal polyps may be experienced. +868). +Liver function is initially +preserved because the pathology is brotic rather than cirrhotic. +S. +Schistosoma japonicum, S. +mekongi and S. +intercalatum +In addition to humans, the adult worm of S. +japonicum infects +the dog, rat, eld mouse, water buffalo, ox, cat, pig, horse and +sheep. +Although other Schistosoma spp. +japonicum. +S. +It also has +a focal distribution in the Philippines, Indonesia and Thailand +(Fig. +11.54). +The related S. +mekongi occurs in Laos, Thailand +and Myanmar, and S. +intercalatum in West and Central Africa. +The pathology of S. +japonicum is similar to that of S. +mansoni, +but as this worm produces more eggs, the lesions tend to be +more extensive and widespread. +The clinical features resemble +those of severe infection with S. +mansoni, with added neurological +features. +sinensis Unexplained fever, tender liver, may be +ectopic, e.g. +subcutaneous fluke +jaundice +Diagnosis Ova in stool or duodenal aspirate As for C. +sinensis As for C. +11 +tropics. +Furthermore, S. +japonicum has so many hosts besides +humans that latrines would have little impact. +Population mass +treatment annually helps prevent S. +haematobium and S. +mansoni +infection but so far has had little success with S. +japonicum. +For personal protection, +contact with infected water must be avoided. +They are +associated with abdominal pain, hepatomegaly and relapsing +cholangitis. +Clonorchis sinensis and Opisthorchis felineus are +major aetiological agents of bile duct cancer. +The three major +liver flukes have similar life cycles and pathologies, as outlined +in Box 11.62. +Other flukes of medical importance include lung and intestinal +flukes (see Box 11.58). +Cestodes (tapeworms) +Cestodes are ribbon-shaped worms that inhabit the intestinal +tract. +They have no alimentary system and absorb nutrients +through the tegumental surface. +The anterior end, or scolex, +has suckers for attaching to the host. +Cross-fertilisation takes place between segments. +11.56). +11.56 Cysticercosis. +Life cycle of Taenia solium. +is ingested, and cysticercosis (systemic infection from larval +migration) if ova are ingested. +saginata, under-cooked +pork containing the larval stage of T. +solium or T. +asiatica, or +under-cooked freshwater sh containing larvae of D. +latum. +Usually, only one adult tapeworm is present in the gut but +up to 10 have been reported. +The ova of all the three Taenia +are indistinguishable microscopically. +However, examination +of scolex and proglottides can differentiate them: T. +asiatica +has a rostellum without hooks on its scolex and is difcult to +differentiate from T. +saginata, except that there are fewer uterine +branches (16–21). +Taenia solium +T. +It is not +as large as T. +saginata. +The adult worm is found only in +humans following the ingestion of pork containing cysticerci. +Cooking pork well prevents +intestinal infection. +Taenia saginata +Infection with T. +saginata occurs in all parts of the world. +Ova may be found in the stool. +Praziquantel is the +drug of choice; niclosamide or nitazoxanide is an alternative. +Prevention depends on efcient meat inspection and the thorough +cooking of beef. +Taenia asiatica +T. +asiatica is a newly recognised species of Taenia, restricted +to Asia. +It is acquired by eating uncooked meat or viscera of +pigs. +Clinical features and treatment are similar to those of +T. +saginata. +Cysticercosis +Human cysticercosis is acquired by ingesting T. +solium tapeworm +ova, from either contaminated ngers or food (Fig. +11.56). +They do not grow further +or migrate. +Common locations are the subcutaneous tissue, +skeletal muscles and brain (Fig. +11.57). +Fig. +11.57 Neurocysticercosis. +Heavy brain infections, especially in children, may cause +features of encephalitis. +More commonly, however, cerebral +signs do not occur until the larvae die, 5–20 years later. +Investigations +Calcied cysts in muscles can be recognised radiologically. +The +subcutaneous tissue should be palpated and any nodule +excised for histology. +Radiological examination of the skeletal +muscles may be helpful. +Antibody detection is available for +serodiagnosis. +Praziquantel (50 mg/kg in 3 divided doses daily for 10 days) +is another option. +In addition, antiepileptic drugs should be given until +the reaction in the brain has subsided. +Operative intervention +is indicated for hydrocephalus. +granulosus. +Hydatid cysts in +liver, lung etc. +Faeces +Ova +C +11 +Dog etc. +Worms in gut +Human +Hydatid cysts in liver, lung etc. +Fig. +11.58 Hydatid disease. +A Life cycle of Echinococcus granulosus. +B Daughter cysts removed at surgery. +C Within the daughter cysts are the +protoscolices. +camels and other animals that are infected from contaminated +pastures or water. +By handling a dog or drinking contaminated +water, humans may ingest eggs (Fig. +11.58). +The resultant cyst +grows very slowly, sometimes intermittently. +Over time, some cysts calcify and +become non-viable. +The disease is common in the Middle East, +North and East Africa, Australia and Argentina. +Foci of infection +persist in the UK in rural Wales and Scotland. +E. +Management and prevention +Hydatid cysts should be excised wherever possible. +Praziquantel +(20 mg/kg twice daily for 14 days) also kills protoscolices +perioperatively. +Prevention is difcult when there is a close association with dogs. +Other tapeworms +Other cestodes’ adult or larval stages may infect humans. +These vary, +depending on the site involved. +In others, a cyst may be found in lung, bone, +brain or elsewhere. +Ectoparasites only interact with the outermost surfaces of the +host; see also page 1241. +The pregnant flea burrows +into the skin around toes and produces large numbers of eggs. +Secondary +infection of lesions is common. +Candidiasis (thrush) +Supercial candidiasis is caused by Candida spp., mainly C. +albicans. +Manifestations include oropharyngeal (pp. +790 and 1240) +and vaginal candidiasis (‘thrush’), intertrigo and chronic paronychia. +Supercial candidiasis often follows antibiotic therapy. +Chronic paronychia is associated with frequent +wetting of the hands. +Supercial candidiasis is treated mainly with +topical azoles (p. +126), oral azoles being reserved for refractory +or recurrent disease. +316). +Recurrent vaginal or +penile candidiasis may be a manifestation of diabetes mellitus. +689). +Other causes +include F. +compacta, Cladophialophora carrionii and Phialophora +verrucosa. +The disease is a cutaneous/subcutaneous mycosis +acquired by traumatic inoculation. +The larvae develop in a subcutaneous space +with a central sinus. +Secondary infection of myiasis is rare and rapid +healing follows removal of intact larvae. +11.59). +(C. +neoformans +shown here) +Examples: +• Aspergillus spp. +(A. +fumigatus +shown here) +• Fusarium spp. +• Dermatophyte fungi (Tricophyton spp., +Microsporum spp. +Fig. +11.59 Classication of medically important fungi. +Fungal classication is based on simple morphological characteristics. +The initial lesion is a papule. +Further +papules develop and coalesce to form irregular plaques. +Nodular +lesions may produce a characteristic ‘cauliflower’ appearance. +The +aetiological agent is conrmed by culture. +Itraconazole and terbinane are the most effective antifungal +agents. +However, posaconazole has also been used with a +good outcome. +disease. +Disease may be supercial, subcutaneous or deep. +Causative agents are +Cladophialophora bantiana, Fonsecaea spp. +and Rhinocladiella +mackenziei, which occurs mainly in the Middle East and is +usually fatal. +Rarer forms +include cutaneous disease presenting with arthritis. +Later, +draining sinuses may form. +Disseminated disease may occur, +especially in patients with HIV. +A latex agglutination test detects S. +schenckii +antibodies in serum. +Localised hyperthermia may be used in +pregnancy (to avoid azole use). +Osteoarticular disease requires +a longer course of therapy (at least 12 months). +Severe or life- +threatening disease is treated with amphotericin B (lipid formulation +preferred). +Many fungi cause eumycetomas, +the most common being Madurella mycetomatis, M. +The disease +occurs mostly in the tropics and subtropics. +Clinical features +The disease is acquired by inoculation (e.g. +from a thorn) and +most commonly affects the foot (Madura foot). +Sinuses heal with scarring, +while fresh sinuses appear elsewhere. +There is little pain and usually no fever or +lymphadenopathy, but there is progressive disability. +Culture is necessary +for species identication and susceptibility testing. +Serological +tests are not available. +Management +Eumycetoma is usually treated with a combination of surgery and +antifungal therapy. +Itraconazole and ketoconazole +(both 200–400 mg/day) are used most commonly. +Amphotericin B is not usually effective. +Therapy is continued for +6–12 months or longer. +In extreme cases, amputation may be +required. +The most common cause is C. +albicans. +Other agents include C. +dubliniensis, C. +glabrata, C. +krusei, C. +parapsilosis and C. +tropicalis. +Candida species identication +often predicts susceptibility to fluconazole: C. +krusei is +universally resistant, many C. +C. +auris is an emerging +species, which has a particular propensity for nosocomial +transmission. +from the blood). +The main predisposing factor is the +presence of a central venous catheter. +Skin lesions (non-tender pink/ +red nodules) may be seen. +This represents a form of immune reconstitution +syndrome (p. +Diagnosis and treatment +of these conditions require specialist mycological advice. +Management +Blood cultures positive for Candida spp. +must never be ignored. +Candidaemia should be treated initially with +an echinocandin (p. +Treatment should +continue for a minimum of 14 days. +Alternative therapies include +voriconazole and amphotericin B formulations. +The duration of the condition may +be reduced by adjuvant therapy with systemic glucocorticoids. +A +B +Fig. +11.60 Cryptococcal disease. +A 23-year-old HIV-positive male +developed headache and left-sided weakness. +A MRI scan of the brain +showed a space-occupying lesion (arrow) with surrounding oedema. +Cryptococcus neoformans was cultured. +Cryptococcosis +Cryptococcosis is a systemic mycosis caused by two environmental +yeast species, Cr. +neoformans and Cr. +gattii. +Cr. +321). +Cr. +Cryptococcosis is acquired by inhalation of yeasts. +These +may disseminate to any organ, most commonly the CNS and +skin. +The manifestations of Cr. +neoformans are most severe in +immunocompromised individuals. +Conversely, Cr. +gattii causes +severe disease in immunocompetent hosts. +CNS manifestations of cryptococcosis include meningitis +(p. +321) and cryptococcoma (Fig. +11.60), the latter more likely with +Cr. +gattii infection. +321). +Fusariosis +Fusarium spp. +cause disseminated disease in patients +with prolonged neutropenia. +Skin lesions may resemble molluscum contagiosum. +skin lesions, bone marrow, +biopsies). +H. +capsulatum +var. +It occurs +sporadically in Australia and India, and is very rare in Europe. +H. +capsulatum var. +duboisii is found in West Africa and Madagascar. +The primary reservoir of H. +Infection is by inhalation of infected dust. +Natural +infections are found in bats, which represent a secondary reservoir +of infection. +In most cases, infection is +asymptomatic. +Disease caused by H. +capsulatum var. +Multiple lesions of the +ribs are common and the bones of the limbs may be affected. +Lung involvement is relatively rare. +Radiological examination may +show rounded foci of bone destruction, sometimes associated +11 +Fig. +11.61 Fusarium infection. +Fusarium +solani was cultured from skin lesions and blood cultures. +A Tender, +erythematous papules/nodules on upper arm. +B Gram stain of Fusarium +in blood culture medium. +antibiotic-resistant fever and evidence of dissemination (e.g. +skin nodules, endophthalmitis, septic arthritis, pulmonary disease; +Fig. +11.61). +In contrast to Aspergillus spp., Fusarium spp. +is +often recovered from blood cultures. +and Rhizopus spp. +Disease patterns include +rhinocerebral/craniofacial, pulmonary, cutaneous and systemic +disease. +High-dose lipid-formulated amphotericin B +is most commonly used. +Acute disseminated histoplasmosis is seen with immuno- +compromise, including HIV infection. +Chronic disseminated disease presents +with fever, anorexia and weight loss. +Cutaneous and mucosal +lesions, lymphadenopathy, hepatosplenomegaly and meningitis +may develop. +Histoplasma +antigen may be detectable in blood or urine. +Culture is denitive +but slow (up to 12 weeks). +Histopathology may show characteristic +intracellular yeasts. +Management +Mild pulmonary disease does not require treatment. +However, +if prolonged, it may be treated with itraconazole. +Lipid formulations of amphotericin B are preferred but their use +is subject to availability. +In subcutaneous and bone infection, +patterns of remission and relapse are more common than cure. +A solitary bony lesion may require local surgical treatment only. +IgM may +be detected after 1–3 weeks of disease by precipitin tests. +IgG +appears later and is detected with the complement xation test. +Change in IgG titre may be used to monitor clinical progress. +in meningitis). +Posaconazole has been +used successfully in refractory disease. +Diagnosis is +by microscopy and culture of lesions, and antibody detection. +Ketoconazole, fluconazole, voriconazole and 2–3-year +courses of sulphonamides are alternatives. +Amphotericin B is +used in severe or refractory disease, followed by an azole or +sulphonamide. +Very occasionally, it is reported from Africa. +The disease usually presents as a chronic pneumonia similar to +pulmonary tuberculosis. +Bones, skin and the genitourinary tract +may also be affected. +Antibody detection is rarely helpful. +Treatment is with +amphotericin B (severe disease) or itraconazole. +posadasii, found in the south-western +USA and Central and South America. +The disease is acquired +by inhalation of conidia (arthrospores). +In 60% of cases it is +asymptomatic but in the remainder it affects the lungs, lymph +nodes and skin. +Pulmonary coccidioidomycosis has two forms: primary and +progressive. +Progressive disease presents +with systemic upset (e.g. +fever, weight loss, anorexia) and features +of lobar pneumonia, and may resemble tuberculosis. +cdc.gov Centers for Disease Control, USA; source of general +information about infectious diseases. +tfortravel.nhs.uk Scottish site with valuable information for travellers. +who.int. +SIVs do not cause disease +in their natural primate hosts. +HIV-1 was transmitted from +chimpanzees and HIV-2 from sooty mangabey monkeys. +It has been estimated that both HIV-1 and HIV-2 rst infected +humans about 100 years ago. +HIV-2 will not be discussed +further in this chapter. +Groups O and N are restricted to West Africa. +Subtype B predominates in Western Europe, +the Americas and Australia. +In Europe, the prevalence of non-B +subtypes is increasing because of migration. +Subtypes A and +D are associated with slower and faster disease progression, +respectively. +Modes of transmission +HIV is transmitted by sexual contact, by exposure to blood +(e.g. +Worldwide, the major route of transmission is heterosexual. +The approximate transmission risk after exposure is given in +Box 12.2. +Factors that increase the risk of transmission are +listed in Box 12.3. +Entry into +the cell commences with binding of gp120 to the CD4 receptor +(Fig. +12.1 Life cycle of HIV. +Chemokine co-receptor binding is +followed by membrane fusion and cellular entry involving gp41. +Integrated virus is known as proviral DNA +and persists for the life of the cell. +The mature virion then infects other CD4 cells +and the process is repeated. +CD4 lymphocytes that are replicating +HIV have a very short survival time of about 1 day. +A small percentage of T-helper lymphocytes enter a post- +integration latent phase. +mycobacteria, herpesviruses). +The immune activation in response to HIV infection does not +completely resolve on effective ART. +However, in the UK, testing is still targeted to +high-risk groups (Box 12.4). +Most tests detect antibodies to both HIV-1 and +HIV-2. +A positive antibody test from two different immunoassays +is sufcient to conrm infection. +‘chemsex’ (p. +2016). +2 Prevalence of diagnosed HIV is 2–5 per 1000 people +aged 15–59. +In this +case, the CD4 percentage will be unchanged. +The normal CD4 count is over 500 cells/mm3. +The rate of +decline in CD4 count is highly variable. +immune +thrombocytopenia) becomes increasingly common as CD4 counts +decline. +Determining the viral load is crucial +for monitoring responses to ART (p. +324). +People with high viral +loads (e.g. +PCR is more sensitive than p24 +antigen detection for diagnosing primary infection. +A number of baseline investigations should be done at the initial +medical evaluation (Box 12.7). +The extent of these investigations +will depend on the resources available. +Two clinical staging systems are used internationally (p. +307). +The incubation period is usually +2–4 weeks after exposure. +The duration of symptoms is variable +but is seldom longer than 2 weeks. +12.2 Virological and immunological +progression of untreated HIV infection. +response. +The median time from infection to the development of +AIDS in adults is about 9 years (see Fig. +12.2). +307). +CDC category C is the most widely used denition of +AIDS. +Atypical lymphocytosis occurs less +frequently than in EBV infection. +Transient lymphopenia, including +CD4 lymphocytes, is found in most cases (Fig. +12.2), which +may result in opportunistic infections, notably oropharyngeal +candidiasis. +Major opportunistic infections like Pneumocystis +jirovecii pneumonia (PJP) may rarely occur. +Thrombocytopenia +and moderate elevation of liver enzymes are commonly present. +Early diagnosis is made by detecting HIV RNA by PCR or p24 +antigenaemia. +Persistent +generalised lymphadenopathy with nodes typically < 2 cm +diameter is a common nding. +Eventually, the lymph nodes +regress, with destruction of node architecture as disease +advances. +All body systems +can be affected by HIV. +The other slide should be xed and sent for +cytology. +If caseous liquid is aspirated, this should be sent for +mycobacterial culture or PCR. +Weight loss +Weight loss is a very common nding in advanced HIV infection. +This is a diagnosis of exclusion. +Painful oral conditions and nausea +from drugs contribute by limiting intake. +Depression is very +common and can cause signicant weight loss. +Erythrocyte sedimentation rate (ESR) is elevated +by HIV infection and is therefore not useful. +The presence of +fever or diarrhoea is helpful in the differential diagnosis of weight +loss (Fig. +12.3). +Fever +Fever is a very common presenting feature. +Common causes +of prolonged fever with weight loss are listed in Figure 12.3. +Symmetrical generalised lymphadenopathy may +occur in disseminated tuberculosis. +Lymphoma typically presents +with large, rm, asymmetric nodes. +12.3 Presentation and differential diagnosis of weight loss. +12.4. +Disseminated histoplasmosis presenting with diffuse +papular rash and fever. +Skin biopsy was diagnostic. +Courtesy of +Professor Graeme Meintjes. +Abdominal imaging, preferably by computed tomography (CT), +should be requested. +Mycobacterial blood cultures, which can +also detect fungi, should be performed. +Bone marrow aspirate +and trephine biopsy are helpful if the full blood count shows +cytopenias. +Liver biopsy may be helpful if the liver enzymes are +elevated but is invasive and seldom necessary. +Mycobacterial and +fungal stains and cultures should be done on all biopsies. +319 +for differential diagnosis). +Disseminated +endemic mycoses (e.g. +12.4). +Skin biopsy for histology and +fungal culture is often diagnostic. +Some common dermatological diseases, +notably psoriasis, are exacerbated by HIV. +The risk of many drug +rashes is increased in HIV-infected patients. +Skin biopsy should +*See Chapter 29 for more information. +Seborrhoeic dermatitis +Seborrhoeic dermatitis is very common in HIV. +The severity +increases as the CD4 count falls. +It presents as scaly red patches, +typically in the nasolabial folds and in hairy areas. +Fungal infections +are thought to play a role in the pathogenesis of this condition. +It responds well to a combined topical antifungal and +glucocorticoid. +Selenium sulphide shampoo is helpful for scalp +involvement. +Fig. +12.5 Severe mucocutaneous herpes simplex. +12.5). +As immune suppression worsens, the ulcers take longer to heal +and become more extensive. +Ulcers that persist for more than +4 weeks are AIDS-dening. +Response to a course of antiviral drug such as +aciclovir is good but relapses are common. +239). +The median CD4 count at the rst episode of zoster is +350 cells/mm3. +Disseminated zoster is rare. +Post-herpetic neuralgia is difcult to manage. +Analgesic adjuvants, +e.g. +amitriptyline and pregabalin, should be commenced in all +patients with prolonged pain. +Topical capsaicin has modest +efcacy. +Kaposi’s sarcoma +Kaposi’s sarcoma (KS) is a spindle-cell tumour of lympho- +endothelial origin. +AIDS-associated KS is always a multicentric disease. +Early +mucocutaneous lesions are macular and may be difcult to +diagnose. +Subsequently, lesions become papular or nodular, +and may ulcerate. +KS lesions typically have a red–purple colour +(Fig. +12.6 and p. +306) but may become hyperpigmented, +especially in dark-skinned patients. +As the disease progresses, +the skin lesions become more numerous and larger. +Lymphoedema is common, as lymphatic vessels are inltrated. +Visceral +disease occasionally occurs in the absence of mucocutaneous +involvement. +B symptoms of fever, night sweats and weight +loss may occur. +KS may respond to ART. +quintana. +306) that can be scraped off to reveal a red raw surface. +Angular cheilitis due to Candida is a common manifestation. +Topical antifungals are usually effective. +Antifungal lozenges are +more effective than antifungal solutions. +Oral hairy leucoplakia (p. +It is usually asymptomatic and +is due to EBV. +Oral ulcers are common. +Herpetiform oral ulcers occur in +primary infection. +Herpes simplex typically affects the nasolabial +area but may cause oral ulcers. +In early disease, minor aphthous +ulcers are common. +In advanced disease, giant aphthous +ulcers occur. +They respond to systemic glucocorticoids and ART. +A number +of disseminated endemic mycoses, notably histoplasmosis +(p. +303), may cause oral ulcers, usually associated with constitutional +symptoms. +KS often involves the mouth, especially the hard palate (see +above and Fig. +12.6). +Nodular oral lesions are associated with +a worse prognosis. +Gingivitis is very common. +Good oral hygiene and regular +dental check-ups are important. +Acute necrotising ulcerative +gingivitis and periostitis (p. +Nail disorders +Fungal infections (onychomycosis, p. +1240) are very common +and often involve multiple nails. +Gastrointestinal disease +Oesophageal diseases +Oesophageal candidiasis (Fig. +12.7) is the most common cause +of pain on swallowing (odynophagia), dysphagia and regurgitation. +Concomitant oral candidiasis is present in about 70% of patients. +Systemic azole therapy, e.g. +fluconazole 200 mg daily for 14 +days, is usually curative but relapses are common (Box 12.11). +Occasionally, herpes simplex +oesophagitis or KS is responsible. +It is a major cause of wasting. +12.3). +The presentation and aetiology of acute diarrhoea are +similar to those in HIV-uninfected patients. +Fig. +12.6 Oral Kaposi’s sarcoma. +multiple subcutaneous nodules or plaques. +Lesions are painful and +may bleed or ulcerate. +The infection may become disseminated +with fevers, lymphadenopathy and hepatosplenomegaly. +Treatment with doxycycline +or azithromycin is effective. +It +is thought to be due to an allergic reaction to insect bites. +In +sub-Saharan Africa, it is the most common skin manifestation of +HIV. +Post-inflammatory hyperpigmentation is common. +Topical +glucocorticoids, emollients and antihistamines are useful but +response is variable. +Measures to reduce insect bites are logical +but difcult to implement in low-income settings. +The most common type is an +erythematous maculopapular rash, which may be scaly. +Details of rashes caused by ART are +given below. +Oral conditions +Oropharyngeal candidiasis is very common. +It is nearly always +caused by C. +albicans (p. +hominis +Enterozoon bieneusi +Encephalitozoon intestinalis etc. +12.7 Oesophageal candidiasis. +Endoscopy showing typical +pseudomembranous candidiasis. +Fig. +12.8 Cryptosporidiosis. +Duodenal biopsy may be necessary to +conrm cryptosporidiosis or microsporidiosis. +The arrow indicates an +oĂścyst. +Bacteraemia is much more common, notably due to non-typhoid +Salmonella (p. +262). +On colonoscopy, ulcers are seen, mostly involving the left +side of the colon. +Biopsy of ulcers shows typical ‘owl’s-eye’ +inclusion bodies. +It typically presents with +chronic watery diarrhoea and wasting without fever. +All three organisms +are intracellular parasites that invade enterocytes. +12.8). +Electron +microscopy is essential for speciation of microsporidia. +About 40% of patients with disseminated MAC infections +have watery diarrhoea. +The natural history of both HBV and HCV is altered by HIV +co-infection. +HBV and HCV are further described on pages 873 and 877. +HBV status should +be checked at baseline in all HIV-infected patients. +876). +HBV co-infection +increases the risk of antiretroviral hepatotoxicity. +Hepatitis C +HCV infection is extremely common in injection drug-users and +haemophiliacs. +HIV cholangiopathy +HIV cholangiopathy, a form of secondary sclerosing cholangitis +(p. +888), may occur in patients with severe immune suppression. +Acalculous cholecystitis is a common complication of +cholangiopathy. +ART may improve the condition. +An approach to the differential diagnosis +of all three conditions is given in Box 12.13. +Dry cough and fever are common. +12.9 Pneumocystis pneumonia: typical chest X-ray appearance. +Note the interstitial bilateral inltrate. +regions (Fig. +12.9) but may be normal initially. +Pneumatoceles may occur and +may rupture, resulting in a pneumothorax. +588). +The diagnosis therefore needs to +be made and therapy commenced promptly. +A trial of +empirical therapy is often started while awaiting the results +of mycobacterial cultures. +12.10). +These atypical +ndings can result in a delayed or missed diagnosis. +The main reason for this is the +absence of pulmonary cavities. +321). +Patients +may have other features of DILS, notably parotidomegaly. +KS often spreads to the lungs. +Bronchoscopy is diagnostic. +An approach to common +presentations is outlined in Figure 12.11. +Meningo-encephalitis may occur at seroconversion. +About 50% of HIV-infected people have abnormal neuropsychiatric +testing. +The proportion of patients with symptomatic +HAND increases with declining CD4 counts. +There is no diagnostic test for HIV-associated dementia. +CT or magnetic resonance imaging (MRI) shows diffuse cerebral +atrophy out of keeping with age. +It is important to exclude +depression, cryptococcal meningitis and neurosyphilis. +ART +usually improves HIV-associated dementia but milder forms of +HAND often persist. +12.10 Chest X-ray of pulmonary tuberculosis in advanced HIV +infection. +12 +commonly presenting with pulmonary inltrates together +with extrapulmonary tuberculosis. +The most common sites +of concomitant extrapulmonary tuberculosis are the pleura +and lymph nodes. +Acid-fast bacilli are more often found on +wide-needle aspirate of nodes than on sputum (p. +313). +Tuberculosis in HIV-infected patients responds well to standard +short-course therapy (p. +592). +pneumoniae is the most common cause, followed +by Haemophilus influenzae, Enterobacteriaceae (e.g. +Klebsiella +pneumoniae) and Staphylococcus aureus. +Treatment is with a broad- +spectrum β-lactam (e.g. +The chest +X-ray appearances are variable. +Cryptococcomas occur less +commonly than in HIV-uninfected people. +Pleural involvement is rare. +12.11 Presentation and differential diagnosis of HIV-related +neurological disorders. +12.12 Progressive multifocal leucoencephalopathy. +Non- +enhancing white-matter lesions without surrounding oedema are seen. +Fig. +12.13 Cerebral toxoplasmosis. +Multiple ring-enhancing lesions with +surrounding oedema are characteristic. +impairment. +Vision is often impaired due to involvement of the +occipital cortex. +PML is caused by the JC virus. +A combination +of characteristic appearances on MRI (Fig. +12.12) and detection +of JC virus DNA in the cerebrospinal fluid (CSF) by PCR is +diagnostic. +No specic treatment exists and prognosis remains +poor despite ART. +Focal signs may also +occur. +Detection of CMV DNA in the CSF supports the diagnosis. +Response to anti-CMV therapy is usually poor. +The most common cause is toxoplasmosis. +12.13). +Denitive diagnosis +is by brain biopsy but this is seldom necessary. +Fig. +12.14 Primary CNS lymphoma. +A single enhancing periventricular +lesion with moderate oedema is typical. +12.14). +The prognosis is poor. +The CSF may +show features consistent with tuberculous meningitis. +of the spine is normal but is an important investigation to exclude +other causes. +Most patients have concomitant HIV-associated +dementia. +Functional recovery is poor +despite treatment with ganciclovir or valganciclovir. +Reactive depression is the most +common disorder. +Diagnosis is often difcult, as many patients +have concomitant HAND. +Substance misuse is common in +many groups of people at risk of HIV. +Some antiretroviral drugs +can cause psychiatric adverse effects and these are detailed +on page 326. +On fundoscopy, the +vitreous is clear. +Haemorrhages and exudates are seen in the +retina (p. +306), often with sheathing of vessels (‘frosted branch +angiitis’). +Stroke +There is a higher incidence of stroke in patients with HIV disease. +HIV vasculopathy, which is thought to be +a vasculitis, can also cause a stroke. +Patients usually present subacutely +with headache, vomiting and decreased level of consciousness. +Neck stiffness is present in less than half. +CSF pleocytosis is often +mild or even absent, and protein and glucose concentrations +are variable. +1120), except +that concomitant tuberculosis at other sites is more common +in HIV infection. +The incidence increases with lower CD4 counts, older +age and increased height. +Sensory symptoms predominate. +Treatment involves foot care, analgesia and analgesic adjuvants. +ART has minimal effect on halting or reversing the process. +It resembles Guillain–BarrĂŠ syndrome (p. +1140), except that CSF +pleocytosis is more prominent. +Mononeuritis may also occur, +commonly involving the facial nerve. +Vacuolar myelopathy is +seen in advanced disease and is due to HIV. +It typically presents +with a slowly progressive paraparesis with no sensory level. +Mild arthralgias and +a bromyalgia-like syndrome are common in HIV-infected people. +Arthritis +HIV can cause a seronegative arthritis, which resembles +rheumatoid arthritis. +A more benign oligoarthritis may also occur. +Reactive arthritis is more severe in HIV infection (p. +1031). +1038). +It is linked to human leucocyte antigen (HLA)-DRB1. +Most patients have a marked CD8 lymphocytosis. +DILS usually +presents in patients with mild immune suppression. +971). +This responds to +glucocorticoids or intravenous immunoglobulin, together with +ART. +979), which has a better prognosis and fewer relapses than +the classical disease. +tenofovir (p. +412), amphotericin +B (p. +HIVAN presents with nephrotic syndrome, +CKD or a combination of both. +ART has some effect in slowing +progression of HIVAN. +Outcomes of renal transplantation are good in patients +on ART. +Cardiac disease +HIV-associated cardiomyopathy resembles idiopathic dilated +cardiomyopathy (p. +539) but progresses more rapidly. +ART +may improve cardiac failure but does not reverse established +cardiomyopathy. +Pericardial disease due to opportunistic +diseases is not uncommon. +Globally, the most common cause +is tuberculous pericardial effusions. +Tuberculous constrictive +pericarditis is less common than in HIV-uninfected people. +KS +and lymphoma may cause pericardial effusions. +Septic pericarditis, +usually due to S. +pneumoniae, is uncommon. +964). +NHL may occur at +any CD4 count but is more commonly seen with counts below +200 cells/mm3. +Almost all NHLs are B-cell tumours and most +are stage 3 or 4. +Fig. +on histology (Fig. +12.15). +Sicca symptoms are common but +usually mild. +Lymphocytic interstitial pneumonitis is the most +common manifestation outside the salivary glands. +Hepatitis, +mononeuritis, polyarthritis and polymyositis may also occur. +The manifestations outside the salivary glands usually respond +to systemic glucocorticoids. +DILS may regress on ART but response is variable. +Haematological abnormalities +Disorders of all three major cell lines may occur in HIV. +In advanced +disease, haematopoiesis is impaired due to the direct effect of HIV +and by cytokines. +Anaemia +Normochromic, normocytic anaemia is very common in advanced +HIV disease. +Opportunistic diseases may cause anaemia of +chronic disease (e.g. +tuberculosis) or marrow inltration (e.g. +MAC, tuberculosis, lymphoma, fungi). +Anaemia is a common +adverse effect of zidovudine, which also causes a macrocytosis. +Red cell aplasia is rare and may be caused either by parvovirus +B19 infection or by lamivudine. +zidovudine, co-trimoxazole, +ganciclovir). +Thrombocytopenia +Mild thrombocytopenia is common in HIV-infected people. +Transient thrombocytopenia is frequently found in primary infection. +Safer +sex will also lower the risk of acquiring herpes simplex virus and +human herpesvirus 8. +Chemoprophylaxis +Chemoprophylaxis is the use of antimicrobial agents to prevent +infections. +Primary prophylaxis is used to prevent opportunistic +infections that have not yet occurred. +Co-trimoxazole prophylaxis is well tolerated. +The most common +side-effect is hypersensitivity, causing a maculo-papular rash. +This is possible only for a few opportunistic +infections, however. +Safe water and food +Cryptosporidiosis, microsporidiosis and cystoisosporiasis may +be water-borne. +If there is no access to safe water, then water +should be boiled before drinking. +Food-borne illnesses are also +important in HIV infection, notably Salmonella species. +Toxoplasma +exposure is related to eating raw or undercooked meat. +Adequate ventilation, masks and safe coughing procedures +reduce the risk of exposure. +The most cost-effective +way to achieve this is by using insecticide-impregnated bed +nets. +Dapsone is equally +effective at reducing the incidence of P. +immune. +Bacille Calmette–GuĂŠrin (BCG) is contraindicated in all HIV-infected +people. +In HIV infection, induration +of 5 mm or more on a Mantoux test is regarded as positive. +MAC is uncommon in low- and middle-income countries and +primary prophylaxis is thus not warranted. +If this is positive, pre-emptive +therapy with fluconazole should be commenced. +Immunisation +There are signicant problems associated with vaccination in HIV +infection. +Secondly, immune +responses to vaccination are impaired in HIV-infected patients. +If +the CD4 count is below 200 cells/mm3, then immune responses +to immunisation are very poor. +All patients should be given a conjugate +pneumococcal vaccine and annual influenza vaccination. +It is seldom necessary to start ART urgently. +Recognition and management of depression +and substance abuse is also important. +Monitoring efcacy +The most important measure of ART efcacy is the viral load. +A +baseline viral load should be measured prior to initiating treatment. +The viral +load should be suppressed after 6 months. +Once the viral load +is suppressed, measurement should be repeated 6-monthly. +Failure of ART is dened by the viral load becoming detectable +after suppression. +In most guidelines, a viral load threshold is +used to dene virological failure, e.g. +more than 200 (UK) or +more than 1000 (WHO) copies/mL. +The CD4 count increases rapidly +in the rst month, followed by a more gradual increase. +If +ART is stopped, the CD4 count rapidly falls to the baseline value +before ART was commenced. +Antiretroviral +drugs differ in their ability to select for resistant mutations. +Some drugs (e.g. +PIs and some NRTIs +(e.g. +Symptomatic +treatments are helpful. +visceral fat, ‘buffalo hump’) or with +subcutaneous fat loss (‘lipoatrophy’, Fig. +12.16), or with both fat +loss and accumulation. +Previously, PIs were thought to be the cause of fat +accumulation. +Rechallenge must never +be attempted after abacavir hypersensitivity, as fatal reactions +may occur. +Drug rashes are very common with NNRTIs. +The rash usually resolves. +If it +worsens or if systemic features develop, the NNRTI should be +discontinued. +Some PIs are associated with dyslipidaemias and may increase +the risk of myocardial infarction. +• Immunity: age-related decline increases the risk of infections. +CD4 responses to ART +decrease with increasing age. +The CD4 count falls by about 25% during pregnancy +due to haemodilution. +The course of HIV disease progression +is not altered by pregnancy. +ART has dramatically reduced the risk of mother-to-child +transmission of HIV to less than 1%. +HIV is also transmitted by breastfeeding. +In high-income +countries, exclusive formula feeding is generally recommended. +Breastfeeding +is therefore now encouraged in resource-poor settings. +Infants +should be exclusively breastfed for the rst 6 months, as mixed +Fig. +PCR should ideally be carried out within 6 weeks of birth to +facilitate early ART initiation. +If the baby is breastfed, the PCR +should be repeated 2 weeks after weaning. +Measures for the prevention of HIV transmission are shown in +Box 12.19. +from sex or injecting drug +use) and is well tolerated. +Regular HIV testing should be done +in people on PrEP. +The rst +dose should be given as soon as possible, preferably within +6–8 hours. +There is no point in starting PEP after 72 hours. +PEP should not be given if the exposed person is +HIV-infected. +HIV antibody testing should be performed at 3 +months after exposure. +bhiva.org British HIV Association. +Sexually transmitted infections: a colour guide. +Churchill Livingstone, Elsevier Ltd; 2000. +(Coronal +papillae, mucopus) From McMillan A, Young H, Ogilvie MM, Scott GR. +Clinical practice in sexually transmissible infections. +Saunders, Elsevier Inc.; 2002. +*A urethral swab can be submitted if the patient is +unable to pass urine. +Clinical practice in sexually transmissible infections. +Saunders, Elsevier Inc.; 2002. +Hepatitis viruses +A, B, C and D (p. +871) may be acquired sexually, as well as by +other routes. +247). +12). +330–331), regardless of the reason +for attendance. +In other settings, less comprehensive investigation +may be appropriate. +The extent of the examination largely reflects the likelihood +of HIV infection or syphilis. +In other words, the extent of the examination +is determined by the sexual history (Box 13.1). +Sexual partners, whether male or +female, and casual or regular, should be recorded. +Possible outcomes are +highlighted in Box 13.2. +• Do you have a regular sexual partner at present? +• If yes: +How long have you been together? +When did you last have sex with anyone else? +• If no: +When did you last have sex? +Was this a regular or a casual partner? +• Do/did you use a condom? +235). +340). +Appropriate treatment for chlamydia +(p. +Non-gonococcal, non-chlamydial urethritis is treated as for +chlamydia. +A small +minority seem not to have an infectious aetiology. +Gonococcal urethritis usually causes symptoms within 7 days +of exposure. +The discharge is typically profuse and purulent. +Tests for other potential causes of urethritis are +not performed routinely. +In MSM, swabs for gonorrhoea and chlamydia should +be taken from the rectum. +Box 13.3 provides a guide to diagnosis. +Tight prepuce and poor hygiene may +be aggravating factors. +Local saline bathing is usually helpful, especially when +no cause is found. +Genital ulceration +The most common cause of ulceration is genital herpes. +Classically, multiple painful ulcers affect the glans, coronal sulcus +or shaft of penis (Fig. +13.2), but solitary lesions occur rarely. +Perianal ulcers may be seen in MSM. +Increasingly, laboratories +will also test for Treponema pallidum by PCR. +338). +Other rare infective causes seen +in the UK include varicella zoster virus (p. +238) and trauma +with secondary infection. +Tropical STIs, such as chancroid, +Fig. +13.1 A Gram-stained urethral smear from a man with +gonococcal urethritis. +1252) +Clinical None or mild topical +glucocorticoid, e.g. +hydrocortisone +Strong topical +glucocorticoid, e.g. +clobetasol +Either ᅚ – – Similar to lesions elsewhere +Dermatoses, e.g. +Clinical Mild topical glucocorticoid, +on skin +eczema or psoriasis +e.g. +1031) +Clinical Mild topical glucocorticoid, +e.g. +341). +Inflammatory causes include Stevens–Johnson syndrome +(pp. +1224 and 1254), Behçet’s disease (p. +1043) and xed +drug reactions. +Genital lumps +The most common cause of genital ‘lumps’ is warts (p. +342). +Perianal warts are surprisingly +common in men who do not have anal sex. +The differential diagnosis includes molluscum contagiosum +and skin tags. +Adolescent boys may confuse normal anatomical +features such as coronal papillae (p. +330), parafrenal glands or +sebaceous glands (Fordyce spots) with warts. +Symptoms include mucopurulent anal discharge, rectal +Fig. +13.2 Penile herpes simplex (HSV-2) infection. +330). +Treatment is directed at the individual infections. +286), Shigella spp. +(p. +265), Campylobacter spp. +(p. +262) +and Cryptosporidium spp. +(pp. +287 and 317). +Presenting problems in women +vulvovaginal inflammation. +331). +331). +Treatment of infections causing vaginal discharge is shown +in Box 13.4. +Local epidemiology is particularly important when assessing +possible causes. +Non-infective causes include retained +tampons, malignancy and/or stulae. +13.3), the likely diagnosis is BV. +13.3 Gram stain of a Clue cell from a patient with bacterial +vaginosis. +The margin of this vaginal epithelial cell is obscured by a +coating of anaerobic organisms. +From McMillan A, Young H, Ogilvie MM, +Scott GR. +Clinical practice in sexually transmissible infections. +Saunders, +Elsevier Inc.; 2002. +2 Avoid in pregnancy and breastfeeding. +3 Avoid alcoholic drinks until 48 hours after +nishing treatment. +Avoid high-dose regimens in pregnancy or breastfeeding. +There +may also be systemic features, such as fever and malaise. +Unfortunately, a denitive diagnosis can only be made +by laparoscopy. +A pregnancy test should be performed (as +well as the diagnostic tests on p. +331) because the differential +diagnosis includes ectopic pregnancy. +Hospital admission +may be indicated for severe symptoms. +Genital ulceration +The most common cause of ulceration is genital herpes. +Increasingly, +laboratories will also test such samples for Treponema pallidum +by PCR. +Inflammatory causes include lichen sclerosus, Stevens–Johnson +syndrome (pp. +1224 and 1254), Behçet’s disease (p. +1043) +and xed drug reactions. +Genital lumps +The most common cause of genital ‘lumps’ is warts. +These +are classically found in areas of friction during sex, such as the +fourchette and perineum. +Perianal warts are surprisingly common +in women who do not have anal sex. +Effective treatment may require regular +oral antifungals, e.g. +fluconazole 150 g once a week, plus a +combined antifungal/glucocorticoid cream. +However, the impact of medical intervention +through improved access alone is likely to be small. +Changing behaviour +The prevalence of STIs is driven largely by sexual behaviour. +ᅚ – Similar to lesions elsewhere on skin Clinical Mild topical glucocorticoid, e.g. +Fig. +13.4 Primary syphilis. +A painless ulcer (chancre) is shown in the +coronal sulcus of the penis. +This is usually associated with inguinal +lymphadenopathy. +Courtesy of Dr P. +Hay, St George’s Hospital, London. +Anal chancres often resemble ssures and may be painful. +Constitutional features, such as mild fever, malaise and headache, +are common. +Scales +may form on the papules later. +Lesions are red, changing to a +‘gun-metal’ grey as they resolve. +Without treatment, the rash may +last for up to 12 weeks. +Generalised non-tender lymphadenopathy is +present in over 50% of patients. +Rarely, confluence produces characteristic ‘snail track +ulcers’ in the mouth. +Neurological involvement +may be more common in HIV-positive patients. +12). +Thereafter, the disease enters the phase +of latency. +Transplacental infection of the fetus +can occur. +The natural history of untreated syphilis is variable. +Infection +may remain latent throughout, or clinical features may develop +at any time. +The classication of syphilis is shown in Box 13.6. +All infected patients should be treated. +Penicillin remains the +drug of choice for all stages of infection. +The primary lesion or chancre (Fig. +13.4) +develops at the site of infection, usually in the genital area. +A +dull red macule develops, becomes papular and then erodes to +form an indurated ulcer (chancre). +The draining inguinal lymph +nodes may become moderately enlarged, mobile, discrete and +rubbery. +Without treatment, the chancre will resolve within 2–6 weeks to +leave a thin atrophic scar. +Late syphilis +Late latent syphilis +This may persist for many years or for life. +Without treatment, over +60% of patients might be expected to suffer little or no ill health. +Skin, mucous membranes, bone, +muscle or viscera can be involved. +Healing with scar formation may impair +the function of the structure affected. +Healing occurs slowly, with +the formation of characteristic tissue-paper scars. +Resolution of active disease +should follow treatment, though some tissue damage may be +permanent. +Paroxysmal cold haemoglobinuria (p. +950) may +be seen. +Cardiovascular syphilis +This may present many years after initial infection. +Aortitis, which +may involve the aortic valve and/or the coronary ostia, is the key +feature. +Clinical features include aortic incompetence, angina +and aortic aneurysm (p. +505). +Neurosyphilis +This may also take years to develop. +Asymptomatic infection +is associated with CSF abnormalities in the absence of clinical +signs. +1125). +Congenital syphilis +Congenital syphilis is rare where antenatal serological screening +is practised. +Antisyphilitic treatment in pregnancy treats the fetus, +if infected, as well as the mother. +The serological tests for syphilis (STS) are listed in Box 13.8. +These are antibody tests that almost always remain positive, +even after successful treatment. +Prolonged untreated infection +results in higher titres that may not decline at all. +for skin or respiratory +tract infections. +All positive results in asymptomatic +patients must be conrmed by repeat tests. +Chronic false- +positive reactions may be associated with autoimmune diseases. +A 10-day course of ceftriaxone +is a further alternative. +Babies should be treated in hospital with +the help of a paediatrician. +Treatment reactions +• Anaphylaxis. +Penicillin is a common cause; on-site facilities +should be available for management (p. +75). +• Jarisch–Herxheimer reaction. +It is common in early syphilis and rare in late +syphilis. +Fetal distress or premature labour can occur in +pregnancy. +In +high-risk situations it is wise to initiate therapy in hospital. +• Procaine reaction. +Symptoms are short-lived, but verbal +assurance and sometimes physical restraint are needed. +The CSF should also be examined in patients +with clinical signs of neurosyphilis (p. +1125) and in both early and +late congenital syphilis. +Examination of CSF is occasionally necessary. +Biopsy +may be required to diagnose gumma. +Endemic treponematoses, such as yaws, endemic (non- +venereal) syphilis (bejel) and pinta (pp. +253 and 254), are caused +by treponemes that are morphologically indistinguishable from +T. +pallidum and cannot be differentiated by serological tests. +In this situation, non-treponemal tests should become +negative within 3–6 months of birth. +A positive EIA test for +antitreponemal IgM suggests early congenital syphilis. +Management +Penicillin is the drug of choice. +Doxycycline is indicated for patients +allergic to penicillin, except in pregnancy (see below). +Azithromycin +is less favoured due to the potential for resistance. +Specic treponemal antibody tests may remain positive +for life. +Transmission is usually the result +of vaginal, anal or oral sex. +Gonococcal conjunctivitis may +be caused by accidental infection from contaminated ngers. +Untreated mothers may infect babies during delivery, resulting in +ophthalmia neonatorum (Fig. +13.5). +Infection of children beyond +the neonatal period usually indicates sexual abuse. +Clinical features +The incubation period is usually 2–10 days. +Examination will usually show a mucopurulent or purulent urethral +discharge. +Proctoscopy may reveal either no abnormality, or clinical evidence +of proctitis (p. +334) such as inflamed rectal mucosa and mucopus. +2If prevalence of quinolone +resistance for Neisseria gonorrhoeae is < 5%. +3 May be available only in specialist +clinics. +Fig. +13.5 Gonococcal ophthalmia neonatorum. +From McMillan A, +Scott GR. +Sexually transmitted infections: a colour guide. +Churchill +Livingstone, Elsevier Ltd; 2000. +About 80% of women who have gonorrhoea +are asymptomatic. +331). +Lower abdominal +pain, dyspareunia and intermenstrual bleeding may be indicative +of PID. +The cervix may be inflamed, with mucopurulent discharge +and contact bleeding. +Pharyngeal gonorrhoea is the result of receptive orogenital +sex and is usually symptomless. +Conjunctivitis must be treated urgently +to prevent corneal damage. +Symptoms include arthritis of one or more joints, pustular skin +lesions, tenosynovitis and fever. +Gonococcal endocarditis has +been described. +13.1). +The alternatives listed +in Box 13.9 are less likely to be effective. +Longer courses of antibiotics are required for complicated +infection. +The partner(s) of patients with gonorrhoea should +be seen as soon as possible. +Delay in treatment may lead to +complications (Box 13.10). +Conjunctivitis is also milder +than in gonorrhoea; pharyngitis does not occur. +The incubation +period varies from 1 week to a few months. +Without treatment, +symptoms may resolve but the patient remains infectious for +several months. +Complications, such as epididymo-orchitis and +sexually acquired reactive arthritis (SARA, p. +1031), are rare. +Treatments for chlamydia are listed in Box 13.11. +NSU is +treated identically. +Chlamydial infection in women +The cervix and urethra are commonly involved. +Lower abdominal pain and dyspareunia are features +of PID. +247), and may facilitate HIV transmission. +The rst symptomatic +episode is usually the most severe. +13.6 and see Fig. +13.2). +Lesions at other sites (e.g. +Constitutional symptoms, such as fever, headache and +malaise, are common. +Oropharyngeal +infection may result from orogenital sex. +Complications, such +1 Safety in pregnancy and breastfeeding has not been fully established. +2 Contraindicated in pregnancy and breastfeeding. +bleeding from the cervix, evidence of PID or no obvious clinical +signs. +Treatment options are listed in Box 13.11. +The patient’s +male partner(s) should be investigated and treated. +Many infections clear spontaneously but others persist. +Other complications include perihepatitis, chronic pelvic pain, +conjunctivitis and SARA (p. +1031). +Perinatal transmission may +lead to ophthalmia neonatorum and/or pneumonia in the neonate. +LGV is also a +cause of proctitis in MSM (p. +334). +1 The genito-ano-rectal syndrome is a late manifestation of LGV. +2 Doxycycline and ciprofloxacin are contraindicated in pregnancy and breastfeeding. +3The safety of +azithromycin in pregnancy and breastfeeding has not been fully assessed. +Treatment may be continued for longer than 5 days if new lesions +develop. +In a few patients, treatment started at the onset of prodromal +symptoms may abort recurrence. +Treatment should be given for a minimum of +1 year before stopping to assess recurrence rate. +Aciclovir 400 mg twice daily is +most commonly prescribed. +Consistent +condom use during pregnancy may reduce transmission of +HSV. +Vaginal delivery should be routine in women who are +symptomless in late pregnancy. +Fig. +13.6 Herpetic ulceration of the vulva. +From McMillan A, Scott GR. +Sexually transmitted infections: a colour guide. +Churchill Livingstone, +Elsevier Ltd; 2000. +as urinary retention due to autonomic neuropathy, and aseptic +meningitis, are occasionally seen. +They occur more often in HSV-2 infection and their +frequency tends to decrease with time. +The first symptomatic episode may be a recurrence +of a previously undiagnosed primary infection. +Recurrent +episodes of asymptomatic viral shedding are important in the +transmission of HSV. +Type-specic +antibody tests are available but are not sufciently accurate for +general use. +Famciclovir 250 mg three times daily or aciclovir 200 mg ve +times daily is an alternative. +Perianal warts (p. +330), while being +more common in MSM, are also found in heterosexual men and in +women. +Rarely, a giant condyloma (Buschke–LĂśwenstein tumour) +develops, with local tissue destruction. +Atypical warts should be +biopsied. +In pregnancy, warts may dramatically increase in size +and number, making treatment difcult. +Vaccination against HPV infection +has been introduced and is in routine use in many countries. +• A nonovalent vaccine protects against ve additional +high-risk types (31, 33, 45, 52 and 58). +Masks should be worn during the +procedure and adequate extraction of fumes should be +provided. +13.7). +Larger lesions may be seen in HIV +infection (p. +306). +Lesions are often multiple and, once established +in an individual, may spread by auto-inoculation. +They are found +on the genitalia, lower abdomen and upper thighs when sexually +acquired. +Facial lesions are highly suggestive of underlying +HIV infection. +Diagnosis is made clinically or very rarely by +electron microscopy. +Typically, lesions persist for several months +before spontaneous resolution occurs. +13 +Fig. +13.7 Molluscum contagiosum of the shaft of the penis. +From McMillan A, Scott GR. +Sexually transmitted infections: a colour +guide. +Churchill Livingstone, Elsevier Ltd; 2000. +Viral hepatitis +The hepatitis viruses A–D (p. +871) may be sexually transmitted: +• Hepatitis A (HAV). +HAV +transmission in heterosexual men and women is also +possible through oroanal sex. +• Hepatitis B (HBV). +Insertive oroanal sex, anal sex and +multiple sexual partners are linked with HBV infection in +MSM. +Hepatitis D (HDV) may also be sexually transmitted. +• Hepatitis C (HCV). +Sexual transmission of HCV is well +documented in MSM but less so in heterosexuals. +Patients with HAV should abstain from all forms of +unprotected sex until non-infectious. +Further information +Books and journal articles +Pattman R, Sankar N, Elawad B, et al. +(eds). +Oxford handbook of +genitourinary medicine, HIV, and sexual health. +Oxford: Oxford +University Press; 2010. +Rogstad KE (ed.). +ABC of sexually transmitted infections, 6th edn. +Oxford: Wiley–Blackwell; 2011. +Sarcoidosis with bilateral leg lymphedema as the initial presentation: a review of the +literature. +Dermatologica Sinica 2016; 34:29–32; (raised jugular venous pressure) Newby D, Grubb N. +Cardiology: an illustrated colour text. +J Clin Neurosci 2013; 20:1327–1328; (photosensitive +rash) Ferri FF. +Ferri’s Color atlas and text of clinical medicine. +Reference intervals for +laboratory results are provided in Chapter 35. +3) +Genetic polymorphisms (Ch. +3) +Variations in rates of drug metabolism (Ch. +2) +Microbial diagnosis (Ch. +15.2 (p. +14.1 Normal distribution of body water and electrolytes. +The Na/K +differential is maintained by the Na,K-adenosine triphosphatase (ATPase) +pump. +14 +pump (Na,K-activated adenosine triphosphatase (ATPase)), which +is present in all cell membranes. +*The term urea and electrolytes (U&Es) refers to urea, electrolyes and creatinine. +In some countries this is abbreviated to EUC (electrolytes/urea/creatinine). +taking a venous sample proximal to the site of an intravenous +infusion. +In a 70 kg man TBW is +therefore about 40 L. +14.1). +Accordingly, total body sodium +is the principal determinant of ECF volume. +Sodium intake +varies widely between individuals, ranging between 50 and +250 mmol/24 hrs. +Functional anatomy and physiology +The functional unit for renal excretion is the nephron (Fig. +14.2). +(More detail on the structure and function of +the glomerulus is given in Ch. +14.3). +The cellular mechanisms are complex but +some of the key features are shown in Figure 14.3A. +Loop of Henle +The thick ascending limb of the loop of Henle (Fig. +14.3C), again driven by +the activity of the basolateral Na,K-ATPase. +This segment is also +impermeable to water, resulting in further dilution of the luminal +fluid. +14.3D). +Chloride ions pass +largely between cells. +14.2 The nephron. +Letters A–D refer to tubular segments shown in +more detail in Figure 14.3. +14.3 Principal transport mechanisms in segments of the nephron. +Amiloride and spironolactone block the ENaC channel in the late distal tubule +and collecting ducts. +See text for further details and abbreviations. +14.4), and controlling those +two processes. +14.2) to form the juxtaglomerular apparatus. +18.18, p. +666). +14.4 Mechanisms involved in the regulation of sodium +transport. +349). +Clinical manifestations of altered ECF volume are +illustrated in Box 14.3. +Hypovolaemia +Hypovolaemia is dened as a reduction in circulating blood +volume. +of sodium-containing fluids or acute blood loss, as summarised +in Box 14.4. +Investigations +Serum sodium concentrations are usually normal in hypovolaemia. +704). +Therefore, crystalloids are the fluid of choice for +resuscitation in acute hypovolaemia. +In Conn’s syndrome (p. +674). +General investigations may reveal evidence of cardiac, renal or +liver disease. +513). +They act by inhibiting sodium reabsorption at various locations +along the nephron (see Fig. +14.3). +Their potency and adverse +effects relate to their mechanism and site of action. +745). +Loop diuretics cause excretion not only of sodium (and with it +water) but also of potassium. +The +apical sodium channel (see Fig. +Osmotic diuretics These act independently of a specic transport +mechanism. +Mannitol is the +most commonly used osmotic diuretic. +• Use for as short a period of time as necessary. +• Monitor regularly for adverse effects. +723). +Combinations of diuretics administered orally may also increase +potency. +Water homeostasis +14 +Daily water intake can vary from about 500 mL to several litres a +day. +These functions are largely achieved by the loop of Henle and the +collecting ducts (see Fig. +14.2). +The countercurrent conguration +of flow in adjacent limbs of the loop (Fig. +14.6 Mechanisms of renal water handling. +(1) Filtrate from the proximal tubule is isosmotic to plasma and cortical interstitial fluid. +(5) The ltrate has a concentration of 100 mOsmol/kg as it leaves the early +distal tubule. +B In the situation of water overload, vasopressin secretion is suppressed and urine remains dilute. +688). +• When water intake is high and plasma osmolality is normal +or low–normal (Fig. +14.6B), vasopressin levels are +suppressed and the collecting ducts remain impermeable +to water. +• When water intake is restricted and plasma osmolality is +high (Fig. +14.6A), or in the presence of plasma volume +depletion, vasopressin levels rise. +If any of these processes is faulty, water retention and +hyponatraemia may result. +Failure of any of these steps may result in inappropriate water +loss and hypernatraemia. +Abnormalities of water balance can result from +disturbances in urinary concentration or dilution. +Hyponatraemia +Hyponatraemia is dened as a serum Na < 135 mmol/L. +The causes are best categorised according +to associated changes in the ECF volume (Box 14.10). +The cause of sodium loss is +usually apparent and common examples are shown in Box 14.10. +Supportive laboratory ndings are +shown in Box 14.11. +14.7). +Artefactual causes of +hyponatraemia should be considered in all cases. +14.7). +The underlying cause should also be treated. +14.7 Hyponatraemia and the brain. +Numbers represent osmolality +(osmo) in mOsmol/kg. +When these conditions have been excluded, serum and +urine electrolytes and osmolality (Fig. +14.8) are usually the only +tests required to clarify the underlying cause. +overload? +14.8 Algorithm for the diagnosis of hyponatraemia. +This can occur because of pituitary damage (cranial +diabetes insipidus, p. +Moreover, the vasopressin response to non-osmotic stimuli +may be brisker in older subjects. +Appropriate water restriction may +be a key part of management. +Both are frequently present in patients with advanced +dementia or following a severe stroke. +Appropriate prescription of fluids is +a key part of management. +14.9 Feedback control of plasma potassium concentration. +hypernatraemia may not progress very far. +Where possible, +the underlying cause should also be addressed (Box 14.13). +Potassium homeostasis +Potassium is the major intracellular cation (see Fig. +Control of body potassium +balance is described below. +The mechanism for potassium secretion in the distal parts of +the nephron is shown in Figure 14.3D. +A number of factors influence the rate of potassium secretion. +In addition to its regulation by the renin–angiotensin system (see +Fig. +18.18, p. +Renal causes of hypokalaemia can be divided into those with +and those without hypertension. +674) or a genetic defect affecting sodium +channels in the distal nephron (Liddle’s syndrome). +The +clinical and biochemical features are similar to those in chronic +treatment with furosemide. +The clinical and biochemical features are similar +to chronic thiazide treatment. +364). +The main +causes of hypokalaemia are shown in Box 14.15. +Typical electrocardiogram (ECG) changes occur, +affecting the T wave in particular (p. +347). +Functional bowel +obstruction may occur due to paralytic ileus. +If the diagnosis remains +unclear, plasma renin should be measured. +Levels are low in +patients with primary hyperaldosteronism (p. +674) and other +forms of mineralocorticoid excess, but raised in other causes +of hypokalaemia. +In most cases, however, some form of +potassium replacement will be required. +The causes +of hyperkalaemia are summarised in Box 14.16. +361). +364). +Clinical features +Mild to moderate hyperkalaemia (< 6.5 mmol/L) is usually +asymptomatic. +The typical ECG changes +are shown on page 347. +However, these characteristic ECG ndings +are not always present, even in severe hyperkalaemia. +Resonium) +orally or rectally +Dialysis +1If severe hyperkalaemia (K+ typically > 6.5 mmol/L). +2If acidosis present. +3If adequate residual renal function. +serum potassium constitutes severe hyperkalaemia and requires +urgent treatment. +Ultimately, a means of removing potassium from the +body is generally necessary. +In renal failure, +dialysis may be required. +Abnormalities of acid–base +balance can occur in a wide range of diseases. +Respiratory compensation for acid–base disturbances can +occur quickly. +555). +The kidneys provide a third line of defence against disturbances +of arterial pH. +Distal nephron segments also have an important role in acid +excretion. +The most common patterns of abnormality in blood gas +parameters are shown in Box 14.18. +Interpretation of +arterial blood gases is also described on page 555. +367). +14.10 Relationship between pH, PCO2 (in mmHg) and plasma +bicarbonate concentration (in mmol/L). +2 PCO2 of 5.33 kPa = 40 mmHg. +3 PCO2 does not rise above 7.33 kPa (55 mmHg) because hypoxia then intervenes to drive respiration. +735) +Accumulation of ketones without +Starvation ketosis +Alcoholic ketoacidosis +hyperglycaemia (p. +725). +14.3). +746). +fall in the plasma bicarbonate. +Renal tubular acidosis +(RTA) is an important cause of metabolic acidosis with a normal +anion gap. +Various subtypes of RTA are recognised and the most common +causes are shown in Box 14.20. +147). +This gap is normally made up of anions, +such as phosphate and sulphate, as well as albumin. +The different subtypes of RTA can be differentiated by various +biochemical features. +Potassium is also lost in +classical distal RTA, while it is retained in hyperkalaemic distal RTA. +In alcoholism and starvation ketosis, intravenous glucose +is indicated. +By stimulating endogenous insulin secretion, this +will reverse hepatic ketone production. +Malnourished patients +may also require thiamin, potassium, magnesium and phosphate +supplements (p. +706). +Use of intravenous bicarbonate in metabolic +acidosis is controversial. +Classical causes +include primary hyperaldosteronism (Conn’s syndrome, p. +674), +Cushing’s syndrome (p. +666) and glucocorticoid therapy (p. +670). +Occasionally, overuse of antacid salts for treatment of dyspepsia +produces a similar pattern. +Hypovolaemic metabolic +alkalosis is the most common pattern. +14.11). +Additionally, the compensatory +rise in PCO2 further enhances tubular acid secretion. +663). +663). +14.11 Generation and maintenance of metabolic alkalosis +during prolonged vomiting. +Loss of H+ Cl− generates metabolic alkalosis, +which is maintained by renal changes. +18). +565). +Magnesium homeostasis +Magnesium is mainly an intracellular cation. +Its overall +effect is to stabilise excitable cell membranes. +Magnesium +reabsorption is also enhanced by parathyroid hormone (PTH). +Excessive +alcohol ingestion can cause magnesium depletion through both +gut and renal losses. +361). +476), central nervous excitation and +seizures, vasoconstriction and hypertension. +Management +The underlying cause should be identied and treated where +possible. +If intravenous access is not +feasible, magnesium sulphate can be given intramuscularly. +Oral +magnesium salts have limited effectiveness due to poor absorption +and may cause diarrhoea. +Hypermagnesaemia +This is a much less common abnormality than hypomagnesaemia. +Calcium gluconate may be given intravenously to +ameliorate cardiac effects. +Dialysis may be necessary in patients +with poor renal function. +24). +The normal plasma +concentration is 0.8–1.4 mmol/L (2.48–4.34 mg/dL). +The causes are +shown in Box 14.22, subdivided into the underlying pathogenic +mechanisms. +413 and 419). +418). +1053). +1053). +The diagnosis of PKU is almost always made by routine +neonatal screening (p. +56). +Treatment involves life-long adherence +to a low-phenylalanine diet. +The enzyme deficiency causes +accumulation of homocysteine and methionine in the blood. +Most forms of GSD are inherited in an autosomal recessive manner. +Occasionally, +a muscle or liver biopsy is required to conrm the enzyme defect. +These disorders have diverse clinical manifestations, typically +including intellectual disability. +There are +also some rare inherited defects, discussed below. +It is usually inherited in an autosomal recessive +manner. +The neonate is unable to metabolise galactose, one of +the hexose sugars contained in lactose. +Failure to thrive is the most +common clinical presentation. +The classic form of the disease +results in hepatomegaly, cataracts and intellectual disability. +Fulminant infection with Escherichia coli is a frequent complication. +Treatment involves life-long avoidance of galactose- and lactose- +containing foods. +Phospholipids are present in cell membranes and are important +signalling molecules. +This is achieved by incorporating lipids within lipoproteins. +14.12). +14.13). +14.13). +The liver may acquire lipids by uptake, synthesis or +conversion from other macronutrients. +Fig. +14.12 Structure of lipoproteins. +14.13 Absorption, transport and storage of lipids. +The LDL particles act as a source of cholesterol for cells +and tissues (Fig. +14.13). +LDL cholesterol is internalised by +receptor-mediated endocytosis through the LDLR. +14.13). +Animal species that lack CETP are +resistant to atherosclerosis. +484). +The combination of LDL +and apolipoprotein (a) is known as lipoprotein (a) (Lp(a)). +These processes also have an adverse effect on +endothelial function. +347) and their relatives +• monitoring of response to diet, weight control and +medication. +Abnormalities of lipid metabolism most commonly come to +light following these tests. +Under these +circumstances, LDL-C may under-estimate risk. +Overt or subclinical +hypothyroidism (p. +Once secondary causes are excluded, primary lipid +abnormalities may be diagnosed. +Clinical consequences of dyslipidaemia vary somewhat +between these causes (pp. +346–347). ++++ +Familial hypertriglyceridaemia TG > TC VLDL Âą Chylo ? +Hyperalphalipoproteinaemia refers to increased levels +of HDL-C. +728) and impaired +absorption of bile acids. +346). +These disorders may also be associated with +increased risk of cardiovascular disease. +It does not compromise normal growth and maturation. +• Smoking: patients should be strongly advised not to smoke. +• Adherence to medication: critically important to the success of +treatment. +Simple regimens should be used and education and +support provided. +LDL-C (Box 14.26). +346). +Affected patients suffer from severe hypercholesterolaemia and +premature cardiovascular disease. +FH may be accompanied +by xanthomas of the Achilles or extensor digitorum tendons +(p. +346), which are strongly suggestive of FH. +The onset of +corneal arcus before age 40 is also suggestive of this condition. +Affected individuals should be managed from childhood +(Box 14.27). +728). +Both +components of mixed hyperlipidaemia may contribute to the risk +of cardiovascular disease. +It results in elevation of cholesterol, +TG or both in different family members at different times. +Premature cardiovascular disease +is common, as is peripheral vascular disease. +It may also result +in the formation of palmar xanthomas, tuberous xanthomas or +tendon xanthomas. +Rare dyslipidaemias +Several rare disturbances of lipid metabolism have been described +(Box 14.28). +487). +16.77, +p. +511). +Public health organisations also recommend target levels for +patients receiving drug treatment. +Explanation, +encouragement and persistence are often required to assist patient +adherence. +700). +All other modiďŹ��able cardiovascular risk factors should be +assessed and treated. +14.14). +Statins +These reduce cholesterol synthesis by inhibiting the HMGCoA +reductase enzyme. +Statins reduce LDL-C by up to 60%, reduce +TG by up to 40% and increase HDL-C by up to 10%. +Statins are generally well tolerated and serious side-effects +are rare (well below 2%). +The resulting depletion of hepatic cholesterol +up-regulates hepatic LDLR production. +This mechanism of +action is synergistic with the effect of statins. +Monotherapy in +a 10 mg/day dose reduces LDL-C by 15–20%. +Slightly greater +(17–25%) incremental LDL-C reduction occurs when ezetimibe +is added to statins. +Plant sterol-supplemented foods, which also reduce +cholesterol absorption, lower LDL-C by 7–15%. +Resins +reduce LDL-C and modestly increase HDL-C, but may increase +TG. +They are safe but may interfere with bioavailability of other +drugs. +14.14 Flow chart for the drug treatment of hyperlipidaemia. +To convert triglyceride (TG) in mmol/L +to mg/dL, multiply by 88. +This causes +levels of LDLR to increase, which markedly reduces LDL-C. +These drugs are well tolerated and highly +effective. +The same may be said of novel agents that inhibit cholesterol +ester transfer protein. +Neither of these HDL-C-raising drugs is +indicated in current lipid management. +14.14). +Fewer large-scale trials have been conducted with brates +than with statins. +Fibrates are usually +well tolerated but share a similar side-effect prole to statins. +In +addition, they may increase the risk of cholelithiasis and prolong +the action of anticoagulants. +EPA and DHA are potent inhibitors of VLDL TG +formation. +Up to 50% reduction in TG may be achieved with 15 g +sh oil per day. +Changes in HDL-C are variable but sh oils do not +routinely reduce LDL-C. +Mixed hyperlipidaemia +Mixed hyperlipidaemia can be difcult to treat. +This includes an increase in low-density lipoprotein +cholesterol, which resolves post-partum. +Remnant dyslipidaemia +and hypertriglyceridaemia may be exacerbated during pregnancy. +Combination therapy is often required. +combination with brates, or other drugs that may interfere with +their clearance. +882), treatment should be discontinued and +alternative therapy sought. +14.15). +14.15 Haem biosynthetic pathway and enzyme defects responsible for the porphyrias. +The enzyme +defects responsible for the diseases are shown in Figure 14.15. +1220). +The skin also becomes sensitised to damage +from minimal trauma. +The other pattern of presentation is with an acute neurological +syndrome. +Neuropsychiatric +manifestations, hyponatraemia due to inappropriate ADH release +(p. +357), and an acute neuropathy may also occur (p. +1138). +The +neuropathy is predominantly motor and may, in severe cases, +progress to respiratory failure. +The oral contraceptive pill is a common precipitating factor. +In a +signicant number, no precipitant can be identied. +All the genes +of the haem biosynthetic pathway have now been characterised. +A normal +metabolite prole under these circumstances effectively excludes +porphyria. +Genetic testing for disease-specic +mutations can clarify the situation. +There are few specic or effective measures to treat the +photosensitive manifestations. +The primary goal is to avoid sun +exposure and skin trauma. +Barrier sun creams containing zinc or +titanium oxide are the most effective products. +New colourless +creams containing nanoparticle formulations have improved +patient acceptance. +Beta-carotene is used in some patients with +erythropoietic porphyria with some efcacy. +Alternatively, a prolonged course of +low-dose chloroquine therapy is effective. +Walsh S, Unwin R. +Renal tubular disorders. +Clin Med 2012; +12(5):476–479. +lipidsonline.org Summarises management strategies for +dyslipidaemia. +porphyria-europe.com and drugs-porphyria.org Excellent resources on +drug safety in porphyria. +Further information +Journal articles +Spasovski G, Vanholder R, Allolio B, et al. +Clinical practice guideline on +diagnosis and treatment of hyponatraemia. +15.22) +14 +Urine microscopy +See Fig. +Inset (Dipstick): From Pitkin J, Peattie AB, Magowan BA. +Obstetrics +and gynaecology: An Iilustrated colour text. +Edinburgh: Churchill Livingstone, Elsevier Ltd; 2003. +proximal tubule termed Bowman’s capsule, which is composed +of epithelial cells. +15.1C and +D). +15.1E). +Mesangial cells lie in the central region of the +glomerulus. +Very little lipid is filtered by the +glomerulus. +This is known as autoregulation. +15.1D). +18.18, p. +666). +15.19, p. +413). +1049). +415). +349), blood pressure +(p. +447), and acid–base (p. +363) and calcium–phosphate +homeostasis (pp. +367 and 368). +15.1A). +The right kidney is +usually a few centimetres lower because the liver lies above +it. +Both kidneys rise and descend several centimetres with +respiration. +These eventually give +rise to afferent glomerular arterioles that supply the glomeruli. +15.1B). +14.2, p. +350, and Fig. +15.1B). +15.1 Functional anatomy of the kidney. +A Anatomical relationships of the kidney. +B A single nephron. +For the functions of different segments, +see Figures 14.2 and 14.3 (pp. +350 and 351). +C Histology of a normal glomerulus. +E Electron micrograph of the ltration barrier. +(GBM = glomerular basement membrane) (C) Courtesy of +Dr J.G. +The function of the bladder is to store and then release urine +during micturition. +The bladder is richly innervated. +The micturition cycle has a storage (lling) phase and a voiding +(micturition) phase. +These actions are coordinated by the pontine micturition centre. +Intravesical pressure remains greater than urethral pressure until +the bladder is empty. +383). +383). +creatinine in Îźmol/L/88 4)−− 1.154 × (age in yrs) 0. +(. +) ( . +(,κκ )Îą ( , ) . +0 0. +Urine investigations +Screening for the presence of blood (p. +391), protein (p. +The presence of leucocytes and nitrites in urine is indicative of +renal tract infection. +Urine pH can provide diagnostic information +in the assessment of renal tubular acidosis (p. +365). +Urine microscopy (Fig. +White cell casts +are strongly suggestive of pyelonephritis. +600 800 +Fig. +15.2 Serum creatinine and the glomerular ltration rate (GFR). +80–100 Îźmol/L; green lines) can therefore indicate a substantial decline in +renal function (e.g. +105–80 mL/min/1.73 m2; conversely, in the high +range, large changes in creatinine (e.g. +400–600 Îźmol/L; blue lines) can +occur with only small declines in renal function (e.g. +20–15 mL/ +min/1.73m2). +To convert creatinine in +mg/dL to Îźmol/L, multiply by 88.4. +15.2). +2Two GFR values 3 months apart are required to assign a stage. +All GFR values are in mL/ +min/1.73 m2. +4 From Hill NR, Fatoba ST, +Oke JL et al. +Global prevalence of chronic kidney disease – a systematic review and meta-analysis. +PLoS One 2016; 11:e0158765. +5 For further information, see page 415. +In clinical practice this is seldom required. +Pancytopenia may occur in SLE or +bone marrow suppression due to myeloma. +Biochemistry +Abnormalities of routine biochemistry are common in renal disease. +In the absence of +the other causes mentioned above, an elevated urea:creatinine +AB +CD +Fig. +15.3 Urine microscopy. +A Erythrocytes due to bleeding from lower +in the urinary tract (×400). +B Dysmorphic erythrocytes due to glomerular +inflammation (×400). +C Hyaline casts in normal urine. +D Erythrocytes +and a red cell cast in glomerulonephritis (×100). +Panels A–C are phase +contrast images; D is a bright eld image. +(A, B) Courtesy of Dr G.M. +Iadorola and Dr F. +Quarello, B. +Bosco Hospital, Turin (from www.sin-italia +.org/imago/sediment/sed.htm). +431). +Other dynamic tests of tubular function, including concentrating +ability (p. +688), ability to excrete a water load (p. +357) and +ability to excrete acid (p. +Serum bicarbonate +may be low in renal failure and in renal tubular acidosis. +726) and raised levels of C-reactive +protein (CRP) in sepsis and vasculitis. +1034). +1040), as may antibodies to GBM in patients with +Goodpasture’s syndrome (p. +401). +renal ultrasound is operator-dependent and the results are often +less clear in obese patients. +15.32A, p. +435). +15.29, p. +432). +15.15, p. +406). +It is very useful for local staging of prostate, +bladder and penile cancers. +The main indication +is to investigate renal artery stenosis (p. +406) or haemorrhage +following renal trauma. +These curl up within +the vessel and promote thrombosis, thereby securing haemostasis. +15.4), renal tumours, cysts or stones. +In addition, it can +reveal other abdominal, pelvic and retroperitoneal pathology. +15.4 Renal ultrasound. +A Normal kidney. +The normal cortex is less echo-dense (blacker) than the adjacent liver. +The thinness of the +parenchyma indicates chronic obstruction. +D A typical renal stone with posterior shadowing. +(AS = posterior acoustic shadow) E A T1b renal tumour. +15.5 Retrograde pyelography. +The best views of the normal +collecting system are shown by pyelography. +A catheter has been passed +into the left renal pelvis at cystoscopy. +The anemone-like calyces are +sharp-edged and normal. +Courtesy of Dr A.P. +Bayliss and Dr P. +Thorpe, +Aberdeen Royal Inrmary. +15.6). +438). +391). +15.5) and again a stent can be inserted to bypass any +obstruction. +L +R +LEFT = 61% RIGHT = 39% +POSTERIOR +Fig. +15.6 DMSA radionuclide scan. +Unilateral ureteric obstruction may not +lead to any noticeable reduction in urine output. +Chronic obstruction rarely produces pain but may +give rise to a dull ache. +437 +and 438). +413). +15.7). +15.8). +15.9). +15.7 Causes of haematuria. +15.8). +Other common causes of visible haematuria are urine +infection and stones. +15.8 Investigation of haematuria. +15.9 Nephritic and nephrotic syndrome. +At one extreme, specic injury to podocytes causes proteinuria and nephrotic syndrome. +The histology to +the left shows diabetic nephropathy. +405). +The presence of larger amounts +of protein is usually indicative of signicant renal disease. +2 Urine protein (mg/L)/urine creatinine (mmol/L). +tract infection. +Orthostatic proteinuria is regarded as a benign +disorder that does not require treatment. +758). +15.10). +15.10 Investigation of proteinuria. +757). +It is sometimes helpful to identify the type of protein in the +urine. +This may occur in +AL amyloidosis (p. +81) and in B-cell dyscrasias but is particularly +important as a marker for myeloma (p. +966). +scarring or deposition of exogenous material such as amyloid +into the glomerulus. +757). +Management of nephrotic syndrome should be directed at the +underlying cause. +Oedema +Oedema is caused by an excessive accumulation of fluid within +the interstitial space. +639) or +systemic sclerosis (p. +1037). +Ascites is common and often an earlier feature in children or young +adults, and in liver disease. +Pleural effusions are common but frank +pulmonary oedema is rare. +Facial oedema on waking is common. +Blood volume may be normal, reduced or increased. +354). +The diseases that cause +nephrotic syndrome all affect the glomerulus (see Fig. +loop diuretic plus thiazide plus amiloride). +420) and because of the exaggerated +cardiovascular risk associated with CKD. +Pathophysiology and +management are discussed on pages 509 and 510. +Acute loin +pain radiating anteriorly and often to the groin is termed renal +colic. +When combined with haematuria, this is typical of ureteric +obstruction due to calculi (p. +431). +433). +By far the +most common cause is urinary tract infection, as described on +page 426. +329) and bladder stones (p. +431). +Frequency +Frequency describes daytime micturition more often than a +patient would expect. +Polyuria +Polyuria is dened as a urine volume in excess of 3 L/24 hrs. +A +24-hour urine collection may be helpful to conrm the severity +of polyuria. +564). +Restriction of sodium intake and fluid +intake may be required. +Specic causes of oedema, +such as venous thrombosis, should be treated. +Hypertension +Hypertension is a very common feature of renal disease. +Investigation and management of suspected +diabetes insipidus are described on page 688. +Nocturia +Nocturia is dened as waking up at night to void urine. +437). +Urinary incontinence +Urinary incontinence is dened as any involuntary leakage of +urine. +436). +436). +15.11 and Boxes 15.8 and 15.10). +15.11). +Genetic disorders associated +with glomerular disease are described later (p. +403). +403), metabolic diseases such as diabetes mellitus +(p. +757), and deposition of abnormal proteins such as amyloid +in the glomeruli (p. +81). +The glomerular cell types that may be +the target of injury are shown in Figure 15.11. +15.9). +minimal +change nephropathy) are not associated with inflammation. +Planted +antigens +SLE – ANA, +anti-dsDNA (serum) +Post-infectious +glomerulonephritis +Fig. +15.11 Glomerulonephritis associated with antibody production. +Diagnostic tests +are shown in italics. +15.12). +757) and +amyloid (p. +81). +It is caused by reversible +dysfunction of podocytes. +On light microscopy, the glomeruli +appear normal (Fig. +15.12A), but fusion of podocyte foot +processes is observed on electron microscopy. +15.12 Histopathology of glomerular disease. +( A – E Light microscopy) A A normal glomerulus. +Note the open capillary loops and thinness of +their walls. +B Focal segmental glomerulosclerosis (GS). +C Focal necrotising glomerulonephritis (GN). +Neutrophils may be seen elsewhere in the glomerulus. +There is surrounding interstitial inflammation (I). +D Membranous glomerulonephritis. +However, there is no gross +cellular proliferation or excess of inflammatory cells. +E Crescentic glomerulonephritis. +This is seen in aggressive inflammatory glomerulonephritis. +Antibody +deposition in the glomerulus. +G Immunoglobulin A (IgA) deposits in the mesangium, as seen in IgA nephropathy. +The glomerular structure is well preserved in all of these examples. +(A, C, +D, E) Courtesy of Dr J.G. +Simpson, Aberdeen Royal Inrmary. +(F, G, H) Courtesy of Dr R. +Herriot.400 • NEPHROLOGY AND UROLOGY +rarely exhibit full-blown nephrotic syndrome. +417). +15.12D and F). +Treatment of +secondary membranous nephropathy is directed at the underlying +cause. +403). +Focal segmental glomerulosclerosis +Primary focal segmental glomerulosclerosis (FSGS) (Fig. +IgA nephropathy +and mesangiocapillary glomerulonephritis (MCGN) typically fall +in this category. +403). +Proteinuria can also occur but is usually a later feature. +Characteristically, +the latency from clinical infection to nephritis is short: a few days +or less. +Occasionally, IgA nephropathy progresses rapidly in association +with crescent formation on biopsy. +It is a systemic vasculitis that often +arises in response to an infectious trigger. +15.12G). +The typical presentation is with proteinuria and haematuria. +Several underlying causes have been identied, as summarised +in Box 15.15. +It can be classied into two main subtypes. +The +rst is characterised by deposition of immunoglobulins within +the glomeruli. +This subtype is associated with chronic infections, +autoimmune diseases and monoclonal gammopathy. +Infection-related glomerulonephritis +RPGN may occur either during or following an infection. +The clinical presentation ranges from mild abnormalities on +urinalysis to RPGN with severe AKI. +Antibiotic therapy is rarely needed, as the renal disease +occurs after the infection has subsided. +Some patients may develop CKD 20–30 years after the original +presentation, however. +15.3). +Renal +biopsy typically shows crescentic lesions (see Fig. +15.12E), +often associated with necrotising lesions within the glomerulus +(Fig. +15.12C), particularly in small-vessel vasculitides. +1040). +It can also be observed in SLE (p. +1034) +and occasionally in IgA and other nephropathies (see Fig. +15.9). +Proteinuria is generally modest +(PCR < 100 mg/mmol) and tubular in type (see Box 15.25, +p. +412). +The urine may contain white blood cells and white cell +casts but is sterile on culture. +Eosinophils are present in up to +70% of patients but this is a non-specic nding. +AIN should +always be considered in patients with non-oliguric AKI. +Investigations +Renal biopsy is usually required to conrm the diagnosis (Fig. +15.13D). +Eosinophils may also be observed, +especially in drug-induced AIN. +Often granulomas may be evident, +especially in drug-induced AIN or sarcoidosis (p. +608). +The +degree of chronic inflammation in a biopsy is a useful predictor +of long-term renal function. +Eosinophiluria may be present but +is not a good discriminator for AIN. +Other specific causes (see Box 15.18) should be +treated, if possible. +15.13 Tubular histopathology. +A Normal +tubular histology. +The tubules are back to back. +Brush borders can be seen on the luminal borders of +cells in the proximal tubule. +B Acute tubular +necrosis. +During the regenerative phase, there is increased +tubular mitotic activity. +The interstitium (I) is +oedematous and inltrated by inflammatory cells. +C Acute bacterial pyelonephritis. +A +widespread inflammatory inltrate that includes many +neutrophils is seen. +Granulocyte casts (G) are forming +within some dilated tubules (T). +Other tubules are +scarcely visible because of the extent of the +inflammation and damage. +D Acute (allergic) +interstitial nephritis. +This inflammation does +not involve the glomeruli (not shown). +Sometimes +eosinophils are prominent. +Transplant rejection looks +similar to this. +In many patients, CIN presents at a late stage +and no underlying cause can be identied. +Genetic causes may +underlie many of these cases (p. +404). +It is encountered occasionally in Scandinavia +and Scotland. +Urinalysis abnormalities are non-specic. +Renal tubular acidosis +(p. +The condition may occasionally occur in other diseases. +The +clinical presentation is variable. +Urinalysis may be normal but more frequently +haematuria and sterile pyuria are present. +Signicant proteinuria +is unusual, unless there is renal failure. +The imaging method of +choice to make the diagnosis is CTU or intravenous pyelography. +Management is based on relieving obstruction, where present, +and withdrawal of the offending drugs. +48). +Mutations in COL4A3 or COL4A4 genes are less common +and cause autosomal recessive disease. +The accumulation of +abnormal collagen results in a progressive degeneration of the +GBM (Fig. +15.14). +Affected patients progress from haematuria to +ESRD in their late teens or twenties. +15.14 Alport’s syndrome. +A Diagrammatic structure of the normal glomerular basement membrane (GBM). +C In Alport’s syndrome, this network is disrupted and +replaced by Îą1 and Îą2 chains. +(B, C) Courtesy of Dr J. +Collar, St Mary’s Hospital, London. +Angiotensin-converting enzyme (ACE) inhibitors may slow +but not prevent loss of kidney function. +The condition may be familial and +some patients are carriers of Alport mutations. +This does not +appear to account for all cases, and in many patients the cause +is unclear. +400). +The histological pattern +of injury is identical to other forms of CIN (p. +402). +This is a +heterogeneous group of inherited disorders. +Only the most common are mentioned +here. +Glucose appears in the +urine in the presence of a normal blood glucose concentration. +It is caused +by mutations in the SLC3A1 amino acid transporter gene. +The +high concentration of cystine in urine leads to cystine stone +formation (p. +431). +Other uncommon tubular disorders include hereditary +hypophosphataemic rickets (p. +1052), in which reabsorption of +ltered phosphate is reduced; nephrogenic diabetes insipidus +(p. +361). +The term ‘Fanconi’s syndrome’ is used to describe generalised +proximal tubular dysfunction. +These syndromes are +described on page 365. +Clinical features +Common clinical features are shown in Box 15.21. +One or both kidneys +may be palpable and the surface may feel nodular. +About 30% +of patients with PKD also have hepatic cysts (see Fig. +22.39, +p. +893) but disturbance of liver function is rare. +Berry aneurysms +of cerebral vessels are an associated feature in about 5% of +patients with PKD. +Cysts may also be +identied by other imaging modalities, such as MRI (Fig. +15.15). +Simple renal cysts may occur in normal individuals but are +uncommon below the age of 30. +Next-generation sequencing allows +faster and simpler genetic screening for PKD1 and PKD2. +<130/80 mmHg) influences renal +outcomes. +These are discussed in more detail below. +The surrounding normal kidney tissue is +compressed and progressively damaged. +It also causes a form +of MODY (p. +733). +Autosomal recessive PKD is caused by mutations in the +PKHD1 gene, encoding brocystin. +It is less common than +autosomal dominant PKD (about 1:20 000 live births). +In tuberous sclerosis (p. +Patients may also develop renal cysts and have a +higher risk of renal cell carcinoma. +The von Hippel–Lindau syndrome +(p. +1132) is associated with multiple renal cysts, renal adenomas +and renal adenocarcinoma. +Most of these seem +to involute during growth, leaving a solitary kidney in adults. +Rare causes include vasculitis, thromboembolism and aneurysms +of the renal artery. +351). +15.15 MRI images of the kidneys. +A Normal kidneys. +It has +now been licensed in many countries for patients at high risk of +progression. +Patients with PKD are usually good candidates for dialysis +and transplantation. +Otherwise, they are usually left in situ unless they are a source +of pain or infection. +In younger patients, bromuscular dysplasia is a more likely +cause of renal artery stenosis. +This is an uncommon disorder of +unknown cause. +1041 and 1042). +This gure increases with more severe degrees of stenosis. +Acute pulmonary +oedema is particularly characteristic of bilateral renovascular +disease. +However, +given the risk of imaging and angiography in patients with renal +disease (see Box 15.4, p. +15.16). +The most commonly used technique is angioplasty. +Fig. +15.16 Renal artery stenosis. +A magnetic resonance angiogram +following injection of contrast. +The abdominal aorta is severely irregular +and atheromatous. +409) from manipulations in a severely diseased +aorta. +Small-vessel disease distal to the stenosis may preclude +substantial functional recovery. +Severe hypertension is common but not universal. +Blood levels +of lactate dehydrogenase (LDH) and CRP are commonly raised. +A reticulocytosis is often seen. +The +organisms most commonly implicated are enterohaemorrhagic +Escherichia coli (p. +263) and Shigella dysenteriae (p. +265). +Most cases are sporadic +but large outbreaks related to poor sanitation may occur. +Recovery is good +in most patients but sometimes RRT may be required for up +to 14 days. +No other specic treatments have been shown to +accelerate renal recovery. +Sporadic cases may be associated with the +development of autoantibodies to complement factor H. +This +distinction is important, as early therapy with plasma exchange +is crucial in TTP. +More details are provided on page 979. +They may also be precipitated by +anticoagulants and thrombolytic agents. +15.17). +There is no specic treatment. +393 and 399). +More information is given +on page 410. +Fig. +Involvement may be at a pre-renal, renal (glomerular or interstitial) +or post-renal level. +Diabetes mellitus +Diabetic nephropathy is the most common cause of CKD in +developed countries. +Management with ACE inhibitors and ARBs to slow progression +is described on page 757. +966). +Hypercalcaemia may +also occur due to bony metastases. +Differentiating true HRS from AKI can +be difcult. +1041). +Recent +studies indicate that rituximab (p. +Medium- to large-vessel vasculitis, such as polyarteritis nodosa +(p. +1037). +There is intense intrarenal vasospasm and plasma +renin activity is markedly elevated. +1038). +(AKI = acute kidney injury; RTA = renal tubular acidosis) +by dialysis and have a poor prognosis. +IgA +nephropathy (p. +400) is more common in patients with chronic +liver disease. +Systemic vasculitis +Small-vessel vasculitis (p. +1040) commonly affects the kidneys, +with rapid and profound impairment of glomerular function. +398, and Fig. +15.12C, p. +399) and often with crescentic changes (see Fig. +15.12C). +In others, pulmonary haemorrhage may +occur, which can be life-threatening. +The most important cause is ANCA vasculitis (p. +1041). +Two subtypes are recognised, microscopic polyangiitis (MPA) +and granulomatosis with polyangiitis. +Sickle-cell nephropathy +Improved survival of patients with sickle-cell disease (p. +Papillary necrosis may also occur (p. +403). +A +minority of patients develop ESRD. +Patients with sickle +trait have an increased incidence of unexplained non-visible +haematuria. +Approximately 7% of all +hospitalised patients and 20% of acutely ill patients develop +AKI. +In uncomplicated AKI mortality is low, even when RRT is +required. +Elderly patients are at higher +risk of developing AKI and have a worse outcome (Box 15.25). +Pathophysiology +There are many causes of AKI and it is frequently multifactorial. +15.18). +In pre-renal AKI, a reduction in perfusion reduces GFR. +15.13B, p. +402). +Dead tubular cells may also be shed into the tubular lumen, +leading to tubular obstruction. +Renal AKI +may be caused by nephrotoxic drugs (p. +426), which can cause +ATN or allergic interstitial nephritis. +416). +Post-renal AKI occurs as the result of obstruction to the renal +tract. +This leads to chronic +Fig. +15.18 Causes of acute kidney injury. +15 +renal injury over time (several weeks). +Recovery of renal +function depends on the duration of obstruction and also the +pre-morbid GFR. +15.22, p. +416). +Patients +with AKI need to be assessed quickly to determine the likely +underlying cause. +The most commonly used are the +KDIGO, AKIN and RIFLE criteria. +Myeloma (cast nephropathy) +2. +15.19). +Uncorrected +renal hypoperfusion causing pre-renal azotaemia may progress +to ATN. +Patients withAcute kidney injury • 413 +Afferent arteriole +Efferent arteriole (p. +362). +363), to +prevent life-threatening cardiac arrhythmias. +Metabolic acidosis +develops unless prevented by loss of hydrogen ions through +vomiting. +Severe acidosis can be ameliorated with sodium +bicarbonate if volume status allows. +Restoration of blood volume +will correct acidosis by restoring kidney function. +Cardiopulmonary complications +Pulmonary oedema (Fig. +15.19 Renal haemodynamics and autoregulation of glomerular +ltration rate (GFR). +Drugs +that are commonly implicated include PPIs, NSAIDs and many +antibiotics. +Post-renal AKI is usually accompanied by hydronephrosis. +15.20 Pulmonary oedema in acute kidney injury. +Temporary respiratory support may also be necessary +using non-invasive ventilation. +Modest +hypocalcaemia is common but rarely requires treatment. +This is particularly important in patients with sepsis and burns +who are hypercatabolic. +Enteral or parenteral nutrition may be +required (p. +707). +If infection is discovered, it should be treated promptly according +to standard principles (Ch. +6). +Medications +Patients with drug-induced kidney injury (p. +402) should have the +offending drug withdrawn. +H2-receptor antagonists or +PPIs should be given to prevent gastrointestinal bleeding. +Non-essential drug +treatments should be stopped. +Renal tract obstruction +In post-renal AKI, the obstruction should be relieved as soon +as possible. +15.21 Recovery from acute kidney injury (AKI). +Many patients +make a full recovery of renal function (1). +(ESRD = end-stage renal disease) +challenge in unstable patients. +422). +The +two main options for RRT in AKI are intermittent haemodialysis +and CRRT (see Box 15.38, p. +424). +Peritoneal dialysis is also +an option if haemodialysis is not available (p. +424). +15.21). +Small acute declines in +renal function may therefore have a signicant impact. +• Creatinine: as muscle mass falls with age, less creatinine is +produced each day. +Serum creatinine can be misleading as a guide +to renal function. +• Renal tubular function: declines with age, leading to loss of +urinary concentrating ability. +AKI in old age is described in Box 15.27. +15.22). +Investigations +The recommended investigations in patients with CKD are shown +in Box 15.29. +Suggested referral criteria are listed +in Box 15.30. +420). +A plot of GFR against time (Fig. +388). +When +death is likely without RRT (CKD stage 5), it is called end-stage +renal disease (ESRD). +Epidemiology +The social and economic consequences of CKD are considerable. +Pathophysiology +Common causes of CKD are shown in Box 15.28. +15.22 Physical signs in advanced chronic kidney disease. +391). +Small kidneys suggest chronicity. +15.23). +15.1D, +p. +385), and so ACE inhibitors or ARBs may exacerbate pre-renal +failure (see Fig. +15.19). +ACE +inhibitors and ARBs reduce proteinuria and retard the progression +of CKD. +365). +There is some evidence +that correcting acidosis may reduce the rate of decline in renal +function. +15.24). +24.3, p. +986) and stimulates parathyroid hormone (PTH) +release and hyperplasia of the parathyroid glands. +The reduced 1,25-dihydroxyvitamin D levels impair intestinal +absorption of calcium. +420). +lisinopril, ramipril +• Angiotensin receptor blockers: medicines ending in ‘-sartan’, e.g. +irbesartan, losartan, candesartan +• Non-steroidal anti-inflammatory painkillers: e.g. +ibuprofen (Brufen), +diclofenac (Voltarol) +• Diuretics: e.g. +Restart when you are well again (after 24–48 hours of eating and +drinking normally). +384). +Urea is a key product of protein degradation and accumulates +with progressive CKD. +15.24 Pathogenesis of renal osteodystrophy. +The raised level of +PTH increases osteoclastic bone resorption. +15 +hyperphosphataemia (p. +369), and osteoporosis in patients with +poor nutritional intake. +These bind to the calcium-sensing receptor in the parathyroid +glands and reduce PTH secretion. +Several mechanisms +are implicated, as summarised in Box 15.33. +The target haemoglobin is usually +between 100 and 120 g/L. +Several decisions need to be taken in discussion with the +patient and family. +421). +This is especially relevant in patients +with signicant comorbidity. +15.23). +Preparations for starting RRT should begin at least 12 months +before the predicted start date. +15.25). +By the end of 2014, almost 59 000 patients were on RRT in +the UK, with a median age of 65 years. +The remaining patients +were on haemodialysis (41%) and peritoneal dialysis (6%). +15.26). +15.25 Options for renal replacement therapy. +Replacement fluid is added to the ltered blood before it is returned to the patient. +C In peritoneal dialysis (PD), fluid is introduced into +the abdominal cavity using a catheter. +The transplanted kidney replaces all functions of the failed kidney. +Indications for starting RRT in both AKI and CKD may +be found in Box 15.35. +Many of these patients enjoy a good quality of life for several +years. +Haemodialysis +Haemodialysis is the most common form of RRT in ESRD and +is also used in AKI. +A failing heart cannot cope with fluid overload, and pulmonary +oedema develops easily. +• Conservative therapy: without dialysis but with adequate support. +100 +80 +60 +40 +20 +Survival (%) +0 1 +3 +Time (years) +510 +Fig. +15.25A). +Epoprostenol can +be used as an alternative but carries a risk of hypotension. +15.27A). +Subclavian lines are avoided where possible, +largely due to bleeding risk. +15.27B). +Most patients notice an improvement in symptoms +during the rst 6 weeks of treatment. +Box 15.37 summarises some of +the problems related to haemodialysis. +Haemoltration +This technique is principally used in the treatment of AKI as CRRT +(Box 15.38). +Solutes are removed via ‘solvent drag’. +If removal of fluid is required, then less fluid is +added back than is removed (see Fig. +15.25B). +It is sometimes used in the treatment of +AKI, often as continuous therapy (Box 15.38). +15.27 Haemodialysis access. +A A tunnelled cuffed dialysis +catheter. +B An arteriovenous stula. +C An arteriovenous graft. +inserted into the vein to provide access for each haemodialysis +treatment. +15.27C). +These are tunnelled under +the skin to reduce infection risk. +88). +Positive tests +predict early rejection and worse graft survival. +15.25D). +*Most CRRT machines may perform all of these treatments. +Continuous +arteriovenous treatments (i.e. +continuous arteriovenous haemoltration) have +fallen out of favour. +It requires the +insertion of a permanent Silastic catheter into the peritoneal cavity +(see Fig. +15.25C). +Two types are in common use. +The patient is mobile and able to undertake normal daily activities. +Allograft dysfunction is often asymptomatic and picked up +during routine surveillance blood tests. +The common causes +at different time points post transplant are summarised in Box +15.40. +Immunosuppressive therapy (see Box 4.26, p. +Anti-lymphocyte +preparations (e.g. +anti-thymocyte globulin, ATG) are used for +glucocorticoid-resistant rejection. +89). +Complications of +immunosuppression include infections and malignancy (p. +89). +Approximately 50% of white patients develop skin malignancy +by 15 years after transplantation. +The prognosis after kidney transplantation is good. +Renal disease in pregnancy +drugs and their metabolites. +Others are concentrated in the medulla by the +operation of the countercurrent system. +The same applies to +certain toxins. +Toxic renal damage may occur by a variety of mechanisms +(Box 15.43). +Numerically, +reactions to NSAIDs and ACE inhibitors are the most important. +15.19, +p. +413). +400) and acute interstitial nephritis +(p. +402). +Analgesic nephropathy (p. +403) is now a rare complication +of long-term use. +385 and 413). +31). +Pregnancy has important physiological effects on the renal system. +1276), are unique to pregnancy. +These are discussed in +detail in Chapter 30. +Some +of the issues and challenges surrounding this transition are +summarised in Box 15.42. +6). +The urinary tract can become infected with various bacteria +but the most common is E. +coli derived from the gastrointestinal +tract. +It is a common +disorder, accounting for 1–3% of consultations in general +medical practice. +• Adherence: young adults moving from parental supervision may +become disengaged. +There may also be reduced adherence to +prophylactic and therapeutic treatment. +coli become adherent. +Instrumentation of the bladder may also introduce +organisms. +Conditions that predispose to UTI are shown in +Box 15.44. +Systemic symptoms are usually slight or absent. +However, +infection in the lower urinary tract can spread to cause acute +pyelonephritis. +340) and urethritis associated with reactive arthritis +(p. +1031). +Among +the most frail in institutional care it rises to 40% in women and +30% in men. +It risks adverse effects from the +antibiotic and promotion of the emergence of resistant organisms. +Bacteriuria should not be treated in the absence of urinary symptoms. +• Incontinence: new or increased incontinence is a common +presentation of UTI in older women. +The absence of both nitrites and leucocyte esterase in the urine +makes UTI unlikely. +Typical organisms causing UTI in the community include +E. +In hospital, E. +coli still predominates +but Klebsiella and streptococci are becoming more common. +Certain strains of E. +coli have a particular propensity to invade +the urinary tract. +Management +Antibiotics are recommended in all cases of proven UTI (Box +15.47). +If urine culture has been performed, treatment may +be started while awaiting the result. +They may be used once cultures conrm that the +organism is sensitive. +Investigations +An approach to investigation is shown in Box 15.45. +2See Hartford nomogram (Fig. +6.18, p. +122). +(IM = intramuscular) +In more severe infection, antibiotics should be continued for +7–14 days. +430). +Other simple measures may help to prevent recurrence (Box +15.48). +Trimethoprim or nitrofurantion is recommended for +prophylaxis. +It is increasingly common in those aged over 65. +Up to 30% will develop symptomatic +infection within 1 year, however. +Treatment is required in infants, +pregnant women and those with urinary tract abnormalities. +Treatment is usually avoided in asymptomatic patients, as this may +promote antibiotic resistance. +Acute pyelonephritis +The kidneys are infected in a minority of patients with UTI. +15.13C, p. +402). +428). +Predisposing factors, such as cysts or renal +scarring, facilitate infection. +Rarely, acute pyelonephritis is associated with papillary +necrosis. +Fragments of renal papillary tissue are passed per +urethra and can be identied histologically. +Xanthogranulomatous +pyelonephritis is a chronic infection that can resemble renal cell +cancer. +Infection of cysts in polycystic kidney disease +(p. +405) calls for prolonged antibiotic treatment. +Intravenous +rehydration may be needed in severe cases. +Tuberculosis +Tuberculosis of the kidney and renal tract is secondary to +tuberculosis elsewhere (p. +588) and is the result of blood-borne +infection. +Calcication in the +kidney and stricture formation in the ureter are typical. +Bladder +involvement should be assessed by cystoscopy. +Radiology of +the urinary tract and a chest X-ray to look for pulmonary +tuberculosis are mandatory. +Anti-tuberculous chemotherapy +follows standard regimens (p. +592). +There may be no history +of overt UTI. +The +risk of renal stone formation is increased. +A number of women +rst present with hypertension and/or proteinuria in pregnancy. +Radionuclide DMSA scans are +more sensitive (see Fig. +15.6, p. +390), and serial imaging by MRI +or CT may be useful in assessing progression. +Abnormalities +may be unilateral or bilateral and of any grade of severity. +Renal scars may be juxtaposed to dilated calyces. +2 Associated with +urine infection. +15.28 Vesico-ureteric reflux (grade IV) shown by micturating +cystogram. +The bladder has been lled with contrast medium through a +urinary catheter. +Courtesy of Dr +A.P. +Bayliss and Dr P. +Thorpe, Aberdeen Royal Inrmary. +15.28). +429). +Urolithiasis +proteins and glycoproteins. +The most common types are +summarised in Box 15.49. +A number of risk factors have been +identied for renal stone formation (Box 15.50). +In +developing countries, bladder stones are common, particularly +in children. +Staghorn calculi ll the whole renal pelvis and branch into the +calyces (Fig. +15.29); they are usually associated with infection +and composed largely of struvite. +Clinical features +The clinical presentation is highly variable. +2 Only if serum calcium or +urinary calcium excretion is high. +Fig. +Courtesy of Dr I. +Mendichovszky, University of Cambridge. +Chemical analysis of +stones is often helpful in dening the underlying cause. +Management +The immediate treatment of renal colic is with analgesia and +antiemetics. +Procedures +vary, depending on the site (Fig. +15.30). +Measures to prevent further stone formation are guided by the +investigations in Box 15.51. +Some general principles apply to +almost every patient with calcium-containing stones (Box 15.53). +More specic measures apply to some types. +The pain steadily increases in intensity to reach a peak +in a few minutes. +There is pallor, sweating and often vomiting. +Frequency, +dysuria and haematuria may occur. +The intense pain usually +subsides within 2 hours but may continue unabated for hours +or days. +It is usually constant during attacks, although slight +fluctuations in severity may be seen. +15.30. +Stones formed in +cystinuria can be reduced by penicillamine therapy. +15.31); they affect more than 10% of infants. +Single kidneys +About 1 in 500 infants is born with only one kidney. +This leads to the formation of +microscopic and large medullary cysts. +Patients often present as +adults with renal stones but the prognosis is generally good. +15.30 Options for removal of urinary stones. +A A patient +undergoing extracorporeal shock wave lithotripsy (ESWL). +The abnormality is likely +to be congenital and is often bilateral. +It can be seen in very +young children but gross hydronephrosis may present at any +age. +Rarely, it is asymptomatic. +It is recognised as part of the spectrum of disorders associated +with elevated IgG4 levels (p. +890). +Rarely, it can be associated +with inflammatory bowel disease. +Patients usually present with +ill-dened symptoms of ureteric obstruction. +Imaging with CT or IVU shows +ureteric obstruction with medial deviation of the ureters. +Ectopic ureter +Megaureter +Ureterocele +Vesico-ureteric +reflux +Urethral valves +Fig. +15.31 Congenital abnormalities of the urinary tract. +It +can become very large and cause lower urinary tract obstruction. +Incision of the pin-hole opening relieves the obstruction. +430), whereas the upper pole moiety +is often associated with a ureterocele. +Megaureter +A megaureter is a ureter dilated to more than 5 mm in diameter. +It may be obstructed or non-obstructed and refluxing or non- +refluxing. +Some 50% of cases are asymptomatic but patients +may present with pain, haematuria or infection. +Patients with symptoms or +reduced renal function are treated. +Ideally, treatment is expectant +with antibiotic prophylaxis. +stones). +Renal cell cancer and bladder +carcinoma are described here, while prostate cancer (p. +438) +and testicular tumours (p. +439) are covered later in this chapter. +It +is twice as common in males. +The peak incidence is between 65 +and 75 years of age and it is uncommon before 40. +The tumour +arises from renal tubular cells. +15.32B). +15.32 Renal cell cancer. +Tumour is +shown extending into the renal vein and inferior vena cava (arrow). +B Pathology specimen showing typical necrosis of a renal cell cancer. +(A, B) Courtesy +of Dr A.P. +Bayliss and Dr P. +Thorpe, Aberdeen Royal Inrmary. +chromophobe and collecting duct tumours comprising the +remainder. +In RCC, there is potentially spread along the renal +vein and the inferior vena cava. +Direct invasion of perinephric +tissues is common. +The patient may present with pyrexia of unknown origin (PUO) +or, rarely, with neuropathy. +The effects disappear when the tumour is +removed but may reappear when metastases develop. +15.32A). +Nephrectomy is commonly performed +laparoscopically, with equivalent outcomes to open surgery. +RCC is resistant to most chemotherapeutic agents. +The bladder is by far the most frequently affected site. +Clinical features +More than 80% of patients present with painless, visible +haematuria. +It should be assumed that such bleeding is from a +tumour until proven otherwise (p. +391). +Patients +with carcinoma in situ have a high risk of progression to invasive +cancer. +The prognosis of bladder tumours depends on tumour stage +and grade. +In +tuberous sclerosis (p. +The von Hippel–Lindau syndrome (p. +1132) is associated with +multiple renal cysts, renal adenomas and clear cell renal cell +cancers. +Urinary incontinence +Urinary incontinence is dened as any involuntary leakage of +urine. +Usually there is an element of both +these factors. +Stress incontinence is very common in women +and seen most frequently following childbirth. +It is rare in men +and usually follows surgery to the prostate. +The presentation +is with incontinence during coughing, sneezing or exertion. +In +women, perineal inspection may reveal leakage of urine when +the patient coughs. +1093). +Continual incontinence may also be seen +in infants with congenital ectopic ureters. +Occasionally, stress +incontinence is so severe that the patient leaks continuously. +Incontinence due to prostatic enlargement can be +regarded as a type of overflow incontinence. +Post-micturition dribble +This is very common in men, even in the relatively young. +It may occur in women +with a urethral diverticulum and may mimic stress incontinence. +Structured questionnaires may help objectively quantify +symptoms. +The patient should be assessed for evidence of +cognitive impairment and impaired mobility. +Perineal sensation and anal sphincter tone +should be assessed. +Investigations +Urinalysis and culture should be performed in all patients. +Imaging +with MRI is indicated when a urethral diverticulum is suspected. +Management +Weight reduction in obese patients will aid resolution of +incontinence. +Women with stress incontinence respond well to +physiotherapy. +The +treatment of incontinence secondary to stula formation is surgical. +Prostate disease +Prostatitis +This results from inflammation of the prostate gland. +This is also known as chronic pelvic +pain syndrome. +The prostate is enlarged and tender. +A 4–6-week course +of antibiotics is required (see Box 15.47, p. +429). +Benign prostatic enlargement +Benign prostatic enlargement (BPE) is extremely common. +Benign prostatic hyperplasia +(BPH) is the histological abnormality that underlies BPE. +2 +Urgency How often have you found it difcult to +postpone urination? +Objective assessment of obstruction is possible by urodynamics +but this is seldom required. +Those with mild to moderate symptoms can be +treated by medication (Box 15.56). +Open surgery is rarely needed, unless the +gland is very large. +It +is uncommon in India but the incidence is increasing. +Prostate +cancer rarely occurs before the age of 50 and has a mean age +at presentation of 70 years. +1 +Weak +How often have you had a weak +2 +urinary stream? +A score of 0–7 indicates mild symptoms, 8–19 moderate symptoms +and 20–35 severe symptoms. +In the example shown, the patient +had moderate symptoms. +This is often precipitated by excessive alcohol intake, +constipation or prostatic infection. +Patients may also present with chronic urinary retention. +Here, +the bladder slowly distends due to inadequate emptying over +a long period of time. +A family history of +prostate cancer greatly increases a man’s chances of developing +the disease. +These options should be considered only in patients with more +than 10 years’ life expectancy. +A small proportion of patients fail to respond to endocrine +treatment. +A larger number respond for a year or two but then +the disease progresses. +1331). +Life +expectancy is not reduced in patients with small foci of tumour. +Testicular tumours are uncommon, with a prevalence of 5 cases +per 100 000 population. +They occur mainly in young men aged +between 20 and 40 years. +Seminoma and teratoma account for 85% of all tumours of the +testis. +Leydig cell tumours are less common. +Seminomas arise from seminiferous tubules and represent a +relatively low-grade malignancy. +Metastases can occur through +lymphatic spread, however, and typically involve the lungs. +Teratomas arise from primitive germinal cells and tend to +occur at a younger age than seminomas. +Occasionally, +teratoma and seminoma occur together. +All suspicious scrotal lumps should be imaged by ultrasound. +Serum levels of AFP and β-hCG are elevated in extensive +disease. +Oestradiol may be elevated, suppressing LH, FSH +and testosterone. +Accurate staging is based on CT of the lungs, +liver and retroperitoneal area. +Management and prognosis +The primary treatment is surgical orchidectomy. +Subsequent +treatment depends on the histological type and stage. +Radiotherapy +is the treatment of choice for early-stage seminoma. +Follow-up +is by CT and assessment of AFP and β-hCG. +Retroperitoneal +lymph node dissection is now performed only for residual or +recurrent nodal masses. +The 5-year survival rate for patients with seminoma is 90–95%. +655) and if +erections occur at any other time. +Psychotherapy involving the patient and sexual partner +may be helpful for psychological problems. +If hypogonadism is detected, it should be +managed as described on page 655. +Further information +Causes of erectile failure are shown in Box 15.58. +Vascular, +neuropathic and psychological causes are most common. +edrep.org/resources Educational resources. +renalfellow.blogspot.co.uk/ Educational blog written by renal trainees +for trainees. +Cardiology: an illustrated colour text. +• Aortic stenosis impedes ventricular +emptying. +If severe, it causes a +slow-rising, weak and delayed pulse +(panel A). +• Sinus rhythm produces a pulse that is +regular in time and force. +Arrhythmias +may cause irregularity. +Atrial brillation +produces a pulse that is irregular in time +and volume (panel B). +In health it is normally just visible above the +clavicle. +• The x descent reflects atrial relaxation +and apical displacement of the tricuspid +valve ring. +The y descent reflects atrial +emptying early in diastole. +These signs +are subtle. +• Tricuspid regurgitation produces giant v +waves that coincide with ventricular +systole. +• The height of the venous pulse varies +with respiration (falls on inspiration) and +position. +• Abdominal compression causes the +venous pulse to rise. +• The venous pulse is not easily palpable +and can be occluded with light pressure. +Place heel of +hand over left sternal edge (2) for a +parasternal heave or ‘lift’. +Assess for +thrills in all areas, including the aortic and +pulmonary areas (3). +Normal position is +the 5th or 6th intercostal space, at the +mid-clavicular line. +Systolic murmurs are synchronous with +the pulse. +Cardiovascular disease will soon +become the leading cause of death on all continents. +Valvular heart disease is common but the aetiology varies +in different parts of the world. +Prompt recognition of the development of heart disease is +limited by two key factors. +Functional anatomy and physiology +aorta. +The LA receives +blood from four pulmonary veins, two from each of the left and +right lungs. +The right +ventricle (RV) is about 2–3 mm thick and triangular in shape. +The LV is more conical in shape and in cross-section is +nearly circular. +It extends from the LA to the apex of the heart. +16.2). +16.3). +Anatomy +The heart acts as two serial pumps that share several electrical +and mechanical components. +16.1). +16.1 Direction of blood flow through the heart. +The blue arrows show deoxygenated blood moving through the right heart to the lungs. +The red arrows show oxygenated blood moving from the lungs to the systemic circulation. +16.4 The cardiac conduction system. +Repolarisation spreads from epicardium to +endocardium (green arrows). +Inferior +vena cava +Mitral valve +Apex of +the heart +Fig. +16.2 Surface anatomy of the heart. +The positions of the major +cardiac chambers and heart valves are shown. +Conduction system +The SA node is situated at the junction of the superior vena +cava and RA (Fig. +16.4). +Nerve supply of the heart +The heart is innervated by both sympathetic and parasympathetic +bres. +Cholinergic nerves +supply the AV and SA nodes via muscarinic (M2) receptors. +16.3 The coronary arteries: anterior view. +The CX gives marginal branches that supply +the lateral, posterior and inferior segments of the LV. +The coronary anatomy varies greatly from person to person and +there are many normal variants. +The RCA supplies the sinoatrial (SA) node in about 60% of +individuals and the AV node in about 90%. +In disease states, the nerve supply to the heart +may be affected. +758) +so that there is little variation in heart rate. +16.5A). +16.5B and C). +16.5E). +16.5D). +The extent to which the sarcomere can +shorten determines stroke volume of the ventricle. +It is maximally +shortened in response to powerful inotropic drugs or marked +exercise. +16.5 Schematic of myocytes and the contraction process within a muscle bre. +A Myocytes are joined together through intercalated discs. +D Actin +laments are composed of troponin, tropomyosin and actin subunits. +E The three stages of contraction, resulting in shortening of the sarcomere. +(1) The +actin-binding site is blocked by tropomyosin. +(2) ATP-dependent release of calcium ions, which bind to troponin, displacing tropomyosin. +The binding site +is exposed. +(3) Tilting of the angle of attachment of the myosin head, resulting in bre shortening. +It is released by atrial myocytes in response to stretch. +Like ANP, it has diuretic properties. +It breaks down ANP, BNP and other +proteins and, in so doing, acts as a vasoconstrictor. +It forms a +therapeutic target in patients with heart failure (p. +466). +stimulation also causes modest dilatation of normal coronary +arteries. +Endothelium +The endothelium plays a vital role in the control of vascular +homeostasis. +This causes a reduction in cardiac output from the LV +and a slight fall in BP. +Blood then passes into the LV, which pumps it into the +aorta (see Fig. +16.1). +In +diastole, the pulmonary and aortic valves close, and the two +AV valves open. +Resistance to blood flow rises with viscosity +and is mainly influenced by the haematocrit. +Coronary blood vessels receive sympathetic and parasym- +pathetic innervation. +544). +This produces a marked fall in BP (> 10 mmHg +fall during inspiration). +the QRS complex is larger than the P wave. +Selective +injury of one of the left fascicles (hemiblock, p. +479) affects the +electrical axis. +Repolarisation is slower and spreads from the +epicardium to the endocardium. +The QT interval represents the total duration of +ventricular depolarisation and repolarisation. +One electrode is attached to each +limb and six electrodes are attached to the chest. +The 12 ‘leads’ of the ECG refer to recordings made +from pairs or sets of these electrodes. +These signals are amplied and either printed +or displayed on a monitor (Fig. +16.6). +During sinus rhythm, the +SA node triggers atrial depolarisation, producing a P wave. +Prolongation denotes +impaired atrioventricular nodal conduction. +A +short PR interval occurs in Wolff–Parkinson– +White syndrome (p. +16.6 The electrocardiogram. +The components correspond to +depolarisation and repolarisation, as depicted in Figure 16.4. +Lead II records the signal between the right arm (negative) and +left leg (positive). +Lead III records the signal between the left arm +(negative) and left leg (positive). +These three leads thus record +electrical activity along three different axes in the frontal plane. +Leads aVR, aVL and aVF are the augmented voltage limb leads. +These record electrical activity between a limb electrode and a +modied central terminal. +16.7). +Similarly augmented signals are obtained from the right +arm (aVR) and left leg (aVF). +These leads also record electrical +activity in the frontal plane, with each lead 120° apart. +16.8 The sequence of activation of the ventricles. +B Normal electrocardiographic complexes +from leads V1 and V6. +The +normal cardiac axis lies between −30° and +90°. +Examples of +left and right axis deviation are shown in Figures 16.7B and C. +16.8). +The LV has the greater muscle mass and contributes the major +component of the QRS complex. +The shape of the QRS complex varies across the chest leads. +The Bruce Protocol is the most commonly used. +During an exercise ECG, BP is recorded and symptoms are +assessed. +Common indications for exercise testing are shown +in Box 16.3. +16.57, p. +490). +16.7 The appearance of the ECG from different leads in the +frontal plane. +A Normal. +B Left axis deviation, with negative deflection +in lead II and positive in lead I. +461). +Cardiac troponins +Troponin I and troponin T are structural cardiac muscle proteins +(see Fig. +493). +Most information is given by a postero-anterior (PA) projection +taken in full inspiration. +628). +Left ventricular hypertrophy produces rounding of the left +heart border (Fig. +16.10). +16.27, p. +Pleural effusions may also occur +in heart failure. +Ambulatory ECG +Ambulatory ECG recordings can be obtained using a portable +digital recorder. +16.32, p. +469). +With some +devices, the recording can be transmitted to hospital electronically. +Circulating levels are elevated in conditions associated with +LV systolic dysfunction. +Stenosed +aortic +valve +LA +Turbulent +flow +Dilated +ascending aorta +Normal-sized +aortic arch +16 +B +Fig. +16.11 Doppler echocardiography in aortic stenosis. +Large left ventricle +Fig. +The +greater the frequency shift, the faster the blood is moving. +This can be used for rapid evaluation of various aspects +of cardiac structure and function. +16.13 Computed tomography coronary angiography, +demonstrating normal coronary arteries (arrows). +A Three- +dimensional image. +B Two-dimensional image. +Contrast scans are very useful for +imaging the aorta in suspected aortic dissection (see Fig. +16.74, +p. +507), and the pulmonary arteries and branches in suspected +pulmonary embolism (p. +619). +However, modern multidetector scanning +allows non-invasive coronary angiography (Fig. +Modern volume scanners are also able +to assess myocardial perfusion, often at the same sitting. +It provides better differentiation of soft tissue structures than CT +Fig. +a colour overlay on a two-dimensional real-time echo picture +(colour-flow Doppler, Fig. +16.12). +In severe aortic stenosis, the peak aortic velocity +may be increased to 5 m/sec (see Fig. +16.11). +MRI is very useful for imaging the aorta, including +suspected dissection (see Fig. +16.73, p. +Myocardial perfusion and viability can also be readily assessed +by MRI. +16.14). +16.15). +Additional anatomical +A B +16 +Fig. +16.14 Cardiac magnetic resonance imaging. +A Recent inferior myocardial infarction with black area of microvascular obstruction (arrow). +A Coronary artery angiogram. +Cardiac output +can also be measured using thermodilution techniques. +206). +It also allows the assessment +of the size and ‘shape’ of the cardiac chambers. +16.58, p. +490). +A close relationship +between symptoms and exercise is the hallmark of heart disease. +Chest pain on effort is the hallmark of angina +pectoris (Fig. +16.16). +16.16 Typical ischaemic cardiac pain. +Characteristic hand +gestures used to describe cardiac pain. +373). +Signs of anaemia (p. +923) or thyrotoxicosis (p. +635) may +be identied, both of which can exacerbate angina. +Cardiovascular +examination may reveal evidence of left ventricular dysfunction +(p. +442) or cardiac murmurs in patients with aortic valve disease +and hypertrophic cardiomyopathy. +449). +These +are discussed in more detail on pages 179 and 557. +Syncope +The term ‘syncope’ refers to loss of consciousness due to reduced +cerebral perfusion. +The differential diagnosis, investigation and +management of syncope are discussed on page 181. +A provisional diagnosis can usually +be made on the basis of a thorough history (Box 16.6 and +Fig. +16.17). +493). +These are +known collectively as the acute coronary syndromes. +Other features, such as arrhythmia, hypotension and heart failure, +may occur. +16 +16.6 How to evaluate palpitation +• Is the palpitation continuous or intermittent? +• Is the heart beat regular or irregular? +• What is the approximate heart rate? +• Do symptoms occur in discrete attacks? +Is the onset abrupt? +How do attacks terminate? +• Are there any associated symptoms? +Chest pain, lightheadedness, polyuria (a feature of +supraventricular tachycardia, p. +473) +• Are there any precipitating factors, such as exercise or alcohol excess? +No Yes +Consider +Ectopic beats +Atrial fibrillation +Are there +discrete attacks +of tachycardia? +(> 120/min) +Fig. +16.18 Ventricular brillation. +521) +• Hypertrophic cardiomyopathy (p. +539) +• Dilated cardiomyopathy (p. +539) +• Arrhythmogenic right ventricular dysplasia (p. +540) +• Congenital heart disease (p. +531) +No structural heart disease (5%) +• Long QT syndrome (p. +476) +• Brugada syndrome (p. +477) +• Wolff–Parkinson–White syndrome (p. +474) +• Adverse drug reactions (torsades de pointes, p. +anaemia, anxiety, +valve disease +Fig. +16.17 A simple approach to the diagnosis of palpitation. +Palpitation associated with pre-syncope or syncope +(p. +Other arrhythmias may +require treatment, as discussed in more detail on page 479. +Death is virtually inevitable, unless effective +treatment is given promptly. +Many of these deaths +are potentially preventable. +Pathogenesis +Coronary artery disease is the most common cause of cardiac +arrest. +Cardiac arrest may be caused by ventricular brillation (Fig. +16.18), pulseless ventricular tachycardia (p. +457), asystole or +pulseless electrical activity. +The +causes are listed in Box 16.7. +496 and 506). +16.19). +Ventricular fibrillation of low amplitude, or ‘fine VF’, may +mimic asystole. +16.20). +16.21). +498). +483) and anti-arrhythmic +drug therapy. +Is the sound cardiac? +16.19 Algorithm for adult basic life support. +For further +information, see www.resus.org.uk. +Advanced life support +Advanced life support (ALS) (Fig. +Once that this has been done, treatment should be +instituted based on the clinical ndings. +16.20 Algorithm for adult advanced life support. +For further information, see www.resus.org.uk. +16.21 The Chain of Survival in cardiac arrest. +• Time the murmur using heart sounds, carotid pulse and the apex +beat. +Is it systolic or diastolic? +How loud is it? +• Listen at the neck, axilla or back +What does it sound like? +16 +• No radiation +• No other cardiac abnormalities +do not. +Is the sound pathological? +What is the origin of the sound? +16.23 The timing and pattern of cardiac murmurs. +Sounds +3rd +4th +2nd +1st +sound +sound +sound +sound +Fig. +crescendo–decrescendo pattern, reflecting the changing velocity of +blood flow (Box 16.11). +Management +Management of patients with additional cardiac sounds depends +on the underlying cause. +514 and 531). +In severe heart failure, symptoms may be present at +rest. +Three types +of heart failure are recognised. +Biventricular heart failure +In biventricular failure, both sides of the heart are affected. +Pathogenesis +Heart failure occurs when cardiac output fails to meet the +demands of the circulation. +16.24). +The causes of +heart failure are discussed below. +Afterload +Contractility +16 +A +B +C +D +Cardiac output or +ventricular performance +Preload +Fig. +16.24 Starling’s Law. +Normal (A), mild (B), moderate (C) and severe +(D) heart failure. +Ventricular performance is related to the degree of +myocardial stretching. +In +heart failure, the curve moves to the right and becomes flatter. +Ventricular dysfunction +Ventricular dysfunction is the most common cause of heart +failure. +This is most commonly found in patients with left +ventricular hypertrophy. +16.25). +Activation of the RAAS causes vasoconstriction and sodium +and water retention. +16.25). +Sympathetic +stimulation also contributes to vasoconstriction and predisposes +to arrhythmias. +16.64, p. +496). +This leads +to further deterioration in ventricular function and worsening +heart failure. +16.25 Neurohumoral activation and compensatory mechanisms +in heart failure. +714), severe +anaemia or thyrotoxicosis. +When there is gradual impairment of +cardiac function, several compensatory changes take place. +The patient appears agitated, pale and clammy. +A new systolic murmur may signify +acute mitral regurgitation or ventricular septal rupture. +There may be an expiratory wheeze. +16.26). +Poor renal perfusion leads to oliguria and +uraemia. +Ascites or +pleural effusion may occur (Fig. +16.26). +Heart failure is not the +only cause of oedema (Box 16.14). +16.26 Clinical features of left and right heart failure. +• Hyponatraemia is a feature of severe heart failure and is a +poor prognostic sign. +• Thromboembolism. +Investigations +A chest X-ray should be performed in all cases. +16.27). +Subsequently, interstitial oedema causes thickened +interlobular septa and dilated lymphatics. +16.27 Radiological features of heart failure. +A Chest X-ray of a +patient with pulmonary oedema. +B Enlargement of lung base showing +septal or ‘Kerley B’ lines (arrow). +B’ lines). +pulse oximetry. +The key elements of management are summarised in Box 16.15. +16.25). +This can be achieved by a combination of drug +treatment or non-drug treatments, as discussed below. +354), which +in turn reduces preload and improves pulmonary and systemic +venous congestion. +16.28 The effect of treatment on ventricular performance +curves in heart failure. +This is especially likely in patients with a marked +diastolic component to their heart failure. +16.29) but +are generally better tolerated. +• Diastolic dysfunction: often prominent, particularly in those with a +history of hypertension. +16.28). +Their use is limited +by pharmacological tolerance and hypotension. +It is ineffective in patients with atrial brillation. +Digoxin Digoxin (p. +482) can be used to provide rate control in +patients with heart failure and atrial brillation. +Amiodarone This is a potent anti-arrhythmic drug (p. +483). +Here, both the LV and RV are paced +simultaneously (Fig. +16.30) to generate a more coordinated +left ventricular contraction and improve cardiac output. +This is +associated with improved symptoms and survival. +Coronary artery disease and dilated cardiomyopathy are the +most common indications. +• Accelerated atherosclerosis. +Angina is +rare because the heart has been denervated. +16468 • CARDIOLOGY +• Infection. +In some patients, VADs may be used as a long-term +therapy if no other options exist. +atria, atrioventricular junction or ventricles, often in +response to catecholamines. +Single depolarisations lead to +atrial, junctional or ventricular premature (ectopic) beats. +Repeated depolarisation leads to atrial, junctional or +ventricular tachycardia. +• Re-entry. +The tachycardia is initiated by an ectopic beat +and sustained by a re-entry circuit (Fig. +16.31). +Most +tachyarrhythmias are caused by re-entry. +• Triggered activity. +This can cause ventricular arrhythmias in +patients with coronary artery disease. +It is a form of +secondary depolarisation arising from an incompletely +repolarised cell membrane. +Arrhythmias may be +supraventricular (sinus, atrial or junctional) or ventricular in +origin. +Extreme bradycardias or tachycardias can precipitate +sudden death or cardiac arrest. +There are many types of cardiac arrhythmia, as discussed +later in this section. +The cardiac cycle +is normally initiated by an electrical discharge from the SA node. +16.4, p. +445). +There are three main mechanisms of tachycardia: +• Increased automaticity. +16.31 The mechanism of re-entry. +(3) Pathway B may recover +while the premature impulse is travelling selectively down pathway A. +Sinus arrhythmia is a normal phenomenon and can be +quite pronounced in children. +758), autonomic involvement in +patients with diseases of peripheral nerves (p. +1138) or increased +sympathetic drive. +Sinus arrhythmia does not require treatment. +Sinus bradycardia +This may occur in healthy people at rest and is a common nding +in athletes. +Some pathological causes are listed in Box 16.19. +If +sinus bradycardia is asymptomatic, then no treatment is required. +Healthy +young adults can produce a rapid sinus rate, up to 200/min, +during intense exercise. +Sick sinus syndrome +Sick sinus syndrome can occur at any age but is most common +in older people. +16.32). +Atrial pacing may prevent episodes of atrial +brillation. +Pacing improves symptoms but not prognosis, and +is not indicated in patients who are asymptomatic. +The ECG (Fig. +16.32 Sinoatrial disease (sick sinus syndrome). +16.33 Atrial ectopic beats. +The rst, second and fth complexes +are normal sinus beats. +III +Fig. +16.34 Atrial flutter. +Simultaneous recording showing atrial flutter +with 4 : 1 atrioventricular block. +Flutter waves are visible only in leads II +and III. +Treatment is rarely necessary but β-blockers can be used if +symptoms are intrusive. +The +ventricular response in rapid atrial tachycardias may be controlled +by AV node-blocking drugs. +Catheter ablation (p. +The ECG shows saw-tooth flutter +waves (Fig. +16.34). +Atrial flutter should always be suspected when +there is a narrow-complex tachycardia of 150/min. +16.35). +479). +471). +Carotid sinus pressure +Fig. +16.35 Carotid sinus pressure in atrial flutter: continuous trace. +It is associated with signicant morbidity and +a twofold increase in mortality. +16.36). +During episodes of AF, the atria beat rapidly but in an +uncoordinated and ineffective manner. +The ventricles are activated +irregularly at a rate determined by conduction through the AV +node. +This produces the characteristic ‘irregularly irregular’ pulse. +The ECG (Fig. +This is +an unusual but potentially treatable cause of AF. +Management of paroxysmal and persistent +AF is discussed below. +In addition, lines of conduction block can be created +Fig. +16.36 Mechanisms initiating atrial brillation. +(1) Ectopic +beats, often arising from the pulmonary veins, trigger atrial brillation. +A +B +16 +Fig. +16.37 Two examples of atrial brillation. +The QRS complexes are +irregular and there are no P waves. +Early treatment of AF can sometimes prevent the arrhythmia +from becoming persistent. +Clinical features +The typical presentation is with palpitation, breathlessness +and fatigue. +Persistent atrial brillation +There are two options for treating persistent AF. +Electrical +DC cardioversion (p. +482) or pharmacological cardioversion may +be used. +Immediate cardioversion is appropriate if AF has been present +for less than 48 hours. +Cardioversion is an alternative treatment and +is often effective when drugs fail. +Digoxin, β-blockers and rate-limiting calcium antagonists, such +as verapamil or diltiazem (p. +479), reduce the ventricular rate +by slowing AV conduction. +This is known as the ‘pace and ablate’ strategy. +This predisposes +patients to stroke and other forms of systemic embolism. +• Symptoms: sometimes asymptomatic but often accompanied by +diastolic heart failure. +• Cardioversion: followed by high rates (~70% at 1 year) of +recurrent atrial brillation. +• Directly acting oral anticoagulants: alternatives to warfarin. +Increasingly, direct-acting +oral anticoagulant drugs (see below) are used as an alternative. +In other patients, clinical scoring systems can be used to +assess the risk of stroke and bleeding. +Several agents can be used to reduce stroke risk in AF. +Eur Heart J 2012; +33:2719–2747. +Fig. +16.38 Supraventricular tachycardia. +The rate is 180/min and the +QRS complexes are normal. +similar appearance on ECG. +16.39A below). +This produces a regular tachycardia with a rate of 120–240/ +min. +Polyuria, mainly due to the release of ANP, +is sometimes a feature. +The ECG (Fig. +Management +Treatment is not always necessary. +However, an acute episode +may be terminated by carotid sinus pressure or by the Valsalva +manœuvre. +Intravenous β-blocker or +flecainide can also be used. +482). +In patients with recurrent SVT, catheter ablation (p. +484) is +the most effective therapy and will permanently prevent SVT +in more than 90% of cases. +This +is known as a concealed accessory pathway. +Agents that reverse the effects of DOACs +have been developed. +A AV node re-entrant +tachycardia. +B Sinus rhythm. +C Orthodromic tachycardia. +This +is the most common form of tachycardia in WPW. +D Atrial brillation. +of the QRS complex, called a delta wave (Fig. +16.39B). +This +is known as a manifest accessory pathway. +The +ECG during this tachycardia is almost indistinguishable from +that of AVNRT (Fig. +16.39A). +Management +Carotid sinus pressure or intravenous adenosine can terminate +the tachycardia. +16.39D). +This is +known as pre-excited atrial brillation and may cause collapse, +syncope and even death. +It should be treated as an emergency, +usually with DC cardioversion. +Catheter ablation is rst-line treatment in symptomatic patients +and is nearly always curative. +Alternatively, prophylactic anti- +arrhythmic drugs, such as flecainide or propafenone (p. +16.40). +16.40). +A run of alternating sinus and ventricular ectopic beats is +known as ventricular ‘bigeminy’. +The signicance depends on +the presence or absence of underlying heart disease. +16.40 Ventricular ectopic beats. +Their conguration varies, so these are multifocal ectopics. +B A simultaneous arterial pressure trace is shown. +catheter ablation can be used. +It is common for VPBs to occur during +the course of an acute MI. +In this situation, anti-arrhythmic +drugs do not improve and may even worsen prognosis. +The +exception is β-blockers, which should be prescribed for other +reasons (p. +500). +Similarly, heart failure of any cause is associated +with VPBs. +While they indicate an adverse prognosis, this is not +improved by anti-arrhythmic drugs. +Effective treatment of the +heart failure may suppress the ectopic beats. +VPBs are also a +feature of digoxin toxicity. +456). +The ECG shows +tachycardia and broad, abnormal QRS complexes with a rate of +more than 120/min (Fig. +16.41). +A 12-lead ECG (Fig. +16.42) or electrophysiology study +(p. +454) may help establish the diagnosis. +When there is doubt, +it is safer to manage the problem as VT. +These episodes +often reflect reperfusion of the infarct territory and may be a +good sign. +They are usually self-limiting and asymptomatic, and +do not require treatment. +Other forms of sustained VT require +treatment, often as an emergency. +16 +Fig. +16.41 Ventricular tachycardia: fusion beat (arrow). +In ventricular +tachycardia, there is independent atrial and ventricular activity. +Synchronised DC +cardioversion is the treatment of choice if systolic BP is less +than 90 mmHg. +481). +Hypokalaemia, hypomagnesaemia, acidosis and +hypoxia should be corrected if present. +Beta-blockers are effective at preventing VT by reducing +ventricular automaticity. +Amiodarone can be added if additional476 • CARDIOLOGY +control is needed. +483). +16.43). +Some of the common causes are listed in Box 16.26. +Long QT syndrome subtypes have different triggers, which are +important when counselling patients. +Arrhythmias are more common during sleep in type 3. +16.42 Ventricular tachycardia: 12-lead ECG. +There are typically +very broad QRS complexes and marked left axis deviation. +*Many other drugs that are not shown can be associated with prolongation of the +QT interval. +See www.crediblemeds.org for a complete list. +Fig. +16.43 Torsades de pointes. +Beta-blockers are effective at preventing syncope in patients +with congenital long QT syndrome. +Left stellate ganglion block may be of +value in patients with resistant arrhythmias. +The only known effective +treatment is an implantable debrillator. +Atrioventricular block +This usually occurs as the result of disease affecting the AV +node. +Reflecting this fact, atrial tachyarrhythmias are often +associated with AV block (see Fig. +16.37). +Several types of AV block are +recognised. +16.44). +It rarely causes symptoms +and does not usually require treatment. +Two subtypes are recognised. +Fig. +16.44 First-degree atrioventricular block. +The PR interval is +In Mobitz type I second-degree AV block (Fig. +16.45), there is +prolonged and measures 0.26 sec. +progressive lengthening of successive PR intervals, culminating +in a dropped beat. +The cycle then repeats itself. +In Mobitz type II second-degree AV block (Fig. +This is usually caused by disease +of the His–Purkinje system and carries a risk of asystole. +In 2 : 1 AV block (Fig. +This is known as AV +dissociation, as shown in Fig. +16.48. +Distal escape rhythms tend +to be slower and less reliable. +There is usually a compensatory increase in stroke volume, +producing a large-volume pulse. +These episodes are characterised by sudden +16 +P PP PP P P P P P P P P +Fig. +16.45 Second-degree atrioventricular block (Mobitz type I – the Wenckebach phenomenon). +The PR interval progressively increases until a P +wave is not conducted. +The cycle then repeats itself. +PP P P P P P P P P P +Fig. +16.46 Second-degree atrioventricular block (Mobitz type II). +The PR interval of conducted beats is normal but some P waves are not conducted. +Pacing +improves prognosis. +16.47 Second-degree atrioventricular block with xed 2 : 1 +block. +Alternate P waves are not conducted. +This may be due to Mobitz +type I or II block. +PP PP P P P +Fig. +16.48 Complete (third-degree) atrioventricular block. +There is +complete dissociation of atrial and ventricular complexes. +The atrial rate is +80/min and the ventricular rate is 38/min. +A brief anoxic seizure (due to cerebral ischaemia) +may occur if there is prolonged asystole. +In distinction to +epilepsy, recovery is rapid. +Sinoatrial disease and neurocardiogenic +syncope (p. +181) may cause similar symptoms. +Management +This depends on the clinical circumstances. +In most cases, the AV +block will resolve within 7–10 days. +Asystole +may ensue and a temporary pacemaker should be inserted +promptly. +Temporary pacing can provide effective rhythm support in the +short term. +I +aVR V1 +V4 +II +aVL +V2 V5 +III V3 V6 +aVF +Fig. +16.49 Right bundle branch block. +16.51 Classication of anti-arrhythmic drugs by site of action. +Fig. +16.50 Left bundle branch block. +16.7, p. +449). +The combination of RBBB +and left anterior or posterior hemiblock is known as bifascicular +block. +This can be treated in +selected patients by cardiac resynchronisation therapy (p. +484). +These strategies are +relevant across a range of indications and are discussed in +more detail here. +16.51). +They block +sodium channels, of which there are several types in cardiac +tissue. +They are used to prevent both atrial +and ventricular arrhythmias. +Quinidine +Now rarely used, quinidine increases mortality and causes +gastrointestinal upset. +Class Ib drugs +These shorten the action potential and tissue refractory period. +Lidocaine +This must be given intravenously and has a very short plasma +half-life. +Mexiletine +This can be given intravenously or orally but has many side-effects. +It may cause torsades de pointes. +These drugs are +very effective at preventing atrial and ventricular tachyarrhythmias. +It is probably the most effective +drug currently available for controlling paroxysmal AF. +Amiodarone +has a very long tissue half-life (25–110 days). +The drug’s effects may last for +weeks or months after treatment has been stopped. +Side- +effects are common (up to one-third of patients), numerous +and potentially serious. +Drug interactions are also common +(see Box 16.30). +It has recently been shown to +be effective at preventing episodes of atrial flutter and AF. +Regular liver function test monitoring is required. +Verapamil +This is the most widely used drug in this class. +Diltiazem +This has similar properties to verapamil. +It is the treatment +of choice for severe bradycardia or hypotension due to vagal +over-activity. +The usual dose is 0.6 mg IV, repeated if necessary +of supraventricular or ventricular arrhythmias. +They are useful for +WPW syndrome because they block conduction in accessory +pathways. +Propafenone +This also has some β-blocker (class II) properties. +Important +interactions with digoxin, warfarin and cimetidine have been +described. +Class II drugs +This group comprises the β-adrenoceptor antagonists (β-blockers). +They can be used to prevent VT and SVT. +Non-selective β-blockers +These act on both β1 and β2 receptors. +Beta2-blockade causes side- +effects, such as bronchospasm and peripheral vasoconstriction. +Propranolol is non-selective and is subject to extensive rst- +pass metabolism in the liver. +Other non-selective drugs include nadolol and carvedilol. +Bisoprolol and metoprolol are examples of +cardioselective β-blockers. +Cardioversion is usually carried +out as an elective procedure under general anaesthesia. +Modern units deliver a biphasic shock, during which +the shock polarity is reversed mid-shock. +This reduces the total +shock energy required to depolarise the heart. +Each complex +is immediately preceded by a ‘pacing spike’ (Fig. +16.52). +Occasionally, temporary atrial or dual-chamber +pacing (see below) is used. +Side-effects are listed in Box 16.30. +16.35) or broad-complex +tachycardia (Boxes 16.30 and 16.32). +Adenosine is given as an +intravenous bolus, initially 3 mg over 2 secs (see Box 16.30). +16.52 Dual-chamber pacing. +rate during exercise. +The sensitivity of the sensor is programmable, +as is the maximum paced heart rate. +ICDs treat ventricular tachyarrhythmias using overdrive pacing, +cardioversion or debrillation. +They are implanted in a similar +manner to pacemakers and carry a similar risk of complications. +The evidence-based indications for ICD implantation are shown +in Box 16.35. +476), +hypertrophic cardiomyopathy (p. +539) and arrhythmogenic right +ventricular dysplasia (p. +540). +This allows +the device settings to be tailored to the patient’s needs. +Here the pacemaker acts as an external sinus +node. +Dual-chamber pacing is most often used in patients with +second- or third-degree AV block. +A code is used to signify the pacing mode (Box 16.34). +A fourth letter, ‘R’, is added if the pacemaker +has a rate response function. +For example, the letters AAIR +indicate an atrial demand pacemaker with a rate response +function. +16.30, p. +467). +These devices +are more effective in patients in sinus rhythm than in those +with AF. +16.53). +It involves inserting +a series of catheter electrodes into the heart through the venous +system. +The +applications of the technique are expanding and it can now be +used to treat some forms of VT. +Catheter ablation techniques +are also employed to prevent AF. +It also has a +devastating effect on quality of life. +In Eastern Europe and much of Asia, however, +the rates of CAD are rapidly rising. +508), +vasculitis (p. +1040) and autoimmune connective tissue diseases +(p. +1034). +16.53 Radiofrequency ablation. +16.54). +16.54). +16.54 The six stages of atherosclerosis. +American Heart Association classication. +From Stary HC, Chandler B, Dinsmore RE et al. +Circulation 1995; 92:1355–1374. +502) and stroke (Ch. +26). +Atherosclerosis may induce complex changes in the media +that lead to arterial remodelling. +Antihypertensive therapy reduces cardiovascular mortality, stroke +and heart failure. +It is often associated with +diffuse disease that is difcult to treat. +730). +977). +Alcohol +Excess alcohol consumption is associated with hypertension +and cerebrovascular disease. +The introduction of a Mediterranean-style diet reduces +cardiovascular events. +Social deprivation +Social deprivation is strongly related to cardiovascular disease. +Management +Two approaches can be employed. +Thresholds for treatment vary +in different countries. +Pathogenesis +Atherosclerosis is by far the most common cause of angina +pectoris. +The underlying mechanisms +and risk factors for atherosclerosis have already been discussed. +The main +causes are discussed in more detail below. +Coronary artery spasm +Angina may result from vasospasm of the coronary arteries. +severe limitation +*Patients may fall between these two categories. +the patient’s pulse, BP and general condition. +Planar or down- +sloping ST segment depression of 1 mm or more is indicative of +ischaemia (Fig. +16.56). +The amount of exercise +that can be tolerated and the extent of ST segment change +(Fig. +16.55). +16.15, p. +453). +491). +symptoms is often unclear. +It may also rarely be found +in association with vasculitis (p. +1040). +Clinical features +The history is the most important factor in making the diagnosis +(p. +454). +10.1, p. +178). +493). +Investigations +Symptoms are a poor guide to the extent of CAD. +Yes +No +Non-anginal chest pain +Yes and normal ECG? +16.55 A scheme for the investigation and +treatment of stable angina on effort. +This scheme +is best adopted for patients without prior known +coronary artery disease. +Similarly, all patients should be prescribed a statin, even +if cholesterol is normal. +Several preparations are available, +Fig. +16.56 Forms of exercise-induced ST depression. +A Planar +ST depression is usually indicative of myocardial ischaemia. +B Down-sloping depression also usually indicates myocardial +ischaemia. +C Up-sloping depression may be a normal nding. +The properties and +side-effects of β-blockers are discussed on page 500. +This is known as the β-blocker withdrawal +syndrome. +They are +particularly useful when β-blockers are contraindicated. +16.57 A positive exercise test (chest leads only). +Subsequent coronary angiography revealed critical three-vessel coronary +artery disease. +At rest During stress +Fig. +16.58 A myocardial perfusion scan showing reversible anterior +myocardial ischaemia. +The images are cross-sectional tomograms +of the left ventricle. +16.59 Percutaneous coronary intervention. +*Once- or twice-daily slow-release preparations are available. +damage. +Minor myocardial damage, as indicated +by elevation of sensitive intracellular markers (p. +497), occurs +in up to 10% of cases. +The main long-term complication of +PCI is restenosis, in up to one-third of cases. +16.61). +Other unwanted effects +include peripheral oedema, flushing, headache and dizziness +(Box 16.44). +If channel antagonist +Ivabradine is the rst of this class of drug. +It induces bradycardia +by modulating ion channels in the sinus node. +It does not inhibit +myocardial contractility and appears to be safe in patients with +heart failure. +16.59). +16.60). +It is mainly used in single- or two-vessel disease. +Stenoses +in bypass grafts can be dilated, as well as those in the native +coronary arteries. +16.61 Coronary artery bypass graft surgery. +B Three- +dimensional reconstruction of multidetector CT of the heart. +should be prescribed indenitely. +Neurological complications are common, with a 1–5% risk of +perioperative stroke. +Between 30% and 80% of patients develop +Fig. +16.60 Primary percutaneous coronary intervention. +A Acute +right coronary artery occlusion. +B Initial angioplasty demonstrates a large +thrombus lling defect (arrows). +C Complete restoration of normal flow +following intracoronary stenting. +to disease in the distal native coronary vessels. +Fewer than 50% of vein +grafts are patent 10 years after surgery. +This +has led many surgeons to consider total arterial revascularisation +during CABG surgery. +PCI and CABG are compared in Box 16.45. +Myocardial infarction +differs from unstable angina, since there is evidence of myocardial +necrosis. +Symptoms of ischaemia +2. +Development of pathological Q waves in the ECG +4. +Imaging evidence of new loss of viable myocardium or new +regional wall motion abnormality +5. +497). +• Comorbid conditions: anaemia and thyroid disease are common +and may worsen angina. +• Calcic aortic stenosis: common and should be sought in all older +people with angina. +Adapted from Thygesen K, Alpert JS, Jaffe AS et al. +Third universal denition of +myocardial infarction. +501). +Pathogenesis +Acute coronary syndrome almost always occurs in patients who +have atherosclerosis. +16.54). +Since the process of infarction progresses +over several hours (Fig. +16.63), most patients present when it +is still possible to salvage myocardium and improve outcome. +176). +Third universal denition of +myocardial infarction. +Eur Heart J 2012; 33:2551–2267. +1. +His +score would be: 20 + 53 + 15 + 58 + 7 + 0 + 28 + 14 = 195. +This gives about a 16% risk of having an in-hospital death. +This gives +about a 0.9% risk of having an in-hospital death. +Fig. +16.62 Risk stratication in the acute coronary syndrome: the GRACE score. +To convert creatinine in Îźmol/L to mg/dL, divide by 88.4. +16.63 The time course of myocardial infarction. +Prompt debrillation restores sinus rhythm and +is life-saving. +483). +In other situations, digoxin or a β-blocker is usually +the treatment of choice. +Anticoagulation +is required if AF persists. +AV +block complicating anterior infarction is more serious because +asystole may suddenly supervene. +A prophylactic temporary +pacemaker should be inserted in these patients (p. +482). +Post-infarct angina occurs in up to 50% +of patients treated with thrombolysis. +Most patients are +breathless and, in some, this is the only symptom. +If syncope occurs, it +is usually caused by an arrhythmia or profound hypotension. +Nausea +and vomiting may also be caused or aggravated by opiates +given for pain relief. +Sometimes infarction occurs in the absence +of physical signs. +It is vital that patients know not to delay calling for +help if symptoms occur. +All the other +complications of MI are more likely to occur when acute heart +failure is present. +The assessment and management of heart +failure is discussed in more detail on pages 463 and 465. +A pericardial rub may be audible. +Opiate-based analgesia should be used. +The symptoms +tend to occur a few weeks or even months after MI and often +subside after a few days. +The diagnosis is conrmed by echocardiography, +and emergency valve replacement may be necessary. +Doppler echocardiography and right +heart catheterisation will conrm the diagnosis. +Treatment is by +emergency surgical repair; without this, the condition is usually fatal. +Ventricular rupture +Rupture of the ventricle may lead to cardiac tamponade and +is usually fatal (p. +Embolism +Thrombus often forms on the endocardial surface of freshly +infarcted myocardium. +This can lead to systemic embolism +and occasionally causes a stroke or ischaemic limb. +This leads +Increased +wall +stress +t +c +r +n +a +f +I +n +o +i +s +n +a +e +x +p +Fig. +16.64 Infarct expansion and ventricular remodelling. +16.64). +As the ventricle dilates, it becomes less efcient +and heart failure may supervene. +Infarct expansion occurs over +a few days and weeks but ventricular remodelling can take +years. +465). +Echocardiography is +diagnostic. +The initial ECG may be normal or non-diagnostic +in one-third of cases. +The earliest ECG change is usually +ST-segment deviation. +These sequential +features (Fig. +16.65) are sufciently reliable for the approximate +age of the infarct to be deduced. +16.65 The serial evolution of ECG changes in transmural +myocardial infarction. +A Normal ECG complex. +B Acute ST elevation +(‘the current of injury’). +D Deep Q wave and T-wave inversion. +This should be compared with the +12-lead ECGs in Figures 16.66–16.68. +II +aVL V2 V5 +III aVF V3 V6 +Fig. +16.67 Acute transmural anterior myocardial infarction. +This ECG +was recorded from a patient who had developed severe chest pain 6 hours +earlier. +Some infarctions (especially inferior) also involve the RV. +This may be identied by recording from additional leads placed +over the right precordium. +Cardiac biomarkers +Serial measurements of serum troponin should be taken. +450; Fig. +16.69 and see Box 16.47). +The +erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) +are also elevated. +16.27, p. +464). +The heart size is often normal but +II +aVL V2 V5 +III aVF V3 V6 +Fig. +16.66 Recent anterior non-ST elevation (subendocardial) +myocardial infarction. +a minor vessel, causing unstable angina or partial-thickness +(subendocardial) MI. +This is usually associated with ST-segment +depression and T-wave changes. +16.66). +The ECG changes are best seen in the leads that ‘face’ the +ischaemic or infarcted area. +16.70). +This often reveals disease that is amenable to PCI or +urgent CABG (see below). +Appropriate medical therapy can reduce the incidence +of these complications by at least 60%. +The key elements of +immediate in-hospital management are shown in Figure 16.70. +Clinical risk factor analysis using tools such +as the GRACE score (see Fig. +III aVF V3 V6 +Fig. +16.68 Acute transmural inferolateral myocardial infarction. +This +ECG was recorded from a patient who had developed severe chest pain +4 hours earlier. +There is ST elevation in inferior leads II, III and aVF and +lateral leads V4, V5 and V6. +There is also ‘reciprocal’ ST depression in leads +aVL and V2. +16.69 Changes in plasma cardiac biomarker concentrations +after myocardial infarction. +there may be cardiomegaly due to pre-existing myocardial +damage. +Eligible for +thrombolysis? +Is delayed +PCI possible? +Failed +reperfusion? +16.70 Summary of treatment for acute coronary syndrome (ACS). +*Not required following PCI. +For details of the GRACE score, see Figure 16.62. +Reperfusion therapy +Immediate reperfusion therapy with PCI (see Fig. +16.70). +Coronary +artery patency is restored in over 95% of patients undergoing PCI. +Thrombolytic therapy +If primary PCI cannot be achieved in a timely manner (see Fig. +16.70), thrombolytic therapy should be administered. +The major hazard of thrombolytic therapy is +bleeding. +16.70). +Emergency +PCI may then be considered, particularly where there is evidence +of cardiogenic shock. +A P2Y12 receptor antagonist should be given in combination +with aspirin for up to 12 months. +16.70). +Verapamil and diltiazem should be used if a β-blocker +is contraindicated. +• Case fatality: rises steeply. +• Survival benet of treatments: not influenced by age. +The +absolute benet of evidence-based treatments may therefore be +greatest in older people. +They should therefore be considered in all patients +with acute coronary syndrome. +94). +Emotional problems, such +as denial, anxiety and depression, are common and must be +addressed. +The +patient’s spouse or partner will also require emotional support, +information and counselling. +483). +In almost one-quarter of all cases of MI, death occurs +within a few minutes without medical care. +Patients with unstable angina +have a mortality of approximately half that of patients with MI. +Early death is usually due to an arrhythmia and is independent +of the extent of MI. +The prognosis is worse for anterior +than for inferior infarcts. +Bundle branch block and high cardiac +marker levels both indicate extensive myocardial damage. +Old +age, depression and social isolation are also associated with a +higher mortality. +On exertion a moderate stenosis +may become ‘critical’. +Nevertheless, diabetic patients with PAD pose a number of +particular problems (Box 16.56). +Clinical features +Symptomatic PAD affects the legs about eight times more +commonly than the arms. +One or more of these segments +may be affected in a variable and asymmetric manner. +In the +arm, the subclavian artery is the most common site of disease. +Peripheral artery disease can present clinically in a variety of +ways, as detailed below. +Intermittent claudication +This is the most common presentation of PAD affecting the +lower limbs. +It is characterised by ischaemic pain affecting the +muscles of the leg. +Resumption of walking leads to a return of the +pain. +When PAD affects +the upper limbs, arm claudication may occur, although this is +uncommon. +The typical progression of symptoms in +CLI is summarised in Figure 16.71. +Rest pain only, with ankle +pressures above 50 mmHg, is known as subcritical limb ischaemia +(SCLI). +Inability to clamp arteries for +the purposes of bypass surgery. +Diabetic patients +often present late with extensive destruction +of the foot. +Scaling and ssuring create a +portal of entry for bacteria. +Interstitial tissue +pressure is increased so arterial perfusion is +further reduced. +Whereas IC +is usually due to single-segment plaque, SLI is always due to +multilevel disease. +These features are non- +specic, however, and inconsistently related to its severity. +Pain on squeezing the calf indicates muscle infarction and +impending irreversible ischaemia. +Rapid development of ulcers and gangrene +Fig. +16.71 Progressive night pain and the development of +tissue loss. +The indications for thrombolysis, if any, remain +controversial. +Irreversible ischaemia mandates early amputation +or palliative care. +Atheroembolism +This may be a presenting feature of PAD affecting the subclavian +arteries. +Management +Key elements of medical management are summarised in Box +16.60. +It is +most common in those from the Mediterranean and North +Africa. +Wrist +and ankle pulses are absent but brachial and popliteal pulses +are present. +It may also affect the veins, giving rise to supercial +thrombophlebitis. +It often remits if the patient stops smoking. +Major +limb amputation is the most frequent outcome if patients continue +to smoke. +It does not progress to +ulceration or infarction, and signicant pain is unusual. +The +underlying cause is unclear and no investigation is necessary. +The patient should be reassured and advised to avoid exposure +to cold. +This may be confused +with Raynaud’s phenomenon (p. +Subclavian steal +This can be a feature of PAD affecting the upper limbs. +In health, +the ABPI is over 1.0, in IC typically 0.5–0.9 and in CLI usually less +than 0.5. +vasodilators such as nifedipine can may be helpful if symptoms are +troublesome. +This is discussed in more detail on page 1035. +The most common site is the +infrarenal abdominal aorta. +484). +508). +The features +and management of this disorder are discussed on page 508. +Clinical features +The clinical presentation is dependent on the site of the aneurysm. +Thoracic aneurysms may typically present with acute severe chest +pain (p. +16.72A). +AAAs affect the +infrarenal segment of the aorta. +They can present in a number of +ways, as summarised in Box 16.62. +For every 10 000 men scanned, 65 ruptures are +prevented and 52 lives saved. +16.72 Types of aortic disease and their complications. +A Types of aortic aneurysm. +B Types of aortic dissection. +replacing open surgery. +It is cost-effective and likely to become +the treatment of choice for infrarenal AAA. +It is possible to treat +many suprarenal and thoraco-abdominal aneurysms by EVAR too. +16.72B). +The aortic valve may be +damaged and the branches of the aorta may be compromised. +16.72B), involving or +sparing the ascending aorta, respectively. +The pain is typically described as ‘tearing’ and very +abrupt in onset; collapse is common. +Unless there is major +haemorrhage, the patient is invariably hypertensive. +A chest +X-ray should be performed. +A left-sided +pleural effusion is common. +There is +sluggish flow in the false lumen (FL), accounting for its grey appearance. +(TL = true lumen) +16 +(CABG = coronary artery bypass grafting) +A B +E +C D +Fig. +C CT scan after endoluminal +repair. +The pleural effusion has been drained but there is a haematoma around the descending aorta. +D Aortogram illustrating the stent graft. +E Three- +dimensional reconstruction of an aortic stent graft. +E, Courtesy of Dr T. +Activities +that are associated with increases in cardiac output are best +avoided. +Surgery to replace the aortic root can be performed +in patients with progressive aortic dilatation. +It is most commonly +due to congenital heart disease (p. +1041) and trauma. +Diagnosis +and management of coarctation are discussed on page 534. +FL +TL +Fig. +16.75 Echocardiograms from a patient with a chronic aortic +dissection. +of acute MI (usually inferior). +16.75). +Initial management +comprises pain control and antihypertensive treatment. +Type A +dissections require emergency surgery to replace the ascending +aorta. +Sodium nitroprusside may be considered +if these fail to control BP adequately. +16.74). +Other rare conditions associated with aortitis include Takayasu’s +disease (p. +1041), reactive arthritis (p. +1031), giant cell arteritis +(p. +1042) and ankylosing spondylitis (p. +1028). +It is inherited in an autosomal dominant manner +but some cases are due to new mutations. +361) +• 11β-hydroxysteroid +dehydrogenase deciency +Drugs +Coarctation of the aorta +Fig. +16.76 Retinal changes in hypertension. +A and B, Courtesy of Dr B. +Cullen. +16 +and cerebrovascular disease, particularly if other risk factors +are present. +461). +These include radio-femoral +delay in patients with coarctation of the aorta (see Fig. +16.93, +p. +534), enlarged kidneys in patients with polycystic kidney +disease (p. +405), abdominal bruits that may suggest renal artery +stenosis (p. +406), and the characteristic facies and habitus of +Cushing’s syndrome (Box 16.65). +Other signs may be observed that are due +to the complications of hypertension. +The optic fundi are often abnormal (see Fig. +In +more than 95% of cases, however, no specic underlying cause +of hypertension can be found. +Such patients are said to have +essential hypertension. +Age is a +strong risk factor in all ethnic groups. +In about 5% of cases, hypertension is secondary to +a specic disease, as summarised in Box 16.65. +Hypertension has a number of adverse effects on the +cardiovascular system. +The vessels dilate +and become tortuous, and their walls become less compliant. +16.76A). +27.8, p. +1176). +Hypertension is +also associated with central retinal vein thrombosis (Fig. +16.76B). +Exercise, anxiety, discomfort and +unfamiliar surroundings can all lead to a transient rise in BP. +675) or complications such as CAD. +16.77 and see +‘Further information’). +Total cardiovascular risk can be estimated by +multiplying CAD risk by 4/3 (i.e. +if CAD risk is 30%, cardiovascular +risk is 40%). +The value of this approach can be illustrated by +comparing the two hypothetical cases on page 487. +666) +• Plasma renin activity and aldosterone: to detect possible primary +aldosteronism (p. +16.77 Example of cardiovascular risk prediction chart for +non-diabetic men. +Modied charts exist for women. +For further details, see www.who.int/ +cardiovascular_diseases/guidelines/Pocket_GL_information. +When resources allow, others with a CVD risk > 20% should be +targeted progressively. +• Smoking status should reflect lifetime exposure to tobacco. +For further +information, see www.bhf.org.uk. +16.78 Management of hypertension: British Hypertension Society guidelines. +1 Signs of papilloedema or retinal haemorrhage. +2 Labile or postural +hypotension, headache, palpitations, pallor and diaphoresis. +16.78). +The thresholds for treatment in the elderly are the same +as for younger patients (Box 16.70). +Moreover, reducing BP below +this level causes no harm. +The targets suggested by the British +Hypertension Society (Box 16.71) are ambitious. +• Target blood pressure: targets be relaxed in older people +to 150/90 mmHg. +• Tolerance of treatment: antihypertensives are tolerated as well as +in younger patients. +Labetalol can be used as +an infusion in malignant phase hypertension (see below). +Other vasodilators A variety of other vasodilators may be +used. +Minoxidil also causes increased facial hair and is +therefore unsuitable for female patients. +Statins Treating hyperlipidaemia can produce a substantial +reduction in cardiovascular risk. +376). +Response to initial therapy and side-effects +guide subsequent treatment. +16.79). +2 Average BP during waking +hours. +of affected individuals. +An appropriate daily dose is 2.5 mg +bendroflumethiazide or 0.5 mg cyclopenthiazide. +Electrolytes and creatinine should be checked before +and 1–2 weeks after commencing therapy. +Side-effects include +rst-dose hypotension, cough, rash, hyperkalaemia and renal +dysfunction. +Side-effects include flushing, palpitations and fluid retention. +The main +side-effect of verapamil is constipation. +3 Caution with ACE inhibitors and ARBs in PAD because of association with +renovascular disease. +4In combination with a thiazide or thiazide-like diuretic. +Spironolactone is a particularly useful addition in patients +with treatment-resistant hypertension. +Left ventricular failure +may occur and, if this is untreated, death occurs within months. +The causes of this are +shown in Box 16.73. +Histologically, brinoid degeneration is seen in the collagen of +connective tissues. +Aschoff nodules are pathognomonic and occur +only in the heart. +There may be no +history of sore throat, however. +Arthritis occurs in approximately +75% of patients. +Other features include rashes, subcutaneous +nodules, carditis and neurological changes (Fig. +16.80). +Other features +include tachycardia, cardiac enlargement and new or changed +Fig. +16.79 Antihypertensive drug combinations. +3 D = thiazide-type +diuretic. +4 Consider a low dose of spironolactone or higher doses of a +thiazide-like diuretic. +Informed consent should be obtained and documented. +From NICE Clinical Guideline 127 – +Hypertension in adults; August 2011. +The principal causes of +valvular disease are summarised in Box 16.74. +Skin lesions +Erythema marginatum occurs in less than 5% of patients. +The resulting red rings or ‘margins’ +may coalesce or overlap (Fig. +16.80). +Subcutaneous nodules +occur in 5–7% of patients. +It occurs in up to one-third of +cases and is more common in females. +Speech may be explosive and halting. +Spontaneous recovery +usually occurs within a few months. +Serology for antistreptolysin +O antibodies (ASO) should be performed. +Management +The aims of management are to limit cardiac damage and +relieve symptoms. +Bed rest +Bed rest is important, as it lessens joint pain and reduces cardiac +workload. +Treatment of cardiac failure +Cardiac failure should be treated as necessary. +16.80 Clinical features of rheumatic fever. +Bold labels indicate +Jones major criteria. +Skin signs in +clinical medicine. +London: Mosby–Wolfe, Elsevier; 1997. +murmurs. +A soft systolic murmur due to mitral regurgitation is +very common. +Pericarditis may cause chest pain, a pericardial friction rub and +precordial tenderness. +Cardiac failure may be due to myocardial +dysfunction or valvular regurgitation. +ECG evidence commonly +includes ST and T wave changes. +Conduction defects, including +AV block, sometimes occur and may cause syncope. +Two-thirds of cases +occur in women. +There is also a rare form of congenital mitral stenosis. +The +patient is usually asymptomatic until the orifice is < 2 cm2. +Atrial brillation is very common due to progressive dilatation of +the LA. +In the absence of AF, a more gradual rise +in left atrial pressure may occur. +Occasionally, AV block may occur but is +seldom progressive and usually resolves spontaneously. +Rarely, +pacemaker insertion may be required. +If the patient is penicillin-allergic, erythromycin or a +cephalosporin can be used. +A +reasonable starting dose is 60 mg/kg body weight/day, divided +into six doses. +Aspirin should be +continued until the ESR has fallen and then gradually tailed off. +There is +no evidence that long-term steroids are benecial. +Clinical features +Effort-related dyspnoea is usually the dominant symptom +(Box 16.77). +Acute pulmonary oedema or pulmonary hypertension +can lead to haemoptysis. +Fatigue is a common symptom due +to a low cardiac output. +Thromboembolism is a common +complication, especially in patients with AF. +Prior to the +advent of anticoagulant therapy, emboli caused one-quarter +of all deaths. +The forces that open and close the mitral valve +increase as left atrial pressure rises. +The rst heart sound (S1) +is therefore loud and can be palpable (tapping apex beat). +16.81). +The murmur +is accentuated by exercise and during atrial systole (pre-systolic +accentuation). +A Echocardiogram showing reduced opening of the mitral valve in diastole. +Coexisting mitral regurgitation causes a pansystolic +murmur that radiates towards the axilla. +16.81). +A typical +chest X-ray is shown in Figure 16.9 (p. +451). +Antibiotic +prophylaxis against infective endocarditis is no longer routinely +recommended. +16.82), although surgical closed +or open mitral valvotomy is an acceptable alternative. +Clinical symptoms and signs are a guide to the severity +Fig. +16.82 Mitral valvuloplasty. +The +inter-atrial septum is punctured, providing access to the left atrium and +mitral valve. +16 +of mitral restenosis but Doppler echocardiography provides a +more accurate assessment. +526). +Mitral regurgitation +may also follow mitral valvotomy or valvuloplasty. +coronary +artery disease, cardiomyopathy) +• Damage to valve cusps and chordae (e.g. +16.83 Mitral regurgitation: murmur and systolic wave in left atrial pressure. +A third heart sound occurs with severe regurgitation. +B This results in a jet of mitral regurgitation on colour Doppler (arrow). +16.83). +Rarely, mitral valve prolapse may occur in +association with Marfan’s syndrome (p. +508). +A click is not always +audible and the physical signs may vary with both posture and +respiration. +This is rare +before the fth or sixth decade of life. +Nevertheless, +the overall long-term prognosis is good. +Endocarditis is an +important cause of acute mitral regurgitation. +The regurgitant jet causes an apical systolic murmur (Fig. +16.83), which radiates into the axilla and may be accompanied +by a thrill. +Investigations +Echocardiography is a pivotal investigation. +An ECG should be performed and commonly shows AF, as +a consequence of atrial dilatation. +Mitral regurgitation often +accompanies left ventricular failure associated with CAD. +Digoxin and anticoagulants should +be given if AF is present (Box 16.83). +All patients should be reviewed at regular intervals, +both clinically and by echocardiography. +The +xed outflow obstruction limits the increase in cardiac output +required on exercise. +Sometimes patients with severe aortic stenosis do not complain +of symptoms. +The characteristic clinical signs of severe aortic stenosis are +shown in Box 16.85. +16.84). +It can demonstrate restricted valve +opening (Fig. +16.11, p. +451). +16.84 Aortic stenosis. +Pressure traces +show the systolic gradient between left ventricle +(LV) and aorta. +Figure 16.11 (p. +451) shows the +typical Doppler signal with aortic stenosis. +16.86 Left ventricular hypertrophy. +Fig. +B Calcic aortic stenosis in diastole; the aortic leaflets are +thick and calcied (arrow). +C Normal in systole; the aortic leaflets are open +(arrows). +D Calcic aortic stenosis in systole; the thickened leaflets have +barely moved (arrows). +From Newby D, Grubb N. +Cardiology: an illustrated +colour text. +Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005. +In +advanced cases, ECG features of hypertrophy (Box 16.86) are +often pronounced (Fig. +• Symptoms: a common cause of syncope, angina and heart failure +in the very old. +The +prognosis without surgery is poor once symptoms have developed. +Nevertheless, the ECG can +be normal, despite severe stenosis. +Patients with symptomatic severe aortic stenosis should +have prompt aortic valve replacement. +This is especially +the case with transcatheter aortic valve implantation (TAVI, +p. +527). +The +causes are summarised in Box 16.88. +The +characteristic murmur is best heard to the left of the sternum +during held expiration (Fig. +16.87); a thrill is rare. +16.87 Aortic regurgitation. +The aortic arch and left ventricle (LV) may become dilated. +The inset shows a Doppler echocardiogram with the regurgitant jet (arrows). +Inset (Colour Doppler echo) From Newby D, Grubb N. +Cardiology: an illustrated colour text. +Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005. +Management +Treatment may be required for underlying conditions, such as +endocarditis or syphilis. +If +systemic hypertension is present, vasodilators should be used +to control systolic BP. +Tricuspid stenosis and regurgitation may also occur in the +carcinoid syndrome (p. +678). +left ventricular end-diastolic pressure. +443). +There is also a mid-diastolic murmur, +best heard at the lower left or right sternal edge. +Balloon +valvuloplasty can be used to treat rare cases of isolated tricuspid +stenosis. +It may +also be the result of other conditions, as summarised in +Box 16.91. +Other features include a pansystolic murmur +at the left sternal edge and a pulsatile liver. +Echocardiography +may reveal dilatation of the RV. +Those with rheumatic damage may require tricuspid valve +replacement. +536). +There may be a thrill, best felt when the patient leans +forwards and breathes out. +The murmur is often preceded +by an ejection sound (click). +Delay in right ventricular ejection +may cause wide splitting of the second heart sound. +Investigations +Doppler echocardiography is the denitive investigation. +Long-term results are very good. +Post-operative pulmonary +regurgitation is common but benign. +532). +Prosthetic valves +Diseased heart valves can be replaced with mechanical or +biological prostheses. +All generate prosthetic sounds +or clicks on auscultation. +Pig or allograft valves mounted on a +supporting stent are the most commonly used biological valves. +They generate normal heart sounds. +All prosthetic valves used +in the aortic position produce a systolic flow murmur. +Starr–Edwards) +Tilting disc (e.g. +Both native and prosthetic valves can be affected. +More +than 50% of patients are over 60 years of age (Box 16.93). +The remaining 32% were not thought +to have a pre-existing cardiac abnormality. +Adjacent tissues +are destroyed and abscesses may form. +Mycotic aneurysms may develop in arteries at the +site of infected emboli. +3.0–4.0 +Bi-leaflet (e.g. +16.88 Transcatheter aortic valve implantation (TAVI): +bioprosthetic valve. +16 +requires anticoagulation anyway. +16.88). +TAVI has several major advantages. +Complications +include stroke (2%) and heart block necessitating pacemaker +implantation (5–15%). +Metallic valves can suffer strut +fracture and fail, causing catastrophic regurgitation. +gallolyticus (from a +colonic source). +Infective endocarditis. +Lancet 2004; 363:139–149. +Microbiology +Over three-quarters of cases are caused by streptococci or +staphylococci. +Viridans streptococci, such as Streptococcus mitis +and Strep. +Other organisms, including Enterococcus +faecalis, E. +faecium and Strep. +gallolyticus subsp. +gallolyticus +(previously known as Strep. +bovis), may enter the blood from the +bowel or urinary tract. +Patients who are found to have endocarditis +caused by Strep. +Staph. +aureus has now overtaken streptococci as the most +common cause of acute endocarditis. +Other causes of acute +endocarditis include Strep. +pneumoniae and Strep. +pyogenes. +The +most common organisms are coagulase-negative staphylococci +such as Staph. +epidermidis, which are part of the normal skin +flora. +There is frequently a history of wound infection with the +same organism. +Another coagulase- +negative staphylococcus, Staph. +Unless accurately identied, +it may also be overlooked as a contaminant. +The aortic valve +is usually affected and there may also be hepatitis, pneumonia +and purpura. +Life-long antibiotic therapy may be required. +These are +slow-growing, fastidious Gram-negative organisms that are +oropharyngeal commensals. +Concomitant bacterial infection may be present. +Clinical features +Endocarditis can take either an acute or a more insidious +‘subacute’ form. +The Duke criteria for diagnosis of +infective endocarditis are shown in Box 16.95. +Less often, it presents +as an embolic stroke or peripheral arterial embolism. +Other +features (Fig. +Digital clubbing is a late sign. +16.89 Clinical features that may be present in endocarditis. +Insets (Petechial rash, nail-fold infarct) From Newby D, Grubb N. +Cardiology: an +illustrated colour text. +Edinburgh: Churchill Livingstone, Elsevier Ltd; 2005. +liver may be considerably enlarged. +Non-visible haematuria is +common. +Clinical stigmata of +chronic endocarditis are usually absent. +Embolic events are +common, and cardiac or renal failure may develop rapidly. +Abscesses may be detected on echocardiography. +Partially +treated acute endocarditis behaves like subacute endocarditis. +Morbidity and mortality are high +and revision surgery is often required. +Patients with two major, or one major and three minor, +or ve minor have denite endocarditis. +6.6, p. +The rst two specimens will detect +bacteraemia in 90% of culture-positive cases. +A meticulous aseptic +technique is essential. +An +in-dwelling line should not be used to take cultures. +Both aerobic +and anaerobic cultures are required. +Failure to +detect vegetations does not exclude the diagnosis. +Measurement of +serum CRP is more reliable than the ESR in monitoring progress. +Proteinuria may occur and non-visible haematuria is usually present. +The chest X-ray may show evidence of cardiac failure +and cardiomegaly. +The same regimen is +used in true penicillin allergy. +Recommended regimens for some of the most common +scenarios are shown in Box 16.96. +2 Pre-dose gentamicin level should be ≤ 1 mg/L, post-dose 3–5 mg/L. +Adjust dose according to levels +and renal function. +3 Pre-dose vancomycin level should be 15–20 mg/L. +Adjust dose according to levels and renal function. +4 Use 6 times daily if weight > 85 kg. +aureus and fungal +infections (Box 16.98). +Antimicrobial therapy must be started +before surgery. +Atrial +septal defects occur because the foramen ovale fails to close +at birth, as is normal. +Similarly, a persistent ductus arteriosus +will remain persistent if it fails to close after birth. +16.90 Changes in the circulation at birth. +the kidneys and intestinal +tract. +The umbilical arteries and the ductus venosus close. +(PV = +pulmonary vein) Adapted from Drews U. +Colour atlas of embryology. +Stuttgart: Georg Thieme; 1995. +and/or artery stenosis, and atrial septal defect. +508) and DiGeorge’s syndrome (deletion in chromosome 22q). +Some defects are +not compatible with extrauterine life and lead to neonatal death. +Clinical signs vary with the anatomical lesion. +Murmurs, thrills or +signs of cardiomegaly may be present. +In coarctation of the aorta, +radio-femoral delay may be noted (Fig. +16.91) and some female +patients have the features of Turner’s syndrome (p. +659). +Cerebrovascular +events and cerebral abscesses may complicate severe cyanotic +congenital disease. +Radial +Femoral +Fig. +16.91 Radio-femoral delay. +The difference in pulse pressures is +shown. +Prolonged +cyanosis is associated with nger and toe clubbing (p. +Cerebral function +can also be affected after cardiac surgery if cerebral perfusion +is compromised. +Syncope can also occur +because of associated arrhythmias. +Progressive changes, including obliteration of +distal arterioles, take place and are irreversible. +At this stage, +central cyanosis occurs and digital clubbing develops. +The ECG shows features of +right ventricular hypertrophy. +This is termed Eisenmenger’s syndrome. +Many with palliated or untreated +disease will tolerate pregnancy well, however. +16.90). +16.92). +16.92). +It is frequently accompanied by a thrill. +Pulses are increased in volume. +Enlargement of the pulmonary artery may be detected +radiologically. +The ECG is usually normal. +• Cyanotic conditions: especially poorly tolerated. +Specialised +pre-conception counselling should explain the increased risks. +• Surgically corrected disease: patients often tolerate +pregnancy well. +The risk may be up to 20% in babies born of women with +left-sided lesions. +RV LV +(dilated) +Fig. +16.92 Persistent ductus arteriosus. +There is a connection between +the aorta and the pulmonary artery with left-to-right shunting. +The murmur +becomes quieter, may be conned to systole or may disappear. +Unfortunately, these treatments do not work if the ductus is +intrinsically abnormal. +1160). +1041). +16.90). +The BP is raised in the upper body but normal +or low in the legs. +The femoral pulses are weak and delayed +in comparison with the radial pulse (see Fig. +16.91). +A systolic +murmur is usually heard posteriorly, over the coarctation. +Investigations +Imaging by MRI is the investigation of choice (Fig. +16.93). +C +B A +D +Fig. +16.93 MRI scan of coarctation of the aorta. +The aorta is severely +narrowed just beyond the arch at the start of the descending aorta (arrow +A). +Unusually, +in this case, there is also a coarctation of the abdominal aorta (arrow D). +Surgical +correction is advisable in all but the mildest cases. +If this is +carried out sufciently early in childhood, persistent hypertension +can be avoided. +The latter may be used as the primary treatment. +16.90). +16.94). +16.95 Transoesophageal echocardiogram of an atrial septal +defect. +The defect is clearly seen (arrow) between the left atrium above +and right atrium below. +Doppler colour-flow imaging shows flow (blue) +across the defect. +RV +(dilated) +Fig. +16.94 Atrial septal defect. +Blood flows across the atrial septum +(arrow) from left to right. +The density of shading is proportional to +velocity of blood flow. +In children with a large shunt, there may be a diastolic flow +murmur over the tricuspid valve. +Unlike a mitral flow murmur, +this is usually high-pitched. +Investigations +Echocardiography is diagnostic. +The precise size +and location of the defect are best dened by TOE (Fig. +16.95). +16.96). +The long-term prognosis thereafter +is excellent, unless pulmonary hypertension has developed. +Fig. +16.96 Percutaneous closure of atrial septal defect. +The defect may be +isolated or part of complex congenital heart disease. +16.97). +The long-term prognosis is generally +very good. +16.98). +The ventricular septal defect is +usually large and similar in aperture to the aortic orice. +This may be found septal defect into the aorta. +Management +Small ventricular septal defects require no specic treatment. +Persisting failure is an +indication for surgical repair of the defect. +Percutaneous closure +devices are under development. +16.97 Ventricular septal defect. +In this example, a large +left-to-right shunt (arrows) has resulted in chamber enlargement. +16.98 Tetralogy of Fallot. +These +attacks are called ‘Fallot’s spells’. +This is called Fallot’s +sign. +This is called acyanotic +tetralogy of Fallot. +Primary surgical correction may be +undertaken prior to the age of 5 years. +Follow-up is needed +to identify residual shunting, recurrent pulmonary stenosis +and arrhythmias. +An implantable defibrillator is sometimes +recommended in adulthood. +Diseases of the myocardium +myocardium. +• Chronic active myocarditis is rare and associated with +chronic myocardial inflammation. +Myocarditis is self-limiting in most patients and the immediate +prognosis is good. +Death may, however, occur due to a ventricular +arrhythmia or rapidly progressive heart failure. +Myocarditis has +been reported as a cause of sudden and unexpected death in +young athletes. +For example, in Chagas’ disease (p. +The +ECG is frequently abnormal but the changes are non-specic. +Blood should be taken for analysis of troponin I and T, and +creatine kinase. +Levels may be elevated in the early phases. +Occasionally, endomyocardial biopsy may be required to conrm +the diagnosis. +Management +Treatment of myocarditis is primarily supportive. +There is no evidence of benet from treatment with +glucocorticoids and immunosuppressive agents. +Rarely, cardiac transplantation may be required. +255) develop myopericarditis, which is +often associated with AV block. +16.99). +They can be inherited or be caused +by infections or exposure to toxins. +In some cases no cause +is identied. +16.99 Types of cardiomyopathy. +A Normal heart. +C Hypertrophic cardiomyopathy: concentric +hypertrophy. +D Hypertrophic cardiomyopathy: apical hypertrophy. +E Dilated cardiomyopathy. +F Arrhythmogenic right ventricular cardiomyopathy. +G Obliterative cardiomyopathy. +H Restrictive cardiomyopathy. +Men are affected more than twice as often as women. +Left ventricular mass is +increased but wall thickness is normal or reduced (Fig. +16.99). +Dilatation of the valve rings can lead to functional mitral and +tricuspid incompetence. +The term ‘dilated cardiomyopathy’ encompasses a heterogeneous +group of conditions. +Alcohol may be an important cause in some +patients. +1143), are associated with cardiomyopathy. +Investigations +Echocardiography and cardiac MRI are the most useful +investigations. +Although ECG changes are common, they are +non-specic. +Genetic testing is indicated if more than one family +member is diagnosed with the condition. +464). +483 and 484). +16.99) or other regions of the heart. +There are three common groups +of mutation with different phenotypes. +Beta-myosin heavy-chain +mutations are associated with elaborate ventricular hypertrophy. +Hypertrophic +cardiomyopathy is the most common cause of sudden death in +young athletes. +Investigations +Echocardiography is the investigation of choice and is usually +diagnostic. +Genetic testing +can be performed and is helpful in screening relatives of affected +individuals. +Arrhythmias often respond to treatment with amiodarone. +No +pharmacological treatment has been identied that can improve +prognosis, however. +An ICD should be considered in patients with +clinical risk factors for sudden death (Box 16.106). +Digoxin and +vasodilators may increase outflow tract obstruction and should +be avoided. +16.99). +In some cases, the LV is also involved +and this is associated with a poorer prognosis. +16.99). +This leads to high +atrial pressures with atrial hypertrophy, dilatation and, later, AF. +Treatment is symptomatic +but the prognosis is usually poor and transplantation may be +indicated. +sublingual nitrate). +16.99). +The mitral and tricuspid +valves become regurgitant. +Heart failure and pulmonary and +systemic embolism are prominent features. +1043). +In tropical +countries, the disease can be responsible for up to 10% of +cardiac deaths. +Mortality is high: 50% at 2 years. +It occurs more frequently in women than in men. +The diagnosis is usually +made at coronary angiography, when CAD is found to be absent +or minimal. +Echocardiography then shows characteristic ‘apical +ballooning’ of the LV. +The dilated apex and narrow outflow of the +LV resemble a Japanese octopus trap, or takotsubo (Fig. +16.100). +These drugs are continued only until +cardiac function has recovered. +1116) can mimic hypertrophic cardiomyopathy. +Treatment and prognosis are determined by the underlying +disorder. +Most +primary tumours are benign (75%) and, of these, the majority are +myxomas. +The remainder are bromas, lipomas, broelastomas +and haemangiomas. +Fig. +16.100 Takotsubo cardiomyopathy. +Left ventriculogram following +injection of contrast in a patient with Takotsubo cardiomyopathy. +Treatment is by surgical excision. +If the pedicle is removed, +fewer than 5% of tumours recur. +16.101) over the affected area, which may be widespread. +PR interval depression is a very specific indicator of acute +pericarditis. +Later, there may be T-wave inversion, particularly +if there is a degree of myocarditis. +A low-grade fever is common. +16.101 ECG in viral pericarditis. +Widespread ST elevation (leads I, +II, aVL and V1 –V6) is shown. +Larger effusions may be accompanied +by a sensation of retrosternal oppression. +Typical physical ndings +are a markedly raised JVP, hypotension, pulsus paradoxus +(p. +448) and oliguria. +16.102). +The QRS voltages on the ECG are often +reduced in the presence of a large effusion. +A pericardial drain may be placed to provide symptomatic +relief. +A +viscous, loculated or recurrent effusion may also require formal +surgical drainage. +In Africa, +a tuberculous pericardial effusion is a common feature of AIDS +(p. +322). +The condition typically presents with chronic malaise, +weight loss and a low-grade fever. +An associated pleural +effusion is often present. +Treatment +requires specific antituberculous chemotherapy (p. +In effect, the heart is encased +in a solid shell and cannot ll properly. +It is +often impossible to identify the original insult. +AF is common and +there is often dramatic ascites and hepatomegaly (Box 16.109). +Breathlessness is not a prominent symptom because the lungs +are seldom congested. +Investigations +A chest X-ray, which may show pericardial calcication (Fig. +16.103), and echocardiography often help to establish the +diagnosis. +CT scanning is useful for imaging the pericardial +calcication. +16.102 Pericardial effusion: echocardiogram (apical view). +Short-axis view of the heart showing a large circumferential pericardial +effusion (arrows). +The ECG may show features of the +underlying disease, such as pericarditis or acute MI. +A chest X-ray shows an enlarged globular heart +but can look normal. +Management +Cardiac tamponade is a medical emergency. +In some cases, surgical drainage may be +required. +Fig. +There is heavy +calcication of the pericardium. +Other clinical features are summarised +in Box 16.110. +jbs3risk.com Joint British Societies for the Prevention of Cardiovascular +Disease: risk calculator. +Journal articles +Gould FK, Denning DW, Elliott TS, et al. +Smith, Papworth Hospital, Cambridge; (serous, mucopurulent and purulent sputum) Courtesy of Dr J. +The practice of respiratory medicine thus requires collaboration +with a range of disciplines. +Expiration is largely passive, driven by elastic recoil of +the lungs. +Major bronchial +and pulmonary divisions are shown in Figure 17.1. +The acinus (Fig. +17.1 The major bronchial divisions +and the ssures, lobes and segments of +the lungs. +The site of a lobe determines whether +physical signs are mainly anterior or +posterior. +Bronchopulmonary segments: +Right Upper lobe: (1) Anterior, (2) Posterior, +(3) Apical. +Middle lobe: (1) Lateral, (2) +Medial. +Left Upper lobe: (1) +Anterior, (2) Apical, (3) Posterior, (4) Lingular. +Lower lobe: (1) Apical, (2) Posterior basal, +(3) Lateral basal, (4) Anterior basal. +17.2 Functional anatomy of the lung. +A The tapering, branching bronchus is armoured against compression by plates of cartilage. +The more +distal bronchioles are collapsible, but held patent by surrounding elastic tissue. +B The unit of lung supplied by a terminal bronchiole is called an acinus. +The bronchiolar wall contains smooth muscle and elastin bres. +The latter also run through the alveolar walls. +Gas exchange occurs in the alveoli, which +are connected to each other by the pores of Kohn. +C Vascular anatomy of an acinus. +The venous drainage to the left atrium follows the interlobular septa. +From +www.Netter.com: Illustrations 155 (bronchus, acinus) and 191 (circulation), Elsevier. +17 +tension. +Type II pneumocytes can divide to reconstitute type I +pneumocytes after lung injury. +575). +Their activity is modulated +by multiple external inputs in health and in disease (see Fig. +They are also sensitised to hypoxia by raised arterial PCO2. +• Muscle spindles in the respiratory muscles sense changes +in mechanical load. +17.2). +• Decline in FEV1: the FEV1/FVC (forced expiratory volume/forced vital +capacity, p. +Smoking accelerates this decline threefold +on average. +Symptoms usually occur only when FEV1 drops below +50% of predicted. +This leads to a reduction in cardiorespiratory reserve and +exercise capacity. +These changes +become important only in the presence of other respiratory +disease. +C +Fig. +17.3 The mucociliary escalator. +as a sphincter, closing to protect the airway during swallowing +and vomiting. +62 and 67). +The innate response in the lungs is characterised by +a number of non-specific defence mechanisms. +Inhaled +particulate matter is trapped in airway mucus and cleared +by the mucociliary escalator. +Macrophages engulf microbes, organic dusts and other +particulate matter. +This may +explain the prominence of lung injury in sepsis syndromes and +trauma. +Lung dendritic cells +facilitate antigen presentation to T and B lymphocytes. +565). +emphysema or brosis) can impair gas diffusion +directly. +during +exercise. +17.3). +Check horizontal ssure from right hilum to sixth rib +at the anterior axillary line +Masses? +Consolidation? +Cavitation? +Lung apices Check behind the clavicles. +Masses? +Consolidation? +Cavitation? +Trachea Central (midway between the clavicular heads)? +Paratracheal mass? +Goitre? +Heart Normal shape? +Cardiothoracic ratio (should be < half the +intrathoracic diameter) +Retrocardiac mass? +Density? +Costophrenic +Acute and well dened (pleural fluid or thickening, +if not)? +17.4). +Increased shadowing may represent accumulation of fluid, +lobar collapse or consolidation. +17.5). +547). +In large pulmonary embolism, relative +oligaemia may cause a lung eld to appear abnormally dark. +17.4 The normal chest X-ray. +The lung markings consist of branching and tapering lines radiating out from the hila. +From Innes JA. +Davidson’s Essentials of medicine. +CT +identies the extent and appearance of pleural thickening (see +Fig. +17.65) and reliably differentiates pleural and pericardial fat +from other pathologies. +17.56), identifying airway thickening, bronchiectasis +(see Fig. +17.29) and emphysema (see Fig. +17.27). +The relative +contribution of competing pathologies to a breathless patient may +be assessed. +17.68), when it may either conrm the suspected embolism +or highlight an alternative diagnosis. +CT may assist +in identifying the cavitation of tuberculosis, fungal infection +(p. +300) and other signs of infection (halo – air crescent). +9PNO[ +TPKKSL +SVIL +9PNO[ +SV^LY +SVIL +Fig. +17.5 Radiological features of lobar collapse caused by bronchial +obstruction. +The dotted line in the drawings represents the normal +position of the diaphragm. +A In a patient with lung +cancer, CT shows some posterior pleural thickening. +B PET scanning reveals FDG uptake in two pleural lesions (arrows). +C The lesions are highlighted in +yellow in the combined PET/CT image. +A–C, From http://radiology.rsnajnls.org. +17.6). +17.6). +17.15). +605). +10.2, p. +179), and can +facilitate endobronchial laser therapy and stenting. +17554 • RESPIRATORY MEDICINE +bronchoscopy. +608) from those caused by +idiopathic pulmonary fibrosis (p. +605) or hypersensitivity +pneumonitis (p. +616). +They may identify a reaction +to fungi such as Aspergillus (p. +596) or to antigens involved in +hypersensitivity pneumonitis, such as farmer’s lung (p. +616). +IgG enzyme immunoassay may be used interchangeably. +17.7 Respiratory function tests in health and disease. +COPD causes slow, prolonged and limited exhalation. +B The same data +plotted as flow/volume loops. +The blue trace illustrates +large airway obstruction, which particularly limits peak flow rates. +C Lung volume measurement. +Volume/time graphs during quiet breathing with a single +maximal breath in and out. +COPD causes hyperinflation with increased residual volume. +In diseases +characterised by airway narrowing (e.g. +Typical laboratory traces are illustrated in +Figure 17.7. +salbutamol); an increase of > 12% and > 200 mL in +FEV1 or FVC indicates signicant reversibility. +567). +To distinguish large airway narrowing (e.g. +tracheal stenosis +or compression; see Fig. +18.12, p. +648) from small airway +narrowing, spirometry data are plotted as flow/volume loops. +17.7B). +This measures the volume of intrathoracic gas +that mixes freely with tidal breaths. +Alternatively, lung volume +may be measured by body plethysmography (p. +175), which +determines the pressure/volume relationship of the thorax. +The terms used to describe lung +volume are shown in Figure 17.7C. +Transfer factor expressed per +unit lung volume is termed KCO. +Common respiratory function +abnormalities are summarised in Box 17.4. +17.8 Changes in blood [H+], PaCO2 and plasma [HCO3−] in +acid–base disorders. +The rectangle indicates normal limits for [H+] and +PaCO2. +The bands represent 95% condence limits of single disturbances +in human blood. +Reprinted with permission from Elsevier (Flenley D. +Lancet 1971; 1:1921). +This is +discussed in detail on pages 363 and 565. +Interpretation of results +is made easier by blood gas diagrams (Fig. +Exercise testing with spirometry before and after can help to +reveal exercise-induced asthma. +These provide simple, repeatable assessments of +disability and response to treatment. +an inspiratory noise (stridor) indicates partial obstruction of a +major airway (e.g. +546). +793). +Bordetella +pertussis infection in adults (p. +582) can result in cough lasting +up to 3 months. +10.2, p. +179). +Distinguishing +characteristics of various causes of cough are detailed in Box 17.5. +Macleod’s Clinical examination, 10th edn. +The causes can +be classied accordingly (Box 17.6). +Key questions are detailed below. +How is your breathing at rest and overnight? +exercise) and in +diseases of the lungs, heart or muscles. +Pathophysiology +Stimuli to breathing resulting from disease processes are shown +in Figure 17.9. +Breathlessness and the effects of treatment can be quantied +using a symptom scale. +Patients tend to report breathlessness +in proportion to the sum of the above stimuli to breathing. +17.9 Respiratory stimuli contributing to breathlessness. +Mechanisms by which disease can stimulate the respiratory motor neurons in the +medulla. +Breathlessness is usually felt in proportion to the sum of these stimuli. +Further explanation is given on page 179. +463) Chronic heart failure (p. +463) +Myocardial ischaemia (angina equivalent) (p. +Did you have breathing problems in childhood or at school? +A history of atopic allergy also increases the +likelihood of asthma. +Do you have other symptoms along with your breathlessness? +These +alarming symptoms may provoke further anxiety and exacerbate +hyperventilation. +Arterial blood gases show normal +PO2, low PCO2 and alkalosis. +kyphoscoliosis or muscular dystrophy). +Acute severe breathlessness +This is one of the most common and dramatic medical +emergencies. +The approach to +patients with acute severe breathlessness is covered on page 179. +17.10). +arteriovenous shunts for dialysis. +It is +sometimes congenital but in over 90% of patients it indicates +a serious underlying disorder. +Clubbing +may recede if the underlying condition resolves, e.g. +following +lung transplantation for cystic brosis. +Haemoptysis +must always be assumed to have a serious cause until this is +excluded (Box 17.9). +Fever, +night sweats and weight loss suggest tuberculosis. +586). +Bronchiectasis +(p. +578) and intracavitary mycetoma (p. +Physical examination may reveal additional clues. +17.10 Finger clubbing. +A Anterior view. +B Lateral view. +From +Douglas G, Nicol F, Robertson C. +Macleod’s Clinical examination, 13th edn. +Edinburgh: Churchill Livingstone, Elsevier Ltd; 2013. +Bronchial arteriography +and embolisation (Fig. +17.11), or even emergency surgery, can +be life-saving in the acute situation. +pulmonary arteriovenous malformation +or small or hidden tumours). +The list of potential causes of pulmonary nodules is extensive +and most are benign (Box 17.10). +These assessments may be +aided by the use of computer prediction models (Box 17.11). +Fig. +17.11 Bronchial artery angiography. +Contrast is seen flowing into the lung. +This +patient had post-tuberculous bronchiectasis and presented with massive +haemoptysis. +Some nodular opacities may be sufciently typical of scarring for +follow-up not to be warranted. +Adapted from MacMahon H, Austin JH, Gamsu G, et al. +Radiology 2005; 237:395–400. +A +Solid non-calcified nodule(s) on CT +Clear features of benign disease (e.g. +Assess risk of lung cancer +Yes according to Fig. +17.13B +17 +No +Yes Nodule <8mm diameter or <300mm3 volume? +17.13 Recommendations on the assessment of a solid pulmonary nodule. +A Initial approach to solid pulmonary nodules. +Herder is a similar model. +17.13, cont’d +B Solid pulmonary nodule surveillance algorithm. +(VDT = volume doubling time) From Callister ME, Baldwin DR, Akram AR, et al. +British Thoracic Society Guidelines on the investigation and management of pulmonary nodules. +Thorax 2015; Suppl. +2:ii1–ii54. +PET scanning provides useful information about nodules of at +least 1 cm in diameter. +Detection of neuro-endocrine tumours +may be improved by the use of 68 Ga-Dotatoc in place of FDG. +If the nodule is small and inaccessible, interval CT scanning +may be employed. +Further interval scans may be arranged, depending +on the clinical context (Fig. +17.13). +The accumulation of frank pus is termed +empyema (p. +564), that of blood is haemothorax, and that of +chyle is a chylothorax. +The physical +signs are detailed on page 547. +547). +Fluid appears to +track up the lateral chest wall. +Around 200 mL of fluid is required in order +for it to be detectable on a PA chest X-ray. +Previous scarring +or adhesions in the pleural space can cause localised effusions. +Ultrasound is more accurate than plain chest X-ray for +determining the presence of fluid. +The presence of +septation most likely indicates an evolving empyema or resolving +haemothorax. +CT scanning is indicated where malignant disease i +s suspected. +Pleural aspiration and biopsy +In some conditions (e.g. +In most other circumstances, however, diagnostic +sampling is required. +The predominant cell type provides +useful information and cytological examination is essential. +Treatment of the underlying cause – e.g. +The management of pleural +effusion in pneumonia, tuberculosis and malignancy is dealt +with below. +Microscopically, neutrophil +leucocytes are present in large numbers. +Both pleural surfaces are covered with a thick, shaggy, +inflammatory exudate. +17.14 Chest X-ray showing a ‘D’-shaped shadow in the left +mid-zone, consistent with an empyema. +empyema itself. +Once an empyema has developed, systemic +features are prominent (Box 17.15). +17.14). +17.15). +CT +provides information on the pleura, underlying lung parenchyma +and patency of the major bronchi. +If the fluid is thick and turbid pus, empyema is conrmed. +However, pH measurement should be avoided if pus is thick, +as it damages blood gas machines. +The pus is frequently +sterile on culture if antibiotics have already been given. +Surgery is also necessary +if a bronchopleural stula develops. +Pathophysiology +When disease impairs ventilation of part of a lung (e.g. +Occasionally, however +(e.g. +severe pneumonia affecting several lobes), mechanical +ventilation may be needed to relieve hypoxia. +Fig. +17.15 Pleural ultrasound showing septation. +Courtesy of Dr P. +Sivasothy, Department of Respiratory Medicine, Addenbrooke’s Hospital, +Cambridge. +Empirical antibiotic treatment (e.g. +Intrapleural brinolytic therapy is of no benet. +625), immediate intubation or emergency +tracheostomy may be life-saving. +198), or occasionally tension pneumothorax (p. +625). +In all such cases, high-concentration (e.g. +202). +In all cases, regular +monitoring of arterial blood gases is important to assess progress. +following intracerebral haemorrhage or head injury). +during ambulance transfers or in emergency +departments. +10.9, p. +191). +Immediate treatment is shown in Box 17.17. +Some patients with advanced lung +disease, e.g. +cystic brosis, also benet from NIV for respiratory +failure. +In these conditions, type II respiratory failure can develop +slowly and insidiously. +Over time, however, CO2 retention +becomes chronic, with renal compensation of acidosis. +In +advanced disease (e.g. +muscular dystrophies or cystic brosis), +daytime NIV may also be required. +Chronic rejection with +obliterative bronchiolitis continues to afflict some recipients, +however. +89), are used to +prevent chronic rejection. +The major factor limiting the availability of lung transplantation +is the shortage of donor lungs. +The prevalence of asthma increased steadily over the latter part +of last century. +17.16). +613) +• Lymphangioleiomyomatosis +(p. +17.16 The burden of asthma, measured by disability life years +(DALYs) per 100 000 population. +The burden of asthma is greatest in +children approaching adolescence and the elderly. +From The Global Asthma Report 2014. +Copyright 2014 +The Global Asthma Network. +• Veno-occlusive disease +• Eisenmenger’s syndrome +(p. +allergen +Reduction in FEV1 (%) +40 +0 +0 1 2345678 24 +Time (hours) +Fig. +17.18 Changes in peak flow following allergen challenge. +A similar biphasic response is observed following a variety of different +challenges. +Occasionally, an isolated late response is seen with no early +reaction. +Increasing concentration of histamine +Fig. +17.17 Airway hyper-reactivity in asthma. +Asthma is commonly +mistaken for a cold or a persistent chest infection (e.g. +longer +than 10 days). +Wheeze apart, there +is often very little to nd on examination. +An inspection for nasal +polyps and eczema should be performed. +1043). +Patients with mild intermittent asthma are usually asymptomatic +between exacerbations. +Particularly when poorly controlled, symptoms such as cough +and wheeze disturb sleep. +Some patients with asthma have a similar inflammatory +response in the upper airway. +613). +In some circumstances, the appearance of asthma is triggered +by medications. +17.17). +17.18). +Allergic mechanisms are also implicated +in some cases of occupational asthma (p. +613). +Heat loss from the respiratory mucosa may +also be important. +Allergic triggers are +less important and airway neutrophilia predominates. +17.19). +If spirometry is not +available, a peak flow meter may be used. +17.20). +A trial of glucocorticoids (e.g. +17.17). +The use of exercise tests is useful when symptoms are +predominantly related to exercise (Fig. +17.21). +596). +A high-resolution +CT scan (HRCT) may be useful to detect bronchiectasis. +17.20 Serial recordings of peak expiratory flow (PEF) in a +patient with asthma. +Note the sharp overnight fall (morning dip) +and subsequent rise during the day. +Fig. +17.19 Reversibility test. +Forced expiratory manœuvres before and +20 minutes after inhalation of a β2-adrenoceptor agonist. +• Labour and delivery: 90% have no symptoms. +• Prostaglandin F2Îą: may induce bronchospasm and should be used +with extreme caution. +• Breastfeeding: use medications as normal. +3.5 +3.0 +2.5 +2.0 Exercise +025 5 10 15 20 30 +Time (minutes) +Fig. +17.21 Exercise-induced asthma. +Note initial rise on +completion of exercise, followed by sudden fall and gradual recovery. +pet, may effect improvement. +So far, improvements in asthma control +following such measures have been difcult to demonstrate. +Smoking cessation (p. +The stepwise approach to the management +of asthma +See Figure 17.22. +A variety of tools/questionnaires have been +validated to assist in assessing asthma control. +Written action +plans can be helpful in developing self-management skills. +17.22 Management approach in adults based on asthma control. +17.23 How to use a metered-dose inhaler. +in its use. +The metered-dose inhaler remains the most widely +prescribed (Fig. +17.23). +However, many patients (and their physicians) +under-estimate the severity of asthma. +A history of a severe +exacerbation should lead to a step-up in treatment. +Oral leukotriene receptor antagonists (e.g. +A nasal glucocorticoid +preparation should be used in patients with prominent upper +airway symptoms. +If the trial of add-on therapy is ineffective, +it should be discontinued. +670). +The risk of osteoporosis in +this group can be reduced by giving bisphosphonates (p. +1047). +17.24). +A chest X-ray is not immediately necessary, unless pneumothorax +is suspected. +Treatment includes the following measures: +• Oxygen. +Failure to achieve appropriate oxygenation is an indication +for assisted ventilation. +• High doses of inhaled bronchodilators. +Short-acting +β2-agonists are the agent of choice. +17.24 Immediate treatment of patients with acute severe asthma. +17 +• Systemic glucocorticoids. +These reduce the inflammatory +response and hasten the resolution of an exacerbation. +They should be administered to all patients with an acute +severe attack. +Potassium supplements may be +necessary, as repeated doses of salbutamol can lower serum +potassium. +If patients fail to improve, a number of further options may +be considered. +PEF should be recorded every 15–30 minutes and then every +4–6 hours. +Exacerbations and +co-morbidities contribute to the overall severity in individual +patients. +Extrapulmonary effects include weight loss and skeletal +muscle dysfunction (Fig. +17.25). +730), osteoporosis, +depression and lung cancer. +Risk factors are shown in Box 17.24. +Pathophysiology +COPD has both pulmonary and systemic components (Fig. +17.25). +The +term ‘cor pulmonale’ is a misnomer in such patients, as they +do not have heart failure. +Depression and anxiety are +also common and contribute to morbidity. +Two classical phenotypes have been described: ‘pink puffers’ +and ‘blue bloaters’. +In practice, +these phenotypes often overlap. +The severity of COPD may be +dened in relation to the post-bronchodilator FEV1 (Box 17.26). +Measurement of lung volumes provides an assessment of +hyperinflation. +This is generally performed by helium dilution +technique (p. +The presence of emphysema is suggested by a low gas transfer +(p. +515). +Pulse +oximetry may prompt referral for a domiciliary oxygen assessment +if less than 93%. +In practice, +the COPD Assessment Test and the COPD Control Questionnaire +are easier to administer. +17.26 The pathology of emphysema. +A Normal lung. +B Emphysematous lung, showing gross loss of the normal surface area +available for gas exchange. +B, Courtesy of the British Lung Foundation. +17 +Emphysema (Fig. +Bullae form in some individuals. +This results in impaired gas +exchange and respiratory failure. +Breathlessness usually prompts presentation to a health +professional. +Physical signs (p. +2 Or FEV1 < 50% with respiratory failure. +0 +25 50 75 +Age (years) +Fig. +17.28 Model of annual decline in FEV1 with accelerated decline +in susceptible smokers. +When smoking is stopped, subsequent loss is +similar to that in healthy non-smokers. +(FEV1 = forced expiratory volume in +1 second) +smokers, and cessation (p. +94) remains the only strategy that +impacts favourably on the natural history of COPD. +17.28). +Bronchodilators +Bronchodilator therapy is central to the management of +breathlessness. +Choice should be informed by patient preference and inhaler +assessment. +Orally active, highly selective phosphodiesterase inhibitors +remain under appraisal. +These advantages may +be accompanied by an increased risk of pneumonia, particularly +in the elderly. +Oral +R +L +Fig. +17.27 Gross emphysema. +High-resolution computed tomogram +showing emphysema, most evident in the right lower lobe. +characterisation and quantication of emphysema (Fig. +17.27) +and is more sensitive than the chest X-ray at detecting bullae. +It +is also used to guide lung volume reduction surgery. +The aim of therapy is to increase the PaO2 to at +least 8 kPa (60 mmHg) or SaO2 to at least 90%. +Oxygen flow rates should be +adjusted to maintain SaO2 above 90%. +Both bullectomy and LVRS can be performed +thorascopically, minimising morbidity. +Lung transplantation may +benet carefully selected patients with advanced disease (p. +567). +Mucolytic agents are +occasionally used but evidence of benet is limited. +Decisions +regarding resuscitation should be addressed in advance of +critical illness. +*See Box 17.25. +The prognosis is inversely related to age and directly related +to the post-bronchodilator FEV1 . +Additional poor prognostic +indicators include weight loss and pulmonary hypertension. +Respiratory +failure, cardiac disease and lung cancer represent common +modes of death. +566). +Bronchodilators +Nebulised short-acting β2 -agonists combined with an +anticholinergic agent (e.g. +salbutamol and ipratropium) should +be administered. +Doses of 30 mg for 10 days are currently recommended but +shorter courses may be acceptable. +670). +It is not useful in patients who cannot protect their +airway. +Mechanical ventilation may be contemplated when there +is a reversible cause for deterioration (e.g. +pneumonia) or when +no prior history of respiratory failure has been noted. +Bronchiectasis +Bronchiectasis means abnormal dilatation of the bronchi. +The result is chronic inflammation and infection in the airways. +Box 17.30 shows the common causes, of which tuberculosis +is the most common worldwide. +an aspirated peanut). +Clinical features +The symptoms are shown in Box 17.31. +Physical signs in the chest may be unilateral or bilateral. +Even +mild cognitive impairment virtually precludes their use. +Frequent +demonstration and re-instruction in the use of all devices are +required. +Patients should +lie in a position in which the lobe to be drained is uppermost. +piperacillin–tazobactam or +ceftazidime) will be required. +Early recognition and treatment of bronchial obstruction are +also important. +17.29 Computed tomogram of bronchiectasis. +Extensive dilatation +of the bronchi, with thickened walls (arrows) in both lower lobes. +breathing. +Frequent cultures are necessary to ensure appropriate treatment +of resistant organisms. +Bronchiectasis, unless very gross, is not usually apparent +on a chest X-ray. +CT is much more +sensitive and shows thickened, dilated airways (Fig. +17.29). +Ciliary +beat frequency may also be assessed from biopsies taken from +the nose. +40 and 48). +It is much less common in people of African +descent and rarer still in Asians. +17.30). +Pre-implantation +and/or prenatal testing may be offered to those known to be +at high risk (p. +56). +At this stage, the lungs are most commonly infected +with Staph. +aureus; however, in adulthood, many patients become +colonised with P. +aeruginosa, Stenotrophomonas maltophilia +or other Gram-negative bacilli. +Other clinical +manifestations are shown in Box 17.32. +This suggests that other ‘modier genes’, +as yet unidentied, influence clinical outcome. +While infections with Staph. +Resistant strains of P. +17.30 Cystic brosis: basic defect in the pulmonary epithelium. +Normal channels +appear to inhibit the adjacent epithelial sodium channels (2). +Osteoporosis secondary to malabsorption and +chronic ill health should be sought and treated. +Improved versions of these treatments +may soon offer similar benets for these patients. +Somatic gene +therapy for CF is also under development. +Trials are under way but more efcient gene delivery methods +are needed to make this practical. +596) also occurs occasionally +in CF. +For advanced CF lung disease, home oxygen and NIV +may be necessary to treat respiratory failure. +The vast majority are caused by viruses (p. +249) +and, in adults, are usually short-lived and rarely serious. +Acute coryza is the most common URTI and is usually the +result of rhinovirus infection. +In addition to general malaise, acute +coryza typically causes nasal discharge, sneezing and cough. +If complicated by a tracheitis +or bronchitis, chest tightness and wheeze typical of asthma +occur. +Bordetella pertussis, the cause of whooping cough, is an +important source of URTI. +It is highly contagious and is notiable +in the UK. +Examination usually conrms +erythematous swollen nasal mucosa and pus may be evident. +Nasal polyps should be sought and dental infection excluded. +Influenza is discussed on page 240. +Streptococcus pneumoniae (Fig. +17.31) remains the +Fig. +The common causative +organisms are shown in Box 17.36. +Clinical features +Pneumonia, particularly lobar pneumonia, usually presents as an +acute illness. +The +appetite is invariably lost and headache frequently reported. +Rust-coloured +sputum may be produced by patients with Strep. +17.32 Hospital CURB-65. +*Dened as a mental test score of 8 or less, or new disorientation in person, place or time. +Less typical +presentations may be seen in the very young and the elderly. +Staph. +aureus is more common +following an episode of influenza. +MERS-coronavirus (Middle East; p. +249), +melioidosis caused by Burkholderia pseudomallei (South-east +Asia and northern Australia; p. +261) and endemic fungal infection +(North, Central or South America; p. +301). +Certain occupations +may be associated with exposure to specic bacteria (p. +618). +17.32). +Chest signs (p. +An assessment of the state of nutrition +is important, particularly in the elderly. +The differential diagnosis of pneumonia is shown in Box 17.37. +606) +17 +identify the development of complications. +In severe or prolonged illness, +nutritional support may be required. +Indications for ITU referral are summarised +in Box 17.39. +It may be +appropriate to discontinue hypertensive agents temporarily. +Otherwise, an adequate oral intake of fluid should be encouraged. +Inotropic support may be required in patients with shock (p. +17.33 Pneumonia of the right middle lobe. +B Lateral view: consolidation conned to the +anteriorly situated middle lobe. +17.39 Indications for referral to ITU +• CURB score of 4–5 (see Fig. +Current regimens are detailed +in Box 17.40. +For the majority, simple +analgesia with paracetamol, co-codamol or NSAIDs is sufcient. +those over 65 or with chronic lung, +heart, liver or kidney disease, diabetes or immunosuppression). +Adapted from British Thoracic Society Guidelines. +17.41 Complications of pneumonia +• Para-pneumonic effusion – common +• Empyema (p. +198) +• Ectopic abscess formation (Staph. +aureus) +• Hepatitis, pericarditis, myocarditis, meningoencephalitis +• Arrhythmias (e.g. +glucocorticoid treatment, diabetes, +malignancy) +• Reduced cough reflex (e.g. +post-operative) +• Disordered mucociliary clearance (e.g. +Late-onset HAP is more often attributable to Gram-negative +bacteria (e.g. +Escherichia coli, Pseudomonas aeruginosa, +Klebsiella spp. +and Acinetobacter baumannii), Staph. +aureus +(including meticillin-resistant Staph. +aureus (MRSA)) and +anaerobes, and the choice of antibiotics ought to cover these +possibilities. +MRSA cover may be provided by +glycopeptides such as vancomycin or linezolid. +A. +Good hygiene is paramount, particularly with regard +to hand-washing and any equipment used. +These +conditions may also complicate local bronchial obstruction from +a neoplasm or foreign body. +aureus or K. +pneumoniae. +Actinomyces infections (mostly A. +The +organism(s) isolated from the sputum include Strep. +pneumoniae, +Staph. +aureus, Streptococcus pyogenes, H. +influenzae and, in +some cases, anaerobic bacteria. +In many cases, however, no +pathogen can be isolated, particularly when antibiotics have +been given. +Lemierre’s syndrome is a rare cause of pulmonary abscesses. +The usual causative agent is the anaerobe Fusobacterium +necrophorum. +• Predisposing factors: other medical conditions may predispose to +infection, e.g. +swallowing difculties due to stroke increase the risk +of aspiration pneumonia. +• Influenza: has a much higher complication rate, and morbidity and +mortality. +Vaccination signicantly reduces morbidity and mortality in +old age but uptake is poor. +Cryptic miliary tuberculosis is an occasional alternative presentation. +aeruginosa, viruses, fungi, mycobacteria, +and less common organisms such as Nocardia spp. +Infection +is often due to more than one organism. +318). +In P. +The clinical features +of invasive pulmonary aspergillosis are dealt with on page 597. +Investigations +The approach is informed by the clinical context and severity +of the illness. +554) offers a relatively safe method +of obtaining microbiological samples. +jirovecii pneumonia, fungi, +viruses and unusual bacteria, e.g. +Nocardia +• cavitation may be seen with N. +596) +• pleural effusions suggest pyogenic bacterial infections and +are uncommon in P. +jirovecii pneumonia. +Factors that favour a bacterial aetiology +include neutropenia, rapid onset and deterioration. +In these +circumstances, broad-spectrum antibiotic therapy should be +commenced immediately, e.g. +The management of P. +jirovecii infection is detailed on +page 318 and that of invasive aspergillosis on page 596. +The clinical features of suppurative pneumonia are summarised +in Box 17.44. +Abscesses are characterised +by cavitation and a fluid level. +Management +Aspiration pneumonia can usually be treated with amoxicillin +and metronidazole. +Parenteral therapy with vancomycin or linezolid +can also be considered. +Prolonged +treatment for 4–6 weeks may be required in some patients with +lung abscess. +Surgery +should be contemplated if no improvement occurs despite +optimal medical therapy. +Removal or treatment of any obstructing +endobronchial lesion is essential. +17.34 Worldwide incidence of tuberculosis +(2014). +Estimated new cases (all forms) per 100 000 +population. +From World Health Organisation. +Global +tuberculosis report, 20th edn. +Geneva: WHO; 2015. +bovis (reservoir cattle) and M. +africanum (reservoir +humans). +None +the less, its impact on world health remains signicant. +17.34). +Pathology and pathogenesis +M. +bovis infection arises mainly drinking non-sterilised milk from +infected cows. +M. +17.35). +17.35 Tuberculous granuloma. +The central area of this focus shows caseous +degeneration (black arrow). +Courtesy of Dr William Wallace, Department of +Pathology, Royal Inrmary of Edinburgh. +(p. +594). +If these reparative processes fail, primary progressive +disease ensues (Fig. +17.36). +17.36 Primary pulmonary tuberculosis. +(2) Direct extension of +the primary focus – progressive pulmonary tuberculosis. +(3) Spread to the +pleura – tuberculous pleurisy and pleural effusion. +Fundoscopy +may show choroidal tubercles. +Anaemia and leucopenia reflect bone marrow +involvement. +‘Cryptic’ miliary TB is an unusual presentation +sometimes seen in old age (Box 17.48). +The onset is usually insidious, +developing slowly over several weeks. +Very occasionally, this form of TB may present +with one of the complications listed in Box 17.50. +17.37). +Clinical tuberculosis. +Lymphadenitis +Lymph nodes are the most common extrapulmonary site of +disease. +Disease may represent primary infection, +spread from contiguous sites or reactivation. +Supraclavicular +lymphadenopathy is often the result of spread from mediastinal +disease. +The nodes are usually painless and initially mobile +but become matted together with time. +The tuberculin test is usually strongly positive. +avium complex. +17.38). +Ileocaecal disease accounts for approximately half of +abdominal TB cases. +Up to 30% of cases present with an acute abdomen. +Barium +enema and small bowel enema reveal narrowing, shortening and +Fig. +17.37 Chest X-ray: major manifestations and differential +diagnosis of pulmonary tuberculosis. +Less common manifestations +include pneumothorax, acute respiratory distress syndrome (ARDS; p. +198), +cor pulmonale and localised emphysema. +distortion of the bowel, with caecal involvement predominating. +Diagnosis rests on obtaining histology by either colonoscopy +or mini-laparotomy. +The main differential diagnosis is Crohn’s +disease (p. +813). +Tuberculous peritonitis is characterised by +abdominal distension, pain and constitutional symptoms. +The +ascitic fluid is exudative and cellular, with a predominance of +lymphocytes. +Laparoscopy reveals multiple white ‘tubercles’ +over the peritoneal and omental surfaces. +Low-grade hepatic +dysfunction is common in miliary disease, in which biopsy reveals +granulomas. +Occasionally, patients may be frankly icteric, with +a mixed hepatic/cholestatic picture. +Pericardial disease +Disease occurs in two forms (see Fig. +17.38 and p. +542): pericardial +effusion and constrictive pericarditis. +Coexistent pulmonary +disease is very rare, with the exception of pleural effusion. +Constriction is associated with an early +third heart sound and, occasionally, atrial brillation. +Diagnosis is +based on the clinical, radiological and echocardiographic ndings +(p. +542). +The effusion is frequently blood-stained. +Open pericardial +biopsy can be performed where there is diagnostic uncertainty. +17.38 Systemic presentations of extrapulmonary tuberculosis. +Unrecognised and untreated, it is rapidly +fatal. +Clinical features, investigations and +management are described on page 1120. +17.38). +Important complications include spinal instability +or cord compression. +TB can affect any joint but most frequently involves the hip or +knee. +Presentation is usually insidious, with pain and swelling; +fever and night sweats are uncommon. +In men, genitourinary +TB may present as epididymitis or prostatitis. +17.39) should prompt +further investigation (Box 17.51). +Direct microscopy of a sputum +smear remains the most important rst step. +Induced sputum may be used in those unable to expectorate. +In selected cases, bronchoscopy and lavage or aspiration of a +lymph node by EBUS may be used. +17.40) or the use +of mercury-vapour fluorescent microscopy. +17.39 Typical changes of tuberculosis. +The chest X-ray shows +bilateral upper lobe airspace shadowing with cavitation. +Fig. +17.40 Positive Ziehl–Neelsen stain. +Mycobacteria (arrow) retain +the red carbol fuchsin stain, despite washing with acid and alcohol. +Courtesy of Adam Hill. +of rapid NAATs (p. +106). +However, while it is +specic to MTB, it is not sufciently sensitive to have replaced +culture. +The diagnosis of extrapulmonary TB can be more challenging. +Rapid identication of rifampicin +resistance is provided by Xpert MTB/RIF. +Treatment of tuberculosis guidelines, 4th edn; 2010. +2 More common in patients with a slow acetylator status and in alcoholics. +pyrazinamide and ethambutol. +Fixed-dose tablets combining two +or three drugs are preferred. +Most patients can be treated at home. +Extrapulmonary TB +must be assessed clinically or radiographically, as appropriate. +Control and prevention +TB is preventable, particularly so in those with latent TB. +They do not develop any signs of active +disease and are non-infectious. +They are however, at risk of +developing active TB disease and becoming infectious. +Latent TB may be identified by the presence of immune +responses to M. +tuberculosis antigens. +Contact tracing is a +legal requirement in many countries. +Cases are commonly identified using the tuberculin skin +test (TST; Fig. +17.41) or an IGRA (Fig. +17.42). +A course of rifampicin and isoniazid for 3 months or +isoniazid for 6 months is effective. +17.42). +In the UK, a dual strategy of TST followed by +IGRA is recommended. +DOT has become +an important control strategy in resource-poor nations. +17.42 The principles of interferon-gamma release assays +(IGRAs). +(ELISPOT = enzyme-linked immunosorbent +spot assay) +Fig. +17.41 The tuberculin skin test. +It is recommended +that all patients with TB should be tested for HIV infection. +Mortality is high and TB is a leading cause of death in HIV +patients. +Full discussion of its presentation and management +is given on page 318. +Globally, an estimated 3.3% of new +TB cases and 20% of previously treated cases have MDR-TB. +In +2014, an estimated 190 000 people died of MDR-TB. +An estimated 9.7% of +people with MDR-TB have XDR-TB. +Box 17.54 lists the factors contributing to +the emergence of drug-resistant TB. +The mortality rate from +MDR-TB is high and that from XDR-TB higher still. +Vaccines +BCG (the Calmette–GuĂŠrin bacillus), a live attenuated vaccine +derived from M. +bovis, is the most established TB vaccine. +It is +administered by intradermal injection and is highly immunogenic. +BCG is very safe, with the occasional +complication of local abscess formation. +It should not be +administered to those who are immunocompromised (e.g. +by +HIV) or pregnant. +There is a small (< 5%) +and unavoidable risk of relapse. +Most relapses occur within +5 months and usually have the same drug susceptibility. +Death is more likely in those who +are smear-positive and those who smoke. +HIV-positive patients have higher mortality rates and a modestly +increased risk of relapse. +The sites +commonly involved are the lungs, lymph nodes, skin and soft +tissues. +The most widely recognised of these mycobacteria, +M. +avium complex (MAC), is well described in severe HIV +disease (CD4 count < 50 cells/mL – p. +324). +The most commonly reported organisms include M. +kansasii, +M. +malmoense, M. +xenopi and M. +abscessus but geographical +variation is marked. +M. +abscessus and M. +fortuitum grow rapidly +but the majority grow slowly. +With the exception +of M. +kansasii, drug sensitivity testing is usually unhelpful in +predicting treatment response. +abscessus in cystic +brosis. +17 +17.55 Site-specic opportunistic +mycobacterial disease +Pulmonary +• M. +xenopi +• M. +kansasii +• M. +malmoense +• MAC +• M. +abscessus (in cystic +brosis) +Lymph node +• MAC +• M. +fortuitum +• M. +chelonei +• M. +malmoense +Soft tissue/skin +• M. +leprae +• M. +ulcerans (prevalent in +Africa, northern Australia and +South-east Asia) +• M. +marinum +• M. +fortuitum +• M. +haemophilum +• M. +genavense +• M. +fortuitum +• M. +chelonae +• BCG +(BCG = bacille Calmette–GuĂŠrin; MAC = Mycobacterium avium complex – +M. +scrofulaceum, M. +intracellulare and M. +‘Mycosis’ is the +term applied to disease caused by fungal infection. +The conditions +associated with Aspergillus species are listed in Box 17.57. +611). +The prevalence of ABPA is +approximately 1–2% in asthma and 5–10% in CF. +Clinical features +Clinical features depend on the stage of the disease. +Diagnostic features +are shown in Box 17.58 and the typical Aspergillus hyphae in +Figure 17.43. +In some +patients, itraconazole (400 mg/day) facilitates a reduction in oral +Fig. +17.43 Branching Aspergillus hyphae seen in allergic +bronchopulmonary aspergillosis. +Aspergillus fumigatus +was subsequently grown on culture. +Courtesy of Mr T. +Russell and Dr M. +Hanson, Department of Microbiology, NHS Lothian. +glucocorticoids; a 4-month trial is usually recommended to assess +its efcacy. +The use of specic anti-IgE monoclonal antibodies is +under consideration. +They are uncommon conditions and +challenging to diagnose and treat. +17.44). +Simple aspergillomas are often asymptomatic. +17.44 Computed tomogram of aspergilloma in the left upper +lobe. +The rounded fungal ball is separated from the wall of the cavity by +an ‘air crescent’ (arrow). +fumigatus. +Less than half exhibit skin +hypersensitivity to extracts of A. +fumigatus. +Rarely, other +filamentous fungi can cause intracavity mycetoma and are +identied by culture. +Asymptomatic cases do not require treatment but haemoptysis +should be controlled by surgery. +17.45). +Treatment usually involves prolonged +courses of itraconazole or voriconazole. +Surgical intervention is fraught with complications +and should be avoided. +Many patients are malnourished and +require nutritional support. +Glucocorticoids should be avoided. +In addition to lung cancer, +the Aspergillus nodule may mimic TB but cavitation is unusual. +17 +Fig. +17.45 Chronic pulmonary aspergillosis. +A The chest X-ray shows +pleural thickening with loss of lung volume at the left apex (arrow). +Courtesy of Professor David Denning, +National Aspergillosis Centre, Manchester, UK. +It is also seen in the presence of COPD, +non-tuberculous mycobacteria or HIV infection. +SIA should be +treated in a similar manner to invasive pulmonary aspergillosis. +Diagnosis is often inferred from a combination of features +(Box 17.60). +Management and prevention +IPA carries a high mortality rate, especially if treatment is +delayed. +The drug of choice is voriconazole. +Second-line agents +include liposomal amphotericin, caspofungin, posaconazole and +isavuconazole. +Other fungal infections +Mucormycosis (p. +303) may present with a pulmonary syndrome +that is clinically indistinguishable from acute IPA. +Pneumocystis jirovecii +pneumonia is described on page 318. +chronic granulomatous +disease or severe combined immune deciency (p. +Tobacco use is the major preventable cause. +1 Must be consistent with the mycological ndings and temporally related to +current episode. +2 May be useful as a preliminary screening tool for invasive +aspergillosis. +(BAL = bronchoalveolar lavage) +Adapted from De Pauw B, Walsh TJ, Donnelly JP, et al. +Clin Infect Dis 2008; +46:1813–1821. +Pathology +Lung cancers arise from the bronchial epithelium or mucous +glands. +The common cell types are listed in Box 17.62. +17.47). +Lymphatic spread to mediastinal and supraclavicular lymph nodes +often occurs before diagnosis. +Blood-borne metastases occur +most commonly in liver, bone, brain, adrenals and skin. +Cough This is the most common early symptom. +It is often dry +but secondary infection may cause purulent sputum. +Haemoptysis Haemoptysis is common, especially with central +bronchial tumours. +The death rate from the disease in +heavy smokers is 40 times that in non-smokers. +Risk falls slowly +after smoking cessation but remains above that in non-smokers +for many years. +It is estimated that 1 in 2 smokers dies from a +smoking-related disease, about half in middle age. +Exposure +to naturally occurring radon is another risk. +1320). +94). +17.46). +17.46 Mortality trends from lung cancer in UK, 1979–2013, by +age and year of death. +A Males. +B Females. +Accessed +January 2017. +Fig. +Intercostal nerve involvement causes pain in the distribution +of a thoracic dermatome. +1091) due to involvement +of the sympathetic nerves to the eye at or above the stellate +ganglion. +Mediastinal spread Involvement of the oesophagus may cause +dysphagia. +If the pericardium is invaded, arrhythmia or pericardial +effusion may occur. +Lassitude, anorexia and weight loss usually indicate +metastatic spread. +546). +X-rays reveal subperiosteal new bone formation. +17.48 Collapse of the right lung: effects on neighbouring +structures. +A Chest X-ray. +B The typical abnormalities are highlighted. +infection, haemoptysis in a smoker should always be investigated +to exclude a lung cancer. +Bronchial obstruction This is another common presentation. +The clinical and radiological manifestations (Figs 17.48 and +17.5, p. +678) +• Gynaecomastia +Neurological (Ch. +17.49 Common radiological presentations of lung cancer. +(1) Unilateral hilar enlargement suggests a central tumour or hilar glandular +involvement. +(2) Peripheral pulmonary opacity (p. +560) is usually irregular but well +circumscribed, and may contain irregular cavitation. +It can be very large. +(3) Lung, lobe or segmental collapse is usually caused by tumour occluding +a proximal bronchus. +Collapse may also be due to compression of a +bronchus by enlarged lymph glands. +(5) Paratracheal lymphadenopathy may +cause widening of the upper mediastinum. +(6) A malignant pericardial +effusion may cause enlargement of the cardiac shadow. +(7) A raised +hemidiaphragm may be caused by phrenic nerve palsy. +Screening will +show paradoxical upward movement when the patient sniffs. +(8) Osteolytic +rib destruction indicates direct invasion of the chest wall or metastatic +spread. +most frequently associated with lung cancer, HPOA can occur +with other tumours. +357) +and ectopic adrenocorticotrophic hormone secretion (p. +670) are +usually associated with small-cell lung cancer. +Associated neurological +syndromes may occur with any type of lung cancer. +Imaging +Lung cancer produces a range of appearances on chest X-ray, +from lobar collapse (see Fig. +17.5, p. +552) to mass lesions, +effusion or malignant rib destruction (Fig. +17.49). +in +establishing whether a tumour is accessible by bronchoscopy +or percutaneous CT-guided biopsy. +17.50). +In those who are unt +17 +Fig. +17.50 Bronchoscopic view of a lung cancer. +for invasive investigation, sputum cytology may reveal malignant +cells, although the yield is low. +In patients with pleural effusions, pleural aspiration and biopsy +is the preferred investigation. +17.51 Tumour stage and 5-year survival in non-small-cell lung cancer. +Based on data from Detterbeck FC, Boffa DJ, Kim AW, Tanoue +T. +The eighth edition lung cancer stage classication. +Chest 2017; 151:193–203. +CT +is used early to detect obvious local or distant spread. +Combined CT and whole-body +PET (see Fig. +17.6, p. +553) is commonly used to detect occult +but metabolically active metastases. +17.51). +Such patients are offered +palliative therapy and best supportive care. +Radiotherapy and, +in some cases, chemotherapy can relieve symptoms. +Highly targeted (stereotactic) radiotherapy +may be given in 3–5 treatments for small lesions. +Obstruction of +the trachea and main bronchi can also be relieved temporarily. +1331). +Combination chemotherapy +leads to better outcomes than single-agent treatment. +in the epidermal +growth factor receptor (EGFR) gene. +Tyrosine kinase inhibitors, +such as erlotinib and monoclonal antibodies to EGFR (e.g. +1353). +The best results are achieved in tumours of the main bronchi. +Effective communication, pain relief and attention to diet +are important. +The management of non-metastatic endocrine manifestations is +described in Chapter 18. +The clinical features and prognosis +of some less common tumours are given in Box 17.65. +These secondary deposits are usually multiple +and bilateral. +Often there are no respiratory symptoms and the +diagnosis is incidental on X-ray. +Endobronchial deposits are uncommon but +can cause haemoptysis and lobar collapse. +Palliation of breathlessness with opiates may +help (p. +1353). +17.52 The divisions of the mediastinum. +(1) Superior mediastinum. +(2) Anterior mediastinum. +(3) Middle mediastinum. +(4) Posterior mediastinum. +Sites of the more common mediastinal tumours are also illustrated. +From Johnson N McL. +Respiratory medicine. +Oxford: Blackwell Science; 1986. +17.53 Intrathoracic goitre (arrows) extending from right upper +mediastinum. +17.53). +CT (or MRI) is the investigation +of choice for mediastinal tumours (e.g. +see Fig. +18.12, p. +648). +Bronchoscopy may reveal a primary lung cancer causing +mediastinal lymphadenopathy. +EBUS may be used to guide +sampling of peribronchial masses. +553). +A dermoid cyst may very occasionally rupture into a +bronchus. +17.54). +usual interstitial pneumonia (UIP) or non-specific interstitial +pneumonia (NSIP). +The most important of these is idiopathic +pulmonary brosis. +sarcoid +Further investigations, e.g. +drugs or association +with connective tissue +disease +Other forms of DPLD, e.g. +Idiopathic interstitial +Granulomatous DPLD, +lymphangioleiomyomatosis, +e.g. +sarcoidosis +pneumonia +histiocytosis X etc. +17.55 Classication of diffuse parenchymal lung disease. +Usually presents at age 40–60 years. +Smoking cessation may +lead to improvement. +Prognosis often poor +Desquamative interstitial pneumonia (DIP) More common in men and smokers. +Presents at age 40–60 years. +Insidious onset of dyspnoea. +Clubbing in 50%. +Systemic features and markedly raised erythrocyte +sedimentation rate common. +Finger clubbing absent. +Investigate for associations with connective tissue +disease or HIV. +There is a strong +association with cigarette smoking. +Constitutional symptoms are +unusual. +Investigations +These are summarised in Box 17.71. +The chest X-ray may be normal +in individuals with early or limited disease, however. +17.56 Idiopathic pulmonary brosis. +A Anteroposterior view. +B Transverse section. +Courtesy of Dr Andrew +Baird, Consultant Radiologist, NHS Lothian, Edinburgh, UK. +(Fig. +17.56). +616) or sarcoidosis (p. +608). +The presence of pleural plaques may suggest asbestosis (p. +618). +However, +lung volumes may be preserved in patients with concomitant +emphysema. +Lung biopsy +should be considered in cases of diagnostic uncertainty or with +atypical features. +UIP is the histological pattern predominantly +encountered in IPF (Fig. +Management +The management options for IPF are improving. +Both of these agents have been +shown to reduce the rate of decline in lung function. +Nintedanib may be accompanied by diarrhoea. +Medication to control +gastro-oesophageal reflux may improve the cough. +Current +smokers should be apprised of the increased risk of lung cancer +and advised to stop. +Influenza and pneumococcal vaccination +should be recommended. +Domiciliary oxygen should +be considered for palliation of breathlessness in severe cases. +Where appropriate, lung transplantation should be considered. +The optimum treatment for acute exacerbations is unknown. +Treatment is largely supportive. +Broad-spectrum antibiotics may608 • RESPIRATORY MEDICINE +A B +Fig. +17.57 Pathology of usual interstitial pneumonia. +This distribution of brosis is typical of usual interstitial pneumonitis. +The brosis may be associated with prominent cystic change known as +‘honeycomb lung’. +Courtesy of Dr William Wallace, Department of Pathology, Royal Inrmary of Edinburgh. +The +nding of high numbers of broblastic foci on biopsy suggests +a more rapid deterioration. +As with UIP, the pulmonary condition may +precede the appearance of connective tissue disease. +HRCT +ndings are less specic than with IPF and lung biopsy may be +required. +17.58). +The condition is more frequently +described in colder parts of northern Europe. +17.58 Sarcoidosis of the lung. +Histology showing non-caseating +granulomas (arrows). +Courtesy of Dr William Wallace, Department of +Pathology, Royal Inrmary of Edinburgh. +rarely affected. +Sarcoidosis +occurs less frequently in smokers. +It may be associated with +common variable immunodeciency (p. +79). +17.59 and Box 17.72). +17.59 Possible systemic involvement in sarcoidosis. +Inset (Erythema nodosum): From Savin JA, Hunter JAA, Hepburn NC. +Skin signs in clinical +medicine. +London: Mosby–Wolfe; 1997. +Pleural disease is +uncommon and nger clubbing is not a feature. +Investigations +Lymphopenia is characteristic and liver function tests may be +mildly deranged. +Hypercalciuria may also be seen and may lead +to nephrocalcinosis. +Chest radiography has +been used to stage sarcoid (Box 17.73). +Exercise tests610 • RESPIRATORY MEDICINE +may reveal oxygen desaturation. +Bronchoalveolar lavage fluid typically contains an increased +CD4:CD8 T-cell ratio. +PET scanning can detect extrapulmonary disease. +Similarly, a typical presentation with classical HRCT +features may also be accepted. +The presence of anergy (e.g. +to tuberculin skin +tests) may support the diagnosis. +17.59) and a stage III/IV chest X-ray. +1006) have been effective. +Selected patients may be referred for consideration +of single lung transplantation. +1021). +Pulmonary brosis +is the most common pulmonary manifestation. +All forms of +interstitial disease have been described but NSIP is probably +the most common. +A rare variant of localised upper lobe brosis +and cavitation is occasionally seen. +Pleural effusion is common, especially in men with seropositive +disease. +Effusions are usually small and unilateral, but can be +large and bilateral. +Most resolve spontaneously. +Rheumatoid pulmonary nodules are usually asymptomatic +and detected incidentally on imaging. +They are most often +multiple and subpleural in site (Fig. +17.60). +The term encompasses a group of disorders of +different aetiology (Box 17.75). +The pathology is usually +that of diffuse alveolar damage. +Diagnosis is confirmed by +BAL, which characteristically demonstrates > 25% eosinophils. +The condition is usually idiopathic but drug reactions should +be considered. +Glucocorticoids invariably induce prompt and +complete resolution. +It is more common in middle-aged females. +BAL reveals a high proportion of eosinophils +Fig. +17.60 Rheumatoid (necrobiotic) nodules. +The nodule in the left lower lobe shows +characteristic cavitation. +diagnoses include pulmonary metastatic disease. +Cavitation +raises the possibility of TB and predisposes to pneumothorax. +The combination of rheumatoid nodules and pneumoconiosis +is known as Caplan’s syndrome (p. +615). +Bronchitis and bronchiectasis are both more common in +rheumatoid patients. +Rarely, the potentially fatal condition called +obliterative bronchiolitis may develop. +Bacterial lower respiratory +tract infections are frequent. +Up to two-thirds of patients have repeated +episodes of pleurisy, with or without effusions. +Effusions may +be bilateral and may also involve the pericardium. +Pulmonary brosis is a relatively uncommon manifestation of +systemic lupus erythematosus (SLE). +Systemic sclerosis +Most patients with systemic sclerosis (p. +Aspergillus fumigatus causing allergic bronchopulmonary +aspergillosis (p. +1042; rare)612 • RESPIRATORY MEDICINE +in the lavage fluid. +Response to prednisolone (20–40 mg daily) +is usually dramatic. +290). +The condition presents with fever, weight loss, dyspnoea +and asthma-like symptoms. +The peripheral blood eosinophilia +is marked, as is the elevation of total IgE. +High antifilarial +antibody titres are seen. +289) as, in +strongyloidiasis, glucocorticoids may cause a life-threatening +hyperinfection syndrome. +Ascariasis (‘larva migrans’) and other +hookworm infestation are covered in Chapter 11. +1041). +Respiratory +symptoms include cough, haemoptysis and chest pain. +Fever, weight loss and anaemia +are common. +Other respiratory complications include tracheal subglottic +stenosis and saddle nose deformity. +401). +It occurs +more commonly in men and almost exclusively in smokers. +respond to glucocorticoid treatment. +The pulmonary effects of +radiation (p. +If the patient survives, +there are long-term risks of lung cancer. +Drugs +Drugs may cause a variety of pulmonary conditions (Box 17.76). +Eosinophilic pulmonary reactions can also +be caused by drugs. +bleomycin), antibiotics (e.g. +sulphonamides), sulfasalazine and the anticonvulsants phenytoin +and carbamazepine. +Patients usually present with breathlessness, +cough and fever. +The chest X-ray characteristically shows patchy +shadowing. +Although delivered in divided +doses, the effects are cumulative. +This may resolve spontaneously but responds to +glucocorticoid treatment. +Changes are often conned to the area irradiated but may +be bilateral. +This syndrome has been reported most +frequently in cases of opiate overdose in drug addicts (p. +Rare interstitial lung diseases +See Box 17.78. +Renal involvement is +more common at presentation and upper respiratory problems are +fewer. +• Increased dyspnoea: coexistent muscle weakness, chest wall +deformity (e.g. +• Surgical lung biopsy: often inappropriate in the very frail. +Many countries encourage the registration of cases of +occupational lung disease. +at weekends and on holidays. +17.61 Peak flow readings in occupational asthma. +The maximum, mean and minimum values are plotted daily. +Days at work are indicated by the shaded areas. +The diurnal variation is displayed at the top. +(PEF = peak expiratory flow) +very high concentrations. +Once developed, the condition often +persists but it is common for symptoms to improve over years. +Occupational COPD is recognised in workers exposed to +coal dust, crystalline silica and cadmium. +As the week progresses, symptoms improve +and the fall in lung function becomes less dramatic. +Not all dusts are pathogenic. +Beryllium causes +an interstitial granulomatous disease similar to sarcoidosis. +Conrmation of occupational asthma +should be sought from lung function tests. +17.61). +In certain circumstances, specic +challenge tests are required to conrm the diagnosis. +Specialist follow-up +in such situations is highly advisable. +569). +The most important pneumoconioses +include coal worker’s pneumoconiosis, silicosis and asbestosis. +Classication is based on the +size and extent of radiographic nodularity. +SCWP does not impair lung function and, once exposure +ceases, will seldom progress. +This syndrome may also +occur in other types of pneumoconiosis. +As the disease progresses, PMF +17 +B +Fig. +17.62 Silicosis. +may develop (Fig. +17.62). +Common causes include +farmer’s lung and bird fancier’s lung. +Other examples are shown +in Box 17.81. +The pathology of HP is consistent with both type III and type IV +immunological mechanisms (p. +83). +The distribution of the +inflammatory inltrate is predominantly peribronchiolar. +Chronic +forms of the disease may be accompanied by brosis. +Chest +auscultation typically reveals widespread end-inspiratory crackles +and squeaks. +17.63). +The +diagnosis may be conrmed by specialised tests of lymphocyte +function. +Baritosis may be seen in barium process workers and stannosis +in tin rening. +Haematite lung occurs in iron ore miners and +resembles silicosis but stains the lung red. +Hypersensitivity pneumonitis is the most common of these +conditions. +player’s lung* +instrument +Penicillium spp. +Cladosporium spp. +pigeon breeders). +drying hay before storage). +Severely hypoxaemic +patients may require high-concentration oxygen therapy initially. +Inhalation (‘humidier’) fever +Inhalation fever shares similarities with HP. +So-called ‘hot tub lung’ appears to be attributable +to Mycobacterium avium. +B +Asbestos-related lung and pleural diseases +Asbestos is a naturally occurring silicate. +17.63 Hypersensitivity pneumonitis. +A High-resolution computed +tomogram showing typical patchy ground-glass opacication. +In this case, there is little in +the way of established lung brosis but this can be marked. +A, Courtesy of +Dr S. +Jackson, Western General Hospital, Edinburgh. +B, Courtesy of Dr +William Wallace, Dept of Pathology, Royal Inrmary of Edinburgh. +Management +If it is practical, the patient should cease exposure to the inciting +agent. +In some cases this may be difcult, however, because +of either implications for livelihood (e.g. +farmers) or addiction to +Fig. +17.64 Asbestos-related benign pleural plaques. +17.64) or thoracic CT scan, particularly +when partially calcied. +They do not cause impairment of lung +function and are benign. +Repeated episodes +may be followed by the development of diffuse (visceral) pleural +thickening. +Earlier manifestations detected by CT scanning include +parenchymal bands (Fig. +17.65) and ‘round atelectasis’. +There +is no treatment and the condition may be progressive in around +one-third of individuals. +In exceptionally severe cases, surgical +decortication may be considered. +A pleural biopsy may be +required to exclude mesothelioma. +About 40% of patients (who usually smoke) develop lung cancer +and 10% may develop mesothelioma. +Its occurrence almost invariably +suggests past asbestos exposure, which may be low-level. +Around 1 in 170 of all British +men born in the 1940s will die of mesothelioma. +Mesothelioma is almost invariably fatal. +Radiotherapy can be used to control +pain and limit the risk of tumour seeding at biopsy sites. +Pleural +effusions are managed with drainage and pleurodesis. +Pneumococcal vaccine is +recommended for welders. +Birds (often +parrots) or budgerigars infected with Chlamydia psittaci can +cause psittacosis. +17.65 Thoracic CT scan showing right-sided pleural thickening +and an associated parenchymal band. +Finger clubbing may be present. +Pulmonary +function tests and HRCT appearances are similar to those of +UIP. +• Does the patient have risk factors for PE? +• Are there any alternative diagnoses that can explain the +patient’s presentation? +A recognised risk factor is present in 80–90% (see +Box 23.65, p. +975). +The presence of one or more risk factors +increases the risk further still. +Investigations +A variety of non-specic radiographic appearances have been +described (Fig. +186). +pneumonia or +pneumothorax. +A metabolic +acidosis may be seen in acute massive PE with cardiovascular +collapse. +An elevated D-dimer (see Fig. +10.6, p. +17.67). +The serum troponin I (see Box +10.3, p. +179) may be elevated, reflecting right heart strain. +CTPA is the rst-line diagnostic test (Fig. +17.68). +199). +Management +General measures +Prompt recognition and treatment are potentially life-saving. +Diuretics and vasodilators should also be avoided, +as they will reduce cardiac output. +17.68 CT pulmonary angiogram. +The arrow points to a saddle +embolism in the bifurcation of the pulmonary artery. +• CT pulmonary angiography: may be performed safely (0.01– +0.06 mGy). +. +Confirm +diagnosis +Not DVT/PE +Fig. +17.67 Algorithm for the investigation of patients with suspected +pulmonary thromboembolism. +Surgical pulmonary embolectomy may +be considered in selected patients but carries a high mortality. +Retrievable caval lters are particularly useful in +individuals with temporary risk factors. +Once anticoagulation is commenced, however, the risk of +mortality rapidly falls. +Simonneau G, Robbins IM, Beghetti M, et al. +Updated clinical classication of pulmonary hypertension. +J Am Coll Cardiol +2009; 54:S43–S54. +The clinical classication of PH is shown +in Box 17.85. +systemic sclerosis), or as a +result of chronic thromboembolic events. +Mutations +in this gene have been identied in some patients with sporadic +PH. +Clinical features +PH presents insidiously and is often diagnosed late. +Typical +symptoms include breathlessness, chest pain, fatigue, palpitation +and syncope. +17.69). +Management +Specialist centres should direct the management of PH. +Diuretic +therapy should be prescribed for patients with right heart failure. +pungent odours or fumes, including strong perfumes, cold +air and dry atmospheres. +In +perennial rhinitis, the symptoms are similar but more continuous +and usually less severe. +beclometasone +dipropionate, fluticasone, mometasone or budesonide. +muscular dystrophy). +In contrast, a small but important group of disorders cause +problems only during sleep. +Of these, the +obstructive sleep apnoea/hypopnoea syndrome is by far the +most common and important. +When this coexists with COPD, +severe respiratory failure can result, even if the COPD is mild. +Fig. +17.69 Chest X-ray showing the typical appearance in +pulmonary hypertension. +above 8 kPa (60 mmHg). +Anticoagulation should be considered +unless there is an increased risk of bleeding. +Digoxin may be useful +in patients who develop atrial tachyarrhythmias. +Pneumococcal and +influenza vaccination should be recommended. +Nitrates should +be avoided owing to the risk of hypotension, and β-blockers +are poorly tolerated. +Cyclizine can aggravate PH and should +also be avoided. +High-dose calcium channel blockers may be appropriate in those +with an acute vasodilator response. +Seasonal antigens include pollens from +grasses, flowers, weeds or trees. +Inspiration +results in negative pressure within the pharynx. +These awakenings are so brief that patients have no +recollection of them. +Nasal obstruction or a recessed +mandible can further exacerbate the problem. +The patient usually feels that he or +she has been asleep all night but wakes unrefreshed. +A more quantitative assessment of daytime +sleepiness can be obtained by questionnaire (Box 17.86). +Overnight studies of breathing, oxygenation and sleep quality +are diagnostic (Fig. +17.70 Sleep apnoea/hypopnoea syndrome: overnight oxygen +saturation trace. +Courtesy of Professor N.J. +Douglas. +Narcolepsy +is a rare cause of sudden-onset sleepiness, occurring in 0.05% +of the population (p. +1105). +In a minority, relief +of nasal obstruction or the avoidance of alcohol may prevent +obstruction. +babies/children) +• Shift work +• Excessive caffeine intake +• Physical illness (e.g. +Rarely, the vagal +trunk itself is involved by tumour, aneurysm or trauma. +Sputum clearance +may also be impaired. +Stridor is occasionally present but seldom severe, except when +laryngeal paralysis is bilateral. +Laryngoscopy is required to establish the diagnosis of laryngeal +paralysis. +The cause should be treated, if possible. +1187). +Laryngoscopy +may be necessary, however, to exclude a physical cause. +Speech therapy may +be helpful. +Important causes +are given in Box 17.89. +When CPAP is +tolerated, the effect is often dramatic (Fig. +17.70), with relief of +somnolence and improved daytime performance, quality of life +and survival. +Unfortunately, 30–50% of patients do not tolerate +CPAP. +There is no +evidence that palatal surgery is of benet. +Laryngeal disorders +The larynx is commonly affected by acute self-limiting infections +(p. +581). +Tumours of the larynx are relatively common, particularly in +smokers. +For further details, the reader should refer to an +otolaryngology text. +Chronic laryngitis +The common causes are listed in Box 17.88. +The chief symptoms +are hoarseness or loss of voice (aphonia). +There is irritation of the +throat and a spasmodic cough. +In some patients, a chest X-ray may reveal an unsuspected +lung cancer or pulmonary tuberculosis. +If these are not found, +laryngoscopy should be performed to exclude a local structural +cause. +When no specic treatable cause is found, the voice must be +rested completely. +This is particularly important in public speakers +and singers. +Smoking should be avoided. +Some benet may be +obtained from frequent inhalations of medicated steam. +Unrelieved, the condition progresses to coma +and death within a few minutes. +Urgent treatment to prevent complete obstruction is needed. +Laryngeal obstruction from all other causes +carries a high mortality and demands prompt treatment. +The +trachea may also be compressed by a retrosternal goitre (see +Fig. +18.12, p. +648). +1041) or trauma. +The choice of treatment depends on the nature of the tumour +and the general health of the patient. +Benign tracheal strictures +can sometimes be dilated but may require resection. +Tracheo-oesophageal stula +This may be present in newborn infants as a congenital +abnormality. +Swallowed liquids enter the trachea and bronchi +through the stula and provoke coughing. +Surgical closure of a congenital stula, if undertaken promptly, +is usually successful. +Primary spontaneous +pneumothorax occurs in patients with no history of lung disease. +Smoking, tall stature and the presence of apical subpleural blebs +are risk factors. +17.71). +17.71 Bimodal age distribution for hospital admissions for +pneumothorax in England. +The incidence of primary spontaneous +pneumothorax peaks in males aged 15–30 years. +17.72 Types of spontaneous pneumothorax. +A Closed type. +B Open type. +C Tension (valvular) type. +pneumothorax is referred to as ‘closed’ (Fig. +17.72A). +17.72B). +This is a tension pneumothorax. +17.72C). +In patients with a small pneumothorax, physical +examination may be normal. +A larger pneumothorax (> 15% of +the hemithorax) results in decreased or absent breath sounds +(p. +547). +547). +Surgical or +chemical pleurodesis is advised in all such patients. +pneumothorax. +CT is used in difcult cases to avoid misdirected +attempts at aspiration. +17.73). +Idiopathic diaphragmatic paralysis +occasionally occurs in otherwise t patients. +CT of the chest and neck is the best way to exclude occult +disease affecting the phrenic nerve. +1140); in disorders affecting the anterior horn cells, e.g. +poliomyelitis (p. +1034 +and 1039). +Hiatus hernia is common (p. +791). +Respiratory disorders that cause pulmonary +hyperinflation, e.g. +emphysema, and those that result in small stiff +lungs, e.g. +diffuse pulmonary brosis, compromise diaphragmatic +function and predispose to fatigue. +17.73 Management of spontaneous pneumothorax. +(1) +Immediate decompression prior to insertion of the intercostal drain. +17 +to the chest wall. +Clamping of an intercostal drain is potentially +dangerous and rarely indicated. +Continued bubbling after 5–7 days is an indication +for surgery. +The deformity may restrict chest expansion and reduce vital +capacity. +Operative correction is rarely performed, and then +only for cosmetic reasons. +Very occasionally, this deformity can +be produced by rickets or be idiopathic. +They can often be +successfully treated with non-invasive ventilatory support +(p. +202). +ginasthma.com Global Initiative for Asthma: comprehensive overview of +asthma. +Diabetes mellitus (described in detail in +Ch. +20) and thyroid disease are the most +common endocrine disorders. +ophthalmopathy, +pretibial myxoedema +• Check for Pemberton’s sign, +i.e. +643) +Diffuse firm goitre +Hashimoto’s thyroiditis (p. +646) +Diffuse tender goitre +Subacute thyroiditis (p. +646) +Multinodular goitre (p. +648) +Âą Retrosternal extension, +tracheal compression +Solitary nodule (p. +Endocrine diseases can therefore affect multiple organs and +systems. +20). +Less common endocrine syndromes +are described later in the chapter. +18.1 An archetypal endocrine axis. +18.1). +These integrated endocrine systems are called ‘axes’ +and are listed in Figure 18.2. +The biological effects of hormones are mediated +by binding to receptors. +Many receptors are located on the +cell surface. +39). +18.1). +However, additional levels of regulation are now +recognised. +Pathology arising within the gland is +often called ‘primary’ disease (e.g. +18.2 The principal endocrine ‘axes’. +Some major endocrine glands are not controlled by the pituitary. +These include the parathyroid glands +(regulated by calcium concentrations, p. +661), the adrenal zona glomerulosa (regulated by the renin–angiotensin system, p. +665) and the endocrine +pancreas (Ch. +20). +Italics show negative regulation. +Some pathological processes can affect multiple +endocrine glands (p. +following +treatment of childhood cancer with chemotherapy and/or +radiotherapy). +adrenal carcinoma and adenoma) +18 +Biochemical investigations play a central role in endocrinology. +Some hormones are labile and need special +collection, handling and processing requirements, e.g. +collection +in a special tube and/or rapid transportation to the laboratory +on ice. +Local protocols for hormone measurement should be +carefully followed. +The principles of investigation are shown in Box +18.2. +Classical syndromes are +described in relation to individual glands in the following sections. +14), hypertension +(Ch. +16), obesity (Ch. +19) and osteoporosis (Ch. +24). +The relationship +between TSH and T4 is classically described as inverse log-linear +(Fig. +18.4). +For this reason, +TSH is usually regarded as the most useful investigation of +thyroid function. +680). +242) can also interfere with the +TSH assay and cause a spurious high or low measurement. +Functional anatomy, physiology and +investigations +Thyroid physiology is illustrated in Figure 18.3. +Selenium +is an integral component of these monodeiodinases. +T4 can also be converted to the inactive +metabolite, reverse T3. +It is +the unbound or free hormones that diffuse into tissues and exert +diverse metabolic actions. +on heart rate, gut motility +CNS activation +Bone demineralisation +Cellular differentiation +etc. +18.3 Structure and function of the thyroid gland. +(1) Thyroglobulin (Tg) is synthesised and secreted into the colloid of the follicle. +(2) Inorganic +iodide (I–) is actively transported into the follicular cell (‘trapping’). +(4) Iodinated tyrosines couple to form T3 and T4. +(5) Tg is endocytosed. +(6) Tg is cleaved by +proteolysis to free the iodinated tyrosine and thyroid hormones. +(7) Iodinated tyrosine is dehalogenated to recycle the iodide. +(8) T4 is converted to T3 by +5′-monodeiodinase. +Their use is described below. +18.4 The relationship between serum thyroid-stimulating +hormone (TSH) and free T4. +Raised Raised Primary thyrotoxicosis +U.D. +Normal1 Raised Primary T3 toxicosis +U.D. +Normal1 Normal1 Subclinical thyrotoxicosis +U.D. +or low Raised Low or +Non-thyroidal illness +normal +Amiodarone therapy +U.D. +or low Low Raised Over-treatment of hypothyroidism with liothyronine (T3) +U.D. +2T3 is not a sensitive indicator of hypothyroidism and should not be requested. +3 Usually lower part of reference range. +4i.e. +Secondary +to pituitary or hypothalamic disease. +Note that TSH assays may report detectable TSH. +(TSH = thyroid-stimulating hormone; U.D. +2 Characterised by negligible radioisotope uptake. +3i.e. +Ovarian +teratoma containing thyroid tissue. +4 Human chorionic gonadotrophin has +thyroid-stimulating activity. +(TSH = thyroid-stimulating hormone) +Figure 18.5. +Tachycardia, palmar erythema and lid lag +are common signs. +Pretibial myxoedema +(p. +Investigations +The rst-line investigations are serum T3, T4 and TSH. +2 Features found particularly in elderly patients. +(Box 18.9). +An electrocardiogram (ECG) may demonstrate sinus +tachycardia or atrial brillation. +In low-uptake thyrotoxicosis, the cause +is usually a transient thyroiditis (p. +646). +illness has resolved +Any features of Graves’ disease? +18.5 Establishing the differential diagnosis in thyrotoxicosis. +Other thyroid antibodies (e.g. +3Scintigraphy is not necessary in most cases of drug-induced thyrotoxicosis. +4 99mTechnetium pertechnetate scans of patients with thyrotoxicosis. +In Graves’ disease there is diffuse uptake of isotope. +Verapamil may be used as an alternative +to β-blockers, e.g. +Moreover, +subclinical thyrotoxicosis (p. +642) is a risk factor for atrial brillation. +Adapted from Burch HB, Wartofsky L. +Life-threatening thyrotoxicosis. +Thyroid +storm. +Endocrinol Metab Clin N Am 1993; 22:263–277. +Dexamethasone (2 mg 4 times daily) and amiodarone +have similar effects. +Oral carbimazole 40–60 mg daily (p. +644) +should be given to inhibit the synthesis of new thyroid hormone. +After 10–14 days the patient can +usually be maintained on carbimazole alone. +Women are affected approximately six +times more frequently than men. +The +Burch–Wartofsky system may be used to help establish the +diagnosis (Box 18.10). +Sodium ipodate (500 mg per day orally) will restore +serum T3 levels to normal in 48–72 hours. +2 Goitre: – absent; +Âą may be present; ++ characteristic. +4 +Possible non-thyroidal illness2 +TSH < 20 mlU/L1 Repeat when acute +Scenario? +illness has resolved +TSH > 20 mlU/L +No +Any features of transient +thyroiditis? +• Amiodarone +• Lithium +Thyroid ablation? +18.6 An approach to adults with suspected primary hypothyroidism. +650), which are usually diagnosed in +childhood. +2The usual abnormality in sick euthyroidism +is a low TSH but any pattern can occur. +4Specialist advice is most appropriate where indicated. +683). +The key discriminatory features in the history and examination +are highlighted in Figure 18.6. +In this situation, serum T4 is low and TSH is elevated, usually in +excess of 20 mIU/L. +Other non-specic abnormalities +are shown in Box 18.9. +18.6). +Management +Treatment is with levothyroxine replacement. +In younger patients, +it is safe to initiate levothyroxine at a higher dose (e.g. +100 Îźg +per day), to allow a more rapid normalisation of thyroid hormone +levels. +Patients +feel better within 2–3 weeks. +The dose of levothyroxine should be adjusted to maintain serum +TSH within the reference range. +This is discussed in more detail on +page 1279 (see also Box 18.18). +680). +Other measures include slow rewarming +(p. +166), cautious use of intravenous fluids, broad-spectrum +antibiotics and high-flow oxygen. +These +can be divided into three categories. +This combination is most often +found in older patients with multinodular goitre. +In patients with non-specic +symptoms, a trial of levothyroxine therapy may be appropriate. +2 Usually tender. +imaging (MRI) or positron emission tomography (PET) scans. +649). +The presence of cervical +lymphadenopathy also increases the likelihood of malignancy. +Thyroid nodules identied on PET scanning have an approximately +33% chance of being malignant. +631). +It is often possible +to distinguish clinically between the three main causes of thyroid +swelling. +Serum T3, T4 and TSH should be measured in all patients with +a goitre or solitary thyroid nodule. +18.5). +In such circumstances, further evaluation +is not necessary. +Ultrasound can +establish whether there is generalised or localised swelling of +the thyroid. +648). +This +should not be routine practice in iodine-sufcient populations. +Nodules in which malignancy is conrmed by formal +histology are treated as described on page 649. +131I therapy +may also cause some reduction in size of a multinodular goitre. +4 and p. +689). +There is overlap between these conditions, +since some patients have multiple autoantibodies. +The most common manifestation is thyrotoxicosis with or without +a diffuse goitre. +The clinical features and differential diagnosis +are described on page 635. +Graves’ disease also causes +ophthalmopathy and, rarely, pretibial myxoedema (p. +646). +18.7). +18 +A +B +C +012345 +Time in years +Thyrotoxic Euthyroid Hypothyroid +Fig. +18.7 Natural history of the thyrotoxicosis of Graves’ disease. +Many of these loci have been implicated in the +pathogenesis of other autoimmune diseases. +In regions of iodine deciency (p. +Management +Symptoms of thyrotoxicosis respond to β-blockade (p. +637) but +denitive treatment requires control of thyroid hormone secretion. +The different options are compared in Box 18.14. +Propylthiouracil is equally effective. +18.3). +Antithyroid drugs can have adverse effects. +The most common is +a rash. +1279), or if an adverse reaction to carbimazole has occurred. +3ln many institutions, 131I is +used more liberally and is prescribed for much younger patients. +18.3). +This regimen is effective in 75% of +patients within 4–12 weeks. +If thyrotoxicosis persists after 6 months, a further +dose of 131I can be given. +Management is very specialised +and is discussed on page 1279 (see also Box 18.18). +The presentation may +be atypical and management challenging, as summarised in +Box 18.15. +18.8) and a rise in retrobulbar pressure. +The eye +is displaced forwards (proptosis, exophthalmos, p. +631) and in +severe cases there is optic nerve compression. +A +B +18 +Fig. +18.8 Graves’ disease. +A Bilateral ophthalmopathy in a 42-year-old +man. +B Transverse CT of the orbits, +showing the enlarged extraocular muscles. +Ophthalmopathy, like thyrotoxicosis (see Fig. +631 and 1088). +If the extraocular muscles +are involved and do not act in concert, diplopia results. +The majority of patients require no treatment other than +reassurance. +Smoking cessation should be actively encouraged. +More severe inflammatory episodes are treated +with glucocorticoids (e.g. +pulsed intravenous methylprednisolone) +and sometimes orbital radiotherapy. +Loss of visual acuity is an indication for +urgent surgical decompression of the orbit. +630). +Treatment is rarely required but in severe cases topical +glucocorticoids may be helpful. +The thyroid is usually palpably enlarged and tender. +Systemic upset is common. +Affected patients are usually females +aged 20–40 years. +The condition can also be precipitated by drugs, including +interferon-Îą and lithium. +As a result, T4 +and T3 levels are raised for 4–6 weeks until the pre-formed colloid +is depleted. +18.9). +Occasionally, however, it may be necessary to prescribe +prednisolone 40 mg daily for 3–4 weeks. +The thyrotoxicosis is mild +and treatment with a β-blocker is usually adequate. +There is an increased risk +of thyroid lymphoma (p. +650), although this is exceedingly +rare. +The nomenclature of autoimmune hypothyroidism is +confusing. +However, these +syndromes can both be considered as variants of the same +underlying disease process. +Around 25% of patients are hypothyroid at presentation. +In those under the age of 20 years, antinuclear factor +(ANF) may also be positive. +Levothyroxine therapy is indicated as treatment for +hypothyroidism (p. +640) and also to shrink an associated goitre. +Thyrotoxic Hypothyroid Euthyroid +Reference +range +T4, T3 +TSH +0246 +Months +Fig. +18.9 Thyroid function tests in an episode of transient thyroiditis. +18.6). +Iodine-induced thyroid dysfunction +Iodine has complex effects on thyroid function. +637) and +prior to thyroid surgery for thyrotoxicosis (p. +645). +18.3). +Induction of thyrotoxicosis by iodine is called the +Jod–Basedow effect. +18.10) and contains huge amounts +of iodine; a 200 mg dose contains 75 mg iodine. +TSH provides the best +indicator of thyroid function. +1279). +Dietary sources of iodine include seafood, dairy products, eggs +and grains. +These complex effects of iodine +supplementation are further discussed below. +1279). +These have +Fig. +18.10 The structure of amiodarone. +18.3). +• type II: thyroiditis due to a direct cytotoxic effect of +amiodarone administration. +Prednisolone is benecial in the type II form. +Potassium perchlorate can also +be used to inhibit iodine trapping in the thyroid. +Occasionally, there +is a tight sensation in the neck, particularly when swallowing. +The +goitre is soft and symmetrical, and the thyroid enlarged to two +or three times normal. +There is no tenderness, lymphadenopathy +or overlying bruit. +No +treatment is necessary and the goitre usually regresses. +Multinodular goitre +The natural history is shown in Figure 18.11. +with ‘simple goitre’; see above) as young +adults may progress to develop nodules. +642), but +sometimes elevated (toxic multinodular goitre; see Fig. +18.5). +18.11 Natural history of simple goitre. +R +Fig. +18.12 Computed tomogram showing retrosternal multinodular +goitre (black arrow). +This is causing acute severe breathlessness and +stridor due to tracheal compression (white arrow). +or sudden painful swelling caused by haemorrhage into a nodule +or cyst. +Very large goitres can cause +mediastinal compression with stridor (Fig. +18.12), dysphagia +and obstruction of the superior vena cava. +The diagnosis can be conrmed by ultrasonography and/or +thyroid scintigraphy (see Fig. +18.5). +17.7, p. +554). +Nodules +should be evaluated for the possibility of thyroid neoplasia, as +described on page 649. +In toxic multinodular goitre, treatment is usually with 131I. +In thyrotoxic patients with +a large goitre, thyroid surgery may be indicated. +Asymptomatic patients with subclinical thyrotoxicosis (p. +Thyroid neoplasia +Patients with thyroid tumours usually present with a solitary +nodule (p. +642). +Most are benign and a few of these, called +‘toxic adenomas’, secrete excess thyroid hormones. +As shown in Box 18.16, it can be classified +according to the cell type of origin. +With the exception of +medullary carcinoma, thyroid cancer is more common in +females. +Toxic adenoma +A solitary toxic nodule is the cause of less than 5% of all cases +of thyrotoxicosis. +The adenoma is usually greater than +3 cm in diameter. +Most patients are female and over 40 years of age. +18.5). +For this reason, permanent +hypothyroidism is unusual. +Hemithyroidectomy is an alternative +management option. +It may be +multifocal and spread is initially to regional lymph nodes. +Follicular carcinoma +This is usually a single encapsulated lesion. +Spread to cervical +lymph nodes is rare. +Metastases are blood-borne and are most +often found in bone, lungs and brain. +Smaller tumours with no adverse +histological features may require only thyroid lobectomy. +Patients usually nd the latter approach preferable but it +is more expensive. +In older patients, median survival is +only 7 months. +961), with a median +survival of 9 years. +Some 98% of tumours are non-Hodgkin’s +lymphomas, usually the diffuse large B-cell subtype. +Treatment is +with combination chemotherapy and external beam radiotherapy +(p. +965). +Medullary carcinoma +This tumour arises from the parafollicular C cells of the thyroid. +As +a consequence, carcinoid syndrome (p. +678) and Cushing’s +syndrome (p. +666) may occur. +Patients usually present in middle age with a rm thyroid +mass. +Cervical lymph node involvement is common but distant +metastases are rare initially. +Serum calcitonin levels are raised and +are useful in monitoring response to treatment. +Treatment is by total thyroidectomy with removal of regional +cervical lymph nodes. +External beam +radiotherapy may be considered in some patients at high risk +of local recurrence. +18.17 The thyroid gland in old age +Thyrotoxicosis +• Causes: commonly due to multinodular goitre. +• Myxoedema coma (p. +641): more likely in the elderly. +Levothyroxine requirements fall with increasing age and few patients +need more than 100 Îźg daily. +There may be +associated mediastinal and retroperitoneal brosis. +Presentation is +with a slow-growing goitre that is irregular and stony-hard. +There +is usually tracheal and oesophageal compression necessitating +partial thyroidectomy. +Congenital hypothyroidism +is thus six times more common than phenylketonuria. +It is +now possible to start levothyroxine replacement therapy within +2 weeks of birth. +Iodine deciency +• Iodine requirements: increased in pregnancy. +The World Health +Organisation (WHO) recommends a minimum intake of 250 Îźg/day. +Transient and usually does not +require antithyroid drug treatment. +18.13 Male reproductive physiology. +Pathways +for synthesis of sex steroids are shown in Figure 18.19 +(p. +667). +The axis can be assessed easily by a random blood sample +for testosterone, LH and FSH. +Testicular +function can also be tested by semen analysis. +tachycardia). +18.14 Female reproductive physiology and the normal menstrual cycle. +The mid-cycle ‘surge’ of LH induces ovulation. +The pathophysiology of male and female reproductive +dysfunction is summarised in Box 18.19. +In the UK, this is by the age of 14 in boys and 13 in +girls. +694). +Clinical assessment +The differential diagnosis is shown in Box 18.20. +Current weight and +height may be plotted on centile charts, along with parental +heights. +Healthy growth usually follows a centile. +There is often a history of delayed +puberty in siblings or parents. +681). +681) +• Functional gonadotrophin deciency: +Chronic systemic illness (e.g. +659 and 660). +Other causes of +primary gonadal failure are shown in Box 18.20. +Investigations +Key measurements are LH and FSH, testosterone (in boys) and +oestradiol (in girls). +Chromosome analysis should be performed +if gonadotrophin concentrations are elevated. +680). +Management +Puberty can be induced using low doses of oral oestrogen in +girls (e.g. +Higher doses carry +a risk of early fusion of epiphyses. +In children +with hypogonadism, the underlying cause should be treated +and reversed if possible. +It is more common in girls +than boys and often no structural cause is identied, i.e. +‘the +physiological clock is running fast’. +1055). +In central PP, development can be arrested +with long-acting GnRH analogues. +In both central and peripheral +PP, treatment of any underlying cause is indicated. +The causes of this common presentation are +shown in Box 18.22. +A history of galactorrhoea +should be sought. +Signicant weight loss of any cause can +cause amenorrhoea by suppression of gonadotrophins. +658). +Investigation of hyperprolactinaemia is described on page 684. +Elevated LH, prolactin and +testosterone levels with normal oestradiol are common in PCOS. +medroxyprogesterone +acetate 10 mg twice daily) can be assessed. +Assessment of bone mineral density by dual X-ray +absorptiometry (DXA, p. +989) may be appropriate in patients +with low androgen and oestrogen levels. +Management +Where possible, the underlying cause should be treated. +The timing of the discontinuation of oestrogen replacement +therapy is still a matter of debate. +Management of infertility in oestrogen-decient women is +described on page 656. +The causes of +hypogonadism are listed in Box 18.20. +730). +Routes of testosterone administration are shown in Box +18.24. +Testosterone replacement +inhibits spermatogenesis; treatment for fertility is described +below. +The main causes are +listed in Box 18.25. +In men, infertility may result from impaired +sperm quality (e.g. +reduced motility) or reduced sperm number. +Both +partners need to be investigated. +The male partner needs a +semen analysis to assess sperm count and quality. +Transvaginal ultrasound can be used to assess uterine and ovarian +anatomy. +In women with anovulatory cycles secondary to PCOS +(p. +For clomifene, ultrasound +monitoring is recommended for at least the rst cycle. +The success of IVF depends on +age, with low success rates in women over 40 years. +Azoospermic men may opt to +use donated sperm but this may be in short supply. +Gynaecomastia +Gynaecomastia is the presence of glandular breast tissue in males. +Normal breast development in women is oestrogen-dependent, +while androgens oppose this effect. +Causes +are listed in Box 18.26. +Prolactin excess +alone does not cause gynaecomastia (p. +684). +Clinical assessment +A drug history is important. +A random blood sample should be taken for +testosterone, LH, FSH, oestradiol, prolactin and hCG. +Elevated +oestrogen concentrations are found in testicular tumours and +hCG-producing neoplasms. +653). +The anti-oestrogen tamoxifen +may also be effective in reducing the size of the breast tissue. +The aetiology +of androgen excess is shown in Box 18.27. +Clinical assessment +The severity of hirsutism is subjective. +666). +Investigations +A random blood sample should be taken for testosterone, +prolactin, LH and FSH. +667). +of testis) +• Human chorionic gonadotrophin-secreting tumour (e.g. +667) +See investigations (p. +667) +Treat the cause (p. +667) +*e.g. +676). +The tumour should then be sought by CT or +MRI of the adrenals and ovaries. +Management +This depends on the cause (Box 18.27). +Options for the treatment +of PCOS and idiopathic hirsutism are similar and are described +below. +Genetic factors probably play a role, since PCOS +often affects several family members. +657) or amenorrhoea/oligomenorrhoea (p. +655). +Infertility +may also be present (p. +656). +18.15). +PCOS probably represents the common endpoint of several different pathologies. +730). +If conservative measures are unsuccessful, anti-androgen +therapy is given (Box 18.29). +Unless weight is lost, hirsutism will return if therapy is +discontinued. +Turner’s syndrome +Turner’s syndrome affects around 1 in 2500 females. +45XO/46XX or 45XO/46XY) and partial deletions of an X +chromosome. +Clinical features +These are shown in Figure 18.16. +There is a wide variation in the spectrum of associated somatic +abnormalities. +The severity of the phenotype is, in part, related to +18 +Fig. +18.15 Polycystic ovary. +This may not require treatment +unless fertility is desired. +Metformin (p. +656) +at restoring fertility as measured by successful pregnancy. +Thiazolidinediones (p. +18.16 Clinical features of Turner’s syndrome (45XO). +The timing of pubertal +induction therefore needs to be carefully planned. +However, +other cytogenetic variants may be responsible, especially +46XY/47XXY mosaicism. +The principal pathological abnormality +is dysgenesis of the seminiferous tubules. +This is evident from +infancy (and possibly even in utero) and progresses with age. +• Sexual activity: many older people remain sexually active. +• ‘Male menopause’: does not occur, although testosterone +concentrations do fall with age. +• Androgens in older women: hirsutism and balding occur. +In those +rare patients with elevated androgen levels, this may be +pathological, e.g. +from an ovarian tumour. +Affected individuals usually have small, rm +testes. +More than 99% of total body calcium is in bone. +1048). +Calcitonin is secreted from the parafollicular C cells of the +thyroid gland. +Although it is a useful tumour marker in medullary +carcinoma of thyroid (p. +650) and can be given therapeutically in +Paget’s disease of bone (p. +1053), its release from the thyroid +is of no clinical relevance to calcium homeostasis in humans. +Disorders of the parathyroid glands are summarised in +Box 18.31. +1051). +Other metabolic bone +diseases are explored on page 1044. +25.55). +When +serum ionised calcium levels fall, PTH secretion rises. +PTH is +a single-chain polypeptide of 84 amino acids. +2ln multiple endocrine neoplasia (MEN) syndromes (p. +688). +Of these, +primary hyperparathyroidism and malignant hypercalcaemia are +by far the most common. +Lithium may cause +hyperparathyroidism by reducing the sensitivity of the calcium- +sensing receptor. +663). +Hypertension is a +common feature of hyperparathyroidism. +Parathyroid tumours +are almost never palpable. +A family history of hypercalcaemia raises the possibility of +FHH or MEN (p. +688). +Investigations +The most discriminatory investigation is measurement of PTH. +967) and +CT as appropriate. +FHH does not require any specic intervention. +Hypocalcaemia +Aetiology +Hypocalcaemia is much less common than hypercalcaemia. +The +differential diagnosis is shown in Box 18.33. +366 +Vitamin D deciency ↓↓ ↓ ↑ p. +This +is characterised by muscle spasms due to increased excitability +of peripheral nerves. +Pedal spasm can also occur +but is less frequent. +Stridor is caused by spasm of the glottis. +1049). +Management +Emergency management of hypocalcaemia associated with tetany +is given in Box 18.34. +Treatment of chronic hypocalcaemia is +described on page 1051. +This is most commonly seen in individuals +with advanced chronic kidney disease (p. +418). +It also occurs in the +familial MEN syndromes (p. +Parathyroid bone disease is now rare +due to earlier diagnosis and treatment. +This may present as bone pain +and tenderness, fracture and deformity. +1016). +A ‘pepper-pot’ appearance may be seen on lateral X-rays of the +skull. +This is usually not evident radiographically +and requires assessment by DXA (p. +989). +In nephrocalcinosis, scattered opacities may be visible within +the renal outline. +There may be soft tissue calcication in arterial +walls and hands and in the cornea. +B After 3 hours, +uptake is evident only in the parathyroid (thin +arrow). +(p. +664). +Parathyroid scanning by 99m Tc-sestamibi scintigraphy +(MIBI; Fig. +Negative imaging does not exclude the diagnosis, however, and +four-gland exploration may be needed. +Experienced surgeons will identify solitary +tumours in more than 90% of cases. +They should be encouraged to +maintain a high oral fluid intake to avoid renal stones. +Occasionally, primary hyperparathyroidism presents with severe +life-threatening hypercalcaemia. +If this is not +effective, then urgent parathyroidectomy should be considered. +Cinacalcet (p. +As a result, higher than normal +calcium levels are required to suppress PTH secretion. +The hypercalcaemia of FHH is +always asymptomatic and complications do not occur. +No treatment +is necessary. +895) +or copper in Wilson’s disease (p. +896). +There are a number of rare congenital or inherited forms of +hypoparathyroidism. +One form is associated with autoimmune +polyendocrine syndrome type 1 (p. +689) and another with DiGeorge +syndrome (p. +79). +49). +The inheritance +of these disorders is an example of genetic imprinting (p. +49). +Recombinant PTH is +available as subcutaneous injection therapy for osteoporosis +(p. +• Primary hyperparathyroidism: more common with ageing. +Older +people can often be observed without surgical intervention. +• Hypercalcaemia: may cause delirium. +the control of the renin–angiotensin system. +However, classical syndromes of adrenal hormone deciency +and excess are relatively rare. +Functional anatomy and physiology +Adrenal anatomy and function are shown in Figure 18.18. +Pathways for the biosynthesis of corticosteroids are shown +in Figure 18.19. +Investigation of adrenal function is described +under specic diseases below. +The different types of adrenal +disease are shown in Box 18.37. +Glucocorticoids +Cortisol is the major glucocorticoid in humans. +Levels are highest +in the morning on waking and lowest in the middle of the night. +Cortisol rises dramatically during stress, including any illness. +The clinical importance of cortisol deficiency is, +therefore, most obvious at times of stress. +It is the free fraction that is biologically active. +18.18 Structure and function of the adrenal glands. +351). +18.18). +They are probably +important in the initiation of puberty (adrenarche). +18.19 The major pathways of synthesis of steroid hormones. +(DHEAS = dehydroepiandrosterone sulphate; HSD = hydroxysteroid dehydrogenase) +prednisolone. +Aetiology +The causes are shown in Box 18.38. +Clinical assessment +The diverse manifestations of glucocorticoid excess are shown +in Figure 18.20. +obesity and depression (Box 18.38). +Features that favour Cushing’s syndrome in an obese patient +are bruising, myopathy and thin skin. +Any clinical suspicion of +cortisol excess is best resolved by further investigation. +A careful drug +history must therefore be taken before embarking on complex +investigations. +Some clinical features are more common in ectopic ACTH +syndrome. +684) are rare. +18.20 Cushing’s syndrome. +A Clinical features common to all causes. +B A patient with Cushing’s disease before treatment. +in isolation. +Accordingly, several tests are usually combined to +establish the diagnosis. +The diagnosis of Cushing’s is a two-step process: +1. +to establish whether the patient has Cushing’s syndrome +(Fig. +18.21) +2. +to dene its cause (Fig. +18.22). +failure to suppress serum cortisol with low doses of oral +dexamethasone +2. +increased 24-hour urine free cortisol (see Fig. +18.21). +For either test, a normal response is +a serum cortisol of < 50 nmol/L (1.8 Îźg/dL). +18.21 Sequence of investigations in suspected spontaneous Cushing’s syndrome. +A serum cortisol of 50 nmol/L is equivalent to 1.8 Îźg/dL. +Techniques for localisation of tumours secreting ACTH or +cortisol are listed in Figure 18.22. +MRI detects around 60% of +pituitary microadenomas secreting ACTH. +673). +Management +Untreated severe Cushing’s syndrome has a 50% 5-year mortality. +Adrenal tumours +Laparoscopic adrenal surgery is the treatment of choice for +adrenal adenomas. +18.22 Determining the cause of conrmed Cushing’s syndrome. +To convert pmol/L to ng/L, multiply by 4.541. +Ectopic ACTH syndrome +Localised tumours, such as bronchial carcinoid, should be +removed surgically. +Equivalent doses of commonly used +glucocorticoids are listed in Box 18.39. +324). +All patients +must be advised to avoid sudden drug withdrawal. +They should +be issued with a steroid card and/or wear an engraved bracelet +(Box 18.40). +This can be achieved by giving glucocorticoid in the +morning. +Giving ACTH to stimulate adrenal recovery is of no +value, as the pituitary remains suppressed. +Once the dose of glucocorticoid +is reduced to a minimum (e.g. +It is potentially fatal and notoriously variable in +its presentation. +Causes are shown in Box 18.41. +683). +Clinical assessment +The clinical features of adrenal insufficiency are shown in +Box 18.42. +Patients may present with chronic features and/or in acute +circulatory shock. +In +primary adrenal insufciency, weight loss is a uniform presenting +feature. +357). +357). +Hyperkalaemia +is common, but not universal, in aldosterone deciency. +Plasma +renin and aldosterone should be measured in the supine position. +in +pituitary apoplexy, p. +(ACTH = adrenocorticotrophic hormone; HPA = hypothalamic–pituitary–adrenal) +may be present. +The crisis is often precipitated by intercurrent +disease, surgery or infection. +Vitiligo occurs in 10–20% of patients with autoimmune +Addison’s disease (p. +630). +Adrenal autoantibodies are +frequently positive in autoimmune adrenal failure. +If antibody tests +are negative, imaging of the adrenal glands with CT or MRI is +indicated. +Tuberculosis causes adrenal calcication, visible on plain +X-ray or ultrasound scan. +310). +Adrenal metastases are a rare cause of adrenal +insufciency. +There is some evidence that adrenal +androgen replacement may also be benecial in women. +Other +treatments depend on the underlying cause. +The emergency +management of adrenal crisis is described in Box 18.44. +These are physiological +replacement doses that should not cause Cushingoid side-effects. +The dose may need to be adjusted for the individual patient but +this is subjective. +Measurement +of serum cortisol levels is not usually helpful. +Advice to patients +dependent on glucocorticoid replacement is given in Box 18.40. +Such lesions are known as +adrenal ‘incidentalomas’. +Eighty-five per cent of adrenal incidentalomas are non- +functioning adrenal adenomas. +Patients with an adrenal incidentaloma are usually asymptomatic. +However, clinical signs and symptoms of excess glucocorticoids +(p. +665), mineralocorticoids (see below), catecholamines (p. +666) +and, in women, androgens (p. +666) should be sought. +Patients +with hypertension should be investigated for mineralocorticoid +excess, as described below. +The larger the lesion, the greater the malignant +potential. +• Conguration. +Homogeneous and smooth lesions are +more likely to be benign. +• Presence of lipid. +• Enhancement. +Causes of excessive activation of mineralocorticoid receptors +are shown in Box 18.46. +Blood pressure is +elevated but accelerated phase hypertension is rare. +Investigations +Biochemical +Routine blood tests may show a hypokalaemic alkalosis. +Imaging and localisation +Imaging with CT or MRI will identify most APAs (Fig. +Other genetic causes include +mutations in SDHA, SDHAF2, TMEN127 and MAX. +There may also be features of the familial +syndromes associated with phaeochromocytoma. +Paragangliomas +are often non-functioning. +Localisation +Phaeochromocytomas are usually identied by abdominal CT or +MRI (Fig. +18.24). +Localisation of paragangliomas may be more +difcult. +Less widely available, 68 gallium dotatate PET/ +CT imaging has high sensitivity for paraganglioma. +18.23 Aldosterone-producing adenoma causing Conn’s +syndrome. +A CT scan of left adrenal adenoma (arrow). +B The tumour is +‘canary yellow’ because of intracellular lipid accumulation. +Up to 20% +of males develop gynaecomastia on spironolactone. +Most are benign but approximately 15% show malignant features. +Around 40% are associated with inherited disorders, including +neurofibromatosis (p. +1131), von Hippel–Lindau syndrome +(p. +1132), MEN 2 and MEN 3 (p. +688). +762 and 763). +This is called ‘non-classical’ or ‘late-onset’ +congenital adrenal hyperplasia. +Defects of all the other enzymes in Figure 18.19 are rare. +Assessment is otherwise as described for adrenal +insufciency on page 672. +Women with late-onset 21-hydroxylase deciency may not +require corticosteroid replacement. +If hirsutism is the main +problem, anti-androgen therapy may be just as effective (p. +659). +Fig. +18.24 CT scan of abdomen showing large left adrenal +phaeochromocytoma. +to allow restoration of normal plasma volume. +If Îą-blockade produces a marked tachycardia, then +a β-blocker such as propranolol can be added. +Metastatic tumours may behave in an aggressive or a very +indolent fashion. +ACTH then stimulates the production of steroids +upstream of the enzyme block. +All of these enzyme +abnormalities are inherited as autosomal recessive traits. +The most common enzyme defect is 21-hydroxylase deciency. +Functional +anatomy and physiology are described on pages 723 and 848. +Diseases associated with abnormalities of these hormones are +listed in Box 18.48. +Most are rare, with the exception of diabetes +mellitus (Ch. +20). +18.25 Differential diagnosis of spontaneous hypoglycaemia. +The main diagnostic test is the prolonged (72-hour) fast. +What is the cause of the hypoglycaemia? +In the acute setting, the underlying diagnosis is often obvious. +salicylates, +quinine and pentamidine – may also be implicated. +Suppressed +plasma β-hydroxybutyrate helps conrm inappropriate insulin +secretion during fasting. +Usually, insulinomas in the pancreas +diabetes mellitus. +18.25). +The symptoms are +usually episodic and relieved by consumption of carbohydrate. +Investigations +Does the patient have a hypoglycaemic disorder? +Continuous dextrose +infusion may be necessary, especially in sulphonylurea poisoning. +Insulinomas are resected when benign, +providing the individual is t enough to undergo surgery. +675) and thyroid (medullary carcinoma, p. +650). +688 and 1131). +NETs may secrete hormones into +the circulation. +Thymic and +bronchial carcinoids occasionally present with ectopic ACTH +syndrome (p. +667). +Pancreatic NETs can also cause hormone excess +(Box 18.50) but most are non-functional. +The features of Zollinger–Ellison syndrome +are described on page 802. +Biopsy of the primary tumour or a +metastatic deposit is required to conrm the histological type. +18.26 Octreotide scintigraphy in a metastatic neuro-endocrine tumour. +B Octreotide scintogram showing patches of increased uptake in the upper abdomen. +Management +Treatment of solitary tumours is by surgical resection. +633). +18.27 Anatomical relationships of the normal pituitary gland +and hypothalamus. +See also Figure 18.2 (p. +633). +A Sagittal MRI. +B Coronal MRI. +By far the most common disorder is an adenoma +of the anterior pituitary gland. +The approach to testing for hormone deciency is outlined +in Box 18.53. +Details are given in the sections on individual +glands elsewhere in this chapter. +Tests for hormone excess vary +according to the hormone in question. +In contrast, growth +hormone is secreted in a pulsatile fashion. +Similarly, in suspected ACTH-dependent Cushing’s +disease (p. +The most common local complication of a large pituitary tumour +is compression of the optic pathway. +The resulting visual eld +defect can be documented using a Goldman’s perimetry chart. +Surgical biopsy is usually only performed as part of a +therapeutic operation. +Younger women with pituitary disease most commonly +present with secondary amenorrhoea (p. +654) or galactorrhoea +(in hyperprolactinaemia). +The most common cause is a pituitary +macroadenoma but other causes are listed in Box 18.54. +Clinical assessment +The presentation is highly variable. +Growth hormone +secretion is often the earliest to be lost. +Later, in the +male there may be gynaecomastia and decreased frequency of +shaving. +18.28 Common symptoms and signs to consider in a patient with suspected pituitary disease. +Chronic anaemia may also occur. +In contrast to primary adrenal insufciency +(p. +Finally, +TSH secretion is lost with consequent secondary hypothyroidism. +This contributes further to apathy and cold intolerance. +The +onset of all of the above symptoms is notoriously insidious. +However, patients sometimes present acutely unwell with +glucocorticoid deciency. +683). +Other features of pituitary disease may be present (Fig. +18.28). +Investigations +The strategy for investigation of pituitary disease is described +in Box 18.53. +In acutely unwell patients, the priority is to +diagnose and treat cortisol deficiency (p. +672). +Other tests +can be undertaken later. +Specic dynamic tests for diagnosing +hormone deciency are described in Boxes 18.43 and 18.55. +Chronic +hormone replacement therapies are described below. +Cortisol replacement +Hydrocortisone should be given if there is ACTH deciency. +Suitable doses are described in the section on adrenal disease +on page 672. +Mineralocorticoid replacement is not required. +The +aim is to maintain serum T4 in the upper part of the reference +range. +1044). +Treatment with GH may +also help young adults to achieve a higher peak bone mineral +density. +18.28), whereas suprasellar masses may be +craniopharyngiomas (see Fig. +18.31). +The most common cause +of a parasellar mass is a meningioma. +Clinical assessment +Clinical features are shown in Figure 18.28. +Optic atrophy may +be apparent on ophthalmoscopy. +Occasionally, pituitary tumours infarct or there is bleeding into +cystic lesions. +Investigations +Patients suspected of having a pituitary tumour should undergo +MRI or CT. +Associated hypopituitarism +should be treated as described above. +Urgent treatment is required if there is evidence of pressure +on visual pathways. +18.29). +Following surgery, usually after 3–6 months, imaging should be +repeated. +Stereotactic radiosurgery allows specic targeting of +residual disease in a more focused fashion. +655). +The differential diagnosis +of hyperprolactinaemia is shown in Box 18.58. +Many drugs, +especially dopamine antagonists, elevate prolactin concentrations. +654). +Important points in the history +include drug use, recent pregnancy and menstrual history. +The +quantity of milk produced is variable and it may be observed only +by manual expression. +In men there is decreased libido, reduced +shaving frequency and lethargy (p. +655). +Further +assessment should address the features in Figure 18.28. +The upper limit +of normal for many assays of serum prolactin is approximately +500 mIU/L (24 ng/mL). +Levels above 5000 mIU/L (236 ng/mL) are highly suggestive of +a macroprolactinoma. +Patients with prolactin excess should have tests of gonadal +function (p. +Patients with a macroadenoma also need tests +for hypopituitarism (see Box 18.53). +Management +If possible, the underlying cause should be corrected (e.g. +cessation of offending drugs and giving levothyroxine replacement +in primary hypothyroidism). +Troublesome physiological +galactorrhoea can also be treated with dopamine agonists (see +Box 18.59). +Management of prolactinomas is described below. +post herpes zoster)The hypothalamus and the pituitary gland • 685 +(4700 ng/mL). +The investigation of prolactinomas is the same +as for other pituitary tumours (see above). +Medical +Dopamine agonist drugs are rst-line therapy for the majority +of patients (Box 18.59). +18.29), but visual eld defects, +if present, may improve within days of rst administration. +Surgery may also be performed in +patients who are intolerant of dopamine agonists. +All patients should be advised to report +headache or visual disturbance promptly. +A +C +T +B +C +T +18 +Fig. +18.29 Shrinkage of a macroprolactinoma following treatment +with a dopamine agonist. +A MRI scan showing a pituitary +macroadenoma (T) compressing the optic chiasm (C). +B MRI scan of +the same tumour following treatment with a dopamine agonist. +All of these agents, especially bromocriptine, must be introduced at low dose and increased slowly. +18.30 Clinical features of acromegaly. +More commonly, GH excess occurs in adult +life and presents with acromegaly. +The clinical features are shown in Figure 18.30. +The most common complaints are headache and sweating. +Additional features include those of any pituitary tumour (see +Fig. +18.28). +In normal subjects, plasma GH suppresses to below 0.5 Îźg/L +(approximately 2 mIU/L). +The rest of pituitary function should be investigated +as described in Box 18.53. +Additional tests in acromegaly may include screening +for colonic neoplasms with colonoscopy. +Treatment is +summarised in Box 18.57. +However, GH levels fall slowly (over many years) +and there is a risk of hypopituitarism. +Medical +therapy may be discontinued after several years in patients +who have received radiotherapy. +They are often cystic, with a +solid component that may or may not be calcied (Fig. +18.31). +In +young people, they are diagnosed more commonly than pituitary +adenomas. +Other +clinical features directly related to hypothalamic damage may +also occur. +Unfortunately, +craniopharyngiomas often recur, requiring repeated surgery. +The underlying causes are listed in Box 18.60. +Clinical features +The most marked symptoms are polyuria and polydipsia. +The +patient may pass 5–20 L or more of urine in 24 hours. +This is +of low specic gravity and osmolality. +18.31 Craniopharyngioma. +Macroprolactinomas, +however, require treatment because of their potential to cause mass +effects. +The principal +hazard is excessive treatment, resulting in water intoxication +and hyponatraemia. +Conversely, inadequate treatment results in +thirst and polyuria. +DDAVP nasal dose 5 Îźg in the morning and 10 Îźg at night). +The polyuria in nephrogenic diabetes insipidus is improved +by thiazide diuretics (e.g. +bendroflumethiazide 5–10 mg/day), +amiloride (5–10 mg/day) and NSAIDs (e.g. +They fall into +four groups, as shown in Box 18.63. +1132) and neurobromatosis type 1 (p. +1131). +In +contrast, loss-of-function mutations of the RET kinase cause +Hirschsprung’s disease (p. +834). +59). +< 600 mmol/kg) in the +presence of increased plasma osmolality (i.e. +> 300 mOsmol/kg). +Thirst can also be assessed during +these tests on a visual analogue scale. +In sick patients, DDAVP should be given by intramuscular +injection. +(APECED = autoimmune poly-endocrinopathy-candidiasis-ectodermal dystrophy) +dystrophy (APECED). +82). +Late effects of childhood cancer therapy +of the chest. +1298). +treatment of hypothyroidism and the investigation +and management of thyroid cancer. +endo-society.org American Endocrine Society: provider of clinical +practice guidelines. +Chronic mesenteric ischemia: How to select patients for invasive treatment. +Sem Vasc +Surg 2010; 23:21–28; (Koilonychia) Habif TP. +Clinical Dermatology, 6th edn. +Philadelphia: Saunders, Elsevier Inc.; 2016; (Gingivitis) Newman MG, Takei H, +Klokkevold PR, et al. +Carranza’s Clinical Periodontology, 12th edn. +Dermatology, 3rd edn. +Points +to note include past medical and surgical +history (e.g. +abdominal or intestinal surgery), +a drug history and a specic diet history. +Evidence of recent weight loss and muscle +wasting should be sought. +Simple, validated +tools are available to screen patients for +nutritional problems. +Body composition +reflects energy balance and is assessed +by clinical anthropomorphic measurements. +Lean patients +6–12 mm; obese patients 40–50 mm. +Measurement of knee height. +19.1). +Inappropriate diets have +been linked to diseases such as coronary heart disease and +cancer. +19.2). +Energy expenditure has several components. +It is most closely predicted by fat-free mass (i.e. +total body +mass minus fat mass), which is lower in females and older +people (Fig. +19.2B). +Extra metabolic energy is consumed during +growth, pregnancy and lactation, and when febrile. +The energy required for +digestion of food (diet-induced thermogenesis; Fig. +19.2C). +Physical activity levels are +usually dened as multiples of BMR. +Energy intake is determined by the ‘macronutrient’ content +of food. +49). +Regulation of energy balance +Energy intake and expenditure are highly regulated (Fig. +19.3). +At the other extreme, anorexia nervosa and +excessive exercise can lead to amenorrhoea (p. +654). +19.3), including +hormones acting on the pituitary gland (see Fig. +18.2, p. +These adjustments can ‘defend’ body weight within +certain limits. +In the low-insulin state of starvation (see Fig. +20.5, +p. +365). +882) and skeletal +muscle. +If hypothalamic function is abnormal (e.g. +19.1 Proportion of key food groups recommended for a healthy, +well-balanced diet. +Crown copyright. +19.2 Determinants of energy balance. +The targets are recommendations as a percentage of food energy only (Source: Dept of +Health 1991). +For WHO targets, see Box 19.4. +In the UK, it is assumed that 5% of energy intake will be derived from alcohol. +C Energy is required for movement and activity. +D Energy is consumed in order to digest food. +craniopharyngioma; see Fig. +18.31, p. +687) or in rare patients +with mutations in relevant genes (e.g. +768), and supply over half the energy in a normal, +well-balanced diet (see Fig. +19.2A). +20.7, p. +730). +19.3 Regulation of energy balance and its link with reproduction. +Պ indicates factors that are stimulated by eating and induce satiety. +Ջ indicates factors that are suppressed by eating and inhibit satiety. +All starches are polymers of glucose, linked by +the same 1–4 glycosidic linkages. +These differences +are the basis for the ‘glycaemic index’ of foods. +in soft drinks) with obesity and type 2 diabetesNutritional factors and disease • 697 +(p. +932). +Sugar alcohols (e.g. +Most dietary fibre is known as +‘non-starch polysaccharides’ (NSPs) (see Box 19.1). +This is essential fuel for the enterocytes and contributes +to bowel health. +The extent of flatus formed is dependent on +the food source. +19.2A). +Free fatty acids are absorbed in chylomicrons +(pp. +371 and 372; see Fig. +21.5, p. +768), allowing access of +complex molecules into the circulation. +Fatty acid structures +are shown in Figure 19.4. +The principal polyunsaturated fatty +acid (PUFA) in plant seed oils is linoleic acid (18 : 2 ω6). +Fish oils are rich in +ω3 PUFA (e.g. +They inhibit thrombosis by competitively +antagonising thromboxane A2 formation. +Replacing saturated +fat (i.e. +they cannot be synthesised +in humans but are required for synthesis of important proteins. +When two different vegetable proteins are eaten together (e.g. +Recommended dietary bre intake is based on avoiding risks +of colonic disease. +The usual recommended protein intake for +a healthy man doing light work is 65–100 g/day. +19 +1 14 +CH2 +CH +CH3 COOH +Saturated fatty acid, e.g. +19.4 Schematic representation of fatty acids. +Over 25% of adults in the UK +were obese (i.e. +BMI ≥ 30 kg/m2) in 2015, compared with 7% +in 1980 and 16% in 1995. +There is increasing public awareness of the health implications +of obesity. +Complications +Obesity has adverse effects on both mortality and morbidity (Fig. +19.5). +Coronary +heart disease (Fig. +For +a female, height is 162 cm and weight 59.0 kg; for a male, height is 175 cm +and weight 68.8 kg. +Weight tends to increase throughout adult life, as BMR and +physical activity decrease (see Fig. +19.2). +In affluent +societies, a signicant proportion of this food supply is discarded. +stair +climbing). +Twin and adoption studies conrm a +genetic influence on obesity. +19.6 Risks of diabetes and cardiovascular disease in +overweight and obese women. +Data are from the Nurses’ Health Study +in the USA, and mostly relate to Caucasian women. +In some ethnic groups +(e.g. +19 +rise in obesity has been accompanied by an epidemic of type +2 diabetes (p. +732) and osteoarthritis, particularly of the knee. +1044). +19.5). +These genes account for less than 5% of the variation +in body weight, however. +A few rare single-gene disorders have been identied that +lead to severe childhood obesity. +19.3). +The latter can +be treated by leptin injections. +Additional genetic conditions in +which obesity is a feature include Prader–Willi (see Box 3.8, +p. +51) and Lawrence–Moon–Biedl syndromes. +Severity of obesity can be quantified using the BMI and +waist circumference. +A dietary history may be helpful in guiding dietary advice +(p. +693) but is notoriously susceptible to under-reporting of food +consumption. +1204), which may be the most important issue to address in +some patients. +Alcohol is an important source of energy intake +and should be considered in detail. +The history of weight gain may help diagnose underlying causes. +639) or Cushing’s syndrome +(p. +666). +Assessment of the diverse complications of obesity (see Fig. +19.5) requires a thorough history, examination and screening +investigations. +The impact of obesity on the patient’s life and work +is a major consideration. +Assessment of other cardiovascular risk +factors is important. +Blood pressure should be measured with a +large cuff, if required (p. +510). +Elevated serum transaminases occur in patients with +non-alcoholic fatty liver disease (p. +884). +Management +The health risks of obesity are largely reversible if identied and +treated early. +743). +A reasonable goal for most +patients is to lose 5–10% of body weight. +19.7). +19.2C). +Where possible, this should +be incorporated in the daily routine (e.g. +walking rather than +driving to work), as this is more likely to be sustained. +Alternative +exercise (e.g. +swimming) may be considered if musculoskeletal +complications prevent walking. +Regular +support from a dietitian or attendance at a weight loss group +may be helpful. +A +signicant industry has developed in marketing diets for weight +loss. +Weight loss is highly variable and +patient adherence is the major determinant of success. +19.7 Therapeutic options for obesity. +Atkins) 10 60 30 Induction of ketosis may suppress hunger +High protein (e.g. +Zone) 43 30 27 Protein has greater satiety effect than other macronutrients +Low fat (e.g. +In some patients, more rapid weight loss is required, e.g. +in preparation for surgery. +Drugs +A huge investment has been made by the pharmaceutical +industry in nding drugs for obesity. +19.8 Effects of orlistat (A), liraglutide +(B) and bariatric surgery (C) on weight loss. +A, Data from Torgerson JS +Hauptman J, Boldrin MS, et al. +Diabetes Care 2004; +27:155–161. +B, Data from le Roux CW, Astrup +A, Fujioka K, et al. +Lancet; published online 22 Feb 2017. +C, Data +from SjĂśstrĂśm L, Narbro K, SjĂśstrĂśm D, et al. +Effects of bariatric surgery on mortality in +Swedish obese subjects. +N Engl J Med 2007; +357:741–752. +The +main adverse effects are dry mouth and constipation. +19.7), and its optimum +timing and duration are controversial. +Treatment can be stopped +in non-responders at this point and an alternative treatment +considered. +19.8). +19.7), +when extensive dietary and drug therapy has been insufciently +effective. +Several approaches +are used (Fig. +19.9) and all can be performed laparoscopically. +19.9 Bariatric surgical procedures. +B Sleeve gastrectomy. +C Roux-en-Y gastric bypass. +Complications depend on the approach. +Cosmetic surgical procedures may be considered in obese +patients after successful weight loss. +This operation is of no value for long-term +weight reduction if food intake remains unrestricted. +Treatment of these is discussed in the relevant +chapters. +693 and Box +19.10). +The +clinical features of severe under-nutrition in adults are listed in +Box 19.12. +Diarrhoea can lead +to depletion of sodium, potassium and magnesium. +In the last stage of starvation, death comes quietly +and often quite suddenly. +The very old are most vulnerable. +All +organs are atrophied at necropsy, except the brain, which tends +to maintain its weight. +small intestinal disease) +• Maldigestion (e.g. +marathon runners) +• Energy loss (e.g. +glycosuria in diabetes) +• Impaired energy storage (e.g. +Treatment of these childhood conditions is not discussed in +this adult medical textbook. +In adults, starvation is the result +of chronic sustained negative energy (calorie) balance. +Causes +are shown in Box 19.11. +Causes of weight loss are considered +further on page 785. +but albumin concentration is often maintained because the liver +still functions normally. +634). +19.2). +The urine has a xed +specic gravity and creatinine excretion becomes low. +There +may be mild anaemia, leucopenia and thrombocytopenia. +The +erythrocyte sedimentation rate is normal unless there is infection. +Tests of delayed skin hypersensitivity, e.g. +to tuberculin, are +falsely negative. +The electrocardiogram shows sinus bradycardia +and low voltage. +It is critical for +the condition to be managed by experts. +Individual +energy requirements can vary by 30%. +Salt should +be restricted and micronutrient supplements (e.g. +potassium, +magnesium, zinc and multivitamins) may be essential. +During refeeding, a weight gain of 5% body weight per +month indicates satisfactory progress. +Under-nutrition is poorly recognised in hospitals and has serious +consequences. +The under-nourished patient +is often withdrawn and this may be mistaken for depressive +illness. +Engagement with treatment and rehabilitation can be +adversely affected. +Scoring +systems, such as the MUST tool (p. +Causes are often complex (see Box 19.11). +Social issues +impact on food choices and may cause or exacerbate disease. +Ileal resection +Ileal resection (p. +In most cases, this means a +decision to intervene to tackle and reverse nutritional difculties. +Enteral feeding +is preferred to parenteral, provided the intestine is accessible +and functioning. +Rapid depletion of (already low) thiamin exacerbates the condition. +of many prescription drugs are nausea and gastrointestinal +disturbance. +Vagotomy and +gastroenterostomy may cause symptoms of dumping syndrome +(p. +801), which can lead to food avoidance and weight loss. +This may impair absorption +of iron, folic acid and vitamin B12. +Enteral tube feeding is usually the intervention +of choice. +In enteral feeding, nutrition is delivered to and absorbed +by the functioning intestine. +Insertion of a nasogastric tube requires care +and training (see Box 21.41, p. +805), as potentially serious +complications can arise (Box 19.16). +Patients with reduced +conscious level may pull at tubes and displace them. +Gastrostomy feeding Gastrostomy is a more invasive insertion +technique with higher costs initially. +It is most suitable for +when longer-term feeding (more than 4 weeks) is required. +A variety of techniques for +radiological insertion have also been introduced subsequently. +The stomach is then punctured percutaneously and a suitable +tube placed (Fig. +19.10). +19.10 Percutaneous endoscopic gastrostomy (PEG) placement. +A Finger pressure on the anterior abdominal wall is noted by the endoscopist. +C The endoscope is withdrawn with the guidewire. +The gastrostomy tube is then attached to the guidewire. +IF can be further classied according to its onset, metabolic +consequences and expected outcome. +• Type 1 IF: an acute-onset, usually self-limiting condition +with few long-term sequelae. +It is most often seen +following abdominal surgery or in the context of critical +illness. +Septic and metabolic problems are seen, along with +complex nutritional issues. +It may or may not be reversible. +Unlike the +jejunum, the ileum can adapt to increase absorption of water +and electrolytes over time. +The absence +of the ileum leads to deciencies of vitamin B12 and fat-soluble +vitamins. +The absorption of various drugs, including thyroxine, +digoxin and warfarin, can be reduced. +21.43, p. +810). +The 10-year survival for patients on long-term home parenteral +nutrition is approximately 90%. +The rst successful small bowel transplant was +carried out in 1988. +Since then, over 2000 transplants have +been performed worldwide. +Use of teduglutide is currently limited by +high costs. +Alternative measurements include arm demispan and knee height +(p. +693), which can be extrapolated to estimate height. +In selected +cases, a decision not to intervene may be appropriate. +Such decisions are not taken lightly and +careful scrutiny of each case is necessary. +It is appropriate to: +• screen for malnutrition (e.g. +MUST, see above) +• assess specic eating difculties (e.g. +19.11). +19.11 Malnutrition in dementia – a vicious circle. +From Volkert +D, Chourdakis M, Faxen-Irving G, et al. +ESPEN guidelines on nutrition in +dementia. +Clin Nutr 2015; 34:1052–1073. +Teratogenic in +excessive amounts. +Vitamin D: to ensure bone and dental development in the infant. +Vitamin B12: in lactation only. +Thiamin: to meet increased fetal energy demands. +Riboflavin: to meet extra demands. +Niacin: in lactation only. +Vitamin C: for the last trimester to maintain maternal stores as +fetal demands increase. +Iodine: in countries with high consumption of staple foods +(e.g. +If dietary intake falls, a vitamin-rich +diet is required to compensate. +This +leads to bone loss and fractures. +1242). +Toxic effects +are most serious with high dosages of vitamins A, B6 and D. +Carotenes +provide most of the total vitamin A in the UK and constitute +the only supply in vegans. +Other countries use different terminology. +Additional +amounts of some micronutrients may be required in pregnancy +and lactation (Box 19.29). +Dietary supplements are recommended for these ‘at-risk’ groups. +Some nutrient deciencies are induced by diseases or drugs. +In vitamin A deciency, mucus-secreting +cells are replaced by keratin-producing cells. +Early deciency causes impaired adaptation to the dark (night +blindness). +19.12). +This also reduces mortality from gastroenteritis and +respiratory infections. +Repeated moderate or high doses of retinol can cause liver +damage, hyperostosis and teratogenicity. +Retinol intake may also +be restricted in those at risk of osteoporosis. +Acute overdose +leads to nausea and headache, increased intracranial pressure +and skin desquamation. +Few foods +contain vitamin D naturally and skin exposure to sunlight is the +main source. +The body store accumulated +during the summer is consumed during the winter. +24.61, +p. +1051). +1309). +Other groups may require such supplementation +only in the winter months of October to March. +An analogue of +vitamin D (calcipotriol) is used for treatment of skin conditions such +as psoriasis. +661). +Vitamin E +There are eight related fat-soluble substances with vitamin E +activity. +The most important dietary form is Îą-tocopherol. +• It helps maintain cell membrane structure. +• It affects DNA synthesis and cell signalling. +• It is involved in the anti-inflammatory and immune systems. +A +19 +B +Fig. +19.12 Eye signs of vitamin A deciency. +A Bitot’s spots +in xerophthalmia, showing the white triangular plaques (arrows). +B Keratomalacia in a 14-month-old child. +A, Courtesy of Institute of Ophthalmology, Moorelds Eye Hospital, +London. +B, From WHO. +It can cause a mild +haemolytic anaemia, ataxia and visual scotomas. +Vitamin K2 is also synthesised by +bacteria in the colon. +Gla residues are found in four of the coagulation factor +proteins (II, VII, IX and X; p. +918), conferring their capacity to +bind to phospholipid surfaces in the presence of calcium. +Vitamin K deciency leads to delayed coagulation and bleeding. +Warfarin and related anticoagulants (p. +939) act by +antagonising vitamin K. +Vitamin K is given routinely to newborn +babies to prevent haemorrhagic disease. +In thiamin deficiency, cells cannot metabolise glucose +aerobically to generate energy as ATP. +1195). +In dry beri-beri, response to thiamin administration is not +uniformly good. +1195). +Korsakoff’s psychosis is irreversible +and does not respond to thiamin treatment. +It is widely distributed in animal +and vegetable foods. +Levels are low in staple cereals but +germination increases its content. +It is destroyed under alkaline +conditions by heat and by exposure to sunlight. +Deciency is +rare in developed countries. +It mainly affects the tongue and +lips and manifests as glossitis, angular stomatitis and cheilosis. +Rapid +recovery usually follows administration of riboflavin 10 mg daily +by mouth. +Niacin (vitamin B3) +Niacin encompasses nicotinic acid and nicotinamide. +Niacin can be synthesised in +the body in limited amounts from the amino acid tryptophan. +It is also seen occasionally in carcinoid syndrome (p. +Pellagra has been called +the disease of the three Ds: +• Dermatitis. +19.13). +The skin lesions may progress to vesiculation, +cracking, exudation and secondary infection. +• Diarrhoea. +• Dementia. +In severe deciency, delirium occurs acutely +and dementia develops in chronic cases. +Treatment is with nicotinamide, given in a dose of 100 mg 3 +times daily orally or parenterally. +The response is usually rapid. +Folate works as a methyl +donor for cellular methylation and protein synthesis. +Liver is +the richest source of folate but an alternative source (e.g. +leafy +vegetables) is advised in early pregnancy because of the high +vitamin A content of liver (p. +712). +Folate deciency has also +been associated with heart disease, dementia and cancer. +Vitamin B12 and folate are particularly important in +DNA synthesis in red blood cells (p. +943). +944). +Several drugs, +including neomycin, can render vitamin B12 inactive. +In severe deciency there is insidious, diffuse and +uneven demyelination. +1138), or there may be cerebral manifestations +(resembling dementia) or optic atrophy. +Vitamin B12 therapy +improves symptoms in most cases. +19.14). +Precipitants and clinical features of scurvy are shown +Fig. +19.13 Dermatitis due to pellagra (niacin deciency). +The lesions +appear on those parts of the body exposed to sunlight. +The classic ‘Casal’s +necklace’ can be seen around the neck and upper chest. +From Karthikeyan +K, Thappa DM. +Pellagra and skin. +Int J Dermatol 2002; 41:476–481. +Toxicity +Excessive intakes of niacin may lead to reversible hepatotoxicity. +PLP is the co-factor for a large number of +enzymes involved in the metabolism of amino acids. +Vitamin B6 +is available in most foods. +Large doses +of vitamin B6 have an antiemetic effect in radiotherapy-induced +nausea. +Very high doses of vitamin B6 taken for several months +can cause a sensory polyneuropathy. +It may also be seen after +long periods of total parenteral nutrition. +The clinical features of +deciency include scaly dermatitis, alopecia and paraesthesia. +Folate (folic acid) +Folates exist in many forms. +The main circulating form is +5-methyltetrahydrofolate. +The natural forms are prone to oxidation. +19716 • NUTRITIONAL FACTORS IN DISEASE +A B +Fig. +19.14 Scurvy. +A Gingival swelling and bleeding. +B Perifollicular hyperkeratosis. +A and B, From Ho V, Prinsloo P, Ombiga J. +Persistent anaemia +due to scurvy. +J New Zeal Med Assoc 2007; 120:62. +Reproduced with permission. +inadequate dietary intake of minerals or excessive loss from +the body. +Toxic effects have also been observed from self- +medication and disordered absorption or excretion. +149), copper (Wilson’s +disease) and selenium (selenosis, seen in parts of China). +661 and 1050). +Calcium requirements +depend on phosphorus intakes, with an optimum molar ratio +(Ca:P) of 1 : 1. +Excessive phosphorus intakes (e.g. +662). +Calcium absorption may be impaired in vitamin D deciency +(pp. +661 and 1050) and in malabsorption secondary to small +intestinal disease. +Calcium deciency causes impaired bone +mineralisation and can lead to osteomalacia in adults. +The potential +benets of high calcium intake in osteoporosis are discussed on +page 1048. +662). +Phosphate deciency in adults occurs: +• in patients with renal tubular phosphate loss (p. +405) +• in patients receiving a prolonged high dosage of aluminium +hydroxide (p. +Deciency causes hypophosphataemia (p. +368) and muscle +weakness secondary to ATP deciency. +A dose of 250 mg vitamin C 3 times daily by +mouth should saturate the tissues quickly. +Intake +of non-carbonic organic acids (which are not metabolised to +carbon dioxide), e.g. +oxalates, may be restricted in individuals +prone to kidney stones. +2Increased amounts are required in women during lactation. +23.18, +p. +942). +A regular loss of only 2 mL of blood +per day doubles the iron requirement. +The major consequence of iron deciency is anaemia (p. +940). +This is one of the most important nutritional causes of ill health +in all parts of the world. +In the UK, it is estimated that 10% +women are iron-decient. +Haemochromatosis results from an inherited increase +in iron absorption (p. +895). +Iodine +Iodine is required for synthesis of thyroid hormones (p. +634). +It is present in sea sh, seaweed and most plant foods grown +near the sea. +The amount of iodine in soil and water influences +the iodine content of most foods. +Iodine is lacking in the highest +mountainous areas of the world (e.g. +the Alps and the Himalayas) +and in the soil of frequently flooded plains (e.g. +Bangladesh). +Goitre is the most common manifestation, affecting +about 200 million people (p. +648). +Zinc +Zinc is present in most foods of vegetable and animal origin. +In +the Middle East, chronic deciency has been associated with +dwarsm and hypogonadism. +634). +Excess +selenium can cause heart disease. +Soft +waters usually contain no fluoride, while very hard waters may +contain over 10 ppm. +Fluoride poisoning is described on page 149. +Pitting of teeth is +a result of too much fluoride as a child. +In the UK, it is suggested +that daily salt intakes are kept well below 6 g. +Copper metabolism is abnormal in Wilson’s disease (p. +896). +Medicine and surgery: an integrated textbook. +Edinburgh: Elsevier Ltd; 2007. +( Exudative maculopathy) +Courtesy of Dr A.W. +Patrick and Dr I.W. +1059) causes +nodules or thickening of the skin and +knuckle pads +• Carpal tunnel syndrome (p. +Courtesy of Dr +A.W. +Patrick and Dr I.W. +Campbell. +Monolaments. +The monolament is +applied gently until slightly deformed at ve +points on each foot. +Callus should be +avoided as sensation is reduced. +Lipohypertrophy of the upper arm. +Proliferative retinopathy. +Courtesy of Dr +A.W. +Patrick and Dr I.W. +It has many +causes (see Box 20.9), most commonly type 1 or type 2 diabetes. +Hyperglycaemia causes both acute and +long-term problems. +Less severe hyperglycaemia is called ‘impaired +glucose tolerance’. +The incidence of diabetes is rising. +It is generally more common in countries closer +to the polar regions. +Type 1 diabetes is most common in +Caucasians, and more people are diagnosed in the winter +months. +Diabetes is a major burden on health-care facilities in all +countries. +<4% +4–5% +5–7% +7–9% +9–12% +>12% +Fig. +20.1 Prevalence (%) of diabetes in those aged 20–79 years, 2015. +Based on estimates from the International Diabetes Federation. +IDF Diabetes +Atlas, 7th edn. +Brussels, Belgium: International Diabetes Federation, 2015. +Glucose is then metabolised by glycolysis +and oxidative phosphorylation. +This makes it a very effective glucose sensor in the +β cell. +20.2). +20.2). +20.2 Pancreatic structure and endocrine function. +Histology is shown in Figure 20.6. +C Schematic representation of the pancreatic β +cell. +(1) Glucose enters the cell via a glucose transporter (GLUT1 or +GLUT2). +This +leads to membrane depolarisation. +Genetic defects in the β cell result in diabetes. +Two groups of drugs act on the β cell to +promote insulin secretion. +20.4 Processing of pro-insulin into insulin and C-peptide. +Measurement +of C-peptide can be used to assess endogenous insulin secretory capacity. +Time +0–5 +mins +classically occurs in two phases (see Fig. +20.3). +20.2B). +Alpha cells make up about +20% of the human islet cell population. +Glucagon is also critically important to the +body’s defence against hypoglycaemia (p. +738). +Blood glucose homeostasis +Blood glucose is tightly regulated and maintained within a narrow +range. +This is essential for ensuring a continuous supply of glucose +to the central nervous system. +20.5). +B +The incretin effect +After oral +glucose +After +intravenous +glucose +Insulin +Time +Fig. +20.3 Insulin secretion in response to intravenous or oral +glucose. +747). +(ADP), which causes closure of an ATP-sensitive potassium +channel (KATP). +20.3), and GLP-1 +and GIP are known as incretin hormones. +20.4). +20.5 Major metabolic pathways of fuel metabolism and the actions of insulin. +Պ indicates stimulation and Ջ indicates suppression by insulin. +In response to a rise in blood glucose, e.g. +It also promotes protein +synthesis and lipogenesis, and suppresses lipolysis. +In the absence of insulin, e.g. +This leads to increased hepatic glucose output via +gluconeogenesis and glycogen breakdown. +The liver now resumes +net glucose production and glucose homeostasis is maintained. +The main substrates for gluconeogenesis are glycerol and amino +acids, as shown in Figure 20.5. +Insulin is the major +regulator not only of glucose metabolism but also of fatty acid +metabolism. +High insulin levels after meals promote triglyceride +accumulation. +Glycosuria always warrants further assessment by +blood testing (see below). +These are used +for capillary (ngerprick) testing to monitor diabetes treatment +(p. +742). +Glucose concentrations are lower in venous than arterial or +capillary (ngerprick) blood. +Venous plasma values are +usually the most reliable for diagnostic purposes (Boxes 20.2 +and 20.3). +20.16, p. +751). +Urine ketone +measurements are semi-quantitative, awkward to perform and +retrospective (i.e. +the urine has accumulated over several hours). +20.4). +It can be +readily measured in blood and urine by sensitive immunoassays. +It is also useful in the +diagnosis of spontaneous hypoglycaemia (p. +676). +757). +laboratories may report glycated haemoglobin as total glycated +haemoglobin (GHb), HbA1 or HbA1c. +In most countries, HbA1c is +the preferred measurement. +in the diagnosis +of diabetes. +Asymptomatic +individuals should have a second conrmatory test. +Diabetes +should not be diagnosed on capillary blood glucose results. +Alternatively, an HbA1c of ≥ 48 mmol/mol is also diagnostic of +diabetes. +in someone with suspected type 1 diabetes +or severe symptomatic hyperglycaemia (p. +734). +The HbA1c criteria +for pre-diabetes are less clear. +insulin-secreting β cells in the pancreatic islets. +This process was seen to +take place over a prolonged period (months to years). +More recent data have led to modications +of this model. +The +destructive process is β-cell-specic. +20.6). +Type 1 diabetes is +associated with other autoimmune disorders (Ch. +4), including +thyroid disease (p. +638), coeliac disease (p. +805), Addison’s +disease (p. +671), pernicious anaemia (p. +944) and vitiligo (p. +1257). +The relationship +is complex and, as indicated, multifactorial. +20.6 Pathogenesis of type 1 diabetes. +Proposed sequence of events in the development of type 1 diabetes. +Environmental triggers are described +in the text. +Insets (normal islet, β-cell destruction) Courtesy of Dr A. +Foulis, Dept of Pathology, University of Glasgow. +Although hypotheses abound, the nature of these environmental +factors is unknown. +they tend to be transmitted +together, with the neighbouring alleles of the HLA-DQA1 and +DQB1 genes. +82). +CD25, PTPN22, SH2B3, IL2RA and IL-10. +20.7 Acute metabolic complications of insulin deciency. +(FFA = free fatty acid) +weight loss. +Ketoacidosis occurs when generation of ketones +exceeds the capacity for their metabolism. +735). +Type 2 diabetes +Pathology +Type 2 diabetes is a diagnosis of exclusion, i.e. +The natural history of typical +type 2 diabetes is shown in Figure 20.8. +20.8 Natural history of type 2 diabetes. +With further β-cell failure, glycaemic control deteriorates and treatment requirements escalate. +B, Adapted from Holman RR. +Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25. +882) and, in women, polycystic ovarian syndrome. +Physical activity is another important determinant of insulin +sensitivity. +882) and +cirrhosis. +20.8B). +more than 40 risk variants) +and others having inherited very few. +698). +Age +Type 2 diabetes is more common in middle-aged and older +individuals (Box 20.8). +Ethnicity +Ethnic origin is a major risk factor for development of diabetes. +decreased physical +activity and increased smoking; and differences in genetic risk. +Intercurrent illness, e.g. +738). +Other forms of diabetes +Other causes of diabetes are shown in Box 20.9. +Half of these are undiagnosed. +Impaired β-cell function +and exaggerated insulin resistance with ageing both contribute. +As a result, the +HbA1c is often normal and microvascular complications are rare. +The HNF1Îą and 4Îą forms respond particularly +well to sulphonylurea drugs. +All types are associated with +microvascular complications. +For further information, +see diabetesgenes.org. +leprechaunism, +lipodystrophies) +• Pancreatic disease (e.g. +IPEX +syndrome) +• Associated with genetic syndromes (e.g. +The +common genes involved in MODY and neonatal diabetes are +shown in Figure 20.2C. +MODY is +dominantly inherited (p. +MODY itself is a heterogeneous condition, +with multiple subtypes. +One form is caused by mutations in +glucokinase (see Fig. +the effects of insulin (Ch. +18); and more generalised diseases +of the pancreas. +It is characteristically a disease of the tropics, with variable +prevalence across these regions. +The aetiology of FCPD is poorly +understood. +Insulin treatment is usually +required at or soon after diagnosis. +20.2C). +727). +20.9). +type 2 diabetes? +20.9 New-onset hyperglycaemia. +Hyperglycaemia causes a wide variety of symptoms (Box +20.11). +The classical clinical features of type 1 and type 2 +diabetes are compared in Box 20.12. +There are many patients +in whom the type of diabetes is not immediately apparent. +Physical signs in patients with type 2 diabetes at diagnosis +depend on the mode of presentation. +Obesity is much less evident in Asians. +Hypertension is present in at least 50% of patients with type 2 +diabetes. +Blood glucose should therefore +be checked in all patients presenting with such pathology. +The +detailed investigation and management of diabetic complications +are described on page 755. +However, an increasing number of patients presenting with DKA +have underlying type 2 diabetes. +This appears to be particularly +prevalent in black and non-Hispanic populations. +20.7). +When this exceeds the capacity to metabolise acidic ketones, +these accumulate in blood. +The resulting metabolic acidosis +forces hydrogen ions into cells, displacing potassium ions. +738). +Clinical assessment +The clinical features of ketoacidosis are listed in Box 20.14. +Mental apathy, delirium or a reduced conscious +level may be present, although coma is uncommon. +In fact, it is imperative that energetic treatment is +started at the earliest possible stage. +Abdominal pain is sometimes a feature of DKA, particularly +in children, and vomiting is common. +Serum amylase may +be elevated but rarely indicates coexisting pancreatitis. +• Urine or blood analysis for ketones (p. +726). +• Electrocardiogram (ECG). +• Infection screen: full blood count, blood and urine +culture, C-reactive protein, chest X-ray. +If available, the +diabetes specialist team should be involved. +Guidelines for the management of DKA are +shown in Box 20.16. +194) or abnormal AVPU scale +score (p. +The Management of Diabetic Ketoacidosis in Adults, 2nd edn; September 2013; abcd.care. +Caution is advised in children and +young adults because of the risk of cerebral oedema. +If the plasma sodium is +greater than 155 mmol/L, 0.45% saline may be used initially. +If the potassium +falls below 3.5 mmol/L, the potassium replacement regimen +needs to be reviewed. +Aim to maintain potassium between +4.0 and 5.5 mmol/L. +Bicarbonate +Adequate fluid and insulin replacement should resolve the acidosis. +The use of intravenous bicarbonate therapy is not recommended. +events or drug therapy (e.g. +glucocorticoids). +The principles of therapy are shown in Box 20.17. +14). +In +hyperglycaemic patients, the corrected [Na+] should be taken +into account. +A mixed picture +of HHS and DKA can occur. +Although typically occurring in older patients, HHS is +increasingly seen in younger adults. +20 +In addition, stress hormones, such as cortisol and growth +hormone, are increased in the blood. +Hypoglycaemia also affects mood, inducing a state of +increased tension and low energy. +Severe +hypoglycaemia can have serious morbidity (e.g. +concurrent illness +or discontinuation of long-term glucocorticoid therapy. +during the night or during exercise). +Such +individuals are at an especially high risk of severe hypoglycaemia. +Oral carbohydrate usually sufces if hypoglycaemia +is recognised early. +Cerebral oedema has a high mortality and morbidity. +The management of self-poisoning with oral antidiabetic agents +is described on page 141. +Prevention of hypoglycaemia +Patient education is fundamental to the prevention of +hypoglycaemia. +Risk factors for, and treatment of, hypoglycaemia +should be discussed. +The only reliable way to identify this problem is +to measure blood glucose during the night. +This occurs most +commonly with prolonged and/or aerobic exercise. +People with diabetes who +recognise developing hypoglycaemia are encouraged to treat +immediately. +Treatment is usually by a relative or by +paramedical or medical staff. +Immediate treatment as below is needed. +Initial investigation and management is outlined in Figure 20.10. +Education is key to achieving and maintaining +a healthy lifestyle and to managing diabetes. +A checklist for follow-up +visits is given in Box 20.22. +510) and dyslipidaemia (p. +373), +and advice on smoking cessation (p. +94). +20 +*Use of 50% dextrose is no longer recommended. +Adapted from Joint British Diabetes Societies. +The hospital management of +hypoglycaemia in adults with diabetes mellitus (2013). +Available at: abcd.care. +management during exercise is particularly useful. +Advice for +patients when travelling is summarised in Box 20.21. +748). +20.10 The recommended approach for the management of type 2 diabetes. +First-line drug treatment should be metformin. +Diabetes Care 2015; 38:140–149. +have been developed that allow for a more detailed examination +of daily glucose proles. +Blood glucose testing can be used for self- +education (i.e. +Early on in +diabetes (i.e. +721) +6 +Upper limit of normal +0 +0369 12 15 +Years from randomisation +Fig. +20.11 Time course of changes in HbA1c during the United +Kingdom Prospective Diabetes Study (UKPDS). +20.8). +Adapted from UK Prospective Diabetes Study Group. +UKPDS 33. +Lancet 1998; 352:837–853. +Patients should be encouraged to +stop smoking. +694). +They should have access +to a dietitian at diagnosis, at review and at times of treatment +change. +Reduction of caloric intake and weight loss should be +the major goals. +Some evidence for the Mediterranean diet, +low-carbohydrate diets and meal replacements is emerging. +table sugar, honey, +20 +(Fig. +This can +be decided by assessing absolute risk of a cardiovascular +disease event (p. +510) and adjusting targets to individual +circumstances. +Management of obesity is described on page 700. +More recently, bariatric surgery (p. +This +can include activities such as walking, gardening, swimming or +cycling. +Supervised and structured exercise programmes may +be of particular benet in type 2 diabetes. +Various guidelines +exist for physical activity in the general population. +Muscle- +strengthening (resistance) exercise is recommended on 2 or +more days of the week. +Recent evidence +also indicates that extended sedentary time (> 90 mins) should +be avoided. +in the UK, the weekly recommended maximum +is 14 units for women and men). +Different foods can be ranked by their effect +on post-prandial glycaemia. +Low-GI foods, such as starchy +foods (e.g. +Increased +consumption of whole grains has not been shown to improve +glycaemic control. +Fat +There is limited evidence on the ideal fat content in the diet of +people with diabetes. +Mediterranean diets rich +in monounsaturated fats appear more benecial (Box 20.23). +Treatment should be evaluated and modied +according to risk of hypoglycaemia. +Weight loss suggests worsening +β-cell function. +Acarbose is also available but is little used in most +countries. +The effects of these drugs are compared in Box 20.26. +in drivers of heavy goods vehicles) +and weight gain. +Biguanides +Metformin is the only biguanide available. +Its long-term benets +were shown in the UK Prospective Diabetes Study (UKPDS, p. +It is also given as an adjunct to insulin +therapy in obese patients with type 1 diabetes. +The main side-effects are diarrhoea, abdominal cramps, bloating +and nausea. +Mechanism of action +The mechanism of action of metformin has not been precisely +defined. +20.10). +The usual maintenance +dose is 1 g twice daily. +Sulphonylureas +Sulphonylureas are ‘insulin secretagogues’, i.e. +they promote +pancreatic β-cell insulin secretion. +756). +20.2C). +Meglitinides (e.g. +20.10). +The main adverse effects of sulphonylureas are +weight gain and hypoglycaemia. +There are a number of sulphonylureas. +Other sulphonylureas include +glimepiride and glipizide. +Acarbose and miglitol are +available and are taken with each meal. +Both lower post-prandial +blood glucose and modestly improve overall glycaemic control. +They can be combined with a sulphonylurea. +The main side-effects +are flatulence, abdominal bloating and diarrhoea. +They are used +widely in the Far East but infrequently in the UK. +Plasma insulin concentrations are not increased +and hypoglycaemia does not occur. +TZDs increase pre- +adipocyte differentiation, resulting in an increase in fat mass and +body weight. +These observations have led to a dramatic +reduction in the use of pioglitazone. +In addition, it has a benecial effect in reducing fatty liver +and NASH (p. +882). +Pioglitazone is usually added to metformin +with or without sulphonylurea therapy (see Fig. +20.10). +20.3). +20.2). +These are +rapidly broken down by dipeptidyl peptidase 4 (DPP-4). +These drugs are very well tolerated and are weight-neutral (see +Box 20.26). +Recent cardiovascular outcome studies have shown +mixed results with the DPP-4 inhibitors. +These agents are not orally active and have to be given by +subcutaneous injection. +Subsequently, +canagliflozin and empagliflozin have also been licensed. +Glucose is +ltered freely in the renal glomeruli and reabsorbed in the proximal +tubules. +SGLT2 is involved in reabsorption of glucose (Fig. +20.12). +Euglycaemic diabetic ketoacidosis (i.e. +Recombinant +DNA technology enabled large-scale production of human insulin. +20.13). +nicotinamide and arginine to insulin +aspart). +20.13). +20.13). +20.12 Glucose ltration and reabsorption +by the nephron. +SGLT2 inhibitors +reduce net reabsorbed glucose by 25%. +This equates to 320 kcal per day and +subsequent weight loss. +20.13 Amino acid structure of insulin and insulin analogues. +The areas in the shaded colours show the modications made to the normal +structure of insulin. +These are important in altering the pharmocokinetic properties of the analogues. +Accidental intramuscular injection +often occurs in children and thin adults. +Absorption +is delayed from areas of lipohypertrophy at injection sites +(p. +Once absorbed into the blood, insulin has a half-life of just +a few minutes. +Rarely, the rate of clearance +can be affected by binding to insulin antibodies. +The more modern, structurally modied, long-acting +insulins (e.g. +glargine, detemir and degludec) are clear and do +not require resuspension. +These are also available +as pre-loaded disposable pens. +738). +The dawn phenomenon is +not a consequence of prior nocturnal hypoglycaemia. +However, in time, more frequent insulin +injections are usually required. +30 : 70 and 50 : 50). +20.14 Proles of plasma insulin associated with different +insulin regimens. +vial several times before administration. +This +increases the risk of hypoglycaemia. +His pre-breakfast +glucose (G) is 12 mmol/L (216 mg/dL). +He is having a breakfast meal +of cereal with milk containing 30 g of carbohydrate (CHO) in total. +He wants to achieve a +glucose target (GT) of 8 mmol/L (144 mg/dL) after eating. +20.15 Insulin pump. +An insulin pump is an alternative means of +delivering insulin in type 1 diabetes. +glucocorticoids), +and a change in fitness levels with exercise on overall +glycaemic control. +An example of an insulin pump is shown in +Figure 20.15. +20.16). +These systems aim to integrate insulin +pumps with continuous glucose monitoring systems (CGMS). +20.17). +Current +1 +3 +20 +2 +Fig. +20.16 Articial pancreas. +Widespread use +may, however, be limited by cost. +Alternative routes of insulin delivery have also been investigated. +4:00 +a.m. +6:00 +a.m. +8:00 +a.m. +10:00 +12:00 +p.m. +2:00 +p.m. +4:00 +p.m. +6:00 +p.m. +8:00 +p.m. +10:00 +p.m. +12:00 +a.m. +a.m. +a.m. +Time through the day +B +16.7 +11.1 +7.8 +5.6 +3.9 +3.3 +0 +12:00 +2.00 +a.m. +4:00 +a.m. +6:00 +a.m. +8:00 +a.m. +10:00 +12:00 +p.m. +2:00 +p.m. +4:00 +p.m. +6:00 +p.m. +8:00 +p.m. +10:00 +p.m. +12:00 +a.m. +a.m. +a.m. +Time through the day +Fig. +20.17 Continuous glucose monitoring (CGM) proles: sensor data. +A CGM prole from an individual without diabetes. +B CGM prole from an +individual with type 1 diabetes. +The green box shows the reference range. +donor pancreas into a person with type 1 diabetes. +The isolated +pancreatic islets are usually infused into the patient’s liver via the +portal vein. +This approach has now been successfully adopted in +a number of centres around the world (Fig. +20.18). +58) mean that this +may still prove the most promising approach in the long term. +20.18 Transplanting islet cells. +(1) Pancreas obtained from suitable human donor. +(3) Islets, once separated and puried, are infused into the hepatic portal vein. +Measurement of HbA1c and/or blood glucose at booking visit is +usually recommended. +Monogenic diabetes (MODY) +should also be considered (see Box 20.10, p. +733). +Periods of rebellion +against parental control, experimentation (e.g. +• Glycaemic control: a temporary deterioration in control is common, +although not universal. +This is more common in females. +Support is +required for the patient and parents. +20 +blood glucose in pregnancy is associated with signicant maternal +and fetal morbidity. +448) +• Assess foot risk (p. +Starvation exacerbates this process by increasing lipolysis. +Finally, management errors in diabetes may cause +dangerous hyperglycaemia or hypoglycaemia. +There is good evidence that a higher HbA1c is +associated with adverse perioperative outcome. +Management of these +children and young adults is difcult. +Current recommendations for screening in type 1 +diabetes are shown in Box 20.33. +728), +while in others it is due to undiagnosed diabetes. +Continue long-acting +insulin (e.g. +Continue long-acting +insulin (e.g. +20.19 Management of diabetic patients undergoing surgery and general anaesthesia. +20.19). +During this time, care must be +taken with fluid balance and electrolyte levels. +360) and +can result in hyponatraemia. +of diabetes still cause significant morbidity and mortality +(Boxes 20.35 and 20.36). +20.20). +730). +Type 1 diabetes is +also associated with increased cardiovascular risk. +20.20 Association between HbA1c and risk of microvascular and +macrovascular diabetes complications. +Macrovascular disease included fatal and non-fatal myocardial +infarction and sudden death. +A 1% change in HbA1c is equivalent to a +reduction of 11 mmol/mol. +No single factor +other than glycaemic control had a signicant effect on outcome. +Subsequently, nodular deposits (Fig. +Microalbuminuria +is a good predictor of progression to nephropathy in type 1 +diabetes. +394), although it is a potentially useful +marker of an increased risk of macrovascular disease. +20.20). +375). +Other causes of visual +loss in type 2 diabetes are also covered in Chapter 27. +15.1D, p. +385). +Both ACE inhibitors and ARBs +increase risk of hyperkalaemia (p. +362) and, in the presence of +renal artery stenosis (p. +406), may induce marked deterioration in +renal function. +Some patients +do progress, however, with worsening renal function. +Renal +replacement therapy (p. +For further +information on management, see Chapter 15. +10 +120 +5 +010 20 +Years +Microalbuminuria +Nephrotic range proteinuria +Sustained proteinuria +Fig. +20.21 Natural history of diabetic nephropathy. +Renal function continues to decline, with the end +stage being reached at approximately 16 years. +Fig. +20.22 Nodular diabetic glomerulosclerosis. +Diabetic neuropathy +Diabetic neuropathy causes substantial morbidity and increases +mortality. +1138). +Pathological features can occur in any peripheral nerves. +Various classifications of diabetic neuropathy have been +proposed. +Clinical features +Symmetrical sensory polyneuropathy +This is frequently asymptomatic. +20.23 Diabetic foot disease. +Patients with diabetes can have neuropathy, peripheral vascular disease or both. +Levin and O’Neal’s The diabetic foot, 7th edn. +Philadelphia: Mosby, Elsevier Inc.; 2008; (Neuropathic foot ulcer) Levy MJ, Valabhji +J. +Vascular II: The diabetic foot. +Surgery 2008; 26:25–28; (Digital gangrene) Swartz MH. +Textbook of physical diagnosis, 5th edn. +Philadelphia: WB +Saunders, Elsevier Inc.; 2006. +Electrophysiological tests (p. +Sometimes +there may also be marked loss of weight (‘neuropathic +cachexia’). +The patient may look extremely ill and be unable to +get out of bed. +Tendon reflexes may be absent on the affected +side(s). +Other lesions involving +this plexus, such as neoplasms and lumbar disc disease, +must be excluded. +Although recovery usually occurs within +12 months, some decits are permanent. +Management is mainly +supportive. +20.23), and loss of tendon reflexes in the lower limbs. +In +symptomatic patients, sensory abnormalities are predominant. +2 Avoid +arm with arteriovenous stula in dialysed patients. +Prevalence rates are estimated to be approximately 5% in type +1 diabetes and 1% in type 2 diabetes. +774, 776 and 777). +Enteral nutrition is rarely required unless gastroparesis +is very severe. +Recommended pharmacological and interventional +therapy is shown in Box 20.43. +Lateral popliteal nerve compression occasionally +causes foot drop. +Autonomic neuropathy +This is not necessarily associated with peripheral somatic +neuropathy. +502 and Fig. +20.23); with infection is a secondary phenomenon +following disruption of the protective epidermis. +20.23 and p. +720). +1048). +Management +Management can be divided into primary prevention and +treatment of an active problem. +All patients should be educated +in preventative measures (Box 20.45). +Combined with the clinical +scenario, these tests guide appropriate referral and monitoring +(Fig. +20.24). +If an ulcer +• Gastric pacemaker; +percutaneous enteral (jejunal) +feeding (see Fig. +19.10, +p. +708) +Diarrhoea (p. +For further information, see page 440. +Management +Management of neuropathies is outlined in Box 20.43. +Tissue necrosis in the feet is a common reason for hospital +admission in diabetic patients. +20.24 Risk assessment and management of foot problems in diabetes. +Adapted from Scottish Intercollegiate Guidelines Network (SIGN) +guideline number 116. +of weight-bearing on the affected foot. +Immobilisation is often +achieved by a total contact plaster cast or ‘aircast’ boot. +The +acute phase frequently lasts 3–6 months and sometimes longer. +N Engl J Med 1993; 329:977–986. +Nathan DM, Cleary PA, Backlud JY, et al. +Intensive +diabetes treatment and cardiovascular disease in patients with type +1 diabetes. +N Engl J Med 2005; 353:2643–2653. +UK Prospective Diabetes Study (UKPDS) Group. +Lancet 1998; 352:837–853, 854–865. +Websites +cdc.gov/diabetes/ Diabetes Public Health Resource. +Useful American +site with resources for patients and health-care professionals. +diabetes.org American Diabetes Association. +Includes information on +research and advocacy issues. +diabetes.org.uk Diabetes UK. +Includes information for patients and +leaflets. +idf.org International Diabetes Federation. +Useful information on +international aspects of care and education. +joslin.org Joslin Diabetes Center. +ndei.org National Diabetes Education Initiative. +Web-based education +for health-care professionals, including case studies and slides. +In cases +of severe secondary infection or gangrene, an amputation may +be required. +This can be limited to the affected toe or involve +more extensive limb amputation. +The initial X-ray +may show bony destruction but is often normal. +Magnetic resonance +imaging (MRI) of the foot is often helpful. +22) +Kidneys (Ch. +• Fever? +• Dehydrated? +The gastrointestinal +tract is the most common site for cancer development. +It has +an upper and a lower sphincter. +A peristaltic swallowing wave +propels the food bolus into the stomach (Fig. +21.1). +21.2). +Normal +high-resolution +manometry +1 +Swallowing begins as a +voluntary process. +The +food enters the stomach +Lower +oesophageal +sphincter +Fig. +21.1 The oesophagus: anatomy and function. +The swallowing wave. +21.3). +Gastrin stimulates acid secretion and mucosal growth +while somatostatin suppresses it. +Small intestine +The small bowel extends from the ligament of Treitz to the +ileocaecal valve (Fig. +21.4). +During fasting, a wave of peristaltic +activity passes down the small bowel every 1–2 hours. +Entry +of food into the gastrointestinal tract stimulates small bowel +peristaltic activity. +21.3 Control of acid secretion. +(ACh-R = +acetylcholine receptor; ATPase = adenosine triphosphatase) +Villi +Paneth +cells +Crypts +Fig. +21.4 Small intestine: anatomy. +The lipids are processed within enterocytes and +pass via lymphatics into the systemic circulation. +Fat absorption +and digestion can be considered as a stepwise process, as +outlined in Figure 21.5. +Protein +The steps involved in protein digestion are shown in Figure 21.6. +Trypsin digests proteins to produce +oligopeptides, peptides and amino acids. +21.5 Fat digestion. +Step 1: Luminal phase. +Fatty acids stimulate cholecystokinin (CCK) release from the duodenum and upper jejunum. +Step 2: Fat solubilisation. +Step 3: Digestion. +Step 4: Absorption. +Mixed micelles diffuse to the brush border of the enterocytes. +Step 5: Re-esterication. +Within the enterocyte, fatty acids are re-esteried to form triglycerides. +Step 6: Transport. +21.6 Protein digestion. +21.7). +Vitamins and trace elements +Water-soluble vitamins are absorbed throughout the intestine. +The absorption of folic acid, vitamin B12, calcium and iron is +described on page 943. +21.8). +21.7 Fluid homeostasis in the gastrointestinal tract. +21.9) and are activated by trypsin. +The endocrine pancreas is discussed in +Chapters 18 and 20. +Colon +The colon (Fig. +21.10) absorbs water and electrolytes. +It also +acts as a storage organ and has contractile activity. +Two types +of contraction occur. +Fig. +21.8 Intestinal defence mechanisms. +See text for details. +21.9 Pancreatic structure and function. +Ductular cells secrete alkaline fluid in response to secretin. +Note the incidental calculi in the gallbladder and common bile duct (arrow). +21.10 The normal colon, rectum and anal canal. +It comprises two major networks +intrinsic to the gut wall. +The metabolic capacity of the gut microbiota is +equivalent to that of the liver. +Generally, we acquire our adult intestinal +microbiota by the age of 2 years. +It can be influenced +by innervation but functions independently. +21.11). +Calcied lymph nodes, gallstones and renal stones +can also be detected. +21.11).Investigation of gastrointestinal disease • 773 +A B +Fig. +21.11 Examples of plain X-rays. +21.12 Examples of contrast radiology. +B Barium follow-through. +There are multiple diverticula (arrows) in this patient with jejunal diverticulosis. +C Barium enema showing severe +diverticular disease. +There is tortuosity and narrowing of the sigmoid colon with multiple diverticula (arrows). +21.13 Examples of ultrasound, CT and MRI. +A Ultrasound showing large gallstone (arrow) with acoustic shadowing. +D Fused CT-PET image showing two liver metastases (arrows). +They are non-invasive and offer detailed images +of the abdominal contents. +Their main applications are summarised in +Box 21.4 and Figure 21.13. +Indications, contraindications and complications are given in +Box 21.5. +the pancreas or lymph nodes. +It can therefore be used to perform ne needle aspiration or +biopsy of mass lesions. +It also plays an important +role in the staging of certain cancers, e.g. +those of oesophagus +and pancreas. +Possible complications of EUS include bleeding, +infection, cardiopulmonary events and perforation. +Capsule endoscopy +Capsule endoscopy (Fig. +After +approximately 8 hours, the capsule is excreted. +21.14 Examples of therapeutic techniques in endoscopy. +A B +Fig. +21.15 Wireless capsule endoscopy. +A Examples of capsules. +B Capsule endoscopy +image of bleeding jejunal vascular malformation. +• Bowel preparation for colonoscopy: can be difcult in frail, +immobile people. +Minimal-preparation CT +colonograms provide an excellent alternative in these individuals. +Glucagon is +preferred if an antiperistaltic agent is needed. +for conrmation and therapy. +Indications, contraindications and +complications are listed in Box 21.6. +Indications, contraindications and complications are +listed in Box 21.7. +Indications, contraindications and +complications of colonoscopy are listed in Box 21.8. +Indications for and +risks of ERCP are listed in Box 21.10. +11). +Breath tests +Non-invasive breath tests for H. +Some of the more common ones are listed +in Box 21.12. +Results can be equivocal. +Accurate urine collection essential. +Faecal +calprotectin is very sensitive at detecting mucosal inflammation. +Oesophageal motility +A barium swallow can give useful information about oesophageal +motility. +Oesophageal manometry (see Fig. +Radioisotope tests +Many different radioisotope tests are used (Box 21.13). +In some, +structural information is obtained, such as the localisation of a +Meckel’s diverticulum. +pylori. +Dysphagia can occur due to problems in the oropharynx or +oesophagus (Fig. +21.16). +Drooling, dysarthria, hoarseness and cranial nerve or other +neurological signs may be present. +Oesophageal disorders cause +dysphagia by obstructing the lumen or by affecting motility. +Swallowing of liquids is +normal until strictures become extreme. +Investigations +Dysphagia should always be investigated urgently. +Endoscopy is +the investigation of choice because it allows biopsy and dilatation +of strictures. +Even if the appearances are normal, biopsies should +be taken to look for eosinophilic oesophagitis. +In +some cases, oesophageal manometry is required. +High-resolution +manometry allows accurate classication of abnormalities. +Figure +21.16 summarises a diagnostic approach to dysphagia and lists +the major causes. +21.16 Investigation of dysphagia. +There are many causes (Box 21.14), +including some arising outside the digestive system. +Heartburn and +other ‘reflux’ symptoms are separate entities and are considered +elsewhere. +An algorithm for the investigation of dyspepsia is outlined in +Figure 21.17. +These symptoms often +occur after meals, on lying down or with bending, straining or +heavy lifting. +The major causes are shown +in Figure 21.18. +Low scores (2 or less) are associated with a very low +risk of adverse outcome. +The common causes are shown in +Figure 21.19. +Syncope +may occur and is caused by hypotension from intravascular +volume depletion. +Symptoms of anaemia suggest chronic +bleeding. +Severe acute +upper gastrointestinal bleeding can sometimes cause maroon or +bright red stool. +Are there +'alarm' features? +Yes No +< 55 years +> 55 years +Urgent +endoscopy +Endoscopy +Test for Helicobacter pylori, e.g. +21.17 Investigation of dyspepsia. +Vomiting +Vomiting is a complex reflex involving both autonomic and somatic +neural pathways. +21.18 Causes of vomiting. +Management of variceal bleeding +is discussed on page 869. +1. +2. +Initial clinical assessment +• Dene circulatory status. +Severe bleeding causes +tachycardia, hypotension and oliguria. +The patient is cold +and sweating, and may be agitated. +• Seek evidence of liver disease (p. +846). +• Identify comorbidity. +3. +Basic investigations +• Full blood count. +Thrombocytopenia may be a clue to the presence +of hypersplenism in chronic liver disease. +• Urea and electrolytes. +This test may show evidence of +renal failure. +• Liver function tests. +These may show evidence of chronic +liver disease. +• Prothrombin time. +Check when there is a clinical +suggestion of liver disease or patients are anticoagulated. +• Cross-matching. +At least 2 units of blood should be +cross-matched if a signicant bleed is suspected. +21.19 Causes of acute upper gastrointestinal haemorrhage. +Frequency is given in parentheses. +(NSAIDs = non-steroidal anti-inflammatory drugs)782 • GASTROENTEROLOGY +4. +Comorbidities should be managed as appropriate. +Patients with +suspected chronic liver disease should receive broad-spectrum +antibiotics. +5. +Oxygen +This should be given to all patients in shock. +6. +Patients who are found to have major endoscopic stigmata of +recent haemorrhage (Fig. +Patients found to have bled from +varices should be treated by band ligation (p. +7. +8. +If available, angiographic embolisation is an effective alternative +to surgery in frail patients. +The choice of operation depends on the site and diagnosis of +the bleeding lesion. +Duodenal ulcers are treated by under-running, +with or without pyloroplasty. +Local excision may be performed, but when neither +is possible, partial gastrectomy is required. +9. +pylori infection should receive eradication +therapy (p. +800). +Successful eradication should be conrmed +by urea breath or faecal antigen testing. +21.20 Major stigmata of recent haemorrhage and endoscopic treatment. +A Active bleeding from a duodenal ulcer. +Diagnosis is often +difcult. +In some +patients, diagnosis is achieved only by laparotomy with on-table +colonoscopy. +The diagnosis is made at colonoscopy. +Resection is required only +in the presence of peritonitis. +Meckel’s diverticulum with ectopic +gastric epithelium may ulcerate and erode into a major artery. +Haemorrhoidal bleeding is bright red and occurs +during or after defecation. +Anal ssure +should be suspected when fresh rectal bleeding and anal pain +occur during defecation. +When +severe life-threatening bleeding continues, urgent CT mesenteric +angiography is indicated. +21.21) and +treat the bleeding source. +Wireless capsule endoscopy is often +used to dene a source of bleeding prior to enteroscopy. +When +all else fails, laparotomy with on-table endoscopy is indicated. +Occult bleeding may reach 200 mL per day and cause iron +deciency anaemia. +832). +11). +A variety of drugs, including antibiotics, +cytotoxic drugs, PPIs and NSAIDs, may be responsible. +Chronic or relapsing diarrhoea +The most common cause is irritable bowel syndrome (p. +824), +which can present with increased frequency of defecation and +loose, watery or pellety stools. +Diarrhoea rarely occurs at night +and is most severe before and after breakfast. +The stool often contains +mucus but never blood, and 24-hour stool volume is less than +200 g. +The symptoms are diverse in +nature and variable in severity. +Abdominal +21 +Fig. +21.22 Possible physical consequences of malabsorption. +Some patients complain +only of malaise and lethargy. +21.22).Presenting problems in gastrointestinal disease • 785 +and hydrolysis of nutrients. +Fat and protein malabsorption +results. +This may also occur with small bowel bacterial +overgrowth. +Routine blood tests may show one or more of the +abnormalities listed in Box 21.19. +Tests to conrm fat and protein +malabsorption should be performed, as described on page 777. +An approach to the investigation of malabsorption is shown +in Figure 21.23. +21.24). +Psychiatric illness +Features of anorexia nervosa (p. +1203), bulimia (p. +1204) and +affective disorders (p. +1198) may be apparent only after formal +psychiatric input. +Alcoholic patients lose weight as a consequence +of self-neglect and poor dietary intake. +Depression may cause +weight loss. +Systemic disease +Chronic infections, including tuberculosis (p. +588), recurrent +urinary or chest infections, and a range of parasitic and protozoan +infections (Ch. +11), should be considered. +Promiscuous sexual activity and drug misuse suggest +HIV-related illness (Ch. +12). +Chronic inflammatory +diseases, such as rheumatoid arthritis (p. +1021) and polymyalgia +rheumatica (p. +1042), are often associated with weight loss. +Gastrointestinal disease +Almost any disease of the gastrointestinal tract can cause weight +loss. +Dysphagia and gastric outflow obstruction (pp. +778 and +801) cause weight loss by reducing food intake. +Malabsorption +from pancreatic diseases (p. +704). +Inflammatory diseases, such as Crohn’s disease or +ulcerative colitis (p. +813), cause anorexia, fear of eating and loss +of protein, blood and nutrients from the gut. +21.23 Investigation for suspected malabsorption. +21.24 Some important causes of weight loss. +588). +Constipation +Constipation is dened as infrequent passage of hard stools. +Constipation may occur in many gastrointestinal and other +medical disorders (Box 21.20). +Careful examination contributes more to the diagnosis than +extensive investigation. +A search should be made for general +medical disorders, as well as signs of intestinal obstruction. +Neurological disorders, especially spinal cord lesions, should be +sought. +It is neither possible nor appropriate to investigate every +person with constipation. +If these are normal, a 1-month trial of dietary +bre and/or laxatives is justied. +803). +Abdominal pain +There are four types of abdominal pain: +• Visceral. +Pain from unpaired +structures is usually, but not always, felt in the midline. +• Parietal. +• Referred pain. +Gallbladder pain, for example, may be +referred to the back or shoulder tip. +• Psychogenic. +Cultural, emotional and psychosocial factors +influence everyone’s experience of pain. +1198 and 1202). +Pain develops gradually, usually over several +hours. +Movement exacerbates the pain; abdominal rigidity and +guarding occur. +• Perforation. +When a viscus perforates, pain starts abruptly; +it is severe and leads to generalised peritonitis. +• Obstruction. +Pain is colicky, with spasms that cause the +patient to writhe around and double up. +Colicky pain +that does not disappear between spasms suggests +complicating inflammation. +In other circumstances, further +investigations are required (Fig. +21.25). +Urinalysis is useful in suspected +renal colic and pyelonephritis. +21.11). +An abdominal ultrasound may help if gallstones +or renal stones are suspected. +21.25 Management of acute abdominal pain: an algorithm. +treatment. +Presentation may be atypical, e.g. +with delirium, collapse and/or +immobility. +Older people with +vague abdominal symptoms should therefore be carefully assessed. +The reasons for this are not clear but may stem from +altered sensory perception. +of which the presence or absence of peritonitis is the most +important. +A treatment summary of some of the more common +surgical conditions follows. +Differentiation between the two is made by water-soluble contrast +enema. +• Persistent symptoms require exclusion of colonic or +small bowel disease. +824). +378), or atypical +presentations of common diseases. +Biopsy is occasionally +necessary for diagnosis. +Symptomatic relief is achieved using local anaesthetic +mouthwashes. +Rarely, patients with very severe, recurrent +aphthous ulcers may need oral glucocorticoids. +Oral cancer may present in many ways (Box 21.26) and a +high index of suspicion is required. +Some tumours +may be amenable to photodynamic therapy (PDT), avoiding the +need for surgery. +White patches are seen on the tongue and buccal +mucosa. +Odynophagia or dysphagia suggests pharyngeal +and oesophageal candidiasis. +Oral thrush is treated +using nystatin or amphotericin suspensions or lozenges. +Resistant cases or immunosuppressed patients may require oral +fluconazole. +Parotitis +Parotitis is caused by viral or bacterial infection. +Mumps causes +a self-limiting acute parotitis (p. +240). +Bacterial parotitis usually +occurs as a complication of major surgery. +Patients present with painful parotid +swelling and this can be complicated by abscess formation. +Broad-spectrum antibiotics are required, while surgical drainage +is necessary for abscesses. +Other causes of salivary gland +enlargement are listed in Box 21.27. +1043) +(p. +The mortality rate is around 50%, largely as a result of +late diagnosis. +• Gustatory and olfactory sensation: declines and chewing power +is diminished. +• Salivation: baseline salivary flow falls but stimulated salivation is +unchanged. +766). +Hiatus hernia +Hiatus hernia (Box 21.29 and Fig. +In addition, the oblique +angle between the cardia and oesophagus disappears. +Poor oesophageal clearance leads to increased +acid exposure time. +Increased +intra-abdominal +pressure +Fig. +21.26 Factors associated with the development of gastro- +oesophageal reflux disease. +Pepsin and bile also contribute to mucosal injury. +The reason is unknown. +Increased intra-abdominal pressure +Pregnancy and obesity are established predisposing causes. +Weight loss may improve symptoms. +The foods +that trigger symptoms vary widely between affected individuals. +The patient is often overweight. +21.27 Types of hiatus hernia. +A Rolling or para-oesophageal. +Inset: Barium meal showing a large para-oesophageal hernia with intrathoracic +stomach. +B Sliding. +irritates the larynx. +Others develop odynophagia or dysphagia. +The true relationship of these features to +gastro-oesophageal reflux disease remains unclear. +21.28). +There is +a poor correlation between symptoms and histological and +endoscopic ndings. +21.29). +The epidemiology +and aetiology of Barrett’s oesophagus are poorly understood. +It is +weakly associated with smoking but not alcohol intake. +21.28 Severe reflux oesophagitis. +There is near-circumferential +supercial ulceration and inflammation extending up the gullet. +may be important in the pathogenesis. +Endoscopic balloon dilatation +or bouginage is helpful. +The diagnosis +is made by chest X-ray (air bubble in the chest) and barium +swallow (see Fig. +21.27B). +Endoscopy is the investigation of choice. +A pH of less than 4 for more than 6–7% of the study time +is diagnostic of reflux disease. +Management +A treatment algorithm for gastro-oesophageal reflux is outlined in +Figure 21.30. +When dysmotility +features are prominent, domperidone can be helpful. +There is +no evidence that H. +pylori eradication has any therapeutic value. +Proprietary antacids and alginates can also provide symptomatic +benet. +H2-receptor antagonist drugs relieve symptoms without +healing oesophagitis. +21.29 Barrett’s oesophagus. +Tongues of pink columnar mucosa +are seen extending upwards above the oesophago-gastric junction. +Surveillance is +expensive and cost-effectiveness studies have been conflicting. +Those with low-grade dysplasia +should be endoscoped at 6-monthly intervals. +The typical presentation +is with dysphagia that is worse for solids than for liquids. +Bolus +obstruction following ingestion of meat causes absolute dysphagia. +Liquid preparations of these drugs should be used in +such patients. +Refractory symptoms sometimes respond to montelukast, a +leukotriene inhibitor. +Many patients have no symptoms but regurgitation, halitosis and +dysphagia can be present. +Some notice gurgling in the throat +after swallowing. +The investigation of choice is a barium swallow +(see Fig. +Endoscopy may be hazardous, since the instrument may enter +and perforate the pouch. +The cause is unknown. +21.30 Treatment of gastro-oesophageal reflux disease: a +‘step-down’ approach. +21.30 Gastro-oesophageal reflux disease in old age +• Prevalence: higher. +• Severity of symptoms: does not correlate with the degree of +mucosal inflammation. +• Recurrent pneumonia: consider aspiration from occult gastro- +oesophageal reflux disease. +microbiota. +pylori eradication is advised in patients requiring PPIs +for more than 1 year. +316). +147). +This may be +complicated by oesophageal perforation with mediastinitis and +by stricture formation. +Loss of the dorsal +vagal nuclei within the brainstem can be demonstrated in later +stages. +Infection with Trypanosoma cruzi in Chagas’ disease +(p. +279) causes a syndrome that is clinically indistinguishable +from achalasia. +Clinical features +The presentation is with dysphagia. +Some patients experience +episodes of chest pain due to oesophageal spasm. +Achalasia +predisposes to squamous carcinoma of the oesophagus. +21.31A). +21.31B). +PPI therapy is often necessary after surgery. +Some cases occur in +response to gastro-oesophageal reflux. +Treatment is based on +the use of PPI drugs when gastro-oesophageal reflux is present. +Oral or sublingual nitrates or nifedipine may relieve attacks of +pain. +Treatment is with nitrates or nifedipine. +The patients are usually elderly and present with +dysphagia and chest pain. +Manometric abnormalities, ranging +from poor peristalsis to spasm, occur. +Treatment is with dilatation +and/or vasodilators for chest pain. +Secondary causes of oesophageal dysmotility +In systemic sclerosis or CREST syndrome (p. +Oesophagitis +is often severe and benign fibrous strictures occur. +These +patients require long-term therapy with PPIs. +Dermatomyositis, +rheumatoid arthritis and myasthenia gravis may also cause +dysphagia. +21.31 Achalasia. +Compare with normal appearances in Figure 21.1 (p. +Tumours of the oesophagus +Benign tumours +The most common is a leiomyoma. +This is usually asymptomatic +but may cause bleeding or dysphagia. +Clinical features +Most patients have a history of progressive, painless dysphagia +for solid foods. +Others present acutely because of food bolus +obstruction. +Investigations +The investigation of choice is upper gastrointestinal endoscopy +(Fig. +21.32) with biopsy. +21.32 Adenocarcinoma of the lower oesophagus. +A polypoidal +adenocarcinoma in association with Barrett’s oesophagus. +Fig. +21.33 Positron emission tomography–computed tomography +(PET-CT) staging of oesophageal carcinoma. +spread and local invasion (Fig. +21.33). +Subcutaneous emphysema, +pleural effusions and pneumothorax develop. +Treatment is surgical. +Delay in diagnosis +is a key factor in the high mortality associated with this condition. +Acute gastritis +Acute gastritis is often erosive and haemorrhagic. +Neutrophils are +the predominant inflammatory cell in the supercial epithelium. +Many cases result from alcohol, aspirin or NSAID ingestion +(Box 21.33). +Treatment should be +directed at the underlying cause. +The predominant inflammatory cells are lymphocytes and +plasma cells. +Correlation between symptoms and endoscopic +or pathological ndings is poor. +pylori eradication. +Circulating antibodies to parietal +cell and intrinsic factor may be present. +944). +The gastritis +itself is usually asymptomatic. +Some patients have evidence of +other organ-specic autoimmunity, particularly thyroid disease. +In the long term, there is a two- to threefold increase in the risk +of gastric cancer (see also p. +803). +As a result, the +Fig. +21.34 Endoscopic ultrasound staging of oesophageal +carcinoma. +There is a supercial adenocarcinoma of the oesophagus (T). +The tumour is +therefore staged T1a, N1. +involvement (Fig. +21.34). +These investigations will dene the +TNM stage of the disease (p. +1322). +Endoscopic laser therapy or +self-expanding metallic stents can be used to improve swallowing. +Quality of life can be improved by nutritional support +and appropriate analgesia. +Malignant, caustic and radiotherapy stricture +perforations require resection or stenting. +iron preparations +• Severe physiological stress, e.g. +burns, multi-organ failure, central +nervous system trauma +• Bile reflux, e.g. +following gastric surgery +• Viral infections, e.g. +CMV, herpes simplex virus in HIV/AIDS (p. +316) +Chronic non-specic gastritis +• H. +CMV, tuberculosis +• Gastrointestinal diseases, e.g. +Crohn’s disease +• Systemic diseases, e.g. +sarcoidosis, graft-versus-host disease +• Idiopathic, e.g. +21.35 Factors that influence the virulence of Helicobacter +pylori. +mucosal folds of the body and fundus are greatly enlarged. +Most +patients are hypochlorhydric. +811) due to exudation +from the gastric mucosa. +pylori eradication may be effective, but +unresponsive patients require partial gastrectomy. +Erosions do not penetrate +the muscularis mucosae. +Pathophysiology +H. +pylori +Peptic ulceration is strongly associated with H. +pylori infection. +In the developing world infection is more common, +affecting up to 90% of adults. +These infections are probably +acquired in childhood by person-to-person contact. +Around 90% of +duodenal ulcer patients and 70% of gastric ulcer patients are +infected with H. +pylori. +pylori eradication strategies. +H. +It uses an adhesin molecule (BabA) to bind to the Lewis b +antigen on epithelial cells. +H. +21.35). +This depends on numerous factors, +notably expression of bacterial cagA and vacA genes. +H. +pylori strains expressing CagA (CagA+) are more +often associated with disease than CagA− strains. +The distribution and severity of H. +pylori–induced gastritis +determine the clinical outcome. +In most people, H. +21.36). +In a much smaller number of +infected people, H. +This phenotype is much more common in Asian countries, +particularly Japan, China and Korea. +21.37). +The effects of H. +pylori are more complex in gastric ulcer patients compared to +those with duodenal ulcers. +The ulcer probably arises because +of impaired mucosal defence resulting from a combination of H. +pylori infection, NSAIDs and smoking, rather than excess acid. +Smoking +Smoking confers an increased risk of gastric ulcer and, to a +lesser extent, duodenal ulcer. +Occasionally, the only symptoms are anorexia and nausea, or +early satiety after meals. +Investigations +Endoscopy is the preferred investigation (Fig. +21.38). +Patients should +be tested for H. +pylori infection. +The current options available are +listed in Box 21.34. +Some are invasive and require endoscopy; +others are non-invasive. +They vary in sensitivity and specicity. +Breath tests or faecal antigen tests are best because of accuracy, +simplicity and non-invasiveness. +21.36 Sequence of events in the pathophysiology of duodenal +ulceration. +21.37 Consequences of Helicobacter pylori infection. +21.38 Endoscopic identication of a duodenal ulcer. +pylori-positive on testing. +H. +H. +pylori eradication +All patients with proven ulcers who are H. +pylori-positive should +be offered eradication as primary therapy. +H. +Other indications for H. +pylori eradication are shown in Box +21.36. +979); the mechanism +for this is unclear. +General measures +Cigarette smoking, aspirin and NSAIDs should be avoided. +Alcohol in moderation is not harmful and no special dietary +advice is required. +Maintenance treatment +Continuous maintenance treatment should not be necessary after +successful H. +pylori eradication. +For the minority who do require +it, the lowest effective dose of PPI should be used. +The reason for this is to exclude an underlyingDiseases of the stomach and duodenum • 801 +cancer. +In most cases +these are minor but in 10% they signicantly impair quality of life. +This leads to abdominal discomfort and diarrhoea +after eating. +Patients +should therefore avoid large meals with high carbohydrate content. +Chemical (bile reflux) gastropathy Duodenogastric bile reflux leads +to chronic gastropathy. +Treatment with aluminium-containing +antacids or sucralfate may be effective. +Diarrhoea often responds +to small, dry meals with a reduced intake of rened carbohydrates. +Anaemia Anaemia is common many years after subtotal +gastrectomy. +Iron deciency is the most common cause; folic +acid and B12 deciency are much less frequent. +pylori infection. +About one-quarter of all perforations occur +in acute ulcers and NSAIDs are often incriminated. +Perforation +can be the rst sign of ulcer and a history of recurrent epigastric +pain is uncommon. +The abdomen is held immobile and there is +generalised ‘board-like’ rigidity. +After some hours, symptoms may +improve, although abdominal rigidity remains. +Later, the patient’s +condition deteriorates as general peritonitis develops. +In at least +50% of cases, an erect chest X-ray shows free air beneath the +diaphragm (see Fig. +21.11B, p. +773). +If not, a water-soluble contrast +swallow will conrm leakage of gastroduodenal contents. +On rare occasions, a ‘Polya’ partial +gastrectomy is required. +Following surgery, H. +pylori should be +treated (if present) and NSAIDs avoided. +Gastric outlet obstruction +The causes are shown in Box 21.39. +The most common is an +ulcer in the region of the pylorus. +The presentation is with nausea, +vomiting and abdominal distension. +Physical examination may show +evidence of wasting and dehydration. +A succussion splash may +be elicited 4 hours or more after the last meal or drink. +Visible +gastric peristalsis is diagnostic of gastric outlet obstruction. +• Causes: high prevalence of H. +pylori, use of non-steroidal +anti-inflammatory drugs and impaired defence mechanisms. +• Atypical presentations: pain and dyspepsia are frequently absent +or atypical. +In some +patients, PPI drugs heal ulcers, relieve pyloric oedema and +overcome the need for surgery. +Bleeding +See page 780. +678) of the pancreas or duodenum (‘gastrinoma’). +It probably accounts for about 0.1% of all cases of duodenal +ulceration. +Pancreatic lipase is inactivated and bile acids are precipitated. +Diarrhoea and steatorrhoea result. +Around 90% of tumours occur +in the pancreatic head or proximal duodenal wall. +At least half +are multiple and tumour size can vary from 1 mm to 20 cm. +Approximately one-half to two-thirds are malignant but are often +slow-growing. +Between 20% and 60% of patients have multiple +endocrine neoplasia (MEN) type 1 (p. +688). +There is a poor response to standard ulcer therapy. +The history is usually short, and bleeding and perforations are +common. +Diarrhoea is seen in one-third or more of patients and +can be the presenting feature. +Serum gastrin levels are grossly elevated (10- to 1000-fold). +Other +treatment options for pancreatic neuro-endocrine tumours are +discussed on page 678. +Overall 5-year survival is 60–75% and +all patients should undergo genetic screening for MEN 1. +Other commonly reported symptoms include early satiety, +fullness, bloating and nausea. +Morning +symptoms are characteristic and pain or nausea may occur on +waking. +Direct enquiry may elicit symptoms suggestive of irritable +bowel syndrome. +There are no diagnostic signs, apart from inappropriate +tenderness on abdominal palpation, perhaps. +Symptoms may +appear disproportionate to clinical well-being and there is no +weight loss. +Patients often appear anxious. +A drug history should +be taken and the possibility of a depressive illness should be +considered. +Pregnancy should be ruled out in young women +before radiological studies are undertaken. +Alcohol misuse +should be suspected when early-morning nausea and retching +are prominent. +Investigations +The history will often suggest the diagnosis. +All patients should +be checked for H. +Management +The most important elements are explanation and reassurance. +Up to 10% of patients benet from H. +pylori eradication therapy +and this should be offered to infected individuals. +Drug +treatment is not especially successful but merits trial. +Antacids,Diseases of the stomach and duodenum • 803 +such as hydrotalcite, are sometimes helpful. +H2-receptor antagonist drugs may be tried if night pain +or heartburn is troublesome. +Low-dose tricyclic agents, such as +amitriptyline, are of value in up to two-thirds. +1190). +Functional causes of vomiting +Psychogenic retching or vomiting may arise in anxiety. +It typically +occurs on wakening or immediately after breakfast, and only +rarely later in the day. +Early morning vomiting also occurs in +pregnancy, alcohol misuse and depression. +In all patients it is essential to exclude other common causes +(p. +780). +Antidepressants in full dose may be effective +(p. +1199). +Treatment is based on +small, frequent, low-fat meals and the use of metoclopramide +and domperidone. +Rates in the UK are 12/100 000 for men. +In most countries, the +Fig. +21.39 Gastric carcinogenesis: a possible mechanism. +incidence is 50% lower in women. +In both sexes, it rises sharply +(CagA = cytotoxin-associated gene) +after 50 years of age. +Pathophysiology +Infection with H. +It is associated with chronic atrophic gastritis, gastric mucosal +atrophy and gastric cancer (Fig. +21.39). +It has been estimated +that H. +pylori infection may contribute to the occurrence of +gastric cancer in 70% of cases. +Although the majority of H. +H. +There is strong evidence that H. +Diets lacking in fresh fruit and vegetables, as well as +vitamins C and A, may also contribute. +Other risk factors are +listed in Box 21.40. +Intestinal carcinomas are more common and arise +against a background of chronic mucosal injury. +Diffuse cancers +tend to be poorly differentiated and occur in younger patients. +pylori in the West. +Diffuse +submucosal inltration by a scirrhous cancer (linitis plastica) is +uncommon. +Early gastric cancer is dened as cancer conned +to the mucosa or submucosa. +It is more often recognised in +Japan, where widespread screening is practised. +Some cases +can be cured by endoscopic mucosal or submucosal resection. +The majority of patients (> 80%) in the West, however, present +with advanced gastric cancer. +Two-thirds of +patients with advanced cancers have weight loss and 50% have +ulcer-like pain. +Dysphagia occurs in tumours of the gastric cardia that +obstruct the gastro-oesophageal junction. +Anaemia from occult +bleeding is also common. +Jaundice or ascites signies metastatic spread. +Metastases arise most commonly +in the liver, lungs, peritoneum and bone marrow. +Investigations +Upper gastrointestinal endoscopy is the investigation of choice +(Fig. +779). +Multiple +biopsies from the edge and base of a gastric ulcer are required. +Once the diagnosis is +Fig. +21.40 Gastric carcinoma. +Endoscopic nding of a large polypoidal +mass arising from the wall of the stomach. +made, further imaging is necessary for staging and assessment of +resectability. +CT will provide evidence of intra-abdominal spread +or liver metastases. +Proximal tumours involving the oesophago- +gastric junction also require a distal oesophagectomy. +More extensive lymph node resection may increase +survival rates but carries greater morbidity. +The biological agent trastuzumab may benet +some patients whose tumours over-express HER2 (p. +1322). +Endoscopic laser ablation for control of dysphagia or recurrent +bleeding benefits some patients. +Imatinib can also provide prolonged +control of metastatic GISTs. +A variety of polyps occur. +Hyperplastic polyps and fundic cystic +gland polyps are common and of no consequence. +Adenomatous +polyps are rare but have malignant potential and should be +removed endoscopically. +Large (> 2 cm) carcinoids may, +however, metastasise and should be removed. +Rarely, small +nodules of ectopic pancreatic exocrine tissue are found. +These +‘pancreatic rests’ may be mistaken for gastric neoplasms and +usually cause no symptoms. +EUS is the most useful investigation. +It can result in malabsorption and +responds to a gluten-free diet. +The condition occurs worldwide +but is more common in northern Europe. +The prevalence in +the UK is approximately 1%, although 50% of these people +are asymptomatic. +21.41). +There is a strong association with human leukocyte antigen +(HLA)-DQ2/DQ8. +21 +Gastric lymphoma +This is a rare tumour, accounting for less than 5% of all gastric +malignancies. +pylori infection. +Indeed, H. +pylori +eradication and close observation, 25% contain t(11: 18) +chromosomal translocations. +In these cases, additional +radiotherapy or chemotherapy is usually necessary. +High-grade +B-cell lymphomas should be treated by a combination of rituximab, +chemotherapy (p. +962), surgery and radiotherapy. +The prognosis depends +on the stage at diagnosis. +21.41 Pathophysiology of coeliac disease. +Clinical features +Coeliac disease can present at any age. +In older children, it may present +with non-specic features, such as delayed growth. +Features +of malnutrition are found on examination and mild abdominal +distension may be present. +Affected children have growth and +pubertal delay, leading to short stature in adulthood. +Other presentations include oral ulceration, dyspepsia +and bloating. +Unrecognised coeliac disease is associated with +mild under-nutrition and osteoporosis. +Duodenal biopsy +Endoscopic small bowel biopsy is the gold standard. +Endoscopic +appearances should not preclude biopsy, as the mucosa usually +looks normal. +21.42). +21.42 Jejunal mucosa. +A Normal. +B Subtotal villous atrophy in coeliac disease. +anti-endomysial antibodies. +High-titre serology in children +can be diagnostic without the need for endoscopy and biopsy. +Antibody titres usually become negative with successful treatment. +IgG antibodies, however, must be +analysed in patients with coexisting IgA deciency. +Dietetic follow-up is key +to management. +There are currently no +additional non-invasive tests to assess small bowel mucosal +healing. +A few patients develop ulcerative jejuno-ileitis. +This may present +with fever, pain, obstruction or perforation. +Treatment is difcult. +The course +is often progressive. +These complications +are less common in those who adhere strictly to a gluten-free diet. +1256). +Immunofluorescence +shows granular or linear IgA deposition at the dermo-epidermal +junction. +The disease occurs mainly +in the West Indies and in southern India, Malaysia and Indonesia. +The changes closely resemble those of coeliac disease. +In visitors to the tropics, the onset of severe +diarrhoea may be sudden and accompanied by fever. +Remissions and relapses may occur. +The important differential diagnosis in visitors to the +tropics is giardiasis (p. +287). +The count +of coliform organisms never exceeds 103/mL. +Pathophysiology +Bacterial overgrowth can occur in patients with small bowel +diverticuli. +Another cause is diabetic autonomic neuropathy +(p. +760), which reduces small bowel motility and affects enterocyte +secretion. +In idiopathic +hypogammaglobulinaemia (p. +287). +There may also +be symptoms from the underlying intestinal cause. +Endoscopic duodenal biopsies are useful in +excluding coeliac disease. +Up to 50% of patients do not respond +adequately and relapse rates are high. +Consideration should be given to the +risk of emerging antimicrobial resistance. +usually resolve quickly and biopsy changes revert to normal in a +few weeks. +The population prevalence is +estimated at around 1% and the disease is often under-diagnosed. +21.43). +Another consequence is the formation of lithogenic +bile, leading to gallstones. +Renal calculi, rich in oxalate, develop. +Normally, oxalate in the colon is bound to and precipitated by +calcium. +Patients have urgent watery diarrhoea or mild steatorrhoea. +An elevated +serum 7Îą-hydroxycholestenone is a useful non-invasive marker +of bile acid diarrhoea. +Aluminium hydroxide can +be used as an alternative. +Short bowel syndrome +This is discussed in detail on page 708. +The risk varies +with total dose, dosing schedule and the use of concomitant +chemotherapy. +Pathophysiology +The rectum, sigmoid colon and terminal ileum are most frequently +involved. +Radiation causes acute inflammation, shortening +of villi, oedema and crypt abscess formation. +When the rectum and colon are involved, +rectal mucus, bleeding and tenesmus occur. +21.43 Consequences of ileal resection. +It leads to fat malabsorption and deciency of fat-soluble vitamins. +Serum cholesterol and +triglyceride levels are low. +21.53, p. +819). +An endoscopic biopsy +from the rectal wall is associated with a 2% risk of stula formation. +The extent of the lesion can be assessed by colonoscopy. +Antibiotics may be +required for bacterial overgrowth. +Nutritional supplements are +necessary when malabsorption is present. +Colestyramine or +colesevelam is useful for bile acid diarrhoea. +Effective treatments +include sucralfate enema and hyperbaric oxygen. +Investigations +The diagnosis is often delayed and a high index of suspicion is +needed. +Treatment consists of a low-fat +diet with medium-chain triglyceride supplements. +Barium studies and enteroscopy +conrm the diagnosis. +rare diseases of enteric smooth muscle and nerves that can +cause this syndrome. +Management +This is often difcult. +Underlying causes should be addressed +and further surgery avoided. +Nutritional and psychological support is also +necessary. +Other investigations should be performed +to determine the underlying cause. +It may be mucosal, muscular or +subserosal. +Peripheral blood eosinophilia is present in 80% of +cases. +Serosal involvement +may produce eosinophilic ascites. +The serum IgE concentration is often raised. +The prognosis is good +in the majority of patients. +Intervention is +unnecessary unless complications occur. +In most populations, +enterocyte lactase activity declines throughout childhood. +In cases of genetically determined (primary) lactase deciency, +jejunal morphology is normal. +Clinical features +In most people, lactase deciency is completely asymptomatic. +The lactose hydrogen breath test is a +useful non-invasive investigation. +83). +The most +common culprits are peanuts, milk, eggs, soya and shellsh. +This is not, however, +an immune-mediated reaction. +Fatal +reactions to trace amounts of peanuts are well documented. +The diagnosis of food allergy is difcult to prove or refute. +In many cases, clinical +suspicion and trials of elimination diets are used. +Teachers and other carers of affected +children should be trained to deal with this. +Gut infection usually +results from human M. +tuberculosis, which is swallowed after +coughing. +Many patients have no pulmonary symptoms and a +normal chest X-ray. +The area most commonly affected is the ileocaecal region. +The +presentation and radiological ndings may be very similar to those +of Crohn’s disease. +Low-grade fever is common but not +invariable. +Granulomatous hepatitis occurs. +Histological conrmation should be sought by +endoscopy, laparoscopy or liver biopsy. +Caseation of granulomas +is not always seen and acid- and alcohol-fast bacteria are often +scanty. +Isoniazid, pyrazinamide and ethambutol is a +common standard regime (p. +590), though the precise choice +will be dependent on local drug resistance patterns. +Benign tumours +The most common are adenomas, GISTs, lipomas and +hamartomas. +Transformation +to adenocarcinoma is rare. +Hamartomatous +polyps with almost no malignant potential occur in Peutz–Jeghers +syndrome (p. +829). +The majority occur in middle age or later. +Kaposi’s +sarcoma of the small bowel may arise in patients with AIDS. +This is a rare cancer, accounting for +less than 5% of all gastrointestinal malignancies. +The non-specic +presentation and rarity of these lesions often lead to a delay +in diagnosis. +Despite advances in imaging and endoscopic +techniques, early diagnosis is difcult. +Enteroscopy, capsule endoscopy, +mesenteric angiography and CT also play a role in investigation. +Treatment is by surgical resection. +Neuro-endocrine tumours +These are discussed in detail on page 678. +Lymphoma +Non-Hodgkin lymphoma (p. +Malabsorption is a feature of diffuse bowel involvement and +hepatosplenomegaly is rare. +The diagnosis is made by small bowel biopsy, radiological +contrast studies and CT. +Staging investigations should be +performed as for lymphomas occurring elsewhere (p. +962). +The condition varies in severity from relatively benign to frankly +malignant. +Enlarged +mesenteric lymph nodes are also common. +Most patients are +young adults who present with malabsorption, anorexia and fever. +Serum electrophoresis conrms the presence of alpha heavy +chains (from the Fc portion of IgA). +The diseases have many +similarities and it is sometimes impossible to differentiate between +them. +The incidence of inflammatory bowel disease (IBD) varies +widely between populations. +Life expectancy in patients +with IBD is similar to that of the general population. +21.44). +There is an association between +microbial dysbiosis and IBD. +21.46). +21.47). +Crypt abscesses +are typical. +21.44 Pathogenesis of inflammatory bowel disease. +Fig. +21.46 Pseudopolyposis in ulcerative colitis. +20% +Perianal disease alone +< 10% +Fig. +21.47 Histology of ulcerative colitis. +(SM = submucosa) +cases, glands become distorted. +The +mesenteric lymph nodes are enlarged and the mesentery is +thickened. +21.48). +The presentation varies, depending on +the site and severity of the disease (see Fig. +21.45), as well as +the presence of extra-intestinal manifestations. +The rst attack +is usually the most severe and is followed by relapses and +remissions. +Proctitis +causes rectal bleeding and mucus discharge, accompanied +by tenesmus. +Constitutional symptoms +do not occur. +Left-sided and extensive colitis causes bloody +diarrhoea with mucus, often with abdominal cramps. +Crohn’s disease +The major symptoms are abdominal pain, diarrhoea and weight +loss. +Ileal Crohn’s disease (Figs 21.49 and 21.50) may cause +Fig. +21.48 Histology of Crohn’s disease. +B At higher power, a characteristic +non-caseating granuloma is seen. +Fig. +21.49 Ileal Crohn’s disease. +subacute or even acute intestinal obstruction. +Almost all patients lose weight because +they avoid food, since eating provokes pain. +21.50 Barium follow-through showing terminal ileal Crohn’s +disease. +Many patients present +with symptoms of both small bowel and colonic disease. +There is abdominal +tenderness, most marked over the inflamed area. +Perianal skin tags, ssures +or stulae are found in at least 50% of patients. +Differential diagnosis +The differential diagnosis is summarised in Box 21.54. +The +most important issue is to distinguish the rst attack of acute +colitis from infection. +Haemorrhage +Haemorrhage due to erosion of a major artery is rare but can +occur in both conditions. +Fistulae +These are specic to Crohn’s disease. +Enteroenteric stulae can +cause diarrhoea and malabsorption due to blind loop syndrome. +Enterovesical stulation causes recurrent urinary infections and +pneumaturia. +An enterovaginal stula causes a faeculent vaginal +discharge. +Thus patients who +have long-standing, extensive colitis are at highest risk. +Oral +mesalazine therapy reduces the risk of dysplasia and neoplasia +in ulcerative colitis. +Tumours +develop in areas of dysplasia and may be multiple. +Family history of +colon cancer is also an important factor to consider. +21.52). +Platelet count +can also be high as a marker of chronic inflammation. +ESR and +CRP are elevated in exacerbations and in response to abscess +formation. +21.53). +In +established disease, colonoscopy may show active inflammation +Fig. +21.51 Plain abdominal X-ray showing a grossly dilated colon +due to severe ulcerative colitis. +21.52 Systemic complications of inflammatory bowel disease. +See also Chapters 17 and 18. +Small bowel imaging is essential +to complete staging of Crohn’s disease. +21.50). +21.53 Sigmoidoscopic view of moderately active ulcerative +colitis. +Mucosa is erythematous and friable with contact bleeding. +Submucosal blood vessels are no longer visible. +with pseudopolyps or a complicating carcinoma. +Dilatation +of the colon (see Fig. +21.51), mucosal oedema (thumb-printing) +or evidence of perforation may be found. +Patients with proctitis +may have features of proximal faecal loading. +Topical and oral aminosalicylates have +no role to play in the acute severe attack. +Response to therapy +is judged over the rst 3 days. +Subtotal colectomy can also +be performed laparoscopically, given sufcient local expertise. +Once-daily oral 5-aminosalicylates are the +preferred rst-line agents. +Management +Drugs that are used in the treatment of IBD are listed in Box +21.56. +A stool softener may be required to treat proximal +constipation. +The topical preparation (1 g foam or liquid enema) is typically +withdrawn after 1 month. +The oral 5-ASA is continued long-term +to prevent relapse and minimise the risk of dysplasia. +Glucocorticoids should never be used +for maintenance therapy. +Patients with evidence of persistently active disease require +further treatment (see below). +Vedolizumab is a possible option +in patients who have not responded to anti-TNF therapy. +It is +a humanised monoclonal antibody against anti-Îą4β7 integrin. +in colonic Crohn’s disease. +With sufcient explanation, encouragement +and motivation, most patients will tolerate it well. +Both infliximab and adalimumab are +licensed for use in the UK. +The +rst step is to dene the site by imaging (usually MRI of the pelvis). +Glucocorticoids +are ineffective. +Thiopurines can be used in chronic disease but do not usually +result in stula healing. +Other options for refractory perianal disease are proctectomy +or diverting colostomy. +The indications are listed in Box 21.60. +Surgery involves removal of the +entire colon and rectum, and cures the patient. +One-third of those +with pancolitis undergo colectomy within 5 years of diagnosis. +Crohn’s disease +The indications for surgery are similar to those for ulcerative +colitis. +In contrast to ulcerative +colitis, surgery is not curative and disease recurrence is the rule. +Antibiotics are +effective in the short term only. +more than one resection or evidence of penetrating disease, +such as stulae or abscess. +Patients with endoscopic +recurrence are then prescribed thiopurines. +708). +Obstructing or stulating small +bowel disease may require resection of affected tissue. +Clinical recurrence +following resectional surgery is present in 50% of all cases at +10 years. +Monitoring of height, weight and sexual development +is crucial. +Pregnancy +A women’s ability to become pregnant is adversely affected by +active IBD. +Pre-conceptual counselling should focus on optimising +disease control. +In the post-partum +period, these changes sometimes reverse spontaneously. +Young women are affected 2–3 times more often +than men. +Panic attacks are also common. +1202). +These factors contribute to but do not cause IBS. +Immune activation +may be associated with altered CNS processing of visceral pain +signals. +There are several other +immunomodulatory drugs in the clinical trial pipeline (see above). +The presentation is with watery diarrhoea. +Small intestinal bacterial +overgrowth (SIBO) may be present in some patients and lead +to symptoms. +Dietary factors are also important. +Their fermentation in the colon +leads to bloating, pain, wind and altered bowel habit. +The bowel +habit is variable. +Passage of mucus +is common but rectal bleeding does not occur. +Patients do not +lose weight and are constitutionally well. +Those who present atypically +require investigations to exclude other gastrointestinal diseases. +Diarrhoea-predominant patients justify investigations to exclude +coeliac disease (p. +805), microscopic colitis (p. +824), lactose +intolerance (p. +812), bile acid diarrhoea (p. +809), thyrotoxicosis +(p. +635) and, in developing countries, parasitic infection. +Management +The most important steps are to make a positive diagnosis and +reassure the patient. +Many people are concerned that they have +developed cancer. +21.54). +Dietary management is effective for many patients +(Box 21.65). +It may act by reducing visceral +sensation and by altering gastrointestinal motility. +Anxiety and +affective disorders may also require specic treatment (pp. +1200 and 1198). +21.54 Management of irritable bowel syndrome. +From Hussain Z, Quigley EMM. +Systematic review: complementary and alternative +medicine in the irritable bowel syndrome. +Aliment Pharmacol Ther 2006; +23:465–471. +some patients with difcult symptoms but are best prescribed +only after specialist referral. +Most patients have a relapsing and remitting course. +Resection is +required for peritonitis. +At +least two of the three vessels must be affected for symptoms to +develop. +Weight loss is common because patients are reluctant to eat +and some experience diarrhoea. +Physical examination shows +evidence of generalised arterial disease. +An abdominal bruit is +sometimes audible but is non-specic. +The diagnosis is made by +mesenteric angiography. +The condition is frequently complicated by intestinal +infarction, if left untreated. +Severe hypotension and venous insufciency are less frequent +causes. +Diagnosis is +often difcult. +Vasculitis and venous occlusion are rare causes. +Patients usually +have evidence of cardiac disease and arrhythmia. +Almost all +develop abdominal pain that is more impressive than the physical +ndings. +Leucocytosis, metabolic acidosis, hyperphosphataemia +and hyperamylasaemia are typical. +Plain abdominal X-rays +show ‘thumb-printing’ due to mucosal oedema. +In patients at high surgical risk, thrombolysis may sometimes +be effective. +Survivors often +have nutritional failure from short bowel syndrome (p. +Small bowel transplantation can be +considered in selected patients. +Investigations for +underlying prothrombotic disorders should be performed (p. +978). +Symptoms usually +resolve spontaneously over 24–48 hours and healing occurs in +2 weeks. +Some may develop a brous stricture or segment of +colitis. +A minority develop gangrene and peritonitis. +The latter include +hamartomas, metaplastic (‘hyperplastic’) polyps and inflammatory +polyps. +These have no malignant potential. +Polyps may be +single or multiple and vary from a few millimetres to several +centimetres in size. +They are more common in the rectum and distal +colon and are either pedunculated or sessile. +Features associated with a higher risk +of subsequent malignancy are listed in Box 21.67. +Adenomas are usually asymptomatic and discovered +incidentally. +Occasionally, they cause bleeding and anaemia. +Villous adenomas can secrete large amounts of mucus, causing +diarrhoea and hypokalaemia. +21.55). +21.55 Large rectal adenomatous polyp. +A Before colonoscopic polypectomy. +B After polypectomy. +1 The polyps themselves are not neoplastic but cancer risk is increased in several syndromes. +2 Rare autosomal recessive variant MUTYH (see text). +Between 10% and 20% of polyps show histological evidence +of malignancy. +Malignant +polyps without these features can be followed up by surveillance +colonoscopy. +Polyposis syndromes are classied by histopathology (Box +21.68). +3). +Around 20% of cases arise as new mutations and have no +family history. +Hundreds to thousands of adenomatous colonic +polyps develop in 80% of patients by age 15 (Fig. +21.56), with +symptoms such as rectal bleeding beginning a few years later. +21.57 Peutz–Jeghers syndrome. +Typical lip pigmentation. +Fig. +21.56 Familial adenomatous polyposis. +There are hundreds of +adenomatous polyps throughout the colon. +The operation of choice is total proctocolectomy with +ileal pouch–anal anastomosis. +If large, these +may be amenable to endoscopic resection. +21.57). +Most cases are asymptomatic, although +chronic bleeding, anaemia or intussusception can occur. +Polyps greater than 1 cm in size should be removed. +Asymptomatic relatives of affected patients should also undergo +screening. +Germline mutations in the SMAD4 gene are often found, as +are PTEN mutations. +This +variant is referred to as MUTYH-associated polyposis (MAP). +Duodenal +adenomas are found in over 90% and are most common around +the ampulla of Vater. +Many extra-intestinal +features are also seen in FAP (Box 21.69). +When present in an at-risk individual, these are 100% +predictive of the presence of FAP. +Early identication of affected individuals before symptoms +develop is essential. +The diagnosis can be excluded if +sigmoidoscopy is normal. +Subsequently, all rst-degree relatives +should also undergo testing (p. +46). +In the UK, the +incidence is 50–60 per 100 000, equating to 30 000 cases per +year. +The condition becomes increasingly common over the +age of 50 years. +21.58). +Colorectal cancer development results from the accumulation of +multiple genetic mutations. +Chromosomal instability (CIN) occurs in +around 85% of colorectal cancers. +Figure 21.59 outlines +some of the common genes affected by CIN. +• Microsatellite instability. +• CpG island methylator phenotype (CIMP). +The +result is functional loss of tumour suppressor genes. +827) +• Long-standing extensive ulcerative colitis or Crohn’s colitis (p. +21.58 Pathogenesis of colorectal cancer (CRC). +21.59 The multistep origin of cancer: molecular events implicated in colorectal carcinogenesis. +The risk is even higher if relatives were affected +at an early age. +The genes responsible for these cases are, +however, unknown. +Over 65% occur +in the rectosigmoid and a further 15% occur in the caecum or +ascending colon. +Synchronous tumours are present in 2–5% of +patients. +Spread occurs through the bowel wall. +Rectal cancers +may invade the pelvic viscera and side walls. +Tumour stage at diagnosis is the most important +determinant of prognosis (Fig. +21.60). +Clinical features +Symptoms vary, depending on the site of the carcinoma. +In +tumours of the left colon, fresh rectal bleeding is common and +obstruction occurs early. +Between +10% and 20% of patients present with iron deciency anaemia +or weight loss. +On examination, there may be a palpable mass, +signs of anaemia or hepatomegaly from metastases. +Low rectal +tumours may be palpable on digital examination. +*These criteria are strict and may miss some families with mutations. +About 5–10% of colon cancers are caused by HNPCC. +In contrast +to sporadic colon cancer, two-thirds of tumours occur proximally. +The diagnostic criteria are listed in Box 21.72. +21.60 Modied Dukes classication and survival in colorectal cancer. +Furthermore, +lesions can be biopsied and polyps removed. +Pelvic +MRI or endoanal ultrasound should be used for local staging of +rectal cancer. +Management +Surgery +All patients should be discussed at a multidisciplinary team +meeting. +The tumour should be removed, along with adequate resection +margins and pericolic lymph nodes. +Continuity should be restored +by direct anastomosis, wherever possible. +All patients should be counselled +pre-operatively about the possible need for a stoma. +Total +mesorectal excision reduces recurrence rates and increases +survival in rectal cancer. +Adjuvant therapy +About 30–40% of patients have lymph node involvement at +presentation (Fig. +21.60) and are therefore at risk of recurrence. +21.61). +The sensitivity +and specicity of these tests need to be improved. +Many countries lack the resources to offer this +form of screening. +21.61 Placement of a colonic stent for an inoperable cancer with impending obstruction. +A The contrast study demonstrates an obstruction. +B The stent is deployed across the tumour. +C A satisfactory position is demonstrated on subsequent CT scanning. +rectosigmoid). +It is recommended in the USA every +5 years in all persons over the age of 50. +• CT colonography is fast and low-risk, and offers +equivalent sensitivity to colonoscopy. +21.62). +Diverticula consist of protrusions of +mucosa covered by peritoneum. +There is commonly hypertrophy +of the circular muscle coat. +Inflammation is thought to result +from impaction of diverticula with faecoliths. +Clinical features +Symptoms are usually the result of associated constipation +or spasm. +Colicky pain is suprapubic or felt in the left iliac +fossa. +During these +episodes, there may be diarrhoea, rectal bleeding or fever. +21.62 The human colon in diverticulosis. +The colonic wall is weak +between the taeniae. +Diverticula +usually emerge through these points of least resistance. +IBD and infection. +These complications are more common +in patients who take NSAIDs or aspirin. +After one attack of +diverticulitis, the recurrence rate is around 3% per year. +Over +10–30 years, perforation, obstruction or bleeding may occur, +each affecting 5% of patients. +Investigations +Investigations are usually performed to exclude colorectal +neoplasia. +21.12C, p. +773). +In severe diverticulosis, +colonoscopy requires expertise and carries a risk of perforation. +Stimulant laxatives (see Box 21.73 below) should be avoided. +Antispasmodics may sometimes help. +Emergency surgery is +reserved for severe haemorrhage or perforation. +Many types of laxative are available, and +these are listed in Box 21.73. +The cause is unknown but some +have ‘slow transit’ with reduced motor activity in the colon. +The condition is often resistant to treatment. +Glycerol suppositories and biofeedback +techniques are used for those with obstructed defecation. +Others +benet from agents such as prucalopride or linaclotide. +Rarely, +subtotal colectomy may be necessary as a last resort. +Faecal impaction +In faecal impaction, a large, hard mass of stool lls the rectum. +Constipating drugs, autonomic neuropathy and painful anal +conditions also contribute. +Megacolon, intestinal obstruction +and urinary tract infections may supervene. +Perforation and +bleeding from pressure-induced ulceration are occasionally +seen. +Stimulants should be avoided. +The condition is +benign and resolves when the laxatives are stopped. +1203 and 1204). +They complain of refractory watery diarrhoea. +Laxative use is usually denied and may continue, even when +patients are undergoing investigation. +Screening of urine for +laxatives may reveal the diagnosis. +The incidence is approximately 1 : 5000. +688). +• Overflow diarrhoea: if faecal impaction develops, paradoxical +overflow diarrhoea may occur. +As a result, the internal anal +sphincter fails to relax. +The rectum is +empty on digital examination. +Histochemical stains +for acetylcholinesterase are also used. +Anorectal manometry +demonstrates failure of the rectum to relax with balloon distension. +Treatment involves resection of the affected segment. +It usually responds to osmotic laxatives. +In adults, acquired megacolon has several causes. +Systemic +sclerosis and hypothyroidism are other recognised causes. +Prokinetics are helpful in a minority +of patients. +Subtotal colectomy is a last resort for the most severely affected +patients. +Bowel sounds are +normal or high-pitched, rather than absent. +Left untreated, it +may progress to perforation, peritonitis and death. +Abdominal X-rays show colonic dilatation with air extending to +the rectum. +Caecal diameter greater than 10 cm is associated with +a high risk of perforation. +Single-contrast or water-soluble barium +enemas demonstrate the absence of mechanical obstruction. +In severe cases, surgical or fluoroscopic +defunctioning caecostomy is necessary. +Common causes of incontinence are listed in Box 21.76. +Patients are often embarrassed to admit incontinence and may +complain only of ‘diarrhoea’. +Management +This is often very difcult. +Attention must be paid to a proper diet +and adequate fluid intake. +They are extremely common in adults. +First-degree piles bleed, while second-degree piles prolapse +but retract spontaneously. +Third-degree piles are those that +require manual replacement after prolapsing. +Bright red rectal +bleeding occurs after defecation. +21.63). +The ulcer is seen at sigmoidoscopy and +biopsies show a characteristic accumulation of collagen. +Symptoms include minor bleeding and mucus per rectum, +tenesmus and perineal pain. +Marked mucosal prolapse is treated +surgically. +Spasm of the internal anal +sphincter exacerbates the condition. +Severe pain occurs on +defecation and there may be minor bleeding, mucus discharge +and pruritus. +Avoidance of constipation with bulk-forming laxatives and +increased fluid intake is important. +Diltiazem cream (2%) +can be used as an alternative. +Manual dilatation under anaesthesia leads +to long-term incontinence and should not be considered. +Ischiorectal +abscesses occur lateral to the sphincters in the ischiorectal fossa. +They usually result from infection of anal glands by normal intestinal +bacteria. +Crohn’s disease (p. +813) is sometimes responsible. +Patients complain of extreme perianal pain, fever and/ +or discharge of pus. +Spontaneous rupture may lead to the +development of stulae. +These may be supercial or track through +the anal sphincters to reach the rectum. +Diseases of the peritoneal cavity +Fig. +21.63 Thrombosed prolapsed haemorrhoids. +Itching may be severe and results in an itch–scratch–itch cycle +that exacerbates the problem. +When no underlying cause is +found, all local barrier ointments and creams must be stopped. +Good personal hygiene is essential, with careful washing after +defecation. +The perineal area must be kept dry and clean. +Bulk-forming laxatives may reduce faecal soiling. +253). +Chlamydial peritonitis is a complication of pelvic inflammatory +disease (p. +336). +Tuberculosis may cause peritonitis and ascites (p. +588). +Tumours +The most common is secondary adenocarcinoma from the +ovary or gastrointestinal tract. +Mesothelioma is a rare tumour +complicating asbestos exposure. +The prognosis is extremely poor. +The overlying mucosa is usually intact. +Low backache is +frequent. +The onset is usually between 20 and 45 years and +the condition is more common in nulliparous women. +Bimanual +examination may reveal tender nodules in the pouch of Douglas. +In some patients, laparoscopy is required. +Treatment +options include laparoscopic diathermy and hormonal therapy +with progestogens (e.g. +norethisterone), gonadotrophin-releasing +hormone analogues or danazol. +The cysts are recognised on +sigmoidoscopy, plain abdominal X-rays or barium enema. +Diseases of the pancreas +*Severity and prognosis worsen as the number of these factors increases. +More +than three implies severe disease. +The causes of acute pancreatitis are +listed in Box 21.80. +Nausea and vomiting are common. +Bowel sounds become quiet or absent as paralytic ileus develops. +In severe cases, the patient becomes hypoxic and develops +hypovolaemic shock with oliguria. +It affects 2–28 per 100 000 of the +population and is increasing in incidence. +It is a potentially serious +condition with an overall mortality of 10%. +About 80% of all +cases are mild and have a favourable outcome. +At admission, it is possible to predict patients +at risk of these complications (Box 21.78). +Triggers for this are many, +including alcohol, gallstones and pancreatic duct obstruction (Fig. +21.64). +21.65 Computed tomogram showing large pancreatic +pseudocyst (C) compressing the stomach (S). +The pancreas is atrophic +and calcied (arrows). +21.64 Pathophysiology of acute pancreatitis. +Various complications may occur and +these are listed in Box 21.81. +21.65). +Such +‘pseudocysts’ are common and usually asymptomatic, resolving +as the pancreatitis recovers. +Large pseudocysts can be detected clinically as a palpable +abdominal mass. +A persistently elevated +serum amylase concentration suggests pseudocyst formation. +Peritoneal amylase concentrations are massively elevated in +pancreatic ascites. +The presence of gas within necrotic +material (Fig. +In addition, serial assessment of +CRP is a useful indicator of progress. +A peak CRP of > 210 mg/L +in the rst 4 days predicts severe acute pancreatitis with 80% +accuracy. +It is worth noting that the serum amylase concentration +has no prognostic value. +All severe cases should be managed in a +high-dependency or intensive care unit. +A central venous line +and urinary catheter should be inserted to monitor patients +with shock. +Nasogastric aspiration is required only if paralytic ileus is +present. +Enteral +feeding decreases endotoxaemia and so may reduce systemic +complications. +Nasogastric feeding is just as effective as feeding +by the nasojejunal route. +Prophylaxis of thromboembolism with +subcutaneous low-molecular-weight heparin is also advisable. +carbapenems or quinolones, and metronidazole. +Pancreatic pseudocysts +can be treated by drainage into the stomach or duodenum. +Diabetes mellitus occurs in advanced cases because +the islets of Langerhans are involved (p. +733). +Pathophysiology +Around 80% of cases in Western countries result from alcohol +misuse. +In southern India, severe chronic calcic pancreatitis +21 +Fig. +21.66 Pancreatic necrosis. +Other causes are listed in Box 21.82. +The +pathophysiology of chronic pancreatitis is shown in Figure 21.67. +Clinical features +Chronic pancreatitis predominantly affects middle-aged alcoholic +men. +Almost all present with abdominal pain. +Pain may be +relieved by leaning forwards or by drinking alcohol. +Approximately +one-fth of patients chronically consume opiate analgesics. +Physical examination +reveals a thin, malnourished patient with epigastric tenderness. +Many patients have features of other alcohol- and smoking-related +diseases. +Complications are listed in Box 21.83. +Investigations +Investigations (Box 21.84 and Fig. +Gallstones do not cause +chronic pancreatitis but may be observed as an incidental nding. +21.67 Pathophysiology of chronic +pancreatitis. +Alcohol and other risk factors may +trigger acute pancreatitis through multiple +mechanisms. +A cycle of inflammation +and brosis ensues, with development of chronic +pancreatitis. +Alcohol is the most relevant risk +factor, as it is involved at multiple steps. +Analgesics, such as pregabalin +and tricyclic antidepressants at a low dose, may be effective. +Unfortunately, even after this operation, some +continue to experience pain. +A PPI is added to optimise +duodenal pH for pancreatic enzyme activity. +Blood tests reveal increased serum IgG or IgG4 and the +presence of other autoantibodies. +The response to +glucocorticoids is usually excellent but some patients require +azathioprine. +A +B +A +B +21 +B +A +Fig. +21.68 Imaging in chronic pancreatitis. +A Computed tomogram +showing a grossly dilated and irregular duct with a calcied stone (arrow +A). +Note the calcication in the head of the gland (arrow B). +A small +cyst is also present (arrow B). +Annular pancreas is associated with malrotation of the intestine, +atresias and cardiac anomalies. +Cystic brosis +This disease is considered in detail on page 580. +The major +gastrointestinal manifestations are pancreatic insufciency and +meconium ileus. +Peptic ulcer and hepatobiliary disease may also +occur. +In cystic brosis, pancreatic secretions are protein- and +mucus-rich. +Steatorrhoea is universal and the large-volume bulky +stools predispose to rectal prolapse. +Supplementary fat-soluble vitamins +are also necessary. +A PPI aids fat digestion by producing an optimal +duodenal pH. +In resistant cases of meconium ileus, surgical resection may +be necessary. +as often as women. +The disease is associated with increasing +age, smoking and chronic pancreatitis. +21.69). +Almost +all patients lose weight and many are cachectic. +Physical examination reveals clear evidence of weight loss. +Investigations +The diagnosis is usually made by ultrasound and contrast- +enhanced CT (Fig. +21.70). +Fit patients with small, localised tumours should +undergo staging to dene operability. +21.70). +For the great majority of +patients, treatment is palliative. +These tumours involve local +structures and metastasise to regional lymph nodes at an early +stage. +Most patients have advanced disease at the time of +presentation. +21.69 Features of pancreatic cancer. +21 +A B +Fig. +21.70 Carcinoma of the pancreas. +A A computed tomogram showing a large, necrotic mass encasing the coeliac axis (arrows). +In t patients, all mucinous +lesions should be resected. +The histology varies from villous +adenomatous change to dysplasia or carcinoma. +Further information +Books and journal articles +Canard JM, Letard J-C, Palazzo L, et al. +Gastrointestinal endoscopy in +practice. +Edinburgh: Churchill Livingstone; 2011. +Feldman M, Friedman LS, Brandt LJ. +Sleisenger and Fordtran’s +Gastrointestinal and liver disease, 10th edn. +Philadelphia: Elsevier +Saunders; 2015. +Websites +bsg.org.uk British Society of Gastroenterology. +crohnsandcolitis.org.uk Crohn’s and Colitis UK. +coeliac.org.uk Coeliac UK. +ecco-ibd.eu European Crohn’s and Colitis Organisation. +gastro.org American Gastroenterological Association and American +Digestive Health Foundation. +Gastroenterology and liver disease. +Edinburgh: Churchill Livingstone, Elsevier Ltd; 1995; (Aspiration) +Strachan M. +Davidson’s Clinical cases. +Edinburgh: Churchill Livingstone, Elsevier Ltd; 2008; (Palmar erythema) Goldman L, Schafter AI. +Goldman’s Cecil +medicine, 24th edn. +alcohol) +• Effects of aetiological agent, e.g. +intoxication, withdrawal, cognitive +impairment versus +• Effects of liver injury from agent, e.g. +The +movements are coarser than those seen in +tremor. +These 25 +numbered circles can normally be joined +together within 30 secs. +• Start in the right iliac fossa. +• Progress up the abdomen 2 cm with each +breath (through open mouth). +• Conrm the lower border of the liver by +percussion. +• Detect if smooth or irregular, tender or +non-tender; ascertain the shape. +• Identify the upper border by percussion. +Constructional apraxia. +Drawing stars and +clocks may reveal marked abnormality.848 • HEPATOLOGY +biliary tree. +The functional unit of the liver is the hepatic acinus (Fig. +22.2). +The +cholangioles converge in interlobular bile ducts in the portal tracts. +Liver cells +Hepatocytes comprise 80% of liver cells. +22.1 Liver blood supply. +called stellate or Ito cells. +22.1). +22.2 Liver structure and microstructure. +A Liver anatomy showing relationship with pancreas, bile duct and duodenum. +B Hepatic lobule. +22.4). +The portal venous contribution is 50–90%. +22.3 Non-parenchymal liver cells. +22.4 Pathogenic mechanisms in hepatic brosis. +Bile is secreted by hepatocytes and flows from +cholangioles to the biliary canaliculi. +22.2). +The common bile duct is approximately 5 cm long and 4–6 mm +wide. +It should be noted, though, that the anatomy of the +lower common bile duct can vary widely. +The function of the gallbladder is to concentrate, +and provide a reservoir for, bile. +22.5 Important liver functions. +converted to glycerol and fatty acids, thus preventing +hyperglycaemia. +724). +14.13, p. +372). +Dysregulation of lipid metabolism is +thought to have a critical role in the pathogenesis of +NAFLD. +22.5). +918). +22.6). +22.7 Biliary transporter proteins. +MDR2 (multidrug resistance 2) +regulates transport of glutathione. +Multidrug resistance protein 2 (MRP2) +transports bilirubin and is induced by rifampicin. +Organic anion transporter +protein (OATP) transports bilirubin and organic anions. +Stercobilinogen +(100 –200 mg/day) +Stercobilin +Stool +Fig. +22.6 Pathway of bilirubin excretion. +Impaired conjugation by this enzyme is +a cause of inherited hyperbilirubinaemias (see Box 22.17). +The conjugated bilirubin is excreted in the bile and passes into +the duodenal lumen. +Biliary obstruction results in reduced stercobilinogen in the stool, +and the stools become pale. +The liver secretes 1–2 L +of bile daily. +Bile contains bile acids (formed from cholesterol), +phospholipids, bilirubin and cholesterol. +Several biliary transporter +proteins have been identied (Fig. +22.7). +The liver is also able to metabolise vitamins to more active +compounds, e.g. +7-dehydrocholesterol to 25(OH) vitamin D. +Immune regulation +Approximately 9% of the normal liver is composed of immune +cells (see Fig. +22.3). +67). +The mechanisms that underlie this phenomenon +have not been fully dened. +A raised bilirubin often occurs earlier in the natural +history of biliary disease (e.g. +PBC) than in disease of the liver +parenchyma (e.g. +cirrhosis), where the hepatocytes are primarily +involved. +Serum albumin levels are often low in patients with liver disease. +This is due to a change in the volume of distribution of albumin, +and to reduced synthesis. +The aims of investigation in patients with suspected liver +disease are shown in Box 22.1. +867 and 868), the Glasgow score in alcoholic hepatitis +(see Box 22.47, p. +858). +Coagulation tests +These are often abnormal in patients with liver disease. +An increased PT is evidence of +severe liver damage in chronic liver disease. +14.8, p. +359). +• Signicantly elevated ferritin suggests haemochromatosis. +Modest elevations can be seen in inflammatory disease, +NAFLD and alcohol excess. +22.8) +or thrombosis in the hepatic vasculature. +Bubble-based contrast media are now +used routinely and can enhance discriminant capability. +22.9 Computed tomography in a patient with cirrhosis. +Fig. +22.8 Ultrasound showing a stone in the gallbladder (A) with +acoustic shadow (S). +and hepatic veins to be investigated. +22.46, p. +906). +22.9). +Hepatic +venography is now rarely performed. +Operative or laparoscopic liver biopsy may sometimes be valuable. +The use of +special histological stains can help in determining aetiology. +Alcohol-related liver disease is particularly +poorly served in this respect. +the FIB4 score, which is based on age, ALT/AST ratio and +platelet count). +Fig. +The proximal common bile duct (CBD) is dilated but the +pancreatic duct (PD) is normal. +cholangiography, PTC). +The latter does not allow the ampulla of +Vater or pancreatic duct to be visualised. +Endoscopic ultrasound +can also provide high-quality biliary imaging safely (see below). +Endoscopic ultrasound +Endoscopic ultrasound (EUS; p. +The main complications are abdominal and/or +shoulder pain, bleeding and biliary peritonitis. +The main causes are +listed in Figure 22.11 and discussed in detail later in the chapter. +22.12). +The +rate of increase is substantially higher in the UK than in other +countries in Western Europe. +In the early stages, patients can be +asymptomatic with fluctuating abnormal LFTs. +22.11 Causes of acute and chronic liver injury. +In alcoholic liver disease this is due to superimposed +alcoholic hepatitis. +22.12 Standardised UK mortality rates +showing the rise in liver-related mortality. +From Williams R, Aspinall R, Bellis M, et al. +Reprinted with permission from Elsevier +(The Lancet 2014; 384:1953–1997). +22.13). +Acute viral hepatitis is the +most common cause worldwide, whereas paracetamol toxicity +(p. +137) is the most frequent cause in the UK. +199) and, rarely, in extensive malignant disease of the +liver. +Papilloedema occurs rarely +and is a late sign. +More general symptoms include weakness, +nausea and vomiting. +Right hypochondrial discomfort is an +occasional feature. +The patient may be jaundiced but jaundice may not be present +at the outset (e.g. +Occasionally, death may occur in fulminant +cases of acute liver failure before jaundice develops. +Fetor +hepaticus can be present. +The liver is usually of normal size +but later becomes smaller. +22.13 Causes of acute liver failure in the UK. +898). +Splenomegaly is uncommon and never prominent. +Ascites and +oedema are late developments and may be a consequence of +fluid therapy. +Other features are related to the development of +complications (see below). +Factor V levels can be used instead +of the PT to assess the degree of liver impairment. +The plasma +bilirubin reflects the degree of jaundice. +Plasma albumin remains +normal unless the course is prolonged. +None, however, has entered +routine clinical use. +Many patients with chronic liver +disease are asymptomatic or have vague, non-specic symptoms. +Apparently asymptomatic abnormal LFTs are therefore a common +occurrence. +The prevalence of abnormal LFTs has been +reported to be as high as 10% in some studies. +The most +common abnormalities are alcoholic (p. +880) or non-alcoholic +fatty liver disease (p. +882). +730), including diabetes and/or obesity (see Box 22.5 and +Fig. +19.5, p. +698). +22.14 Suggested management of abnormal liver function tests in asymptomatic patients. +*No further investigation needed. +An algorithm for investigating abnormal LFTs is provided +in Figure 22.14. +The causes of jaundice overlap +with the causes of abnormal LFTs discussed above. +This does not apply to +newborns, who have less capacity to metabolise bilirubin. +Other inherited disorders of bilirubin metabolism +are very rare. +899) +• Inherited cholestatic liver +disease, e.g. +hepatitis A or B), drugs +(e.g. +paracetamol) or hepatic ischaemia. +The causes of cholestatic +jaundice are listed in Box 22.15. +Cholestasis may result from +defects at more than one of these levels. +Pruritus may be a dominant feature and can be accompanied +by skin excoriations. +Peripheral stigmata of chronic liver disease +are absent. +22.15 Investigation of jaundice. +Cirrhosis can be associated with either hepatomegaly +or reduced liver size in advanced disease. +Hepatomegaly +may resolve in patients with alcoholic cirrhosis when they stop +drinking. +Ascites +Ascites is present when there is accumulation of free fluid in the +peritoneal cavity. +Dilated +supercial abdominal veins may be seen if the ascites is due +to portal hypertension. +Splanchnic vasodilatation is +thought to be the main factor leading to ascites in cirrhosis. +Systemic arterial pressure falls due +to pronounced splanchnic vasodilatation as cirrhosis advances. +that jaundice is due to a malignant biliary obstruction (e.g. +pancreatic cancer). +22.15). +The ascites resolves on removal of the +tumour. +Laparoscopy can be valuable in detecting peritoneal +disease. +The ascites in this context has a characteristic milky-white +appearance. +864). +During management +of ascites, the patient should be weighed regularly. +Restriction of sodium intake to 100 mmol/24 hrs +(‘no added salt diet’) is usually adequate. +Salt +and water +retention +Lymph +formation +exceeds +lymph return +Ascites +Fig. +22.16 Pathogenesis of ascites. +of the kallikrein–kinin system (Fig. +22.16). +These systems tend to +normalise arterial pressure but produce salt and water retention. +The appearance of ascitic fluid may +point to the underlying cause (Box 22.22). +In up to 30% of patients, however, the total protein concentration +is > 30 g/L (3.0 g/dL). +A gradient of > 11 g/L (1.1 g/dL) is 96% +predictive that ascites is due to portal hypertension. +Other non-functional causes of renal failure +must be excluded before the diagnosis is made. +Haemodialysis +should not be used routinely because it does not improve the +outcome. +Ascitic culture +in blood culture bottles gives the highest yield of organisms. +The mortality at 1 year is 50% following the +rst episode of bacterial peritonitis. +As it progresses, delirium is followed by coma. +When an episode develops acutely, a precipitating +factor may be found (Box 22.25). +The earliest features are very +• Effervescent preparations (e.g. +Paracentesis +First-line treatment of refractory ascites is large-volume paracen- +tesis. +Paracentesis can be used +as an initial therapy or when other treatments fail. +Complications +Renal failure +Renal failure can occur in patients with ascites. +Hepatorenal syndrome +This occurs in 10% of patients with advanced cirrhosis +complicated by ascites. +Convulsions sometimes occur. +847), and, as the condition progresses, hyper-reflexia +and bilateral extensor plantar responses. +Ammonia has traditionally been considered +an important factor. +The +arterial ammonia is usually increased in patients with hepatic +encephalopathy. +It can be used in addition, or as an +alternative, to lactulose if diarrhoea becomes troublesome. +Chronic +or refractory encephalopathy is one of the main indications for +liver transplantation. +Variceal bleeding +Acute upper gastrointestinal haemorrhage from gastro-oesophageal +varices (Fig. +22.17) is common in chronic liver disease. +1133) +• Drug or alcohol intoxication (pp. +1194 and 1195) +• Delirium tremens/alcohol withdrawal (p. +1194) +• Wernicke’s encephalopathy (p. +1195) +• Primary psychiatric disorders (p. +1191) +• Hypoglycaemia (p. +738) +• Neurological Wilson’s disease (p. +22.17 Varices: endoscopic views. +A Oesophageal varices (arrows) at the lower end of the oesophagus. +B Gastric varices (arrows). +898). +Hepatomegaly is common when the cirrhosis is due to alcoholic +liver disease or haemochromatosis. +The liver is often hard, irregular +and non-tender. +Jaundice is mild when it rst appears and is +due primarily to a failure to excrete bilirubin. +Palmar erythema +Cirrhosis is characterised by diffuse hepatic brosis and nodule +formation. +It can occur at any age, has signicant morbidity and +is an important cause of premature death. +It is the most common +cause of portal hypertension and its complications. +The causes of cirrhosis are listed in Box 22.26. +Pathophysiology +Following liver injury, stellate cells in the space of Disse (see +Fig. +22.3, p. +849) are activated by cytokines produced by +Kupffer cells and hepatocytes. +22.4, p. +849). +Cirrhosis is a histological diagnosis (Fig. +22.18). +These changes +usually affect the whole liver but in biliary cirrhosis (e.g. +PBC) +they can be patchy. +• Macronodular cirrhosis, characterised by larger nodules of +various sizes. +Areas of previous collapse of the liver +architecture are evidenced by large brous scars. +Clinical features +The clinical presentation is highly variable. +Some patients are +asymptomatic and the diagnosis is made incidentally at ultrasound +or at surgery. +Others present with isolated hepatomegaly, +splenomegaly, signs of portal hypertension (p. +868) or hepatic +insufficiency. +22.18 Histological features in normal liver, hepatic brosis and +cirrhosis. +A Normal liver. +Columns of hepatocytes 1–2 cells thick radiate +from the portal tracts (PT) to the central veins. +C A cirrhotic liver. +The liver architecture +is disrupted. +They vary +in size from 1 to 2 mm in diameter and are usually found only +above the nipples. +Gynaecomastia is common and can be due to drugs such as +spironolactone. +Easy bruising becomes more frequent as cirrhosis +advances. +Ascites also signies advanced disease. +Evidence of hepatic encephalopathy also becomes common +with disease progression. +Non-specic features of chronic liver +disease include clubbing of the ngers and toes. +Chronic liver failure +develops when the metabolic capacity of the liver is exceeded. +It is characterised by the presence of encephalopathy and/ +or ascites. +to screen for oesophageal varices (p. +869) and repeated every +2 years. +890). +Chronic liver failure due to cirrhosis can also be treated by liver +transplantation. +This currently accounts for about three-quarters +of all liver transplants (p. +900). +Prognosis +The overall prognosis is poor. +Laboratory tests give only a rough guide to prognosis in +individual patients. +22.19). +22.19 Survival in cirrhosis by Child–Pugh score. +(INR = International Normalised Ratio; MELD = Model for End-stage Liver +Disease) +Fig. +22.20 Classication of portal hypertension according to site of +vascular obstruction. +*Most common cause. +Note that splenic vein +occlusion can also follow pancreatitis, leading to gastric varices. +Portal hypertension +Portal hypertension frequently complicates cirrhosis but has +other causes. +Increased vascular resistance +is common. +22.20). +294). +846). +862) or cirrhosis. +Variceal +bleeding is often severe, and recurrent if preventative treatment is +not given. +Stomal varices can also occur at the site +of an ileostomy. +Increased portal flow contributes to portal +hypertension but is not the dominant factor. +Investigations +The diagnosis is often made clinically. +This is an indirect measurement of portal vein pressure. +22.17). +Child–Pugh C). +Management of acute variceal bleeding is described in Box +22.32 and illustrated in Figure 22.21. +The measures used to control acute variceal bleeding include +vasoactive medications (e.g. +Yes +No +Fig. +22.22 Sengstaken–Blakemore tube. +Banding is best +suited to the treatment of oesophageal varices. +It is associated +with a lower risk of oesophageal perforation or stricturing than +sclerotherapy. +Active bleeding may make endoscopic therapy difficult. +22.22). +Endotracheal intubation prior to tube insertion reduces +the risk of pulmonary aspiration. +The safest technique is +Fig. +22.21 Management of acute bleeding from oesophageal +varices. +It reduces portal blood flow and/or intrahepatic resistance +and hence brings down portal pressure. +It lowers mortality in +the setting of acute variceal bleeding. +In +countries where terlipressin is not available, octreotide is a +frequently used alternative. +22.17C). +It stops +variceal bleeding in 80% of patients and can be repeated if +bleeding recurs. +The occluded +varix subsequently sloughs with variceal obliteration. +Gentle traction is essential to maintain pressure on the +varices. +22.23). +Further bleeding necessitates investigation and treatment (e.g. +angioplasty) because it is usually associated with shunt narrowing +or occlusion. +Hepatic encephalopathy may occur following TIPSS +and is managed by reducing the shunt diameter. +In selected individuals, +TIPSS may also be considered in this setting. +Rarely, similar lesions occur more +distally in the gastrointestinal tract. +These areas may become +eroded, causing bleeding from multiple sites. +Reduction of the portal pressure using propranolol +(80–160 mg/day) is the best initial treatment. +If this is ineffective, +a TIPSS procedure can be undertaken. +Infections and the liver +The liver may be subject to a number of different infections. +These include hepatotropic viral infections and bacterial and +protozoal infections. +Each has specic clinical features and +requires targeted therapies. +The causes are listed +in Box 22.33. +They differ in their tendency to cause acute +and chronic infections. +The features of the major hepatitis +viruses are shown in Box 22.34. +Vomiting +and diarrhoea may follow and abdominal discomfort is common. +22.23 Transjugular intrahepatic portosystemic stent shunt +(TIPSS). +urine) are less infectious than others. +Hepatitis A +The hepatitis A virus (HAV) belongs to the picornavirus group +of enteroviruses. +HAV is highly infectious and is spread by the +faecal–oral route. +Infection is also more common in areas +of overcrowding and poor sanitation. +In occasional outbreaks, +water and shellsh have been the vehicles of transmission. +In +contrast to hepatitis B, a chronic carrier state does not occur. +Titres of this antibody fall to low levels within about 3 months of +recovery. +Its presence indicates immunity to HAV. +Immunisation should be considered for individuals with chronic +hepatitis B or C infections. +The protective effect of immune serum globulin +is attributed to its anti-HAV content. +There are +usually few physical signs. +The liver is often tender but only +minimally enlarged. +Occasionally, mild splenomegaly and cervical +lymphadenopathy are seen. +These features are more frequent +in children or those with Epstein–Barr virus (EBV) infection. +Symptoms rarely last longer than 3–6 weeks. +Complications +may occur but are rare (Box 22.35). +The plasma bilirubin +reflects the degree of liver damage. +The ALP rarely exceeds twice +the upper limit of normal. +The white cell count is usually +normal with a relative lymphocytosis. +Serological tests conrm +the aetiology of the infection. +Management +Most individuals do not need hospital care. +Drugs such as +sedatives and narcotics, which are metabolised in the liver, +should be avoided. +No specic dietary modications are required. +Alcohol should not be taken during the acute illness. +People travelling to +endemic areas are best protected by vaccination. +Acute liver failure is rare in hepatitis A (0.1%) and chronic +infection does not occur. +In adults, a cholestatic phase with elevated ALP levels may +complicate infection. +There is no role for antiviral drugs in the +therapy of HAV infection. +The core +of the virus is surrounded by surface protein (Fig. +22.24). +Humans are the only source of infection. +Many individuals with chronic hepatitis B are also asymptomatic. +22.25). +The persistence of HBsAg for longer than 6 months indicates +chronic infection. +22.24 Schematic diagram of the hepatitis B virus. +Hepatitis B +surface antigen (HBsAg) is a protein that makes up part of the viral +envelope. +22.25 Natural history of chronic hepatitis B virus (HBV) infection. +There is an initial immunotolerant phase with high levels of virus and normal +liver biochemistry. +High risk +++ – ++ Raised Moderate/severe +necroinflammation +of cirrhosis or HCC if prolonged. +Anti-HBc is initially of IgM type, with +IgG antibody appearing later. +22.26 and Box 22.38). +Hepatitis B e antigen Hepatitis B e antigen (HBeAg) is an +indicator of viral replication. +22.26 Serological responses to hepatitis B virus infection. +22.27 The site of hepatitis B virus (HBV)-DNA mutations. +The pre-C and C regions encode a core protein and an e antigen. +Mutations also occur in the DNA polymerase during antiviral +treatment with lamivudine. +Specic +HBV genotypes (A–H) can also be identied using PCR. +Full recovery occurs in 90–95% of adults following acute HBV +infection. +Fulminant liver failure due +to acute hepatitis B occurs in less than 1% of cases. +Persistence of HBeAg beyond this time indicates +chronic infection. +Combined HBV and hepatitis delta virus (HDV) +infection causes more aggressive disease. +Viral load and genotype +HBV-DNA can be measured by PCR in the blood. +22.27). +22.25). +Cirrhosis +develops in 15–20% of patients with chronic HBV over 5–20 years. +This proportion is higher in those who are e antigen-positive. +One major concern +is the selection of antiviral-resistant mutations with long-term +treatment. +the ‘YMDD variant’), which lead to viral resistance. +Antiviral resistance mutations occur in only 1–2% after 3 years +of entecavir drug exposure. +The vaccine +is ineffective in those already infected by HBV. +needlestick injury, contamination +of cuts or mucous membranes). +Vaccine can be given together +with HBIg (active–passive immunisation). +Hepatitis B serology +should then be checked at 12 months of age. +Up to half of injection drug users with HIV +are co-infected with HBV. +Treatment can also be problematic. +tenofovir +with emtricitabine or lamivudine. +HDV has a worldwide distribution. +In +non-endemic areas, transmission is mainly a consequence of +parenteral drug misuse. +This antibody generally disappears within 2 months but +persists in a few patients. +Management +Effective management of hepatitis B prevents hepatitis D. +Hepatitis C +This is caused by an RNA flavivirus. +Acute symptomatic infection +with hepatitis C is rare. +There is no active or passive protection +against hepatitis C virus (HCV). +Hepatitis C is +the most common cause of what used to be known as ‘non-A, +non-B hepatitis’. +Once cirrhosis has developed, the 5- and 10-year survival rates +are 95% and 81%, respectively. +Once cirrhosis is present, 2–5% per year will +develop primary hepatocellular carcinoma. +Genotype has no effect on progression of +liver disease but does affect response to treatment. +Knowledge of viral +genotype still remains relevant in guiding selection of drugs to +treat HCV. +Jaundice is rare and only usually +appears in end-stage cirrhosis. +The degree of inflammation +and brosis can be scored histologically. +Management +The aim of treatment is to eradicate infection. +The infection is cured +in more than 99% of patients who achieve an SVR. +Since 2011, new classes of direct-acting antiviral agents (DAAs) +have been developed. +22.28). +Sofosbuvir plus velpatasvir achieves similar +results and is pan-genotypic. +Hepatitis E +Hepatitis E is caused by an RNA virus that is endemic in India +and the Middle East. +The clinical presentation and management of hepatitis E +are similar to those of hepatitis A. +If +treatment is required for chronic infection, agents such as ribavirin +may be used. +Blood donations are now routinely screened for +hepatitis E. +In acute infection, IgM antibodies to +hepatitis E virus (HEV) are positive. +Herpes simplex is a rare cause +of hepatitis in adults, most of whom are immunocompromised. +Herpes simplex virus hepatitis can be very severe in pregnancy. +Abnormal LFTs are also common in chickenpox, measles, rubella +and acute HIV infection. +22.28 Direct-acting antiviral agents. +Older patients and those +with multiple abscesses have a higher mortality. +Pathophysiology +Infection can reach the liver in several ways (Box 22.43). +They can +also complicate dental sepsis or colonic pathology, e.g. +cancer, +diverticulitis or inflammatory bowel disease causing portal pyaemia. +This topic is discussed in more detail +on page 317. +In the UK, a unit of alcohol contains 8 g of ethanol (Box +22.44). +An upper threshold of 14 units/week in women and +21 units/week in men is generally considered safe. +The risk threshold for developing ALD is variable but begins at +30 g/day of ethanol. +There is no clear linear relationship between +dose and liver damage, however. +The average alcohol +consumption of a man with cirrhosis is 160 g/day for over +8 years. +Some of the risk factors for ALD are: +• Drinking pattern. +It is +therefore recommended that people should have at least +two alcohol-free days each week. +The type of beverage +does not affect risk. +• Gender. +This may be +related to the reduced volume of distribution of alcohol. +• Genetics. +Alcoholism is more concordant in monozygotic +than dizygotic twins. +883). +• Nutrition. +Obesity increases the incidence of liver-related +mortality by over vefold in heavy drinkers. +Immunocompromised +patients are particularly likely to develop liver abscesses. +Escherichia coli and various streptococci, particularly Strep. +Clinical features +Patients are generally ill with fever and sometimes rigors and +weight loss. +The pain may be pleuritic in +nature. +Tender hepatomegaly is found in more than 50% of +patients. +Mild jaundice may be present, becoming severe if large +abscesses cause biliary obstruction. +Necrotic colorectal metastases can +be misdiagnosed as hepatic abscess. +Needle aspiration under +ultrasound guidance conrms the diagnosis and provides pus for +culture. +Blood cultures are +positive in 50–80%. +Hydatid cysts and amoebic liver abscesses +These are described on pages 299 and 287. +Leptospirosis +This is described on page 257. +In +about 80% of patients with severe alcoholic hepatitis, cirrhosis +will coexist at presentation. +Iron deposition is common and does +not necessarily indicate haemochromatosis. +The liver +is often enlarged in ALD, even in the presence of cirrhosis. +1194). +It has a good +prognosis and steatosis usually disappears after 3 months of +abstinence. +It has a signicantly +worse prognosis than AFLD. +Cirrhosis often coexists; if not present, it is the +likely outcome if drinking continues. +Even if they abstain, it may take up to 6 months for jaundice to +resolve. +In patients presenting with jaundice who subsequently +abstain, the 3- and 5-year survival is 70%. +Fig. +22.29 Factors involved in the pathogenesis of alcoholic liver +disease. +value and may contribute to weight gain. +It is metabolised almost exclusively by the liver via one of two +pathways (Fig. +22.29). +Acetaldehyde +is then metabolised to acetyl-CoA and acetate by aldehyde +dehydrogenase. +Cytochrome CYP2E1 +is an enzyme that oxidises ethanol to acetate. +All of these cytokines have been implicated in the pathogenesis +of liver brosis (see Fig. +22.4, p. +849). +However, +most who survive the initial illness and who become abstinent +will survive beyond 5 years. +The presence of jaundice may suggest alcoholic +hepatitis. +Determining the extent of liver damage often requires +a liver biopsy. +Life-long abstinence is the +best advice. +Treatment +of alcohol dependency is discussed on page 1195. +Neither glucocorticoids nor pentoxifylline improved +survival at 90 days or 1 year, however. +In many centres, ALD is a common indication for +liver transplantation. +22.30B). +NAFLD is considered by many to be the hepatic manifestation +of the ‘metabolic syndrome’ (p. +730), as it is strongly associated +with obesity, dyslipidaemia, type 2 diabetes and hypertension. +22.30 Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). +A Features. +Rate of progression is determined by +environmental (dietary) and genetic factors. +B The spectrum of NAFLD. +The overall +prevalence of NAFLD in patients with type 2 diabetes ranges +from 40% to 70%. +22.30A). +acute +fatty liver of pregnancy (p. +1283), or in other situations, e.g. +Reye’s syndrome (p. +241) or drug toxicity (sodium valproate, +tetracyclines), or with bacterial toxins (e.g. +Bacillus cereus). +These factors help with identication of ‘high-risk’ +patient groups. +Biochemical tests +There is no single diagnostic blood test for NAFLD. +Elevations +of serum ALT and AST are modest, and usually less than twice +the upper limit of normal. +This allows care to focus on +those most likely to have advanced disease. +22.30A) with a mainly centrilobular, +acinar zone 3 distribution. +These +may be accompanied by Mallory–Denk bodies (also known +as Mallory’s hyaline). +Perisinusoidal brosis is a characteristic +feature of NASH. +Histological scoring systems are widely used +to assess disease severity semi-quantitatively. +Online +calculators for these are widely available. +(HCC = hepatocellular carcinoma; +M probe = medium probe; XL = large probe) +and physical exercise. +Autoimmune liver and biliary disease +The liver is an important target for autoimmune injury. +The +formal classication into disease types has fallen out of favour +in recent years. +Adult onset of anti-LKM can be seen +in chronic HCV infection. +This was classied as type II disease +in the old system. +Clinical features +The onset is usually insidious, with fatigue, anorexia and eventually +jaundice. +This acute presentation +can lead to extensive liver necrosis and liver failure. +Other features +include fever, arthralgia, vitiligo and epistaxis. +Amenorrhoea can +occur. +Anti-microsomal antibodies (anti-LKM) occur particularly in children +and adolescents. +If +the diagnosis of autoimmune hepatitis is suspected, liver biopsy +should be performed. +It typically shows interface hepatitis, with +or without cirrhosis. +Maintenance therapy should only be instituted +once LFTs are normal (as well as IgG if elevated). +This, in turn, leads to brosis +and cirrhosis of the liver. +Epidemiology +The prevalence of PBC varies across the world. +It is relatively +common in northern Europe and North America but is rare in Africa +and Asia. +Pathophysiology +Immune mechanisms are clearly involved. +IL-12 +and its receptor). +A model of the natural history of the disease process +is shown in Figure 22.32. +Clinical features +Systemic symptoms such as fatigue are common and may +precede diagnosis by years. +Jaundice is +rarely a presenting feature. +The itching is usually worse on the +limbs. +Although there may be right upper abdominal discomfort, +fever and rigors do not occur. +Initially, patients are well nourished but weight loss can occur +as the disease progresses. +22.32 Natural history of primary biliary cholangitis. +(AMA = antimitochondrial antibody; LFTs = liver function tests) +patients with severe pruritus. +Jaundice is prominent only late in +the disease and can become intense. +Xanthomatous deposits +occur in a minority, especially around the eyes. +Liver failure may supervene. +1038), +systemic sclerosis, coeliac disease (p. +805) and thyroid diseases. +Hypothyroidism should always be considered in patients with +fatigue. +Diagnosis and investigations +The LFTs show a pattern of cholestasis (see Box 22.2, p. +853). +Ultrasound examination shows no sign of biliary +obstruction. +Liver biopsy is necessary only if there is diagnostic +uncertainty. +Its use +is recommended in all clinical guidelines. +None shows overall benet when given +to unselected patients. +Serum bilirubin remains the most reliable marker of +declining liver function. +Pruritus +This is the main symptom requiring treatment. +A dose of 4–16 g/day orally is used. +a +molecular adsorbent recirculating system, MARS). +Fatigue +Fatigue affects about one-third of patients with PBC. +The cause +is unknown but it may reflect intracerebral changes due to +cholestasis. +The impact on patients’ lives can be substantial. +Coeliac disease should be excluded since its +incidence is increased in PBC. +Baseline bone density +should be measured (p. +989) and treatment started with +replacement calcium and vitamin D3. +Bisphosphonates should +be used if there is evidence of osteoporosis. +Osteomalacia is rare. +In such individuals, a trial of glucocorticoid +therapy may be benecial. +The incidence is about 6.3/100 000 +in Caucasians. +Cholangiocarcinoma develops in about 10–30% +of patients during the course of the disease. +PSC is twice as common in young men. +The causes of secondary +sclerosing cholangitis are shown in Box 22.51. +The prevalence of PSC is lower in patients +with Crohn’s colitis (about 1%). +22.34 Primary sclerosing cholangitis. +Note onion skin scarring +(arrows) surrounding a bile duct. +Fig. +There is intrahepatic +bile duct beading, stricturing and dilatation. +The extrahepatic bile duct is +also diffusely strictured. +Courtesy of Dr Dilip Patel, Royal Inrmary of +Edinburgh. +Attacks +of acute cholangitis are uncommon and usually follow biliary +instrumentation. +The condition may +be associated with many other diseases (Box 22.52). +22.33). +22.34). +UDCA is widely used, although the evidence +to support this is limited. +UDCA may have benet in terms of +reducing colon carcinoma risk. +The course of PSC is variable. +About 75% of asymptomatic patients survive 15 years +or more. +A close link with HLA haplotype +A1-B8-DR3-DRW52A has been identied. +This haplotype is +commonly found in association with other organ-specific +autoimmune diseases (e.g. +autoimmune hepatitis). +The antibody is not specic for PSC and +is found in other chronic liver diseases (e.g. +Symptomatic patients often have pruritus. +Management is as +for PBC. +Fatigue appears to be less prominent than in PBC, +although it is still present in some patients. +Management of complications +Broad-spectrum antibiotics (e.g. +Fat-soluble vitamin replacement is necessary in jaundiced patients. +Metabolic bone disease (usually osteoporosis) is a common +complication that requires treatment (p. +1044). +Cholangiocarcinoma +is a contraindication to transplantation. +841). +The risk is between +1% and 5% in cirrhosis caused by hepatitis B and C. +The risk of HCC is +0.4% per year in the absence of cirrhosis and 2–6% in cirrhosis. +The risk is four times higher in HBeAg-positive individuals than in +those who are HBeAg-negative. +The risk is higher in men and rises with age. +Lymph node metastases are common, +while lung and bone metastases are rare. +Clinical features +Patients typically present with HCC in one of two ways. +Other +characteristic symptoms can include weight loss, anorexia and +abdominal pain. +Examination may reveal hepatomegaly or +a right hypochondrial mass. +The advanced nature of disease that presents in +this way makes curative therapy unlikely. +The second presentation is through screening of patients at +risk of HCC. +Investigations +Serum markers +Alpha-fetoprotein (AFP) is produced by 60% of HCCs. +Imaging +Ultrasound will detect focal liver lesions as small as 2–3 cm. +Ultrasound may +also show evidence of portal vein involvement and features of +coexistent cirrhosis. +22.35). +MRI can be +used instead. +Angiography is now seldom performed and has +been superseded by the above techniques. +If biopsy will not change management, then +its appropriateness should be considered carefully. +Management +This is different for patients with cirrhosis and those without. +An algorithm for managing those with cirrhosis is shown +in Figure 22.36. +Screening has +improved the outlook through early detection. +Hepatic resection +This is the treatment of choice for non-cirrhotic patients. +The +5-year survival in this group is about 50%. +Recurrence rates (50% at 3 years) are similar to those +following surgical resection. +22 +Fig. +22.35 Computed tomogram showing a large hepatocellular +carcinoma (arrows). +Courtesy of Dr D. +22.36 Management of hepatocellular carcinoma complicating cirrhosis. +Performance status (PST; see Box 33.3, p. +Child–Pugh score: see Box 22.29, p. +867. +N1, M1: lymph node +involvement and metastases (for TNM classication, see Box 33.4, p. +EASL–EORTC clinical practice guidelines: Management of hepatocellular carcinoma. +J Hepatol 2012; 56:908–943. +Unfortunately, any survival benet +is lost at 4 years. +Chemotherapy +Sorafenib improves survival from 7.9 to 10.7 months in cirrhotic +patients. +malignant hepatocytes surrounded by a dense brous stroma. +The treatment of choice is surgical resection. +Other primary malignant tumours +These are rare but include haemangio-endothelial sarcomas. +They may be single or multiple. +Peritoneal dissemination frequently results in ascites. +There is liver enlargement and weight +loss; jaundice may be present. +Imaging shows lling defects (Fig. +22.37); +laparoscopy may reveal the tumour and facilitates liver biopsy. +The tumours are often large at presentation +and the AFP is usually normal. +Histology of the tumour revealsDrugs and the liver • 893 +Fig. +22.38 Magnetic resonance image showing a haemangioma +(arrows) in the liver. +Courtesy of Dr D. +Redhead, Royal Inrmary of +Edinburgh. +Fig. +22.37 Computed tomogram showing multiple liver metastases +(arrows). +Resection +is indicated for the relief of symptoms. +Hepatic adenomas can +increase in size during pregnancy. +Large or rapidly growing +adenomas can rarely rupture, causing intraperitoneal bleeding. +Most are smaller than +5 cm and rarely cause symptoms (Fig. +22.38). +Surgery is needed only for very +large symptomatic lesions or where the diagnosis is in doubt. +Focal nodular hyperplasia +Focal nodular hyperplasia is common in women under the age +of 40. +Histologically, they +Fig. +22.39 Computed tomogram showing multiple cysts in the liver +and kidneys in polycystic disease. +consist of nodular regeneration of hepatocytes without brosis. +They may be multiple but only rarely need resection. +They can +be associated with polycystic renal disease (Fig. +22.39). +In such cases, percutaneous or +surgical debulking can be attempted but recurrence is typical. +Liver abscesses are discussed on page 879. +32). +The presence of jaundice indicates +more severe liver damage. +Types of liver injury +Different histological patterns of liver injury may occur with +drug injury. +Anabolic glucocorticoids used +by body-builders may also cause a cholestatic hepatitis. +Granulomas may be seen in liver injury +following the use of allopurinol. +Recreational +drugs, including cocaine and ecstasy, can also cause severe +acute hepatitis. +Hepatic brosis +Most drugs cause reversible liver injury and hepatic brosis is +very uncommon. +The mechanisms by which HFE +regulates iron absorption are unclear. +HHC may promote accelerated liver +disease in patients with alcohol excess or hepatitis C infection. +Iron loss in menstruation and pregnancy can delay the onset +of HHC in females. +Fatigue and arthropathy are +early symptoms but are frequently absent. +Once again, absence of this feature does not preclude +the diagnosis. +Cardiac failure or cardiac +dysrhythmia may occur due to iron deposition in the heart. +Transferrin saturation of more than 45% is suggestive of iron +overload. +Signicant liver disease is unusual in patients with ferritin +lower than 1000 Îźg/L (100 Îźg/dL). +Very signicant ferritin elevation can be seen in adult Still’s disease. +In terms of imaging techniques, MRI has high specicity for iron +overload but poor sensitivity. +An HII of more than 1.9 suggests genetic +haemochromatosis (Fig. +22.40). +The aim is to reduce ferritin to under 50 Îźg/L +(5 Îźg/dL). +Thereafter, venesection is continued as required to +keep the serum ferritin normal. +It may be +primary or secondary to other diseases (Box 22.56). +The important organs involved are the liver, +pancreatic islets, endocrine glands, joints and heart. +At least 200 different mutations +have been described. +Most cases are compound heterozygotes +with two different mutations in ATP7B. +Clinical features +Symptoms usually arise between the ages of 5 and 45 years. +These +features can occur alone or simultaneously. +25). +Unusual clumsiness for age may be an +early symptom. +22.40 Liver histology: haemochromatosis. +This Perls stain shows +accumulating iron within hepatocytes, which is stained blue. +There is also +accumulation of large fat globules in some hepatocytes (macrovesicular +steatosis). +Iron also accumulates in Kupffer cells and biliary epithelial cells. +Type 2 diabetes does +not resolve after venesection. +Other therapy includes that for +cirrhosis and diabetes. +Asymptomatic disease should also be treated by +venesection until the serum ferritin is normal. +This is probably because liver function is +well preserved at diagnosis and improves with therapy. +Screening +for hepatocellular carcinoma (p. +846). +They disappear with treatment. +Investigations +A low serum caeruloplasmin is the best single laboratory clue +to the diagnosis. +Management +The copper-binding agent penicillamine is the drug of choice. +Care must be taken to +ensure that re-accumulation of copper does not occur. +The value of liver +transplantation in severe neurological Wilson’s disease is unclear. +Prognosis is excellent, provided treatment is started before +there is irreversible damage. +One of its main anti-protease functions +is the breakdown of neutrophil elastase. +Alpha1 -AT- +containing globules can be demonstrated in the liver (Fig. +22.41) +Fig. +22.41 Liver histology in Îą1 -antitrypsin deciency. +but this is not necessary to make the diagnosis. +There is no specic treatment. +860). +It can be inherited +in a dominant fashion when there is a missense mutation in the +gene. +There are no stigmata of chronic liver disease +other than jaundice. +There is no bilirubinuria +because the hyperbilirubinaemia is predominantly unconjugated. +An underlying thrombophilia needs +to be excluded. +868). +Ascites is unusual in non-cirrhotic portal hypertension, +unless the albumin is particularly low. +Chronic portal vein thrombosis can be a cause of portal +hypertension. +The hypoxia +is due to intrapulmonary shunting through direct arteriovenous +communications. +Nitric oxide (NO) over-production may be +important in pathogenesis. +621). +22.20, p. +868). +Congestive +hepatomegaly and ascites are, however, the most consistent +features. +This places it at risk of ischaemic injury in settings +of impaired perfusion. +prolonged seizures). +Liver synthetic dysfunction and +encephalopathy are uncommon but can occur. +Liver failure is very +rare. +Diagnosis typically rests on clinical suspicion and exclusion +of other potential aetiologies. +Treatment is aimed at optimising +liver perfusion and oxygen delivery. +It can cause +signicant liver damage. +It usually causes severe upper abdominal pain with or without +signs of circulatory shock. +Patients usually survive if the liver and portal blood +supply are otherwise normal. +Atheroma, vasculitis, +bacterial endocarditis and surgical or biopsy trauma are the +main causes. +Treatment is radiological or surgical. +Any of the vasculitides +can affect the hepatic artery but this rarely causes symptoms. +23). +More gradual occlusion causes gross ascites and, often, +upper abdominal discomfort. +Hepatomegaly, frequently with +tenderness over the liver, is almost always present. +Peripheral +oedema occurs only when there is inferior vena cava obstruction. +Features of cirrhosis and portal hypertension develop in those +who survive the acute event. +CT and MRI may also demonstrate occlusion of the +hepatic veins and inferior vena cava. +Ascites is initially treated medically but often with only limited +success. +Short hepatic venous strictures can be treated with +angioplasty. +Occasionally, a web can be resected or +an inferior vena caval stenosis dilated. +Progressive liver failure is +an indication for liver transplantation and life-long anticoagulation. +A +3-year survival of 50% is reported in those who survive the initial +event. +by widespread occlusion of the small central hepatic veins. +The clinical features are similar to +those of the Budd–Chiari syndrome (see above). +Transjugular liver biopsy (with portal pressure +measurements) may facilitate the diagnosis. +461); usually, the clinical features are +predominantly cardiac. +Very rarely, long-standing cardiac failure +and hepatic congestion give rise to cardiac cirrhosis. +Severe +left ventricular dysfunction is a cause of ischaemic hepatitis. +Cardiac causes of acute and chronic liver disease are typically +under-diagnosed. +It is believed to be due +to damage to small hepatic arterioles and portal venules. +Liver function is good +and the prognosis is very favourable. +Management is based on +treatment of the portal hypertension. +• This represents a genuine pregnancy-associated liver injury +process. +Joint management +between hepatologists and obstetricians is essential. +Complications of portal hypertension +may be a particular issue in the second and third trimesters. +Gallstones (p. +903) are more common during pregnancy and +may present with cholecystitis or biliary obstruction. +The diagnosis +can usually be made with ultrasound. +Despite this, 10% of those listed for +liver transplantation will die while awaiting a donor liver. +Most patients are under 60 years +of age and only 10% are aged between 60 and 70 years. +Indications for elective transplant assessment are listed in Box +22.58. +22.42). +Patients with alcoholic liver disease need +to show a capacity for abstinence. +In many parts of the world, the MELD score (see Box 22.30, +p. +868) is used to identify and prioritise patients for transplantation. +ALP levels can rise due to the +contribution of placental ALP. +Autoimmune liver disease can flare up post-partum. +Gallstones are more common in pregnancy and post-partum, and are +a cause of a raised ALP level. +Biliary imaging with ultrasound and +magnetic resonance cholangiopancreatography is safe. +Maternal and fetal mortality +and morbidity are reduced by expediting delivery. +868) +• Child–Pugh grade C (Box 22.29, p. +Portal vein thrombosis is rare. +Some patients can eventually +be maintained on a single agent. +This normally responds to 3 days of high-dose intravenous +methylprednisolone. +Herpes simplex virus reactivation or, rarely, +primary infection may occur. +Metabolic syndrome (p. +730) is +common, being described in about 50% of transplant recipients +within 6 months in the USA. +Chronic vascular rejection is rare, +occurring in only 5% of cases. +The 1-year +survival is 65% and falls only a little to 59% at 5 years. +The +1-year survival for patients with cirrhosis is over 90%, falling to +70–75% at 5 years. +22.42 Indications for elective adult liver transplantation in the +UK, 2016. +This practice has led +to an increase in procedures despite a shortage of donor +organs. +• Living donor transplantation. +This is normally performed using +the left lateral segment or the right lobe. +The donor +mortality is signicant at 0.5–1%. +Pre-operative +assessment includes looking at donor liver size and +psychological status. +Treatment is supportive +until recovery of function. +Occasionally, recovery is not seen and +re-transplantation is necessary. +• Hepatitis A: causes more severe illness and runs a more protracted +course. +• Primary biliary cholangitis: one-third of cases are over 65 years. +• Liver abscess: more than 50% of all cases in the UK are over +60 years. +Chemical cholestasis +Pure cholestasis can occur as an inherited condition (p. +895), as +a consequence of cholestatic drug reactions (p. +894) or as acute +cholestasis of pregnancy (p. +1284). +Episodes start with pruritus, while painless jaundice develops +later. +LFTs show a cholestatic pattern. +Liver biopsy shows +cholestasis during an episode but is normal between episodes. +Recurrent attacks of cholangitis (see Box +22.18, p. +861) may cause hepatic abscesses. +Complications +include biliary stones and cholangiocarcinoma. +Antibiotics are +required for episodes of cholangitis. +The renal +tubules may show cystic dilatation (medullary sponge kidney; +p. +433), and eventually renal cysts may develop. +The condition +can be inherited as an autosomal recessive trait. +The prognosis is good because liver function is +preserved. +Treatment may be required for variceal bleeding and +occasionally cholangitis. +Patients can present during childhood +with renal failure if the kidneys are severely affected. +Cystic brosis +Cystic brosis (p. +580) is associated with biliary cirrhosis in +about 5% of individuals. +Splenomegaly and an elevated ALP +are characteristic. +22.43 Classication and frequency of choledochal cysts. +From +Shearman DC, Finlayson NDC. +Diseases of the gastrointestinal tract and +liver, 2nd edn. +Edinburgh: Churchill Livingstone, Elsevier Ltd; 1989. +malabsorption). +890). +Choledochal cysts +This term applies to cysts anywhere in the biliary tree (Fig. +22.43). +The last type merges with Caroli’s disease (see +above). +In the neonate, they may present with jaundice or biliary +peritonitis. +Recurrent jaundice, abdominal pain and cholangitis may +arise in the adult. +Excision of the cyst with hepatico-jejunostomy is the treatment +of choice. +Carcinomas rarely cause +secondary biliary cirrhosis because few patients survive long +enough. +879). +Cirrhosis, ascites and portal hypertension are late +features. +Relief of biliary obstruction may require endoscopic or +surgical intervention. +Gallstones are less frequent in India, the +Far East and Africa. +Biliary lipoproteins may also have a role in solubilising cholesterol. +Fasting, parenteral nutrition and pregnancy are also associated +with sludge formation. +If a gallstone becomes acutely impacted in the cystic +duct, the patient will experience pain. +779). +Acute and chronic cholecystitis +is described below. +906) in approximately +15% of patients and cause biliary colic. +Rarely, stulae develop +between the gallbladder and the duodenum, colon or stomach. +If +this occurs, air will be seen in the biliary tree on plain abdominal +X-rays. +The resultant intestinal +obstruction may be followed by ‘gallstone ileus’. +Cancer of the gallbladder is growing in frequency (p. +907) but in +over 95% of cases is associated with the presence of gallstones. +Investigations +Ultrasound is the investigation of choice for diagnosing gallstones. +22.8, p. +854). +CT, MRCP (Fig. +Minor +increases of transaminases and amylase may be encountered. +Amylase should be measured to detect acute pancreatitis (p. +837), +which may be a potentially serious complication of gallstones. +Moderate pain can be treated with NSAIDs +but more severe pain should be managed with opiates. +Nasogastric aspiration is needed only for persistent +vomiting. +Operation should +be carried out within 5 days of the onset of symptoms. +Delayed surgery after 2–3 months is no longer favoured. +Recurrent +biliary colic or cholecystitis is frequent if the gallbladder is not +removed. +Various techniques can be used +to treat common bile duct stones (Box 22.64). +The pathogenesis +is unclear but the initial inflammation is possibly chemically +induced. +At the time of surgery, approximately +50% of cultures of the gallbladder contents are sterile. +Differentiation between biliary colic (p. +Fever is present but rigors are unusual. +Gallbladder +perforation occurs in 10–15% of cases and gallbladder empyema +may arise. +The clinical features are similar to +those of acute calculous cholecystitis but milder. +Patients may +recover spontaneously or following analgesia and antibiotics. +They are usually advised to undergo elective laparoscopic +cholecystectomy. +22.46 Endoscopic ultrasound image in a patient with +cholangitis. +The dilated common bile duct (CBD) contains a small stone +(arrow), which causes acoustic shadowing. +EUS is extremely accurate at identifying +bile duct stones. +MRCP is non-invasive and is indicated when +intervention is not necessarily mandatory (e.g. +the patient with +possible bile duct stones but no jaundice or sepsis). +Blood cultures should be +taken before the antibiotics are administered. +Patients also require +urgent decompression of the biliary tree and stone removal. +External drainage of the common bile +duct by T-tube is rarely required nowadays. +It is now possible +to achieve these goals laparoscopically in specialist centres. +Recurrent pyogenic cholangitis +This disease occurs predominantly in South-east Asia. +Patients present with recurrent attacks of upper abdominal pain, +fever and cholestatic jaundice. +Eventually, the liver +becomes scarred and liver abscesses and secondary biliary +cirrhosis develop. +The condition is difcult to manage and requires +Fig. +22.45 Endoscopic retrograde cholangiopancreatogram showing +common duct stones (arrows). +22.45), which have +usually migrated from the gallbladder. +297 and 289 ). +The pain is usually in the right upper quadrant, and +fever, pruritus and dark urine may be present. +Rigors may be +a feature; jaundice is common and usually associated with +pain. +Investigations +The LFTs show a cholestatic pattern and there is bilirubinuria. +If cholangitis is present, the patient usually has a leucocytosis. +This shows +dilated extrahepatic and intrahepatic bile ducts, together with +gallbladder stones (Fig. +More than 90% +are adenocarcinomas; the remainder are anaplastic or, rarely, +squamous tumours. +Individuals with a calcied gallbladder (‘porcelain gallbladder’; +p. +A +gallbladder mass may be palpable in the right hypochondrium. +LFTs show cholestasis, and porcelain gallbladder may be found +on X-ray. +The tumour can be diagnosed by ultrasonography +and staged by CT. +It accounts for only 1.5% of all cancers but +the incidence is increasing. +22.43). +The +presentation is usually with obstructive jaundice. +About 50% of +patients also have upper abdominal pain and weight loss. +The +diagnosis is made using a combination of CT and MRI (see +Fig. +22.10, p. +855) but can be difcult to conrm in patients +with sclerosing cholangitis. +In the setting of +biliary obstruction, ERCP may result in positive biliary cytology. +22.47). +Jaundice may be intermittent +or persistent. +Ampullary carcinoma must be differentiated from carcinoma of +22 +A B +Fig. +22.47 Cholangiocarcinoma. +EUS is the most sensitive method of assessing and +staging ampullary or periampullary tumours. +If resection is impossible, palliative surgical bypass or +stenting may be necessary. +Severe post-cholecystectomy +syndrome occurs in only 2–5% of patients. +The main causes +are listed in Box 22.65. +The LFTs may be abnormal and sometimes show +cholestasis. +The possibility of +a functional illness should also be considered. +This may cause pancreaticobiliary +pain, deranged LFTs or recurrent pancreatitis. +They have often had a +cholecystectomy but the gallbladder may be intact. +The gold standard for diagnosis is sphincter of Oddi +manometry. +Hepatobiliary +scintigraphy (e.g. +If such complications supervene, mortality may reach +20%. +• Cancer of the gallbladder: a disease of old age, with a 1-year +survival of 10%. +Management +All patients with organic stenosis are treated with endoscopic +sphincterotomy. +Medical +therapy with nifedipine and/or low-dose amitriptyline may be +tried. +Prophylactic administration of rectal NSAIDs +(e.g. +Books and journal articles +Anstee QM, Targher G, Day CP. +Progression of NAFLD to diabetes +mellitus, cardiovascular disease or cirrhosis. +Nat Rev Gastroenterol +Hepatol 2013; 10:330–344. +EASL Clinical practice guidelines: Autoimmune hepatitis. +J Hepatol +2015; 63:971–1004. +EASL Clinical practice guidelines: Liver transplantation. +J Hepatol +2016; 64:433–485. +EASL Recommendations on treatment of hepatitis C 2015. +J Hepatol +2015; 63:199–236. +J Hepatol 2016; 64:1388–1402. +Neuberger J, Gimson A, Davies M, et al. +Selection of patients for liver +transplantation and allocation of donated livers in the UK. +Gut 2008; +57:252–257. +Williams R, Aspinall R, Bellis M, et al. +Lancet 2014; 384:1953–1997. +Websites +aasld.org American Association for the Study of Liver Diseases +(guidelines available). +bsg.org.uk British Society of Gastroenterology (guidelines available). +easl.eu European Association for the Study of the Liver (guidelines +available). +eltr.org European Liver Transplant Registry. +unos.org United Network for Organ Sharing: US transplant register. +Color atlas of clinical hematology, 4th edn. +Philadelphia: Mosby, Elsevier Inc.; 2010; +(Petechiae) Young NS, Gerson SL, High KA (eds). +Clinical hematology. +Anaemia +Symptoms and signs help to indicate the +clinical severity of anaemia. +A full history +and examination is needed to identify the +underlying cause. +The clinical points to clarify are +shown in the box. +dental abscess) +• Other general examination (e.g. +liver +disease +Examination +There are two main patterns of bleeding: +1. +Mucosal bleeding +Reduced number or function of platelets +(e.g. +bone marrow failure or aspirin) or +von Willebrand factor (e.g. +Coagulation factor deciency +(e.g. +• To help palpate small spleens, roll the +patient on to the right side and examine +as before. +at times of increased demand. +23.1). +Megakaryocytes are large cells that produce and +release platelets into vascular sinuses. +Stem cells +All blood cells are derived from pluripotent haematopoietic stem +cells. +These comprise only 0.01% of the total marrow cells, but +they can self-renew (i.e. +23.2). +The bone marrow also contains stem cells that can differentiate +into non-haematological cells. +However, red marrow can expand in response +to increased demands for blood cells. +23.2 Stem cells and growth factors in haematopoietic cell development. +This is termed stem cell plasticity and may have exciting clinical +applications in the future (Ch. +3). +23.3). +Increased +numbers of circulating reticulocytes (reticulocytosis) reflect +increased erythropoiesis. +Failure of erythropoietin production in patients with +renal failure (p. +darbepoetin. +Normal mature red cells circulate for about 120 days. +23.4). +23.8D). +23.4). +The ABO and Rhesus systems are the +most commonly recognised (p. +931) but over 400 blood group +antigens have been described. +Haemoglobin +Haemoglobin is a protein specially adapted for oxygen transport. +23.3 Maturation pathway of red cells, granulocytes and platelets. +The image on the right is a normal blood lm. +23.4 Normal structure of red cell membrane. +Red cell membrane flexibility is conferred by attachment of cytoskeletal proteins. +Antigens on the red blood cell determine an individual’s blood group. +931). +The ABO genetic locus has three main allelic forms: A, B and O. +People with the O allele produce an O antigen, which lacks either of these added sugar groups. +Rh antigens are transmembrane proteins. +metabolism, binds to the haemoglobin molecule and lowers +its oxygen afnity. +These complex interactions produce the +sigmoid shape of the oxygen dissociation curve (Fig. +23.5). +when red cells reach hypoxic tissues. +135). +951). +Defects in haem synthesis cause the porphyrias (p. +Their +main function is to recognise, ingest and destroy foreign particles +and microorganisms (p. +64). +A large storage pool of mature +neutrophils exists in the bone marrow. +Neutrophils spend 6–10 hours in the circulation before +being removed, principally by the spleen. +Eosinophils +Eosinophils represent 1–6% of the circulating white cells. +233). +They are also involved in allergic reactions (e.g. +atopic asthma, +p. +567; see also p. +84). +They contain dense +black granules that obscure the nucleus. +Mast cells resemble +basophils but are found only in the tissues. +These cells are +involved in hypersensitivity reactions (p. +66). +The former phagocytose debris, apoptotic cells +and microorganisms (see Box 4.1, p. +64). +Lymphocytes +Lymphocytes are derived from pluripotent haematopoietic stem +cells in the bone marrow. +68). +The majority (about 80%) of lymphocytes in the circulation are +T cells. +23.5 The haemoglobin–oxygen dissociation curve. +To convert kPa to +mmHg, multiply by 7.5. +23.12). +23.3). +This takes about 14 days. +23.6). +Dysfunction of any of these +components may result in haemorrhage or thrombosis. +Platelets +Platelets are formed in the bone marrow from megakaryocytes. +Large numbers +of platelets then fragment off from each megakaryocyte into the +circulation. +Platelets +circulate for 8–10 days before they are destroyed in the reticulo- +endothelial system. +Some 30% of peripheral platelets are normally +pooled in the spleen and do not circulate. +Under normal conditions, platelets are discoid, with a diameter +of 2–4 Îźm (Fig. +23.7). +500). +Fig. +23.6 The stages of normal haemostasis. +A Stage 1. +Pre-injury conditions encourage +flow. +Platelets and +coagulation factors circulate in a non-activated +state. +A +Vascular endothelium +Heparans +Nitric oxide Prostacyclin +Platelet +Red cell +B Stage 2. +Early haemostatic response: +platelets adhere; coagulation is activated. +At the +site of injury, the endothelium is breached, +exposing subendothelial collagen. +Small amounts +of tissue factor (TF) are released. +23.7). +Activated +factors are designated by the sufx ‘a’. +Some of these reactions +require phospholipid and calcium. +23.6D). +The carboxylase enzyme +responsible for this in the liver is vitamin K-dependent. +939). +Congenital (e.g. +haemophilia) and +acquired (e.g. +liver failure) causes of coagulation factor deciency +are associated with bleeding. +It is important to appreciate, however, that a +D +brinogen to produce +brin. +Fibrin monomers are cross-linked by +factor XIII, which is also activated by thrombin. +E Stage 4. +Limiting clot formation: natural +anticoagulants reverse activation of coagulation +factors. +Once haemostasis has been secured, +the propagation of clot is curtailed by +anticoagulants. +Tissue +factor pathway inhibitor (TFPI) binds to and +inactivates VIIa and Xa. +PC and PS are vitamin K-dependent +and are depleted by coumarin anticoagulants +such as warfarin. +F Stage 5. +Fibrinolysis: plasmin degrades brin +to allow vessel recanalisation and tissue repair. +The insoluble clot needs to be broken down for +vessel recanalisation. +Plasmin, the main +brinolytic enzyme, is produced when +plasminogen is activated, e.g. +by tissue +plasminogen activator (t-PA) or urokinase in the +clot. +Plasmin hydrolyses the brin clot, producing +brin degradation products, including the +D-dimer. +Fig. +23.7 Normal platelet structure. +23.9). +913), +there are recommended screening tests (Box 23.3). +23.6D). +The result of the test sample is compared with +normal controls. +The tissue factor (‘extrinsic’) pathway (see Fig. +The approximate reference ranges and causes of +abnormalities are shown in Box 23.3. +23.8). +Analysers cannot identify abnormalities of red +cell shape and content (e.g. +23.8 Appearance of red blood cells. +A Microcytosis. +B Macrocytosis. +C Target cells. +D Spherocytes. +E Red cell fragments. +F Nucleated +red blood cells. +G Howell–Jolly bodies. +H Polychromasia. +I Basophilic stippling. +196 and 978). +However, most centres have abandoned +the use of this test. +adenosine triphosphate, adenosine diphosphate and their ratio +to each other (ATP/ADP). +23.9 Bone marrow aspirate and trephine. +A Trephine biopsy needle. +B Macroscopic appearance of a trephine biopsy. +C Microscopic +appearance of stained section of trephine. +D Bone marrow aspirate needle. +E Stained macroscopic appearance of marrow aspirate: smear (left) and +squash (right). +F Microscopic appearance of stained marrow particles and trails of haematopoietic cells. +warfarin. +Monitoring of heparin therapy is, on the whole, required only +with unfractionated heparins. +When monitoring is indicated, +an anti-Xa activity assay rather than APTT should be used. +10.6, p. +187). +Examples of possible indications for +testing are given in Box 23.5. +In most patients, the results do +not affect clinical management (p. +975) but they may influence +the duration of anticoagulation (e.g. +antiphospholipid antibodies, +p. +977), justify family screening in inherited thrombophilias +(p. +975), or suggest additional management strategies to reduce +thrombosis risk (e.g. +in myeloproliferative disease and paroxysmal +nocturnal haemoglobinuria; p. +950). +DIC) +Fibrinogen +1.5–4.0 g/L Hypobrinogenaemia, e.g. +liver failure, DIC +concentration +1 N.B. +2 Ranges are approximate and +may vary between laboratories. +70). +The clinical features +of anaemia reflect diminished oxygen supply to the tissues +(p. +912). +A rapid onset of anaemia (e.g. +due to blood loss) causes +more profound symptoms than a gradually developing anaemia. +Individuals with cardiorespiratory disease are more susceptible +to symptoms of anaemia. +Clinical assessment +• Iron deciency anaemia (p. +940) is the most common type +of anaemia worldwide. +A thorough gastrointestinal history +is important, looking in particular for symptoms of blood +loss. +in +pregnancy or during periods of rapid growth; pp. +712, 945 +and 1284). +• A drug history may reveal the ingestion of drugs that +cause blood loss (e.g. +aspirin and anti-inflammatory +drugs), haemolysis (e.g. +sulphonamides) or aplasia (e.g. +chloramphenicol). +Haemolytic anaemias can cause jaundice. +1138). +Sickle-cell anaemia +(p. +951) may result in leg ulcers, stroke or features of pulmonary +hypertension. +977). +• Ratio of bone marrow cells to marrow fat: falls. +In +truly healthy older people, the ESR range is very similar to that in +younger people. +23 +assays. +Sideroblastic +Low +Hb electrophoresis +? +23.10 Investigation of anaemia with normal or low mean cell volume (MCV). +Myelodysplasia ? +Sideroblastic +anaemia +? +Bleeding ? +Haemolysis +Fig. +23.11 Investigation of anaemia with high mean cell volume (MCV). +23.10). +23.10). +23.11). +Specic types of anaemia and their management are described +later in this chapter (p. +940). +Causes of +polycythaemia are shown in Box 23.8. +970). +930). +The main causes are listed +in Box 23.9 and Figure 23.12. +Drug-induced neutropenia is not +uncommon (Box 23.10). +Clinical manifestations range from no +symptoms to overwhelming sepsis. +Fever is the rst and +often only manifestation of infection. +A sore throat, perianal pain or +skin inflammation may be present. +Management +is discussed on page 224. +Lymphopenia +This is an absolute lymphocyte count of less than 1 × 109/L. +The causes are shown in Box 23.9. +Salmonella), protozoal (e.g. +gold, sulphonamides +• Vasculitis: e.g. +23.12 Appearance of white blood cells. +A Neutrophil. +B Eosinophil. +C Basophil. +D Monocyte. +E Lymphocyte. +and human herpesvirus 8 (HHV-8)). +Lymphopenia without any +obvious cause is common with advancing age. +This is usually due to an increase in a specic type +of cell (see Box 23.9). +It is important to realise that an increase +in a single type of white cell (e.g. +The normal neutrophil +count depends on age, race and certain physiological parameters. +The causes of a neutrophilia are shown in Box 23.9. +233), allergy +(e.g. +eczema, asthma, reactions to drugs; p. +84), immunological +disorders (e.g. +polyarteritis, sarcoidosis) or malignancy (e.g. +lymphomas) (see Box 23.9). +Usually, such eosinophilia is +short-lived. +In the rarer primary disorders, there is a persistently raised, often +clonal, eosinophilia, e.g. +Eosinophil inltration can damage many organs (e.g. +In adults, this is greater than +3.5 × 109/L. +Infants and children have higher counts; age-related +reference ranges should be consulted. +Causes are shown in Box +23.9; the most common is viral infection. +with amyloid). +Associated lymphadenopathy +is suggestive of lymphoproliferative disease. +Rarely, spontaneous or traumatic rupture and +bleeding may occur. +Investigation should focus on the suspected cause. +A chest X-ray +or CT of the thorax will detect mediastinal lymphadenopathy. +Screening for infectious +or liver disease (p. +852) may be appropriate. +1043) +• Vasculitis (p. +1040) +• Paraproteinaemias +• Purpura fulminans, e.g. +Fig. +23.13 Petechial purpura. +• Duration of history. +It may be possible to assess whether +the disorder is congenital or acquired. +• Precipitating causes. +• Surgery. +Ask about operations. +Dental extractions, +tonsillectomy and circumcision are stressful tests of the +haemostatic system. +• Family history. +Recessive +disorders are more common in cultures where there is +consanguineous marriage. +• Drugs. +Use of antithrombotic, anticoagulant and brinolytic +drugs must be elicited. +Drug interactions with warfarin and +drug-induced thrombocytopenia should be considered. +Some ‘herbal’ remedies may result in a bleeding diathesis. +Clinical examination may reveal different patterns of skin +bleeding. +Petechial purpura is minor bleeding into the dermis +that is flat and non-blanching (Fig. +23.13). +Petechiae are typically +found in patients with thrombocytopenia or platelet dysfunction. +500). +A careful clinical evaluation is the key to diagnosis of bleeding +disorders (p. +970). +It is important to consider the following: +• Site of bleeding. +Ecchymosis, or bruising, +is more extensive bleeding into deeper layers of the skin. +The +lesions are initially dark red or purple but become yellow as +haemoglobin is degraded. +Retroperitoneal bleeding presents with +a flank or peri-umbilical haematoma. +Telangiectasia of lips and +tongue points to hereditary haemorrhagic telangiectasia (p. +970). +Joints should be examined for evidence of haemarthroses. +Investigations +Screening investigations and their interpretation are described on +page 920. +921). +Investigations are directed at the possible causes listed in Box +23.14. +A blood lm is the single most useful initial investigation. +Treatment (if required) depends on the underlying cause. +Pancytopenia +Pancytopenia refers to the combination of anaemia, leucopenia +and thrombocytopenia. +Causes are shown in Box 23.16. +A bone +marrow aspirate and trephine are usually required to establish +the diagnosis. +Examples include: +• Coagulation factors. +• Immunoglobulins. +971) +and Guillain–BarrĂŠ syndrome (p. +1140). +Anti-zoster immunoglobulin has +a role in the prophylaxis of varicella zoster (p. +239). +• Human albumin. +This is available in two strengths. +395) and ascites in chronic liver disease +(p. +864). +It is hyperoncotic and expands plasma volume by +more than the amount infused. +Blood components and their use are summarised in Box 23.17. +23.14). +Platelet concentrates may be tested for bacterial +contamination. +The need for other microbiological tests depends +on local epidemiology. +For example, testing for Trypanosoma +cruzi (Chagas’ disease; p. +279) is necessary in areas of South +America and the USA where infection is prevalent. +224 and 925). +931), and transmission +of infectious agents. +ABO compatibility with recipient essential. +1127). +23.4). +The +ABO and Rhesus D antigens are the most important in routine +transfusion and antenatal practice. +ABO blood groups +The frequency of the ABO antigens varies among different +populations. +The ABO blood group antigens are oligosaccharide +chains that project from the red cell surface. +These chains are +attached to proteins and lipids that lie in the red cell membrane. +23.14 Blood donation, processing and storage. +2In the UK, plasma for fractionation is imported as a precautionary measure against vCJD. +They are, therefore, capable of mounting a humoral immune +response to these ‘foreign’ antigens. +This activates the full complement pathway +(p. +This prevents the formation of +antibodies that could cause HDN. +Additional anti-D is +also given after potential sensitising events antenatally (e.g. +early +bleeding). +Doses vary according to national recommendations. +the transfused red cells in the circulation (intravascular haemolysis). +23.4). +In other populations (e.g. +in Chinese and Bengalis), only 1–5% +are Rhesus-negative. +RhD-negative individuals do not normally +produce substantial amounts of anti-RhD antibodies. +This can cause +severe neurological damage or death due to haemolytic disease +of the newborn (HDN). +These antigens include Rhc, RhC, RhE, Rhe, and the Kell, +Kidd and Duffy antigen systems. +937). +Variant CJD is a human prion disease linked to bovine +spongiform encephalitis (BSE; p. +1127). +Some +patients, e.g. +23.15). +Management of suspected transfusion reactions is +shown in Figure 23.16. +23.15 Bedside procedures for safe blood transfusion. +Yes +• Bronchospasm, angioedema, +abdominal pain, hypotension +No +Bacterial contamination? +23.16 Investigation and management of acute transfusion reactions. +*Use size-appropriate dose in children. +daunorubicin, doxorubicin, idarubicin +Antimetabolites +• Inhibit DNA and RNA synthesis, e.g. +vincristine, vinblastine +Topoisomerase II inhibitors +• Prevent DNA repair, e.g. +Cryoprecipitate +should be given if the brinogen level falls below 1.5 g/L. +Chemotherapy +Chemotherapy refers to the use of drugs to treat cancer (Box +23.21; see also Fig. +33.2, p. +1317). +1330). +More +details of specic chemotherapies are given later in the chapter. +Stem cells can be harvested from +the bone marrow or from the blood. +leukaemias) +• Failure of haematopoiesis (e.g. +aplastic anaemia) +• Major inherited defects in blood cell production (e.g. +Considerable morbidity and mortality are associated with +HSCT. +Reduced-intensity conditioning +has enabled treatment of older or less t patients. +Complications +These are outlined in Boxes 23.23 and 23.24. +The risks and +outcomes of transplantation depend upon several patient- and +disease-related factors. +247) +phase) +and therapy +Bacterial, fungal 0–4 weeks (aplastic +As for acute leukaemia +(p. +242) +immune deciency) +Antigen screening in +blood (PCR) and +pre-emptive therapy +(e.g. +ganciclovir) +Varicella zoster +After 13 weeks Aciclovir prophylaxis +(p. +238) +and therapy +Pneumocystis +8–26 weeks Co-trimoxazole +jirovecii (p. +The long-term survival for patients undergoing allogeneic +HSCT in acute leukaemia is around 50%. +This may cause either an acute or a chronic form of GVHD. +Acute GVHD occurs in the rst 100 days after transplant in +about one-third of patients. +Chronic GVHD may follow acute GVHD or arise independently; +it occurs later than acute GVHD. +Chronic GVHD results in an increased infection risk. +Autologous HSCT +This procedure can also be used in haematological malignancies. +The patient’s own stem cells from blood or marrow are rst +harvested and frozen. +The most common indications are lymphomas and myeloma. +The preferred source of stem cells for autologous transplants +is peripheral blood (PBSCT). +There is +no risk of GVHD and no immunosuppression is required. +975) and management of atrial brillation (p. +471). +491). +A wide range of anticoagulant and antithrombotic drugs +is used in clinical practice. +These drugs and their modes of +action are given in Box 23.26. +These agents enhance the natural +anticoagulant activity of antithrombin (see Fig. +23.6E). +LMWHs +preferentially augment antithrombin activity against factor Xa. +The count may still be in the reference range. +Investigations +The pre-test probability of the diagnosis is assessed using the +4Ts scoring system. +Individuals at low risk need no further test. +Patients with established +thrombosis have a poorer prognosis. +23.6D). +This results in anticoagulation due to an +effective deciency of these factors. +This is monitored by the INR, +a standardised test based on measurement of the prothrombin +time (p. +922). +Recommended target INR values for specic +indications are given in Box 23.25. +Patients +who require rapid initiation of therapy may receive higher +initiation doses of warfarin. +Patients without an urgent need for anticoagulation +(e.g. +atrial brillation) can have warfarin introduced slowly using +lower doses. +weight and with a glomerular ltration rate below +30 mL/min). +UFH is useful in patients with a high risk of bleeding, +e.g. +those who have peptic ulceration or who may require urgent +surgery. +It is also favoured in the treatment of life-threatening +thromboembolism, e.g. +major pulmonary embolism with signicant +hypoxaemia, hypotension and right-sided heart strain. +It is usual to +aim for a patient APTT that is 1.5–2.5 times the control time of +the test. +This results in platelet activation and a prothrombotic state, +with a paradoxical thrombocytopenia. +23.17). +Reticulocytes +are larger than mature red cells, so when the reticulocyte +count is raised – e.g. +in haemolysis – this may also increase +the MCV. +780). +Worldwide, hookworm and +schistosomiasis are the most common causes of gut blood loss +(pp. +288 and 294). +advanced liver disease, +haemophilia, thrombocytopenia +• Pre-existing structural lesions, e.g. +Fatal +haemorrhage, which is most commonly intracranial, occurs +in about 0.25% per annum. +There are also some specic contraindications to +anticoagulation (Box 23.28). +• In the event of bleeding, withhold further warfarin. +Minor +bleeding can be treated with 1–2.5 mg of vitamin K IV. +The DOACs are direct specic inhibitors of key proteases in the +common pathway. +Dabigatran inhibits thrombin while rivaroxaban, +apixaban and edoxaban inhibit Xa. +Iron deficiency +Thalassaemia +Sideroblastic +anaemia +e.g. +23.17 Factors that influence the size of red cells in anaemia. +In microcytosis, the MCV is < 76 fL. +In macrocytosis, the MCV is > 100 fL. +Very rarely, chronic haemoptysis +or haematuria may cause iron deciency. +716). +23.18). +805). +The mean cell volume (MCV) may increase by 5 fL. +A progressive +neutrophilia occurs. +Gestational thrombocytopenia (rarely +< 60 × 109/L) is a benign phenomenon. +• Vitamin B12: serum levels are physiologically low in pregnancy but +deciency is uncommon. +712). +23.18 The regulation of iron absorption, uptake and distribution in the body. +A transferrin saturation (i.e. +In difcult cases, it may still be necessary to examine a bone +marrow aspirate for iron stores. +Serum anti-transglutaminase antibodies and possibly a duodenal +biopsy are indicated (p. +806) to detect coeliac disease. +In the tropics, stool +and urine should be examined for parasites (p. +Doses required can be calculated based on the patient’s starting +haemoglobin and body weight. +Observation for anaphylaxis +following an initial test dose is recommended. +It occurs in the setting of chronic infection, +chronic inflammation or neoplasia. +23.18). +Hepcidin production +is induced by pro-inflammatory cytokines, especially IL-6. +Inhibition or blockade of +hepcidin is a potential target for treatment of this form of anaemia. +Box 23.30 summarises the investigations +and results. +Examination of the marrow may ultimately be required +to assess iron stores directly. +A trial of oral iron can be given +in difcult situations. +A positive response occurs in true iron +deciency but not in ACD. +Measures that reduce the severity +of the underlying disorder generally help to improve the ACD. +945). +Iron stores are usually raised. +The mature red cells are +large and oval, and sometimes contain nuclear remnants. +If severe, a pancytopenia may be present +in the peripheral blood. +The most common manifestations +are sensory, with peripheral paraesthesiae and ataxia of gait. +Levels of cobalamins fall +in normal pregnancy. +In the absence of intrinsic factor, less than 1% +of dietary vitamin B12 is absorbed. +18) or a family history of these or pernicious anaemia. +This is corrected to some extent by +appropriate antibiotics. +A small number of people heavily infected with the fish +tapeworm (p. +297) develop vitamin B12 deciency. +Bile also contains vitamin B12 +that is available for reabsorption in the intestine. +Total body stores of +folate are small and deciency can occur in a matter of weeks. +Vitamin B12 deciency +Vitamin B12 deficiency is treated with hydroxycobalamin. +The reticulocyte count will peak +by the 5th–10th day after starting replacement therapy. +The +haemoglobin will rise by 10 g/L every week until normalised. +If an initial +response is not maintained and the blood lm is dimorphic (i.e. +shows a mixture of microcytic and macrocytic cells), the patient +may need additional iron therapy. +712). +haemolytic anaemias). +There are many causes, as +shown in Figure 23.19. +Anaemia +occurs only if the rate of destruction exceeds this increased +production rate. +Results of investigations that establish the presence of haemolysis +are shown in Box 23.36. +Red cell destruction overloads pathways +for haemoglobin breakdown in the liver (p. +850), causing a +modest rise in unconjugated bilirubin in the blood and mild +jaundice. +860 and 915). +Red cell destruction releases LDH into the serum. +Coeliac disease, small bowel surgery +Increased demand +• Cell proliferation, e.g. +haemolysis +• Pregnancy +Drugs* +23 +• Certain anticonvulsants (e.g. +phenytoin) +• Contraceptive pill +• Certain cytotoxic drugs (e.g. +methotrexate) +*Usually only a problem in patients decient in folate from another cause. +PK +•Hexose monophosphate shunt, +e.g. +G6PD +•Pyrimidine 5´ nucleotidase +Haemoglobin +•Deficiency, e.g. +thalassaemias +•Abnormality, e.g. +SLE, RA +•Drugs, e.g. +L-dopa, methyldopa, mefenamic +acid, penicillin, quinidine, fludarabine +•Lymphoid malignancy, e.g. +CLL, myeloma, +lymphoma +•Other malignancy, e.g. +lung, colon, kidney, +ovary, thymoma +•Others, e.g. +ulcerative colitis, HIV +Primary idiopathic +Secondary +•Infection, e.g. +mycoplasma, +EBV, syphilis +•Lymphoprolifer- +ative disorders, +e.g. +DIC, HUS, TTP +•March +haemoglobinuria +Infection +•Intracellular +organisms, e.g. +malaria +•Toxins, e.g. +C. +perfringens +Chemical/physical +•Oxidative drugs, +e.g. +23.19 Causes and classication of haemolysis. +A Inherited causes. +B Acquired causes. +• Sickle cells suggest sickle-cell disease. +• Red cell fragments indicate microangiopathic haemolysis. +23.19). +The appearances ofAnaemias • 947 +plasma. +In most haemolytic states, haemolysis is predominantly +extravascular. +To conrm the haemolysis, patients’ red cells can be labelled +with 51 chromium. +However, it is seldom +performed in clinical practice. +When intravascular +red cell destruction occurs, free haemoglobin is released into the +plasma. +Free haemoglobin is toxic to cells and binding proteins +have evolved to minimise this risk. +When fulminant, this gives rise to +black urine, as in severe falciparum malaria infection (p. +274). +Causes of haemolytic anaemia +These can be classied as inherited or acquired (Fig. +23.19). +Red cell membrane defects +The structure of the red cell membrane is shown in Figure 23.4. +Each time such cells pass through the spleen, +they lose membrane relative to their cell volume. +The most +common abnormalities are deciencies of beta spectrin or ankyrin +(see Fig. +23.4). +The severity of spontaneous haemolysis varies. +Pigment +gallstones are present in up to 50% of patients and may cause +symptomatic cholecystitis. +• An aplastic crisis occurs in association with parvovirus +(erythrovirus) infection (p. +237). +Patients present with severe anaemia +and a low reticulocyte count. +This may +be all that is required to conrm the diagnosis. +Haemoglobin +levels are variable, depending on the degree of compensation. +The blood lm will show spherocytes but the direct Coombs +test (Fig. +23.20) is negative, excluding immune haemolysis. +Management +Folic acid prophylaxis, 5 mg daily, should be given for life. +Guidelines for the management +of patients after splenectomy are presented in Box 23.37. +935). +1. +Autoimmune haemolytic anaemia +2. +Haemolytic disease of newborn +3. +1. +Antibody screen in pre-transfusion testing +2. +23.20 Direct and indirect antiglobulin tests. +The blood lm is often very abnormal and +immediate differential diagnosis is broad. +alpha spectrin or protein 4.1 (see Fig. +23.4). +Inheritance may be autosomal dominant or recessive. +The antibodies may be IgG or IgM, or more rarely +IgE or IgA. +The majority are IgG and often react against +Rhesus antigens. +• Cold antibodies bind best at 4°C but can bind up to +37°C in some cases. +They are usually IgM and bind +complement. +To be clinically relevant, they must act within +the range of normal body temperatures. +They account for +the other 20% of cases. +No underlying cause is +identied in up to 50% of cases. +The remainder are secondary +to a wide variety of other conditions (see Fig. +23.19B). +Investigations +There is evidence of haemolysis, spherocytes and polychromasia +on the blood lm. +The diagnosis is conrmed by the direct +Coombs or antiglobulin test (see Fig. +23.20). +The direct Coombs test can +be negative in the presence of brisk haemolysis. +The standard +Coombs reagent will miss IgA or IgE antibodies. +Around 10% +of all warm autoimmune haemolytic anaemias are Coombs +test-negative. +homozygous females (p. +48), but it is carried by females. +49). +Over 400 subtypes of G6PD are described. +Clinical features and investigation findings are shown in +Box 23.38. +Acute transfusion +support may be life-saving. +Pyruvate kinase deciency +This is the second most common red cell enzyme defect. +It +results in deciency of ATP production and a chronic haemolytic +anaemia. +It is inherited as an autosomal recessive trait. +Enzyme activity is only +5–20% of normal. +Transfusion support may be necessary during +periods of haemolysis. +These include immunomodulation/suppression +and splenectomy. +Splenectomy is associated with a good response in 50–60% +of cases. +The operation can be performed laparoscopically with +reduced morbidity. +It may cause intravascular haemolysis if complement xation +occurs. +The latter is due +to red cell agglutination in the small vessels in these colder, +exposed areas. +Monoclonal +IgM usually has anti-I or, less often, anti-i specicity. +Treatment +is primarily by transfusion support but may also be directed at +any underlying lymphoma. +Patients must keep extremities warm, +especially in winter. +Some patients respond to glucocorticoid +therapy and rituximab. +All patients should receive +folic acid supplementation. +It has two main causes, occurring after: +• unmatched blood transfusion (p. +933). +• March haemoglobinuria. +• Thermal injury. +• Microangiopathic haemolytic anaemia. +Fibrin deposition in +capillaries can cause severe red cell disruption. +408), +thrombotic thrombocytopenic purpura (p. +979) and +disseminated intravascular coagulation (p. +978). +Infection +Plasmodium falciparum malaria (p. +Clostridium +perfringens sepsis (p. +Arsenic gas, copper, chlorates, nitrites and +nitrobenzene derivatives may all cause haemolysis. +960 and 969). +Standard care now +includes the anti-complement C5 monoclonal antibody eculizimab. +Haemoglobinopathies +haemoglobin. +It +is inherited as an autosomal recessive trait (p. +48). +Epidemiology +The heterozygote frequency is over 20% in tropical Africa (see +Fig. +23.21). +In black American populations, sickle-cell trait +has a frequency of 8%. +Normal +haemoglobin is composed of two alpha and two non-alpha globin +chains. +Thus, disorders +affecting the beta chains do not present until after 6 months of +age. +The geographical distribution of the common haemoglobin- +opathies is shown in Figure 23.21. +The haemoglobinopathies +can be classied into qualitative or quantitative abnormalities. +The +best-known example is haemoglobin S, found in sickle-cell +anaemia. +23.21 The geographical distribution of the haemoglobinopathies. +From Hoffbrand AV, Pettit JE. +Essential haematology, 3rd edn. +23.22 Clinical and laboratory features of sickle-cell disease. +produce characteristic sickle-shaped cells (Fig. +23.22). +The +polymerisation is reversible when re-oxygenation occurs. +Clinical features +Sickling is precipitated by hypoxia, acidosis, dehydration and +infection. +Irreversibly sickled cells have a shortened survival and +plug vessels in the microcirculation. +This results in a number of +acute syndromes, termed ‘crises’, and chronic organ damage +(Fig. +23.22): +• Painful vaso-occlusive crisis. +Plugging of small vessels in +the bone produces acute severe bone pain. +Patients usually have a systemic +response with tachycardia, sweating and a fever. +This is +the most common form of crisis. +• Stroke. +The single most devastating consequence of +sickle-cell disease is stroke. +Stroke or silent stroke occurs +in 10–15% of children with sickle-cell disease. +• Sickle chest syndrome. +• Sequestration crisis. +In children, the spleen is the most common +site. +Massive splenic enlargement may result in severe +anaemia, circulatory collapse and death. +In adults, the liver may +undergo sequestration with severe pain due to capsular +stretching. +Priapism is a complication seen in affected men. +• Aplastic crisis. +A high HbF level inhibits polymerisation of HbS and reduces +sickling. +Patients with sickle-cell disease and high HbF levels +have a mild clinical course with few crises. +937). +The diagnostic features are summarised in Box 23.40. +Intermediate grades of severity occur. +Management and prevention +See Box 23.41. +Cure is now a possibility for selected children, +with allogeneic HSCT (p. +937). +• Vaccination status: should be updated before conception. +• Testing of partner: testing for haemoglobinopathy status is advised. +• Folic acid: should be taken in high dose (5 mg daily) prior to and +throughout pregnancy. +• Hydroxycarbamide: should be discontinued 3 months prior to +conception. +• Angiotensin-converting enzyme (ACE) inhibitors: should be +discontinued prior to conception. +• Pulmonary hypertension: should be excluded prior to conception. +• Aspirin 75 mg: should be given throughout pregnancy. +• Transfusion: extended cross-matched blood for Rhesus and Kell +status should be provided. +Blood should be cytomegalovirus- +negative. +self-limiting red cell aplasia. +This results in profound +anaemia, which may cause heart failure. +Unlike in all other +sickle crises, the reticulocyte count is low. +• Pregnancy. +Pregnancy in sickle-cell disease requires +planning and multidisciplinary management. +The blood lm shows sickle cells, +target cells and features of hyposplenism from a young age. +A reticulocytosis is present. +Both parents of the affected +individual will have sickle-cell trait. +Seasonal vaccination against influenza is also +advised in these patients. +Transfusion should be with fully genotyped +blood wherever possible. +Simple top-up transfusion may be +used in a sequestration or aplastic crisis. +Alpha-thalassaemia +Reduced or absent alpha-chain synthesis is common in South- +east Asia. +• If one is deleted, there is no clinical effect. +• If two are deleted, there may be a mild hypochromic +anaemia. +• If three are deleted, the patient has haemoglobin H +disease. +• If all four are deleted, the baby is stillborn (hydrops fetalis). +Involvement of pluripotent stem cells produces the +most aggressive acute leukaemias. +The course of leukaemia may vary from a few days or +weeks to many years, depending on the type. +Acute leukaemia occurs at all ages. +Acute lymphoblastic leukaemia shows a peak of incidence in +children aged 1–5 years. +When a low haemoglobin does occur, it +is generally due to disease. +• Anaemia can never be considered ‘normal’ in old age. +• Symptoms: may be subtle and insidious. +• Ferritin: if lower than 45 Îźg/L in older people, is highly predictive +of iron deciency. +• Most common cause of iron deciency: gastrointestinal +blood loss. +Adolescent patients may be most appropriately managed in +specialist centres. +Following a myelodysplastic syndrome +Therapy-related myeloid neoplasms +• e.g. +23.2). +Acute leukaemia +There is a failure of cell maturation in acute leukaemia. +Eventually, this proliferation +spills into the blood. +In children, the proportions are reversed, the +lymphoblastic variety being more common. +The clinical features +are usually those of bone marrow failure (anaemia, bleeding or +infection; pp. +923, 927 and 930). +Investigations +Blood examination usually shows anaemia with a normal or raised +MCV. +The leucocyte count may vary from as low as 1 × 109/L +to as high as 500 × 109/L or more. +Chronic leukaemias occur mainly +in middle and old age. +The cause of the leukaemia is unknown in the majority of +patients. +Several risk factors have been identied (Box 23.44). +Severe thrombocytopenia is +usual but not invariable. +A bone marrow examination will conrm the diagnosis. +23.23). +In these patients, supportive treatment can effect considerable +improvement in well-being. +There are three phases: +• Remission induction. +In this phase, a fraction of the +tumour is destroyed by combination chemotherapy. +Quality of life is highly +dependent on achieving remission. +• Remission consolidation. +In poor-prognosis leukaemia, this may include +allogeneic HSCT. +• Remission maintenance. +This may extend for up to 3 years if +relapse does not occur. +Fig. +23.23 Acute myeloid leukaemia. +23.24 Investigation of acute lymphoblastic leukaemia (ALL). +ALL blasts are +positive for both CD19 and CD10 (arrow). +Coagulation abnormalities occur and need accurate diagnosis and +treatment (p. +971). +218). +Parenteral +broad-spectrum antibiotic therapy is essential. +gentamicin) +and a broad-spectrum penicillin (e.g. +piperacillin/tazobactam) or +a single-agent beta-lactam (e.g. +meropenem). +Gram-positive infection +may require vancomycin or teicoplanin therapy. +a liposomal amphotericin B preparation, +voriconazole or caspofungin) is added. +Patients with ALL are susceptible to infection with Pneumocystis +jirovecii (p. +318), which causes a severe pneumonia. +Prophylaxis +with co-trimoxazole is given during chemotherapy. +Diagnosis may +require either induced sputum, bronchoalveolar lavage or open +lung biopsy. +Oral and pharyngeal Candida infection is common. +In systemic Candida infection +intravenous catheters should be removed. +Reactivation of herpes simplex infection (p. +Herpes zoster +manifesting as chickenpox or, after reactivation, as shingles +(p. +The isolation can be psychologically +stressful for the patient. +Renal toxicity +occurs with some antibiotics (e.g. +aminoglycosides) and antifungal +agents (amphotericin). +Thereafter, specic therapy is discontinued and the patient +observed. +The detail of the schedules for these treatments can be found +in specialist texts. +The drugs most commonly employed are listed +in Box 23.47. +Drugs used for this purpose include +hydroxycarbamide and mercaptopurine. +The aim is to reduce +the blast count without inducing bone marrow failure. +The following problems +commonly arise. +Anaemia Anaemia is treated with red cell concentrate transfusions. +Bleeding Thrombocytopenic bleeding requires platelet +transfusions, unless the bleeding is trivial. +This +may lead to renal failure. +Allopurinol and intravenous hydration +are given to try to prevent this. +Occasionally, dialysis may +be required. +Psychological problems Psychological support is a key aspect +of care. +Haematopoietic stem cell transplantation +This is described on page 936. +Prognosis +Without treatment, the median survival of patients with acute +leukaemia is about 5 weeks. +This may be extended to a number +of months with supportive treatment. +Patients who achieve +remission with specic therapy have a better outlook. +However, the relapse rate continues to be high. +Box +23.48 shows the survival in ALL and AML and the influence of +prognostic features. +Advances in treatment have led to steady improvement in +survival from leukaemia. +Maturation of +cells proceeds fairly normally. +The disease occurs chiefly between +the ages of 30 and 80 years, with a peak incidence at 55 years. +It is found in all races. +The break on +chromosome 22 occurs in the breakpoint cluster region (BCR). +1318), influencing cellular +proliferation, differentiation and survival. +• An accelerated phase (not always seen), in which disease +control becomes more difcult. +Prior to imatinib therapy (see below), +approximately 10% of patients per year would transform. +A friction rub may be +heard in cases of splenic infarction. +Hepatomegaly occurs in +about 50%. +Lymphadenopathy is unusual. +There is usually a +normocytic, normochromic anaemia. +The leucocyte count can +vary from 10 to 600 × 109/L. +23.3). +Myeloblasts +usually constitute less than 10% of all white cells. +Blast transformation is characterised by a dramatic +increase in the number of circulating blasts. +Basophilia tends to +increase as the disease progresses. +Blood LDH levels are elevated and the uric acid level +may be high due to increased cell breakdown. +These specically inhibit BCR +ABL tyrosine kinase activity. +The T315I mutation has been particularly +problematic, as this provides wide-ranging resistance. +The +third-generation TKI ponatinib is effective, however. +Allogeneic +HSCT (p. +937) is now reserved for patients who fail TKI therapy. +Hydroxycarbamide and interferon were previously used for +control of disease. +Accelerated phase and blast crisis +Management is more difcult. +When blast transformation occurs, the type of blast cell should be +determined. +The male-to-female +ratio is 2 : 1 and the median age at presentation is 65–70 years. +Clinical features +The onset is usually insidious. +Indeed, in around 70% of patients, +the diagnosis is made incidentally on a routine FBC. +This is known as monoclonal +B lymphocytosis of uncertain signicance. +949). +In those able to +be treated with chemotherapy and rituximab, 90% are alive +4 years later. +Rarely, CLL transforms to an aggressive high-grade +lymphoma, called Richter’s transformation. +The characteristic cell is a large lymphocyte with a prominent +nucleolus. +Treatment is generally unsuccessful and the prognosis +very poor. +Leukapharesis, splenectomy and chemotherapy may +be tried. +Hairy cell leukaemia +This is a rare chronic B-cell lymphoproliferative disorder. +The +male-to-female ratio is 6 : 1 and the median age at diagnosis +is 50 years. +Presenting symptoms are general ill health and +recurrent infections. +Splenomegaly occurs in 90% but lymph +node enlargement is unusual. +As +such, they are pre-leukaemic and represent genetic steps in the +development of leukaemia. +Blast cells may be increased +but do not reach the 20% level that indicates acute leukaemia. +This test +should be performed in all patients prior to the initiation of therapy. +Life expectancy is usually normal in +older patients. +Drugs that can +inhibit this pathway are now available and show great promise. +Bone marrow failure or autoimmune cytopenias may respond +to glucocorticoid treatment. +The majority are of B-cell origin. +The normal architecture of the +lymph node is outlined in Figure 23.25. +23.26). +The epidemiology of HL is shown in Box 23.53 and its +histological WHO classication in Box 23.54. +Nodular lymphocyte-predominant HL is slow-growing, localised +and rarely fatal. +of chromosome 5 or 7. +The WHO classication of MDS is shown +in Box 23.51. +There are five prognostic +groups. +23.25 Schema of lymph node architecture. +B cells are +selected for antigen in the follicle centre. +Fig. +23.26 Hodgkin lymphoma. +Isolated +subdiaphragmatic nodes occur in fewer than 10% at diagnosis. +Hepatosplenomegaly may be present but does not always +indicate disease in those organs. +• FBC may be normal. +If a normochromic, normocytic +anaemia or lymphopenia is present, this is a poor +prognostic factor. +An eosinophilia or a neutrophilia may be +present. +• ESR may be raised. +• Renal function tests are required to ensure function is +normal prior to treatment. +• Liver function may be abnormal in the absence of disease +or may reflect hepatic inltration. +An obstructive pattern +may be caused by nodes at the porta hepatis. +• LDH measurements showing raised levels are an adverse +prognostic factor. +• Chest X-ray may show a mediastinal mass. +• CT scan of chest, abdomen and pelvis permits staging. +Bulky disease (> 10 cm in a single node mass) is an +adverse prognostic feature. +23.27). +23.28). +The nodular +sclerosing type is more common in young patients and in women. +Mixed cellularity is more common in the elderly. +Lymphocyte-rich +HL usually presents in men. +Biopsy +needle +Enlarged +lymph nodes +rate and decades of life ahead of them. +Patients continuing to +smoke after lung irradiation are at particular risk of lung cancer. +The incidence +of infertility and secondary myelodysplasia/AML is low with this +regimen. +Patients with advanced-stage disease are most commonly +managed with chemotherapy alone. +Standard treatment in +the UK is 6–8 cycles of ABVD, followed by an assessment of +response. +937). +Those with resistant disease might benet from an allogeneic +23 +Fig. +23.28 CT-guided percutaneous needle biopsy of retroperitoneal +nodes involved by lymphoma. +The ABVD regimen (doxorubicin, bleomycin, vinblastine and +dacarbazine) is widely used in the UK. +322) +• Specic lymphoma types are associated with viruses: +e.g. +Historically, between 50 and 70% of those with advanced-stage +HL were cured. +The epidemiology of NHL is shown in Box 23.57. +Previous +classications were based principally on histological appearances. +Clinically, the most important factor is grade, +which is a reflection of proliferation rate. +23.29). +Patients present with +lymph node enlargement (Fig. +23.30), which may be associated +with systemic upset: weight loss, sweats, fever and itching. +Hepatosplenomegaly may be present. +Bone marrow involvement +is more common in low-grade (50–60%) than high-grade (10%) +disease. +• Immunophenotyping of surface antigens to distinguish +T-cell from B-cell tumours. +This may be done on blood, +marrow or nodal material.Haematological malignancies • 965 +A +B +Fig. +23.29 Histology of non-Hodgkin lymphoma. +A (Low-grade) +follicular or nodular pattern. +B (High-grade) diffuse pattern. +Fig. +From Howard MR, Hamilton PJ. +Haematology: An illustrated colour text, +4th edn. +Edinburgh: Elsevier Ltd; 2013. +• Immunoglobulin determination. +• Measurement of uric acid levels. +• HIV testing. +HIV is a risk factor for some lymphomas and +affects treatment decisions. +• Hepatitis B and C testing. +This should be done prior to +therapy with rituximab. +target surface antigens on tumour cells and to induce +tumour cell apoptosis directly. +As yet, however, rituximab maintenance has not shown a +survival benet. +New and more potent monoclonal +antibodies are also in development and trials of +obinutuzumab (p. +960) have been completed. +• Kinase inhibitors. +Idelalisib is approved for relapsed follicular +lymphoma and ibrutinib (p. +• Transplantation. +Asymptomatic patients may not require therapy and are +managed by ‘watching and waiting’. +In follicular lymphoma, the options are: +• Radiotherapy. +This can be used for localised stage I +disease, which is rare. +• Chemotherapy. +• Monoclonal antibody therapy. +Humanised monoclonal +antibodies (‘biological therapy’; p. +• Monoclonal antibody therapy. +• Radiotherapy. +• HSCT. +Autologous HSCT (p. +937) benets patients with +relapsed disease that is sensitive to salvage +immunochemotherapy. +As with HL, achieving PET +negativity prior to autologous transplantation is desirable. +Transformation to +a high-grade NHL occurs in 3% per annum and is associated +with poor survival. +around 1% per annum). +There is no certain way of predicting progression in an individual +patient. +Patients with an abnormal ratio should be monitored +for progression on an annual basis. +It is a rare tumour occurring in the elderly and more +commonly affects males. +A high proportion of patients +have a mutation in the MYD88 gene. +Fludarabine may be more effective in this +disease but has more side-effects. +Rituximab alone +can cause a rapid release of IgM and increase in viscosity. +The +median survival is 5 years. +Multiple myeloma +This is a malignant proliferation of plasma cells. +68). +In addition, they may be +present with no underlying disease. +Gammopathies are detected +by plasma immunoelectrophoresis. +23.31 Clinical and laboratory features of multiple myeloma. +The clinical features are demonstrated in Figure 23.31. +Bone marrow aspiration, plasma and urine electrophoresis, +and a skeletal survey are thus required. +Normal immunoglobulin +levels, i.e. +the absence of immunoparesis, should cast doubt +on the diagnosis. +Management +If patients are asymptomatic with no evidence of end-organ +damage (e.g. +to kidneys, bone marrow or bone), treatment may +not be required. +So-called asymptomatic myeloma should be +monitored closely for the development of end-organ damage. +Immediate support +• High fluid intake to treat renal impairment and +hypercalcaemia (p. +661). +• Analgesia for bone pain. +The +frequency of different isotypes of monoclonal protein in myeloma +is shown in Box 23.58. +The resulting +lytic lesions cause bone pain, fractures and hypercalcaemia. +Marrow involvement can result in anaemia or pancytopenia. +1047). +• Allopurinol to prevent urate nephropathy. +• Plasmapheresis, if necessary, for hyperviscosity. +Treatment is administered until +paraprotein levels have stopped falling. +This is termed ‘plateau +phase’ and can last for weeks or years. +When myeloma progresses, treatment is given to induce +a further plateau phase. +Responding patients may benet from a +second autologous HSCT. +Bisphosphonates +Long-term bisphosphonate therapy reduces bone pain and +skeletal events. +These drugs protect bone (p. +1047) and may +cause apoptosis of malignant plasma cells. +Increasingly, cytogenetic +analysis is used to identify poor-risk patients, e.g. +t(4;14), +del(17/17p), t(14;16), t(14;20), non-hyperdiploidy and gain(1q). +Use of autologous HSCT and advances in drug therapy with the +newer agents have increased survival. +The outlook may improve further with new drugs +and combinations of treatments. +The disease is +much more common in certain other parts of the world, e.g. +east Asia. +An FBC demonstrates pancytopenia, low reticulocytes and +often macrocytosis. +Bone marrow aspiration and trephine +reveal hypocellularity. +The severity of aplastic anaemia is graded +according to the Camitta criteria (Box 23.60). +• Chemotherapy: may be less well tolerated. +• Cure rates: similar to those in younger patients, in those who do +tolerate treatment. +937). +Older patients (35–50) may be candidates if they +have no comorbidities (p. +937). +Unrelated donor allografts are considered for suitable patients +who fail IST. +The thrombopoietin receptor agonist eltrombopag +(p. +950), +myelodysplastic syndrome (p. +960) and AML (p. +955). +Patients +with aplastic anaemia must be followed up long-term. +Secondary aplastic anaemia +Causes of this condition are listed in Box 23.61. +It is not practical +to list all the drugs that have been suspected of causing aplasia. +It is important to check the reported side-effects of all drugs taken +over the preceding months. +Frequently, this is an incidental nding, with no +ill health. +It probably has an immune basis but this is difcult +to prove. +PRV to myelobrosis. +Less +commonly, mutations can be detected in the thrombopoietin +receptor gene MPL. +As the disease +progresses, the marrow becomes brosed. +Most patients present over the age of 50 years, with lassitude, +weight loss and night sweats. +Urate levels may be high due +to increased cell breakdown, and folate deciency is common. +The presence of a JAK-2 mutation +supports the diagnosis. +Treatment is directed at control of symptoms, +e.g. +red cell transfusions for anaemia. +Folic acid should be given +to prevent deciency. +HSCT may be considered +for younger patients. +The presence of a JAK-2, CALR or, rarely, MPL mutation +supports the diagnosis but is not universal. +Agents include oral +hydroxycarbamide or anagrelide, an inhibitor of megakaryocyte +maturation. +Some patients present with manifestations of peripheral +arterial or cerebrovascular disease. +Venous thromboembolism may +also occur. +Peptic ulceration is common, sometimes complicated +by bleeding. +Patients are often plethoric and many have a +palpable spleen at diagnosis. +Investigation of polycythaemia is discussed on page 925. +Management and prognosis +Aspirin reduces the risk of thrombosis. +Venesection gives prompt +relief of hyperviscosity symptoms. +Median survival after diagnosis in treated patients exceeds +10 years. +23.6A, p. +918; +also known as ‘primary haemostasis’) may fail in thrombocytopenia +(p. +929), von Willebrand disease (p. +974), and also in platelet +function disorders and diseases affecting the vessel wall. +1040) or scurvy. +These predispose to paradoxical embolism, +resulting in stroke or cerebral abscess. +Local cautery or laser therapy +may prevent single lesions from bleeding. +A variety of medical +therapies have been tried but none has been found to be +universally effective. +Classical +joint hypermobility (p. +The key to diagnosis is the dietary history (p. +715). +Platelet function disorders +Bleeding may result from thrombocytopenia (see Box 23.14, +p. +929) or from congenital or acquired abnormalities of platelet +function. +938). +Inherited platelet +function abnormalities are relatively rare. +Congenital abnormalities +may be due to deficiency of the membrane glycoproteins, +e.g. +a deciency of dense (delta) granules (see Fig. +23.7, p. +920) giving rise to storage pool disorders. +RUNX-1-associated thrombocytopenia). +phagocytosis of sensitised platelets by reticulo-endothelial cells. +The condition may become chronic, with remissions and +relapses. +Relapses should be treated by re-introducing +glucocorticoids. +If a patient has two relapses or primary +refractory disease, second-line therapies are considered. +Where splenectomy +is considered, the precautions shown in Box 23.40 need to +be in place. +The TPO-RAs induce response in around 75% +of cases, usually within 10–14 days. +Coagulation disorders +Normal coagulation is explained in Figure 23.6 (p. +918). +Von Willebrand disease is the most +common inherited bleeding disorder. +Acquired disorders may be due to under-production (e.g. +in liver failure), increased consumption (e.g. +acquired haemophilia A). +Haemophilia A +Factor VIII deciency resulting in haemophilia A affects 1/10 000 +individuals. +It is the most common congenital coagulation factor +deciency. +It is +protected from proteolysis in the circulation by binding to von +Willebrand factor (vWF). +Genetics +The factor VIII gene is located on the X chromosome. +As the factor VIII gene +is on the X chromosome, haemophilia A is a sex-linked disorder +(p. +48). +Antenatal +diagnosis by chorionic villous sampling is possible in families with a +known mutation. +Thrombocytopenia +Thrombocytopenia occurs in many disease processes, as listed +in Box 23.14 (p. +929), many of which are discussed elsewhere +in this chapter. +The clinical presentation and pathogenesis +are similar, however, whatever the cause of ITP. +Clinical features and investigations +The presentation depends on the degree of thrombocytopenia. +Spontaneous bleeding typically occurs only when the platelet +count is below 20 × 109/L. +At higher counts, the patient may +complain of easy bruising or sometimes epistaxis or menorrhagia. +Many cases with counts of more than 50 × 109/L are discovered +by chance. +In adults, ITP more commonly affects females and may have +an insidious onset. +Unlike ITP in children, it is unusual for there to +be a history of a preceding viral infection. +Retroperitoneal and intracranial +bleeding is also a feature. +The major morbidity of recurrent bleeding in severe haemophilia +is musculoskeletal. +Bleeding is typically into large joints, especially +knees, elbows, ankles and hips. +Muscle haematomas are also +characteristic, most commonly in the calf and psoas muscles. +23.32). +Complications of muscle haematomas depend on their location. +Management +The key to the management of severe haemophilia A (and B; +p. +974) in more affluent countries is prophylactic coagulation factor +replacement. +49). +23.32 Clinical manifestations of haemophilia. +(HCV = +hepatitis C virus) Inset (Massive bruising) From Hoffbrand VA. +Color atlas of clinical hematology, 3rd edn. +Philadelphia: Mosby, Elsevier Inc.; 2000. +of pooled blood products should be offered hepatitis A and B +immunisation. +The vasopressin receptor agonist desmopressin (p. +Alternatively, the same effect can be achieved +by intranasal administration of 300 Îźg. +23 +Management is described in Chapters 22 and 12. +Concern that the infectious agent that causes vCJD (p. +931), and in +one recipient of factor VIII. +Such antibodies rapidly +neutralise therapeutic infusions, making treatment relatively +ineffective. +Infusions of activated clotting factors, e.g. +VIIa or +factor VIII inhibitor bypass activity (FEIBA), may stop bleeding. +This disorder is clinically +indistinguishable from haemophilia A but is less common. +23.7, +p. +920). +vWF also forms bridges between platelets and +subendothelial components (e.g. +collagen; see Fig. +23.6B, p. +This needs to be borne in mind when making a diagnosis +of von Willebrand disease. +Patients with type 2 disorders inherit vWF +molecules that are functionally abnormal. +The patterns of laboratory abnormality +accompanying these types are described in Box 23.64. +Supercial +bruising, epistaxis, menorrhagia and gastrointestinal haemorrhage +are common. +Investigations +The disorder is characterised by reduced activity of vWF and +factor VIII. +In addition, analysis for mutations in the vWF +gene is informative in most cases. +Tranexamic +acid may be useful in mucosal bleeding. +Bleeding in +type 3 patients responds only to factor VIII/vWF concentrate. +They are rare but are associated with severe +bleeding. +Typical features include haemorrhage from the umbilical +stump and intracranial haemorrhage. +Factor XIII deciency in +women is typically associated with recurrent fetal loss. +Factor XI deciency may occur in heterozygous or homozygous +individuals. +Bleeding is very variable and is not accurately predicted +by coagulation factor levels. +In general, severe bleeding is conned +to patients with levels below 15% of normal. +In severe parenchymal liver disease, bleeding may arise +from many different causes. +Clearance +of plasminogen activator is reduced. +Thrombocytopenia may +occur secondary to hypersplenism in portal hypertension. +Vitamin K deciency can be +readily corrected with parenteral administration of vitamin K. +Treatment is by dialysis +to reduce the urea concentration. +This can be achieved in several ways. +One option is to use LMWH +followed by a coumarin anticoagulant, such as warfarin. +Treatment +of acute VTE with LMWH should continue for a minimum of +5 days. +Patients treated with warfarin should achieve a target INR +of 2.5 (range 2–3; pp. +922 and 938) with LMWH continuing until +the INR is above 2. +Alternatively, patients may be treated with +a DOAC. +619). +The optimal initial period of anticoagulation is between +6 weeks and 6 months. +186) and/or +pulmonary embolism (PE; see also p. +1128) and intra-abdominal venous thrombosis (e.g. +Budd– +Chiari syndrome; p. +898). +VTE has an annual incidence of approximately 1 : 1000 +in Western populations. +The relative incidence of DVT:PE is +approximately 2 : 1. +Mortality 30 days after DVT is approximately +10%, compared to 15% for PE. +Figure 23.33 +illustrates some of the causes and consequences of VTE. +23.33 Causes and consequences of venous thromboembolic disease and its treatment. +This plateaus at around +30–40% recurrence at 5 years. +Several factors predict risk of recurrence following +an episode of unprovoked VTE. +Thrombolysis for PE is discussed on +page 621. +Post-thrombotic syndrome is due to damage of +venous valves by the thrombus. +The most +severe complication of this syndrome is ulceration around the +medial malleolus (Fig. +23.33). +Both medical and surgical patients are at +increased risk. +A summary of the risk categories is given in Box +23.66. +ThereThrombotic disorders • 977 +anticoagulation, as discussed on page 975. +Patients who +are deemed to be at high risk of thrombosis, e.g. +Heparins and fondaparinux achieve their therapeutic effect +by potentiating the activity of AT. +23.6F, p. +919). +• There is little evidence that detection of these +abnormalities predicts recurrence of VTE. +• None of these conditions per se requires treatment with +anticoagulants. +solid tumours and leukaemias +• Tissue destruction, e.g. +pancreatitis, burns +• Vascular abnormalities, e.g. +vascular aneurysms, liver +haemangiomas +• Toxic/immunological, e.g. +• Thrombosis: incidence of thromboembolic disease rises with +increasing age. +Life-threatening or +fatal bleeds on warfarin are signicantly more common in those +over 80 years. +response, or by the release of procoagulant substances such +as tissue factor. +Investigations +DIC should be suspected when any of the conditions listed in Box +23.68 are met. +Measurement of coagulation times (APTT and PT; +p. +Management +Therapy is primarily aimed at the underlying cause. +Prophylactic doses of heparin should +be given, unless there is a clear contraindication. +Patients +with DIC should not, in general, be treated with antibrinolytic +therapy, e.g. +tranexamic acid. +Thrombotic thrombocytopenic purpura +Like DIC and also heparin-induced thrombocytopenia (p. +263) and malignancy. +It should +be treated by emergency plasma exchange. +Glucocorticoids, +aspirin and rituximab also have a role in management. +cibmtr.org International Bone Marrow Transplant Registry. +ukhcdo.org UK Haemophilia Centre Doctors’ Organisation. +Make another +mark in midline 10 cm +above first. +Ask patient +to bend forwards. +In the UK, about 25% of new consultations in general +practice are for musculoskeletal symptoms. +The +principal manifestations are pain and impairment of locomotor +function. +The main components of +the musculoskeletal system are depicted in Figure 24.1. +At the end of puberty, the +increased levels of sex hormones halt cell division in the growth +plate. +The cartilage remnant then disappears as the epiphysis +fuses and longitudinal bone growth ceases. +Two types of bone tissue are present in the normal skeleton +(Fig. +24.1). +Cortical bone is dense +and forms a hard envelope around the long bones. +Bone +Bones fall into two main types, based on their embryonic develop- +ment. +914). +When bone is broken down +by osteoclasts, the cross-links are released into the circulation. +24.2 The bone remodelling cycle. +Bone is renewed and repaired +by the process of bone remodelling. +This begins by removal of old and +damaged bone by osteoclasts during the phase of bone resorption. +The acid dissolves the mineral and cathepsin +K degrades collagen. +Osteocytes also produce sclerostin (SOST), +which is a potent inhibitor of bone formation. +Key regulators of bone remodelling are summarised +in Box 24.1. +Osteoblasts, which are derived from bone marrow stromal cells, are responsible for bone formation. +They +are found where a wide range of movement is needed (Fig. +24.4). +Articular cartilage +This avascular tissue covers the bone ends in synovial joints. +24.5). +The +most abundant GAGs in aggrecan are chondroitin sulphate and +keratan sulphate. +These changes differ from those found in osteoarthritis +(p. +It is an ultraltrate of plasma, into which synovial cells secrete +hyaluronan and proteoglycans. +The most clinically important are the +menisci of the knee. +Ligaments are discrete, +regional thickenings of the capsule that act to stabilise joints (see +Fig. +24.4). +Bursae are hollow sacs lined with synovium and contain a small +amount of SF. +They help tendons and muscles move smoothly +in relation to bones and other articular structures. +Skeletal muscle +Skeletal muscles are responsible for body movements and +respiration. +The molecular mechanisms of skeletal +muscle contraction are the same as for cardiac muscle (p. +446). +24.4 Structure of a synovial joint. +24.5 Ultrastructure of articular cartilage.988 • RHEUMATOLOGY AND BONE DISEASE +perimysium). +24.6B). +It contains few cells. +High concentrations +of urate crystals or cholesterol can make SF appear white. +Non-uniform blood-staining usually reflects needle trauma to +the synovium. +1059) but can occur in severe inflammatory synovitis. +24.6A). +24.21, p. +1010). +24.40, p. +1030). +In tophaceous +gout, well-dened punched-out erosions may occur (see Fig. +24.27, p. +1015). +24.28, +p. +It involves +A B +Fig. +24.6 Compensated polarised light microscopy of synovial fluids +(× 400). +Looser’s zones) +• Complex regional pain syndrome (p. +1055) +• Sclerosing bone disorders (e.g. +hypertrophic pulmonary +osteoarthropathy; p. +24.7). +24.8). +Fig. +24.7 Magnetic resonance image showing joint synovitis. +Courtesy of Dr I. +Beggs. +24 +Fig. +24.8 Ultrasound image showing synovitis. +Lateral image of a +metacarpophalangeal joint in inflammatory arthritis. +The periosteum (P) of +the phalanx shows as a white line. +The dark, hypo-echoic area indicates +an effusion. +The coloured areas demonstrated by power Doppler indicate +increased vascularity. +The inset shows a transverse image of the same +joint. +Courtesy of Dr N. +McKay. +Measurements at lumbar +spine, hip and sometimes forearm are obtained. +24.9). +Radiographic correlation is then advisable. +948) and the dilute Russell viper venom test (a functional +assay for a lupus anticoagulant; p. +978). +24.9 Typical output from a dual X-ray absorptiometry (DXA) +scan. +A Image from hip DXA scan. +ANAs are not associated with disease severity or +activity. +ANA has high sensitivity for SLE (100%) but +low specicity (10–40%). +A negative ANA virtually excludes SLE +but a positive result does not conrm it. +Anti-DNA antibodies are routinely tested by +enzyme-linked immunosorbent assay (ELISA; see also p. +1036). +interpretation of CRP and ESR changes is given on page 72. +Immunology +Autoantibody tests are widely used in the diagnosis of rheumatic +diseases. +Although the +specicity is poor, about 70% of patients with RA test positive. +High RF titres are associated with more severe disease and +extra-articular disease. +Muscle biopsy plays an important role in the investigation of +myopathy and inflammatory myositis. +Since myositis can be patchy in nature, +MRI is sometimes used to localise the best site for biopsy. +Repeat biopsies are sometimes used to monitor the +response to treatment. +Electromyography +Electromyography (p. +977). +4.4, p. +66). +Low C4 is less specic for SLE activity. +1026). +Other potential causes are shown in +Box 24.11. +Pigmented villonodular synovitis (p. +1059) also +presents with synovial swelling and a large effusion, although the +onset is gradual. +Investigations +Aspiration of the affected joint is mandatory. +If sepsis is suspected +in a large joint, arthroscopic washout is advisable. +Blood cultures should also be taken in patients +suspected of having septic arthritis. +Ruling out primary hyperparathyroidism +is essential if there is pseudogout. +Management +If there is any suspicion of sepsis, intravenous antibiotics (see Box +24.50, p. +1020) should be given promptly, pending the results +of cultures. +Otherwise, management should +be directed towards the underlying cause. +The possible causes are listed +in Box 24.12. +The most important diagnoses +to consider are PsA, RA and inflammatory small joint OA. +PsA is strongly +associated with enthesitis. +Viral arthritis (p. +1020), Poncet’s +disease (in regions where tuberculosis is highly prevalent; +p. +588), polyarticular JIA (in children) and post-streptococcal +arthritis should also be considered. +The pattern of involvement can be helpful in reaching a +diagnosis (Fig. +24.10). +Inflammatory OA can appear similar to small-joint PsA in the +pattern of joint involvement. +In PsA there may be nail pitting or +early onycholysis. +Psoriasis may not be present. +1035). +24994 • RHEUMATOLOGY AND BONE DISEASE +AB C D +Fig. +24.10 Patterns of joint involvement in different forms of polyarthritis. +Sacroiliitis (often +asymmetrical) may occur. +An early accurate and specic diagnosis +is very important. +1059). +Myeloma (p. +If these results are positive, a radiological skeletal +survey should be obtained. +In Paget’s disease, ALP may be elevated but can +be normal in localised disease. +Laboratory investigations are normal in patients with FM alone +and in hEDS. +Management +Management should be directed towards the underlying cause. +In Western countries, back pain is the most +common cause of sickness-related work absence. +In the UK, 7% +of adults consult their GP each year with back pain. +Globally, low +back pain is thought to affect about 9% of the population. +The +most important causes are summarised in Box 24.17. +Mechanical back +pain is the most common cause of acute back pain in people +aged 20–55. +It +is exacerbated by activity and is generally relieved by rest (Box +24.18). +This can be achieved either by the +use of an external cast or splint, or by internal xation. +1046). +Options for management of painful vertebral fracture +are discussed on page 1002. +Fibromyalgia (FM) syndrome (p. +1018) presents with +generalised pain that particularly affects the trunk, back and neck. +Accompanying features include fatigue, poor concentration and +focal areas of hyperalgesia. +Widespread pain may also occur +24996 • RHEUMATOLOGY AND BONE DISEASE +is generally good. +After 2 days, 30% are better and 90% have +recovered by 6 weeks. +Back pain secondary to serious spinal pathology has different +characteristics (Box 24.19). +Degenerative disc disease is a common cause of chronic low +back pain in middle-aged adults. +Examination may reveal a positive sciatic or femoral stretch +test. +About 70% of patients improve by 4 weeks. +It is associated with morning stiffness and improves with +movement. +Spondylolisthesis (p. +1059) +• Scheuermann’s disease +(p. +The causes are +shown in Box 24.21. +is typically aggravated by standing and walking. +Occasionally, +diffuse idiopathic skeletal hyperostosis (DISH; p. +1058) can cause +back pain but it is usually asymptomatic. +Arachnoiditis is a rare +cause of chronic severe low back pain. +Investigations +Investigations are not required in patients with acute mechanical +back pain. +If metastatic disease is suspected, bone scintigraphy +should be considered. +Management +Education is important in patients with mechanical back pain. +Regular +analgesia and/or NSAIDs may be required to improve mobility +and facilitate exercise. +Return to work and normal activity should +take place as soon as possible. +Bed rest is not helpful and may +increase the risk of chronic disability. +Low-dose tricyclic antidepressant drugs +may help pain, sleep and mood. +Varying pain patterns associated with common lesions +are shown in Figure 24.12. +Pain and tenderness are well localised to the tendon +lesions. +There is often early-morning ‘claw-like’ digit +stiffness. +This test is not specic +for this lesion alone. +• Raynaud’s phenomenon: digital vasospasm triggered +mostly by cold (p. +1035). +• C6, C7 or C8 radiculopathy. +24.13). +Patients who report ‘hip pain’ sometimes point to greater +trochanter or buttock areas. +Pain at this site may also be referred from the lumbosacral +spine. +Referred pain from the hip may present at the knee and +is reproduced by hip, not knee, movement. +Pain from periarticular +lesions is well localised to the involved structure (Box 24.25). +24.12 Pain patterns around the shoulder. +The dark shading +indicates sites of maximum pain. +less good in older people. +Adhesive capsulitis is commonly associated +with diabetes mellitus and neck/radicular lesions. +Complete recovery sometimes takes up to +2 years. +Management +is by rest, analgesics and topical or systemic NSAIDs. +Local +glucocorticoid injections may be required in resistant cases. +24.13 Pain patterns of hip disease and trochanteric pain +syndrome. +The dark shading indicates sites of maximum pain. +24 +a manifestation of enthesitis. +Pain affecting the back of the heel +may be due to Achilles tendinitis or enthesitis. +The MTP joints +of the feet are commonly involved symmetrically in RA. +Patients with +active inflammation of the MTP joints have pain when the forefoot +is squeezed (p. +982). +The hallux also a classical target in acute gout. +Women are most commonly affected (tight shoes can be to +blame). +Local sensory loss and a palpable tender swelling between +the metatarsal heads may be detected. +from overuse and/or an SpA condition. +Pain from the subtalar joint (from the same lesions) is also worse +on weight-bearing. +These diagnoses can be associated with hindfoot +tenosynovitis (peroneal or posterior tibial). +Pain under the heel is +typically due to plantar fasciitis. +The former +is a non-specic manifestation of many systemic conditions. +The causes are shown in Box 24.26. +370). +A strong family history +and onset in childhood or early adulthood suggest muscular +dystrophy (p. +1143). +Alcohol excess can cause an inflammatory +myositis and atrophy of type 2 muscle bres. +Polymyositis +and dermatomyositis (p. +1039) are associated with coexisting/ +co-presenting malignancy, especially gonadal tumours. +Clinical +examination should document the presence, pattern and severity of +muscle weakness (p. +1081), assessed using the Medical Research +Council (MRC) scale (no power (0) to full power (5)). +These aims are interrelated and success in one area often +benefits others. +Successful management requires careful +assessment of the person as a whole. +The simplest and safest interventions should be tried rst. +The mechanisms are unclear but in part +may result from improved adherence. +Benets are modest but +potentially long-lasting, safe and cost-effective. +1049) +• Hypercalcaemia +Genetic +• Muscular dystrophy (various; p. +Various +manipulative techniques may also help improve restricted +movement. +The combination of these with education and therapist +contact enhances their benets. +Prolonged rest must be avoided, however. +Orthoses are more permanent appliances used to reduce instability +and excessive abnormal movement. +These may then +be addressed by changes in attitude and behaviour, as shown +in Box 24.28. +Involvement of the spouse or partner in mutual goal-setting +can improve partnership adjustment. +700). +Patients should therefore be advised to maintain BMI within +the 20–25 g/m2 range. +The main aims of surgery are to provide pain relief and improve +function and quality of life. +It is well tolerated +and has few adverse effects and drug interactions. +Paracetamol can be combined with codeine (co-codamol) or +dihydrocodeine (co-dydramol). +24.14). +24.14 Mechanism of action of non-steroidal anti-inflammatory +drugs. +Inflammation also up-regulates COX-2 in the spinal cord, where +it modulates pain perception. +Interstitial nephritis, asthma and +anaphylaxis can also occur but are rare. +Recommendations for +NSAID prescribing are summarised in Box 24.32. +They may +be used as monotherapy or as an adjunct to oral analgesics. +The most common +indications are summarised in Box 24.34. +Monitoring +requirements for commonly used DMARDs are also summarised +in Box 24.34. +If toxicity occurs, treatment may need to be +stopped temporarily and resumed at a lower dose. +If toxicity +is severe, therapy may have to be withdrawn completely and +another drug substituted. +Methotrexate +Methotrexate (MTX) is the core DMARD in RA, JIA and +PsA. +If pneumonitis occurs, treatment should be withdrawn +and high-dose glucocorticoids given. +Sulfasalazine +Sulfasalazine (SSZ) can be used alone and or combination with +MTX and another DMARD. +Its mechanism of action is incompletely +understood. +Elderly patients +are more likely to die if they suffer NSAID-associated bleeding or +perforation. +• Cardiovascular disease: use NSAIDs with caution in patients with +cardiovascular disease. +Therapy with NSAIDs may exacerbate +hypertension and heart failure. +• Renal disease: use of NSAIDs may cause renal impairment. +Orange staining of urine and contact lenses may occur. +Its mechanism of action +is incompletely understood. +A wide range of side-effects can +potentially occur but HCQ is usually well tolerated in practice. +It has low +marrow toxicity but may cause liver dysfunction, hypertension and +hirsutism. +It must be co-prescribed with robust contraception in +women of child-bearing potential. +Treatment must be stopped +for a period of 2 years in advance of planning a pregnancy. +Azathioprine +Azathioprine is most commonly used in vasculitis and SLE. +Bone marrow suppression is the most important side-effect but +nausea may also occur. +Apremilast +Apremilast is used in the treatment of PsA. +Apremilast is given orally in a dose of 30 mg twice +daily. +It is +mainly used to induce remission in life-threatening systemic +vasculitis and SLE. +MMF is +frequently used in SLE and vasculitis in doses of 2–4 g daily +orally. +Haematological toxicity is the main adverse effect. +Gold (sodium aurothiomalate, myocrisin) is indicated for RA. +Its +mechanism of action is unknown. +It is given by intramuscular +injection of 50 mg weekly after an initial test dose of 10 mg. +Penicillamine is indicated for RA +but is poorly tolerated. +Ciclosporin A is a +calcineurin inhibitor that inhibits lymphocyte activation. +It is +occasionally used in RA at a dose of 2.5–4 mg/kg/day orally. +Glucocorticoids +Glucocorticoids have powerful anti-inflammatory and +immunosuppressive effects. +1026). +Methylprednisolone +is one of the most widely used, typically in doses of 40–80 mg. +24.15). +Their mechanisms of action, dosages and indications +are summarised in Box 24.35. +Anti-TNF therapy +A variety of inhibitors of the pro-inflammatory cytokine TNF have +been developed. +They are usually given as monotherapy +in AxSpA unless there is peripheral joint involvement. +In ANCA-positive +vasculitis, a single cycle of treatment may last for up to 18 months. +Rituximab is sometimes used off-label in SLE, even though +clinical trials did not show efcacy. +1123), a serious and potentially fatal infection of the +CNS caused by reactivation of JC virus. +Belimumab +Belimumab is indicated in SLE. +24.15 Targets for biologic therapies in +inflammatory rheumatic diseases. +See page 64 for more details. +Ustekinumab +Ustekinumab is an antibody to the p40 protein, which is a +subunit of IL-23 and IL-12. +Secukinumab +Secukinumab is a monoclonal antibody to IL-17A. +Adverse +effects include an increased risk of infections, nasopharyngitis +and headache. +Anakinra +Anakinra is a decoy receptor for IL-1. +It is occasionally used +in RA but is less effective than other biological drugs. +A more +frequent indication is for the treatment of adult-onset Still’s +disease (p. +1040) and in cryopirin-associated periodic syndromes +(p. +81). +It is a monoclonal +antibody directed against the pro-inflammatory cytokine IL-1β. +The usual maintenance dose in adults is 150–300 mg SC every +8 weeks. +Genetic factors are recognised as +playing a key role in the pathogenesis of OA. +69). +The main adverse effect is an increased risk of infections. +Tocilizumab +Tocilizumab is a monoclonal antibody to the IL-6 receptor. +There is a +strong association between obesity and OA, particularly of the +hip. +Degeneration of articular cartilage is the dening feature of +OA. +24.16A). +24.5, p. +987). +24.16B), localised chondrocyte +death and decreased cartilage thickness. +24.16C). +Bone +Fig. +24.16 Pathological changes in osteoarthritis. +B Fibrillation of cartilage in OA. +24.10). +The main presenting symptoms are pain and +functional restriction. +Pain may also +result from bursitis and enthesopathy secondary to altered joint +mechanics. +Typical OA pain has the characteristics listed in Box +24.37. +24.17 Nodal osteoarthritis. +It is stronger at the hip than +at the knee, and poor at most small joints. +Generalised nodal OA +Characteristics of this common form of OA are shown in Box +24.38. +24.17). +Once OA +is fully established, symptoms may subside and hand function +often remains good. +24.18). +24.18 X-ray appearances in hand osteoarthritis. +24 +impairment. +People with nodal OA are also at +increased risk of OA at other sites, especially the knee. +24.19). +It may be isolated or occur +as part of generalised nodal OA. +Most patients have bilateral +and symmetrical involvement. +In men, trauma is often a more +important risk factor and may result in unilateral OA. +The pain is usually localised to the anterior or medial aspect +of the knee and upper tibia. +Patello-femoral pain is usually +worse going up and down stairs or inclines. +Posterior knee pain +suggests the presence of a complicating popliteal cyst (Baker’s +cyst). +CPPD crystal deposition in association with OA is common +at the knee. +1016), which may be associated +with more rapid radiographic and clinical progression. +Hip OA +Hip OA most commonly targets the superior aspect of the +joint (Fig. +24.21). +It is often bilateral at presentation and can be associated +with generalised nodal OA. +The hip shows the best correlation between symptoms and +radiographic change. +Obesity is associated with more rapid progression of hip OA. +B +Fig. +24.19 X-ray appearances in knee osteoarthritis. +There is almost complete loss of joint space and lateral displacement of +the patella. +C +N S +O +O +Fig. +24.20 Typical varus knee deformity resulting from marked +medial tibio-femoral osteoarthritis. +a car, or bending to put on shoes and socks may be difcult. +24.21 X-ray of hip showing changes of osteoarthritis. +It +is unclear whether erosive OA is part of the spectrum of hand +OA or a discrete subset. +Non-weight-bearing postero-anterior views of the pelvis are +adequate for assessing hip OA. +If nerve root compression or spinal +stenosis is suspected, MRI should be performed. +Synovial fluid aspirated from an affected +joint is viscous with a low cell count. +895), or +disorganised architecture in neuropathic joints. +Management +Treatment follows the principles outlined on pages 1000–1007. +Measures that are pertinent in older people are summarised in +Box 24.40. +24.22 X-ray of spine showing typical changes of osteoarthritis. +24.22). +Spine OA may occur in +isolation or as part of generalised OA. +The pain is typically relieved +by rest and worse on movement. +Early-onset OA +Unusually, typical symptoms and signs of OA may present before +the age of 45. +In most cases, a single joint is affected and there +is a clear history of previous trauma. +There is +no age limit for joint replacement surgery. +1026) +• Metabolic or endocrine disease: +Haemochromatosis (p. +895) +Ochronosis +Acromegaly (p. +Quadriceps strengthening exercises are particularly +benecial in knee OA. +Local +physical therapies, such as heat or cold, can sometimes give +temporary relief. +Addition of a topical NSAID, and +then capsaicin, for knee and hand OA can also be helpful. +Oral NSAIDs should be considered in patients who remain +symptomatic. +Strong opiates +may occasionally be required. +In the +UK they have not been considered to be cost-effective by NICE. +Total joint replacement surgery is by far the most common +surgical procedure for patients with OA. +Other surgical +procedures are performed much less frequently. +Several +factors influence crystal formation (Fig. +24.23). +Gout +Gout is the most common inflammatory arthritis in men and in +older women. +It is caused by deposition of monosodium urate +monohydrate crystals in and around synovial joints. +730), of which hyperuricaemia is an integral component. +The risk of developing gout increases with age and with serum +uric acid (SUA) levels. +24.23 Mechanisms of crystal formation. +Fig. +24.24 Uric acid metabolism. +population. +SUA levels are higher in men, increase with age and +are positively associated with body weight. +Levels are higher +in some ethnic groups (such as Maoris and Pacic islanders). +24.24). +The causes of hyperuricaemia are shown in Box 24.42. +Lead poisoning may +cause gout (saturnine gout). +Some patients develop gout because they over-produce +uric acid. +This is seldom +connected with gout but can be associated with acute kidney +injury (p. +411). +24.25). +Other common sites are the ankle, midfoot, knee, small joints +of hands, wrist and elbow. +The axial skeleton and large proximal +joints are rarely involved. +During the attack, the joint shows signs of marked synovitis, +swelling and erythema. +As the attack subsides, pruritus and desquamation +of overlying skin are common. +The main differential diagnosis is +septic arthritis, infective cellulitis or reactive arthritis. +Many patients describe +milder episodes lasting just a few days. +Some have attacks in +more than one joint. +Simultaneous polyarticular attacks are unusual. +Some people never have a second episode and in others +several years may elapse before the next one. +Tophi have a white colour (Fig. +24.26), differentiating them from +rheumatoid nodules. +This is particularly common in patients with chronic tophaceous +gout who are on diuretic therapy. +24.6A, p. +988). +Gout is often +associated with osteoarthritis. +Joints of the upper limbs are +more frequently affected. +Low doses of allopurinol (50 mg/day) should be given and increased +gradually to avoid toxicity. +Fig. +24.25 Podagra. +It works by inhibiting +microtubule assembly in neutrophils. +The most common adverse +effects are nausea, vomiting and diarrhoea. +Local +ice packs can also be used for symptomatic relief. +Allopurinol is the drug of rst choice. +The recommended starting dose is 100 mg daily, or +50 mg in older patients and in renal impairment. +Acute flares of gout +often follow initiation of urate-lowering therapy. +The patient should +be warned about this and told to continue therapy, even if an +attack occurs. +24.26 Tophus with white monosodium urate monohydrate +crystals visible beneath the skin. +Diuretic-induced gout in a patient with +pre-existing nodal osteoarthritis. +Fig. +24.27 Erosive arthritis in chronic gout. +24 +turbid due to an elevated neutrophil count. +Between attacks, +aspiration of an asymptomatic rst MTP joint or knee may still +reveal crystals. +Tophaceous +gout may be accompanied by a modest but chronic elevation +in ESR and CRP. +24.27). +Tophi may also be visible on X-rays as soft +tissue swellings. +In the longer term, annual monitoring of +uric acid levels is recommended. +In most patients, urate-lowering +therapy needs to be continued indenitely. +Febuxostat also inhibits xanthine oxidase. +Febuxostat undergoes hepatic metabolism and no +dose adjustment is required for renal impairment. +It is highly effective +at controlling hyperuricaemia and can cause regression of tophi. +Lifestyle measures are equally important as drug therapy in +the treatment of gout. +Risk factors are shown in Box 24.45. +In many +patients, chondrocalcinosis is asymptomatic and an incidental +nding on X-ray. +24.28), associated with joint damage and +functional limitation. +Pathophysiology +The underlying mechanisms of crystal deposition are poorly +understood. +• Primary hyperparathyroidism +• Hypomagnesaemia +• Wilson’s disease +O +H +M N +Fig. +24.28 Chondrocalcinosis of the knee. +There is also narrowing (N) of the medial tibio-femoral +compartment and osteophyte (O) formation. +In hypophosphatasia (see Box 24.75, p. +24.23). +Fever is common +and the patient may appear confused and ill. +The knee is most +commonly affected, followed by the wrist, shoulder, ankle +and elbow. +Trigger factors include trauma, intercurrent illness, +dehydration and surgery. +Septic arthritis and gout are the main +differential diagnoses. +Acute attacks of pseudogout may be superimposed. +Affected joints usually show features of OA, with varying degrees +of synovitis. +Effusion and synovial thickening are usually most +apparent at knees and wrists. +Inflammatory features may be sufciently pronounced to +suggest RA. +Inflammatory changes can occur at entheses and +may involve tendons and the ligamentum flavum. +24.6B, p. +988) and to +permit distinction from gout. +Signs of OA are +frequently present. +Since most patients +with pseudogout are elderly, NSAIDs and colchicine must be +used with caution. +Early active mobilisation is also important. +Chronic pyrophosphate-induced arthropathy should be managed +as for OA (p. +1011). +When these protective mechanisms break down, +abnormal calcication occurs. +There are many causes (Box +24.46). +The most +commonly affected site is the supraspinatus tendon (Fig. +24.29) +but other sites may also be involved, including the tendons +around the hip, feet and hands. +The overlying skin may be hot and red, raising the +possibility of infection. +Attacks sometimes occur spontaneously +but can also be triggered by trauma. +664) +(lcSScl = localised cutaneous systemic sclerosis) +Fig. +24.29 Shoulder X-ray showing supraspinatus tendon +calcication (arrow). +and fever are common. +Tendon calcication may be seen on +X-ray. +During an acute attack, there may be a neutrophilia +with an elevation in ESR and CRP. +Routine biochemistry is +normal. +Treatment is with analgesics and NSAIDs. +Attacks may +also respond to a local injection of glucocorticoid. +It may present with +pseudogout or be an incidental nding. +It is more common in women than in men. +X-rays show joint space narrowing, osteophytes and calcication. +The differential diagnosis is end-stage avascular +necrosis, chronic sepsis or neuropathic joint. +There is no acute +phase response and synovial fluid cultures are negative. +The clinical outcome is poor, however, and most patients require +joint replacement. +Usually, the deposits +are asymptomatic but they may be associated with pain and +local ulceration. +The mechanism by which this occurs is unclear +and there is no specic treatment. +24.30 Possible causative mechanisms in bromyalgia. +It is frequently associated with medically +unexplained symptoms in other systems (p. +1187). +The prevalence +in the UK and US is about 2–3%. +There is a +strong female predominance of around 10: 1. +FM arises in a variety of races and cultures. +It is characteristically +diffuse and unresponsive to analgesics and NSAIDs. +Physiotherapy +often makes FM pain worse. +24.31). +Wherever possible, education should +include the spouse, family or carer. +The +model of a self-perpetuating cycle of poor sleep and pain (see +Fig. +24.30) is a useful framework for problem-based management. +Understanding the diagnosis can often help the patient come +to terms with the symptoms. +24.31 Typical tender points in bromyalgia. +The most important risk factor for +mortality is increasing age. +Box 24.49 describes the particular considerations +in old age. +Clinical features +The usual presentation is with acute or subacute monoarthritis +and fever. +The joint is usually swollen, hot and red, with pain +at rest and on movement. +Many people with FM, however, are +intolerant of even small doses of amitriptyline. +A graded +increase in aerobic exercise can improve well-being and sleep +quality. +• Gram-negative bacilli: more frequent pathogens than in younger +people. +• Cephalosporins: contraindicated due to the high risk of Clostridium +difcile. +• Septic arthritis: mortality is high in elderly patients. +targeted. +Patients with pre-existing arthritis may present with +multiple joint involvement. +In young, sexually +active adults, gonococcus may be responsible. +Disseminated +gonococcal infection occurs in up to 3% of patients with untreated +gonorrhoea. +Painful pustular skin +lesions may also be present. +The synovial fluid is usually turbid or blood- +stained but may appear normal. +Prosthetic joints should only be aspirated in theatre. +Serial measurements of CRP and ESR are useful in following +the response to treatment. +Management +The principles of management are summarised in Box 24.50. +Local guidelines +should be followed where available. +depending on the organism that is isolated. +Joint +aspiration should be performed using a large-bore needle once +or twice daily. +If this is not possible, arthroscopic or open surgical +drainage may be needed performed. +255). +It is generally +a late manifestation, which usually affects large joints. +These conditions are discussed on +pages 254 and 255. +Where possible, cultures should be obtained by open or imaging- +guided biopsy of the lesion. +Evidence of osteopenia, localised +osteolysis and osteonecrosis may be seen on X-ray. +Blood +cultures should be taken, which may also reveal the causative +organism. +Resection +of the infected bone and subsequent reconstruction may be +required. +Complications of chronic osteomyelitis include secondary +amyloidosis (p. +81) and skin malignancy at the margin of a +discharging sinus (Marjolin’s ulcer). +Human parvovirus arthropathy (mainly B19; p. +The diagnosis can +be conrmed by a rise in specic IgM. +Management is symptomatic, +with NSAIDs and analgesics. +Osteomyelitis +In osteomyelitis, the primary sites of infection are bone and +bone marrow. +The +organisms most frequently implicated are Staph. +aureus, Staph. +epidermidis and streptococci. +Staph. +aureus is the most common +pathogen. +If the diagnosis is suspected, an MRI should be performed and +blood cultures taken. +The presentation is with pain, swelling and +fever. +Medical management is described on +page 592. +The prevalence is lower in South-east Asia (0.4%). +The highest +prevalence in the world is in Pima Indians (5%). +Synovial macrophages +are activated by TNF and interferon gamma (IFN-Îł), produced +by T cells. +Systemic release of IL-6 triggers production of acute +phase proteins by the liver. +24.32). +Pathophysiology +RA is a complex disease with both genetic and environmental +components. +The strongest association is with +variants in the HLA region. +The non-HLA loci generally lie within or close to genes involved +in regulating the immune response. +However, no single specic pathogen +has been identied as a cause. +Remission may occur during pregnancy and sometimes RA rst +presents post-partum. +24.32 Pathophysiology of rheumatoid arthritis. +B +*European League Against Rheumatism/American College of Rheumatology 2010 +criteria. +Later, brous or bony ankylosis may occur. +Muscles adjacent +to inflamed joints atrophy and may be inltrated with lymphocytes. +This leads to progressive biomechanical dysfunction and may +further amplify destruction. +Granulomatous lesions may +occur in the pleura, lung, pericardium and sclera. +Large joint involvement, systemic symptoms +and extra-articular features may also occur. +Clinical criteria for +the diagnosis of RA are shown in Box 24.52. +This occurs more +commonly in old age. +Another presentation is with proximal muscle +stiffness mimicking polymyalgia rheumatica (p. +1042). +Examination typically reveals swelling and tenderness of the +affected joints. +Erythema is unusual and its presence suggests +coexistent sepsis. +24.33). +Triggering +of ngers may occur because of nodules in the flexor tendon +Fig. +24.33 The hand in rheumatoid arthritis. +B ‘Swan neck’ deformity of the ngers. +sheaths. +Systemic features +Anorexia, weight loss and fatigue may occur throughout the +disease course. +Osteoporosis is a common complication +(p. +1044) and muscle-wasting may occur as the result of systemic +inflammation and reduced activity. +Most are due to serositis, granuloma and nodule formation +or vasculitis (Box 24.53). +24.34). +1038). +Clinical features and management are +discussed in more detail on page 1172. +Pericardial effusion and +constrictive pericarditis may rarely occur. +Pulmonary involvement +Pulmonary brosis may occur but is often asymptomatic. +24.35). +It can lead to cord compression or sudden death following minor +trauma or manipulation. +81) +Fig. +24.34 Rheumatoid nodules and olecranon bursitis. +Nodules were +palpable within, as well as outside, the bursa. +are frequently asymptomatic but some may be complicated by +ulceration and secondary infection. +Vasculitis +This is uncommon but may occur in seropositive patients. +The +presentation is with systemic symptoms, such as fatigue and fever +and nail-fold infarcts. +24.35 Subluxation of cervical spine. +B Extension, showing reduction in this +space. +In those with suspected Baker’s cyst, ultrasound may +be required to establish the diagnosis. +This data are entered into a calculator to +generate a numerical score. +The higher the value, the more +active the disease (Fig. +24.36). +This involves a combination of +pharmacological and non-pharmacological therapies. +A typical algorithm is shown in Figure 24.37. +Similarly, RF is also +positive in about 70% of cases, most of whom also test positive +for ACPA. +RF is less specic than ACPA, however, and positive +tests can occur in other diseases (p. +991). +24.36 Calculation of the Disease Activity Score 28 (DAS28). +*Erythrocyte sedimentation rate or C-reactive protein can be used for the +calculation. +• Paracetamol: the oral analgesic of choice during pregnancy. +• Biologic therapies: experience is limited but they may be +relatively safe during pregnancy. +• Breastfeeding: methotrexate, leflunomide and cyclophosphamide +are contraindicated. +Continue +triple +therapy +Change +Add +DMARD or +biologic +add low-dose +prednisolone +Fig. +24.37 Algorithm for the management of rheumatoid arthritis. +1002). +24.37). +1006). +The annual incidence is +approximately 1 per 10 000 children and young people. +In young children, effective disease control +can repair joint damage before puberty. +Oligoarthritis is the most common form of JIA, accounting +for about 60% of cases. +It is more common in females and +tends to affect large joints in an asymmetrical pattern. +There is +an association with uveitis and many patients are ANA-positive. +Autoantibody tests are negative. +This form of JIA is associated with haemophagocytic syndrome. +ERA can progress +over time into a more obviously dened spondyloarthropathy. +Low haemoglobin is likely to be due to anaemia +of chronic disease rather than iron deciency. +A positive ANA +occurs in 40–75% of cases of JIA and indicates an increased +risk of eye disease. +Ultrasound is the radiological investigation of +choice to conrm synovitis or tenosynovitis. +The false-negative +rate is higher in foot and ankle disease than in other joints. +Arthroscopy should be avoided unless a biopsy is required. +Alternative treatment includes leflunomide, +sulfasalazine and hydroxychloroquine. +Azathioprine and ciclosporin +can be used to treat JIA with uveitis. +All (not +just those who are ANA-positive) need ophthalmic screening for eye +involvement. +• Persistence into adulthood: occurs in 50% of cases, especially in +systemic disease. +Specic supportive management through +transition from adolescence to adulthood should be planned. +• Therapy: methotrexate is standard treatment, used after NSAIDs +alone are insufcient. +Drug combinations are not well studied in JIA. +Tocilizumab is also effective in sJIA, and has +been approved by NICE for use in the UK. +Psychological support of affected +children and their families is associated with improved outcome. +Oligo-JIA often resolves at puberty. +Polyarticular disease and sJIA +remain active into adulthood in about 50% of cases. +Common +issues around the transition of adolescent patients into adulthood +are shown in Box 24.58. +In axial spondylitis and ankylosing spondylitis, the axial skeleton +(i.e. +the central core skeleton) is predominantly affected. +Dactylitis, inflammation of a whole nger or toe, may also +occur (see Fig. +24.43). +There is a striking +association with HLA-B27, particularly for ankylosing spondylitis +(> 95%). +65). +Not all patients with axSpA will go +on to develop AS. +24.38). +improved by exercise +2. +not relieved by rest +3. +insidious onset +4. +night pain +5. +24.38 Pathophysiology of axial spondyloarthropathy. +class I molecule HLA-B27. +4.3, +p. +65). +HLA-B27 molecules may +also misfold, causing increased endoplasmic reticulum stress. +Symptoms +are exacerbated by inactivity and relieved by movement. +Fatigue is common. +24.39). +Other ndings +24 +Fig. +24.39 Magnetic resonance imaging appearances in sacroiliitis. +Faecal calprotectin is a useful +screening test for associated inflammatory bowel disease. +These medications have no impact +on spinal symptoms or disease progression. +1007). +It +is clear that axSpA can remain mild and/or episodic in many +patients for many years. +There is a +male-to-female ratio of about 3 : 1. +The overall prevalence of AS +is below 0.5% in most populations. +Over 75% of patients are +able to remain in employment and enjoy a good quality of life. +Clinical features +Clinical features are the same as in axSpA. +Fatigue is a major complaint and is common to all SpAs, but +its cause is unknown. +Other extra-articular features are occasionally observed but are +rare (Box 24.61). +Bridging syndesmophytes may also be seen. +These +are areas of calcication that follow the outermost bres of the +annulus (Fig. +24.40). +24.40 Radiographic changes in spondyloarthritis. +A Fine symmetrical marginal syndesmophytes typical of ankylosing spondylitis (arrow). +The known triggers are Chlamydia, Campylobacter, +Salmonella, Shigella and Yersinia. +The arthritis associated with rheumatic fever (p. +515) is also an +example of a reactive arthritis that is not associated with HLA-B27. +1031). +Lower limb joints and +entheses are predominantly affected. +In all types of ReA, there +may be considerable systemic disturbance, with fever and weight +loss. +Achilles insertional enthesitis/tendonitis or plantar fasciitis may +also be present. +Fig. +24.41 ‘Bamboo’ spine of advanced ankylosing spondylitis. +typical ‘bamboo’ spine (Fig. +24.41). +Erosive changes may be +seen in the symphysis pubis, ischial tuberosities and peripheral +joints. +Osteoporosis is common and vertebral fractures may +occur. +Atlanto-axial dislocation can arise as a late feature. +MRI +is more sensitive for detection of early sacroiliitis than X-rays +(see Fig. +24.39) and can also detect inflammatory changes in +the lumbar spine. +DXA scanning is important as part of a fragility +fracture assessment. +Autoantibodies, +such as RF, ACPA and ANA, are negative. +Mobilising exercises +are important and are shown on many online resource sites (e.g. +National Ankylosing Spondylitis Society, UK). +A long-acting NSAID +at night is helpful for alleviation of morning stiffness. +Oral glucocorticoids may be required for acute uveitis but do +not help spinal disease. +Severe hip, knee or shoulder arthritis +with secondary OA may require arthroplasty. +High vaginal swabs +may reveal Chlamydia on culture. +RF, +ACPA and ANA are negative. +24.40B). +Radiographic changes in the peripheral joints and spine +are identical to those seen in psoriasis. +Management +Acute ReA should be treated with rest, NSAIDs and analgesics. +For DMARD-recalcitrant cases, +anti-TNF therapy should be considered. +It is likely the true prevalence is considerably +higher but this has not been extensively studied. +Early PsA may present as +axSpA. +The onset is usually between 25 and 40 years of age +but juvenile forms exist. +Many +of these variants overlap with those implicated in psoriasis +(p. +1247), where there are more than 40 susceptibility loci. +There is increasing evidence that the IL-23/ +IL-17 pathway plays a pivotal role in PsA. +These patterns are not mutually +exclusive. +Destructive arthritis and disability are uncommon, except in the +case of arthritis mutilans. +24.43A). +Symmetrical polyarthritis +This accounts for about 25% of cases. +PsA DIP joint disease is +associated with psoriatic nail disease (Fig. +24.43B). +24.42 Pathogenesis of psoriatic arthritis. +Prominent cartilage and +bone destruction results in marked instability. +Symptoms can be extensive or localised. +The characteristic rash of psoriasis (p. +Investigations +The diagnosis is made on clinical grounds. +X-rays may be normal or show erosive change +with joint space narrowing. +Features that favour PsA over RA +include the characteristic distribution (see Fig. +24.10, p. +Management +Therapy with NSAIDs and analgesics may be sufficient to +manage symptoms in mild disease. +Intra-articular glucocorticoid +injections can control isolated synovitis or enthesitis. +Patients with spondylitis should +be prescribed the same exercise and posture regime as in +axSpA/AS. +NSAIDs are best avoided, since they can exacerbate IBD. +Instead, judicious use of glucocorticoids, sulfasalazine and +methotrexate may be considered. +Some 90% of affected patients are +female and the peak age at onset is between 20 and 30 years. +From an immunological standpoint, the +characteristic feature of SLE is autoantibody production. +Fig. +24.43 Psoriatic arthropathy. +A Dactylitis. +B Distal interphalangeal +joint pattern with accompanying nail dystrophy (pitting and onycholysis). +for skin disease (see EULAR guidelines, ‘Further information’, +p. +1060). +Other DMARDs may also be helpful, including +sulfasalazine, ciclosporin and leflunomide. +Adverse effects include weight loss, +depression and suicidal ideation. +Involvement +of the peripheral joints is seen in about 20% of IBD patients. +Oligoarticular disease predominantly affects the large lower +limb joints (knees, ankles and hips). +Tenosynovitis +may also occur but clinically apparent synovitis with joint swelling +is rare. +Raynaud’s phenomenon +Raynaud’s phenomenon (p. +504) is common and may antedate +other symptoms by months or years. +SLE can present with +Raynaud’s phenomenon, along with arthralgia or arthritis. +If Raynaud’s +phenomenon is severe, digital ulceration can occur (Fig. +24.44). +The +main types of skin involvement are: +• The classic facial rash (up to 20% of patients). +24.45). +Rosacea is a mimic of this rash. +• Diffuse, usually non-scarring alopecia, which may also +occur with active disease. +• Urticarial eruptions. +• Livedo reticularis (Fig. +24.46), which is also a feature of +antiphospholipid syndrome (p. +977) and can become +frankly vasculitic, if severe. +The typical renal lesion is a proliferative glomerulonephritis +(p. +397), characterised by heavy haematuria, proteinuria and +casts on urine microscopy. +Cardiovascular +The most common manifestation is pericarditis. +Myocarditis and +Libman–Sacks endocarditis can also occur. +This is thought to be multifactorial +Fig. +24.44 Severe secondary Raynaud’s phenomenon leading to +digital ulceration. +Fig. +24.45 Malar rash of systemic lupus erythematosus, sparing the +nasolabial folds. +The risk of +thromboembolism is increased, especially in patients with +antiphospholipid antibodies. +24.46 Livedo reticularis (systemic lupus erythematosus and +anti-phospholipid syndrome). +peripheral blood cells. +The degree of lymphopenia is a good +guide to disease activity. +Gastrointestinal +Mouth ulcers may occur and may or may not be painful. +Peritoneal +serositis can cause acute pain. +Hepatitis is a recognised, though rare, +feature. +Patients with active SLE test positive +for ANA. +Some authorities believe that ANA-negative SLE occurs +(e.g. +66). +damage and maintain normal function. +Its role +in patients with renal and neurological disease is still under +investigation. +It is characterised typically by Raynaud’s +phenomenon, digital ischaemia (Fig. +24.47), sclerodactyly, and +cardiac, lung, gut and renal disease. +Some patients with lcSScl have calcinosis and telangiectasia. +The prognosis in dcSScl is poor (5-year survival about 70%). +Pathophysiology +The cause of SScl is not completely understood. +The disease occurs in all ethnic groups +and race may influence severity. +This +results in symmetrical thickening, tightening and induration of the +skin (scleroderma). +Subsequently, the skin becomes shiny and taut, and +distal skin creases disappear. +There can be capillary loss. +The +face and neck are often involved, with thinning of the lips and +radial furrowing. +In some patients, skin thickening stops at this +stage. +24.48). +Raynaud’s phenomenon +This is a universal feature and can precede other features by +many years. +Musculoskeletal features +Arthralgia and flexor tenosynovitis are common. +Muscle weakness and wasting can +result from myositis. +24 +Fig. +24.47 Systemic sclerosis. +Fig. +Involvement of the +stomach causes early satiety and occasionally outlet obstruction. +It +usually presents with insidiously evolving exertional dyspnoea +and signs of right heart failure. +Dyspnoea can evolve slowly over time or rapidly in +occasional cases. +514) and renal failure. +ANA is +positive in about 70%. +About 30% of patients with dcSScl have +antibodies to topoisomerase 1 (Scl70). +About 60% of patients +with lcSScl syndrome have anticentromere antibodies (p. +991). +High-resolution lung CT is +recommended if interstitial lung disease suspected. +A barium +swallow can assess oesophageal involvement. +A hydrogen breath +test can indicate bacterial overgrowth (p. +808). +The focus of management, +therefore, is to slow the effects of the disease on target organs. +• Raynaud’s phenomenon and digital ulcers. +Courses of +intravenous prostacyclin are used for severe disease and +critical ischemia (e.g. +6–8 hours daily for 5 days). +• Gastrointestinal complications. +Oesophageal reflux should +be treated with proton pump inhibitors and anti-reflux +agents. +Rotating courses of antibiotics may be required for +bacterial overgrowth (e.g. +• Hypertension. +Aggressive treatment with ACE inhibitors is +needed, even if renal impairment is present. +• Joint involvement. +This may be treated with analgesics +and/or NSAIDs. +If synovitis is present and both RA (i.e. +• Progressive pulmonary hypertension. +Early treatment with +bosentan is required. +In severe or progressive disease, +heart–lung transplant may be considered. +• Interstitial lung disease. +Most patients have anti-RNP antibodies. +Management focuses +on treating the components of the disease (see other sections). +The typical age of onset is between +40 and 50, with a 9 : 1 female-to-male ratio. +The disease may +occur with other autoimmune diseases (secondary SjĂśgren’s +syndrome). +Oral involvement +manifests as a dry mouth (xerostomia). +There is a high incidence +of dental caries and high risk of dental failure. +Other sites of +extraglandular involvement are listed in Box 24.64. +Often the +most disabling symptom is fatigue. +24.49 Typical eyelid appearance in dermatomyositis. +Note the +oedema and telangiectasia. +In DM, characteristic skin changes also occur. +Both diseases are rare, with an incidence of 2–10 cases per +million/year. +Systemic features of fever, weight loss and fatigue +are common. +24.49). +Similar rashes occur on the +upper back, chest and shoulders (‘shawl’ distribution). +Periungual +nail-fold capillaries are often enlarged and tortuous. +24.50). +Electromyography is very useful for highlighting non-autoimmune/ +non-inflammatory myopathies. +ANA-negative disease exists. +Anti-Ro +and anti-La antibodies are commonly present (see Box 24.10, +p. +992). +Knowing ACPA status can help +(it is positive in RA). +A chest X-ray +and lung function tests should be performed. +Adequate postprandial oral +hygiene and prompt treatment of oral candidiasis are essential. +Vaginal dryness is treated with lubricants. +Clinical monitoring and periodic autoimmune serological testing +of all patients is sensible. +Splenomegaly, hepatomegaly +and lymphadenopathy may be present. +Canakinumab or anakinra can be used for patients +with resistant disease. +Principal sites of involvement for the main +types of vasculitis are summarised in Figure 24.51. +Systemic vasculitis should +be considered in any patient with fever, weight loss, fatigue, +Fig. +24.50 Muscle biopsy from a patient with polymyositis. +Intravenous +immunoglobulin (IVIg) may be effective in refractory cases. +One risk of treatment is glucocorticoid-induced myopathy. +Many clinical features are +similar to those in the adult disease. +In some cases, polycyclic JDM +can be chronic and life-long. +It is ulcerative in 10–20%. +As in +adults, calcinosis occurs in about 30%. +Cyclophosphamide is used for lesional ulceration. +IVIg is given +in resistant cases. +24.51 Types of vasculitis. +24.52 Eye involvement in antineutrophil cytoplasmic antibody- +associated vasculitis. +Management for organ-threatening or acute–severe disease +is with high-dose glucocorticoids (e.g. +Plasmapheresis should be considered for fulminant lung +disease. +The typical age at onset is +25–30 years, with an 8 : 1 female-to-male ratio. +It has a worldwide +distribution but is most common in Asia. +It presents +with claudication, fever, arthralgia and weight loss. +Clinical +examination may reveal loss of pulses, bruits, hypertension and +aortic incompetence. +With successful treatment, the +5-year survival is 83%. +Kawasaki disease +Kawasaki disease is a vasculitis that mostly involves the coronary +vessels. +It presents as an acute systemic disorder, usually affecting +children under 5 years. +The combined incidence is about 10–15/1 000 000. +Two main subtypes are recognised. +Patients are usually myeloperoxidase (MPO) antibody-positive. +A minority of patients present with glomerulonephritis. +24.52). +Disturbance of colour +vision is an early feature of optic nerve compression. +Untreated +nasal disease ultimately leads to destruction of bone and cartilage. +Patients with active disease usually have a leucocytosis with +elevated CRP, ESR and PR3. +Complement levels are usually +normal or slightly elevated. +1059) +• Lambert–Eaton syndrome +(p. +Both diseases are rare under the age of 60 years. +The average +age at onset is 70, with a female-to-male ratio of about 3 : 1. +The overall prevalence is about 20 per 100 000 in those over +the age of 50 years. +Jaw pain develops in some patients, brought +on by chewing or talking. +With PMR, there may +be stiffness and painful restriction of active shoulder movements +on waking. +Muscles are not otherwise tender, and weakness +and muscle-wasting are absent. +Other conditions that cause +PMR-like symptoms are shown in Box 24.66. +CRP may also be +elevated and abnormal liver function can occur. +Rarely, PMR and +GCA can present with a normal ESR. +More objective evidence +for GCA should be obtained whenever possible. +A negative biopsy +does not exclude the diagnosis. +On ultrasound examination, +affected temporal arteries show a ‘halo’ sign. +A strongly positive +19 FDG PET scan is highly specic but sensitivity is low. +Caution +is needed in interpreting weakly positive images. +Low-grade +vascular uptake may occur in atheromatous arterial disease. +Response +Fig. +24.53 Rash of systemic vasculitis (palpable purpura). +is thought to be an abnormal immune response to an infectious +trigger. +Treatment is with aspirin (5 mg/kg daily for 14 days) +and IVIg (400 mg/kg daily for 4 days). +The annual +incidence is about 2/1 000 000. +The most common skin +lesions are palpable purpura (Fig. +24.53), ulceration, infarction and +livedo reticularis (see Fig. +24.46). +Nephritis can also occur and may present up to +4 weeks after the onset of other symptoms. +Biopsy of affected +tissue shows a vasculitis with IgA deposits in the vessel wall. +Cryoglobulins are classied into three +types (see Box 4.21, p. +84). +Types II and III are associated +with vasculitis. +875 and 878). +In severe cases, plasmapheresis can be considered. +Oral ulcers are universal (Fig. +24.54). +Unlike aphthous ulcers, +they are usually deep and multiple, and last for 10–30 days. +Genital ulcers are also a common problem, occurring in 60–80% +of cases. +Ocular involvement is common and may include +anterior or posterior uveitis or retinal vasculitis. +The +rate of reduction should then be slowed by 1 mg per month. +Most patients need glucocorticoids +for an average of 12–24 months. +For advice on prophylaxis +against giant cell-induced osteoporosis, see page 1047. +It is associated with +eosinophilia. +Pulmonary +inltrates and pleural or pericardial effusions due to serositis may +be present. +Up to 50% of patients have abdominal symptoms +provoked by mesenteric vasculitis. +Patients with active disease +have raised levels of ESR and CRP and an eosinophilia. +24 +Fig. +All of these fractures become more common with increasing +age (Fig. +24.55). +The risk of fracture increases markedly with age in +both genders (Fig. +24.55). +This is mostly attributable to an +increased risk of falling with age (p. +1308) but is also due in part +to an age-related decline in bone mass, especially in women +(Fig. +24.56). +24.2, p. +985). +24.3, p. +986). +Rarely, osteoporosis +may be caused by mutations in single genes. +Recurrent thromboses also occur. +Renal involvement is extremely rare. +Colchicine can be effective for erythema nodosum +and arthralgia. +Glucocorticoids and +immunosuppressants are indicated for uveitis and neurological +disease. +Around 30% of patients have coexisting autoimmune or connective +tissue disease. +Cartilage biopsy +shows an inflammatory inltrate in the perichondrium. +Both +ESR and CRP are raised in active disease. +Diseases of bone +Osteoporosis +Osteoporosis is the most common bone disease. +24.55 Fractures associated with osteoporosis. +A X-ray of wrist. +B Vertebrae. +C Humerus. +D Hip. +E and F The changing incidence of +each of these fractures with age in women and men, respectively. +From Curtis EM, van der Velde R, Moon RJ, et al. +Bone 2016; 87:19–26. +Clinical features +Osteoporosis does not cause symptoms until a fracture occurs. +Non-vertebral fractures are almost always caused by a traumatic +event, most usually a simple fall. +These are typical of osteoporosis. +24.57 +and p. +988). +The clinical signs of fracture are pain, local +tenderness and deformity. +The presentation +of vertebral fractures is variable. +Some patients present with +acute severe back pain. +176). +24.56 Changes in bone mass and microstructure with age. +Changes in men (blue line) and women (red line). +24 +or risk factor is operative. +The most important causes are +summarised in Box 24.69. +24.9, p. +990). +1060) has returned an elevated value. +1303). +Screening for secondary +causes of osteoporosis should be performed, as summarised +in Box 24.71. +24.57 Relation between bone mineral density (BMD) and fractures. +24.58 Algorithm for the investigation of patients with suspected +osteoporosis. +Fracture risk is assessed using FRAX or QFracture (see +‘Further information’, p. +1060). +Fig. +24.59 Mechanism of action of bisphosphonates. +(p. +1308). +The dosages, mode of administration +and indications are summarised in Box 24.72. +More detail on +the individual drugs is provided below. +Bisphosphonates Bisphosphonates are the rst-line treatment +for osteoporosis. +The bisphosphonate is released within the osteoclasts and +impairs bone resorption. +24.59). +2Seldom required. +24.2, p. +985). +Denosumab may rarely cause +osteonecrosis of the jaw and atypical subtrochanteric fractures. +Because of this, many experts advise giving a +bisphosphonate following cessation of denosumab. +A typical daily dosage is 1000 mg calcium +and 800 IU vitamin D. +Teriparatide Teriparatide (TPTD) is the 1-34 fragment of human +PTH. +It is an effective treatment for osteoporosis, which works by +stimulating new bone formation. +It is given by a self-administered +subcutaneous injection in a dose of 20 Îźg daily for 2 years. +Upper +gastrointestinal upset occurs in about 5% of cases. +This is self-limiting but can be treated with +paracetamol or NSAIDs if necessary. +It predominantly occurs +after the rst exposure and tolerance develops thereafter. +Other +adverse effects are shown in Box 24.73. +It increases bone formation, inhibits bone resorption and +increases BMD. +Vertebroplasty is sometimes used in the treatment of painful +vertebral compression fractures. +It has +similar efcacy to vertebroplasty but adverse effects are more +common. +1308). +inhibitor of bone resorption should be administered to maintain +the increase in BMD. +The most common adverse effects are headache, +muscle cramps and dizziness. +Monitoring of serum calcium is not required during +TPTD treatment. +Abaloparatide Abaloparatide is the 1-34 fragment of PTH-related +protein. +It works in a similar way to TPTD to stimulate bone +formation. +It is given as a self-administered injection of 80 Îźg +daily for 18 months. +Adverse effects +are similar to those of TPTD. +It is primarily indicated for the prevention +of osteoporosis in women with an early menopause (p. +Bazedoxifene is a related SERM that has similar effects +to raloxifene. +Tibolone Tibolone has partial agonist activity at oestrogen, +progestogen and androgen receptors. +Other causes are summarised in Box +24.75 and are discussed in more detail below. +The likelihood of developing vitamin D deciency is strongly +related to sunlight exposure. +Vitamin D deciency is also common in women +who, for cultural reasons, cover their skin and face. +Sometimes, low 25(OH) +D levels may be observed in the presence of a normal PTH +concentration. +25(OH)D (nmol/L) +0 +Summer Autumn Winter Spring +Fig. +24.60 Seasonal changes in vitamin D concentrations. +To convert +nmol/L to ng/mL, multiply by 2.5. +Adapted from McDonald HM, Mavroeidi +A, Fraser WD, et al. +Osteoporosis Int 2011; +22:2461–2472. +deciency is more common in the winter and spring, and less +common in summer and autumn (Fig. +24.60). +24.61 Vitamin D metabolism. +Vitamin D is produced in the skin from 7-dehydrocholesterol (7-DHC) by ultraviolet B (UVB) light. +See text for details. +Investigations +The diagnosis can be made by measurement of serum 25(OH)D. +Serum ALP, calcium and phosphate levels +are normal in uncomplicated vitamin D deciency. +Management +The clinical benet of treating biochemical vitamin D deciency +is uncertain. +The benet of treating seasonal +vitamin D deciency or vitamin D insufciency is uncertain. +Osteomalacia in adults can present with fractures +and low BMD, mimicking osteoporosis. +Other symptoms include +bone pain and general malaise. +24.62A). +In children, there is +thickening and widening of the epiphyseal plate. +24.62B). +Management +Osteomalacia and rickets respond promptly to treatment with +vitamin D. +A wide variety of doses can be used. +Both are recessive disorders and consanguinity +is common. +Clinical features +These are as described above for infantile rickets. +In type II VDRR, 25(OH)D is +normal but PTH and 1,25(OH)2 D3 values are raised. +Calcium +supplements are not necessary unless there is dietary deciency. +A +B +Fig. +24.62 Osteomalacia. +This hormone +is produced by osteocytes (see Fig 24.3, p. +986) and enters +the circulation, where it is normally inactivated by proteolytic +cleavage. +Production of FGF23 by osteocytes is under tonic +inhibition by DMP1 and PHEX. +Serum levels of vitamin D are normal and PTH is +normal or slightly elevated. +Serum concentrations of FGF23 +are markedly elevated. +The causal mutation can be dened by +genetic testing. +be identied by whole-body MRI or CT. +Chondrocalcinosis may also occur. +Other causes of osteomalacia +These are summarised in Box 24.75. +418). +It is usually asymptomatic and healing occurs +when treatment is stopped. +The condition reverses when fluoride +intake is reduced. +It is rare in Scandinavia, the Indian subcontinent and +the rest of Asia. +Biochemical ndings are as described for hereditary +hypophosphataemic rickets. +The underlying tumour can sometimes1054 • RHEUMATOLOGY AND BONE DISEASE +A B +Fig. +24.63 Paget’s disease. +cause of classical PDB. +Involvement of subchondral +bone can compromise the joint and predispose to OA. +Clinical signs include bone deformity and expansion, +and increased warmth over an affected bone. +24.63B). +Levels of ALP can be normal if +only a single bone is affected. +24.63A). +If the bone scan is positive, +X-rays should be taken to conrm the diagnosis. +A +positive response indicates that the pain was due to increased +metabolic activity. +There is no specic treatment. +Management +should focus on controlling pain and encouraging mobilisation +(p. +1000). +It has a strong genetic +component and may be inherited in an autosomal dominant +manner. +Rarely, corrective surgery may be required if +there is severe deformity. +The characteristic presentation is with bone pain and +pathological fractures. +24.65), +and focal increased uptake on bone scan. +Management is +symptomatic. +Orthopaedic surgery may be required for treatment +of fracture and deformity. +Endocrine manifestations, such as +precocious puberty (p. +654), may require specic treatment. +Mutations +Fig. +24.64 Complex regional pain syndrome (osteodystrophy). +99mTc-labelled bisphosphonate scintigraphy showing increased uptake in +femoral condyle. +The diagnosis is primarily clinical, +based on the features shown in Box 34.12 (p. +1349). +24.64). +X-rays show localised +osteoporosis. +Haematology, biochemistry and immunology +are normal. +The aims of treatment are to control pain and encourage +mobilisation. +Osteonecrosis +Osteonecrosis describes death of bone due to impairment of its +blood supply. +The most commonly affected sites are the femoral +head, humeral head and femoral condyles. +Management is +difcult. +24.3, p. +986). +There is no effective treatment. +The mutations render the LRP receptors resistant to the +inhibitory effects of SOST. +Treatment is not usually +required. +Glucocorticoids can +help the bone pain, although usually analgesics are also required. +Paget’s disease of bone (p. +1053) accounts +for most cases of osteosarcoma occurring above the age of 40. +Osteosarcoma +This is a rare tumour with an incidence of 0.6–0.85 per 100 000 +population. +It is the most common primary bone tumour. +Most +Fig. +24.65 McCune–Albright syndrome. +X-ray of tibia in a patient with +McCune–Albright syndrome showing expansile osteolytic lesion. +Many patients have no +family history. +Some of these have new mutations whereas +others may have recessive forms of the disease. +The Sillence +classication is commonly used to grade severity. +The +presentation is with local pain and swelling. +Patients suspected of having osteosarcoma should +be referred to a specialist team for biopsy. +Chondrosarcoma +This is the second most common primary bone tumour. +Presentation is as described for osteosarcoma. +The +prognosis is good for low-grade tumours but poor for anaplastic +tumours. +Presentation is as described +for osteosarcoma. +Treatment is by local excision and surgical +resection. +The prognosis is excellent for patients who present +before metastasis has occurred. +Management is discussed +in Chapter 33. +Both resolve with levothyroxine replacement. +Primary +hyperparathyroidism (p. +Diabetes mellitus (Ch. +Acromegaly (p. +It does not improve with treatment of the acromegaly. +The most common examples are described here. +The most common causes +are bronchial carcinoma and mesothelioma (pp. +598 and 618). +Bone scans show increased periosteal uptake before new bone +is apparent on X-ray. +895) is complicated by an arthropathy in +about 50% of cases. +It typically presents between the ages of 40 +and 50, and may predate other features of the disease. +Haemophilia (p. +Sickle-cell disease (p. +952) may be associated with bone +pain, osteonecrosis and osteomyelitis. +Thalassaemia (p. +The presentation is with subacute or chronic monoarthritis. +X-rays show +disorganisation of normal joint architecture and often multiple +loose bodies (Fig. +24.66), and either no (atrophic) or gross +(hypertrophic) new bone formation. +Management principally +involves orthoses and occasionally arthrodesis. +Treatment +is by surgical decompression. +It presents with +numbness, tingling and pain in a median nerve distribution (p. +1139). +In some patients, no underlying cause may be identied. +24.67). +It is usually an +Fig. +24.66 Wrist X-ray showing a neuropathic (Charcot) joint in a +patient with syringomyelia. +Fig. +24.67 Diffuse idiopathic skeletal hyperostosis (DISH). +Inclusion body myositis typically +presents with distal muscle weakness. +In time, muscles atrophy. +Investigation is the same as for polymyositis (p. +1039). +There is +typically a slightly elevated creatine kinase and myopathic changes +on EMG. +Therapeutic response to glucocorticoids and +immunosuppressants is notably poor. +There is anecdotal report +of efcacy with IVIg but trial evidence is lacking. +They +are discussed in more detail on page 81. +The +presentation is with joint swelling, limitation of movement +and local discomfort. +The diagnosis can be confirmed by +MRI or synovial biopsy. +Treatment is by surgical or radiation +synovectomy. +The ring and little ngers are usually the rst +and worst affected. +It is age-related, usually bilateral +and more common in men. +There is a strong genetic component +and sometimes may be familial, with dominant inheritance. +It is very +slowly progressive. +Hypermobility syndromes +Hypermobility is characterised by increased joint laxity and joint +pain. +Causes include Marfan’s syndrome, resulting from mutations +in the FBN1 gene (p. +508); osteogenesis imperfecta (p. +970). +It may also occur in association with connective tissue disorders, +such as Marfan’s syndrome. +Spinal X-rays can be used to +conrm the diagnosis and assess severity. +Spondylolysis +Spondylolysis describes a break in the integrity of the neural arch. +This may be congenital, post-traumatic +or degenerative. +Rarely, it can result from metastatic destruction +of the posterior elements. +Occasionally, symptoms of +nerve root or spinal compression may occur. +Advice on posture +and muscle-strengthening exercises is required in mild cases. +Surgical fusion is indicated for severe and recurrent low back +pain. +Further information +Journal articles +Campion EW. +Calcium pyrophosphate deposition disease. +N Engl J +Med 2016; 374:2575–2578. +Compston J. +Osteoporosis: advances in risk assessment and +management. +Clin Med (Lond) 2016; 16(Suppl 6): s121–s124. +Gossec L, Smolen JS, Ramiro S, et al. +Ann +Rheum Dis 2016; 75:499–510. +Mukhtyar C, Flossman O, Hellmich B, et al. +Ann Rheum Dis 2008; 67:1004–1010. +Ralston SH. +Paget’s disease of bone. +N Engl J Med 2013; 368:644–650. +Scott DL, Woolf F, Huizinga TW. +Rheumatoid arthritis. +Lancet 2010; +376:1094–1108. +Taurog JD, Avneesh C, Colbert RA. +Ankylosing spondylitis and axial +spondyloarthritis. +N Engl J Med 2016; 374:2563–2567. +Teng MWL, Bowman EP, McElwee JJ, et al. +Nat Med 2015; 21:719–729. +Zhang W, Doherty M, Bardin T, et al. +EULAR recommendations for +gout. +Part II: Management. +Ann Rheum Dis 2006; 65:1312–1324. +Websites +4s-dawn.com/DAS28 Calculator for this measure of activity in +rheumatoid arthritis. +asas-group.org Repository of resources to aid assessment of +spondyloarthritis. +basdai.com/BASDAI.php BASDAI calculator for assessing ankylosing +spondylitis. +omim.org Online Mendelian Inheritance in Man (OMIM): genetic +diseases. +shef.ac.uk/FRAX/ and qfracture.org/ Fracture risk assessment tools. +thefreelibrary.com Information on drug-induced myopathies. +vasculitis.org/ Vasculitis resources from the European Vasculitis +Society. +It most commonly +presents in children and young or middle-aged adults. +It can arise spontaneously or in association with +inflammatory diseases such as RA. +The development of specic, effective treatments has made +accurate diagnosis essential. +If the presentation is not +an emergency, time can be taken to reach a diagnosis. +In addition to neurons, there are three types of +glial cells. +1080) +• Stroke (if thrombolysis available) (p. +1158) +• Guillain–BarrĂŠ syndrome (p. +1140) +• Myasthenia gravis (if bulbar and/or respiratory) (p. +1141) +• Spinal cord compression (p. +1136) +• Subarachnoid haemorrhage (p. +1160) +• Neuroleptic malignant syndrome (p. +25.1 Cells of the nervous system. +25.1). +Peripheral nerves have +axons invested in myelin made by oligodendrocytes (Schwann +cells). +Ependymal cells line the cerebral ventricles. +25.2). +Each neuronal cell body may receive synaptic input from +thousands of other neurons. +This effect probably underlies more +complex processes such as long-term memory. +25.2 Neurotransmission and neurotransmitters. +(5) +Neurotransmitters are taken up at the pre-synaptic membrane and/or +metabolised. +Each cerebral hemisphere has four functionally specialised lobes +(Box 25.2 and Fig. +Frontal lobes are concerned with executive function, movement, +behaviour and planning. +The parietal lobes integrate sensory perception. +The primary +sensory cortex lies in the post-central gyrus of the parietal lobe. +The supramarginal and angular gyri of the dominant parietal +lobe form part of the language area (p. +1088). +Close to these +are regions dealing with numerical function. +The non-dominant +parietal lobe is concerned with spatial awareness and orientation. +The temporal lobes contain the primary auditory cortex and +primary vestibular cortex. +The occipital lobes are responsible for visual interpretation. +phosphenes, zigzag lines) +1 Grasp reflex, palmomental response, pout response. +2Inability to determine three-dimensional shape by touch. +4Inability to ‘read’ numbers or letters drawn on hand, with the eyes shut. +5Inability to recognise familiar objects, e.g. +25.4 Anatomy of the +cerebral cortex. +and appetite control. +CSF is formed in the lateral ventricles and protects and +nourishes the CNS. +25.44, p. +1132). +25.5). +They also relay autonomic messages, including +pupillary, salivary and lacrimal functions. +25.6). +Inputs from the brainstem are +largely inhibitory. +25.6 The motor system. +The activity in the motor cortex is modulated by influences from the +basal ganglia and cerebellum. +Pathways descending from these structures +control posture and balance (B). +resulting in weakness and reduced muscle tone. +Except in the +tongue, these are usually perceptible only on electromyography +(EMG; p. +1076). +Fasciculations therefore imply chronic denervation with partial +re-innervation. +the +extensors of the lower limbs and the flexors of the upper limbs). +Spasticity may not be present until some weeks after +the onset of an upper motor neuron lesion. +25.6). +Involuntary movements are also a feature of extrapyramidal lesions +(p. +1084), and tremor in combination with rigidity produces typical +‘cogwheel’ rigidity. +A lesion in a cerebellar hemisphere causes lack of coordination +on the same side of the body. +The distances of targets are misjudged (dysmetria), resulting in +‘past-pointing’. +The central vermis of the cerebellum is concerned with the +coordination of gait and posture. +Disorders of this area therefore +produce a characteristic ataxic gait (see below). +Vision +The neurological organisation of visual pathways is shown in +Figure 25.7. +25.8). +The MLF is particularly +important in coordinating horizontal movements of the eyes. +The pupillary size is determined by a combination of +parasympathetic and sympathetic activity. +25.7 Visual pathways and visual eld defects. +25.9 Areas of the cerebral cortex involved in the generation of +spoken language. +Fig. +25.8 Control of conjugate eye movements. +Downward projections +pass from the cortex to the pontine lateral gaze centre (A). +Here they lie just medial to the (already crossed) +spinothalamic pathway. +Pain +Pain is a complex perception that is only partly related to activity in +nociceptor neurons (p. +1338 and Fig. +34.2). +Modication of psychological and psychiatric sequelae +is a vital part of pain management (p. +1343). +The temporal speech comprehension region is called Wernicke’s +area (Fig. +25.9). +This receives input +from the temporal and parietal lobes via the arcuate fasciculus. +25.10). +Sensory information +ascends in two anatomically discrete systems (Fig. +25.11). +25.10 The areas supplied by specic levels of the spinal cord. +These are approximations and in practice there is much overlap. +A Anterior. +B Posterior. +Personality and mood +The physiology and pathology of mood disorders are discussed +elsewhere (Ch. +Conversely, mood disorder may have a signicant effect on +perception and function. +Sleep +The function of sleep is unknown but it is required for health. +Sleep is controlled by the reticular activating system in the +upper brainstem and diencephalon. +It is composed of different +stages that can be visualised on electroencephalography (EEG). +REM phases lengthen as sleep progresses. +25.5). +25.11 The main somatic sensory pathways. +which tracts/nuclei are affected, usually invoking the fewest +number of lesions. +1082, 1083, 1087 and 1093). +The uses and limitations of each of these are shown in Box +25.4. +PET scanning +can display glucose metabolism in dementia and epilepsy. +Investigation may include assessment of structure (imaging) +and function (neurophysiology). +Head and orbit +Plain skull X-rays now have a very limited role in neurological +disease. +CT or MRI is needed for intracranial imaging. +CT +is good for demonstrating bone and calcication well. +MRI resolution is unaffected by bone and so is more useful +in posterior fossa disease. +Different MRI techniques can selectively suppress1074 • NEUROLOGY +AB +D +C +Fig. +25.12 Different techniques of imaging +the head and brain. +A Computed tomogram +showing complete middle cerebral artery infarct +(arrows). +B Magnetic resonance image +showing widespread areas of high signal in +multiple sclerosis (arrows). +D Normal positron emission tomogram (PET +scan) of brain. +A–C, Courtesy of Dr D. +Collie. +signal from fluid or fat, for example, and so increase sensitivity +for more subtle pathologies. +Examples of brain imaged by the various techniques are +shown in Figure 25.12. +Abnormal EEGs result from a number of conditions. +1100). +EEG remains useful in progressive and continuous +disorders such as reduced consciousness (p. +They have some usefulness +in dynamic imaging, e.g. +flexion/extension of the spine, in +the assessment of instability. +25.13 Different techniques of imaging the cervical spine. +A Lateral X-ray showing bilateral C6/7 facet dislocation. +B Myelogram showing +widening of cervical cord due to astrocytoma (arrows). +A–C, Courtesy of Dr D. +Collie. +A B +1 +2 +3 +4 +5 +5432 +10 987 +15 14 13 12 +1 +1 6 +16 +6 +7 +8 +9 +10 +1 +25 +1 +Secondary generalised +seizure +Fig. +25.14 Electroencephalograms in epilepsy. +(p. +1121), and certain dementias such as Creutzfeldt–Jakob +disease (p. +1127). +25.14). +Digital +recording has enhanced sensitivity and reproducibility of these +tiny potentials. +Healthy nerves at room temperature will conduct at a +speed of 40–50 m/sec. +Such changes in NCS may be +diffuse (as in a hereditary demyelinating peripheral neuropathy, +p. +1138), focal (as in pressure palsies, p. +1139) or multifocal +(e.g. +Guillain–BarrĂŠ syndrome, p. +1140; mononeuritis multiplex, +p. +1140). +1139). +25.15). +Repetitive nerve stimulation (RNS) at 3–15/sec provides +consistent CMAPs in healthy muscle. +In myasthenia gravis +(p. +1143). +Motor unit action potentials are recorded +during muscle contraction. +Axonal loss or destruction will result +in fewer motor units. +Resultant sprouting of remaining units will +lead to increasing size of each individual unit on EMG. +If a +stimulus is provided – e.g. +to the eye, the tiny EEG response +can be discerned when averaging 100–1000 repeated stimuli. +25.15 Motor nerve conduction tests. +A prolonged +L1 (L = latency) would be caused by dysfunction +distally in the median nerve (e.g. +in carpal tunnel +syndrome). +A prolonged L2 is caused by slow +nerve conduction (as in demyelinating +neuropathy). +1111) +and it is likely that further conditions will turn out to have an +immune basis. +56). +1114); myotonic dystrophy +(p. +1143); and some types of spinocerebellar ataxia (p. +1115). +Mitochondrial DNA can also be sequenced to diagnose relevant +disorders (p. +1144). +1133). +In this condition, the LP itself is therapeutic. +1160). +Routine analysis involves a cell count, as well as glucose +and protein concentrations. +Normal values and abnormalities found in specic +conditions are shown in Box 25.6. +1128). +About 30% of LPs are followed by a postural headache, +due to reduced CSF pressure. +25.16 Visual evoked potential (VEP) recording. +information about the integrity of the relevant pathway. +MRI now +provides more information about CNS pathways, thus reducing +reliance on EPs. +25.16). +Again, +MRI has made this technique largely redundant, other than for +research. +Specic blood tests will be highlighted in the relevant +subsections of this chapter. +Aseptic +technique renders secondary infections such as meningitis +extremely rare. +History-taking is a highly active process. +It is important to be clear about what patients mean by certain +words. +These should +remain uppermost in the doctor’s mind while the history is +being elicited. +Some common combinations of symptoms may +suggest particular locations for a lesion (Box 25.10). +Epidemiology must be borne in mind. +How likely is it that this +particular patient has any specic condition under consideration? +Nerve biopsy can help in the investigation of peripheral +neuropathy. +Usually, a distal sensory nerve (sural or radial) is +targeted. +Brain biopsy is required when imaging fails to clarify the +nature of intracerebral lesions, e.g. +• If intermittent, how often do symptoms occur and how long do they +last? +• Speed of onset: seconds, minutes, hours, days, weeks, months, +years, decades? +• Better, worse or the same over time? +25.8 The key diagnostic questions +Where is the lesion? +• Is it neurological? +• If so, to which part of the nervous system does it localise? +Central versus peripheral +Sensory versus motor versus both +What is the lesion? +• Limb tone: more difcult to assess because of poor relaxation and +concomitant joint disease. +• Ankle reflexes: may be absent. +• Sensory testing: especially difcult when there is cognitive +impairment. +• Vibration sense: may be reduced distally in the legs. +Determining the evolution, speed of onset and progression of +a disease is important (Box 25.11). +Destructive lesions of the trigeminal +nerve usually cause numbness rather than pain. +While detailed questioning will be dealt with in the relevant section +(p. +Persisting seizure activity has a recognised mortality and is a +medical emergency. +As seizure activity becomes prolonged, +movements may become more subtle. +Treatment +and investigation are outlined in Box 25.12. +Many neurological symptoms are not explained by disease. +Functional symptoms require considerable experience in diagnosis +and are frequently missed (p. +1094). +184). +The emergency +clinical assessment of headaches is dealt with on page 185. +Ocular +pain and headache are also discussed on page 1170. +Facial pain +Pain in the face can be due to dental or temporomandibular +joint problems. +Facial pain is not uncommon in migraine but some syndromes +can present solely with facial pain. +194). +Clarication of cause +and prognosis may require specialist neurological input. +Amnesia +Memory disturbance is a common symptom. +In the absence of +signicant functional impairment (e.g. +It can also be seen in conjunction +with other types of dementia. +It is important to identify and treat depression (p. +1185) +in patients with memory loss. +1191). +Points to consider are shown +on Figure 25.17 and in Boxes 25.13 and 25.14. +Pain +may restrict movement and thus mimic weakness. +Paradoxically, +sensory neglect (p. +1083) may leave patients unaware of severe +weakness. +1112). +Investigation and treatment of the dementias are +discussed elsewhere (p. +1191). +These are usually distinguished on the basis of +the history. +Consciousness is preserved and +patients may perform even complex motor acts normally. +During +the attack there is retrograde amnesia for the events of the past +few days, weeks or years. +25.17 Patterns of motor loss according +to the anatomical site of the lesion. +Clinical examination is often +variable (e.g. +Vesicles in the ear or on the palate +may indicate primary herpes zoster infection (p. +239). +Patients unable to close the eye should be referred +urgently to an ophthalmologist. +About 80% of patients recover +spontaneously within 12 weeks. +Plastic surgery may be considered +for the minority left with facial disgurement after 12 months. +Recurrence is unusual and should prompt further investigation. +Unlike Bell’s palsy, lesions with an upper motor neuron origin +may spare the upper face. +Sensory disturbance +Sensory symptoms are common and frequently benign. +While +neurological disease can cause sensory symptoms, systemic +disorders can also be responsible. +Tingling in both hands and +around the mouth can occur as the result of hyperventilation +(p. +558) or hypocalcaemia (p. +662). +Numbness and paraesthesia +The history may give the best clues to localisation and pathology. +Rarely, unpleasant paraesthesia of sensory epilepsy spreads +within seconds. +1202). +25.18). +If smaller nerve bres are preferentially affected (e.g. +Pain is often felt in the +myotome rather than the dermatome. +The nerve root involved +may be deduced from the dermatomal pattern of sensory loss +(p. +1071), although overlap may lead to this being smaller than +expected. +Clinical +examination may reveal dissociated sensory loss, i.e. +different +patterns in the spinothalamic and dorsal columnar pathways. +1084). +Lesions in the centre of the spinal cord (such as syringomyelia: +see Box 25.83 and Fig. +25.51, pp. +An isolated lesion of the dorsal columns is not uncommon +in multiple sclerosis. +25.18 Patterns of sensory loss. +A Generalised peripheral neuropathy. +B Sensory roots: some common examples. +C Single dorsal column lesion +(proprioception and some touch loss). +D Transverse thoracic spinal cord lesion. +F Central cord lesion: ‘cape’ distribution of spinothalamic loss. +H Hemisphere (thalamic) lesion: contralateral loss on one side of face and body. +ipsilateral facial sensory disturbance. +For example, pain resembling +trigeminal neuralgia can be seen in patients with multiple sclerosis. +1070). +1066). +The initial points of +entry into the cortex are the respective primary cortical areas (see +Fig. +25.4, p. +1067). +Cortical lesions are more likely to cause a mixed motor and +sensory loss. +Treatment of these syndromes can be difcult. +Electrical stimulation has occasionally proved +successful. +For further information, see page 1347. +Functional movement disorders are +common and may mimic all of the organic syndromes below. +The most important hypokinetic disorder is Parkinson’s disease +(p. +1112). +They suggest +disease in the caudate nucleus (as in Huntington’s disease, +p. +1114) and are a common complication of levodopa treatment +for Parkinson’s disease. +Other causes are shown in Box 25.17. +The lesion localises to the contralateral subthalamic +nucleus and the most common cause is stroke. +Dystonia +Sustained involuntary muscle contraction causes abnormal +postures or movement. +Dystonic tremor +is associated, and is asymmetrical and of large amplitude. +Myoclonus +Myoclonus consists of brief, isolated, random jerks of muscle +groups. +This is physiological at the onset of sleep (hypnic jerks). +Myoclonus may occur in disorders of the +cerebral cortex, such as some forms of epilepsy. +Unlike dyskinesias, +the patient may be able to suppress them, although only for a +short time. +Isolated tics are common in childhood and usually +disappear. +Tics may also occur in Huntington’s and Wilson’s diseases, or +after streptococcal infection. +Examples of complex motor +activities include dressing, using cutlery and geographical +orientation. +The results of damage to particular lobes of the brain +are given in Box 25.2 (p. +1066). +vestibulospinal, rubrospinal and reticulospinal tracts). +Disorders of balance can therefore arise from any part of this +process. +The patient +may complain of different symptoms, depending on the location +of the lesion. +A careful +history is vital. +Examination of such patients may yield physical signs that +again depend on the site of the lesion. +1090), impaired vestibular function (p. +1104) or lack of joint position sense. +Leg weakness, if present, will be detectable +on examination of the limbs. +Bilateral labyrinthine dysfunction often causes +some unsteadiness. +Benign paroxysmal positional vertigo +(p. +1104) lasts a few seconds on head movement. +A careful +history will reveal the likely cause in most patients. +Abnormal gait +Many neurological disorders can affect gait. +Pyramidal gait +Upper motor neuron lesions cause characteristic extension of +the affected leg. +Foot drop +In normal walking, the heel is the rst part of the foot to hit the +ground. +Inability to walk heel to toe may be the only sign of less severe +cerebellar dysfunction. +Proprioceptive defects can also cause an ataxic gait. +The +impairment of joint position sense makes walking unreliable, +especially in poor light. +The patient may be able +to carry out complex motor tasks (e.g. +bicycling motion) while +recumbent and yet cannot formulate the motor act of walking. +Marche Ă  petits pas +This gait is characterised by small, slow steps and marked +instability. +Extrapyramidal gait +The rigidity and bradykinesia of basal ganglia dysfunction +(p. +Combinations of speech and +swallowing problems are explained below (p. +1093). +Dysphonia +Dysphonia describes hoarse or whispered speech. +Language function is not affected. +Dysarthria is discussed further in the section on +bulbar symptoms (p. +1093). +Dysphasia +Dysphasia (or aphasia) is a disorder of the language content of +speech. +It can occur with lesions over a wide area of the dominant +hemisphere (Fig. +25.19). +Dysphasia may be categorised according +to whether the speech output is fluent or non-fluent. +‘Pure’ aphasias are selective impairments in reading, writing +or the recognition of words. +These disorders may be quite +selective. +For example, a person is able to read but not write, +or is able to write but not read. +Examples include pure alexia, +agraphia and pure word deafness. +Frontal lobe +lesions are a rare cause. +Positive olfactory symptoms may arise +in Alzheimer’s disease or epilepsy. +Eye movements may be +disturbed, giving rise to double vision (diplopia) or blurred vision. +Loss of vision is also discussed on page 1170. +Patterns of visual eld loss are +explained by the anatomy of the visual pathways (see Fig. +25.7, +p. +1069). +Associated clinical manifestations are described in +Box 25.19. +Visual symptoms affecting one eye only are due to +lesions anterior to the optic chiasm. +Simple +flashes of light (phosphenes) may indicate damage to the retina +(e.g. +detachment) or to the primary visual cortex. +25.19 Classication of cortical speech problems. +(1) Wernicke’s +aphasia: fluent dysphasia with poor comprehension and poor repetition. +(2) Conduction aphasia: fluent aphasia with good comprehension +and poor repetition. +(3) Broca’s aphasia: non-fluent aphasia with good +comprehension and poor repetition. +(4) Transcortical sensory aphasia: +fluent aphasia with poor comprehension and good repetition. +(5) +Transcortical motor aphasia: non-fluent aphasia with good comprehension +and good repetition. +Closing either +eye in turn will abort binocular diplopia. +25.20 Examination ndings in 3rd, 4th and 6th nerve palsy. +Diplopia tends to be more obvious on lateral gaze compared to primary position. +neuromuscular junction (see Fig. +25.8, p. +1070). +fatigability in +myasthenia) provide further clues to the cause. +The causes of ocular motor nerve palsies are listed in Box +25.20. +Examination ndings are illustrated in Figure 25.20. +Nystagmus +Nystagmus describes a repetitive to-and-fro movement of the +eyes. +Nystagmus may be horizontal, vertical or torsional, and usually +involves both eyes synchronously. +The brainstem and the cerebellum are involved in maintaining +eccentric positions of gaze. +Other signs of brainstem dysfunction may be evident. +Brainstem disease may also cause vertical nystagmus. +Central vestibular nystagmus is more persistent. +Nystagmus also occurs as a consequence of drug toxicity +and nutritional deciency (e.g. +thiamin). +Structural damage to the iris itself can also result in pupillary +abnormalities. +Causes are given in Box 25.22. +An example is +shown in Figure 25.22. +CPEO +25 +Fig. +25.21 Differential diagnosis of unilateral ptosis. +Disc margins become indistinct and haemorrhages +may occur in the retina (Fig. +25.23). +Lack of papilloedema never +excludes raised intracranial pressure. +Other causes of optic disc +swelling are listed in Box 25.23. +Some normal variations of disc +appearance (e.g. +optic nerve drusen, p. +1178) can mimic disc +swelling. +Optic disc swelling is also discussed on page 1171. +25.24). +A pale disc (optic +Fig. +25.22 Right-sided Horner’s syndrome due to paravertebral +metastasis at T1. +25.23 Mechanism of optic disc oedema (papilloedema). +A Normal. +B Disc oedema (e.g. +due to cerebral tumour). +(CSF = cerebrospinal fluid) C, Courtesy of Dr B. +Cullen. +methanol) +• Inltration of optic disc +• Sarcoidosis +• Glioma +• Lymphoma +Fig. +25.24 Fundus photograph of the left eye of a patient with +familial optic atrophy. +Friedreich’s ataxia, p. +1116). +Prominent deafness may suggest a +mitochondrial disorder (see Box 25.93, p. +1144). +Structural +causes of dysphagia are considered on page 778. +Intermittent fatigable +muscle weakness (including dysphagia) would suggest myasthenia +gravis. +More slowly developing dysphagia suggests +a myopathy or possibly a brainstem or skull-base tumour. +The tongue may be wasted and fasciculating, and +palatal movement is reduced. +Causes of these are shown +in Box 25.24. +Abnormalities in these functions considerably +reduce quality of life for patients. +Incontinence and its management +are discussed elsewhere (pp. +397, 835 and 1309). +In the absence of conscious control (e.g. +The bladder is small +and highly sensitive to being stretched. +This results in frequency, +urgency and urge incontinence. +This +manifests as both urgency and an inability to pass urine, which +is distressing and painful. +Coexisting +cognitive impairment may result in inappropriate micturition. +1072) +(lacunar) infarction +Degenerative Motor neuron +Motor neuron disease +Syringobulbia +disease (p. +1116) +Inflammatory/ +Multiple sclerosis +infective +(p. +1106) +Cerebral vasculitis +25 +Myasthenia (p. +1140) +Guillain–BarrĂŠ syndrome +(p. +1140) +Poliomyelitis (p. +1123) +Lyme disease (p. +Clinical features and +management are summarised in Box 25.25. +speech, motor planning and organisation. +Sleep disturbance +Disturbances of sleep are common and are not usually due to +neurological disease. +For further information on erectile dysfunction, see page 440. +1066). +The nature of any change may help localise +the lesion. +1187). +Some of these are +psychogenic (or conversion) disorders. +Hoover’s sign, p. +1082) +• Situational provocation of events (e.g. +It is of constant +character and generalised, but often radiates forwards from +the occipital region. +Tension-type headache is rarely disabling and +patients appear well. +The pain often progresses throughout the +day. +The concept of medication overuse headache needs +careful explanation. +Investigation is rarely required. +an arachnoid cyst, Chiari I malformation or +vascular abnormality). +The value of such ‘reassurance’ is usually +over-estimated by doctors and patients alike. +Some clinical +features may hint at a functional origin for symptoms (Box 25.26). +Activation of the trigeminovascular system is probably important. +1052) or mitochondrial disease (p. +1144). +184). +Primary headache syndromes are described here. +Isolated aura may occur (i.e. +the neurological +symptoms are not followed by headache). +Movement makes the pain worse and patients prefer +to lie in a quiet, dark room. +This persistent migrainous +aura may occur with or without evidence of brain infarction. +Nausea may require an antiemetic such as metoclopramide or +domperidone. +Severe attacks can be aborted by one of the +‘triptans’ (e.g. +sumatriptan), which are potent 5-hydroxytryptamine +(5-HT, serotonin) agonists. +These can be administered via the +oral, subcutaneous or nasal route. +Caution is needed with +ergotamine preparations because they may lead to dependence. +Overuse of any analgesia, including triptans, may contribute to +medication overuse headache. +If attacks are frequent (more than two per month), prophylaxis +should be considered. +Management is by withdrawal of the responsible analgesics. +Although uncommon, it is the most common of the +trigeminal autonomic cephalalgia syndromes. +Functional imaging +studies have suggested abnormal hypothalamic activity. +Patients +are more often smokers with a higher than average alcohol +consumption. +The pain, though severe, is characteristically brief +(30–90 minutes). +The brevity of +the attack probably prevents other migraine therapies from +being effective. +1200). +Other compressive lesions, usually +benign, are occasionally found. +Clinical features +The pain is repetitive, severe and very brief (seconds or less). +It +may be triggered by touch, a cold wind or eating. +There is a tendency for +the condition to remit and relapse over many years. +Management +The pain often responds to carbamazepine. +It is wise to start with +a low dose and increase gradually, according to effect. +Patients +develop a sudden, severe headache with exertion, including sexual +activity. +Subarachnoid haemorrhage +needs to be excluded by CT and/or CSF examination (see +Fig. +26.14, p. +1162) after a rst event. +The pathogenesis of +these headaches is unknown. +The syndrome +may recur, and prevention may be necessary with propranolol +or indometacin. +Epilepsy is the tendency to have unprovoked seizures. +298). +a single seizure in the presence of a cortical lesion). +Such changes may lead to an observed increase in epilepsy +incidence. +25.25 The pathophysiological classication of seizures. +In vivo, epileptic +cortex shows repetitive discharges involving large groups +of neurons. +When both +hemispheres become involved, the seizure becomes generalised +(Fig. +25.25). +25.25) and spreading rapidly. +GGEs almost +always become apparent before the age of 35. +Seizure activity is usually apparent on EEG as spike and wave +discharges (see Fig. +25.14, p. +1075). +Any triggers should be identied (Box 25.29). +Where activity remains focal, the +classification will be obvious. +They are +caused by localised cortical activity with retained awareness. +The +localisation of such symptoms is described above. +Causes +of focal seizures are given in Box 25.30. +During this phase, breathing stops and central cyanosis +may occur. +During the attack, +urinary incontinence and tongue-biting may occur. +Subsequently, the patient +usually feels unwell and sleepy, with headache and myalgia. +Some may not describe the tonic or clonic phase +and may not mention cyanosis or tongue-biting. +Causes of +generalised tonic–clonic seizures are listed in Box 25.31. +Absence seizures Absence seizures (previously ‘petit mal’) always +start in childhood. +The attacks are rarely mistaken for focal +seizures because of their brevity. +Myoclonic seizures These are typically brief, jerking movements, +predominating in the arms. +1144) +• Storage diseases +• Phakomatoses (e.g. +tuberous +sclerosis, p. +1264) +• von Hippel–Lindau disease +(p. +1132) +• Neurobromatosis (p. +1129) +Trauma (including neurosurgery) +Infective (p. +1118) +Inflammatory +• Systemic lupus erythematosus +• Multiple sclerosis (uncommon; +(p. +1106) +(p. +1992) +(rarely; p. +They occur only in the context of epilepsy +syndromes that involve other forms of seizure. +They are usually seen +as part of an epilepsy syndrome and are unlikely to be isolated. +Clonic seizures Clonic seizures are similar to tonic–clonic seizures. +The clinical manifestations are similar but there is no preceding +tonic phase. +EEG may help +to assess prognosis once a rm diagnosis has been made. +Further seizures are less likely if an identied trigger can +be avoided (see Box 25.29). +Other investigations for infective, toxic and metabolic causes +(Box 25.34) may be appropriate. +Structural lesion? +• CT • MRI +Metabolic disorder? +Advice +should be given that on no account should anything be inserted +into the patient’s mouth. +The management of status epilepticus +is described on page 1080. +This +applies at work, at home and at leisure. +At home, only shallow +baths (or showers) should be taken. +The risk of harm from epilepsy should be discussed around the +time of diagnosis. +Treatment decisions should +always be shared with the patient, to enhance adherence. +A +wide range of drugs is available. +In +the majority of patients, full control is achieved with a single drug. +Dose regimens should be kept as simple as possible. +The EEG may help to establish the type of epilepsy +and guide therapy. +Investigations should be revisited if the +epilepsy is intractable to treatment. +Indications for imaging are summarised in Box 25.35. +Imaging +cannot establish a diagnosis of epilepsy but identies any structural +cause. +It is not required if a condent diagnosis of a recognised +GGE syndrome (e.g. +juvenile myoclonic epilepsy) is made. +N.B. +Use as few drugs as possible at the lowest possible dose. +Occult lesion? +Overall, the +recurrence rate after drug withdrawal depends on the individual’s +epilepsy history. +1146). +are listed in Box 25.39. +Monitoring therapy +Some practitioners confuse epilepsy care with serum level +monitoring. +Sodium valproate and levetiracetam have no interaction with +hormonal contraception. +There is usually concern about +teratogenesis associated with AEDs. +The risks of abrupt +AED withdrawal to the mother should be stressed. +Oral contraception can interact with +individual AEDs (Box 25.41). +• Non-convulsive status epilepticus: can present as delirium in the +elderly. +A seizure may occur +with an overt stroke or with occult vascular disease. +Fear may make some educational institutions unduly restrictive. +• Alcohol: may affect sleep pattern; excess may be associated with +poor AED adherence. +• Illicit drugs: may affect seizure threshold and be associated with +poor AED adherence. +• Sleep disturbance: may be worsened by social activities and +computer games. +• Oral contraception: interactions with AED can occur. +Use may not +always be disclosed to parents. +Prognosis +The outcome of newly diagnosed epilepsy is generally good. +The presence of a structural +lesion reduces the chances of freedom from seizures. +The overall +prognosis for epilepsy is shown in Box 25.37. +Status epilepticus +Presentation and management are described on page 1080. +It may cause only altered awareness, delirium or +wandering with automatisms. +• Fetal malformation: risk is minimised if a single drug is used. +Carbamazepine and lamotrigine have the lowest incidence of +major fetal malformations. +The risk with sodium valproate is higher but should be carefully +balanced against its benets. +Levetiracetam may be safe but avoid other newer drugs if +possible. +• Haemorrhagic disease of the newborn: enzyme-inducing +antiepileptic drugs increase risk. +• Pharmacokinetic effects of pregnancy: carbamazepine levels +may fall in the third trimester. +Lamotrigine and levetiracetam levels +may fall early in pregnancy. +Some advocate monitoring of levels. +251104 • NEUROLOGY +have no abnormal EEG discharges. +Such attacks may be very +prolonged, sometimes mimicking status epilepticus. +Cyanosis and +severe biting of the tongue are rare but incontinence can +occur. +Distress and crying are common following non-epileptic +attacks. +They are not necessarily associated +with formal psychiatric illness. +Patients and carers may need +reassurance that hospital admission is not required for every +attack. +Prevention requires psychotherapeutic interventions +rather than drug therapy (p. +1202). +During the acute attack, nystagmus (p. +1090) will be present +for a few days. +It +may follow minor head injury but typically is spontaneous. +25.26). +1146). +Over the years, +patients may develop progressive deafness (typically low-tone on +audiometry). +Examination is typically normal in between attacks. +The diagnosis is clinical, supported by abnormal audiometry. +Central (brain) causes of vertigo are rare by comparison, with +the exception of migraine (p. +1095). +It usually presents as isolated severe vertigo with +vomiting and unsteadiness. +It begins abruptly, often on waking, +and many patients are initially bed-bound. +The vertigo settles +A B +Fig. +25.26 The Hallpike manœuvre for diagnosis of benign paroxysmal positional vertigo (BPPV). +A Perform rst with the right ear down. +B Perform next with the left ear down. +The examiner looks for nystagmus (usually accompanied by vertigo). +Its onset is usually delayed a few seconds and it lasts 10–20 seconds. +Management includes a low-salt diet, vestibular sedatives for acute +attacks (e.g. +Many symptoms +and disorders may affect sleep and sleep quality (e.g. +pain, +depression/anxiety, parkinsonism). +Excessive daytime sleepiness +(hypersomnolence) +There are primary and secondary causes (Box 25.44). +The most +common causes are impaired sleep due to lifestyle issues or +sleep-disordered breathing (p. +622). +Sleepiness may be measured +using the Epworth Sleepiness Score (see Box 17.86, p. +623). +Other characteristic features +help distinguish this from excessive daytime sleepiness (Box +25.45). +Symptoms may be due to loss of hypocretin-secreting +hypothalamic neurons. +Diagnosis requires sleep study with +sleep latency testing (demonstrating rapid onset of REM sleep). +Parasomnias +Parasomnias are abnormal motor behaviours that occur around +sleep. +They may arise in either REM or non-REM sleep, with +characteristic features and timing. +Non-REM parasomnias tend to +occur early in sleep. +1101). +History from a sleeping partner or other witness is +essential. +Patients have +little or no recollection of the episodes, even though they appear +‘awake’. +The episodes may be triggered by alcohol or unfamiliar +sleeping situations, and can be familial. +Treatment is usually not +required but clonazepam can be used. +They are easily roused from this +state, with recollection of their dream, unlike in non-REM states. +1111), perhaps preceding more typical symptoms of these +conditions by years. +Polysomnography will conrm absence of +atonia during REM sleep. +Clonazepam is the most successful +treatment. +25.27). +After the acute +attack, gliosis follows, leaving a shrunken scar. +25.28). +Recent +changes to diagnostic criteria mean that MS may be diagnosed +after an isolated episode (i.e. +Symptoms and signs of MS usually evolve +over days or weeks, resolving over weeks or months. +Rarely, a +more rapid stroke-like presentation may occur. +25.28). +Frequent relapses with incomplete +recovery indicate a poor prognosis. +The physical signs observed +in MS are determined by the anatomical site of demyelination. +clinical (Box 25.46). +It has a strong familial tendency and can +present with daytime somnolence due to poor sleep. +Treatment, if +required, is with dopaminergic drugs (dopamine agonists or +levodopa, p. +1113) or benzodiazepines. +The pathological signicance of PLMS +is uncertain and it often occurs in normal health. +There is an +overlap with RLS. +Treatment is most successful with clonazepam +or dopaminergic drugs. +Monozygotic twins have a concordance +rate of 30%. +25.27 Multiple sclerosis. +B Brain magnetic resonance imaging in multiple sclerosis. +Multiple +high-signal lesions (arrows) seen particularly in the paraventricular region +on T2 image. +If there is incomplete +association, the diagnosis is ‘possible MS’. +2 Assumes other possible causes for +central nervous system inflammation (e.g. +sarcoidosis, systemic lupus +erythematosus) have been excluded. +3 MS-typical regions = periventricular, +juxtacortical, infratentorial, spinal cord. +From Polman CH, Reingold SC, Branwell B, et al. +Diagnostic criteria for multiple +sclerosis. +Courtesy of Prof. +D.A.S. +Compston. +Prognosis is good for patients with optic neuritis and only sensory +relapses. +25.29). +MS mimics should be excluded (see +below). +MRI is the most sensitive technique for imaging lesions in +Fig. +25.29 Investigations in a patient suspected of having multiple +sclerosis. +brain and spinal cord (Fig. +25.30) and for excluding other causes +that have provoked the neurological decit. +The CSF may show a lymphocytic pleocytosis in the acute +phase and unique (i.e. +absent from the serum) oligoclonal bands +of IgG in 70–90% of patients between attacks. +These can appear in +other disorders, which should be excluded by examination and +investigation. +A Sagittal plane. +B Axial plane. +Prophylaxis to prevent glucocorticoid-induced osteoporosis +(p. +1045) should be considered in patients requiring multiple +courses of glucocorticoids. +They are not indicated for treatment of early or pre-clinical MS. +Clinical trials involving stem cells are ongoing. +When and if +disability occurs, patients and their relatives need appropriate +support. +The clinical picture may be very similar +to a rst relapse of MS. +It is usually thought to be +post-infectious in origin. +MRI should +distinguish this from an external lesion affecting the spinal +cord. +CSF examination shows cellular pleocytosis, often with +polymorphs at the onset. +Oligoclonal bands are usually absent. +Treatment is with high-dose intravenous methylprednisolone. +Some clinical features may suggest a higher risk of MS +after transverse myelitis. +The disease has +been recognised for many years, particularly in Asia. +The majority +of cases are associated with an antibody to a neuronal membrane +channel, aquaporin 4. +provision of aids at home, reducing handicap. +Bladder care is +particularly important. +Urgency and frequency can be treated +pharmacologically (see Box 25.25, p. +1094) but this may lead +to a degree of retention with an attendant risk of infection. +Sexual dysfunction is +a frequent source of distress. +Seizures or coma may occur. +A minority of patients +who recover have further episodes. +1065). +The +CSF often shows an increased protein and lymphocyte count +with oligoclonal bands. +Treatment is directed at the primary tumour. +Some improvement may occur +following administration of intravenous immunoglobulin. +The causes are not yet known, although +genetic influences are important. +Alzheimer’s disease (p. +1192) +and Parkinson’s disease are the most common. +Movement disorders +Movement disorders present with a wide range of symptoms. +They may be genetic or acquired, and the most important is +Parkinson’s disease. +1084), with associated increased tone (rigidity), +tremor and loss of postural reflexes. +There are many causes (Box +25.54) but the most common is Parkinson’s disease (PD). +PD +has an annual incidence of about 18/100 000 in the UK and a +prevalence of about 180/100 000. +Average age of onset is about 60 years +and fewer than 5% of patients present under the age of 40. +It is progressive and incurable, +with a variable prognosis. +25.31). +The loss of dopaminergic neurotransmission +is responsible for many of the clinical features. +The motor symptoms are almost always initially +asymmetrical. +Tremor is an early feature but may not be present +in at least 20% of people with PD. +It is typically a unilateral rest +tremor (p. +1085) affecting limbs, jaw and chin but not the head. +In +some patients, tremor remains the dominant symptom for many +years. +Rigidity causes stiffness and a flexed posture. +As the disease advances, +speech becomes softer and indistinct. +There are a number of +abnormalities on neurological examination (Box 25.55). +Although features are initially unilateral, gradual bilateral +involvement evolves with time. +25.31 Parkinson’s disease. +Courtesy of Dr J. +25.32 Imaging in Parkinson’s disease. +B Normal. +Debate +continues about when and what treatment should be started. +Some non-motor symptoms, such as anxiety or +depression, may respond to drug or non-drug treatments. +Many other non-motor symptoms +are resistant to treatment. +Drugs for PD should not be stopped +abruptly, as this can precipitate malignant hyperthermia. +Levodopa Levodopa is the precursor to dopamine. +This peripheral conversion +is responsible for the high frequency of adverse effects. +Madopar is also available as a dispersible +tablet for more rapid-onset effect. +Investigations +The diagnosis is clinical. +Functional +dopaminergic imaging (SPECT or PET) is abnormal, even in the +early stages (Fig. +In younger patients, specific +investigations may be appropriate (e.g. +exclusion of Huntington’s +or Wilson’s diseases). +The ergot-derived agonists are no longer recommended +because of rare but serious brotic effects. +MAOI-B inhibitors Monoamine oxidase type B facilitates breakdown +of excess dopamine in the synapse. +Two inhibitors are used in +PD: selegiline and rasagiline. +The effects of both are modest, +although usually well tolerated. +Neither is neuroprotective, despite +initial hopes. +Two +inhibitors are available: entacapone and tolcapone (which also +inhibits central COMT). +Entacapone has a modest effect and +is most useful for early wearing-off. +The more potent tolcapone is less used +because of rare but serious hepatotoxicity. +Anticholinergic drugs These were the main treatment for PD +prior to the introduction of LD. +Several anticholinergics are available, including trihexyphenidyl +(benzhexol) and orphenadrine. +Surgery +Destructive neurosurgery was commonly used before the +introduction of LD. +Intracranial delivery of fetal grafts or specic growth +factors remains experimental. +They typically +have a more rapid progression than PD and tend to be resistant +to treatment with LD. +They are defined pathologically and +identication during life is difcult. +It is much less common than PD, with a prevalence +of about 4/100 000. +Cognition is usually unaffected. +It is therefore a tauopathy rather than +synucleinopathy. +The prevalence is about 5/100 000, with average +survival similar to that in MSA. +There is no treatment, and the +parkinsonism usually does not respond to LD. +A number of other +diseases may present with a corticobasal syndrome, including +other dementias. +896). +It is due +to expansion of a trinucleotide CAG repeat in the Huntingtin gene +on chromosome 4 (p. +43). +The prevalence is +about 4–8/100 000. +There is always a family history, although +this may be concealed. +59). +Brain imaging may show +caudate atrophy but is not a reliable test. +There are a number +of HD mimics. +Management is symptomatic. +The chorea may respond to +neuroleptics such as risperidone or sulpiride, or tetrabenazine. +Depression and anxiety are common and may be helped by +medication. +A signicant proportion +of cases remain idiopathic despite investigation. +Tremor disorders +25 +Tremor (p. +The +head and voice may be involved. +The tremor improves in about +50% of patients with small amounts of alcohol. +It may, +however, be symptomatic and secondary to structural lesions. +In refractory cases, microvascular +decompression may be considered. +Annual incidence is +about 2/100 000, with a prevalence of about 7/100 000. +Most +cases are sporadic but 10% of cases are familial. +The most common form of MND (Fig. +25.33) is amyotrophic lateral sclerosis (ALS), and many use the +terms MND and ALS interchangeably. +The +average age of onset is 65, with 10% presenting before 45 years. +Clinical features +Diagnosis can be difcult and is often delayed. +MND typically +presents focally, either with limb onset (e.g. +Sensory, autonomic and visual +symptoms do not occur, although cramp is common (Box +25.60). +Dystonia also occurs as a primary disorder. +Task-specic symptoms (e.g. +writer’s cramp, musician’s +dystonia) are often dystonic. +Treatment is difcult but botulinum +toxin injections or DBS may be useful. +The spasms are exacerbated by talking, eating and stress. +25.33 Patterns of involvement in motor neuron disease. +EMG will usually conrm the typical features of +widespread denervation and re-innervation. +Spinal fluid analysis is +not usually necessary. +Involvement +is usually symmetrical but occasional localised forms occur. +brisk reflexes in wasted, fasciculating +muscles) without sensory involvement (Fig. +25.33). +About 10% of +patients presenting with FTD will develop ALS within a few years +of dementia onset. +Investigations +Clinical features are often typical but alternative diagnoses should +be excluded. +1140) and cervical myeloradiculopathy, is essential. +Where specic immunisation is not employed, the mumps virus +is a common cause. +The headache is usually the most severe feature. +There may be a high pyrexia but focal neurological signs are rare. +Investigations +The diagnosis is made by lumbar puncture. +CSF usually contains +an excess of lymphocytes. +While glucose and protein levels are +commonly normal, the latter may be raised. +Management +There is no specic treatment and the condition is usually benign +and self-limiting. +The patient should be treated symptomatically +in a quiet environment. +Recovery usually occurs within days, +although a lymphocytic pleocytosis may persist in the CSF. +Whatever the virus, complete recovery +without specic therapy is the rule. +The major infections of the nervous system are listed in Box +25.61. +The frequency of these varies geographically. +Meningism is not specic to meningitis and can occur in patients +with subarachnoid haemorrhage. +Abnormalities in the CSF (see Box 25.6, +p. +1078) are important in distinguishing the cause of meningitis. +Causes of meningitis are listed in Box 25.62. +It is much less serious than bacterial meningitis unless +there is associated encephalitis. +meningitidis (subtypes +and adult +B, C, Y, W) +Strep. +pneumoniae +L. +monocytogenes +M. +tuberculosis +Staphylococcus aureus +(skull fracture) +H. +influenzae +Empirical antibiotics (Box 25.65) +Transfer to critical care facility +signicant. +The organism invades +through the nasopharynx, producing sepsis and leading to +meningitis. +In India, H. +influenzae B and +Strep. +pneumoniae are probably the most common causes of +bacterial meningitis, especially in children. +Streptococcus suis +is a rare zoonotic cause of meningitis associated with porcine +contact. +Pus then forms in layers, which may +later organise to form adhesions. +Hearing loss is a +frequent complication. +Clinical features +Headache, drowsiness, fever and neck stiffness are the usual +presenting features. +Complications of meningococcal sepsis are listed in +Box 25.64. +25.34 The investigation of meningitis. +with recurrent fever, sweating, joint pains and transient rash. +In pneumococcal +and Haemophilus infections there may be an accompanying +otitis media. +259). +It can also +cause meningitis in neonates. +Investigations +Lumbar puncture is mandatory unless there are contraindications +(p. +1077). +This should not, +however, delay treatment of presumed meningitis. +25.34). +Gram lm and +culture may allow identication of the organism. +Blood cultures +may be positive. +PCR techniques can be used on both blood +and CSF to identify bacterial DNA. +These methods are useful in +detecting meningococcal infection and in typing the organism. +Management +There is an untreated mortality rate of around 80%, so action +must be swift. +The only contraindication is a history of penicillin anaphylaxis. +198). +In adults, a +single dose of ciprofloxacin is an alternative. +588). +The use of +glucocorticoids in addition to antituberculous therapy has been +controversial. +Surgical ventricular drainage may be needed if obstructive +hydrocephalus develops. +Other forms of meningitis +Fungal meningitis (especially cryptococcosis; p. +321). +257, 255 and 337), +rickettsiae (typhus fever; p. +270) or protozoa (amoebiasis; p. +286). +Meningitis can also be due to non-infective pathologies. +In Europe, +the most serious cause of viral encephalitis is herpes simplex +(p. +247), which probably reaches the brain via the olfactory nerves. +Varicella zoster is also an important cause. +The epidemiology of some of these infections is +changing. +Japanese encephalitis (p. +Clinical features +The clinical features and staging criteria are listed in Box 25.68. +Onset is much slower than in other bacterial meningitis – over +2–8 weeks. +Investigations +Lumbar puncture should be performed if the diagnosis is +suspected. +The CSF is under increased pressure. +It is usually +clear but, when allowed to stand, a ne clot (‘spider web’) may +form. +The +distribution of lesions varies with the type of virus. +Meningism occurs in many patients. +Rabies presents +a distinct clinical picture and is described below. +Lumbar puncture should be performed once imaging has excluded +a mass lesion. +The CSF may be normal in up to 10% of cases. +Some viruses, +including the West Nile virus, may cause a sustained neutrophilic +CSF. +The protein content may be elevated but the glucose is +normal. +This should be given early to all +patients suspected of having viral encephalitis. +Some survivors will have residual epilepsy or cognitive +impairment. +For details of post-infectious encephalomyelitis, +see page 1110. +Antiepileptic treatment may be required +(p. +1101) and raised intracranial pressure may indicate the need +for dexamethasone. +The CSF is lymphocytic, with a normal glucose. +The causative agent is presumed to be viral. +It is +usually conveyed by saliva through bites or licks on abrasions +or on intact mucous membranes. +Humans are most frequently +infected from dogs and bats. +In Europe, the maintenance host is +the fox. +Severe bites, especially if on the head or neck, are associated +with shorter incubation periods. +Human rabies is a rare disease, +even in endemic areas. +Clinical features +At the onset there may be fever, and paraesthesia at the site +of the bite. +Cranial nerve lesions develop and +terminal hyperpyrexia is common. +Death ensues, usually within +a week of the onset of symptoms. +Management +Established disease +Only a few patients with established rabies have survived. +Otherwise, only palliative treatment is possible once +symptoms have appeared. +The patient should be heavily sedated +with diazepam, supplemented by chlorpromazine if needed. +Nutrition and fluids should be given intravenously or through +a gastrostomy. +Rabies can +usually be prevented if treatment is started within a day or two +of biting. +Delayed treatment may still be of value. +For maximum +protection, hyperimmune serum and vaccine are required. +The safest antirabies antiserum is human rabies immunoglobulin. +Infection usually occurs through +the nasopharynx. +There is +a particular propensity to damage anterior horn cells, especially +in the lumbar segments. +Clinical features +The incubation period is 7–14 days. +Figure 25.35 illustrates the +various features of the infection. +Many patients recover fully after +the initial phase of a few days of mild fever and headache. +Weakness may start later +in one muscle group and can progress to widespread paresis. +Epidemics +vary widely in terms of the incidence of non-paralytic cases +and in mortality rate. +Death occurs from respiratory paralysis. +Muscles showing no signs of recovery after a month will probably +not regain useful function. +Poliomyelitis virus may be cultured from +CSF and stool. +At the onset of +respiratory difculties, a tracheostomy and ventilation are required. +Subsequent treatment is by physiotherapy and orthopaedic +measures. +Prophylaxis +Prevention of poliomyelitis is by immunisation with live (Sabin) +vaccine. +Full details are given on page 239. +It occurs in children +and adolescents, usually many years after the primary virus +infection. +319) or secondary to immunosuppression, +e.g. +following organ transplantation or use of disease-modifying +drugs for MS. +25.35 Poliomyelitis. +Untreated congenital heart disease is a +recognised risk factor. +Haematogenous +spread may lead to multiple abscesses. +Seizures, raised intracranial pressure and focal +hemisphere signs occur alone or in combination. +Distinction +from a cerebral tumour may be impossible on clinical grounds. +25.36). +There may be an elevated white blood cell count +and ESR in patients with active local infection. +The possibility +of cerebral toxoplasmosis or tuberculous disease secondary to +HIV infection (p. +320) should always be considered. +Management and prognosis +Antimicrobial therapy is indicated once the diagnosis is made. +The +likely source of infection should guide the choice of antibiotic (see +Box 25.69). +In neurosurgical patients, the addition of vancomycin +should be considered. +Epilepsy +frequently develops and is often resistant to treatment. +A +B +Fig. +A Unenhanced computed tomography (CT) image. +B Contrast- +enhanced CT image. +The +patient then becomes drowsy, with seizures and focal signs +such as a progressive hemiparesis. +The diagnosis rests on a strong clinical suspicion in patients +with a local focus of infection. +Management requires aspiration of +pus via a burr hole and appropriate parenteral antibiotics. +Any +local source of infection must be treated to prevent re-infection. +Features of the +primary focus of infection may be less obvious and thus can be +overlooked. +Decompressive +laminectomy with abscess drainage relieves the pressure on the +dura. +Organisms may be grown from the pus or blood. +Surgery, +together with appropriate antibiotics, may prevent complete and +irreversible paraplegia. +255). +Paralleled future +increases in neurosyphilis are inevitable. +The clinical manifestations +are diverse and early diagnosis and treatment are essential. +Neurological +examination reveals signs indicative of the anatomical localisation +of lesions. +1092), may accompany any neurosyphilitic syndrome but +most commonly tabes dorsalis. +Investigations +Routine screening for syphilis is warranted in many neurological +patients. +Treponemal antibodies (p. +1092) +involvement is suspected. +338). +Evidence of clinical progression at any time is an indication for +renewed treatment. +Infection enters the body through wounds, which may +be trivial. +In tetanus, the tonic rigidity spreads to involve the muscles +of the face, neck and trunk. +There is rigidity of the muscles at the neck +and trunk of varying degree. +The back is usually slightly arched +(‘opisthotonus’) and there is a board-like abdominal wall. +Autonomic involvement may cause +cardiovascular complications, such as hypertension. +Investigations +The diagnosis is made on clinical grounds. +It is rarely possible +to isolate the infecting organism from the original locus of entry. +For those +allergic to penicillin, erythromycin should be used. +For those already immunised, only a booster dose of toxoid is +required. +Anaerobic conditions are necessary for the organism’s growth. +Wound botulism +is a growing problem in injection drug-users. +Criteria +for the clinical diagnosis are shown in Box 25.72. +The same diseases can occur in an inherited form, due to +mutations in the PrP gene. +Creutzfeldt–Jakob disease +Creutzfeldt–Jakob disease (CJD) is the best-characterised human +TSE. +Some 10% of cases arise from a mutation in the gene +coding for the prion protein. +The sporadic form is the most +common, occurring in middle-aged to elderly patients. +These are particularly +common in CJD transmitted by inoculation (e.g. +by infected dura +mater grafts). +Death occurs after a mean of 4–6 months. +There +is no effective treatment. +25.37 Magnetic resonance imaging in variant Creutzfeldt–Jakob +disease. +Arrows indicate bilateral pulvinar hyperintensity. +earlier. +25.37). +Brain histology is distinct, with very florid +plaques containing the prion proteins. +The clinical +features depend on the site of the mass, its nature and its rate of +expansion. +Symptoms and signs (see Box 25.75) are produced +by a number of mechanisms. +298) +Hydatid cyst (p. +Clinical features +In adults, intracranial pressure is less than 10–15 mmHg. +The features of RICP are listed in Box 25.75. +The speed of +pressure increase influences presentation. +Vomiting, coma, bradycardia and arterial +hypertension are later features of RICP. +The rise in intracranial pressure from a mass lesion may +cause displacement of the brain. +a large hemisphere mass may cause ‘temporal coning’ (Fig. +25.38). +25.39). +This may result in +brainstem haemorrhage and/or acute obstruction of the CSF +pathways. +As coning progresses, coma and death occur unless +the condition is rapidly treated. +Management +Primary management of RICP should be targeted at relieving the +cause (e.g. +25.39 Tonsillar cone. +Downward displacement of the cerebellar +tonsils below the level of the foramen magnum. +Intensive care support may be +needed (p. +208). +The most common benign +brain tumour is a meningioma. +Primary brain tumours do not +metastasise due to the absence of lymphatic drainage in the +brain. +The rate is higher with primaries in the bronchus, +breast and gastrointestinal tract (Fig. +25.40). +Clinical features +The presentation is variable and usually influenced by the rate +of growth. +The primary lesion was +a lung carcinoma. +isolated stable headache is almost never due to intracranial +tumour. +The more malignant tumours are more likely to demonstrate +contrast enhancement on imaging. +If the tumour appears +metastatic, further investigation to nd the primary is required. +Prolactin- or growth hormone-secreting pituitary adenomas +(p. +Clearly, if a tumour occurs in +an area of brain that is highly important for normal function +(e.g. +Meningiomas and acoustic neuromas +offer the best prospects for complete removal and thus cure. +Some meningiomas can recur, however, particularly those of +Fig. +A Axial +image. +B Coronal image. +the sphenoid ridge, when partial excision is often all that is +possible. +Pituitary adenomas may be removed by a +trans-sphenoidal route, avoiding the need for a craniotomy. +In this situation, patient and family should always +be involved in decisions regarding treatment. +Advances have been made recently in terms of therapeutic +outcome. +Benets are more likely in well-debulked patients who +are younger and tter. +Implantation of chemotherapy gives a +small survival benet. +Older patients do not tolerate this, however. +Benets +may be superior in breast cancer but there is little to separate +other pathologies. +2 (see below). +When sporadic, acoustic neuroma occurs after +the third decade and is more frequent in females. +Acoustic neuromas account for 80–90% of tumours +at the cerebellopontine angle. +Vertigo is an unusual +symptom, as slow growth allows compensatory brainstem +mechanisms to develop. +The tumour may be identied incidentally +on cranial imaging. +Investigations +MRI is the investigation of choice (see Fig. +25.42). +Management +Surgery is the treatment of choice. +Stereotactic radiosurgery +(radiotherapy) may be appropriate for some lesions. +25.43), and may affect numerous systems (Box 25.77). +B +25 +B +A +Acoustic neuroma +Fig. +They are discussed in full on page 1110. +25.44). +The causes are listed in Box 25.78. +25.45). +25.44 The circulation of cerebrospinal fluid (CSF). +(4) It is then absorbed into the dural venous sinuses +via the arachnoid villi. +Malignant change may occur in NF1 neurobromas but is rare +in NF2 schwannomas. +The prevalence of NF1 and NF2 is about +20–50 per 100 000 and 1.5 per 100 000, respectively. +A number of drugs may be associated, including tetracycline, +vitamin A and retinoid derivatives. +Clinical examination reveals papilloedema but little else. +False +localising cranial nerve palsies (usually of the 6th nerve) may +be present. +It is important to record visual elds accurately for +future monitoring. +Investigations +Brain imaging is required to exclude a structural or other +cause (e.g. +cerebral venous sinus thrombosis, p. +1162). +The +ventricles are typically normal in size or small (‘slit’ ventricles). +Weight loss in overweight patients may +be helpful if it can be achieved. +Brain injury is more +likely with skull fracture but can occur without. +Individual cranial +nerves may be damaged in fractures of the facial bones or skull +base. +Whatever pathology occurs, the resultant RICP may lead to +coning (see Figs 25.38 and 25.39). +Haematomas are identied +by CT and management is by surgical drainage, usually via a +burr hole. +Penetrating skull fractures lead to increased infection +risk. +There may or may not be a history of trauma. +Headache may +not be present. +The diagnosis should always be considered in +those who present with reduced conscious level. +Fig. +25.45 Magnetic resonance image of hydrocephalus due to +aqueduct stenosis. +Idiopathic intracranial hypertension +This usually occurs in obese young women. +The annual incidence +is about 3 per 100 000. +RICP occurs in the absence of a structural +lesion, hydrocephalus or other identiable cause. +25.47). +MRI is the investigation of choice in those +with radicular symptoms. +25.46). +1087), speech or eye movements. +It is important +to recognise when the spinal cord is at risk of compression +(p. +1136) so that urgent action can be taken. +Cervical spondylosis +Cervical spondylosis is the result of osteoarthritis in the cervical +spine. +It is characterised by degeneration of the intervertebral +discs and osteophyte formation. +Spondylosis may +be associated with neurological dysfunction. +25.46). +More gradual onset may be due to osteophytic +encroachment of the intervertebral foramina. +The neck is held rigidly +and neck movements may exacerbate pain. +Paraesthesia and +Fig. +Root +C5 +C6 +C7 +Sensory loss +(see Fig 25.10, +p. +Sensory manifestations in the legs are much less common. +Investigations +MRI (see Fig. +25.46) (or rarely myelography) will direct surgical +intervention. +The former provides information on the state of the +spinal cord at the level of compression. +The decision as to whether surgery +should be undertaken may be difcult. +Prognosis +The prognosis of cervical myelopathy is variable. +In many patients, +the condition stabilises or even improves without intervention. +Clinical features +The onset may be sudden or gradual. +Alternatively, repeated +episodes of low back pain may precede sciatica by months or +years. +Pain is exacerbated +by coughing or straining but may be relieved by lying flat. +Investigations +MRI is the investigation of choice if available, since soft tissues +are well imaged. +CT can provide helpful +images of the disc protrusion and/or narrowing of exit foramina. +Physical examination at rest shows +preservation of peripheral pulses with absent ankle reflexes. +The symptoms are shown +in Box 25.80. +The signs +vary according to the level of the cord compression and the +structures involved. +Interruption of bres in +the spinal cord causes sensory loss (p. +The distribution of these signs +varies with the level of the lesion (Box 25.81). +The Brown–SĂŠquard syndrome (see Fig. +25.18E, p. +25.11, p. +1072). +This should be followed by appropriate antituberculous +chemotherapy (p. +592) for an extended period. +Traumatic lesions +of the vertebral column require specialised neurosurgical +treatment. +A list of these disorders is given in Box 25.83. +25.18F, p. +1084) can occur only +with intrinsic disease such as syringomyelia. +Investigation of intrinsic disease starts with imaging to exclude +a compressive lesion. +25.51) or intrinsic tumours. +Non-specic signal change may be +seen in the spinal cord in inflammatory (see Fig. +25.30, p. +1109) +or infective conditions and metabolic disorders such as vitamin +B12 deciency. +Lumbar puncture or blood tests may be required +to make a specic diagnosis. +N +SC +Fig. +25.49 Axial magnetic resonance image of thoracic spine. +Fig. +25 +investigation of choice is MRI (Fig. +25.49), as it can dene the +extent of compression and associated soft-tissue abnormality (Fig. +25.50). +Plain X-rays may show bony destruction and soft-tissue +abnormalities. +Routine investigations, including chest X-ray, +may provide evidence of systemic disease. +Management +Treatment and prognosis depend on the nature of the underlying +lesion. +Benign tumours should be surgically excised, and a +Fig. +25.51 Sagittal magnetic resonance image showing descent of +cerebellar tonsils and central syrinx. +1076). +Neuropathies can occur in +association with many systemic diseases, toxins and drugs +(Box 25.85). +Clinical features +Motor nerve involvement produces features of a lower motor +neuron lesion (p. +1082). +Symptoms and signs of sensory nerve +involvement depend on the type of sensory nerve involved +(p. +1083); small-bre neuropathies are often painful. +Investigations +The investigations required reflect the wide spectrum of causes +(Box 25.86). +Most neuropathies are of the chronic +axonal type. +Symptoms and signs of entrapment neuropathy +are listed in Box 25.87. +Weakness progresses over a maximum +of 4 weeks (usually less). +Rapid deterioration to respiratory failure +can develop within hours. +Examination shows diffuse weakness +with loss of reflexes. +Miller Fisher syndrome presents with internal +and external ophthalmoplegia, ataxia and areflexia. +Investigations +The CSF protein is raised, but may be normal in the rst 10 days. +1076). +Antibodies to the ganglioside +GM1 are found in about 25%, usually the motor axonal form. +Other causes of an acute neuromuscular paralysis should be +excluded (e.g. +Supportive measures to prevent +pressure sores and deep venous thrombosis are essential. +Diabetes mellitus +is the most common cause but in about 25–50% no cause +can be found. +diabetes). +Sensory +symptoms and signs develop in an ascending ‘glove and stocking’ +distribution (p. +1083). +The hallmark is an acute paralysis evolving +over days or weeks with loss of tendon reflexes. +The members of this group of +syndromes have different clinical and genetic features. +The clinical features depend on the anatomical site +of the damage (Box 25.89). +600) or damage by therapeutic +irradiation. +The appearance of vesicles should indicate the +alternative diagnosis of motor zoster. +Spinal root lesions +Spinal root lesions (radiculopathy) are described above. +Pain in the muscles innervated by the affected roots +may be prominent. +25.52). +Myasthenic patients are more likely to have associated +organ-specic autoimmune diseases. +Triggers are not always +evident but some drugs (e.g. +In older patients, males are more commonly affected. +It tends to run a relapsing and remitting course. +Worsening of symptoms towards the end of the day +or following exercise is characteristic. +Respiratory muscles may be involved and +respiratory failure is an avoidable cause of death. +Aspiration may +occur if the cough is ineffectual. +Ventilatory support is required +where weakness is severe or of abrupt onset. +25.52 Myasthenia gravis and Lambert–Eaton myasthenic syndrome (LEMS). +Myasthenic symptoms can be transiently improved by +inhibition of acetylcholinesterase (e.g. +with Tensilon – edrophonium bromide), which normally removes the acetylcholine. +Cover with intravenous atropine is +necessary to avoid bradycardia. +Planning assessment beforehand +(e.g. +speech or limb movements) allows some objectivity in +gauging the effect. +1076) if the +muscle has been clinically affected. +Screening for associated +autoimmune disorders, particularly thyroid disease, is important. +The duration of action of acetylcholine is prolonged by inhibiting +acetylcholinesterase. +The most commonly used anticholinesterase +drug is pyridostigmine. +Muscarinic side-effects, including diarrhoea +and colic, may be controlled by propantheline. +Immunological treatment of myasthenia is outlined in Box +25.90. +Thymectomy may improve overall prognosis but awaits +clinical trial conrmation. +Prognosis is variable and remissions +may occur spontaneously. +When myasthenia is entirely ocular, +prognosis is excellent and disability slight. +Rapid progression of the disease more than 5 years after onset +is uncommon. +Diseases of muscle +Muscle disease, either hereditary or acquired, is rare. +Most +typically, it presents with a proximal symmetrical weakness. +Myotonic +dystrophy is the most common, with a prevalence of about +12/100 000. +Clinical features +The pattern of the clinical features is dened by the specic +syndromes. +Weakness is usually proximal, except +in myotonic dystrophy type 1, when it is distal. +Antibodies to pre-synaptic voltage- +gated calcium channels (see Fig. +25.52) impair transmitter release. +Patients may have autonomic dysfunction (e.g. +Treatment is with 3,4-diaminopyridine, +or pyridostigmine and immunosuppression. +Screening for an associated cardiac +abnormality (cardiomyopathy or dysrhythmia) is important. +Genetic +counselling is important. +They +typically present with muscle weakness and pain. +Mitochondrial disorders +Mitochondrial diseases are discussed on page 49. +49). +Mutations may be due either to +point mutations or to deletions of mitochondrial DNA. +Three point mutations +account for more than 90% of LHON cases. +Genetic testing is available. +25.53). +headinjurysymptoms.org Symptoms and management of mild and +moderate head injury. +neurosymptoms.org Advice on managing functional neurological +symptoms. +ninds.nih.gov National Institute of Neurological Disorders and Stroke. +wfneurology.org World Federation of Neurology. +Further information +Journal articles +Scolding N, Barnes D, Cader S, et al. +Pract Neurol 2015; +0:1–7. +Websites +aneuroa.org/ American Neurological Association. +Ataxic +Hemiparetic gait pattern +1 +General appearance +Conscious level +Posture: leaning to one side? +It includes a range of disorders of the central +nervous system (Fig. +26.1). +Vascular dementia is described +on page 1191. +The +vertebral and basilar arteries perfuse the brainstem, mid-brain +and cerebellum (Fig. +26.2). +26.1 A classication of stroke disease. +26.2 Arterial circulation of the brain. +A Horizontal view. +B Lateral view.Investigations • 1151 +areas of the brain are described on page 1064. +This autoregulatory mechanism +can be disrupted after stroke. +26.3). +It allows the rapid identication +of intracerebral bleeding and stroke ‘mimics’ (i.e. +pathologies +other than stroke that have similar presentations), such as +tumours. +26.4). +Contraindications to MRI include cardiac pacemakers +and claustrophobia on entering the scanner. +1072). +26.5). +Blood flow in the +intracerebral vessels can be examined using transcranial Doppler. +to delineate a saccular aneurysm, an arteriovenous +malformation or vasculitis. +Blood tests +These identify underlying causes of cerebrovascular disease, e.g. +blood glucose (diabetes mellitus), triglycerides and cholesterol +Fig. +26.3 Venous circulation of the brain. +(hyperlipidaemia) or full blood count (polycythaemia). +A CT may +show no evidence of early infarction. +A and B, Courtesy of Dr A. +Farrell and Prof. +J. +Wardlaw.1152 • STROKE MEDICINE +A B +C D +Fig. +26.5 Different techniques for imaging blood vessels. +A Doppler scan showing 80% stenosis of the internal carotid artery (arrow). +C MR angiogram showing giant aneurysm at +the middle cerebral artery bifurcation (arrow). +D Intra-arterial angiography showing arteriovenous malformation (arrow). +A–D, Courtesy of Dr D. +Collie. +992), may +be required when vasculitis is suspected. +Lumbar puncture +Lumbar puncture (p. +1077) is reserved for investigation of SAH. +Cardiovascular investigations +Electrocardiography (ECG; p. +448), including ECG monitoring +and echocardiography (p. +451), may reveal abnormalities that +may cause cardiac embolism in stroke. +1082). +Upper motor +neuron weakness of the face (7th cranial nerve) is often present. +1087). +Dysphasia indicates damage +to the dominant frontal or parietal lobe (see Box 25.2, p. +1088). +1086), sometimes +misdiagnosed as delirium. +Weakness +Unilateral weakness is the classical presentation of stroke and, +much more rarely, of CVT. +The weakness is sudden, progresses +rapidly and follows a hemiplegic pattern (see Fig. +25.17, p. +1082). +There is rarely any associated abnormal movement. +1086) and there may be associated +brainstem features such as diplopia (p. +1088) and vertigo (p. +1086). +The differential diagnosis includes vestibular disorders (p. +1104). +Although headache is +common in acute ischaemic stroke, it is rarely a dominant feature +(p. +1080). +Headache also occurs in cerebral venous disease. +Coma +Coma is uncommon, though it may occur with a brainstem event. +194). +26.1). +About 5% +are due to rare causes, including vasculitis (p. +1040), endocarditis +(p. +527) and cerebral venous disease (see below). +26.6). +26.6 Homeostatic responses to falling perfusion pressure in the +brain following arterial occlusion. +As the cerebral blood flow +declines, different neuronal functions fail at various thresholds +(Fig. +26.7). +However, if blood flow falls further, +a level is reached at which irreversible cell death starts. +Glutamate opens membrane channels, allowing influx of +calcium and more sodium into the neurons. +Calcium activates +intracellular enzymes that complete the destructive process. +The infarction process is worsened by anaerobic production of +lactic acid (Fig. +26.8) and consequent fall in tissue pH. +Higher brain temperature, e.g. +The infarct swells +with time and is at its maximal size a couple of days after stroke +onset. +26.7 Thresholds of cerebral ischaemia. +Full recovery can occur if this level of flow is returned to normal +but not if it is sustained. +↓Oxygen ++glucose +Anaerobic +metabolism +Thromboxane +Prostaglandins +1 +Free fatty +acids +Fig. +26.8 The process of neuronal +ischaemia and infarction. +(1) Reduction of +blood flow reduces supply of oxygen and hence +adenosine triphosphate (ATP). +H+ is produced by +anaerobic metabolism of available glucose. +Free fatty acid release +activates pro-coagulant pathways that +exacerbate local ischaemia. +26.9). +The +risk factors and underlying causes of intracerebral haemorrhage +are listed in Box 26.2. +1127). +abrupt loss of function without positive features +such as abnormal movement). +If symptoms progress over +hours or days, other diagnoses must be excluded. +Delirium and +memory or balance disturbance are more often due to stroke +mimics. +Transient symptoms, e.g. +10.3, p. +182, and Box +26.4). +26.1). +These +will both have a bearing on management, such as suitability for +carotid endarterectomy. +26.9 CT scans showing intracerebral +haemorrhage. +A Basal ganglia +haemorrhage with intraventricular extension. +B Small cortical haemorrhage. +A and B, +Courtesy of Dr A. +Farrell and Prof. +J. +Different combinations +of these decits dene several stroke syndromes (Fig. +leg only, +arm only, face) +Isolated higher cerebral +dysfunction (e.g. +aphasia, +neglect) +Mixture of higher cerebral +dysfunction and motor loss +(e.g. +26.10 Clinical and radiological features of the stroke syndromes. +The anatomical locations of cerebral functions are shown with the nerve tracts in green. +• Stroke describes those events in which symptoms last +more than 24 hours. +Where there is uncertainty about +the nature of the stroke, further investigations are indicated. +CT remains the most practical and widely +available method of imaging the brain. +26.9). +Changes often develop over time (see Fig. +26.13) but small +cerebral infarcts may never show up on CT scans. +977) +Systemic lupus erythematosus ANA +Vasculitis (e.g. +CT/MRI +Is it ischaemic or haemorrhagic? +CT/MRI +Is it a subarachnoid +CT/lumbar puncture +haemorrhage? +Is there any cardiac source of +ECG +embolism? +CTA +Contrast angiography +What are the risk factors? +Full blood count +Cholesterol +Blood glucose +Is there an unusual cause? +CT +perfusion scanning). +This can be useful in guiding immediate +treatment of ischaemic stroke. +MRI is not as widely available as CT and scanning times are +longer. +26.4). +CT and MRI may reveal clues as to the nature of the +arterial lesion. +26.10). +More recently, CTA is being used to show +vessel occlusion suitable for clot retrieval (see later). +26.11 Emergency management of stroke. +*Varies with patient +selection and delay in treatment. +26.5), or occasionally by intra-arterial +contrast radiography as above. +Dysphagia is common and can +be detected by an early bedside test of swallowing. +Such ndings may lead on to specic +cardiac treatment. +Management +Management (Fig. +26.12 Complications of acute stroke. +26.11). +Intravenous thrombolysis with recombinant tissue1160 • STROKE MEDICINE +haemorrhage. +Such patients have a greater +than average risk of stroke recurrence. +The presenting history often includes minor injury and +face or neck pain. +Decision aids have been developed to assist (see +‘Further information’). +26.11). +26.11); it may be given by rectal suppository or by +nasogastric tube in dysphagic patients. +Intracranial haemorrhage must be excluded on brain +imaging before considering anticoagulation. +This most commonly arises in those +on warfarin therapy. +There is no evidence that clotting factors +are useful in the absence of a clotting defect. +Management of risk factors +The approaches used are summarised in Figure 26.13. +26.1) and affects +about 6/100 000 of the population. +Women are affected more +commonly than men and the condition usually presents before +the age of 65. +26.2), particularly in the region of the circle of Willis. +405) and congenital connective tissue defects such as +Ehlers–Danlos syndrome (p. +970). +Warfarin with target INR 2–3 +(or 3.5 if mechanical +prosthetic valve). +Direct oral +anticoagulants (DOACs) +offer safe, effective alternative +Fig. +26.13 Strategies for secondary prevention of stroke. +(2) Other statins can be used as an alternative to simvastatin in patients on warfarin or digoxin. +(3) Warfarin and +aspirin have been used in combination in patients with prosthetic heart valves. +carotid stenosis). +It commonly occurs on physical exertion, straining +and sexual excitement. +26.14). +On examination, the patient is usually distressed and +irritable, with photophobia. +There may be neck stiffness due to +subarachnoid blood but this may take some hours to develop. +Investigations +CT brain scanning and lumbar puncture are required. +26.14). +1077). +If either of these tests is positive, cerebral angiography +(see Fig. +26.5) is required to determine the optimal approach to +prevent recurrent bleeding. +1043) +• Thrombophilia (p. +26.14 Investigation of subarachnoid haemorrhage. +Cerebral venous disease +(focal or generalised). +The deficit can increase if spreading +thrombophlebitis occurs. +Investigations and management +MR venography demonstrates a lling defect in the affected +vessel. +In +selected patients, endovascular thrombolysis has been advocated. +Otherwise, the treatment of choice is +anticoagulation. +The main causes +are listed in Box 26.10. +The clinical features vary according to +the sinus involved (Box 26.11 and see Fig. +26.3). +stroke.cochrane.org Systematic reviews of stroke treatments. +In this book neuro-ophthalmology is +covered in Chapter 25. +It does not therefore represent the totality of the medical +ophthalmologist’s workload. +Its secretions (tears) wash away surface irritants +and convey emotion. +Extraocular muscles +The extraocular muscles (Fig. +27.1) consist of four recti, two +obliques and one levator. +They extend +forwards to insert into the anterior sclera. +Eye +The optic vesicle develops from the diencephalon. +The eye +is therefore contiguous with the brain. +Orbit +The orbit is the fat-lled cavity in which the eye is suspended. +It is shaped like a hollow square pyramid, its base the orbital +rim. +The eyelids contain the orbital septum and the tarsal plate. +573) +Optic disc oedema (type 2 respiratory +failure) +Cystic brosis (p. +580) Diabetic retinopathy +Tuberculosis (p. +928) Horner’s syndrome (p. +27.1 The extraocular musculature (right eye). +Adapted from +Batterbury M, Bowling B, Murphy C. +Ophthalmology. +An illustrated colour +text, 3rd edn. +Churchill Livingstone, Elsevier Ltd; 2009. +1088) +The major structures of the eye are shown in Figure 27.2. +Laterally, these cilia form the outer segments +of the photoreceptors. +Initially, the hyaloid artery supplies the lens and vitreous. +Sclera/cornea +The sclera lends shape to the eye and provides attachment +for the ocular musculature. +It makes up ve-sixths of the eyeball, +the other sixth being formed by transparent cornea. +The stem +cells allow continuous regeneration of the corneal epithelium. +27.2 The main structures of the eye. +The inset +shows the arrangement of the retinal cells. +Inset adapted +from Douglas G, Nicol F, Robertson C (eds). +Macleod’s +Clinical examination, 13th edn. +Churchill Livingstone, +Elsevier Ltd; 2013. +The sclera is pierced posteriorly by the optic nerve at the +lamina cribrosa, a sieve-like conduit. +The ciliary muscle encircles the eye within the ciliary +body. +The iris bows gently forwards as it lies against the lens. +Retina +The retina consists of the neurosensory retina and the retinal +pigment epithelium. +The two layers are adherent only adjacent +to the optic disc and at the edge of the pars plana. +At the centre +of the macula, the neurosensory retina dips to form the fovea. +The neurosensory retina initiates the visual pathway. +Its flexibility enables objects over a +range of distances to be focused on the retina. +It has a capsule, +a central nucleus and a peripheral cortex. +It continues to grow +throughout life, becoming less flexible with age. +Vitreous +The vitreous gel is 99% water and 1% collagen/hyaluronic acid. +Lesser degrees of adhesion occur at the +parafoveal retina and along the retinal vessels. +Several arterial circles are formed. +Investigation of visual disorders +Fig. +27.3 Amsler chart. +The Amsler chart is a grid of 0.5 cm squares +with a dot in the centre. +An automated version is available. +Most automated perimetry assesses only central vision. +Imaging +See Figure 27.4. +Photography +Digital photography is utilised to document surface anatomy. +Colour images are ideal for lesions affecting the skin and cornea. +All methods of perimetry are subjective and rely on +patient cooperation and mental agility. +Amsler chart +The Amsler chart (Fig. +27.4 Ocular imaging. +A Colour retinal photograph from a healthy subject. +B Red-free retinal photograph from a healthy subject. +C Optical +coherence tomogram of a normal eye, showing the layers of the retina. +In this image, the macula shows normal foveal indentation. +D Fundus +autofluorescence (FAF) of the right eye in a normal subject. +E Fundal fluorescein angiogram of a normal adult retina. +F Ocular ultrasound image showing typical biconvex appearance of a +choroidal melanoma. +A, B, C and F, Courtesy of Aberdeen Royal Inrmary. +D, From Schmitz-Valckenberg S, Fleckenstein M, Hendrik PN, et al. +Fundus +autofluorescence and progression of age-related macular degeneration. +Survey Ophthalmol 2009; 54(1):96–117. +E, From Witmer MT, SzilĂĄrd K. +Wide-eld +imaging of the retina. +Survey Ophthalmol 2013; 58(2):143–154. +Electrophysiology requires cooperation, correction of refractive +errors and the ability to xate. +Voluntary suppression of the +electrical responses is possible by simply not focusing on the +target. +Pain on eye movement is a cardinal feature of optic neuritis +and scleritis. +1096), which is often misdiagnosed as +scleritis. +Diagnosis can be +made by demonstrating choroidal shutdown on fluorescein +angiography. +Common causes are corneal abrasion, acute anterior uveitis +and contact lens-related keratitis. +1118). +It +is a relatively common indication for surgery. +Some symptoms associated with visual +loss require urgent ophthalmological assessment (Box 27.8). +The most common cause is choroidal +neovascularisation. +Macropsia, where objects look bigger than normal, is +uncommon. +631 and 645, and Fig. +18.8). +The rst muscle to be affected in thyroid eye disease is the +inferior rectus. +The enlarged muscle tethers the eye and restricts +upgaze. +In thyrotoxicosis, increased sympathetic nervous activity +leads to bilateral eyelid retraction. +This, however, resolves with +beta-blockade and treatment of thyrotoxicosis. +Neurological causes of optic disc swelling are +discussed in on page 1090. +Accompanying eyelid +retraction is a typical feature of thyroid eye disease. +By far the +most common cause is thyroid eye disease, when proptosis is +termed exophthalmos. +Proptosis is a sign of retro-orbital expansion and may be +intraconal or extraconal. +When outside, the eye is additionally +displaced to the side. +In addition, +there may be double vision. +In thyroid eye disease, diplopia +may be absent if the disease is symmetrical. +To the patient, however, the overarching concern is often the +change in appearance. +1028). +1039). +hypromellose) and +reducing tear loss by humidification and avoidance of dry +environments. +Pain and +redness are helpful indicators but may not always be present. +Sectoral redness of the episclera is usual, although nodules +can form. +Syphilis can cause all forms of uveitis. +adalimumab, infliximab) – may trigger demyelination. +1027); it is rarely caused directly by infection. +Inadequate treatment can lead to +pupil block glaucoma and cataract. +Treatment is challenging. +Corneal +grafting may be required but the risk of recurrence remains. +It is usually caused +by Fusarium. +Fungal keratitis has no particular distinguishing +features and delayed diagnosis is common. +Corneal transplantation is often required. +Endophthalmitis +Endophthalmitis is infection of the anterior and posterior chambers +of the eye. +It may be exogenous (e.g. +The causes of endogenous endophthalmitis are therefore the +causes of bacteraemia and fungaemia (p. +225). +340). +Allergic conjunctivitis is also common, either as a component +of hay fever (allergic rhinitis, p. +622) or as an allergy to +chloramphenicol, which is commonly used to treat conjunctivitis. +1254 and 1264). +The secondary effects of loss of conjunctival +function can be devastating to the cornea. +Other causes of +conjunctival scarring include trachoma (p. +273), chemical burns +and orbital radiotherapy. +Central ulceration is always +more serious than peripheral, through involvement of the visual +axis. +27.5). +27 +Coagulase-negative staphylococci and +Propionibacterium spp. +ofloxacin) +Subsequent treatment depends on sensitivity testing results +Fungi +Fusarium sp. +Aspergillus sp. +Candida sp. +27.5 Infective keratitis. +A Herpes simplex dendritic ulcer stained with fluorescein. +B Fusarium keratitis. +An irregularly edged lesion suggests a +fungal cause but is not pathognomonic. +A, Courtesy of McPherson Optometry, Aberdeen. +B, From Macsai MS, Fontes BM. +Rapid diagnosis in ophthalmology: +anterior segment. +Elsevier Inc.; 2008. +27.7 Sunflower cataract and Kayser–Fleischer ring (arrow) in +Wilson’s disease. +From Kaiser PK, Friedman NJ (eds). +Massachusetts Eye +and Ear Inrmary Illustrated manual of ophthalmology, 4th edn. +Saunders, +Elsevier Inc.; 2014. +Fig. +27.6 Focal chorioretinitis in clinically suspected endogenous +Candida endophthalmitis. +This patient was an intravenous drug user and +improved with empirical oral fluconazole. +From Ryan SJ (ed). +Retina, 5th +edn. +Saunders, Elsevier Inc.; 2013. +(Case courtesy of Jeffrey K. +Wilson’s disease +(hepatolenticular degeneration, p. +896) causes a characteristic +‘sunflower’ cataract. +The characteristic symptoms of cataract are progressive +loss of vision and glare. +Other common ophthalmological ndings in old age are shown +in Box 27.11. +The +prevalence of diabetic retinopathy increases with the duration +of diabetes. +Clinical presentation is with visual blurring and/or visual loss, +which are usually unilateral. +27.6). +Vitrectomy may also be required. +Cataract +Cataract is permanent opacity of the lens (Fig. +27.7). +• Lens opacities: cataract is ubiquitous but requires treatment only if +symptomatic. +• Drusen: common from mid-life onwards. +Once it is +identied, both eyes are always treated to prevent development/ +recurrence. +• Impaired upgaze: common. +It is differentiated from progressive +supranuclear palsy (p. +A high +skin crease and preserved ability to elevate help differentiate it from +other causes (p. +1090). +Increased risk of retinal +detachment and choroidal neovascular membrane formation. +Often mistaken for +papilloedema, particularly in the setting of coincidental daily +headache. +Hard contact lenses are +the mainstay of therapy. +Further progression may be prevented +through ‘cross-linking’ surgery. +Puberty may accelerate progression. +1031). +Untreated coexistent genital tract infection may cause infertility. +Transition to adult services +• Neurobromatosis type 1: see page 1131. +• Optic nerve astrocytoma/glioma: often develops in late childhood or +early adolescence. +with amblyopia. +retinopathy after 20 years. +Fortunately, most patients develop +only mild forms of retinopathy. +27.8). +These signs are best seen on +fluorescein angiography. +Most patients can taper treatment during +pregnancy. +Mycophenolate mofetil is teratogenic. +Glucocorticoids +and tacrolimus appear safe. +Retinal screening each trimester is recommended. +• HELLP/pre-eclampsia/eclampsia (p. +1284): retinal features of +accelerated hypertension (p. +514) may be seen, including optic disc +oedema, flame haemorrhages and cotton wool spots. +Occasionally, +exudative retinal detachments occur. +All features +tend to resolve with delivery or control of blood pressure. +271176 • MEDICAL OPHTHALMOLOGY +AB +E +C D +Fig. +27.8 Diabetic retinopathy. +A–E, Courtesy of Aberdeen Royal Inrmary. +The vitreous is strongly adherent to the pars plana. +It +pulls back on the new vessel, triggering further bleeding, growth, +inflammation and scarring. +If the scarring is sufficient, then +tractional retinal detachment and complete blindness may occur. +Other retinal lesions, not unique to capillary occlusion, are also +seen in diabetic retinopathy. +These include flame haemorrhages +and cotton wool spots (soft exudates). +Flame haemorrhages +are horizontal streaky haemorrhages in the retinal nerve-bre +layer. +They are also seen in any severe anaemia, e.g. +bacterial +endocarditis and leukaemia. +A cotton +wool spot combined with an enclosing flame haemorrhage is +termed a Roth spot. +Intravitreal injections of anti-vascular endothelial growth +factor (e.g. +This often +occurs during hospitalisation for other reasons. +Historically, annual screening has been advocated. +In pregnancy, the placenta is a source of angiogenic growth +factors. +A rare type of ‘snowflake’ cataract occurs in young +patients with poorly controlled diabetes. +This does not usually +affect vision but tends to make fundal examination difcult. +27.9). +27 +Fig. +Courtesy of Aberdeen Royal Inrmary.1178 • MEDICAL OPHTHALMOLOGY +A B +Fig. +27.10 Retinal artery occlusion. +A, From Duker JS, Waheed NK, Goldman DR. +Handbook of retinal OCT. +Saunders, Elsevier Inc.; 2014. +B, From Bowling B. +Kanski’s Clinical +ophthalmology, 8th edn. +Elsevier Ltd; 2016. +Where an underlying risk factor for +arteriosclerosis is clearly present (p. +484), then secondary prevention +measures should be commenced. +Retinal artery occlusion +Retinal artery occlusion is usually an embolic phenomenon. +The next most common cause is vasculitis, +mainly giant cell arteritis (p. +1042). +1152). +27.10). +In branch occlusions there is +no cherry-red spot and the retinal pallor is regional. +There are two basic +forms: atrophic (dry) and neovascular (wet). +Large (geographic), central patches of atrophy are seen with +areas of adjacent hyperpigmentation. +Apart from age the main risk factor +appears to be smoking. +The current +edition (ICD-10) comprises 22 chapters. +Psychiatric disorders are among the most common of all +human illnesses. +As with most clinical conditions, the +prevalence of mental disorders varies with the setting. +From WHO. +International Classication of Disease, 10th edn (ICD-10). +The level of +consciousness should be determined, especially in the assessment +of possible delirium. +‘Pressure of speech’ describes +rapid speech that is difcult to interrupt. +Mood +This can be judged by facial expression, posture and movements. +Are they +anxious, worried or tense? +Is mood elevated with excess energy +and a reduced need for sleep, as in (hypo)mania? +Thoughts +The content of thought can be elicited by asking ‘What are +your main concerns?’. +Is thinking negative, guilty or hopeless, +suggesting depression? +Are there thoughts of self-harm? +If so, +enquiry should be made about plans. +Are patients excessively +worried about many things, suggesting anxiety? +The form of thinking may also be abnormal. +1196). +1184). +Abnormal perceptions +Illusions are misperceptions of real stimuli. +1184). +28.1). +It is designed to be easy to use +and is freely available online in many different languages. +Do 2 trials, even if 1st trial is successful. +Do a recall after 5 minutes. +The subject must tap with his hand at each letter A. +The cat always hid under the couch when dogs were in the room. +28.1 Montreal Cognitive Assessment (MoCA). +A widely used screening tool for cognitive impairment. +Š Z. +These resources are +available online (see ‘Further information’). +The failure of a +patient to understand their own symptoms is referred to as +‘lack of insight’. +These will be discussed later in this chapter. +These pathways are implicated in several psychiatric disorders +but, as yet, in non-specic ways. +Behaviour +A person’s behaviour may predispose to the development or +perpetuation of a disorder. +The +causes, assessment and management are described on page 209. +Alcohol misuse +Misuse of alcohol is a major problem worldwide. +It presents in +a multitude of ways, which are discussed further on page 1194 +and in Box 28.22. +It is used in specialist services to complement information derived +from tests of MCV and GGT. +Management +The prevention and management of alcohol-related problems +are discussed on page 1195. +Substance misuse +The misuse of drugs of all kinds is also widespread. +As well as +the general headings listed for alcohol problems in Box 28.22 +(p. +Assessment and management are described on page 1195. +It is common to classify delusions on the basis of +their content. +They can occur in any sensory modality +but most commonly are visual or auditory. +Typical examples are +hearing voices when no one else is present, or seeing ‘visions’. +Hallucinations and delusions often co-occur. +Incongruence between hallucinations, delusions and mood +suggests schizophrenia. +184 and 1192). +Certain principles +apply, however, whatever the underlying cause. +Patients +will often seek reassurance from the doctor. +1197). +It is important to note that depression has +physical as well as mental symptoms (Box 28.6). +If so, how long have they +been feeling low? +Are they still able to enjoy things? +To what do +they attribute their low mood? +1199). +Where a patient’s mood is extremely low, the clinician +should ask about suicide. +The assessment of suicide risk is +described on page 1185. +1199). +Mania is the converse of depression. +Recreational, herbal and over-the-counter preparations should +also be considered. +Second-line investigations include tests +for Cushing’s disease (p. +666), thyrotoxicosis (p. +635), syphilis +(p. +337) and encephalitis (p. +1121). +Management +The management of bipolar affective disorder is discussed on +page 1200. +Management of organic mania involves identifying +and addressing the underlying cause. +The management of +disturbed or aggressive behaviour is discussed on page 1188. +1201). +Other more +persistent forms of anxiety are described in detail on page 1200. +Management +The management of specic anxiety disorders is discussed later +in this chapter (p. +1200). +Specic factors are shown +in Box 28.10. +The most common psychiatric diagnoses in the +medically ill are anxiety and depressive disorders. +The symptoms of anxiety are both psychological and +physical (Box 28.8). +The differential diagnosis of anxiety is shown +in Box 28.9. +Treatment is by psychological and/or pharmacological +therapies, as described on page 1189. +Medically unexplained somatic symptoms +The incidence of SH varies over time and between countries. +In the UK, the lifetime prevalence of suicidal ideation is 15% and +that of acts of SH is 4%. +SH is more common in women than +men, and in young adults than the elderly. +In many +cases, however, no psychiatric diagnosis can be made. +Management +A thorough psychiatric and social assessment should be +attempted in all cases (Fig. +28.2), although some patients will +discharge themselves before this can take place. +Topics to be covered when assessing a patient are listed in Box +28.13. +While these symptoms may be an expression of a medical +condition, they often are not (see Fig. +28.6). +Almost any symptom can be medically unexplained. +The most frequent psychiatric +diagnoses associated with MUS are anxiety or depressive +disorders. +When these are absent, a diagnosis of somatoform +disorder may be appropriate. +Somatoform disorders are discussed +in more detail on page 1202. +Most cases of SH involve overdose, of either prescribed or +non-prescribed drugs (Ch. +7). +Self-cutting is common and +often repetitive, but rarely leads to contact with medical services. +Factors associated +with suicide after an episode of SH are listed in Box 28.12. +28.3). +The +assistance of hospital security staff and sometimes the police +may be required. +When the patient +is cooperative, these are best determined at interview. +Observation of the patient’s behaviour may also yield useful +clues. +Do they appear to be responding to hallucinations? +Are +they alert or variably drowsy and confused? +Are there physical +features suggestive of drug or alcohol misuse or withdrawal? +Are there new injuries or old scars, especially on the head? +Do +they smell of alcohol or solvents? +Do they bear the marks of +drug injection? +Are they unwashed and unkempt, suggesting a +gradual development of their condition? +28.2 Assessment of patients admitted following self-harm. +before and after the act, and especially any evidence of planning. +• Disturbed behaviour: delirium is the most common cause. +• Depression: common. +• Self-harm: associated with an increased risk of completed suicide. +• Medically unexplained symptoms: common and often associated +with depressive disorder. +Does it seem likely to be caused +by mental disorder? +Yes No +Consider calling +security/police +Is the behaviour putting the patient +or others at risk? +The +benefits of sedation must always be balanced against the +potential risks. +Flumazenil +(p. +142) can be used to reverse respiratory depression caused by +benzodiazepines. +Monitor +and review +1. +Ensure availability of adequate personnel +to provide ‘overwhelming force’ +2. +Try to attain a safe and quiet environment +3. +28.3 Acute management of disturbed behaviour. +It is useful +to consider management strategies within a bio-psycho-social +framework. +identify the cause and to protect the patient and other people +from harm. +The main biological treatments are psychotropic +drugs. +These are widely used for various purposes; a pragmatic +classication is set out in Box 28.16. +is supplemented by ‘homework’ or tasks to complete between +treatment sessions. +General psychotherapy +General psychotherapy should be part of all medical treatment. +A triad of +‘cognitive errors’ has been described in depression (Box 28.17). +It is the most widely +available and extensively researched psychological treatment. +Frontal lobotomies are never done +now, and pre-frontal leucotomies are very rare. +Operations these +days usually target specic sub-regions and tracts of the brain. +They are based on talking with +patients, either individually or in groups. +Patients can be +helped to address these problems themselves by being taught +problem-solving. +It affects 5% of those over 65 and 20% +of those over 85. +Simple bedside tests, such as the MoCA (p. +It is important to exclude a focal brain lesion. +This +is done by determining that there is cognitive disturbance in +more than one area. +The course may +also help to distinguish types of dementia. +Investigations +The aim is to seek treatable causes and to estimate prognosis. +This is done using a standard set of investigations (Box 28.20). +Tackling risk factors +may slow deterioration, e.g. +Alzheimer’s disease +Alzheimer’s disease is the most common form of dementia. +It +increases in prevalence with age and is rare in people under +45 years. +Pathogenesis +Genetic factors play an important role and about 15% of cases +are familial. +Mutations in several +genes have been described but most are rare and/or of small +effect. +Histochemical staining demonstrates signicant +quantities of amyloid in the plaques (Fig. +Many +different neurotransmitter abnormalities have also been described. +Short- and long-term memory are both affected +but defects in the former are usually more obvious. +28.5 Fronto-temporal dementia. +A and B, +Courtesy of Dr J. +Xuereb. +B +Fig. +28.4 Alzheimer’s disease. +Courtesy of Dr J. +Xuereb. +often brought to medical attention by their carers. +Depression is +commonly present. +Cognitive +testing and neuroimaging can be helpful but in themselves are +not diagnostic. +Pick’s disease is a common cause of the rst two in particular. +28.5). +In contrast to Alzheimer’s disease, +memory is relatively preserved in the early stages. +There is no +specic treatment. +25.31, p. +1112). +The cognitive state +often fluctuates and there is a high incidence of visual hallucinations. +The criteria for alcohol +dependence, a more restricted term, are shown in Box 28.21. +Genetic factors predispose to +dependence. +Attempted and completed suicide are associated with alcohol +misuse. +Conversely, alcohol withdrawal increases anxiety. +Alcohol withdrawal syndrome +The features are described in Box 28.22. +Symptoms usually +become maximal about 2–3 days after the last drink and +can include seizures. +It has a signicant mortality and morbidity +(Box 28.22). +Acute alcohol intoxication causes ataxia, slurred speech, emotional +incontinence and aggression. +864). +Effects on other organs +These are protean and virtually any organ can be involved (Box +28.22). +These effects are discussed in detail in other chapters +in this book. +There +is no treatment for Wernicke–Korsakoff syndrome once it has +arisen. +It blocks the metabolism of alcohol, causing +acetaldehyde to accumulate. +When alcohol is consumed, an +unpleasant reaction follows, with headache, flushing and nausea. +Disulram is always an adjunct to other treatments, especially +supportive psychotherapy. +Although +such treatment may be successful, there is a high relapse rate. +Sustaining abstinence +is more challenging than achieving it, however. +Drugs of misuse are described in +detail in Chapter 7. +They can be grouped as follows. +Overdosage with sedatives can be fatal, +primarily as a result of respiratory depression (Ch. +7). +Intravenous opiate users are prone to bacterial infections, +hepatitis B (p. +873), hepatitis C (p. +877) and HIV infection +(Ch. +12) through needle contamination. +Examination reveals tachycardia, hypertension, mydriasis and +facial flushing. +Stimulants +Stimulant drugs include amphetamines and cocaine. +Chronic ingestion can cause a paranoid psychosis +similar to schizophrenia. +A ‘toxic psychosis’ (delirium) can occur +with high levels of consumption. +A toxic confusional state can occur after heavy cannabis +consumption. +Paranoid psychoses have been +reported in association with ecstasy. +A chronic psychosis has +also been documented after regular LSD use. +Organic solvents +Solvent inhalation (glue snifng) is popular in some adolescent +groups. +Pathogenesis +Many of the causal factors for alcohol misuse also apply to +substance misuse. +Most drug users take a range +of drugs – so-called polydrug misuse. +Management +The rst step is to determine whether patients wish to stop using +the drug. +Some specialist units offer +inpatient detoxication. +For details of the medical management of +overdose, see page 135. +Schizophrenia +Schizophrenia is characterised by delusions, hallucinations +and lack of insight. +Schizophrenia occurs +worldwide in all ethnic groups with a prevalence of about 0.5%. +It is more common in men (1.4 to 1). +The usual +age of onset is the mid-twenties but can be older, particularly +in women. +44). +The characteristic clinical features are listed in Box 28.23. +Hallucinations are typically auditory but can occur in any sensory +modality. +They commonly involve voices from outside the head +that talk to or about the person. +Sometimes the voices repeat +the person’s thoughts. +These +are required only in patients with neurological or other organic +symptoms or signs. +In some cases, they may be at risk of +harming themselves or others. +Subsequent acute relapses and +chronic schizophrenia are now usually managed in the community. +Treatment is then ideally continued to prevent +relapse. +A number of antipsychotic agents are available (Box 28.25). +All work by +blocking D2 dopamine receptors in the brain. +Clozapine should not be stopped suddenly because of +the likelihood of relapse. +Adverse effects of antipsychotic drugs +are listed in Box 28.26. +Two serious adverse effects deserve +special mention. +A graded return to employment +and sometimes a period of supported accommodation are +required. +This now +tends to be in supported accommodation in the community. +Prognosis +About one-third of those who develop an acute schizophrenic +episode have a good outcome. +Most affected +patients cannot work or live independently. +Schizophrenia is +associated with suicide and up to 10% of patients take their +own lives. +It is a major cause of disability and suicide. +Pathogenesis +There is a genetic predisposition to depression, especially +when of early onset. +Adversity and emotional +deprivation early in life also predispose to depression. +2Second-generation +antipsychotics. +and delirium. +Characteristic laboratory ndings are an elevated +creatinine phosphokinase and leucocytosis. +Treatment includes +ensuring hydration and reducing hyperthermia. +Dantrolene sodium +and bromocriptine may be helpful. +Mortality is 20% untreated +and 5% with treatment. +479). +CBT may help patients to cope with symptoms. +Diagnosis +The symptoms are listed in Box 28.6. +Depression may be mild, +moderate or severe. +It may also be recurrent or chronic. +Management +Pharmacological and psychological treatments both work in +depression. +In practice, the choice is determined by patient +preference and local availability. +Severe depression complicated by +psychotic symptoms, dehydration or suicide risk may require ECT. +Commonly +used antidepressants are shown in Box 28.27. +The dose should +then be tapered off over several weeks to avoid discontinuation +symptoms. +The therapeutic effect is noticeable within +a week or two. +Antidepressant +drugs are, however, preferred for severe depression. +Drug and +psychological treatments can be used in combination. +The lifetime risk of developing bipolar disorder is +approximately 1–2%. +Onset is usually in the twenties, and men +and women are equally affected. +Pathogenesis +Bipolar disorder is strongly heritable (approximately 70%). +Relatives +of patients have an increased incidence of both bipolar and +unipolar affective disorder. +Diagnosis +The diagnosis is based on clear evidence of episodes of depression +and mania. +This is described as an +affective psychosis. +Management +Depression should be treated as described above. +Manic episodes and +psychotic symptoms usually respond well to antipsychotic drugs +(see Box 28.25). +Caution must be exercised when stopping these drugs, as a +relapse may follow. +Lithium carbonate is the drug of rst choice. +Toxic effects include nausea, +vomiting, tremor and convulsions. +687) and +renal failure can occur. +Thyroid and renal function should be +checked before treatment is started and regularly thereafter. +Lithium may be teratogenic and should not be prescribed during +the rst trimester of pregnancy. +Olanzapine can cause +significant weight gain. +There is a substantially increased +lifetime risk of suicide of 5–10%. +Anxiety may +be stress-related and phobic anxiety may follow an unpleasant +incident. +Many patients with anxiety also have depression. +A generalised phobia of going out alone or being in crowded +places is called ‘agoraphobia’. +Phobic responses can develop +to medical procedures such as venepuncture. +The symptoms +are in part due to involuntary over-breathing (hyperventilation). +Panic disorder may coexist +with agoraphobia. +Generalised anxiety disorder +This is a chronic anxiety state associated with uncontrollable +worry. +Drug treatment +Antidepressants are the drugs of rst choice (p. +1199). +A β-blocker, such as propranolol, can help when +somatic symptoms are prominent. +Diagnosis +The diagnosis is made on the basis of the typical history, as +described above. +Relapses are common, however, and the condition +often becomes chronic. +The symptoms are transient and usually resolve completely +within a few days. +The lay media often describes this as ‘shock’. +There may also be anger, +aggressive behaviour and associated excessive alcohol use. +Grief reactions following bereavement are a particular +type of adjustment disorder. +‘Pathological +grief’ describes a grief reaction that is abnormally intense or +persistent. +PTSD may also sometimes occur after +distressing medical treatments or intensive care. +Antidepressant drugs are +moderately effective. +Prognosis +The condition runs a fluctuating course, with most patients +recovering within 2 years. +In a small proportion, the symptoms +become chronic. +Organic disease +may precipitate dissociation and provide a model for symptoms. +For example, non-epileptic seizures often occur in those with +epilepsy. +Treatment with CBT may be of benet. +It is also +known as Briquet’s syndrome after the physician who first +described the presentation. +The disorder is much more +common in women. +Treatment with CBT can be helpful. +Patients who suffer delusions may benet from antipsychotic +medication. +The condition may become chronic. +People with this +condition may make inappropriate requests for cosmetic surgery. +Treatment with CBT or antidepressants may be helpful. +The derivation of the term +‘somatoform’ is ‘body-like’. +Clinical features +Somatoform disorders can present in several different ways, +as described below. +Antidepressant drugs and CBT may be helpful. +CBT and multidisciplinary pain +management teams are also useful. +Symptoms +overlap with those of depression and anxiety. +Ninety per cent of people affected are female. +Anxiety and depressive +symptoms are common accompaniments. +Downy hair (lanugo) +may develop on the back, forearms and cheeks. +Diagnosis +Diagnostic criteria are shown in Box 28.32. +Explanation +Patients need a positive explanation for their symptoms. +It is +unhelpful to say that symptoms are psychological or ‘all in the +mind’. +Drug treatment +Antidepressant drugs are often helpful, even if the patient is +not depressed. +Psychological treatment +There is evidence for the effectiveness of CBT. +Other psychological +treatments such as IPT may also have a role. +It +is believed to be more common than AN, with a similar gender +ratio. +Peak age of onset is slightly later than for AN, typically +late adolescence or early adult life. +Diagnosis +Diagnostic criteria are shown in Box 28.32. +Management +Treatment of bulimia with CBT achieves both short-term and +long-term improvements. +Guided self-help and IPT may also +be of value. +Treatment +is usually given on an outpatient basis. +There is a limited evidence base +for CBT-based psychological treatments. +Family behaviour +therapy (FBT) has efcacy among adolescent but not adult +patients. +Weight gain is best achieved in a collaborative fashion. +While this may produce +a short-term improvement in weight, it rarely changes long-term +prognosis. +Prognosis +Two-thirds of patients with AN no longer meet diagnostic criteria +at 5-year follow-up. +Approximately 20% of patients develop a chronic, +intractable disorder. +Clinical features +PD can present in various ways. +A patient who +meets diagnostic criteria for one subtype may also meet criteria +for others. +Management +PDs usually persist throughout life and are not readily treated. +They typically become less extreme with age but can re-emerge in +the context of cognitive decline. +Pathogenesis +It is difcult to understand what motivates a person to act in this +way. +Factitious disorder is uncommon and is important to distinguish +from somatoform disorders. +A suggested diagnostic algorithm +is shown in Figure 28.6. +Are symptoms fully explained +by organic disease? +Yes +‘Medically unexplained’ +Is patient consciously feigning? +No +Organic disease +No Yes +Is there a preoccupation with +symptoms or diagnosis? +Is there an identifiable gain? +Patients +characteristically travel widely, sometimes visiting several hospitals +in one day. +Although the condition is rare, such patients are +memorable because they present so dramatically. +Some emergency departments hold lists of +such patients. +Malingering +Malingering is a description of behaviour, not a psychiatric +diagnosis. +Post-partum blues +This is characterised by irritability, labile mood and tearfulness. +About 80% of women are affected to some degree. +Diagnosis, explanation and reassurance +are important. +The usual psychological and drug treatments +for depression should be considered (p. +1199) to minimise the +impact on the mother and child at what is a very important time +for both. +A number of helpful guidelines are available to inform +prescribing decisions. +It is a rare but serious complication +affecting approximately 1 in 500 women. +There is a strong +association with a personal or familial history of bipolar disorder. +1200), are teratogenic and should be +avoided whenever possible. +• Post-partum low mood (‘blues’): weeks 1–3; most cases are +transient. +• Persistent low mood and anhedonia: may indicate depressive +illness. +A comprehensive post-partum risk +management plan should be agreed during pregnancy. +Psychiatry and the law +that balances the restrictions imposed. +There should also be +provisions for appeals and oversight. +Further information +Books and journal articles +Hofer H, Pozzi A, Joray M, et al. +Safe refeeding management of +anorexia nervosa inpatients: an evidence-based protocol. +Nutrition +2014; 30:524–30. +Steel RM. +Factitious disorder (Munchausen’s syndrome). +J R Coll +Physicians Edinb 2009; 39:343–7. +Taylor D, Meader N, Bird V, et al. +Br J Psychiatry 2011; 198:179–88. +Whiteford HA, Degenhardt L, Rehm J, et al. +Lancet 2013; 382: +1575–86. +Websites +cebmh.com Centre for Evidence-based Mental Health. +mind.org.uk Information on depression. +mocatest.org Montreal Cognitive Assessment. +neurosymptoms.org A guide to medically unexplained neurological +symptoms. +niaaa.nih.gov/ Information on alcoholism. +nice.org.uk National Institute for Health and Care Excellence: treatment +guidelines for depression. +ocdaction.org.uk Useful information about obsessive–compulsive +disorder. +rcpsych.ac.uk/info/index.htm Royal College of Psychiatrists: mental +health information. +who.int/mental_health/ World Health Organisation: mental health and +brain disorders. +www4.parinc.com/ Mini-Mental State Examination. +Other countries may have very different +provisions. +May also be genital +involvement +Joint involvement +e.g. +Consider the following: +• Age +• General health +• Distress +• Scratching +Flexor, e.g. +This is a mistake; take a history, then examine the skin and the rest of the patient. +1. +History-taking 2. +Drug/allergy history +3. +Examination of skin 5. +General examination +4. +cardiovascular +disease in psoriasis); +many systemic +diseases have +dermatological +features (e.g. +diabetes) +6. +Other definitions are provided in the chapter. +Score activity +Tools for objective assessment of disease severity (e.g. +Skin diseases affect all ages and there are more than 2000 +different types and presentations. +Their prime function is antigen +presentation to lymphocytes. +Other dermal antigen- +presenting dendritic cells are also present. +• Melanocytes: these occur predominantly in the basal layer +and are of neural crest origin. +Their embryological derivation is unclear. +Basement membrane +The basement membrane (Fig. +Anchoring laments +extend through the lamina lucida to attach to the lamina densa. +Dermis +The dermis is vascular and supports the epidermis structurally +and nutritionally. +It varies in thickness from just over 1 mm on +the inner forearm to 4 mm on the back. +The highest density of hair follicles is +on the scalp (500–1000/cm2). +The duration of each phase varies by site. +The epidermis is attached +to, but separated from, the underlying dermis by the basement +membrane. +Below it is the subcutis, consisting of adipose tissue. +Keratinocytes make up approximately 90% of epidermal cells +(Fig. +29.1). +The main proliferative compartment is the basal layer. +1049). +Mutations +of certain keratin genes can result in blistering disorders (p. +1254) +and ichthyosis (characterised by scale without major inflammation). +1245). +The skin is a barrier against physical stresses. +Diseases that affect +desmosomes, such as pemphigus (p. +29.1 Structure of normal skin. +telogen around 3 months. +The length of hair at different sites +reflects the differing lengths of anagen. +In animals, sebum is important for hair 29 +waterproong but its role in humans is unclear. +Their coiled +ducts open directly on to the skin surface. +Toenails develop slightly +later. +The anatomy of the nail apparatus is covered later in the +chapter (p. +1260). +Capillary loops arise from terminal +arterioles in the horizontal papillary plexus. +Sympathetic signals are important in mediating autonomic-induced +vasoconstriction. +Skin changes associated with ageing are +shown in Box 29.2. +In +hypopigmentation, such as in vitiligo, it can help in appreciating +the extent of disease. +Diascopy is simply pressing on the lesion with a glass slide. +86). +Alternatively, specific immunoglobulin E (IgE) levels +to antigens can be measured in serum. +86). +Phototesting +Phototesting is extremely valuable in the assessment of suspected +photosensitivity. +1220). +1227). +useful for tumour diagnosis. +Microbiology +Bacteriology +Bacterial swabs may identify a causative infective agent. +106). +Potential allergens (see Box 29.22, p. +This is a common clinical scenario and one that it is critical to +resolve correctly. +• The precise nature of the change should be determined +(as above). +Listen to the patient and pay attention to +subtle changes, as people know their skin well. +• Is there a positive family history of melanoma? +Loss of normal skin markings in a pigmented +lesion may be suggestive of melanoma. +Patients with one major or one minor feature should be referred +for further evaluation. +Rash +A rash is the other common presentation in dermatology. +The +main categories of scaly rashes are listed in Box 29.4. +The most +common type of rash presentation is maculopapular. +Diagnosis +can often be made on clinical grounds, although a biopsy may +be required. +Presenting problems in skin disease +The major presentations in dermatology are outlined below. +1211). +A new or changing lump is one of the key dermatology +presentations. +What is the nature of the change +– size, colour, shape or surface change? +Has change +been rapid or slow? +29.9, p. +1223)? +• Patient: What is the patient’s age? +Are they fair-skinned +and freckled? +Has there been much sun exposure? +Have +they used sunbeds or lived in sunny climates? +Have they +used photoprotection? +• Site: Is it on a sun-exposed or covered site? +• Are there other similar lesions? +These might include actinic +keratoses (see Fig. +29.13, p. +1231) or basal cell +papillomas (see Fig. +29.17, p. +1234). +29.19, p. +29.13, p. +1231) and ulceration +must be assessed. +29.11, p. +1229). +It is +invaluable for assessing pigmented and vascular lesions +(Fig. +29.2).Presenting problems in skin disease • 1217 +A B +C D +Fig. +29.2 Dermatoscopy. +A A changing lesion. +B +Dermatoscopy highlights the +abnormal pigment network and +other features suggestive of +melanoma. +C Another changing +lesion. +1247) +Silvery scale +Drug eruption +Widespread Macules and papules +Erythema and scale +(p. +1240) +Lichen planus +Distal limbs +Flexural aspect of wrists +(p. +337) +History of chancre +Systemic symptoms, e.g. +Duration of +individual lesions is also important, as in urticaria, for +example. +• Body site at onset and distribution. +• Itch. +Eczema is usually extremely itchy and psoriasis may +be less so. +• Preceding illness and systemic symptoms. +The morphology of the rash and the characteristics of individual +lesions are important (Box 29.4). +An initial management plan should also +be implemented. +Blisters +A blister is a fluid-lled collection in the skin. +The term vesicle +is used for small lesions and bulla for larger lesions (p. +1211). +29.1). +1254). +This occurs in pemphigus +foliaceus, staphylococcal scalded skin syndrome (see +Fig. +29.20, p. +1236) and bullous impetigo. +29.41, p. +1254). +• If the split is subepidermal, then tense-roofed blisters are +seen. +This occurs in bullous pemphigoid (see Fig. +29.42, +p. +1256), epidermolysis bullosa acquisita and porphyria +cutanea tarda (see Fig. +29.52, p. +1264). +• If there are foci of separation at different levels of the +epidermis, as in dermatitis (p. +1244), then multilocular +bullae made up of coalescing vesicles can occur. +29.3 A systematic approach to the diagnosis of blistering diseases. +A history +of onset, progression, mucosal involvement, drugs and +systemic symptoms should be sought. +Clinical assessment of +the distribution, extent and morphology of the rash should be +made. +A systematic +approach to diagnosis is required (Fig. +29.3). +Itch +Itch describes the unpleasant sensation that leads to +scratching or rubbing. +Even when the mechanism +is peripheral, there are not always signs of primary skin +disease. +The nerve endings that signal itch are in the epidermis or near +the dermo-epidermal junction. +The underlying mechanisms of +itch are not fully understood. +There is an inhibitory relationship between pain +and itch. +The mechanisms of itch in most systemic diseases remain +unclear. +The itch of kidney disease, for example, may be mediated +by circulating endogenous opioids. +Many common +primary skin disorders are associated with itch (Box 29.6). +If +itch is not connected with primary skin disease, other causes +should be considered (Box 29.7). +Itch is common in pregnancy and may +be due to one of the pregnancy-specic dermatoses. +29.4). +Psychogenic itch should be considered only if organic disease +has been ruled out. +If a clear-cut diagnosis cannot be made, non-specic +approaches can be used for symptom relief. +29.4 An overall approach to the investigation and management +of itch (pruritus). +1227). +Chronic +UVR exposure increases skin cancer risk and photo-ageing +(p. +1215). +Acute exposure can induce erythema (redness) as a +normal response (Fig. +29.5). +Photo-aggravated skin diseases +are exacerbated by sunlight but not caused by it. +Most common in elderly males. +Predominantly UVB, but also often UVA and visible light photosensitivity. +Most also +have contact allergies +Solar urticaria Immediate-onset urticaria on photo-exposed sites. +Usually UVA and visible light +photosensitivity. +Can occur at any age +Actinic prurigo Uncommon, presents in childhood. +Often familial, with strong HLA association. +Exaggerated sunburn and exfoliation. +378). +Photo-exposed site dermatitis due to tryptophan deciency (see Fig. +14.15, p. +378) +Photogenodermatoses Xeroderma pigmentosum Rare. +Defect in DNA excision repair, abnormal photosensitivity, photo-ageing and +skin cancer. +1266) +Erythema multiforme p. +1264 +pre-existing conditions +Rosacea p. +UVB is absorbed by window glass, +whereas UVA and visible light are transmitted through glass. +Seasonal pattern and distribution of rash +are important. +Key sites are the face (particularly nose, cheeks +and forehead), top of ears, neck (Fig. +29.7), bald scalp, back +of hands and forearms. +It can be misleading if there is covered site involvement. +Patients who are sensitive to UVA and visible light may be +affected through clothing. +1215), +if feasible. +Other investigations will often include provocation, +Fig. +29.5 Sunburn. +Sensitivity depends on +the individual’s constitutive skin phototype. +• UVA (315–400 nm), which is the most abundant UVR +component reaching the Earth’s surface. +29.6 The electromagnetic spectrum. +The action spectrum for non-melanoma skin cancer mirrors that for erythema. +The action spectrum for melanoma is not known but +includes ultraviolet (UV) B. +(UVR = ultraviolet radiation) +mechanism of desensitisation is uncertain. +1052). +29.6). +Sunscreen protection levels are described by sun protection +factor (SPF). +29.7 Chronic actinic dermatitis. +patch or photopatch testing and screening for lupus and the +porphyrias (p. +1263). +Management depends on the cause. +Patient counselling is therefore important with +regard to adequate application of sunscreen. +The site and +surrounding skin should be assessed. +Varicose veins are often +present, although not inevitably. +Assessment of the venous and +arterial vasculature and neurological examination are critical. +The site of ulceration may also help to indicate the underlying +primary cause (Fig. +29.8). +The rst symptom in venous ulceration is often heaviness of the +legs, followed by oedema. +1247) subsequently develop. +This progresses to +lipodermatosclerosis – rm induration due to brosis of the dermis +Fig. +29.8 Causes of lower limb ulceration. +The main types of leg ulcer +tend to affect particular sites. +and subcutis, which may produce the well-known ‘inverted +champagne bottle’ appearance. +Ulceration, often precipitated +by trauma or infection, follows. +Venous ulcers typically occur on +the medial lower leg (Fig. +29.9). +Risk factors include smoking, +hypertension, diabetes and hyperlipidaemia. +The foot is cold and +dusky, and the skin atrophic and hairless. +Peripheral pulses are +absent or reduced. +A vascular surgical assessment should be +sought urgently (p. +502). +Microangiopathy also contributes to ulceration in +diabetes (p. +758). +The ulcers occur over weight-bearing areas, +such as the heel. +In the presence of neuropathy, protection of +skin from trauma is essential to prevent ulceration. +• Urea and electrolytes to assess renal function. +• Urinalysis for glycosuria. +• Doppler ultrasound to assess arterial circulation. +However, +arterial calcication, such as in diabetes, can produce a +spuriously high ABPI. +Pulse oximetry may also be useful, +although ABPI is the preferred investigation if feasible. +Management +General advice on exercise, weight loss and smoking cessation +is important in all cases. +Underlying factors, such as diabetes or anaemia, must be treated. +Occasionally, leeches may be used +topically for ulcers with heavy adherent exudate. +Surrounding eczema should be suppressed with a topical +glucocorticoid. +1215). +Leg ulcers can +be very persistent. +Symptomatic relief, including oral analgesics +and sometimes chronic pain management, is important. +Once +the ulcer has healed, ongoing use of compression hosiery may +limit the risk of recurrence. +Investigations will depend +on the presentation. +Further details of the specic conditions are +included on page 1257. +Conditions causing hair loss (alopecia) are listed in Box +29.30 (p. +1259). +Nail changes may be a marker for systemic +disease (e.g. +iron deciency) or be a feature of certain skin +conditions (e.g. +psoriasis). +Acute skin failure +Acute skin failure is a medical emergency. +Several conditions +can cause widespread and acute failure of many skin functions +(see Box 29.1, p. +1214), including thermoregulation, fluid balance +control and barrier to infection. +1254). +Clinical assessment +Detailed history-taking and full examination are required. +Eczema, psoriasis, drug eruptions +and cutaneous T-cell lymphoma (SĂŠzary’s syndrome, p. +1232) are +among the diseases that can either present with, or progress to, +erythroderma. +29.35D, p. +1249). +Older people are at +greatest risk, especially if they have comorbidities. +Erythroderma +may appear suddenly or evolve slowly. +In dark skin, the presence +of pigmentation may mask erythema, giving a purplish hue. +Peripheral oedema is common in erythroderma, owing +to low albumin and high-output cardiac failure. +Skin biopsy may be necessary if the +cause is unclear. +Insensible fluid loss can be many litres +above normal losses. +impact of the disease on quality of life and the person’s support +network. +Selection of the appropriate active drug/ingredient and vehicle +is essential. +However, patients nd creams easier to apply +and so adherence may be better. +Gels and lotions can be +easier to use on hair-bearing sites. +Occlusion under +dressings also increases absorption. +The properties of different vehicles are listed +in Box 29.11. +White +soft parafn is the most effective and is widely used. +29.10 Striae and atrophy induced by excess prolonged potent +topical glucocorticoid use. +cessation of use. +Nevertheless, glucocorticoids are invaluable +for many sites, particularly the flexures. +Antibiotics can be used either for their anti-infective +properties (p. +1236) or for their anti-inflammatory properties +(pp. +1242 and 1244). +1239). +1244). +Dressings +A ‘wound’ covering is called a dressing. +Box 29.13 shows the +indications for their use. +The active agent, vehicle and ‘wound’ +type should be considered. +Careful choice of drug and dose is therefore essential. +Leukotriene +receptor antagonists, such as montelukast, may be added to +antihistamine regimes. +They promote +differentiation of skin cells and have anti-inflammatory effects. +Isotretinoin (13-cis-retinoic acid) is widely used for moderate +to severe acne (p. +1243). +Alitretinoin and +bexarotene can cause hypothyroidism. +1004). +Ciclosporin (p. +1005) +has a rapid onset of action and is effective in inducing clearance +of psoriasis and eczema. +Monitoring of blood pressure and +renal function is required. +Dressings for +venous leg ulcers are described on page 1224. +Psoralens are natural photosensitisers found in a number of +plants. +Psoralens are +therefore prodrugs that are activated only in skin that is exposed +to UVA. +Phototherapy or PUVA may +be offered as a whole-body or localised treatment. +Long-term use of ciclosporin is not +advised. +1256). +Haemolysis, methaemoglobinaemia and +hypersensitivity can occur, and monitoring is required (pp. +123 +and 269). +Hydroxychloroquine is of particular value in cutaneous +lupus. +Rituximab, which +causes depletion of B cells, may be used in pemphigus vulgaris. +86 and 572). +1039) and occasionally may be indicated in other dermatological +diseases. +affecting epidermis and upper dermis, such as benign naevi +and skin tags. +It is most commonly used for basal cell carcinoma (p. +1229). +Liquid nitrogen can be applied either with a cotton bud or, +more effectively, with a spray gun. +Cryotherapy +should not be used to treat melanocytic naevi. +Laser therapy +Laser therapy involves treatment with monochromatic light. +Melanin lasers can also be +used for hair removal if the hair is pigmented. +Light delivery in +short pulses restricts damage to the treated site. +1229). +Knowledge of local anatomy is essential, +particularly the locations of vessels and nerves. +Excision biopsy +This involves surgical removal of the lesion followed by histological +examination. +The most common indication is suspicion of +malignancy. +It +is important to excise down to the appropriate anatomical plane. +Depending on body site, a range of procedures can minimise +the resulting defect. +Healing by secondary intention may also +achieve good cosmetic results. +Supercial radiotherapy is now rarely employed to treat +benign dermatoses. +Chronic inflammation is a risk +factor for SCC, which may arise in chronic skin ulcers (p. +1254), in which up to 50% of patients develop SCC. +In Europe, the ratio of BCC to SCC is 4–5 : 1 in +immunocompetent patients. +The incidence increases with age and males +are more commonly affected. +Lesions may ulcerate and invade +locally; hence the term ‘rodent ulcer’. +29.11). +There may be some pigmentation or a cystic component. +It is subdivided into non-melanoma skin cancer +(NMSC) and melanoma. +1321). +Interestingly, many of +the mutations seen in SCC also occur in the pre-cancers AK and +BD. +The genetics of melanoma are discussed on page 1232. +Interestingly, +patients who have received high treatment numbers of PUVA +A B +29 +Fig. +29.11 Basal cell carcinoma. +A A nodular BCC showing the +translucent nature of the tumour and the abnormal arborising vessels. +Essentially, +treatment will be either surgical or, in some cases, medical +(Box 29.14). +Curettage and cautery may also be effective for selected +lesions. +PDT is an effective treatment for low-risk, predominantly +supercial BCC, as well as AK and BD. +Rarely, advanced BCC may be locally invasive or even +metastasise. +The risk of SCC is also increased in HIV infection. +Standard +excision with a 4–6 mm margin is advised and the cure rate is +approximately 90–95%. +Mohs’ surgery is an option but is used +less frequently for SCC than for BCC. +Such patients +and those with metastatic disease require management via a +multidisciplinary team. +Radiotherapy may be indicated if surgical excision is +not feasible. +29.13). +The rate of progression to +SCC is less than 0.1% and spontaneous resolution is possible. +However, SCC can also arise de novo and without progression +from AK. +Management +Several treatments are available for AK (see Box 29.14). +Emollients +and photoprotection, including high-factor sunscreens, may sufce +for mild disease. +Single or low numbers of lesions of AK can be +effectively treated with cryotherapy. +A B +29 +Fig. +29.12 Squamous cell carcinoma. +A A centrally keratinous, +symmetrical, well-differentiated SCC. +Clinically, this could be confused with +keratoacanthoma. +B An SCC arising from an area of epidermal dysplasia. +Fig. +29.13 Actinic keratosis. +29.14 Intra-epidermal carcinoma (Bowen’s disease). +The lower +leg is a common site and lesions are often treated non-surgically. +Melanoma +Melanoma is a malignant tumour of epidermal melanocytes. +While only 4% of skin cancers are melanomas, they account +for 80% of skin cancer deaths. +A +family history of melanoma increases the risk but a strong family +history is unusual. +In these patients, the lifetime risk of melanoma is more than +50%. +It +is rare before puberty. +The classication of invasive malignant +melanoma is shown in Box 29.15. +29.2, p. +1217). +If there is any +doubt, excision is advised. +29.14) but other sites can also be involved. +It may also +be hard to distinguish from supercial BCC. +Transformation into +SCC occurs in 3% or less. +Diagnosis +Incisional biopsy is usually undertaken to conrm the diagnosis. +This shows an intra-epidermal carcinoma with no invasion through +the basement membrane. +Cutaneous lymphomas +The most common form of cutaneous T-cell lymphoma is mycosis +fungoides (MF). +This can persist for years in patch and plaque +stages, often resembling eczema or psoriasis. +B-cell lymphomas, on the other hand, usually +present as nodules or plaque-like tumours. +Treatment is symptomatic and there is no evidence that it alters +prognosis. +The presence of ulceration may lead to under-estimation of the +Breslow thickness. +There is no evidence that more radical +surgery with 4–6 cm margins is benecial. +The majority of tumours +can be excised without the need for grafting. +If the biopsy is positive, +local lymphadenectomy is usually offered. +Local recurrence of disease and palpable +local node involvement should be treated surgically. +Other biological and gene therapies and vaccines +are also being investigated. +29.15 Supercial spreading melanoma. +B A nodular malignant +melanoma arising de novo and with Breslow thickness of 3.5 mm. +approximately 2 years. +29.15A). +Approximately 50% of melanomas arise from a +pre-existing naevus. +29.15B). +They +often present as a rapidly growing nodule that may bleed and +ulcerate. +A rim of pigmentation may, however, +be seen under the dermatoscope. +Lesions may develop de novo +or from a pre-existing naevus or SSM. +Lentigo maligna melanoma +This arises from a prolonged pre-invasive phase termed lentigo +maligna. +This indicates that +UVR exposure may not be implicated in acral melanoma risk. +Subungual melanoma +This form of melanoma is rare. +Diagnosis and management +The diagnosis is made by excision biopsy of a suspicious lesion. +Survival rates fall to less +than 10% for those with advanced nodal or metastatic disease. +Keratoacanthoma, while +benign, is also commonly considered to be invasive SCC on +clinical grounds. +29.16). +Clinically and histologically, the lesion often resembles SCC (see +Fig. +29.12A). +There is a familial tendency. +Clinically, freckles are +brown macules that darken following UVR exposure. +They can vary in colour from light to very dark brown. +Distinction +from melanoma is essential and histology may be required. +29.17), which present as pink/ +red papules on the upper half of the body. +The dermatoscope is helpful for this (see +Fig. +29.2, p. +1217). +29.17). +They may be flat, raised, pedunculated or warty-surfaced, and +can appear to be ‘stuck on’. +They occur in both sexes +and with increasing age, and are most common on the face +and trunk. +If there is a suspicion of melanoma, excision or diagnostic biopsy +should be undertaken. +It is quite normal to have 20–50, although, +interestingly, individuals with red hair have fewer. +Genetic and +environmental factors are implicated. +Monozygotic twins have +higher concordance in naevi numbers than dizygotic twins. +Individuals who have had greater sun exposure have higher +numbers of naevi. +The +onset of a new mole is less common after the age of 25 years. +Congenital melanocytic naevi occur at or shortly after birth. +Fig. +29.17 A typical basal cell papilloma. +Fig. +However, they may +sometimes be confused with melanocytic naevi. +Cryotherapy or snip or shave excision may be appropriate in +that situation. +A variant, angiolipoma, is typically painful. +Junctional Compound Intradermal +Fig. +29.18 Classication of melanocytic naevi. +Classication is based +on microscopic location of the nests of naevus cells. +29.18). +Junctional naevi are usually macular, circular or oval, and mid- to +dark brown. +Intradermal naevi are usually less pigmented than compound +naevi. +Their surface may be smooth, cerebriform, hyperkeratotic +or papillomatous. +Some may be very dark or pink and may show a +depigmented or inflamed halo. +If these naevi are removed, then +‘dysplastic changes’ are often seen. +Such naevi are known +to occur in some rare families with an inherited melanoma +predisposition. +Advice on photoprotection is important for +fair-skinned individuals with multiple naevi. +Light +scattering means that the pigment appears blue rather than +brown. +They may be difcult to distinguish from nodular melanoma +and are therefore often excised. +29.19), which can be +caused by either Staphylococcus aureus or streptococci, or both +together. +Staphylococcus spp. +Outbreaks can arise in conditions of overcrowding +29 +Fig. +29.19 Non-bullous impetigo.1236 • DERMATOLOGY +and poor hygiene or in institutions. +A widespread form can occur +in neonates. +Dried exudate, forming golden +crusting, arises on an erythematous base. +Lesions may be single +or multiple and coalesce. +Constitutional symptoms are uncommon. +The use of topical antiseptics and soap and water to remove +infected crusts is also helpful. +In severe cases, an oral antibiotic, such as flucloxacillin +or clarithromycin, is indicated. +401). +Underlying disease, such as infestations, must be treated and +cross-infection minimised. +Scarring does not occur but there +may be temporary dyspigmentation. +29.20). +It is caused by systemic +circulation of epidermolytic toxins from a Staph. +aureus infection. +The same toxins are implicated in bullous impetigo, which is a +localised form of SSSS. +The focus of infection may be minor skin +trauma, the umbilicus, urinary tract or nasopharynx. +The child +presents with fever, irritability and skin tenderness. +Erythema +usually begins in the groin and axillae, and around the mouth. +Bacterial +swabs should be obtained from possible primary sites of infection. +A skin snip should also be taken for urgent histology. +29.41, p. +1254). +Systemic antibiotics and intensive +supportive measures should be commenced immediately. +252). +It is +caused by staphylococcal toxins and early cases were thought +to arise with tampon use. +Intensive supportive care and systemic +antibiotics are required. +A +B +Fig. +29.20 Staphylococcal scalded skin syndrome. +A Extensive +erythema and supercial peeling of the skin. +B The condition was rapidly +diagnosed by examination of a frozen section of skin snip. +A, From Savin +JA, Dahl M, Hunter JAA. +Clinical dermatology, 3rd edn. +Oxford: Blackwell; +2002. +It occurs worldwide but is more common in the tropics. +In Europe, it occurs more frequently in children. +It is commonly seen in drug abusers, +and minor trauma can predispose to lesion development. +Supercial folliculitis +The primary lesions are follicular pustules and erythema. +Supercial +folliculitis is often infective, caused by Staph. +Staphylococcal +folliculitis is most common in children and often occurs on +the scalp or limbs. +Pustules usually resolve without scarring in +7–10 days but can become chronic. +In older children and adults, +they may progress to a deeper form of folliculitis. +The conditionCommon skin infections and infestations • 1237 +Fig. +29.21 Staphylococcal carbuncle. +is often self-limiting and may respond to irritant removal and +antiseptics. +More severe cases may require topical or systemic +antibiotics and treatment of Staph. +aureus carrier sites. +Deep folliculitis (furuncles and carbuncles) +A furuncle (boil) is an acute Staph. +aureus infection of the hair +follicle, usually with necrosis. +It is most common in young adults +and males. +It is usually sporadic but epidemics occasionally occur. +Malnutrition, diabetes and HIV predispose, although most cases +arise in otherwise healthy people. +Any body site can be involved +but neck, buttocks and anogenital areas are common. +Infection +is often associated with chronic Staph. +Friction caused by tight +clothing may be contributory. +Initially, an inflammatory follicular +nodule develops and becomes pustular, fluctuant and tender. +Crops of lesions sometimes occur. +There may be fever and +mild constitutional upset. +Lesions rupture over days to weeks, +discharge pus, become necrotic and leave a scar. +If a deep Staph. +29.21). +Discharge, necrosis and +scarring are usual. +Bacterial swabs must be taken and treatment +is with anti-staphylococcal antibiotics, e.g. +flucloxacillin, and +sometimes incision and drainage. +Other staphylococcal toxins may also be pathogenic. +For +example, Panton–Valentine leukocidin-producing Staph. +29.22). +In contrast, erysipelas is bacterial infection +of the dermis and upper subcutaneous tissue (Fig. +29.23), +although in practice it may be difcult to distinguish between +them. +Diabetes and +immunosuppression are predisposing factors. +The patient usually +Fig. +29.22 Acute cellulitis of the leg. +Note the chronic lymphoedema +and the haemorrhagic blistering. +Blister fluid was positive for group G +streptococci. +Fig. +29.23 Erysipelas. +Note the blistering and the crusted rash with +raised, erythematous edge. +The yellow discoloration is due to topical iodine +treatment. +has malaise, fever and leucocytosis, and streptococcal serology +will often be positive. +Blistering often occurs and may be haemorrhagic. +Regional lymphadenopathy is common. +Milder +cases may be treated with oral antibiotics. +267). +Skin manifestations depend on the route of infection, +previous sensitisation and host immunity. +Culture of organisms may be tricky but PCR can assist +with diagnosis. +588). +Resolution may also take place spontaneously or +after destructive therapies, such as cryotherapy. +281). +Necrotising soft tissue infections and anthrax +See pages 226 and 266, respectively. +Warmth and humidity predispose to this +infection, which usually occurs in flexures and toe clefts. +It +is asymptomatic or mildly itchy and lesions are well dened, +red–brown and scaly. +C. +minutissimum has characteristic coral- +pink fluorescence under Wood’s light. +A topical azole +(clotrimazole or miconazole) or fusidic acid is usually effective. +Oral erythromycin can be used for extensive or resistant disease. +Antiseptics can be used to prevent disease recurrence. +It is usually +asymptomatic. +Treatment is as for erythrasma. +There has been a marked increase in +incidence of syphilis. +Skin signs may be subtle; for example, +secondary syphilis may be misdiagnosed as pityriasis rosea. +Lesions on palms, soles and mucosae should raise suspicion. +Lyme disease is described on page 255. +Systemic antivirals are indicated +for signicant viral skin disease. +For example, systemic aciclovir +should be prescribed for eczema herpeticum (see Fig. +11.14, +p. +247). +242). +The relationship between skin HPV +and skin cancer is unclear. +They are most common +on the hands (Fig. +29.24) but can occur on the face, genitalia +and limbs, and are often multiple. +Paring reveals capillary loops +that distinguish plantar warts from corns. +29.25 Molluscum contagiosum. +Note the central umbilication. +Fig. +29.24 Viral wart on the nger. +The capillary loops are evident +within the warty hyperkeratosis. +Periungual sites are common and more +difcult to treat. +No +specic treatment is required, unless there is secondary infection. +Erythema multiforme (p. +1264) can be provoked by orf. +Other viral exanthems +See page 236. +29.26). +1215). +Indeed, prolonged +courses of systemic treatment may be needed for nail involvement. +However, +asymptomatic warts generally should not be treated. +Treatments are destructive. +Cryotherapy is +usually the next step and is repeated 2–4-weekly. +Molluscum contagiosum +Molluscum contagiosum is caused by a DNA poxvirus skin +infection. +It is most common in children over the age of 1 year, +particularly those with atopic dermatitis. +It also occurs frequently +in immunosuppressed patients, including those with HIV (p. +306). +Lesions are dome-shaped, ‘umbilicated’, skin-coloured papules +with central punctum (Fig. +29.25). +Spontaneous resolution occurs but can take +months. +Prior to resolution, they often become inflamed and +may leave small, atrophic scars. +Gentle squeezing with forceps after bathing can +hasten resolution. +Efcacy with imiquimod has also been reported. +291240 • DERMATOLOGY +A B +Fig. +29.26 Dermatophyte infections. +A Trichophyton rubrum infection of the groin +(tinea cruris). +B Microsporum canis infection of +the scalp (tinea capitis). +choice. +However, +glucocorticoid use is controversial, with no good evidence of +benet. +Tinea corporis +Tinea corporis should feature in the differential diagnosis of a +red, scaly rash (p. +1217). +There may also be pustules at the active edge. +Lesions are +usually asymmetrical and may be single or multiple. +The degree +of inflammation is dependent on the organism involved and the +host immune response. +Microsporum canis (from dogs) and +Trichophyton verrucosum (from cats) are common culprits. +Tinea cruris +This is extremely common worldwide and is usually caused +by Trichophyton rubrum. +29.26A). +rubrum, T. +interdigitale and Epidermophyton +floccosum. +It typically presents as an itchy rash between the +toes, with peeling, ssuring and maceration. +Involvement of one +sole or palm (tinea manuum) with ne scaling is characteristic +of T. +rubrum infection. +Vesiculation or blistering is more often +seen with T. +mentagrophytes. +Tinea capitis +This is a dermatophyte infection of scalp hair shafts and is most +common in children. +29.26B). +Infection may be within the shaft (endothrix, most +commonly caused by T. +verrucosum). +Usually, some nails are spared, there is asymmetry and toenails +are more commonly involved. +300). +316). +sympadialis +or M. +furfur, It occurs in men and women and in different races. +Hypopigmentation is more obvious after sun exposure and +tanning. +It spreads in +households and environments where there is intimate personal +contact. +234 and Fig. +29.27) and visualising +the mite (by extracting with a needle or using a dermatoscope). +In small children, the palms and soles can be involved, with +pustules. +Pruritus is prominent. +Involvement of the +genitals in males and of the nipples commonly occurs. +Even +after successful treatment, itch can continue and occasionally +nodular lesions persist. +Head lice +Infestation with the head louse, Pediculus humanus capitis, is +common. +It is highly contagious and spread by direct head-to- +head contact. +Scalp itch leads to scratching, secondary infection +and cervical lymphadenopathy. +The empty egg cases (‘nits’) are +easily seen on the hair shaft (p. +1210) and are hard to dislodge. +Treatment is recommended for the affected individual and +any infected household/school contacts. +Eradication in school +populations is difcult because of poor adherence and treatment +resistance. +Rotational treatments within a community may avoid resistance. +Vaseline should +be applied to eyelashes/brows twice daily for at least a fortnight. +High-temperature washing of clothing and bedding is required. +Treatment resistance and recurrence can be problematic. +Poor hygiene and overcrowded +conditions predispose. +Dry-cleaning and high-temperature washing or insecticide +treatment of clothes are required. +Treatment options are as for +head lice. +For heavy infestation, oral ivermectin may be indicated. +Pubic (crab) lice +Usually, these are sexually acquired and very itchy. +Management +is as for head and body lice and whole-body treatment should +be undertaken. +Pubic hair may need to be shaved. +Depression and suicideal ideation may occur. +Acne vulgaris +Acne is chronic inflammation of the pilosebaceous units. +29 +Fig. +29.27 Scabies. +A Burrows evident on the palm of the hand. +B A +mite still in its egg, seen on light microscopy of scrapings over a burrow. +29.28 Pathogenesis of acne. +29.28). +Severity of acne +is associated with sebum excretion rate, which increases at +puberty. +Clinical features +Acne usually affects the face and often the trunk. +Greasiness +of the skin may be obvious (seborrhoea). +29.28). +Inflammatory papules, nodules and cysts occur and may arise +from comedones (Fig. +29.29). +Scarring may follow deep-seated +or supercial acne and may be keloidal. +It is rare, usually affecting adult males, +and most commonly occurs on trunk and upper limbs. +It is usually found on the trunk in adolescent +males. +Costochondritis can occur. +Fig. +29.29 Cystic acne in a teenager. +A Before treatment. +B After +prolonged systemic antibiotic treatment. +It usually +affects teenage girls, and underlying psychological +problems are common. +Virilisation should also raise +suspicion of an androgen-secreting tumour. +Investigations +Investigations are not required in typical acne vulgaris. +657). +Management +Mild to moderate disease +Mild disease is usually managed with topical therapy (p. +1225). +If comedones predominate, then topical benzoyl peroxide or +retinoids should be used. +Benzoyl peroxide has both anti- +comedogenic and antiseptic effects. +1227; Fig. +29.29B). +Oxytetracycline must be taken on an +empty stomach, in a dose of up to 1.5 g a day. +It has a good +safety prole, even with long-term use, but adherence may be a +challenge. +Doxycycline is +another option but commonly causes photosensitivity. +If the patient fails to respond, then alternatives include +erythromycin or trimethoprim. +658). +1227). +acnes colonisation and inflammation. +Oral isotretinoin is usually used at a dose of 0.5–1 mg/kg over +4 months. +1227). +29.30 Rosacea. +Typical erythematous papulopustular rosacea +and drained, or excised under local anaesthetic. +Scarring may +affecting the mid-face. +be prevented by adequate treatment of active acne. +Keloid +scars may respond to intralesional glucocorticoid and/or silicone +dressings. +There is no convincing evidence +to support a causal association between diet and acne. +The cause is unknown. +Rosacea is distinct +from acne vulgaris; sebum excretion is normal and comedones +are absent. +The convexities of nose, forehead, cheeks and chin are +typically involved (Fig. +29.30). +Conjunctivitis and blepharitis may also occur. +Facial +lymphoedema can be an added complication. +Investigations +Usually, no investigations are required and the diagnosis is obvious +clinically. +1227). +Relapse may require intermittent or +chronic antibiotic use. +Skin scrapings to rule out secondary fungal infection +should also be considered. +Patch tests +should be performed if contact allergic dermatitis is suspected +(see Box 29.22 below). +Skin biopsy is not usually required unless +there is diagnostic doubt. +29.31). +Treatment is once to twice daily +(p. +1225). +29.10, p. +1226). +The clinical features of eczema influence the choice of topical +treatment. +Vasodilatation and +T-cell lymphocytic inltration of the upper dermis also occur. +29.31 General management +approaches: atopic eczema. +Bacterial and viral skin infection risk may be increased +due to immunosuppression. +Atopic eczema +This is the most common subtype of eczema. +The contributing roles of the microbiome are also being +explored. +29.32). +Widespread cutaneous dryness +(also known as xeroderma or xerosis) is another feature. +The +distribution and character of the rash vary with age (Box 29.19). +Complications are listed in Box 29.20. +Investigations +The diagnosis of atopic eczema is made using clinical criteria +(Box 29.21). +Sedating antihistamines may +help to break the itch/scratch cycle. +Identication and avoidance +of allergens are important. +Phototherapy is generally the next step, if topical therapies are +insufcient (see Fig. +29.31). +Narrowband UVB is usually the initial +phototherapy of choice and can also be used in children. +Phosphodiesterase 4 inhibitors are also being investigated. +It is associated with, and may be due to, overgrowth of +Malassezia yeasts. +When severe, it may resemble psoriasis. +314). +Treatment often needs +to be repeated due to disease recurrence. +Judicious antibiotic use may also be +required for acute flares. +Fig. +29.32 Atopic eczema. +B Lichenication of chronic flexural eczema secondary to +rubbing and scratching. +29.33 Allergic contact eczema. +This was caused by the application +of an antihistamine cream. +The acute eczematous reaction and bilateral +periorbital oedema are typical. +Irritant eczema +Detergents, alkalis, acids, solvents and abrasives are common +irritants. +Individual susceptibility varies +and the elderly, atopic and fair-skinned are predisposed. +Irritant avoidance, including +protective clothing (such as gloves), is essential. +Emollients and +topical glucocorticoids are indicated. +Common allergens are +listed in Box 29.22. +The +distribution of eczema can be very informative with regard to +possible culprits. +Oedema may also be a feature (Fig. +29.33). +Asteatotic eczema +This occurs in dry skin and is common in the elderly. +Emollients are a mainstay, +in combination with topical glucocorticoids. +Oedema and ulceration are treated by leg elevation +and compression bandages (p. +1224). +Common +sites include the neck, lower legs and anogenital region. +The underlying +cause must be treated or removed. +Pathogenesis +Both genetic and environmental factors are important. +The +age at onset and severity of disease are often similar in familial +cases. +Environmental triggers for psoriasis are shown in (Box 29.23). +There is also an +association between psoriasis and metabolic syndrome (p. +730). +The histological changes of psoriasis are shown in Figure +29.34. +The initiating event for psoriasis is unknown. +Proliferation rate is also increased +in non-lesional skin but to a lesser extent. +29.35 Psoriasis. +A Chronic plaque +psoriasis, most prominent on extensor +surfaces. +B Nail involvement, with coarse +pitting and separation from the nail plate +(onycholysis). +C Guttate psoriasis +following a streptococcal throat infection. +D Erythrodermic psoriasis. +Clinical features +Psoriasis has several different presentations (Fig. +29.35). +Plaque psoriasis +This is the most common presentation and usually represents +more stable disease. +The typical lesion is a raised, well-demarcated +erythematous plaque of variable size (Fig. +29.35A). +The +most common sites are the extensor surfaces, notably elbows +and knees, and the lower back. +Others include: +• Scalp: involvement is seen in approximately 60% of +patients. +Occipital +involvement is common and difcult to treat. +Temporary +hair loss can occur but permanent loss is unusual. +29.35B), subungual hyperkeratosis and periungual +involvement (p. +1210). +• Palms: psoriasis of the palms can be difcult to distinguish +from eczema. +29.35C). +It may present shortly after +a streptococcal throat infection and evolves rapidly. +Guttate psoriasis often heralds +the onset of plaque psoriasis in adulthood. +Erythrodermic psoriasis +Generalised erythrodermic psoriasis is a medical emergency +(Fig. +29.35D). +Pustular psoriasis +Pustular psoriasis may be generalised or localised. +Generalised +pustular psoriasis is uncommon, unstable and life-threatening. +1224). +1210). +A +localised form of sterile pustulosis of a few digits (acropustulosis) +can also occur. +It is unclear whether these localised forms of +pustulosis are truly psoriatic. +1035). +Joint involvement is more likely in patients +with psoriatic nail disease. +1211) is essential. +730). +HIV testing should be considered in severe or recalcitrant +psoriasis. +Information and services +must be available for patients. +Psoriasis can have a major impact +on all aspects of life and this must not be under-estimated. +Reassurance is also needed, as the condition is generally not +life-threatening. +Associated diseases, such as hypertension +and diabetes, should be treated. +Extent of disease +and impact on quality of life must be taken into account. +29.36). +Topical treatments, including emollients, are the first-line +approach. +Vitamin D analogues can cause +irritation but this is often temporary. +Although often effective, they are messy +and time-consuming. +29.36 General management approaches: psoriasis. +Alternatively, immunosuppressants, such as methotrexate +or ciclosporin, may be required. +1005 and Fig. +29.37). +Common +adverse effects are flushing and diarrhoea. +Lymphopenia is +also expected at effective doses. +Apremilast is indicated for +moderate to severe psoriasis resistant to standard measures. +29.37 Developments in understanding of key pathways and drug targets in psoriasis. +This diagrammatic image +is illustrative of key pathways and drug targets but is not comprehensive. +Individualised management is essential. +Thus, whilst +a stepwise general approach to management (see Fig. +Individual lesions also have a collarette of +scale. +An inverse variant with flexural involvement can occur. +Mucosal involvement is rare. +There is a small risk of recurrence. +Symptomatic relief can be achieved with emollients and mild +topical glucocorticoids. +Post-inflammatory hyperpigmentation +can supervene, particularly in darker skin types. +The aetiology is unclear but the condition is part of a +spectrum and remits spontaneously. +The more chronic variety presents +as a persistent, widespread, scaly eruption. +Characteristically, +lesions are brown papules with a mica-like scale (‘cornflake’). +The condition fluctuates but can persist for months or years. +Emollients, topical glucocorticoids and long-term oral erythromycin +can occasionally be helpful. +UVB phototherapy or PUVA is usually +effective, although recurrences are high. +1265). +Other causes +Secondary syphilis (p. +337), pityriasis versicolor (p. +1240) and +fungal infection with Tinea corporis (p. +Investigations +A skin biopsy should be performed if there is diagnostic doubt. +Screening +for underlying disease, such as hepatitis, must be considered. +1266). +Graft-versus-host disease +In the acute stage of graft-versus-host disease (GVHD, p. +937), +there is a distinctive dermatitis associated with hepatitis. +Lichen planus +Lichen planus occurs worldwide. +It typically presents as a pruritic +rash; the mucosae, hair and nails may also be involved. +1141) and thymoma. +There are +also similarities with graft-versus-host disease (GVHD, p. +937). +The dermo-epidermal junction has +a ‘sawtooth’ appearance. +29.38), and on the lower back. +Post-inflammatory pigmentary change is common, particularly +in darker skin types. +1210) and tongue. +These oral changes +are often asymptomatic and should be sought on examination. +Genital and other mucosal surfaces can also be affected (pp. +334 +and 336). +1261). +If +oedema involves subcutaneous or submucosal layers, the term +angioedema is used. +75). +29.38 Lichen planus. +29.39) last for +less than 24 hours; if they persist, urticarial vasculitis needs to +be considered. +History-taking should probe for possible causes, including +medications (Box 29.24). +Examination may +be unremarkable or weals may be evident (Fig. +29.39). +29.40). +• Erythrocyte sedimentation rate (ESR) or plasma viscosity: +elevated in vasculitis. +• Total IgE and specic IgE to possible allergens: shellsh, +peanut, house-dust mite. +Particularly relevant if there is +angioedema. +29.39 Urticaria. +Note the absence of epidermal changes. +29.40 Pathogenesis of urticaria. +Mast cell degranulation occurs in a variety of ways. +(1) Type I hypersensitivity causes degranulation. +(2) +Spontaneous mast cell degranulation in chronic urticaria. +(3) Chemical mast cell degranulation. +(4) Autoimmunity, with IgE antibodies directed against IgE +receptors or IgE itself. +Histamine and the leukotrienes are especially relevant mediators in urticaria. +• Infection screen: hepatitis screen and HIV may be +indicated. +• Skin biopsy: if urticarial vasculitis is suspected. +• Challenge tests: to conrm physical urticarias, such as +dermographism, pressure, heat, cold. +For chronic urticaria, narrowband +UVB phototherapy is valuable and has proven efcacy. +The management of anaphylaxis and +hereditary angioedema is discussed on pages 76 and 87. +It is usually drug-induced (see Box 29.35, p. +Sheets of blisters coalesce +and denude, and the underlying skin is painful and erythematous +(Fig. +29.41). +Mucous membrane involvement and +blistering are usual. +Blistering of skin and mucosae may be +haemorrhagic. +A disease severity score (Box 29.26) is used to +predict outcome. +The main differential diagnosis is staphylococcal +scalded skin syndrome (p. +1236), although the diagnosis is +usually obvious in an adult patient with a culprit drug. +Skin +Fig. +29.41 Toxic epidermal necrolysis. +Note the extensive erythema, +oedema and epidermal loss secondary to carbamazepine. +This section concentrates on +primary blistering skin diseases. +SCORTEN: a severity-of- +illness score for toxic epidermal necrolysis. +J Invest Dermatol 2000; +115:149–153. +1213).Bullous diseases • 1255 +snip may allow early diagnosis. +Identication and discontinuation of the causative drug are +essential. +Sepsis and multi-organ failure are major risks. +Urethral +and ocular involvement is common and must be looked for +and treated symptomatically. +Ocular and urethral scarring can +be problematic in survivors. +The key investigation is an elliptical biopsy taken from +the edge of a recent blister (Box 29.28). +Serum should +also be sent for indirect immunofluorescence in suspected +immunobullous disease (p. +1215). +29.42A). +Milia (denition: small epidermal keratin cysts) +may develop due to basement membrane disruption. +Mucosal +involvement is uncommon. +Erosions +are common and the Nikolsky sign is positive. +The trunk is +usually affected. +The condition is associated with signicant +morbidity and mortality. +The titres of circulating epidermal +autoantibodies can also be used to monitor disease activity. +Often, +long-term treatment is required to prevent relapse. +806). +It is unclear why some CD patients develop DH and others do +not. +Direct immunofluorescence shows +granular IgA in the papillary dermis. +The condition usually responds +to a gluten-free diet but, if not, dapsone can also be used. +Drugs, notably vancomycin, can be a secondary cause. +Blisters +Split +Dermis +Fig. +29.42 Bullous pemphigoid. +A Large, tense, unilocular blisters. +Direct immunofluorescence demonstrates the +presence of IgG and C3 at the basement membrane (Fig. +29.42B). +Indirect immunofluorescence may show positive +titres of circulating anti-epidermal antibodies. +The condition +often burns out over a few years. +Dapsone, sulfapyridine, prednisolone, colchicine or intravenous +immunoglobulin may be effective. +Blisters +often follow trauma and milia develop. +Mainstays of treatment include systemic +glucocorticoids in combination with dapsone or colchicine. +1221 and 1266). +Porphyria is discussed in more +detail on page 378. +of patches of hypopigmentation. +Trauma and sunburn may (through the KĂśbner phenomenon) +precipitate the appearance of vitiligo. +29.43). +The hair of the scalp, beard, eyebrows and lashes +may also depigment. +Segmental vitiligo is restricted to one part +of the body but not necessarily a dermatome. +Sensation in the +depigmented patches is normal (unlike in tuberculoid leprosy, +p. +267). +Wood’s light examination enhances the contrast between +pigmented and non-pigmented skin. +Camouflage +cosmetics may be benecial, particularly in those with dark skin. +In fair skin, photoprotection and cosmetic cover may be all that is +required. +Topical pimecrolimus +or tacrolimus may also have a role as a glucocorticoid-sparing +agent. +Phototherapy with narrowband UVB or PUVA can also +be used. +369) and hypopituitarism. +Vitiligo +Vitiligo is an acquired condition affecting 1% of the population +worldwide. +Focal loss of melanocytes results in the development Fig. +29.43 Vitiligo. +Symmetrical localised patches of depigmented skin. +The impact of vitiligo differs markedly between populations. +Oculocutaneous albinos are at grossly increased risk of sunburn +and skin cancer. +Management +Strict photoprotection (p. +Early diagnosis and treatment of skin tumours is +essential. +895). +• Endocrine pigmentation: may occur in several conditions. +The mechanism for this +localised increased hormonal sensitivity is unknown. +671), Cushing’s syndrome (p. +666), Nelson’s syndrome +(p. +669). +• Drug-induced pigmentation (Box 29.29): may be diffuse or +localised. +Establishing the cause is important. +Photoprotection may +minimise the risk of increasing pigmentation. +Alopecia +Alopecia is characterised by loss of hair. +These conditions are discussed elsewhere. +It is also found in women, +particularly post-menopausal ones. +Scrapings +and pluckings should be sent for mycology if there is localised +inflammation. +Alopecia can +have a major impact on quality of life and psychological support +is usually required. +It is particularly important to establish realistic +expectations. +There may be some response to topical or intralesional +glucocorticoids. +Some males with androgenetic alopecia may be helped by +systemic nasteride. +In females, +anti-androgen therapy, such as cyproterone acetate, can be +used. +Wigs are often appropriate for extensive alopecia. +When the hypertrichosis +follows a male pattern, it is called hirsutism. +Fig. +29.44 Alopecia areata. +29 +scalp (Fig. +29.44). +A diffuse pattern can uncommonly occur on the scalp. +Eyebrows, eyelashes, beard and body hair can be affected. +Nail pitting may +occur (p. +1261). +Hirsutism +Hirsutism is the growth of terminal hair in a male pattern in a +female (p. +657). +If +there is diagnostic doubt, a biopsy may be needed. +• Psoriasis: nail involvement is common (see Fig. +29.35B, +p. +1249). +The nails can be affected by both local and systemic disease. +29.45). +The cells of the matrix and, to a lesser extent the bed, produce +the keratinous plate. +29.46) and the boggy inflammation +of paronychia. +Normal variants +Longitudinal ridging and beading of the nail plate occur with age. +White transverse patches (striate leuconychia) are often caused +by airspaces within the plate. +Nail trauma +• Nail biting/picking is a very common habit. +• Splinter haemorrhages are ne, linear, dark brown +longitudinal streaks in the plate (see Fig. +16.89, p. +529). +They are usually caused by trauma, especially if distal. +Uncommonly, they can occur in nail psoriasis and are also +a hallmark of infective endocarditis. +29.47). +These haematomas are usually due to trauma, +although a history of this may not be clear. +The main +A +B +Fig. +29.46 Dermatomyositis. +A Photo-aggravation. +B Note the +prominent periungual involvement. +Proximal nail fold +Matrix +Nail plate +Hyponychium +Cuticle +Nail bed +Distal phalanx +Fig. +29.45 The nail plate and bed. +Arrows indicate the direction of nail +growth. +Fig. +Fine +pitting can occur. +Paronychia is common. +• Alopecia areata: nail-plate pitting and trachyonychia can +occur. +29.48B). +29.48C). +• Clubbing: in the early stages, the angle between the +proximal nail and nail fold is lost. +• Nail discoloration: whitening may occur in +hypoalbuminaemia. +‘Half-and-half’ nails (white proximally +and red/brown distally) may be found in renal failure. +Antimalarials and some other drugs occasionally +discolour nails. +Skin disease in general medicine +Many skin conditions present to other medical specialties. +24.53, p. +1042). +Underlying causes and their treatment are discussed +on page 1040. +29.49). +Investigation should be made with these associations in mind. +The +diagnosis is largely clinical, as histology is not specic. +29.48 The nail in systemic disease. +A Normal nail. +B Beau’s +line. +C Koilonychia. +D and E Digital clubbing.1262 • DERMATOLOGY +Fig. +29.50 Scarring inflammatory alopecia. +This patient had systemic +lupus erythematosus and additional cutaneous features of scarring +Fig. +29.49 Pyoderma gangrenosum. +This young patient had Crohn’s inflammatory discoid lupus erythematosus. +disease. +Note the cribriform pattern of re-epithelialisation, which is +characteristic of this condition. +The features of +SLE are discussed on page 1035. +Drug-induced DLE +and SCLE should always be considered (see Box 24.78, +p. +1057, and Boxes 29.34 and 29.35 below). +If the scalp is involved, +scarring alopecia usually occurs (Fig. +29.50). +Most patients with +DLE do not develop SLE. +Systemic +involvement is uncommon and the prognosis usually good. +There +is a strong association with antibodies to Ro/SS-A antigen. +A +diagnosis of cutaneous lupus is conrmed by histopathology and +direct immunofluorescence. +Cutaneous lupus may respond to +topical glucocorticoids, antimalarials or immunosuppressants. +Paradoxically, low-dose +UVA1 phototherapy can be effective for lupus. +Dilated +nail-fold capillaries and ragged cuticles are frequent. +The clinical +features and management are described on page 1037. +Morphoea +Morphoea is a localised cutaneous form of scleroderma that +can affect any site at any age. +It usually presents as a thickened +dressings are important. +Tetracyclines may be added for their anti-inflammatory +effects. +Treatment with TNF-Îą inhibitors and ustekinumab may +be effective in severe recalcitrant PG. +Once healing has taken +place, recurrences are typically only intermittent. +There can be damage +to vessels (‘vasculopathy’) but usually no frank vasculitis. +They are associated with considerable +morbidity, mortality and expense to health services. +Predisposing factors, such as anaemia and poor nutrition, should +be corrected. +Once established, signicant infection must be +treated and necrotic tissue debrided. +Plaques can become generalised. +Linear forms exist and, if in the +scalp, are associated with scarring hair loss (en coup de sabre). +There is usually no systemic involvement. +Photo-aggravation of the cutaneous features is often prominent +(see Fig. +29.46A, p. +1260). +The clinical features and management +are described on page 1039. +Fig. +29.51 Necrobiosis lipoidica. +Atrophic yellow plaques with +violaceous edges, on the shins of a patient with diabetes mellitus. +An association between generalised disease and +diabetes has been proposed but not conrmed. +Lesions often +resolve spontaneously. +The +lesion has a characteristic yellow, waxy, atrophic appearance, +often with violaceous edge (Fig. +29.51). +Underlying blood vessels +are easily seen because of tissue atrophy. +Necrobiosis lipoidica +typically appears on the shins and is prone to ulceration after +trauma. +Sarcoidosis +This condition is characterised by the presence of non-caseating +granulomas. +The cause is unknown, although infectious and +genetic factors have been proposed. +It is usually a multisystem +disease (p. +608), with skin lesions in about one-third of +patients. +17.59, p. +609). +Investigation is described on +page 609. +1226–1228). +Clinical features and management of systemic +disease are discussed on pages 608 and 610. +Cutaneous Crohn’s disease +Cutaneous Crohn’s disease (p. +These changes are +termed ‘metastatic’ Crohn’s and histology shows non-caseating +granulomas. +Reactive skin changes can also occur in the form +of erythema nodosum and pyoderma gangrenosum (pp. +1265 +and 1261). +Treatment is of the underlying disease (p. +820). +Porphyrias +The porphyrias (described on p. +379). +It is caused by an underlying +chronic liver disease, in association with hepatic iron overload. +Amyloid inltration of blood vessels may manifest as ‘pinch +purpura’ following skin trauma. +Potent topical glucocorticoids +can be benecial, although it is often treatment-resistant. +Genetic disorders +Neurobromatosis +This is described in detail on page 1131. +The hallmark +is hamartomas in many systems. +The disease is likely to have +an immunological basis. +Lesions are multiple, erythematous, +annular, targetoid ‘bull’s eyes’ (Fig. +29.53) and may blister. +Stevens–Johnson syndrome (pp. +Identication and removal/treatment of any trigger are essential. +Analgesia and topical glucocorticoids may provide symptomatic +relief. +Supportive care is required in Stevens–Johnson syndrome, +including ophthalmology input. +Fig. +29.52 Porphyria cutanea tarda. +skin presentation and it is thus an important diagnosis not to miss. +29.52). +Less common +features include facial hypertrichosis, hyperpigmentation and +morphoea-like changes. +1265), can +occur in VP and HCP but not in PCT. +It is an important diagnosis to consider. +The presentation is usually +in early childhood, although the diagnosis is often delayed. +346 and p. +373). +Erythema chronicum migrans +can be associated with Lyme disease (Borrelia burgdorferi, +p. +255). +Erythema marginatum can occur in rheumatic fever +(p. +515) or Still’s disease (p. +1040). +An underlying trigger must be sought and +removed or treated. +Topical glucocorticoids or phototherapy +may be helpful for chronic disease. +The flexures, especially axillae and, in +dark-skinned people, sides of neck, are involved (pp. +1325, +1326 and 720). +There are several types, mainly associated with +insulin resistance. +Drug eruptions +Virtually all drugs may have cutaneous adverse effects (Fig. +Fig. +29.53 Erythema multiforme in a young woman. +Herpes simplex +virus infection was the trigger. +29.10, p. +17.59, p. +609). +An identied trigger is +often present (Box 29.33). +Lesions are typically painful, indurated +violaceous nodules on the shins and lower legs. +Systemic upset, +arthralgias and fever are common. +Spontaneous resolution occurs +over a month or so, leaving bruise-like marks. +Any underlying +cause should be identied and removed or treated. +Bed rest, leg +elevation and an oral NSAID frequently offer symptomatic relief. +It presents as keratotic papules, particularly in patients with +diabetes and chronic renal disease. +Treatment with topical +glucocorticoids, retinoids, PUVA or UVA1 therapy may help. +There +are other related perforating dermopathies, with characteristic +histology. +1264 +Erythema nodosum Tender, painful, dusky, erythematous nodules on shins See Box 29.33, p. +29.54 Drug eruption. +Possible drug causes of rash should always +be considered. +This was doxycycline-induced photosensitivity in a farmer. +sign.ac.uk Scottish Intercollegiate Guidelines Network: no. +Clinical features +Cutaneous drug reactions typically present in specic patterns (Box +29.35). +with azathioprine (p. +1227), +and provide exciting opportunities for therapeutic personalised +medicine. +Investigations and management +The suspected drug must be stopped. +1215). +Rechallenge with drug +is not usually undertaken unless the reaction is mild, as this +can be risky. +Drug withdrawal may not be straightforward and +substitute drugs may be required. +The management +of anaphylaxis is described on page 76. +Dermatology secrets plus, 5th edn. +Philadelphia: Elsevier Inc.; 2016; (Melasma) From Lawrence +CM, Cox NH. +Color atlas and text of physical signs in dermatology. +London: Wolfe; 1993; (Jaundice) From Morse SA, Ballard RC, Holmes KK, et al. +Atlas of +sexually transmitted diseases and AIDS, 4th edn. +Saunders, Elsevier Inc.; 2010; (Varicella pneumonia) From Voore N, Lai R. +Varicella pneumonia in an +immunocompetent adult. +Can Med Assoc J 2012; 184(17):1924; (Linea nigra) From Bolognia JL, Schaffer JV, Duncan KO, et al. +Dermatology essentials. +Philadelphia: Elsevier Inc.; 2014; Courtesy of Jean L. +Bolognia; (Striae gravidarum) From Buchanan K, Fletcher HM, Reid M. +Int J Gynecol Obstet 2009; 108(2010):65–68; (Striae albicans) From Cantisano-Zilkha M. +Aesthetic oculofacial rejuvenation. +Philadelphia: Saunders, Elsevier Inc.; 2010; (Peripheral oedema) From Huang H-W, Wong L-S, Lee C-H. +Sarcoidosis with bilateral leg lymphedema as the +initial presentation: a review of the literature. +These are necessary to support +the growing fetus, to prepare for delivery and to support lactation. +deviation of up to 15°. +Supraventricular and ventricular beats are common. +Echocardiography shows a modest increase in the dimensions +of the cardiac chambers. +30.1). +The raised levels +of T3 and T4 feed back to the pituitary and reduce TSH secretion. +30.1). +30.1 Hormonal changes in pregnancy. +increased GFR. +hypercoagulable state that increases the risk of venous and arterial +thrombosis. +These changes are required to +meet the 20% increase in oxygen demand that occurs during +pregnancy. +Respiratory rate is unaffected by +pregnancy. +Investigations that can be performed in pregnancy are +shown in Box 30.2. +However, gadolinium-containing contrast agents should be used +only if absolutely necessary. +Patients with post-partum +haemorrhage may also benet from uterotonic agents such as +oxytocin. +If the bleeding fails to settle, surgical intervention or +interventional radiology may be required. +Other causes of nausea and vomiting are summarised +in Box 30.4. +Obstetric causes include pulmonary embolism, haemorrhage and +amniotic fluid embolism (AFE). +Ante-partum haemorrhage is dened +as bleeding from the vagina after 24 weeks’ gestation. +This +should be considered in patients who are also hypertensive +and those with proteinuria. +Further details are on page 1276. +Seizures +The causes and management of seizures during pregnancy are +summarised in Box 30.5. +Pregnancy Hypertens 2014; 4:97–104. +oedema and proteinuria. +The +causes and classication are summarised in Box 30.6. +Risk factors for pre-eclampsia at antenatal +booking: systematic review of controlled studies. +Pneumonia in pregnancy. +Thorax 2001; 56:398–405. +120). +Viral infections +Viral pneumonia is more common and often more severe during +pregnancy. +1270). +Untreated +TB is associated with premature delivery and low birth weight. +Transmission to the fetus can occur but is unusual. +Wernicke’s encephalopathy may develop as the result of thiamin +deciency. +Recurrence is common in successive pregnancies. +Oedema +of face, +hands, +legs +Intrauterine +death +Fetal growth +restriction +Proteinuria +Fig. +30.2 Symptoms and signs of pre-eclampsia. +Eclampsia occurs in about 1% of pregnancies and is associated +with signicant mortality. +Treatment is with +intravenous magnesium sulphate and delivery of the fetus as soon +as possible. +The management is very similar to that in non-pregnant +individuals. +Diagnosis and management are +broadly the same as in non-pregnant patients. +Thiamin and glucocorticoids may be required in +the most severe cases. +Risk factors for gestational diabetes +are shown in Box 30.11. +753). +If pharmacological treatment is +necessary, metformin, glibenclamide or insulin can all be used. +Other oral therapies +or injectable incretin-based therapies should not be given in +pregnancy. +After delivery, maternal glucose usually returns to pre-pregnancy +levels. +743). +This is often difcult to +achieve, however. +These risks need to be carefully discussed before a woman +with diabetes is considering pregnancy. +Rarely, +hypothyroidism may present during pregnancy with weight gain, +constipation and lethargy. +The diagnosis is easily missed since +these symptoms are common in normal pregnancy. +651). +Despite this, a fully suppressed TSH is +usually indicative of Graves’ disease. +Antithyroid drugs are the treatment of first choice for +thyrotoxicosis in pregnancy. +Thyroid function should be monitored periodically in +the breastfed child. +Post-partum thyroiditis +Post-partum thyroiditis typically presents 3–4 months after +delivery. +It is discussed in more detail on page 647. +The World Health Organisation recommends a daily +iodine intake of 250 Îźg/day for pregnant women. +If parathyroidectomy +is required, it should ideally be performed during the second +trimester. +Rarely, adrenal insufciency can present for the rst +time during pregnancy. +672) can be falsely normal. +Specialist +assessment is required. +In some societies, routine HIV testing is recommended +at an early stage in pregnancy in all women. +Experience with other biological therapies +during pregnancy is limited. +Connective tissue disease in pregnancy. +Clin Med 2013; 131:580–584. +The management of patients with antiphospholipid +antibodies (aPL) is described below. +This +applies to primary APS and that associated with connective +tissue diseases such as SLE. +fetus. +In milder forms of the disease, however, the prognosis is +better (Box 30.13). +There is also a higher risk of lupus flare during the +puerperium. +Most patients can be managed medically +with β-blockers, LMWH and furosemide as necessary. +Myocardial infarction +Pregnancy increases the risk of myocardial infarction. +The vast majority of cases +in pregnancy are ‘type A’, involving the ascending aorta (see +Fig. +16.72, p. +It is a +diagnosis of exclusion, made when other causes of heart failure +have been ruled out. +Many women recover within 3–6 months of diagnosis +but the prognosis is variable. +There is a signicant chance of +reduction in cardiac function in subsequent pregnancies. +Management is +as described for PPCM. +Renal disease +Renal tract infection +Pregnancy predisposes women to urinary tract infection. +30.3). +Pregnancy can also cause +acceleration of maternal renal decline. +Renal disease and hypertension in pregnancy. +Clin Med 2014; 13:57–62. +30.3 Adverse pregnancy outcomes in chronic kidney disease. +Creatinine is in Îźmol/L. +To convert to mg/dL, multiply by 0.011. +Data from +Williams D, Davison D. +Chronic kidney disease in pregnancy. +BMJ 2008; +336:211–115. +Adapted from Ch’ng CL, Morgan M, Hainsworth I, et al. +Prospective study of liver +dysfunction in pregnancy in Southwest Wales. +Gut 2002; 51:876–880. +Despite this, many women receiving renal replacement +therapy have successful pregnancies. +The outcome is best +for women with a well-functioning graft, with no proteinuria or +hypertension. +Liver disease +Specic causes of liver disease during pregnancy are discussed +below. +Rarely, fulminant +liver failure may occur. +A liver biopsy is rarely needed to make the diagnosis but +shows microvascular steatosis. +Management is with supportive +care and by delivery of the fetus. +It usually presents antenatally but can also +appear for the rst time in the postnatal period. +HELLP can be complicated by liver haematoma +and capsular rupture. +Laboratory testing reveals raised levels of bile acids and +abnormal LFTs. +Aqueous cream with menthol can +also be effective in soothing pruritus. +The risk of recurrence in future pregnancies is high. +Pregnant +women are at greater risk of contracting hepatitis E than the +non-pregnant population. +However, it can cause fulminant hepatic failure in up to 20% +of pregnant women. +safety prole in pregnancy, such as lamotrigine, levetiracetam or +carbamazepine. +The mode of delivery is +not affected by IIH and spinal analgesia can be given as normal. +If necessary, prophylaxis can be given with aspirin, β-blockers or +tricyclic antidepressants. +Safety data on use of triptans during +pregnancy are limited but reassuring. +Triptans can therefore be +used for the treatment of migraine if other therapies are ineffective. +Stroke +Stroke is twice as common in pregnant women as in non- +pregnant women of the same age. +The risk is highest during +the third trimester and puerperium. +The management of stroke +during pregnancy is similar to that in non-pregnant patients. +The +risk of cerebral venous thrombosis is greatly increased during +pregnancy. +The presentation is with headache, seizures and +neurological decits such as hemiparesis. +If the diagnosis is +suspected, neuroimaging should be performed with MRI or CT +venography. +These disorders +are discussed in more detail on page 1206 and in Box 28.33. +Haematological disease +Anaemia +The causes of anaemia during pregnancy are summarised in +Box 30.17. +Iron deciency anaemia is most commonly due to +a 20% increased demand for iron. +Measurement +of D-dimer is not useful in pregnancy because levels rise as +part of normal pregnancy. +Further information +British Thoracic Society/Scottish Intercollegiate Guidelines Network. +SIGN 141 – British guideline on the management of asthma. +Edinburgh: Health Improvement Scotland; 2014. +Useful asthma +guidelines. +Royal College of Obstetricians and Gynaecologists. +Thromboembolic +disease in pregnancy and the puerperium: acute management. +Green top guideline. +London: RCOG; April 2015. +A useful +evidence-based guideline on the investigation of pulmonary +embolism in pregnancy. +More details are provided on page 933 and in Box 23.19. +Thrombocytopenia +The causes of thrombocytopenia during pregnancy are +summarised in Box 30.18. +It is not +associated with adverse pregnancy outcomes and requires no +specic intervention. +Pregnancy may occur in women with pre- +existing idiopathic thrombocytopenic purpura (ITP, p. +971). +Thrombocytopenia may also occur as a +component of haemolytic uraemic syndrome (HUS, p. +408) and +thrombotic thrombocytopenic purpura (TTP, p. +979). +Platelet transfusion should be +avoided. +31.2 Lifestyle changes during transition to adulthood. +Fig. +31.2). +Likewise, obesity +needs consideration in terms of prescribing and drug doses. +The key components are +summarised in Box 31.2. +Describes condition, effects and prognosis +2. +Understands medication purpose and effects +3. +Understands treatment purposes and effects +4. +Knows key team members and their roles +(S) Self-advocacy +1. +Can attend part/whole clinic appointment on their own +2. +Knows how to make appointments/alter appointments +3. +Has understanding of condentiality +4. +Orders repeat prescriptions +5. +Takes some/complete responsibility for medication/other treatment +6. +Knows where to get help +(H) Health and lifestyle +1. +Understands importance of diet/exercise/dental care +2. +Understands impact of smoking/alcohol/substance use +3. +Self-care/meal preparation +2. +Independent travel/mobility +3. +Trips/overnight stays away from home +4. +Benets/nancial independence +(V) Vocational +1. +Current and future education/impact of condition on career plans +2. +School attendance and performance +3. +Work experience and access to careers advice +4. +Outside activities and interests +5. +Disclosure to school/employer +(P) Psychosocial +1. +Self-esteem/self-condence +2. +Body/self-image +3. +Peer relationships/bullying +4. +Support networks/family/disclosure to friends +5. +Coping strategies +(T) Transition +1. +Understands concept of transition +2. +Agrees transition plan +3. +Attends transition clinic +4. +Visits adult unit (if appropriate) +5. +31.3 Timing of transition. +a care plan developed. +A number of organisations have published guidelines to planning +transition services. +When should transition happen? +Transition should generally +be initiated at around 12 years of age. +Most commonly, full transition occurs +between 16 and 18 years of age (Fig. +31.3). +Marriage and children often follow. +Insulin +production also rises by about 30% during puberty. +Menstruation +typically starts after the rate of growth has peaked. +31.5). +654). +During +this phase, several physical, biochemical and emotional changes +occur. +The most important are discussed in more detail below. +31.4 Hormonal events of puberty. +Androgens are also produced in small amounts by theca cells in response to LH (not shown). +B In the male, +LH acts on interstitial Leydig cells to stimulate testosterone production. +FSH with testosterone acts on Sertoli cells to stimulate spermatogenesis. +Netter’s Obstetrics and gynecology, 2nd edn. +31.5 Tanner staging of puberty. +Finally, young adults begin to develop rm +belief systems, autonomy and independence. +Receiving appropriate +benets/support? +Financial or other practical +concerns? +Living with parents/left +home? +It is important +to use age-adjusted biochemical reference ranges until puberty +has been completed. +Some of the key changes in biochemical markers are outlined +in Box 31.4. +More detail on reference ranges for specic analytes +is provided in Box 35.9 (p. +1363). +If there are concerns about +capacity, clarify key decision-makers. +assessment. +Teenagers may also have varying adherence levels within their +treatment regimen. +It also implies partnership +and cooperation between the patient and the care-giver. +More +recently, clinicians have moved to seeking patients’ concordance +with management plans. +2011. +Despite their maturing +skills, they may remain self-centred and feel invincible. +Factors that +positively and negatively affect adherence are outlined in Box 31.6. +Interventions to improve adherence are summarised in Box 31.7. +The PFC +and its connections are structurally unable to provide sufcient +control. +Older males and those of lower educational +status are higher risk takers. +It is not easy to affect behaviour during this period of non- +adherence. +Adolescence: what the cystic brosis team needs to know. +Epilepsy presents several problems during transition. +Driving restrictions may +also limit options for some other occupations (p. +1103). +Teenage pregnancy rates are high across +the world (Box 31.9). +The key issues to consider for a number +of the most common LTCs of childhood are discussed below. +1097). +1143). +Physicians should ensure that the whole family are +aware of the wider genetic issues. +Although fertility +is reduced, young men with these conditions may themselves +father children. +Male offspring will be unaffected but all female +infants of affected males will be carriers. +At the present +time, there is no denitive treatment. +42). +Patients with DMD +usually require social and nancial support. +It is important to +consider end-of-life care plans with patients and family members. +580). +With improved supportive +care, the median survival in the UK is now more than 50 years. +Women also need to be advised about the effects of antibiotics on +OCP effectiveness. +These drugs are having a positive effect on +symptom control and are potentially disease-modifying. +Common issues encountered during transition of CF patients are +summarised in Box 17.34 (p. +581). +Among birth defects, +CHD is the leading cause of mortality. +Overall, the most +common congenital valvular anomalies are aortic and pulmonary +stenosis. +The most common structural anomaly is ventricular +septal defect. +More details are provided on +page 531 and in Box 16.103 (p. +537). +Hypertrophic obstructive cardiomyopathy +Hypertrophic obstructive cardiomyopathy (HOCM, p. +It +may present for the rst time during adolescence with cardiac +arrest or sudden cardiac death. +necrosis, and angina or myocardial infarction arising from vaso- +occlusion or vasospasm. +Renal disease +Chronic kidney disease (CKD, p. +415) accounts for some of +the most complex long-term illnesses in childhood. +The most +common causes during childhood and adolescence are shown +in Box 31.10. +Radiotherapy to +the neck can cause hypothyroidism and increases the risk of +thyroid cancer. +Chemotherapy and radiotherapy in childhood +signicantly reduce ovarian reserves. +Cardiomyopathy is another complication of anthracyclines such +as doxorubicin and daunorubicin. +Rates of +non-adherence are highest among adolescents and young adults. +This offers the opportunity to improve graft +survival. +There is no clear difference between children and adults in +survival of transplanted kidneys. +Alternate-day regimes are +generally considered preferable in childhood. +The different rates +possibly relate to the varying degrees of immunosuppression +required. +753). +Current treatment aims +are outlined in Box 31.13. +707). +Hypophosphataemic rickets +Hypophosphataemic rickets is described in more detail on +page 1052. +They are a patient group that can display complex and often +abnormal illness behaviour. +Ciclosporin is probably more effective than infliximab in teenagers +with refractory UC. +1026). +Adherence to and concordance with medication remain +a challenge, as in other chronic diseases. +Functional limitation +secondary to joint damage may limit employment opportunities. +Contraceptive advice is important in patients on methotrexate. +It is important to ensure adequate calcium +and vitamin D intake and to supplement if necessary. +Osteogenesis imperfecta +Osteogenesis imperfecta (p. +1055) typically presents with multiple +low-trauma fractures during infancy and childhood. +Strategies to enhance patient adherence: +Making it simple. +MedGenMed 2005; 7:4. +Crowley R, Wolfe I, Lock K, McKee M. +Improving the transition +between paediatric and adult healthcare: a systematic review. +Arch Dis Child 2011; 96:548–553. +Segal TY. +Adolescence: what the cystic brosis team needs to know. +J R Soc Med 2008; 101(Suppl 1):15–27. +Websites +acpm.org/?Adherence American College of Preventive Medicine: +detailed review of adherence. +GotTransition.org Sample clinical tools and measurement resources for +quality improvement purposes. +19) +Insets (Wasted hand, kyphosis) From Afzal Mir M. +Atlas of clinical diagnosis, 2nd edn. +Edinburgh: Saunders, Elsevier Inc.; 2003; (Senile purpura) Forbes +CD, Jackson WF. +Clinical medicine, 3rd edn. +Edinburgh: Mosby, Elsevier Inc.; 2004; (Venous ulceration) Mosti G. +Compression and venous surgery for leg +ulcers. +Has the patient noticed +memory problems? +Can the +patient perform all household +tasks? +A normal performance takes +less than 12 seconds. +32 +Difficulty rising? +Unsteady gait? +Unsteady on +Unsteady on +Unsteady on +turning? +standing? +32). +1303). +Accordingly, there is often little high-quality evidence on +which to base practice. +Demography +The demography of all countries has changed rapidly in recent +decades. +32.1 Number of people aged 65 years and over projected in the +world population. +to live for a further 10 years. +The rate of population ageing +is much faster in developing countries (Fig. +32.1) and so there +will be less time to adjust to its impact. +There is evidence that variants in many +genes contribute to ageing. +41) and insulin signalling. +When telomeres +are sufciently eroded, cells stop dividing. +These damage structure and function of the +affected protein, which becomes resistant to breakdown. +There is evidence in some organisms that this interplay is +mediated by insulin signalling pathways. +Some changes of ageing, such as +depigmentation of the hair, are of no clinical signicance. +Figure +32.2 shows the many changes that occur with ageing that are +clinically important. +The same stresses would cause little upset in a t person of +the same age. +After recovery, function is largely stable and the +patient may otherwise be in good health. +It can be specically identied, +however, by assessing function in a number of domains. +1302). +It is iterative in nature, management being followed +by reassessment and a new management plan. +Comprehensive Geriatric Assessment is performed by a +multidisciplinary team (p. +1303). +On the other hand, +disability should never be dismissed as due to age alone. +So how do doctors decide when and how +far to investigate? +A key issue is to establish +what the patient wants from investigation and treatment. +*Varies between populations. +If the patient wishes, the +views of relatives can also be taken into account. +However, families should never be +made to feel responsible for difcult decisions. +Do they have the aerobic +capacity to undergo bronchoscopy? +Will delirium prevent them +from remaining still in the magnetic resonance imaging (MRI) +scanner? +Will the investigation alter management? +The presence +of comorbidity and frailty is more important than age itself in +determining this. +Will management benet the patient? +Most +problems are multifactorial and there is rarely a single unifying +diagnosis. +All contributing factors have to be taken into account +and attention to detail is paramount. +Two patients who share +the same presenting problem may have completely disparate +diagnoses. +There are a number of features +that are particular to older patients. +Stroke may present with falls +rather than symptoms of focal weakness. +Myocardial infarction +may present as weakness and fatigue, without chest pain or +dyspnoea. +The reasons for these atypical presentations are +not always easy to establish. +The pyretic response is blunted in old +age so that infection may not be obvious at rst. +Cognitive +impairment may limit the patient’s ability to give a history of +classical symptoms. +The possibility that an acute illness has +been the precipitant must always be considered. +These share some underlying causes and may precipitate +each other. +Call these people by phone if they are not +present. +• Check all medication. +Have there been any recent +changes? +• Search for and treat any acute illness (Box 32.3). +• Identify and reverse predisposing risk factors. +These +depend on the presenting problem. +Femoral neck BMD (g/cm2) +Fig. +32.3 Age and bone mineral density (BMD) interact to influence +fracture risk. +181 and 1080). +1303) require further assessment. +The risk factors for falls (Box 32.4) should be +considered. +Common pathologies identied include cerebrovascular disease +(Ch. +26), Parkinson’s disease (p. +1112) and osteoarthritis of +weight-bearing joints (p. +1007). +32.3). +Management will vary according to the +underlying cause. +Suspicion +should be high when falls have suddenly occurred over a period +of a few days. +Common underlying illnesses include infection, +stroke, metabolic disturbance and heart failure. +Thorough +examination and investigation are required (Box 32.3). +Once the underlying acute illness has been treated, +falls may stop. +Blackouts +A proportion of older people who ‘fall’ have, in fact, had a syncopal +episode. +It can be disabling in its +own right and is also a risk factor for falls. +1086) +• unsteadiness/poor balance, suggestive of joint or +neurological disease. +Antihypertensive medications may exacerbate these +conditions. +Further investigation and treatment are described +on page 181. +Vertigo in older patients is most commonly due to benign +positional vertigo (p. +Differential diagnosis, +assessment and management are discussed on page 183. +It may lead to skin +damage if severe and can be socially restricting. +32.4). +The initial assessment should seek to identify and address +contributory factors. +If osteoporosis is diagnosed, specic drug therapy should be +considered (p. +1046). +32.4 Assessment and management of urinary incontinence in +old age. +See also page 436 and NICE guideline on the Management of +Incontinence in Women: nice.org.uk. +A timed/prompted toileting programme may +help. +However, the more drugs that are taken, +the greater the risk of an adverse drug reaction (ADR). +ADRs +and the effects of drug interactions are discussed on page 21. +Non-adherence to drug therapy also rises with the number of +drugs prescribed. +Thoughtless adherence to guidelines quickly leads +to polypharmacy that may be inappropriate. +Deprescribing is as important as prescribing in older people. +If +any of the above issues is problematic, the medication should +be deprescribed. +Relevant sections in other chapters are referenced in +Box 32.9. +It entails: +• Assessment. +• Goal-setting. +• Intervention. +The patient and carer(s) must be active +participants. +• Re-assessment. +Interventions +may be modied as a result. +1303). +Good communication and mutual respect are essential. +32.9 Other presenting problems in old age +• Hypothermia p. +166 +• Dizziness and blackouts p. +181 +• Delirium p. +183 +• Infection pp. +218 and 228 +• Fluid balance problems p. +360 +• Heart failure p. +466 +• Atrial brillation p. +472 +• Hypertension p. +512 +• Under-nutrition p. +710 +• Diabetes mellitus p. +732 +• Peptic ulceration p. +801 +• Anaemia p. +954 +• Painful joints p. +992 +• Bone disease and fracture pp. +994 and 1049 +• Stroke p. +1147 +• Dementia p. +It also reduces mortality after stroke and hip fracture. +qfracture.org Fracture risk calculator validated in the UK population. +Includes a wider range of risk factors than FRAX. +Includes option to calculate +with or without measurement of hip bone mineral density. +*The 20-point version is illustrated. +Genome instability and mutation 1316 +2. +Resisting cell death 1316 +3. +Sustaining proliferative signalling 1317 +4. +Evading growth suppressors 1318 +5. +Enabling replicative immortality 1318 +6. +Inducing angiogenesis 1318 +7. +Activating invasion and metastasis 1319 +8. +Reprogramming energy metabolism 1319 +9. +Tumour-promoting inflammation 1319 +10. +• Is the umbilicus everted, suggesting ascites? +1334)? +• Is there smooth hepatomegaly – possibly primary liver cancer or heart failure? +• Is the liver rm or knobbly, suggesting metastasis? +• Is the ascites too tense to demonstrate hepatomegaly? +• Are other masses palpable in the abdomen? +• Are there signs of obstruction or paralytic ileus with absence of bowel sounds? +The most common solid organ malignancies arise in the +lung, breast and gastrointestinal tract (Fig. +33.1), but the most +common form worldwide is skin cancer. +The 10 hallmarks of cancer +1. +2. +Apoptosis +This is programmed cell death. +33.1 The most commonly diagnosed cancers in the UK. +3. +33.2). +40). +TP53, TP21, TP16 +genes). +33.2 The cell cycle and sites of action of chemotherapeutic agents. +(CDK = cyclin-dependent kinase; RB = retinoblastoma gene)1318 • ONCOLOGY +4. +This contact inhibition is +typically absent in many cancer cell populations. +Mutations within inhibitory proteins are common in cancer. +5. +6. +collagenase +tissue metalloproteinases +Loss of cell adhesion molecules +e.g. +E-cadherin +↑ Angiogenesis +to support +tumour growth +(see Fig. +33.4) +Fig. +33.3 Oncogenesis. +33.4 Angiogenesis, invasion and metastasis. +A For +any cancer to grow beyond 1 mm3, it must evoke a blood +supply. +(VEGF= +vascular endothelial growth factor) +Loss of +inhibition +Angiogenic +factors +BC +7. +33.3). +8. +While under anaerobic conditions, +glycolysis is favoured to produce adenosine triphosphate (ATP). +This has been termed ‘aerobic glycolysis’. +9. +10. +4.12, p. +80). +These +are often tumour type-specic but some general principles do +apply. +Hiroshima) Leukaemia +Solid tumours, e.g. +thyroid +Diagnostic exposure (e.g. +CT) Cholangiocarcinoma following Thorotrast usage +Occupational exposure (e.g. +For carcinomas of the +bowel and breast, there is strong evidence of an environmental +component. +1314–1315). +• Presence of melanin favours melanoma. +• Psammoma bodies are a feature of ovarian cancer (mucin ++) and thyroid cancer (mucin −). +Positive +results indicate that the tumour may be sensitive to +hormonal manipulation. +These favour germ-cell tumours. +• Prostate-specic antigen (PSA) and prostatic acid +phosphatase (PAP). +These favour prostate cancer. +• Carcinoembryonic antigen (CEA), cytokeratin and epithelial +membrane antigen (EMA). +These favour epithelial +carcinomas. +• HER2 receptor. +This can be +achieved by IHC staining of biopsy samples or flow cytometry. +Electron microscopy +Electron microscopy (EM) can sometimes be of diagnostic value. +Cytogenetic analysis +Some tumours demonstrate typical chromosomal changes that +help in diagnosis. +In some cases, +gene amplication can be detected via FISH (e.g. +determining +over-expression of HER2/neu). +For some tumours, such as +colon cancer, the Dukes system (p. +832) is used rather than +the UICC classication. +It can be used for +guiding biopsies of tumours in breast and liver. +It is widely +employed for the staging of rectal, cervical and prostate cancers. +33.5). +Tumour markers in routine use are outlined in Box 33.5. +A +B +Fig. +33.5 Positron emission tomography–computed tomography +(PET–CT) images. +Courtesy of Dr J. +Wilsdon, Freeman Hospital, Newcastle upon Tyne. +Transient elevation in liver diseases. +Raised in any cause of ascites, +pleural effusion or heart failure. +PSA is a serine protease that liquees semen in +excretory ducts of prostate. +This can result +in a wide variety of presentations, as summarised in Box 33.9. +The management of +hypercalcaemia associated with malignancy is discussed below. +• Peripheral neuropathy results from axonal degeneration or +demyelination. +Encephalomyelitis is due to perivascular +inflammation and selective neuronal degeneration. +Most +cases are caused by small cell lung cancer (75%). +Diagnosis is by MRI or CT, which may +show cerebellar atrophy. +If left untreated, it may lead to blindness. +• Lambert–Eaton myasthenic syndrome (LEMS) is due to +underlying cancer in about 60% of cases. +Uptake is low despite +increasing incidence with age. +• Presentation: may be later for some cancers. +• Rate of progression: malignancy may have a more indolent +course. +Symptom control may be all +that is possible or desired by the patient. +of brinolysis. +central venous catheters). +In some patients, the thromboembolism +is the rst presenting feature of the underlying cancer. +1143). +• Dermatomyositis or polymyositis may be the rst +presentation of some cancers. +Clinical features and +management of these conditions are discussed on +page 1039. +• Pemphigus may occur in lymphoma, Kaposi’s sarcoma +and thymic tumours. +The clinical features and management of these skin conditions +are discussed in Chapter 29. +The most common causes of extrinsic +compression are lung cancer, lymphoma and metastatic +tumours. +Accordingly, +symptoms may develop rapidly or gradually. +Clinical features +are summarised in Box 33.12. +The thoracic +region is most commonly affected. +Clinical features +The earliest sign is back pain, particularly on coughing and lying +flat. +Finally, sphincter disturbance, causing urinary +retention and bowel incontinence, is observed. +Involvement of +the lumbar spine may cause conus medullaris or cauda equina +compression (Box 33.10). +This alone often results in clinical improvement. +Concurrently, +intravenous bisphosphonates should be given to inhibit bone +resorption. +Neutropenic fever +Neutropenia is a common complication of malignancy. +Examination is usually unhelpful +in dening a primary source of the infection. +High-dose intravenous antibiotics should then be commenced, +pending the results of cultures. +in patients +with central lines). +Antibiotics should be adjusted according to +culture results, although these are often negative. +CT of the head may be indicated if cerebral oedema is suspected. +This relieves symptoms within 2 weeks in +50–90% of patients. +The principles of management are outlined in Box 33.13. +331328 • ONCOLOGY +(liposomal amphotericin B). +More rarely, it +can occur spontaneously. +Good hydration and urine output should be +maintained throughout treatment administration. +In high-risk patients, hydration should be commenced 24 hours +before the start of treatment. +Investigations and management +The diagnosis can be conrmed by CT or contrast-enhanced +MRI. +Lung metastases +These are common in breast cancer, colon cancer and tumours +of the head and neck. +The presentation is usually with a lesion +on chest X-ray or CT. +Patients with two or more pulmonary nodules can +be assumed to have metastases. +The approach to treatment +depends on the extent of disease in the lung and elsewhere. +For +solitary lesions, surgery should be considered, with a generous +wedge resection. +In selected cases, resection +of the metastasis can be contemplated. +Tumours that typically metastasise to the brain +are shown in Box 33.14. +Practices vary, however, for +patients with more advanced brain metastases. +In these cases, +median survival without treatment is approximately 1 month. +If these are not feasible, +symptoms may respond to systemic chemotherapy. +Bone metastases +Bone is the third most common organ involved by metastasis, +after lung and liver. +relief of tumour impingement on +normal structure). +Surgical intervention may be warranted where there is evidence +of skeletal instability (e.g. +anterior or posterior spinal column +fracture) or an impending fracture (e.g. +a large lytic lesion on a +weight-bearing bone with more than 50% cortical involvement). +In certain types of +cancer, such as breast and prostate, hormonal therapy may be +effective. +In some settings (e.g. +breast carcinoma), +chemotherapy may be used in the management of bony +metastases. +• Identify a suitable site for aspiration. +• As you advance the needle, aspirate at each step prior to injecting +the local anaesthetic. +• Drain the pleural effusion, to a maximum of 1.5 L. +If the effusion is +larger than this, repeat the procedure on further occasions as +necessary. +or pleuritic in nature. +Diagnosis and management of ascites are +discussed on page 863. +Ideally, pleurodesis +should be attempted once effusions recur after initial drainage. +The goal of treatment should be recorded +in the medical notes. +As a result, the treatment should be well +tolerated and should aim to minimise adverse effects. +The focus is on achieving an +improvement in disease-free and overall survival. +Surgical treatment +Surgery has a pivotal role in the management of cancer. +There +are three main situations in which it is necessary. +Cytology can be obtained with ne +needle aspiration but a biopsy is usually preferred. +This can be +a core biopsy, an image-guided biopsy or an excision biopsy. +Excision +The main curative management of most solid cancers is surgical +excision. +In early, localised cases of colorectal, breast and lung +cancer, cure rates are high with surgery. +Systemic chemotherapy +Chemotherapeutic drugs are classied by their mode of action. +A course of +treatment often uses up to 6 cycles of treatment. +An increase +in effectiveness can be achieved by changing the approach to +treatment. +This can be minimised by using G–CSF. +• Alternating therapy involves giving different drugs in an +alternating manner. +33.6 Adverse effects of chemotherapy and radiotherapy. +Acute effects are shown in pink and late effects in blue. +of normal and tumour tissue. +Biological differences between normal and tumour tissues +are used to obtain therapeutic gain. +Both normal and malignant tissues vary widely in their sensitivity +to radiotherapy. +The side-effects +of radiotherapy (see Fig. +33.6) depend on the normal tissues +treated, their radiosensitivity and the dose delivered. +• Brachytherapy: direct application of a radioactive source +on to or into a tumour. +The biological effect of ionising +radiation is to cause lethal and sublethal damage to DNA. +Hormonal manipulation may be +effective in other cancers. +In prostate cancer, hormonal therapy +(e.g. +Progestogens are active in the treatment of endometrial and +breast cancer. +In the metastatic setting, progestogen use (e.g. +megestrol acetate) is associated with response rates of 20–40% +in endometrial cancer. +Their exact mechanism in this setting +is not fully understood. +965). +958), and it does this extremely effectively. +gastric cancer). +435 +Colorectal cancer p. +827 +Familial cancer syndromes p. +56 +Gastric cancer p. +803 +Hepatocellular carcinoma p. +890 +Leukaemia p. +954 +Lung cancer p. +598 +Lymphoma p. +961 +Mesothelioma p. +618 +Myeloma p. +966 +Oesophageal cancer p. +796 +Pancreatic cancer p. +842 +Prostate cancer p. +438 +Renal cancer p. +434 +Seminoma p. +439 +Skin cancer p. +1229 +Teratoma p. +439 +Thyroid cancer p. +649 +intent, the patient is young and more patients are living longer. +Egg or embryo banking +after in vitro fertilisation may be an option for young women. +Additional social or psychological support +may be required. +Infertility and pubertal delay are potential late +effects of therapy in children, especially boys. +The survival for breast cancer +by stage is outlined in Box 33.18. +Other risk factors include obesity, alcohol +intake, nulliparity and late rst pregnancy. +There is no denite +evidence linking use of the contraceptive pill to breast cancer. +If distant spread is suspected, +CT of the thorax and abdomen and an isotope bone scan are +required. +This may allow more targeted +selection of therapies in future. +Lymph +node sampling is performed at the time of surgery. +Adjuvant +radiotherapy is given to reduce the risk of local recurrence to +4–6%. +Aromatase inhibitors also have benet in this setting but are +still under investigation. +Adjuvant chemotherapy is considered for patients at higher +risk of recurrence. +Advanced ER-negative disease +may be treated with combination chemotherapy. +Ovarian cancer +Ovarian cancer is the most common gynaecological tumour in +Western countries. +Pathogenesis +Genetic and environmental factors play a role. +Serum levels of the +tumour marker CA-125 are often measured. +These +regimens are associated with a response rate of 10–40%. +The +best responses are observed in patients with a treatment-free +interval of more than 12 months. +The majority of patients are +post-menopausal, with a peak incidence at 50–60 years of +age. +Mortality from endometrial cancer is currently falling. +The incidence is decreasing in developed countries +but continues to rise in developing nations. +Occasionally, patients present with distant metastases to bone +and lung. +342). +Investigations +Diagnosis is made by smear or cone biopsy. +A routine chest X-ray should be obtained to help +rule out pulmonary metastasis. +Management +This depends on the stage of disease. +Presentation depends +on the location of the primary tumour and the extent of disease. +Tissue +biopsies should be taken from the most accessible site. +In many cases, a subsequent biopsy reveals adenocarcinoma +but the primary site is not always clear. +For all patients, histological examination of an accessible site +of metastasis is required. +The greater volume of tissue permits the use +of immunohistochemistry. +The overriding principle is to ensure that a curable +diagnosis has been excluded. +Oxford handbook of +oncology, 4th edn. +Oxford: Oxford University Press; 2015. +Dark GG. +Oncology at a glance. +Chichester: Wiley–Blackwell; 2013. +Hanahan D, Weinberg RA. +The hallmarks of cancer: the next +generation. +Cell 2011; 144:646–674. +Tobias J, Hochhauser D. +Cancer and its management, 7th edn. +Chichester: Wiley–Blackwell; 2014. +Websites +cancer.org American Cancer Society: clinical practice guidelines. +ctep.cancer.gov/reporting/ctc.html Common toxicity criteria. +It is one of the most +common symptoms for which people seek health-care advice. +1065 and 1068). +Here, discussion +will focus on the mechanisms and mediators that are involved +in pain processing. +Peripheral nerves +Peripheral nerves contain several types of neuron. +25.10, p. +1071). +Anatomical features of the afferent pain pathway are illustrated +in Figure 34.2. +Pain signals are transmitted from the periphery +to the spinal cord by sensory neurons. +They are +situated mainly in the epidermis. +34.1 The biopsychosocial model of pain. +34.2 Ascending and descending pain pathways. +Ascending pathways are shown in blue and descending in red. +Thereafter, the pain signal is +transmitted to the cerebral cortex. +1072). +This is termed the pain neuromatrix (Fig. +34.2). +Over recent years, there has +been increasing interest in the role that glial cells (see Fig. +25.1, +p. +1064) play in pain processing. +Sensitisation +Sensitisation is one of the key features of pain processing. +This adaptive process is called +neuronal plasticity. +34.3). +34.4). +This phenomenon is termed ‘after-discharge’. +34.3 Mechanisms of peripheral sensitisation. +A Sensory nerve terminating with nociceptor in skin. +B Peripheral nociceptors express various +receptors and ion channels that act as mediators of pain. +Adapted from Bennett DL, Woods CG. +Painful and painless channelopathies. +Reprinted with permission from Elsevier (The Lancet Neurol +2014; 13:587–599). +34.4 Mechanisms of central sensitisation. +In contrast, magnesium +ions block receptor activation. +that the heritability of CWP ranges between 30% and 50%. +Few variants +have been identied with robust evidence of association with +CWP. +Imaging +is seldom helpful in individuals with CWP. +Full details are provided in +Box 25.86 (p. +1139). +A simple set of tools +can be used in the clinical setting (Fig. +34.5). +They can be used to help differentiate between central and +peripheral neuropathic pain. +They do not, however, effectively +examine small nerve bre function. +34.5 Equipment for bedside sensory testing. +Some of the most widely used are listed in Box 34.4. +1187). +Strategies that can be used to overcome these difculties are +summarised in Box 34.5. +Under these circumstances, several management +options are available. +Supported self-management +Self-management strategies are useful in the treatment of chronic +pain. +The aim is for patients to +maximise their quality of life and function despite ongoing pain. +There are a number of useful online self-help resources (see +‘Further reading’). +This may include normal household +activities, as well as targeted exercises and stretches. +There are many reasons +for this, including genetic variations in the enzymes that metabolise +drugs. +Specic drug +treatments are described below. +For migraine and tension-type +headache it has moderate efcacy at a dose of 1000 mg. +These drugs +can be given systemically or locally and are discussed in more +detail on page 1002. +1350). +Opioid analgesics +Opioids are a class of drugs that target opioid receptors. +Opioid receptors +are G-protein-coupled receptors. +The +dosages and characteristics of commonly prescribed opioids are +shown in Box 34.9. +Additionally, there is increasing concern +about potential harm from long-term use. +A suggested strategy for using strong opioids in chronic +pain is shown in Box 34.10. +The overall aim is to reduce negative +thoughts and beliefs, and develop positive coping strategies. +Acupuncture (Fig. +34.6) has been used successfully in Eastern +medicine for centuries. +The mechanisms are incompletely +understood, although endorphin release may explain, in part, +Fig. +34.6 Acupuncture. +the analgesic effect. +Grapefruit may also increase the +risk of serotonergic effects with some antidepressants. +Ginkgo +biloba may interact with paracetamol to increase bleeding time. +The clinical features of neuropathic pain are +summarised in Box 34.11. +An +algorithm for the management of neuropathic pain is provided +in Figure 34.7. +Are there clinical features of +neuropathic pain? +34.7 Algorithm for pharmacological management of neuropathic +pain. +Pharmacotherapy for neuropathic pain in +adults: a systematic review and meta-analysis. +Clinical features and management of bromyalgia are discussed +in more detail on page 1018. +It is described +in more detail on page 1059. +The focus of palliative care is on symptom control alongside +supportive care. +Palliative may therefore be applied to any +chronic disease state. +34.8). +The diagnosis is primarily clinical, based on the +features shown in Box 34.12. +1055). +Prompt diagnosis and early treatment with physiotherapy +may prevent progression of symptoms. +Management is as +for neuropathic pain, additional approaches including graded +motor imagery. +Cancer +Organ failure +Physical and cognitive frailty +High +Function +Death +Low +Time +Fig. +34.8 Archetypal trajectories of dying. +Reproduced from Murray +SA, Kendall M, Boyd K, et al. +Illness trajectories and palliative care. +BMJ +2005; 330:7498; reproduced with permission from the BMJ Publishing +Group. +Many traditional hospice services are designed to meet +the needs of people on this trajectory. +The most common symptoms in palliative +care are discussed in the next section. +Presenting problems in palliative care +Pain +Pain is a common problem in palliative care. +34.9), in which analgesia that is appropriate +for the degree of pain is prescribed rst. +This can be prescribed separately or in the +form of the compound analgesic co-codamol. +Opioids +Opioid analgesia plays a key role in patients with moderate +to severe pain. +34.9 The WHO analgesic ladder. +From WHO. +Cancer pain relief, +2nd edn. +Geneva: WHO; 1996. +Nausea and vomiting +can occur initially but usually settle after a few days. +Drowsiness +is usually transient at opioid initiation and dose increase. +If it is +persistent, an alternative opioid and/or a non-opioid should be +considered. +Tolerance usually develops to nausea, vomiting and drowsiness +but not to constipation or dry mouth. +The median effective +morphine equivalent dose for cancer pain is about 200 mg per +24 hours. +As a rule of thumb, +this additional dose should be one-sixth of the total 24-hour +dose of opioid. +The patient or +carer should note the timing of any breakthrough doses and the +reason for them. +This can be a risk in metastatic bone pain. +Some patients may have concerns about using opioids and +it is vital for these to be explored. +Patients should be reassured +341352 • PAIN AND PALLIATIVE CARE +antagonists, such as naloxone. +Pain should be reassessed to ensure that appropriate adjuvants +are being used. +Parenteral rehydration is often helpful to speed +up excretion of active metabolites of morphine. +The dose of +opioid may need to be reduced or the opioid changed to a +strong alternative. +Different opioids have different side-effect profiles in +different people. +If a patient develops side-effects, switching +to an alternative strong opioid may be helpful. +Commonly +used adjuvant analgesics in the palliative care setting are shown +in Box 34.15. +Coeliac plexus +blocks can be helpful for visceral pain, such as in pancreatic +cancer. +If symptoms persist, additional measures may be necessary. +A cycle of panic and breathlessness, often +associated with fear of dying, can be dominant. +Opioids, through both their +central and their peripheral action, can palliate breathlessness. +Both oral and parenteral opioids are effective. +Cough +Persistent unproductive cough can be helped by opioids, which +have an antitussive effect. +780). +34.10 Mechanisms of nausea. +Vomiting related to raised intracranial pressure is worse +in the morning. +Different receptors are activated, depending on +the cause or causes of the nausea (Fig. +34.10). +Reversible causes, such as +hypercalcaemia and constipation, should be treated appropriately. +Drug-induced causes should be considered and the offending +drugs stopped if possible. +Delirium and agitation +Many patients become confused or agitated in the last days of +life. +It is important to identify and treat potentially reversible causes +(p. +183), unless the patient is too close to death for this to be +feasible. +Early diagnosis and effective management of delirium +are extremely important. +The management of delirium +is detailed on page 209. +Comfort +and avoidance of distress in the family are the primary aims. +Each decision should be individual and +discussed with the patient’s family. +This can +be problematic when a specic treatment worsens another +symptom. +Occasionally, a nasogastric tube is required +to reduce gaseous or fluid distension. +It is therefore +important to realise that these symptoms are not inevitable in +advanced cancer. +1199). +A clear +decision that the patient is dying should be agreed and recorded. +Medication and investigation are justiable only if they contribute +to these ends. +Management should not be changed without discussion with the +patient and/or family. +Medicines should always be prescribed for +the relief of symptoms. +It is important +to discuss and agree the aims of care with the patient’s family. +Families and other carers are often unprepared for the challenge +of caring for a dying person. +An advance +directive is a previously recorded, written document of a patient’s +wishes (p. +1307). +It is impossible to +provide holistic care for a patient without this comprehension. +The legal framework for decision-making varies in +different countries. +Reversible causes, such as +pain or depression, should be treated. +hospiceuk.org A resource from UK hospices. +mdanderson.org Brief Pain Inventory (Short Form) questionnaire. +nhmrc.gov.au Australia and New Zealand College of Anaesthetists and +Faculty of Pain Medicine. +Acute pain management: scientic +evidence, 3rd edn; 2010. +npcrc.org Short-form McGill Pain questionnaire. +paintoolkit.org Pain toolkit self-help resource for managing pain. +palliativecareguidelines.scot.nhs.uk Regularly reviewed, evidence-based +clinical guidelines. +palliativedrugs.com Practical information about drugs used in palliative +care. +sign.ac.uk SIGN guideline 136 – Management of chronic pain. +Journal articles +Finnerup NB, Attal N, Haroutounian S, et al. +Pharmacotherapy for +neuropathic pain in adults: a systematic review and meta-analysis. +Lancet Neurol 2015; 14:162–173. +The SI unit system is, however, recommended. +Values are shown +in both SI units and, where appropriate, non-SI units. +A specic requirement for one or the other may depend +on a kit manufacturer’s recommendations. +In other instances, the +distinction is critical. +For +convenience, however, the litre (L) is +used as the unit of volume in +laboratory work. +Refer to local laboratory handbook. +2. +3. +Non-SI units also differ; those +shown here are amongst those most widely used. +Interpret in context of clinical presentation. +This can vary widely. +The values quoted are appropriate to a +‘Western’ diet. +Values in CSF are typically approximately +two-thirds of plasma levels. +2 A crude index of increase in IgG attributable to +intrathecal synthesis. +Reference +ranges for hormone results are described according to the +Tanner stages of puberty (p. +1290). +Further information +Abbassi-Ghanavati M, Greer LG, Cunningham FG. +Pregnancy and +laboratory studies: a reference table for clinicians. +Obstet Gynecol +2009; 114:1326–1331. +Tanner JM, Whitehouse RH. +1  Fever of Unknown Origin +William F. +Wright and Philip A. +3 +2  The Acutely Ill Patient +with Fever and Rash +David J. +Weber, Myron S. +Cohen, and William A. +Nodular lesions are suggestive of mycobacteria or +fungal inf ections. +• Most ac utely ill patients with skin lesions will require systemic therapy. +5 +B  Upper Respiratory Tract Infections +3  The Common Cold +Ronald B. +MICROBIOLOGY +• The r hinoviruses are responsible for the majority of common cold illnesses. +• Coinfection with more than one pathogen is common in these illnesses. +DIAGNOSIS +• The di agnosis of the common cold is a clinical diagnosis. +PREVENTION +• There a re no proven interventions for prevention of the common cold. +6 +4  Pharyngitis +Anthony R. +Flores and Mary T. +• Generally a primary disease, pharyngitis may be associated with systemic disorders. +• Specific techniques should be used to identify other causes where appropriate. +• Given the potential severity of complications from pharyngitis caused by F. +Modified from Alcaide ML, Bisno AL. +Pharyngitis and epiglottitis. +Infect Dis Clin North Am. +2007;21:449-469, vii; +with permission. +Modified from Shulman ST, Bisno AL, Clegg HW, et al. +Clin Infect +Dis. +2012;55:e86-e102; and Kociolek LK, Shulman ST. +In the clinic. +Pharyngitis. +Ann Intern Med. +2012;157:ITC3- +1-ITC3-16; with permission. +Empirical validation of guidelines for the management of pharyngitis +in children and adults. +JAMA. +2004;291:1587-1595; with permission. +Pharyngitis and epiglottitis. +Infect Dis Clin North Am. +2007;21:449-469, vii; +with permission. +10 +5  Acute Laryngitis +Mary T. +• More cases are diagnosed in the colder months of the year. +MICROBIOLOGY +• A viral upper respiratory tract infection is often associated (see Table 5-1). +• Bacterial infections of the upper respiratory tract have also been implicated. +DIAGNOSIS +• Clinical diagnosis is based on the appropriate history and changes of the voice. +THERAPY +• Treatment is based on the underlying cause of the laryngeal pathologic process. +• Often, symptomatic therapy with voice rest, analgesics, and humidification is sufficient. +DIAGNOSIS +• Diagnosis is clinical, although radiographs of the upper airway may be helpful. +THERAPY +• Home r emedies including mist and cold air have not been proven to be effective. +• A sin gle dose of a systemic corticosteroid decreases the severity and length of croup. +12 +7  Otitis Externa, Otitis Media, +and Mastoiditis +Jerome O. +Mastoiditis +• The ep idemiology of mastoiditis parallels that of otitis media. +• Pseudomonas aeruginosa is a f requent cause of swimmer’s ear and malignant otitis externa. +• Respiratory viruses are frequent causes of AOM alone or associated with bacterial pathogens. +aureus a nd +P. +aeruginosa. +• Swimmer’s ear is identified by edema, swelling, and erythema of the canal wall. +• Systemic antimicrobial therapy, including activity against P. +aeruginosa, is n ecessary to +manage in vasive external otitis. +Otitis Media +• High-dose amoxicillin is the preferred drug for patients with AOM. +• If a moxicillin fails, amoxicillin-clavulanate or parenteral ceftriaxone is preferred. +• Some c hildren with AOM improve without use of antimicrobial agents. +Mastoiditis +• Antimicrobial therapy is similar to that of AOM. +• Incision and drainage may be necessary when abscesses form in the mastoid air cells. +• Influenza virus vaccines reduce the incidence of AOM during the winter respiratory season. +Mastoiditis +• Prevention is similar to that of AOM. +14 +8  Sinusitis +Gregory P. +DeMuri and Ellen R. +Wald +DEFINITION +• Sinusitis is defined as an inflammatory disorder of the paranasal sinuses. +• The f requency of isolation of S. +pneumoniae is de creasing recently with an increase in +β-lactamase–producing H. +influenzae. +• Surgical drainage is indicated for the complications of acute bacterial sinusitis. +15 +9  Epiglottitis +Jennifer L. +Nayak and Geoffrey A. +• Before r outine infant immunization with H. +Cough is distinctly +uncommon. +DIAGNOSIS +• Airway management should be promptly evaluated as soon as the diagnosis is considered. +• Peripheral leukocytosis is common but not universal. +Emergent tracheotomy or cricothyroidotomy is rarely required. +influenzae, a nd m eningococci. +PREVENTION +• Chemoprophylaxis for household contacts of children with H. +influenzae t ype b or meningococcal infection. +17 +10  Infections of the Oral Cavity, +Neck, and Head +Anthony W. +These include Lemierre syndrome and +Ludwig’s a ngina. +*For Staphylococcus aureus infections in which methicillin-resistant S. +aureus, S. +pyogenes, S. +pyogenes, S. +aureus, S. +†For Staphylococcus aureus infections in which methicillin-resistant S. +MICROBIOLOGY +• Acute b ronchitis is primarily caused by viral infections. +23 +12  Acute Exacerbations of Chronic +Obstructive Pulmonary Disease +Leopoldo N. +Segal, Michael D. +Weiden, and +Harold W. +“ Atypical” bacteria are not frequently +isolated. +A cquisition of new pathogen is associated with exacerbation. +DIAGNOSIS +• Acute exacerbation is defined by increased sputum purulence, volume, and dyspnea. +PREVENTION +• Avoid exposure to particulate matter and cease smoking. +• Administer influenza, pneumococcal, and pertussis vaccines. +24 +13  Bronchiolitis +John Bower and John T. +THERAPY +• Therapy is supportive and includes hydration, oxygen, and respiratory support as needed. +• Corticosteroids and bronchodilators are not generally beneficial. +• Monoclonal antibody prophylaxis may prevent or mitigate infection in high risk infants. +25 +14  Acute Pneumonia +Richard T. +Ellison III and Gerald R. +• Predominant pathogens of patients recently hospitalized or nursing home residents include +S. +• Gram s tain and culture of sputum samples remain valuable diagnostic assays. +• Chest radiographs should be obtained on all patients with suspected pneumonia. +Coverage for S. +PREVENTION +• Provide immunization as appropriate with influenza and pneumococcal vaccines. +• Encourage cessation of tobacco smoking. +aureus. +aAzithromycin, clarithromycin, or erythromycin. +For patients with +community-acquired pneumonia in the ICU, coverage for S. +pneumoniae and Legionella species must always be +considered. +pneumoniae and H. +influenzae infections. +aeruginosa, Klebsiella species, and other gram- +negative bacteria. +jData suggest that older adults receiving aminoglycosides have worse outcomes. +Modified from Mandell LA, Wunderink RG, Anzueto A, et al. +Clin Infect +Dis. +2007;44(suppl 2):S27-S72; and American Thoracic Society, Infectious Diseases Society of America. +Am J Respir Crit Care Med. +2005;171:388-416. +Septimus +DIAGNOSIS +• Fluid in the pleural space may be transudative or exudative (see Table 15-1). +An exudative +effusion with pus in the pleural space is called an empyema. +Send blood for LDH and protein to determine pleural fluid–to-serum ratio. +pneumoniae, S. +One or more cavities. +EPIDEMIOLOGY +• Primary lung abscess: bad teeth, altered consciousness, aspiration. +Secondary: airway +obstruction or immunosuppression. +MICROBIOLOGY +• Polymicrobial. +Predominantly mouth anaerobes and streptococci. +Klebsiella or Staphylo­ +coccus aureus un commonly. +DIAGNOSIS +• Radiograph or computed tomography (CT): thick-walled cavity with air-fluid level. +Putrid +sputum in h alf of cases. +THERAPY +• β-Lactam/β-lactamase combination or clindamycin. +PREVENTION +• Maintain oral hygiene. +Elevate head of bed for those with altered consciousness. +31 +17  Chronic Pneumonia +Peter G. +• Culture f or routine bacteria, fungi, and acid-fast bacilli when possible. +33 +18  Cystic Fibrosis +Ahmet Uluer and Francisco M. +The prevalence of other bacterial infections varies between countries and CF +clinics. +Many other pathogens, including methicillin- +resistant S. +DIAGNOSIS +• Newborn screening is now available in the United States and other countries. +• Acute pulmonary exacerbations are usually linked to progression of disease (see Table 18-1). +Respiratory viruses may trigger pulmonary exacerbations. +Severity +of exacerbation will determine whether oral or intravenous antibiotics will be used. +These include aminoglycosides, penicillins, +and cephalosporins. +• In addition to the CFTR modulator ivacaftor—U.S. +High Moderate B +Azithromycin with P. +aeruginosa +For individuals with CF, 6 yr of age and older, with P. +aeruginosa +For individuals with CF, 6 yr of age and older, +without P. +Low — I +Oral antipseudomonal +antibiotics +For individuals with CF, 6 yr of age and older, with +P. +†CF Foundation personnel did not participate in any activity related to ivacaftor. +From Mogayzel PJ, Naureckas ET, Robinson KA. +Cystic fibrosis pulmonary guidelines. +Am J Respir Crit Care Med. +2013;187:680-689. +*Generally defined as the presence of four of the above. +From Cystic Fibrosis Foundation. +Treatment of pulmonary exacerbations of cystic fibrosis. +In: Clinical Practice +Guidelines for Cystic Fibrosis. +Bethesda, MD: Cystic Fibrosis Foundation; 1997. +37 +D  Urinary T ract Infections +19  Urinary T ract Infections +Jack D. +• With c hronic pyelonephritis there is uneven scarring. +• With p apillary necrosis one or more pyramids may slough. +• Virulence factors facilitate microorganism persistence in the urinary tract. +• Adaptive immunity, both antibody- and cell-mediated mechanisms, has a limited protective +role. +• Genetic susceptibility to UTI is still minimally recognized and understood. +EPIDEMIOLOGY AND NATURAL HISTORY +• Escherichia coli is t he m ost common infecting organism. +• Resistant E. +• Resistant bacteria are increased in complicated UTI. +• Asymptomatic bacteriuria is common and of little consequence except in a few groups. +• UTIs o ccur in 1% to 2% of infants, about 5% of girls, and 0.5% or less of boys. +• UTIs a re much more common in women than men and are most often asymptomatic. +• Two t o fi ve percent of women have recurrent UTIs with a genetic predisposition. +• Renal infection rarely causes end-stage renal disease without other underlying disease. +DIAGNOSIS +• Urine dipsticks for pyuria and bacteriuria are useful screening tests. +• A negative test for pyuria makes UTI unlikely. +• Negative tests for bacteriuria are common in UTI because of low titers of bacteria. +• One third of young women with cystitis have fewer than 105 bacteria/mL urine. +Controversial exceptions are some young children and after renal transplantation. +• Nonantimicrobial prevention measures are directed at reinfections and reducing risk factors. +• Treatment for complicated UTI is urine culture and then fluoroquinolone. +Cystitis nitrofu- +rantoin and fosfomycin are options. +• Treatment of relapses is prolonged therapy or chronic suppression. +Complicated UTI or +prostatitis is possible. +Drugs and Doses: +CP, ciprofloxacin orally 500 mg twice/day or 1000 mg once/day. +LV, levofloxacin orally 750 mg once/day. +TMP-SMX, trimethoprim-sulfamethoxazole orally 160/800 mg twice/day. +CT, ceftriaxone parenterally 1 g/day. +FQ, fluoroquinolone parenterally—ciprofloxacin 500 mg twice/day or levofloxacin 750 mg once/day. +AM, aminoglycoside parenterally (e.g., gentamicin 5 mg/kg/day). +Amoxicillin orally 875 mg twice/day. +Ampicillin parenterally 2 g every 4 hr. +Linezolid orally 600 mg twice/day. +Vancomycin parenterally 15 mg/kg twice/day. +Nitrofurantoin orally 100 mg twice/day. +Fosfomycin orally 3 g once. +Pivmecillinam orally 400 mg twice/day. +Cephalexin orally 500 mg four times/day. +†TMP-SMX should be avoided in the third trimester. +40 +E  Sepsis +20  Sepsis, Severe Sepsis,  +and Septic Shock +Robert S. +Munford and Anthony F. +Suffredini +DEFINITIONS +• Sepsis is the body’s harmful systemic reaction to microbial infection. +• Septic shock is sepsis-associated hypotension that requires pharmacologic reversal. +EPIDEMIOLOGY +• Most commonly affected persons are the very young and older adults. +• Major outcome determinants are age and comorbidity, especially immunosuppressive illness. +MICROBIOLOGY +• Virtually any microbe can trigger sepsis. +coli +Klebsiella +species +Enterobacter +species +Proteus spp. +Staphylococcus +aureus (? +For MDRO, resistance usually includes carbapenems. +42 +F  Intra-abdominal Infections +21  Peritonitis and Intraperitoneal  +Abscesses +Matthew E. +Levison and Larry M. +EPIDEMIOLOGY +• Primary peritonitis accounts for approximately 1% of all peritonitis cases. +• It recurs in 20% to 30% and is the primary reason for a switch to hemodialysis. +• Staphylococcus aureus is rarely isolated in primary peritonitis. +• Enterococci and Candida spp. +can often be isolated, the significance of which is +controversial. +Modified from Solomkin JS, Mazuski JE, Bradley JS, et al. +Clin Infect Dis. +2010;50:133-164. +aureus, a nd Streptococcus s pp.) in 60% to 80% of cases. +• Fungal a nd mycobacterial species are occasionally involved. +14 +Pseudomonas aeruginosa 14 +Proteus mirabilis 5 +Enterobacter spp. +5 +Anaerobic +Bacterioides fragilis 35 +Other Bacterioides spp. +71 +Clostridium spp. +29 +Prevotella spp. +12 +Peptostreptococcus spp. +17 +Fusobacterium spp. +9 +Eubacterium spp. +17 +Gram-Positive Aerobic Cocci +Streptococcus spp. +38 +Enterococcus faecalis 12 +Enterococcus faecium 3 +Enterococcus spp. +8 +Staphylococcus aureus 4 +Modified from Solomkin JS, Mazuski JE, Bradley JS, et al. +Clin Infec Dis. +2010;50:133-164. +bApplies mainly to community-acquired intra-abdominal infections. +dIn vitro activity may be less, compared to alternative antibiotics. +coli to fluoroquinolones. +fRisk of mortality may be greater compared with alternative antimicrobials. +Modified from Piraino B, Bailie GR, Bernardini J, et al. +Peritoneal dialysis-related infections recommendations: 2005 +update. +Perit Dial Int. +2005;25:107-131. +Sifri and Lawrence C. +Acalculous cholecystitis is a similar process in the absence of +gallstones. +• Cholangitis is inflammation/infection of the bile ducts. +Th ey affect men about 10 times more frequently than women. +• Approximately 120,000 cholecystectomies occur each year in the United States. +• Amebic liver abscesses are caused by invasive strains of Entamoeba histolytica. +DIAGNOSIS +• Symptoms are often nonspecific, and a high index of suspicion is required. +For pyogenic liver abscesses, it is often coupled with +diagnostic/therapeutic aspiration. +49 +23  Pancreatic Infection +Miriam Baron Barshak +DEFINITION +• Infection of pancreatic tissue. +• Up to 70% of patients with pancreatic necrosis may develop pancreatic infection. +• Tissue sampling is required to identify infection. +PREVENTION +• Avoid too-early enteral feeding. +From Bradley EL. +A clinically based classification system for acute pancreatitis. +Arch Surg. +1993;128:586-590. +Necrosis not defined. +Predominant effect on gram-negative pancreatic +infection (8% in SGD group vs. +33% in conventional treatment +group). +Nonpancreatic infections also reduced (15% vs. +49%, P < .01). +Rate of +culture-proven sepsis not statistically significant. +Only urinary +tract infections were reduced significantly. +Bassi et al Pefloxacin (400 mg bid) vs. +CT confirmed at least 50% necrosis. +Continued +52 +Part I  Major Clinical Syndromes +AUTHOR ANTIBIOTIC NO. +controls (15.3%). +Subgroup analysis of β-lactam treatment: +Significantly less mortality (6.3% vs. +No significant differences with +quinolone plus imidazole treatment. +β-Lactams associated with +significantly decreased mortality and infected pancreatic +necrosis. +Rokke et al Prospective randomized +controlled trial, imipenem +(500 mg tid for 5-7 days) +vs. +“None of the studies +included in this review were adequately powered. +*P < .05. +Modified from Toouli J, Brooke-Smith M, Bassi C, et al. +Guidelines for the management of acute pancreatitis. +J Gastroenterol Hepatol. +2002;17(suppl):S15-S39. +controls (15.3%). +Subgroup analysis of β-lactam treatment: +Significantly less mortality (6.3% vs. +No significant differences with +quinolone plus imidazole treatment. +β-Lactams associated with +significantly decreased mortality and infected pancreatic +necrosis. +Rokke et al Prospective randomized +controlled trial, imipenem +(500 mg tid for 5-7 days) +vs. +“None of the studies +included in this review were adequately powered. +*P < .05. +Modified from Toouli J, Brooke-Smith M, Bassi C, et al. +Guidelines for the management of acute pancreatitis. +J Gastroenterol Hepatol. +2002;17(suppl):S15-S39. +54 +24  Splenic Abscess +Lawrence C. +• Splenic a bscesses are present in 0.2% to 0.7% in general autopsy series. +• There i s a bimodal age distribution, with peaks in the third and sixth decades of life. +• Anaerobes are rare. +55 +25  Appendicitis +Costi D. +Sifri and Lawrence C. +• Complications include perforation, peritonitis, and intra-abdominal abscesses. +• Lifetime risk for appendicitis is 8.6% in men and 6.7% in women. +• Over 300,000 appendectomies are performed annually in the United States. +• A l arge variety of microbes have been isolated from acute appendicitis and related abscesses. +THERAPY +• Surgical removal of the appendix, often done laparoscopically, is curative. +56 +26  Diverticulitis and Typhlitis +Costi D. +Sifri and Lawrence C. +• Bacteremia or fungemia occurs in 14% to 44% of patients with typhlitis. +a re co mmon causes of bloodstream infections in patients with +typhlitis. +58 +G  Cardiovascular Infections +27  Endocarditis and  +Intravascular Infections +Vance G. +Fowler, Jr., W. +Michael Scheld, +and Arnold S. +• In the current era, health care contact and injection drug use are the primary risk factors. +• Historically, viridans group streptococci were the most common cause of endocarditis. +• Bartonella spp. +are the most common cause of culture-negative IE in the United States. +Other +common causes of culture-negative IE are summarized in Table 27-1. +DIAGNOSIS +• Results of blood cultures remain the cornerstone of diagnosis of endocarditis. +• Clinical evaluation alone is insufficient to exclude the possibility of endocarditis. +• Antibiotic therapy involves extended courses of antibiotics. +Treatment is highly pathogen +specific and is summarized in Table 27-2. +Guidelines for treatment of IE were published in +2005 and are currently being updated. +• Addition of adjunctive low-dose, short-course gentamicin to standard antibiotic treatment +of S. +Guidelines have been published from the American Heart Association. +B. +henselae: exposure to cats or cat +fleas +B. +See +above cautions about gentamicin use. +Goal vancomycin trough +level 15-20 µg/mL is recommended. +Daptomycin, 6 mg/kg IV qd × 4-6 wk Daptomycin is U.S. +Food and Drug +Administration–approved for treatment of +right-sided S. +Goal vancomycin trough level 15-20 µg/mL +is recommended. +Nutritionally variant streptococci +are often penicillin tolerant. +This +regimen is associated with enhanced risk +of nephrotoxicity. +Penicillin desensitization +should be considered as an alternative to +this regimen when possible. +Some +species exhibit inducible resistance to +third-generation cephalosporins. +Consultation with an infectious diseases +specialist is recommended. +Treat for a minimum of +6-8 wk. +Long-term/ +lifelong suppressive therapy with oral +antifungal agents is often required. +Consultation with a specialist in infectious +diseases is recommended. +aDosages assume normal renal function. +bPrimarily relevant to left-sided IE. +cEnterococci must undergo antimicrobial susceptibility testing. +dAmpicillin, 12 g/day, can be used instead of penicillin. +eThe need to add an aminoglycoside has not been demonstrated for penicillin-resistant streptococci. +fLimited data exist.Modified from Baddour LM, Wilson WR, Bayer AS, et al. +Infective endocarditis: diagnosis, +antimicrobial therapy, and management of complications. +Circulation. +2005;111:e394-e433. +Knoll, Larry M. +Baddour, +and Walter R. +• Health care–associated PVE is increasing in incidence. +• Staphylococcus aureus is the most common cause of PVE. +aureus and coagulase-negative staphylococci +(CoNS). +• S. +DIAGNOSIS +• Modified Duke criteria have been used to define suspect cases of PVE. +Cefazolin 2 g IV q8h may be substituted for nafcillin or +oxacillin. +Cefazolin can be used in non–immediate-type allergic reaction to penicillin. +Consider skin testing for +patients with history of immediate-type allergy to penicillin. +Vancomycin is recommended only in patients unable +to tolerate penicillins and cephalosporins. +Renal function and serum gentamicin concentrations should be closely monitored. +Goal trough level is <1 µg/mL +and peak level (1 hr postdose) is 3-4 µg/mL. +§Vancomycin dosage should be adjusted to a trough level of 10-15 µg/mL. +From Baddour LM, Wilson WR, Bayer AS, et al. +Circulation. +2005;111:e394-e434. +Rizwan Sohail, Walter R. +Wilson, and Larry M. +• Hematogenous seeding of CIED leads is rare with gram-negative bacteremia from a distant +source. +• Blood cultures should be obtained in all patients at initial presentation. +• Complete removal of the CIED system is required for eradication of infection. +A 2-week delay is +recommended for patients with valvular endocarditis. +http://internalmedicinebook.com +67 +30  Prophylaxis of Infective +Endocarditis +David T. +EPIDEMIOLOGY +• The incidence of IE is increasing in developing countries. +MICROBIOLOGY +• Staphylococci have superseded viridans streptococci as the predominant pathogens. +• Antibiotics can prevent IE in vivo in experimental animals. +Circulation. +2007;116:1736-1754. +*Only for patients with highest risk of adverse outcome of infective endocarditis; see Table 30-1. +†Single dose, 30 to 60 minutes before procedure. +‡Not to exceed adult dose. +Modified from Wilson W, Taubert KA, Gewitz M, et al. +Circulation. +2007;116:1736-1754. +http://internalmedicinebook.com +69 +31  Myocarditis and Pericarditis +Kirk U. +Knowlton, Anna Narezkina, Maria C. +Savoia, +and Michael N. +• Evidence of coincident viral infection, either by culture or serology, is circumstantial. +Treatment +• Supportive care and management of CHF are essential. +• The benefit of immunosuppressive therapy is not established. +• The efficacy of intravenous immunoglobulin therapy is also not established. +These may be present individually or in combination. +Monitoring for cardiac tamponade is important. +• Bacteria rarely may cause purulent pericarditis, usually as a complication of pneumonia. +This is a major problem in Africa in association with acquired immunodefi- +ciency syndrome. +Diagnosis +• Etiology is often undetermined in individual cases. +• Pericardiocentesis may yield an etiologic agent but is negative in the majority of patients. +NSAIDs are generally continued for 1 to 2 weeks, or until symptoms resolve. +• Purulent pericarditis usually requires drainage together with appropriate antibiotics. +Van Schooneveld and Mark E. +32-1). +Fever, wound drainage, cellulitis, and chest pain are usually +present. +• Computed tomography is the preferred diagnostic imaging for all forms of mediastinitis. +THERAPY +• Broad-spectrum antimicrobials targeted to expected pathogens are essential. +• Post–cardiac surgery mediastinitis requires sternal and mediastinal débridement. +• The role, if any, for antifungal therapy in fibrosing mediastinitis is not established. +aureus. +Tunkel, Diederik van de Beek, +and W. +• For H. +influenzae type b, the availability of conjugate vaccines has decreased the number of +cases of H. +influenzae type b meningitis more than 90%. +http://internalmedicinebook.com +78 +34  Chronic Meningitis +John E. +Surgical biopsy has a low yield. +The same issue arises with corticosteroid treatment of suspected sarcoid +or autoimmune meningitis. +The benefit of corticosteroids +in empirical regimens is usually outweighed by the harm. +David Beckham and Kenneth L. +MICROBIOLOGY +• Up to 60% of encephalitis cases result from an unidentified etiologic agent. +• Viruses, bacteria, and autoimmune inflammation cause the majority of known encephalitis +cases. +Diagnosis and treatment of acute encephalitis. +Neurologist. +2000;6:145-159. +Modified from Tunkel AR, Glaser CA, Bloch KC, et al. +Clin Infect Dis. +2008;47:303-327. +http://internalmedicinebook.com +84 +36  Brain Abscess +Allan R. +• The incidence of brain abscess is also affected by the general health of the population. +aureus strains have been reported. +• Most patients with bacterial brain abscess require surgical management for optimal therapy. +†Add vancomycin when infection caused by methicillin-resistant Staphylococcus aureus is suspected. +‡Use ceftazidime or cefepime as the cephalosporin if Pseudomonas aeruginosa is suspected. +§Trimethoprim-sulfamethoxazole; include if a Nocardia spp. +is suspected. +‖Additional agents should be added based upon other likely microbiologic etiologies. +Tunkel +DEFINITION +• Subdural empyema refers to a collection of pus between the dura and arachnoid. +Spinal subdural empyema originates hematogenously. +THERAPY +• Subdural empyema is a medical and surgical emergency. +Drake, and Allan R. +• In patients with CSF drains, the incidence of ventriculitis has ranged from zero to 22%. +Later, the drain is removed and a new shunt is placed. +Pasternack and Morton N. +These, in turn, may coalesce, leading to carbuncle formation. +EPIDEMIOLOGY +• Significant skin and soft tissue infection may occur throughout the age spectrum. +Minor +local trauma as the initial pathogenic event is a common feature of these processes. +aureus +(MRSA), are the most common causes of superficial cutaneous infection. +*Morton N. +Parenteral therapy targeted +more broadly against gram-positive organisms, including S. +• Necrotizing infections require urgent surgical débridement. +• Individuals with recurrent cellulitis may benefit from chronic antibiotic suppression. +http://internalmedicinebook.com +92 +40  Myositis and Myonecrosis +Mark S. +Pasternack and Morton N. +septicum, C. +sordellii). +aureus (including methicillin-resistant S. +aureus) and +*Morton N. +http://internalmedicinebook.com +94 +41  Lymphadenitis and Lymphangitis +Mark S. +Pasternack and Morton N. +capsulatum var. +bancrofti; B. +Immunocompetent persons are +occasionally affected. +MICROBIOLOGY +• Candida species, herpes simplex virus (HSV), and cytomegalovirus are most common. +†Not approved by the U.S. +Food and Drug Administration for this indication. +http://internalmedicinebook.com +100 +43  Nausea, Vomiting, and +Noninflammatory Diarrhea +David A. +Bobak and Richard L. +EPIDEMIOLOGY +• Noninflammatory gastroenteritides are among the most common infections of humans. +As +a group, they are second in incidence only to viral upper respiratory infections. +health care facility–acquired infections). +• Most cases of this syndrome are self-limited, and no specific etiology is identified. +• In most cases of noninflammatory gastroenteritis, specific antimicrobial therapy is not used. +http://internalmedicinebook.com +102 +44  Bacterial Inflammatory Enteritides +Aldo A. +M. +Lima, Cirle A. +Warren, and Richard L. +difficile infection. +coli are +derived from multiple origins of E. +coli and form a single pathovar. +coli strains that had exhibited enteropathogenic E. +coli +traits of attachment and effacement, was a Shiga toxin–producing enteroaggregative E. +coli +strain. +• Campylobacter spp. +have a small genome (1.6 to 2.0 Mb) and can cause intestinal and sys- +temic infections. +• The primary virulence factors that are known to cause clinical disease in C. +difficile infection +are the two large toxins: C. +difficile toxin (Tcd)A, or toxin A (308 kDa), and TcdB, or toxin +B (270 kDa). +Harris and Edward T. +Injectable typhoid conjugate vaccines are in late-stage development. +No vaccine effective +against paratyphoid A is currently commercially available. +http://internalmedicinebook.com +105 +46  Foodborne Disease +Rajal K. +Mody and Patricia M. +However, most foodborne diseases do not occur in the context of an outbreak. +• Many intoxications must be diagnosed based on clinical suspicion alone. +• Antimicrobial agents are used to treat parasitic infections and selected bacterial infections. +• Individuals can reduce their risk of illness by adhering to safe food handling practices. +http://internalmedicinebook.com +107 +47  Tropical Sprue: Enteropathy +Christine A. +MICROBIOLOGY +• No single agent associated with causality, small bowel overgrowth common. +Response to +folate and tetracycline ultimately confirms diagnosis. +THERAPY +• Removal from area of risk, treatment with folate and tetracycline. +PREVENTION +• Good hygiene practices. +Most infections are monarticular; 10% to 20% are polyarticular. +The knee +is most often involved. +predominate. +• Prevalence rates of gonococcal arthritis have markedly decreased. +• It is caused by infection of the joint space or by immune-mediated inflammation. +• It may occasionally cause prolonged or chronic arthritis after acute infection. +• Diagnostic imaging should include plain film radiography. +The polymerase chain reaction (PCR) assay continues to show +promise. +• Empirical selection should be based on synovial fluid Gram stain (see Table 48-1). +Chronic Infectious Arthritis +• It is usually monarticular, involving the large peripheral joints. +Etiology includes Mycobacterium tuberculosis +and nontuberculosis mycobacteria. +• Therapy of M. +tuberculosis arthritis is similar to pulmonary tuberculosis. +• Many fungal arthritides are difficult to treat and result in chronic joint disability. +Treatment +varies by infecting organism. +aUnless noted otherwise, dosages are IV for persons with normal renal function. +bTherapeutic monitoring should target a serum trough of 15-20 mg/L. +cFor patients allergic to, or intolerant of, vancomycin. +dEquivocal gram-negative morphology should be considered as gram-negative rods. +hDoripenem, 500 mg every 8 hr; imipenem, 500 mg every 6 hr; or meropenem, 1 g every 8 hr. +• More than 80% of cases are due to Staphylococcus aureus. +aureus (CA-MRSA) are recom- +mended pending culture and sensitivity. +http://internalmedicinebook.com +111 +49  Osteomyelitis +Elie F. +Berbari, James M. +Steckelberg, +and Douglas R. +contiguous), and the presence of +vascular insufficiency. +GENERAL PRINCIPLES +• The diagnosis of osteomyelitis is suspected on clinical grounds. +Confirmation usually entails +a combination of radiologic, microbiologic, and pathologic tests. +• Bone biopsy or needle aspiration is best for organism identification. +• S. +aureus, coagulase-negative staphylococci, Mycobacterium tuberculosis, and Brucella spp. +are the most common microorganisms encountered in vertebral osteomyelitis. +• MRI of the spine is highly accurate in the diagnosis of vertebral osteomyelitis. +• Image-guided aspiration and biopsy is highly specific but lacks sensitivity. +• This category of osteomyelitis is often polymicrobial. +• The most common recovered microorganism is S. +aureus. +*Antimicrobial selection should be based on in vitro sensitivity data. +• Granulocyte function around the implant is impaired (activation and degranulation). +• Cure is only possible with adequate surgery combined with long-term antibiotic therapy. +• A treatment algorithm (see Fig. +Microbiology +• Microbiology is comparable with that of PJI. +Staphylococci are the most important +pathogens. +Pathogenesis +• The exogenous route plays a more important role than the hematogenous. +• Infection may also occur via an adjacent focus (contiguous). +FIGURE 50-1  Surgical treatment algorithm for prosthetic joint infections. +(Modified from Trampuz A, Zimmerli W. +Prosthetic joint infections: update in diagnosis and  +treatment. +Swiss Med Wkly. +Other local features are absent in the +beginning and become apparent in the course of disease. +• Chronic symptoms: Sinus tract, pain, implant loosening. +Treatment +• Bone fractures are less susceptible to infection if stabilized. +• In delayed infections, implant must be removed after healing of bone fracture. +• These lesions occur primarily among individuals who are sexually active. +• Disease may be modified in populations that are immunocompromised. +• Laboratory examination using microscopy and serologic testing is often helpful. +• Gram staining and light microscopy help to identify H. +ducreyi and Candida. +• Darkfield microscopy is used to identify Treponema pallidum. +• Serology helps to diagnose T. +pallidum and herpes simplex virus. +• Cell culture is used to diagnose herpes simplex virus. +• Nucleic acid amplification tests are used to identify C. +trachomatis. +THERAPY +• Therapy is best chosen based on the likely or specific etiologic agent. +• Syphilis is treated with penicillin and tetracyclines. +• Herpes simplex virus infection is treated with acyclovir, valacyclovir, and famciclovir. +• C. +trachomatis causing LGV should be treated with tetracyclines. +Augenbraun and William M. +EPIDEMIOLOGY +• Urethritis occurs worldwide. +DIAGNOSIS +• Light microscopy of urethral discharge can be helpful. +The presence of polymorphonuclear +leukocytes is highly suggestive of inflammation. +THERAPY +• Treatment is directed toward the known or suspected pathogen. +Infection with Chlamydia trachomatis responds to azalides and +tetracyclines. +Culture +can provide option for susceptibility testing. +http://internalmedicinebook.com +118 +53  Vulvovaginitis and Cervicitis +William M. +McCormack and Michael H. +EPIDEMIOLOGY +• Trichomoniasis is a sexually transmitted condition. +• Vulvitis and desquamative inflammatory vaginitis are not sexually transmitted. +• Cervicitis may be sexually transmitted or idiopathic. +MICROBIOLOGY +• Trichomoniasis is caused by Trichomonas vaginalis. +• Candidiasis is caused by Candida albicans and other fungal species. +• Bacterial vaginosis is associated with a complex bacterial microbiota. +DIAGNOSIS +• Trichomoniasis and cervical infections due to N. +gonorrhoeae, M. +genitalium, and C. +• Vulvovaginal candidiasis is diagnosed clinically and by the identification of C. +albicans or +other fungal species in cultures of vaginal fluid. +THERAPY +• Trichomoniasis is treated with the oral administration of metronidazole or tinidazole. +• Desquamative inflammatory vaginitis is best treated with intravaginal clindamycin. +• Intravaginal administration of boric acid or corticosteroids provides symptomatic relief. +PREVENTION +• Judicious choice of sexual partners and regular use of condoms is preventative. +http://internalmedicinebook.com +119 +54  Infections of the Female Pelvis +David E. +• Acute bacterial prostatitis is associated with lower urinary tract infection and sepsis. +• Acute epididymitis and orchitis are usually due to infectious agents or local trauma. +Fifty +percent of men may experience symptoms in their lifetimes. +Prevalence is 2% to 16%. +• Nearly 90% of men evaluated for genitourinary symptoms have CP/CPPS. +• Sexually transmitted epididymitis is most common in young men. +• Isolated orchitis is rare. +MICROBIOLOGY +• Gram-negative Enterobacteriaceae cause most episodes of bacterial prostatitis. +Enterococci +account for a small percentage. +• Etiology of epididymitis and orchitis reflects patient age. +• Most orchitis is caused by viral infections. +DIAGNOSIS +• Careful history, physical examination, urinalysis, and urine culture are essential. +• The lower urinary tract localization test (see Table 55-2) is the gold standard. +• Epididymitis and orchitis should be evaluated with a urethral swab for C. +trachomatis and +N. +gonorrhoeae. +THERAPY +• Fluoroquinolones are preferred oral treatment. +Quinolone resistance is increasingly common, +especially after genitourinary tract instrumentation. +• Septic patients should receive empirical broad-spectrum parenteral therapy. +gonorrhoeae infections. +bIn expressed prostatic secretions, semen, postmassage urine, or prostate tissue. +dSystemic findings frequently include fever and rigors and may include signs of bacteremia. +eFormerly termed nonbacterial prostatitis. +fFormerly termed prostatodynia. +From Krieger JN, Nyberg L Jr, Nickel JC. +NIH consensus definition and classification of prostatitis. +JAMA. +1999;282:236-237. +In these patients, direct culture of prostatic secretions is +particularly useful. +From Stamey T. +Pathogenesis and Treatment of Urinary Tract Infections. +Baltimore: Williams & Wilkins; 1980. +http://internalmedicinebook.com +122 +M  Eye Infections +56  Microbial Conjunctivitis +Scott D. +Barnes, Nalin M. +Kumar, +Deborah Pavan-Langston, and Dimitri T. +EPIDEMIOLOGY +• Conjunctivitis affects males and females of all ages. +Itching is uncommon. +Unlike viral and chlamydial conjunctivitis, there +is no preauricular lymphadenopathy. +Laboratory tests are not usually +necessary. +HSV +conjunctivitis in newborns should be treated with intravenous acyclovir. +The use of oral azithromycin has also been found +to be effective. +http://internalmedicinebook.com +124 +57  Microbial Keratitis +Scott D. +Barnes, Joelle Hallak, Deborah Pavan-Langston, +and Dimitri T. +EPIDEMIOLOGY +• Disease burden is higher in developing than developed countries. +• Nonsurgical ocular trauma is the main cause of keratitis in developing countries. +• Trachoma is encountered more commonly in developing countries. +MICROBIOLOGY +• Pathogens can be gram-negative organisms, such as Pseudomonas aeruginosa. +• Pathogens can be gram-positive organisms, such as Staphylococcus and Streptococcus spp. +• Viral pathogens include herpes simplex virus, varicella-zoster virus, adenovirus. +• Fortified topical administration is the most common route of antimicrobial therapy. +• Fortified cefazolin and aminoglycoside should be used for more severe bacterial keratitis. +• Monotherapy with a fourth-generation fluoroquinolone is used for bacterial keratitis. +http://internalmedicinebook.com +125 +58  Endophthalmitis +Marlene L. +CLINICAL MANIFESTATIONS +• Decreased vision and eye pain are usually present. +Hypopyon (layer of white blood cells in +aqueous humor) is commonly seen. +CATEGORIES AND MICROBIOLOGY (SEE TABLE 58-1) +• Acute postcataract endophthalmitis. +Incidence is 0.1% to 0.2% of cataract surgeries, with onset +within 1 week postoperatively in 75%. +Etiology is contamination of aqueous from ocular +surface flora. +• Chronic postcataract endophthalmitis. +It may respond to topical corticosteroids +initially but recurs as the drug dosage is tapered. +The cause is Propionibacterium acnes in +most cases. +• Postinjection endophthalmitis. +Injections +are typically given once monthly. +• Bleb-related endophthalmitis. +• Post-traumatic endophthalmitis. +Coagulase-negative staphylococci and Bacillus cereus are major pathogens; B. +cereus is +most feared and causes fulminant infection. +• Endogenous bacterial endophthalmitis. +• Candida endophthalmitis. +Aspergillus and Fusarium are +the most common pathogens. +Endogenous cases with positive blood cultures are +usually presumed to be due to the same organism. +• Approximately 10% of anterior uveitis cases have an infectious etiology. +• Approximately 50% of posterior uveitis cases have an infectious etiology. +• Infectious causes of intermediate uveitis are rare and include Lyme disease. +• Infectious causes of panuveitis include syphilis, TB, and Candida endophthalmitis. +DIAGNOSIS +• Varies by etiology. +THERAPY +• Varies by etiology. +Referral patterns of uveitis in a tertiary eye care center. +Arch Ophthalmol. +1996;114:593-599). +http://internalmedicinebook.com +129 +60  Periocular Infections +Marlene L. +Acute sinusitis is the most common cause of orbital +infections. +aureus, streptococci; also gram­negative bacilli +• Orbital infections: S. +aureus including methicillin­resistant S. +Mixed infections common. +Preseptal cellulitis has none of these features—only lid edema and erythema. +Computed +tomography (CT) scan should be performed on any patient with orbital findings. +Subperiosteal abscesses usually require surgical +drainage, and orbital abscesses almost always do. +Drainage of an adjacent infected sinus may +be indicated. +http://internalmedicinebook.com +130 +N  Hepatitis +61  Viral Hepatitis +Jules L. +Dienstag and Andrew S. +• Illness ranges from asymptomatic to fulminant. +• Asymptomatic infections are 10 to 30 times more common than symptomatic ones. +CHRONIC HEPATITIS +• Chronic hepatitis affects more than 500 million people worldwide. +• HBV, HCV, and HDV cause chronic hepatitis. +• HEV causes protracted and chronic hepatitis only in immunosuppressed patients. +• HAV is transmitted via the fecal-oral route. +• HAV is more severe in patients with preexisting chronic hepatitis B or C. +• Relapsing and cholestatic hepatitis may occur. +• Diagnosis is by serology (IgM anti-HAV) (see Table 61-2). +• Treatment is usually not necessary beyond supportive care. +• Worldwide, 350 million people are infected chronically with HBV. +‡Cirrhosis can occur after chronic infection, which is confined to immunosuppressed patients. +Modified from Longo D, Fauci A, Kasper D, et al. +Harrison’s Principles of Internal Medicine. +18th ed. +New York: +McGraw Hill; 2011. +*If liver biopsy reveals advanced necroinflammatory activity or fibrosis, consider treatment. +†Inactive carrier. +‡>102 to 103 IU/mL. +§If decompensated, coordinate care with a liver transplantation center. +25% 44% 21% 67% 60% 76% + HBeAg-negative ? +These comparisons are head to head only for PEG IFN vs. +LAM, ETV vs. +LAM, +TBV vs. +LMV, and TDF vs. +ADV. +†Creatinine monitoring recommended. +‡At 32% 24 wk after therapy. +§When these studies were conducted, HBV DNA was measured with insensitive hybridization assays. +untreated patients. +• Acute coinfection can occur and follows the clinical course of acute HBV infection. +• HCV requires host lipid membrane assembly/secretion apparatus for replication. +• The annual incidence of HCC in persons with HCV-associated cirrhosis is 1% to 4%. +• HCV is the leading indication for liver transplantation in the United States. +61-1). +• Genotype 2: SOF 400 mg daily with RBV (weight-based, 1000 to 1200 mg daily) for +12 weeks. +Week 4 <1 log10 HCV RNA reduction: consider PEG IFN/RBV + BOC for 44 weeks after lead-in (no RGT). +• It spreads by fecally contaminated water in endemic areas. +• HEV causes acute, self-limited hepatitis, similar to HAV, in normal hosts. +• Diagnosis is by serologic tests (IgM antibody to HEV) or PCR in blood or stool. +One (Hecolin) has been recently licensed in China. +DIAGNOSIS +• Diagnosis proceeds from history, physical examination, and laboratory studies. +• A variety of formats are available, and rapid tests are now U.S. +Food and Drug Administration +approved for HIV screening and confirmation (see Table 62-2). +If positive, proceed to Step 2.† +Step 2: HIV-1/HIV-2 antibody differentiation immunoassay. +†No further testing is required for specimens that are nonreactive on the initial immunoassay. +CDC, Centers for Disease Control and Prevention; HIV, human immunodeficiency virus. +*Names and manufacturers of individual testing kits are available at www.fda.gov. +• Specific guidelines are available for testing for treatment and prophylaxis purposes. +Careful evaluation to rule out HIV infection is +necessary. +Sterling and Richard E. +• Symptoms generally resolve within 10 to 15 days. +• In patients treated with antiretroviral therapy, previously involuted nodes may enlarge. +ORAL DISEASE +• Oral candidiasis, oral hairy leukoplakia, gingivitis, and periodontitis may occur. +• Myocarditis and pericarditis are also found. +Modified from Niu MT, Stein DS, Schnittman SM. +J Infect Dis. +1993;168:1490-1501. +Sax and Kevin L. +• Most complications occur in those not receiving antiretroviral therapy (ART). +• Findings on chest radiography can help guide the differential diagnosis (see Table 64-1). +• Patients with PCP typically report cough and fever of at least several weeks’ duration. +• Serum (1→3)-β-D-glucan is also highly sensitive for the diagnosis of PCP. +tuberculosis +Legionella spp. +Rhodococcus equi +Hilar Adenopathy +M. +tuberculosis +H. +capsulatum +Coccidioides spp. +tuberculosis +C. +neoformans +R. +equi +Aspergillus spp. +Nocardia spp. +Mycobacterium avium complex +P. +jirovecii +Nodules or Masses +M. +tuberculosis +C. +neoformans +Aspergillus spp. +H. +capsulatum +Nocardia spp. +Non-Hodgkin’s lymphoma +Kaposi sarcoma +Lung cancer +Normal Radiograph +P. +jirovecii +M. +• Noninfectious causes include reflux esophagitis and pill esophagitis. +• Malignant causes include esophageal carcinoma, lymphoma, and Kaposi sarcoma. +• Presumptive diagnoses can often be made with a careful history and physical examination. +• Upper endoscopy with biopsy of lesions is highly sensitive in many cases. +• Helicobacter pylori, CMV, and Kaposi sarcoma are common causes of gastric disorders. +• Upper endoscopy and gastric biopsies are often needed for definitive diagnosis. +• CMV, Cryptosporidium, and microsporidia are most commonly implicated. +• Didanosine and systemic pentamidine can cause pancreatitis. +jirovecii, and +CMV have been described, often in disseminated disease. +• Clostridium difficile is the most common cause of diarrhea in HIV-infected patients. +• HIV-associated enteropathy causes culture-negative diarrhea and may improve with ART. +Salmonella spp. +Shigella flexneri +Aeromonas hydrophila +Plesiomonas shigelloides +Yersinia enterocolitica +Vibrio spp. +Siddiqi and Igor J. +EPIDEMIOLOGY +• Ten percent of HIV-positive patients initially present with neurologic disease. +• Thirty to fifty percent of HIV-positive patients have neurologic complications. +• Eighty percent of HIV-positive patients have nervous system involvement at autopsy. +Incidence depends on the seroposi- +tivity of the population. +• Diagnosis is one of exclusion. +• Etiology is unclear. +• Clinical and electrophysiologic manifestations are indistinguishable from DSNP. +Symptoms +can improve upon discontinuation of offending medication. +Weinberg and George K. +Siberry +EPIDEMIOLOGY +• A remarkable decline in U.S. +N. +Tsibris and Martin S. +THERAPY CHOICES +• Antiretroviral therapy targets and inhibits HIV-specific enzymes. +†Pharmacokinetic properties are similar to those of the component drugs used separately. +*Elvitegravir is not available as a single drug. +Some are transmitted person to person, whereas others are present in +certain environmental niches. +Immunization is also an +important part of routine infection prevention strategy. +• Recommendations for discontinuing or restarting prophylactic medications are available. +Whenever possible, +patients should be tested +for G6PD before use of +dapsone or primaquine. +Alternative therapy should +be used in patients found +to have G6PD deficiency. +The dose +can be increased gradually +(desensitization), reduced, +or the frequency modified. +Adjunctive corticosteroid +improves survival for TB +meningitis and pericarditis. +RIF is not recommended +for patients receiving HIV +PI because of its induction +of PI metabolism. +RFB is a less potent +CYP3A4 inducer than RIF +and is preferred in patients +receiving PIs. +For severe IRIS reaction, +consider prednisone and +taper over 4 wk based on +clinical symptoms. +NSAIDs can be used for +patients who experience +moderate to severe +symptoms attributed to +IRIS. +The +recommendations listed are suggested empirical therapy. +The regimen should be modified as needed once +microbiologic results are available. +Patients should be afebrile +for 48-72 hr and clinically +stable before stopping +antibiotics. +Antimotility agents should +be avoided. +Must +weigh benefit against risks +of long-term antibiotic +exposure. +Effective ART may reduce +the frequency, severity, +and recurrence of +Salmonella infections. +Suppressive therapy usually +not recommended unless +patients have frequent or +severe recurrences. +Dosage should +be adjusted in patients +with renal insufficiency. +Opening pressure should +always be measured when +an LP is performed. +Corticosteroids and +mannitol are ineffective in +reducing ICP and are not +recommended. +These interactions are +complex and can be +bidirectional. +Random serum +concentration of +itraconazole + +hydroitraconazole should +be >1 µg/mL. +It +can also occur in +HIV-infected patients with +CD4 counts >250 cells/ +mm3. +These interactions are +complex and can be +bidirectional. +IRU may develop in the +setting of immune +reconstitution. +Treatment of IRU: +Periocular corticosteroid or +short courses of systemic +corticosteroid. +Duration: 21-42 days or +until symptoms have +resolved. +Continue until lesions are +completely healed. +Topical formulations of +trifluridine and cidofovir +are not commercially +available. +The main +treatment approach is to +reverse the +immunosuppression +caused by HIV. +Initiate ART immediately +in ART-naïve patients. +Optimize ART in patients +who develop PML in +phase of HIV viremia on +ART. +*Pyrimethamine and leucovorin doses are the same as for preferred therapy. +Available at http://aidsinfo.nih.gov/guidelines. +Accessed May 5, 2014. +Prophylaxis should be +initiated if seroconversion +occurred. +Rifampin 600 mg PO +daily × 4 mo, or +Rifabutin (dose adjusted +based on concomitant +ART) × 4 mo. +PPV23 0.5 mL IM at least +8 wk after the PCV13 +vaccine. +Live-attenuated influenza +vaccine is contraindicated +in HIV-infected patients. +Note: VariZIG is available +through Cangene, +Canada. +Hepatitis A vaccine 1 mL +IM × two doses at 0 and +6-12 mo. +Revaccinate with a +second vaccine series. +Some experts +recommend revaccinating +with 40-µg doses of +either HBV vaccine. +Available at http://aidsinfo.nih.gov/guidelines. +Accessed May 5, 2014. +172 +P  Miscellaneous Syndromes +70  Chronic Fatigue Syndrome +N. +• CFS occurs in women three to seven times more frequently than in men. +• It occurs in all socioeconomic strata and among all races. +• Prior or concurrent history of psychiatric disorders is common. +• There is no valid laboratory test to rule in or to rule out CFS. +• No antimicrobial and immune therapies have been proven to be helpful. +PREVENTION +• There are no known preventive measures. +Modified from Fukuda K, Straus SE, Hickie I, et al. +The chronic fatigue syndrome: a comprehensive approach +to its definition and study. +International Chronic Fatigue Syndrome Study Group. +Ann Intern Med. +1994;121: +953-959. +Postexertional malaise,* and +3. +Unrefreshing sleep* +At least one of the following manifestations is also required: +1. +Cognitive impairment* or +2. +Orthostatic intolerance +*Frequency and severity of symptoms should be assessed. +207 3 +Mycoplasma spp. +Petersen and Inger K. +Petersen and Inger K. +179 +73  Herpes Simplex Virus +Joshua T. +EPIDEMIOLOGY +• HSV-1 a nd HSV-2 have a worldwide distribution and have no known animal reservoirs. +• HSV-1 i s acquired more frequently and earlier than HSV-2. +More than 90% of adults have +antibodies t o HSV-1 by the fifth decade of life. +• Global incidence of HSV-2 has been estimated at 23 million new cases per year. +• Viral r eplication occurs through nuclear and cytoplasmic phases. +CLINICAL MANIFESTATIONS +• HSV h as been isolated from nearly all visceral and mucosal sites. +Complications include aseptic meningitis, trans- +verse m yelitis, and sacral radiculopathy. +Extragenital lesions may occur during the course of +primary g enital infection. +Magnetic resonance imaging is the neuroimaging technique +of choice to identify abnormalities. +• Neonatal infections may occur through contact with HSV secretions. +Individuals with frequent recurrences may be treated with suppressive therapy. +• Acyclovir-resistant HSV strains can be treated with foscarnet or cidofovir. +Débridement +may be required; topical corticosteroids may +worsen disease. +IV acyclovir, +15 mg/kg/day, should be considered. +Disseminated HSV Infections +No controlled studies exist. +IV acyclovir, +10 mg/kg q8h, nevertheless should be given. +No definite evidence indicates that therapy +decreases the risk of death. +Therapy +should be initiated 48 hr before surgery and +continued for 3-7 days. +IV cidofovir, +5 mg/kg once weekly, might also be +effective. +These topical preparations should +be applied to the lesions once daily for 5 +consecutive days. +Note: I, II, III, IV, and V represent level of evidence. +Modified from Cernik C, Gallina K, Brodell RT. +The treatment of herpes simplex infections: an evidence-based +review. +Arch Intern Med. +2008;168:1137-1144; and Spruance S, Aoki FY, Tyring S, et al. +J Fam Pract. +2007;56:30-36. +EPIDEMIOLOGY +• Chickenpox is the primary infection occurring primarily in childhood. +• Disease i s more likely to occur in late winter and early spring. +• Herpes zoster causes significant pain in many individuals. +• There i s no seasonal predilection for occurrence of herpes zoster. +MICROBIOLOGY +• Varicella-zoster virus is a double-stranded DNA virus. +Following primary infection, latency +is es tablished in sensory ganglia. +DIAGNOSIS +• The di agnosis of chickenpox and herpes zoster is usually clinical. +• Herpes zoster is usually a unilateral vesicular rash. +Dissemination can occur in immuno- +compromised patients. +• Viral c ulture can be used to make a diagnosis, but it is less sensitive than PCR. +THERAPY +• Three dr ugs are licensed for the treatment of VZV infections. +For older patients, the dosage of acyclovir is 800 mg +5 t imes a d ay. +• Herpes zoster can be treated with acyclovir at 800 mg five times daily for 7 to 10 days. +• Herpes zoster can be treated with valacyclovir at 1 g three times daily for 7 to 10 days. +• Herpes zoster can be treated with famciclovir at 500 mg three times daily for 7 to 10 days. +• A VZV vaccine is available to prevent chickenpox. +185 +75  Cytomegalovirus (CMV) +Clyde S. +Recent evidence +points t o g reat genomic variability during replication in a single patient. +Healthy y oung adults can develop CMV mononucleosis. +In immunocompromised AIDS +patients, CMV retinitis leads to vision loss. +The potential role of HCMV in cardiovascular +disease i s b eing increasingly investigated. +Thi s assay uses international units and permits comparison among clinical trials. +Detection o f CMV pp65 antigen in infected neutrophils remains a valuable diagnostic tool. +THERAPY +• Ganciclovir (GCV) and valganciclovir (VGC) are the mainstays of treatment. +Foscarnet is +mainly u seful for GCV-resistant CMV infection and disease. +Cidofovir may be used for +treatment o f failures with other anti-CMV drugs. +PREVENTION +• GCV a nd VGC are used as prophylaxis in the transplantation setting. +GCV and VGC are +also u sed a s preemptive therapy. +An effective CMV vaccine has not yet been developed. +Johannsen and Kenneth M. +Primary +Epstein-Barr virus (EBV) infection is the most common cause of this syndrome. +• Seroprevalence approaches 95% in adults, and EBV is distributed throughout the world. +• In c hildhood, primary EBV infection is usually asymptomatic or a nonspecific illness. +MICROBIOLOGY +• EBV i s a gamma-1 herpesvirus, genus Lymphocryptovirus. +• EBV i s a double-stranded DNA virus that is enveloped. +• EBV i s a lso known as human herpesvirus 4. +• Antiviral therapy is of no proven benefit in infectious mononucleosis. +PREVENTION +• There i s currently no EBV vaccine. +188 +77  Human Herpesvirus Types 6 +and 7 (Exanthem Subitum) +Jeffrey I. +They can also cause encephalitis in immunocompromised hosts. +EPIDEMIOLOGY +• Most adults are seropositive for HHV-6 and HHV-7. +• The average age for infection with HHV-6 is about 1 year old and for HHV-7 is 2 years old. +MICROBIOLOGY +• HHV-6 and HHV-7, like cytomegalovirus, are betaherpesviruses. +189 +78  Kaposi’s Sarcoma–Associated +Herpesvirus (Human +Herpesvirus 8) +Kenneth M. +• Transmission is predominantly the result of exposure to infected saliva. +• Primary infection is usually asymptomatic and rarely recognized. +• KSHV malignancy usually occurs in the setting of immune suppression. +MICROBIOLOGY +• KSHV i s a gamma-2 herpesvirus, genus Rhadinovirus. +• KSHV i s an enveloped, double-stranded DNA virus. +• KSHV i s also known as HHV-8. +DIAGNOSIS +• KS c an b e diagnosed by its clinical appearance and confirmed by biopsy. +• Primary effusion lymphoma and multicentric Castleman’s disease are diagnosed by biopsy. +• KSHV c an be detected serologically, although assays are not standardized. +PREVENTION +• There i s currently no KSHV vaccine. +190 +79  Herpes B Virus +Jeffrey I. +Cohen* +DEFINITION +• Herpes B virus is a macaque virus that can cause fatal encephalitis in humans. +• Intravenous ganciclovir (5 mg/kg q12h) is recommended for persons with CNS disease. +From Cohen JI, Davenport DS, Stewart JA, et al. +Clin Infect Dis. +2002;35:1191-1203. +192 +80  Adenoviruses +Elizabeth G. +Rhee and Dan H. +• Transmission is via respiratory droplets or fecal-oral transmission. +Virus secretion may +persist f or p rolonged periods after acute infection resolves. +• Typically, the disease is subclinical or mildly symptomatic and self-limited. +• HAdVs were originally isolated from adenoid tissues, leading to the virus name. +DIAGNOSIS +• Diagnosis is not routinely pursued because most infections are mild and self-limited. +193 +Chapter 80  Adenoviruses +THERAPY +• There a re no approved therapies available. +C linical trial of brincidofovir in transplant patients is underway. +EPIDEMIOLOGY +• Cutaneous warts are predominantly a disease of school-aged children. +They are acquired +from c lose contacts, predominantly in the family environment. +• Most o f the sexually active population will have been exposed to genital HPV in a lifetime. +P ersistence is a risk factor for the development of cancer. +These viruses are not routinely +cultivatable. +• HPV t ypes 1, 2, and 4 are the most common types found in cutaneous warts. +• HPV t ypes 6 and 11 account for most genital warts. +DIAGNOSIS +• The di agnosis of cutaneous warts and of genital warts is typically clinical. +• HPV D NA testing supplements screening cytology. +They can be divided into medical and physical approaches. +PREVENTION +• Male co ndoms have some effectiveness in protecting against genital infections. +• Pap sm ears are essential for the prevention of cervical cancer. +• Two hig hly effective vaccines are available. +Th e vaccines are given intramuscularly in three doses. +• A 9-va lent vaccine (Gardasil 9) has been approved by the U.S. +Food and Drug Administration +in D ecember 2014. +It covers HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58, in addition +to t he f our listed earlier. +196 +82  JC, BK, and Other Polyomaviruses: +Progressive Multifocal +Leukoencephalopathy (PML) +C. +Sabrina Tan and Igor J. +Epidemiology +• JCV inf ects 40% to 86% of the general population worldwide. +• Up t o 82% of PML patients are infected with human immunodeficiency virus. +Microbiology +• JCV i s a member of the Polyomaviridae. +• It i s a do uble-stranded DNA virus without an envelope. +• After p rimary infection, JCV remains latent in the kidney epithelial cells. +Therapy +• There a re no effective antiviral medications. +Prevention +• Measures should be taken to prevent immunosuppression. +• BKV c an be detected in the urine of asymptomatic healthy individuals. +• BKV n ephropathy occurs in up to 10% of kidney transplant patients. +Microbiology +• BKV i s a member of the Polyomaviridae. +• Reactivation of BKV causes hemorrhagic cystitis and nephropathy. +Diagnosis +• BKV i s detected by PCR assay in blood and sustained viruria in urine. +• Cytopathologic changes may be detected on a kidney biopsy specimen. +Therapy +• There i s no effective antiviral medication. +• The highest HBV prevalence is in Asia, Africa, and parts of the Middle East. +• Chronic hepatitis B is the leading cause of end-stage liver disease worldwide. +• Transmission of HBV is through percutaneous or sexual routes. +Perinatal transmission is +also common. +• About 5% of people with chronic hepatitis B have evidence of exposure to HDV. +• HDV is primarily transmitted via the parenteral route, but there is some sexual transmission. +Perinatal transmission is uncommon. +• HBV replication is through an RNA intermediate, so it has a reverse transcriptase. +• HDV is a small, defective RNA virus that relies on host cell machinery for replication. +• HDV requires the envelope of HBV for viral assembly and transmission. +• Clinical presentation of HDV is also variable but can present as acute severe hepatitis. +• The first-line nucleos(t)ide agents are entecavir 0.5 mg daily or tenofovir 300 mg daily. +• HDV is treated with 180 µg PEG IFN-α weekly for a minumum of 48 weeks. +*Occasionally individuals with past infection have isolated anti-HBc only. +In such cases, an HBV DNA test may prove useful. +†Chronic hepatitis B with a pre-core mutant is HBeAg− and anti-HBe+. +*All data are for 1 year unless otherwise noted. +†Dose adjustment for creatinine clearance. +‡Higher end of range for HBeAg-negative disease. +§None; otherwise, 7% if preexisting lamivudine resistance. +Modified from Lok AS, McMahon BJ. +Chronic hepatitis B. +Hepatology. +2009;50:661-662. +If mother’s HBsAg status is unknown, admin- +ister vaccine within 12 hr and test mother. +If mother is HBsAg positive, administer HBIG within 1 week. +‡Special formulation. +§Birth dose should be monovalent vaccine only; subsequent doses can be combination. +202 +84  Human Parvoviruses, +Including Parvovirus B19V +and Human Bocaparvoviruses +Kevin E. +Brown +DEFINITION +• At le ast f our different types of parvovirus infect humans. +• Disease associations with Parv4 infection are not clear. +EPIDEMIOLOGY +• Parvovirus B19 infection is a common infection in children and young adults. +By age 15, +50% o f c hildren in America and Europe will have been infected and have IgG. +• Diagnosis of B19V rash is by detection of B19V IgM in serum. +• Following infection, low levels of B19V DNA may be detected lifelong. +THERAPY +• Treatment for all parvovirus infections is mainly symptomatic. +PREVENTION +• A vaccin e for parvovirus B19 is in development. +203 +85  Orthoreoviruses and Orbiviruses +Roberta L. +DeBiasi and Kenneth L. +Tyler +DEFINITION +• Reoviruses are linear double-stranded RNA viruses with broad host ranges. +EPIDEMIOLOGY +• Infection of humans is common but is rarely associated with significant disease. +THERAPY +• No s pecific therapy is available. +PREVENTION +• No s pecific preventative measures are recommended—reoviruses are ubiquitous. +204 +86  Coltiviruses and Seadornaviruses +Roberta L. +DeBiasi and Kenneth L. +• The di stribution of CTFV coincides with the range of the principal tick vector. +Coltiviruses have 12 gene segments enclosed within two capsids. +• Patients may have cerebrospinal fluid pleocytosis. +Leukopenia is common. +• Virus c an also be isolated in cell culture. +THERAPY +• No s pecific therapy is available. +205 +87  Rotaviruses +Philip R. +VIRAL STRUCTURE AND REPLICATION +• The v iral particle is a triple-layered icosahedron. +• Genome consists of 11 segments of double-stranded RNA. +• The v irus binds cell surface carbohydrates. +• Cells a re entered by viral penetration of the cellular membrane. +• After t he outer layer is removed, a subviral particle transcribes and extrudes mRNA. +• Main sy mptoms are diarrhea and vomiting. +Severe dehydration and death can result. +PATHOGENESIS +• The v irus primarily infects epithelial cells at the tips of the intestinal villi. +SEROLOGIC CLASSIFICATION +• Group A rotaviruses cause most human disease. +• There i s an extensive diversity of antigenic types. +• Genetic classification is starting to replace serologic classification. +EPIDEMIOLOGY +• Infection is universal in the first years of life. +• Infection may be symptomatic or asymptomatic. +• Severe i llness is most common between 6 months and 2 years of age. +• Reinfection occurs throughout life. +• Serotype influences but does not determine protection from reinfection. +• VP4 a nd VP7 each contain serotype-specific and heterotypic neutralizing epitopes. +• Neutralizing antibodies block the functions of the outer capsid proteins in cell entry. +• Cellular immunity contributes to clearance of infection. +• Rotavirus interferes with the innate immune response by several mechanisms. +• There i s increasing use of nucleic acid–based testing for epidemiologic investigations. +• No s pecific antiviral therapy is available. +• Mild a nd moderate dehydration can be treated effectively with oral rehydration solutions. +• All h uman pathogenic alphaviruses are mosquito borne. +EPIDEMIOLOGY +• The p resence of infected mosquitoes is required for disease outbreak. +Human-to-human +transmission does not occur. +• At l ater t imes, recovery is mediated by virus-neutralizing antibodies and cytotoxic T cells. +DIAGNOSIS +• Knowledge of the patient’s travel history is of major importance in diagnosis. +L ouis encephalitis viruses. +THERAPY +• At p resent, there are no products licensed for treatment. +• For en cephalitis, supportive measures and intensive nursing care are currently indicated. +• Vaccines are under development, particularly against CHIK. +One promising approach is the +use o f CHIK virus–like particles for immunization. +209 +89  Rubella Virus (German Measles) +Anne A. +• Many p ostnatal infections are asymptomatic. +• Rubella vaccine was developed primarily to prevent congenital rubella from occurring. +• Rubella i s somewhat less contagious than measles. +• Widespread vaccination in the Americas led to the elimination of rubella as of 2009. +THERAPY +• None i s available. +210 +90  +Flaviviruses (Dengue, Yellow Fever, +Japanese Encephalitis, West Nile +Encephalitis, St. +Thomas, Timothy P. +Endy, Alan L. +Rothman, +and Alan D. +• Yellow fever (YF) is found in tropical South America and sub-Saharan Africa. +Disease is +severe with high morbidity and mortality. +• Dengue is widely distributed throughout the tropics and subtropics. +Severe disease is infre- +quent (~2% to 4% of apparent cases) but potentially fatal. +Nonsevere disease (outpatient) +accounts for much of dengue’s global socioeconomic impact. +Chronic morbidity and mortality are high in symptomatic cases. +• West Nile virus (WNV), St. +Most infections are subclinical. +Nonstructural +proteins make up the remainder of the genome. +• Mutations and replication errors are high. +DIAGNOSIS +• Diagnostic approaches are dictated by the disease course. +Army or the U.S. +Department of Defense. +THERAPY +• No licen sed or specific antiviral therapies are available. +• Treatment is supportive, and outcomes are variable. +PREVENTION +• U.S.-licensed vaccines exist for YF and JE. +Vaccines exist for TBE and KFDV. +• Numerous vaccine development efforts are underway for additional flaviviruses. +212 +91  Hepatitis C +Stuart C. +Ray and David L. +MICROBIOLOGY +• HCV is roughly spheroid and is 55 nm in diameter. +91-1). +• HCV has six major genotypes and provisionally a seventh. +• Extensive quasispecies variation is present in each infected individual. +EPIDEMIOLOGY +• More than 185 million persons are HCV antibody positive worldwide. +• Transmission occurs most commonly by percutaneous exposure to blood. +• In developed countries, most HCV infections are associated with IV drug abuse. +• In the developing world, transmission occurs from unsafe medical practices. +• Fulminant hepatitis due to HCV infection is uncommon in Western countries. +• RNA tests are also used to assess the effects of treatment. +• Liver biopsies and noninvasive liver tests are used to assess the stage of liver diseases. +FIGURE 91-1 Organization of the hepatitis C virus (HCV) genome and viral polyprotein. +The 5′ UTR contains an internal ribosomal entry site (IRES). +• Development of vaccines against HCV is challenging because of extensive viral diversity. +EPIDEMIOLOGY +• Community-acquired CoV infections cause about 15% of common colds. +They are typically +epidemic in the winter months. +They mutate and also recombine frequently. +THERAPY +• There a re no accepted effective antiviral drugs for CoVs. +PREVENTION +• Prevention is through epidemiologic methods. +216 +93  Parainfluenza Viruses +Michael G. +Clinically, PIV-1 is strongly associated with croup in children. +• PIV-4 is associated with milder disease, typically limited to the upper airway. +It includes PIV-1, PIV-2, PIV-3, and PIV-4. +• A number of novel antivirals are currently under development. +• A number of live-attenuated vaccine candidates are undergoing development. +217 +94  Mumps Virus +Nathan Litman and Stephen G. +• Incubation period is usually 16 to 18 days with a range of 2 to 4 weeks. +• Since 1967, there has been more than a 99% decline in the annual U.S. +incidence of mumps. +MICROBIOLOGY +• Mumps i s an enveloped, single-stranded RNA virus. +• Only o ne serotype of mumps virus exists, but there are 13 genotypes. +THERAPY +• Therapy for mumps is symptomatic and supportive. +218 +95  Respiratory Syncytial Virus (RSV) +Edward E. +EPIDEMIOLOGY +• RSV circulates annually during the winter months in temperate climates. +• RSV is the leading cause of bronchiolitis in infants. +• RSV is primarily transmitted by direct contact with infected persons or their secretions. +MICROBIOLOGY +• RSV is an enveloped nonsegmented RNA virus in the Paramyxoviridae family. +• RSV isolates can be classified into antigenically distinct groups, A and B. +THERAPY +• Treatment for most infants and adults is supportive only. +*Caren Hall passed away in 2012. +She was the author for this and other chapters for previous editions of +this book. +This chapter is dedicated to her memory. +219 +96  Human Metapneumovirus +Ann R. +EPIDEMIOLOGY +• Distribution is worldwide. +• Infection is most common in winter and spring in temperate climates. +• Infection is universal by age 5 years. +• Reinfections occur throughout life. +• Diverged from avian metapneumoviruses 200 to 300 years ago. +• Two m ajor genotypes (A and B) and four subgroups (A1, A2, B1, and B2). +• Bronchiolitis, asthma exacerbations, and pneumonia occur in children. +THERAPY +• Therapy is supportive. +PREVENTION +• No vaccine is available. +220 +97  Measles Virus (Rubeola) +Anne A. +Gershon +DEFINITION +• Measles is a highly contagious viral infection, usually of childhood. +• Initially, before the rash appears, measles can resemble influenza. +• There i s usually accompanying conjunctivitis, cough, and coryza. +• Measles is also contagious for a few days after rash onset. +• The v irus spreads by droplets and also by the airborne route. +• Measles vaccination has been shown to be unrelated to development of autism. +DIAGNOSIS +• Clinically, measles may be confused with Kawasaki disease. +• Measles virus is difficult to culture. +THERAPY +• No s pecific therapy has been proven to be useful. +• The m echanism of action of vitamin A is thought to be by immunomodulation. +222 +98  Zoonotic Paramyxoviruses: +Nipah, Hendra, and Menangle +Anna R. +Additional outbreaks involving humans occurred in +2004, 2008, and 2009. +Menangle virus has caused an influenza-like illness in +two p eople. +224 +99  Vesicular Stomatitis Virus +and Related Vesiculoviruses +Steven M. +• Endemic disease occurs in areas of Central and South America. +THERAPY +• Therapy in humans is generally not required. +• There i s no known antiviral treatment, so therapy consists of supportive measures. +PREVENTION +• Quarantine of animals from infected ranches is commonly instituted. +• Protective clothing and gloves should be worn when handling infected animals. +• An exp erimental vaccine is in trials. +A killed vaccine for animals is approved, but its efficacy +is un known. +225 +100  Rabies (Rhabdoviruses) +Kamaljit Singh, Charles E. +Rupprecht, and Thomas P. +EPIDEMIOLOGY +• Rabies i s one of the oldest human diseases, with the highest case fatality rate. +• Approximately 3.3 billion people live in regions where rabies is enzootic. +• An es timated 55,000 people die from rabies each year. +• Bites b y rabid dogs cause 99% of human deaths globally. +• In t he U nited States, bats account for most human rabies cases. +• Rabies v irus transmission may also occur through tissue or organ transplantation. +• Rabies v irus is the type species of the Lyssavirus g enus. +• Paralytic rabies is characterized by ascending flaccid quadriparesis and coma. +THERAPY +• There i s no proven antiviral therapy. +PREVENTION +• Annually, more than 10 million people receive rabies postexposure prophylaxis. +EPIDEMIOLOGY +• Human outbreaks occur sporadically in regions of Central Africa. +• Recent e vidence suggests that bats may play a role as a reservoir host. +TREATMENT +• There a re no approved postexposure treatments for filovirus infections. +• Appropriate personal protection equipment (PPE) is essential for health care workers. +• Isolation of infected patients and close contacts is essential. +228 +102  Influenza (Including Avian +Influenza and Swine Influenza) +John J. +Three types (A, B, and C) are recognized, as well as many subtypes +within the type A viruses. +Therapy is most effective when used +early in the course of illness (see Table 102-1). +Antiviral drugs can also be used prophylactically in +selected circumstances. +They may be considered if sensitivities become +reestablished. +*Immunization providers should check U.S. +†For adults and older children, the recommended site of vaccination is the deltoid muscle. +The preferred site for +infants and young children is the anterolateral aspect of the thigh. +Modified from Centers for Disease Control and Prevention. +Available at http://www.cdc.gov/flu/professionals/acip/2013-summary-recommendations +.htm#table1. +• Hantaviruses are maintained in nature through persistent infection of rodents. +Diagnostic tests are typically performed in reference laboratories. +THERAPY +• No s pecific therapy is available, and treatment is typically supportive. +However, compre- +hensive c linical trials have not been conducted. +• Transmission is by rodents, with generally high species specificity of reservoir vectors. +TREATMENT +• Supportive treatment may be lifesaving. +If +available, single rooms with negative pressure should be utilized. +234 +105  Human T-Lymphotropic +Virus (HTLV) +Edward L. +Murphy and Roberta L. +It is hyperendemic among injection drug users in North America +and E urope. +• Most inf ected individuals are asymptomatic. +• Therapy for HAM is currently unsatisfactory. +Corticosteroids may produce improvement, +but side eff ects limit the duration of therapy. +Interferon-α a nd in terferon-1β h ave b een u sed +with s ome s uccess. +The anabolic steroid danazol may relieve bladder symptoms. +• The u se of condoms should be recommended to prevent sexual transmission. +• Injection drug users with HTLV infection should be instructed not to share needles. +• The U .S. +Food and Drug Administration recommends HTLV testing of all donated blood +and t issue. +No vaccine is currently available. +236 +106  Human Immunodeficiency Viruses +Marvin S. +Reitz, Jr., and Robert C. +AR T c an also decrease the rate of transmission of infection. +237 +107  Poliovirus +José R. +Romero and John F. +Only three serotypes exist (1 to 3). +EPIDEMIOLOGY +• Wild-type poliovirus type 2 no longer circulates worldwide. +Serotypes 1 and 3 have been +eradicated f rom most of the world. +MICROBIOLOGY +• The p olioviruses are members of the genus Enterovirus, fa mily P icornaviridae. +THERAPY +• No s pecific therapy is available. +238 +108  Coxsackieviruses, +Echoviruses, and Numbered +Enteroviruses (EV-D68) +José R. +Romero and John F. +EPIDEMIOLOGY +• The en teroviruses are found worldwide. +• A l arge outbreak of EV-D68 occurred in the United States in 2014. +• Serotype identification is accomplished by sequencing of the major capsid protein VP1. +THERAPY +• Therapy is supportive. +239 +109  Human Parechoviruses +José R. +Romero and John F. +At least 16 types have been identified. +EPIDEMIOLOGY +• HPeVs a re found worldwide. +• The m ajority of HPeV infections occur during the summer and autumn months. +• Type identification is accomplished by sequencing of the major capsid protein, VP1. +THERAPY +• Therapy is supportive. +No specific antiviral therapy is available. +PREVENTION +• Contagion can be prevented by hand washing. +240 +110  Hepatitis A Virus +Francisco Averhoff, Yury Khudyakov, and Beth P. +Three genotypes infect humans (I, II, and III). +• HAV is relatively resistant to heat but can be inactivated at higher temperatures. +EPIDEMIOLOGY +• Transmission is fecal-oral with peak viral shedding before onset of symptoms. +• Humans are the only important reservoir for HAV. +Large community-wide epidem- +ics previously common are now rare. +• Globally, hepatitis A is one of the leading causes of vaccine-preventable deaths. +DIAGNOSIS +• Hepatitis A is not clinically distinguishable from other forms of viral hepatitis. +• Chronic hepatitis A does not occur. +*Hepatitis A vaccine is not licensed for children <12 months. +From Centers for Disease Control and Prevention. +Prevention of hepatitis A through active or passive immuniza- +tion. +Recommendations of the Advisory Committee on Immunization Practices. +MMWR Morb Mortal Wkly Rep. +2006;55(RR-7):1-23; and Centers for Disease Control and Prevention. +MMWR Morb Mortal Wkly Rep. +2009;58:1006-1007. +†Postexposure prophylaxis should be given as soon as possible after exposure. +243 +111  Rhinovirus +Ronald B. +DIAGNOSIS +• The co mmon cold is the characteristic clinical manifestation. +• Exacerbations of asthma in children are frequently associated with rhinovirus infection. +• Rhinoviruses may cause bronchiolitis in young children. +THERAPY +• Despite multiple studies, no specific antiviral therapy has been established. +PREVENTION +• There i s no proven intervention to prevent rhinovirus infection. +244 +112  Noroviruses and +Sapoviruses (Caliciviruses) +Raphael Dolin and John J. +• Sapoviruses cause gastroenteritis less frequently than noroviruses. +MICROBIOLOGY +• Noroviruses and sapoviruses are single-stranded, positive-sense RNA viruses. +Each is divided +into fi ve g enogroups and has multiple genotypes. +• Neither noroviruses nor sapoviruses have been cultivated in vitro. +• Illness u sually lasts 12 to 60 hours and remits spontaneously. +246 +113  Astroviruses and Picobirnaviruses +Raphael Dolin and John J. +Treanor +DEFINITION +• Astrovirus causes acute gastroenteritis. +Transmission +is li kely b y t he fecal-oral route. +Picobirnaviruses are double-stranded +RNA v iruses with a bisegmented genome. +Illness may be somewhat less severe than that seen with +rotaviruses. +THERAPY +• Treatment is supportive. +247 +114  Hepatitis E Virus +Stephen R. +Person-to-person transmission is uncommon. +• Chronic hepatitis E infection has recently been described in immunosuppressed patients. +• Four g enotypes and 24 subgenotypes have been described. +THERAPY +• Acute HEV infection is generally self-limited and requires only supportive care. +Severe acute +cases h ave b een treated successfully with ribavirin. +Bosque and Kenneth L. +EPIDEMIOLOGY +• Human prion disease is rare; its incidence is 1 × 10−6 w orldwide. +• About 90% of cases are sporadic. +• About 10% of cases are genetic. +• Infectious transmission accounts for less than 1% of human cases. +MICROBIOLOGY +• The c ausative agent is composed of an aggregate of misfolded forms of PrP. +• The p rion contains no information-bearing nucleic acid. +DIAGNOSIS +• Treatable mimics of prion disease should be excluded before making the diagnosis. +THERAPY +• No eff ective therapy exists for prion infection. +• Additional precautions are needed for neurosurgical cases. +• Tissue f rom persons with prion disease must not be transplanted. +• Dietary exposure to ruminant animal prions should be avoided. +• The o cular disease trachoma is the leading infectious cause of blindness worldwide. +• Lymphogranuloma venereum (LGV), caused by distinct serovars of C. +• Transmission during vaginal delivery can lead to neonatal conjunctivitis and pneumonia. +• C. +MICROBIOLOGY +• C. +trachomatis is a g ram-negative bacterium, but Gram stain is not used for identification. +• The o rganism is cultivated in cell culture because it does not grow and divide axenically. +• The b acterium replicates within a cytoplasmic inclusion in the host cell. +Treatment of sex +partners is crucial to prevent repeated infection. +• LGV is treated with doxycycline for 21 days. +Uptake of screening +in the United States is relatively low. +• Screening of all pregnant women is recommended. +MICROBIOLOGY +• The et iologic agent is Chlamydia psittaci of t he fa mily Chlamydiaceae. +THERAPY +• Doxycycline or tetracycline is treatment of choice. +PREVENTION +• Treat im ported birds and birds that have suspected infection. +254 +118  Chlamydia pneumoniae +Margaret R. +Hammerschlag, Stephan A. +Kohlhoff, +and Charlotte A. +THERAPY +• C. +pneumoniae is s usceptible to macrolides, quinolones, and tetracyclines. +Data on efficacy +are limi ted, including optimal dose and duration of therapy. +255 +D  Mycoplasma Diseases +119  Mycoplasma pneumoniae  +and Atypical Pneumonia +Robert S. +Holzman and Michael S. +ETIOLOGIC AGENT +• M. +pneumoniae +• Detection of M. +pneumoniae–specific a ntigens +• Detection of M. +The l atter t wo only recently were assigned to separate +species. +There is evidence that they may persist in children into adulthood. +• The ep idemiology of infection with M. +genitalium c losely p arallels that of Chlamydia tracho- +matis a nd Neisseria gonorrhoeae. +CLINICAL MANIFESTATIONS +• U. +urealyticum c auses ur ethritis, whereas U. +parvum a ppears to be a colonizer. +Only relatively +sexually in experienced men are susceptible to U. +• M. +• M. +genitalium is a c ause of urethritis in men and endocervicitis in women. +It is likely a cause +of p elvic infl ammatory disease but appears to cause milder disease than N. +gonorrhoeae a nd +C. +trachomatis. +Only M. +The ureaplasmas require special media for growth, and M. +genitalium +cannot b e c ultured at all outside research laboratories. +THERAPY +• Tetracycline class drugs are active against most ureaplasmas and M. +hominis b ut n ot a gainst +M. +genitalium. +M acrolides are effective for the ureaplasmas but not for M. +hominis a nd a re +only p artially effective for M. +genitalium. +Q uinolones, especially moxifloxacin, are active +against a ll o f the genital mycoplasmas. +Walker and Lucas S. +RMSF a lso occurs in Central and South America. +• In t he U nited States, RMSF is most prevalent in the South Atlantic and South Central regions. +Infections u sually occur during the late spring and summer, when ticks are most active. +Other t ick-borne SFG rickettsiae with a broad range of distribution include R. +conorii +(Europe, A frica, and South Asia), R. +sibirica (e astern R ussia and Asia), R. +africae (s ub- +Saharan A frica and West Indies), R. +parkeri (N orth a nd South America), and R. +slovaca +(Europe). +• Rickettsia felis c auses fle a-borne spotted fever and has a worldwide distribution. +CLINICAL MANIFESTATIONS +• RMSF t ypically manifests with fever early in the course. +Other manifestations include head- +ache, m yalgias, nausea, vomiting, and abdominal pain. +• Rash i s common but may not occur in the first few days of illness. +Rash typically starts on +the w rists a nd ankles before spreading proximally. +Involvement of the palms and soles occurs +in 36% t o 82% but is often a late sign. +DIAGNOSIS +• The in direct immunofluorescence assay is the serologic method of choice. +• Treatment should not be withheld while awaiting laboratory confirmation. +• Azithromycin and clarithromycin are alternatives for less severe SFG rickettsioses. +EPIDEMIOLOGY +• Found w orldwide but is particularly common in New York City. +MICROBIOLOGY +• Infection caused by intracellular Rickettsia akari. +THERAPY +• Doxycycline, 100 mg twice daily for 7 days. +PREVENTION +• Mouse eradication from buildings will prevent transmission to humans. +260 +123  Coxiella burnetii (Q Fever) +Thomas J. +Infections are divided into acute and chronic forms. +• Cattle, s heep, and goats are the most common reservoirs. +Infected parturient cats are impor- +tant in t he s pread of Coxiella in s ome a reas. +• There i s an extensive wildlife reservoir. +• The en vironment is contaminated at the time of parturition by an infected animal. +DIAGNOSIS +• In m ost instances, an indirect immunofluorescent serologic test is the best one. +• Isolation of C. +• Polymerase chain reaction assay can be used to amplify C. +burnetii D NA f rom a variety of +clinical s pecimens, such as heart valves and joint fluid. +Blanton and David H. +• An extracellular dormant form remains infectious in louse feces for months or longer. +• Lice become infected while feeding on rickettsemic patients. +• In North America, an extrahuman reservoir of R. +• Untreated illness may progress to cause pulmonary edema, encephalitis, and death. +DIAGNOSIS +• The indirect immunofluorescence assay is the mainstay of serologic diagnosis. +• Polymerase chain reaction assay and immunohistochemical detection of R. +prowazekii in +blood or tissue, respectively, can establish the diagnosis during acute illness. +• Treatment should not be withheld while awaiting laboratory confirmation. +Chloramphenicol +is an alternative treatment. +Human pathogens in body and head lice. +Emerg Infect Dis. +2002;8:1515-1518; data for Ethiopia from Perine PL, Chandler BP, Krause DK, et al. +A clinico- +epidemiological study of epidemic typhus in Africa. +Clin Infect Dis. +1992;14:1149-1158. +264 +125  Rickettsia typhi (Murine Typhus) +Lucas S. +Blanton, J. +Stephen Dumler, and David H. +Walker +DEFINITION +• Murine t yphus is caused by Rickettsia typhi. +• R. +typhi is an o bligately intracellular gram-negative bacterium. +• The di sease is transmitted by the inoculation of infected flea feces into a flea bite wound. +• Rash i s common as illness progresses. +• Elevations in serum hepatic aminotransferase levels are frequent laboratory findings. +DIAGNOSIS +• Early di agnosis of murine typhus is based on clinical suspicion and epidemiology. +• Immunohistochemical detection of R. +Chloramphenicol +is a n a lternative treatment. +• Prevention is directed toward the control of flea vectors and potential flea hosts. +Polymerase chain reaction assay of +swab o r t issue of eschar pretreatment is very sensitive. +The Weil-Felix test is unreliable but +widely u sed. +Stephen Dumler and David H. +• The m ammalian target cell of Neoehrlichia mikurensis is n ot k nown. +EPIDEMIOLOGY +• Human monocytotropic ehrlichiosis (HME) and human E. +• Human E. +• Human N. +mikurensis inf ection o ccurs in Europe and northern China, where I. +persulcatus +clade t icks a nd small mammals serve as vectors and reservoirs. +• Rash i s infrequent or rare. +• Early t herapy improves outcomes and prevents severe complications or sequelae. +• Chloramphenicol should not be used. +• Rifampin has been successfully used in children. +Alternatives include clindamycin +or trimethoprim-sulfamethoxazole orally or intravenously). +• Partner drug for combinations: rifampin. +• Benefit of aminoglycosides not well demonstrated. +aureus (MRSA) as exemplified by sequence type 5 (ST5). +ST5 belongs  +to clonal cluster 5 (CC5), which gathers S. +(Modified from Robinson  +DA,  Enright  MC. +Evolutionary  models  of  the  emergence  of  methicillin-resistant  Staphylococcus +aureus. +Antimicrob Agents Chemother. +Pxp + + +cap8 Chromosome Polysaccharide capsule  +type 8 +Antiphagocytosis? +Pxp + – +sspB Chromosome Cysteine protease Processing enzyme? +? +Expression: +, upregulated; –, downregulated. +†agr, accessory gene regulator; PVL, Panton-Valentine leukocidin; saeRS, S. +aureus exoproteins; rot, repressor of  +toxins; sarA, Staphylococcus accessory regulator. +‡Controversial. +§SaPI, S. +aureus pathogenic island. +Modified from Cheung AL, Projan SJ, Gresham H. +Curr Infect Dis Rep. +2002;4:400-410; and Novick RP, Geisinger E. +Quorum  +sensing in staphylococci. +Ann Rev Genet. +2008;42:541-564. +aur eus surface  +protein B +937 SrtA LPDTG Undetermined — +sasC S. +aur eus surface  +protein C +2186 SrtA LPNTG Undetermined — +sasD S. +aur eus surface  +protein D +241 SrtA LPAAG Undetermined — +sasF S. +aur eus surface  +protein F +637 SrtA LPKAG Undetermined — +sasG S. +Modified fr om Roche FM, Massey R, Peacock SJ, et al. +Microbiology. +2003;149:643-654; Clarke S, Foster S. +Surface adhesins of Staphylococcus aureus. +Adv Microb Physiol. +2006;51:187-224; and Dedent A, Marraffini L,  +Schneewind O. +Staphylococcal sortases and surface proteins. +In: Fischetti V, Novick RP, Ferretti J, et al, eds. +Gram- +Positive Pathogens. +2nd ed. +Washington, DC: ASM Press; 2006:486-495. +Relieve isolation and swab weekly  +for follow-up cultures. +S. +Note: Phage and SaPI families based on homology of integrase genes and insertion site. +NI, Element present but  +no identified virulence or resistance gene. +RF122 has two phage fragments. +*Integrated plasmid. +Modified fr om Lindsay J. +S. +aureus evolution: lineages and mobile genetic elements (MGEs). +In: Lindsay J, ed. +Staphylococcus aureus Molecular Genetics. +Norfolk, UK: Casiter Academic Press; 2008:45-69. +Rupp and Paul D. +aureus by t heir in ability to produce coagulase. +S. +• Other n oteworthy species of coagulase-negative staphylococci include S. +hae- +molyticus, o ften r esistant to glycopeptides; and S. +lugdunensis, a m ore v irulent coagulase- +negative s taphylococcus that mimics infections due to S. +aureus. +EPIDEMIOLOGY +• S. +• Strains o f S. +THERAPY +• Most n osocomial S. +I solates of S. +In general, infected devices should be +removed w henever possible. +A number of biofilm-directed therapeutic modalities appear to +hold p romise. +277 +130  Streptococcus pyogenes +Amy E. +Bryant and Dennis L. +EPIDEMIOLOGY +• The m ost common infection is streptococcal pharyngitis. +• Superficial skin and soft tissue infections include impetigo, erysipelas, and cellulitis. +MICROBIOLOGY +• S. +pyogenes is a g ram-positive, β-hemolytic s treptococcus that is catalase negative. +More than +150 diff erent strains have been identified based on different M-protein types. +DIAGNOSIS +• Diagnosis of S. +• Invasive S. +THERAPY +• Penicillin remains the drug of choice for the treatment of all streptococcal infections. +• Severe c ases of S. +Oral +penicillin f or 7 to 10 days is reasonable, although no definitive studies have been done. +Shulman and Alan L. +• APSGN can follow group A streptococcal infections of the skin or throat. +The molecular basis +of r heumatogenicity is unknown. +The specific antigen(s) involved in this immune-complex nephritis is +still s omewhat unclear. +Immunosuppressives are not beneficial. +• Because APSGN only very rarely recurs, no preventative antibiotic therapy is indicated. +Rheumatic Fever and Streptococcal Infection. +New York: Grune & Stratton; 1975. +From Gerber MA, Baltimore RS, Eaton CB, et al. +Prevention of rheumatic fever and diagnosis and treatment of +acute streptococcal pharyngitis. +Circulation. +2009;191:1541-1551. +281 +132  Streptococcus pneumoniae +Edward N. +Janoff and Daniel M. +• Streptococcus pneumoniae is c atalase-negative but produces hydrogen peroxide. +pneumoniae. +THERAPY +• A β-lactam a ntibiotic is the mainstay of therapy for pneumococcal infection. +pneumoniae. +C ombined therapy with a β-lactam a nd macrolide may improve +outcomes. +The effic acy of the 23-valent polysaccharide vaccine against adult pneumonia is less clear. +Both P PSV23 and PCV13 are now approved independently for use in older adults. +283 +133  Enterococcus Species, +Streptococcus gallolyticus Group, +and Leuconostoc Species +Cesar A. +Arias and Barbara E. +• Enterococcus faecalis a nd Enterococcus faecium a re t he m ost clinically relevant species. +• The f ormer Streptococcus bovis g roup is n ow divided into three main species: S. +gallolyticus, +S. +pasteurianus, a nd S. +infantarius. +• Specific hospital-associated genetic lineages of E. +faecium a nd E. +faecalis h ave e volved to +become s uccessful in the nosocomial environment. +• Infection control measures are critical to prevent acquisition of these microorganisms. +• Infective endocarditis and bacteremia caused by S. +gallolyticus is hig hly a ssociated with +gastrointestinal malignancies. +• Enterococci are one of the leading causes of nosocomial urinary tract infections. +• S. +gallolyticus g roup of o rganisms have been associated with infective endocarditis. +THERAPY AND ANTIMICROBIAL RESISTANCE +• Whereas most E. +faecalis i solates a re susceptible to ampicillin and vancomycin, E. +• Ampicillin plus ceftriaxone is an alternative therapy for E. +faecalis en docarditis. +• Therapy of severe infections caused by E. +faecium is c hallenging, and no reliable therapy is +currently a vailable. +• Linezolid and quinupristin-dalfopristin are two U.S. +Food and Drug Administration– +approved dr ugs for multidrug resistant E. +• The t herapy of choice for endocarditis caused by S. +• Ampicillin or penicillin is the drug of choice for the treatment of Leuconostoc inf ections. +285 +134  Streptococcus agalactiae +(Group B Streptococcus) +Morven S. +Edwards and Carol J. +• Distribution is worldwide, but rates vary geographically. +MICROBIOLOGY +• β-Hemolytic streptococci exhibit a narrow zone of hemolysis on blood agar. +• Growth of GBS from blood or another normally sterile site is diagnostic. +†Optimal timing for prenatal GBS screening is at 35-37 weeks’ gestation. +§NAAT for GBS is optional and might not be available in all settings. +Prevention of perinatal group B streptococcal +disease—revised guidelines from CDC, 2010. +MMWR Recomm Rep. +2010;59(RR-10):1-32. +Sinner and Allan R. +• Some s pecies of groups C and G streptococci, along with S. +289 +136  Streptococcus anginosus Group +Cathy A. +Petti and Charles W. +anginosus, +S. +constellatus, a nd S. +intermedius. +They are generally susceptible to β-lactam +antibiotics. +PREVENTION +• Not a pplicable. +Asymptomatic carriage is important in transmission. +Diphtheria is now rare in the West and +endemic in the Third World, especially Southeast Asia. +Fewer than 5000 annual cases have +been r eported worldwide since 2000. +MICROBIOLOGY +• The b acillus is nonsporulating, unencapsulated, and nonmotile. +Four biovars and 86 ribotypes have been identified for tracking. +Circulating +toxin c auses potentially fatal carditis and motor neuropathy. +Cutaneous infection causes +indolent u lcers. +Th e dose depends on the duration and extent of disease. +Test patients first for horse +protein h ypersensitivity. +Consider tracheostomy to protect airway. +Cardiographic monitor- +ing i s w ise b ecause of toxin cardiotoxicity. +Td boosters should be +given a t 10-year intervals. +292 +138  Other Coryneform Bacteria +and Rhodococci +Rose Kim and Annette C. +MICROBIOLOGY +• Coryneform bacteria readily grow on standard culture media. +For lipophilic strains, growth +is en hanced with addition of Tween 80. +• Serology not useful for invasive disease. +MICROBIOLOGY +• Short, gram-positive rod; grows readily on blood agar; tumbling motility. +• May be mistaken for diphtheroid contaminant. +• Will grow in refrigerated food. +EPIDEMIOLOGY +• Zoonosis, particularly herd animals. +• Highest food risks from delicatessen-style meats and unpasteurized cheeses. +Notify laboratory for special stool +cultures if outbreak of febrile gastroenteritis. +CLINICAL SETTINGS +• Neonatal sepsis or meningitis. +• Fever in pregnancy, especially third trimester. +• Outbreak of foodborne febrile gastroenteritis. +TREATMENT +• Ampicillin (2 g IV every 4 hours). +Add gentamicin (5 mg/kg per day) for CNS infection or +endocarditis. +• Trimethoprim-sulfamethoxazole (5/25 mg/kg IV every 8 hours) for penicillin allergic. +• Food safety recommendations for those at risk (see Table 139-2). +• Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole prevents listeriosis. +Even if the +produce will be peeled, it should still be washed first. +Scrub firm produce, such as melons and cucumbers, with a clean produce brush. +Dry the produce with a clean cloth or paper towel. +Be aware that Listeria monocytogenes can grow in foods in the refrigerator. +The refrigerator should be 40° F +or lower and the freezer 0° F or lower. +Use precooked or ready-to-eat food as soon as you can. +Do not store the product in the refrigerator beyond +the use-by date. +Use leftovers within 3 to 4 days. +Refrigerate after opening. +Canned and shelf stable tuna, salmon, and other fish products are safe to eat. +Be sure that your scrub brush is sanitized after each use. +Promptly consume cut melon or refrigerate promptly. +Keep your cut melon refrigerated for no more than +7 days. +Discard cut melons left at room temperature for more than 4 hours. +296 +140  Bacillus anthracis (Anthrax) +Gregory J. +Martin and Arthur M. +• Naturally acquired human cases are usually associated with animal products. +• Spore-forming gram-positive bacillus grows readily in the laboratory. +• Spores, when protected from ultraviolet light, remain viable for decades or longer. +• Pathogenicity is associated with edema and lethal toxins and a capsule. +After skin inoculation, a +pruritic papule forms in 2 to 5 days. +Vesicles rupture, leading to formation of a black eschar +at the base of a shallow ulcer. +Surgical débridement may be +required. +Culture of material +is frequently positive. +Direct fluorescent antibody (DFA) test and polymerase chain reaction +(PCR) assay also may be used. +It is primarily a mediastinal (not +an airspace) process. +Blood and pleural fluid cultures are positive. +Pleural fluid Gram stain +may be positive. +DFA test or PCR assay may give most rapid results. +Blood, stool, and ascites should all be +obtained for culture, DFA testing, and PCR assay. +Gram staining of ascitic fluid may reveal +gram-positive bacilli. +Death occurs within 24 hours in 75% of cases. +Cerebrospinal fluid reveals +gram-positive bacilli, and cultures are positive. +DFA test and PCR assay may provide the +most rapid diagnosis. +THERAPY +• Rapid initiation of antibiotics for all stages is crucial (see Table 140-1). +• For cutaneous anthrax, ciprofloxacin or doxycycline alone is used. +government. +A Bactericidal Agent (β-Lactam) +a. +Will +require prophylaxis to complete an antibiotic course +of up to 60 days from onset of illness. +aDrug names in boldface are preferred agents. +cIncreased risk for seizures associated with imipenem/cilastatin therapy. +eRifampin is not a protein synthesis inhibitor but may be used based on in vitro synergy. +fShould only be used if other options are not available, owing to toxicity concerns. +Data from Hendricks KA, Wright ME, Shadomy SV, et al; Workgroup on Anthrax Clinical Guidelines. +Emerg +Infect Dis. +2014;20. +doi: 10.3201/eid2002.130687. +clindamycin, rifampin, or chloramphenicol. +Consider central nervous system penetration of +antibiotics for treatment of potential meningitis. +• Gram quantities of stable spores are easy to transport and could cause thousands of cases. +• Nasal swabs are used to identify exposure areas, not to determine individual exposures. +• Exposed patients should be decontaminated with soap and water. +• Infection in humans is usually due to occupational exposure. +MICROBIOLOGY +• It i s a n aerobe or facultative anaerobe. +• Most s trains produce hydrogen sulfide, a diagnostically important reaction. +• It i s s ometimes confused with other gram-positive bacilli. +• Vitek 2 a nd the API Coryne system are reliable for identification. +• Standard methods for culturing blood or biopsy tissue suffice. +THERAPY +• E. +• Most s trains are resistant to vancomycin, sulfa drugs, and aminoglycosides. +• Penicillin is the drug of choice for all forms of infection. +• Commercial vaccines are available for veterinary use. +• T. +whipplei is f ound f requently in the stools of children with acute diarrhea. +• T. +whipplei c an c ause c ulture-negative endocarditis. +MICROBIOLOGY AND PATHOGENESIS +• T. +whipplei is a g ram-positive bacterium with high guanine and cytosine content. +• T. +whipplei is r esistant to glutaraldehyde. +whipplei. +• WD o ccurs in a localized form (e.g., endocarditis or central nervous system disease). +• WD o ccurs in various clinical manifestations in association with immunosuppression. +THERAPY +• IV in duction therapy with ceftriaxone for 2 to 4 weeks. +• Followed by long-term therapy with oral trimethoprim-sulfamethoxazole for 1 year. +• Close f ollow-up of treatment success over several years. +PREVENTION +• Ubiquitous bacterial agent, prevention not yet possible. +301 +144  Neisseria meningitidis +David S. +Stephens and Michael A. +MICROBIOLOGY +• N. +BIOLOGY AND PATHOGENESIS +• Meningococcal biology and pathogenesis are defined by (1) N. +These factors influence disease incidence and +severity and prevention strategies. +EPIDEMIOLOGY +• Disease occurs worldwide, but incidence is variable. +144-1). +meningitidis. +Rash may or may not be +present. +• Long-term sequelae occur in 11% to 19% of cases. +• Family and community impact is significant. +• Adjuvant therapy and supportive care should be provided. +FIGURE 144-1  Epidemiology of meningococcal disease by serogroup. +Group B outbreaks  +are noted by country and year of onset. +(Modified from Stephens DS, Greenwood B, Brandtzaeg P. +Epidemic men- +ingitis, meningococcaemia, and Neisseria meningitidis. +Lancet. +Modified from Shin SH, Kwang Kim SK. +Treatment of bacterial meningitis: an update. +Exp Opin Pharmacother. +2012;13:2189-2206. +Not recommended for pregnant  +women. +Not recommended for pregnant  +or lactating women. +•  Ceftriaxone is recommended for pregnant women. +•  May want to avoid ciprofloxacin or azithromycin in individuals at risk of QT-prolongation. +Marrazzo and Michael A. +EPIDEMIOLOGY +• Gonorrhea occurs most commonly in adolescents and young adults worldwide. +• N. +• The gonococcus is naturally competent. +This is a factor that has led to the rapid acquisition +of antimicrobial resistance. +• N. +gonorrhoeae is an exclusive human pathogen. +It utilizes different pathogenic mechanisms +to infect the epithelium of men and women. +THERAPY +• Options are limited, given widespread resistance to numerous antibiotic classes. +• Condoms are very effective in preventing transmission. +Azithromycin, given as a single oral dose of 1 g, is preferred. +Test of cure at 7 days is recommended if the ceftriaxone regimen is not used. +Alternative +parenteral regimens include cefotaxime, ceftizoxime, and spectinomycin. +See www.cdc.gov/std/treatment for +specific regimens. +‡Topical antibiotic therapy alone is inadequate for treatment of ophthalmia neonatorum. +Modified from Centers for Disease Control and Prevention. +MMWR +Morb Mortal Wkly Rep. +2012;61:590-594; and www.cdc.gov/std/treatment. +307 +146  Moraxella catarrhalis, Kingella, +and Other Gram-Negative Cocci +Timothy F. +EPIDEMIOLOGY +• M. +catarrhalis is r ecovered exclusively from humans. +• Nasopharyngeal colonization is common in infancy and childhood and decreases with age. +• K. +Infections occur sporadically, but occasional clusters are seen. +MICROBIOLOGY +• M. +• M. +catarrhalis p roduces o xidase, catalase, and DNAse, which are used for speciation. +DIAGNOSIS +• An et iologic diagnosis of the most common clinical manifestations of M. +• A di agnosis of K. +THERAPY +• Most i solates of M. +catarrhalis p roduce β-lactamase and are thus resistant to ampicillin. +• K. +kingae i solates a re susceptible to penicillins and cephalosporins. +catarrhalis inf ections, including otitis media and exacerbations of COPD. +308 +147  Vibrio cholerae +Matthew K. +Waldor and Edward T. +Ryan +MICROBIOLOGY AND EPIDEMIOLOGY +• Vibrio cholerae is a c urved motile gram-negative bacillus. +• V. +cholerae is a n oninvasive intestinal pathogen. +• V. +cholerae O1 a nd O139 serogroup organisms are the causes of epidemic cholera. +• Non-O1 and non-O139 V. +cholerae c an c ause i solated cases of usually mild gastroenteritis. +• V. +cholerae h as an aq uatic reservoir, particularly in brackish estuarine water. +• The f ecal-oral transmission is associated with unsafe water and inadequate sanitation. +• Cholera is now endemic in more than 50 countries. +• Cholera can lead to explosive epidemics and outbreaks. +• The c urrent pandemic is caused by V. +• Vomiting, ileus, and muscle cramps are common. +• The p resence of fever should prompt consideration of additional diagnoses. +Aspiration pneumonia from vomiting may also occur. +Death from cholera almost always +results f rom dehydration. +• Rapid a ntigen tests are available, including dipstick stool assays. +Both LRS and NS +can be supplemented +with dextrose. +Dhaka +solution more closely +approximates losses +during cholera, but is not +readily available. +A homemade preparation +of ORS could be used in +an emergency situation. +Sodium losses in cholera +stools exceed those seen +in other causes of +diarrheal illness. +Modified from Harris JB, Larocque RC, Qadri F, et al. +Cholera. +Lancet. +2012;379:2466-2476. +Rare reports of +macrolide resistance. +Empirical use often reserved +for outbreaks caused by +documented susceptible +isolates. +Tetracyclines are +not recommended for +pregnant women or children +less than 8 yr. +Doxycycline 4-6 mg/kg × single +dose +300 mg × single +dose +bid, twice a day; qid: four times a day. +*Pediatric doses, based on weight; should not exceed maximum adult dose. +Modified from Harris JB, Larocque RC, Qadri F, et al. +Cholera. +Lancet. +2012;379:2466-2476. +• Antibiotics decrease the duration of diarrhea and may limit secondary transmission. +• Additional cholera vaccines are under development. +Does not require buffer +to administer vaccine. +Currently more +affordable than +Dukoral. +Has been safely +administered to +individuals infected +with HIV. +*Per manufacturer. +Modified from Harris JB, Larocque RC, Qadri F, et al. +Cholera. +Lancet. +2012;379:2466-2476. +312 +148  Other Pathogenic Vibrios +Marguerite A. +Neill and Charles C. +J. +• They m ay also be found in freshwater sources. +• The h alophilic vibrios require higher concentrations of salt for growth. +• V. +THERAPY +• Rapid r ecognition of possible V. +PREVENTION +• No vaccine is available for the noncholera vibrios. +314 +149  Campylobacter jejuni +and Related Species +Ban Mishu Allos, Nicole M. +Iovine, and Martin J. +Blaser +DEFINITION +• Campylobacter s pp. +The diarrhea is frequently bloody and is associated +with a bdominal pain. +C. +jejuni is t he m ost common human clinical isolate, but many other +Campylobacter s pp. +h ave b een identified. +EPIDEMIOLOGY +• Campylobacter s pp. +a re f ound in a variety of animals and are a common cause of human +diarrheal di sease worldwide. +Transmission to humans occurs +most co mmonly from consumption or handling of poultry. +MICROBIOLOGY +• Many, b ut not all, Campylobacter s pp. +t hrive at 42° C. +The organisms are quite small (0.3 to +0.6 µm in di ameter) and motile. +They are microaerophilic and grow best at an oxygen con- +centration o f 5% to 10%. +A ntibiotics may shorten the duration of symptoms. +Erythromycin, 250 mg four times +per d ay f or 5 to 7 days, will treat most infections. +Extended-spectrum macrolides are equally +efficacious. +No effective vaccine is currently +available. +315 +150  Helicobacter pylori and Other +Gastric Helicobacter Species +Timothy L. +Cover and Martin J. +• Most H. +pylori–colonized persons remain asymptomatic, but the presence of H. +pylori is +associated with an increased risk of peptic ulceration and gastric cancer. +EPIDEMIOLOGY +• H. +• The p revalence of H. +pylori in de veloped countries has been declining over the past several +decades. +MICROBIOLOGY +• H. +pylori is a ur ease-positive, gram-negative, spiral-shaped bacterium. +DIAGNOSIS +• Noninvasive approaches are serology, urea breath test, and stool antigen test. +• Invasive approaches are endoscopy and analysis of gastric tissue. +PREVENTION +• Prevention of H. +pylori acq uisition by immunization is not routinely practiced. +316 +151  Enterobacteriaceae +Michael S. +a mong others +• Salmonella s pp., Shigella s pp., Yersinia s pp. +• P. +• Other Pseudomonas s pecies, in cluding P. +fluorescens, P. +luteola, P. +putida, a nd P. +• P. +• P. +Long-term acute care hospitals have very high rates of infections caused +by P. +aeruginosa +• Characteristic infections caused by P. +• Resistance to single and multiple antimicrobial agents is rising rapidly. +MICROBIOLOGY OF P. +AERUGINOSA +• P. +aeruginosa is an aer obic rod-shaped bacteria. +They do not ferment glucose, and many +clinical i solates tend to give a weak oxidase reaction. +• Slow-growing morphotypes, known as small-colony variants of B. +cepacia a nd S. +Patient-to-patient transmission is believed to +contribute t o colonization. +• Community-acquired S. +CLINICAL MANIFESTATIONS +• S. +maltophilia m ay in volve any organ. +Lungs are frequent sites of infection. +Pulmonary infec- +tion i s o ften preceded by respiratory tract colonization. +Lobular or lobar consolidation is +common, w hereas pleural effusions are seldom noted. +• Most S. +Non–catheter-related bacteremia is often seen in patients with prolonged +neutropenia. +• S. +• In p atients with cystic fibrosis, after initial B. +cepacia inf ection, 50% of patients with B. +cenocepacia r etain b acterial presence after the initial infection episode. +COMPLICATIONS +• Lack o f acute inflammation may underwhelm initial clinical presentation of S. +maltophilia +pneumonia in the immunosuppressed patient. +• Non–catheter-related S. +• B. +cepacia co mplex g enomovars. +• B. +DIAGNOSIS +• Early di agnosis requires a high level of suspicion for S. +maltophilia l ung inf ection. +cepacia a nd S. +maltophilia. +• The n ewer fluoroquinolones, such as moxifloxacin, show improved activity against S. +malto- +philia. +• Carbapenems, TMP/SMX, chloramphenicol, and tetracycline are active against most +B. +cepacia co mplex i solates. +Treatment pending susceptibility testing will depend on experi- +ence o f t he institution. +• Most ac tive drugs against B. +cepacia in clude minocycline (38%), meropenem (26%), and +ceftazidime (23%). +multivorans a nd B. +cenocepacia a ppear p romising. +320 +154  Burkholderia pseudomallei +and Burkholderia mallei: +Melioidosis and Glanders +Bart J. +• Glanders is a disease primarily of horses resulting from infection with Burkholderia mallei. +• Most cases occur during the rainy season, and clusters can follow severe weather events. +MICROBIOLOGY +• B. +pseudomallei is a small, gram-negative, oxidase-positive, motile, aerobic bacillus. +• B. +mallei is a small, gram-negative, oxidase-positive, nonmotile aerobic bacillus. +• B. +mallei evolved in animals from the environmental pathogen B. +pseudomallei. +DIAGNOSIS: MELIOIDOSIS +• Most infections with B. +pseudomallei are asymptomatic. +• Identification of B. +pseudomallei and B. +mallei by various methods can be problematic. +• Locally developed antigen and DNA detection techniques are available in some locations. +Serology has poor specificity because of background positivity in endemic regions. +Australia data from Currie BJ, Fisher DA, Howard DM, et al. +Clin Infect Dis. +2000;31:981-986. +*Not listed: malignancy, steroid therapy, iron overload, cardiac failure. +Thailand data from Punyagupta S. +Melioidosis: review of 686 cases and presentation of a new clinical classifica- +tion. +In: Punyagupta S, Sirisanthana T, Stapatayavong B, eds. +Melioidosis. +Bangkok: Bangkok Medical; 1989:217- +229; Chaowagul W, White NJ, Dance DA, et al. +Melioidosis: a major cause of community-acquired septicemia in +northeastern Thailand. +J Infect Dis. +1989;159:890-899; Suputtamongkol Y, Chaowagul W, Chetchotisakd P, et al. +Risk factors for melioidosis and bacteremic melioidosis. +Clin Infect Dis. +1999;29:408-413; and Limmathurotsakul +D, Chaowagul W, Chierakul W, et al. +Risk factors for recurrent melioidosis in northeast Thailand. +Clin Infect Dis. +2006;43:979-986. +‡Blood culture not done. +From Currie BJ, Ward L, Cheng AC. +PLoS Negl Trop Dis. +2010;4:e900. +• Cystic fibrosis patients should consider avoiding travel to high-risk areas. +• Vaccines are under development for both melioidosis and glanders. +†Defined as enlargement of any hilar or mediastinal lymph node to greater than 10-mm diameter. +‖Most commonly presenting as mycotic aneurysm. +• A. +baumannii a nd t he c losely related and phenotypically indistinguishable A. +pittii a nd +A. +THERAPY +• Antimicrobial treatment is based on antimicrobial susceptibility testing. +• The em ergence of A. +324 +156  Salmonella Species +David A. +Pegues and Samuel I. +MICROBIOLOGY +• There a re more than 2500 Salmonella s erotypes. +• Obtain b lood cultures for patients suspected of bacteremia or vascular infection. +• Serogrouping is performed with commercially available antisera. +325 +157  Bacillary Dysentery: Shigella and +Enteroinvasive Escherichia coli +Herbert L. +MICROBIOLOGY +• Shigella s pp. +a re sm all gram-negative rods in the family Enterobacteriaceae. +• Similar t o strains of Shigella, en teroinvasive E. +coli p ossesses s omatic antigens and a plasmid +that co ntrols invasiveness. +• The s ooner a stool specimen is cultured, the higher the yield for Shigella. +dysenteriae 1). +• The t reatment of choice for adults is a fluoroquinolone antibiotic given for 3 days. +• For c hildren, cephalosporin, ciprofloxacin, or azithromycin may be used. +• Vaccines are in development to prevent Shigella inf ection. +326 +158  Haemophilus Species, +Including H. +influenzae +and H. +ducreyi (Chancroid) +Timothy F. +Murphy +DEFINITION +• Gram-negative coccobacillus with fastidious growth requirements. +• Encapsulated H. +• Other Haemophilus s pecies a re unusual causes of human disease. +EPIDEMIOLOGY +• The e cologic niche is the human respiratory tract. +• Colonization of the nasopharynx by nontypeable H. +• Invasive H. +influenzae t ype b inf ections are rare in regions of the world where H. +• Fastidious growth requirements are used to distinguish the species in the laboratory. +• Invasive infections caused by H. +• H. +• Chancroid: azithromycin, 1 g orally (single dose) or ceftriaxone, 250 mg IM (single dose). +327 +Chapter 158  +Haemophilus +Species, +  +Including +  +H. +influenzae +  +and +  +H. +ducreyi +  +(Chancroid) +PREVENTION +• All c hildren should receive the H. +• Sexual contacts of patients with chancroid should be treated, even if asymptomatic. +328 +159  Brucellosis (Brucella Species) +H. +The +preferred serology is the tube agglutination test with a titer of at least 1 : 160. +The Rose-Bengal +card agglutination test is useful for screening. +Brucella canis requires a separate serology. +MICROBIOLOGY +• Brucella melitensis, Brucella suis, Brucella abortus, and, rarely, B. +canis cause brucellosis and +are nonmotile gram-negative coccobacilli. +Lymphadenopathy or hepatosplenomegaly may occur. +Onset can be acute or +insidious and persist for weeks or months if untreated. +TREATMENT +• Doxycycline with streptomycin is the standard regimen. +For alternatives and treatment of +neurobrucellosis, see Table 159-1. +Penn +DEFINITION +• Tularemia is the zoonotic disease caused by Francisella tularensis. +• Tularemia peaks in the late spring and summer in the United States. +• Lagomorphs and rodents are important animal reservoirs. +• Tularemia spread by aerosol is a potential bioterrorist weapon. +MICROBIOLOGY +• Francisella organisms are small, aerobic, pleomorphic gram-negative coccobacilli. +• F. +• Although there are three species in the genus Francisella and four F. +tularensis subspecies +(see Table 160-1), only F. +tularensis subsp. +tularensis and F. +tularensis subsp. +holarctica are +relatively common. +• Infections caused by F. +tularensis subsp. +tularensis are generally more severe than those +caused by F. +tularensis subsp. +holarctica. +• F. +• Recovery from infection depends on development of host cell-mediated immunity. +• There are six major patterns of illness: ulceroglandular (see Fig. +160-1), glandular, oculoglan- +dular, pharyngeal, typhoidal, and pneumonic (see Fig. +• Secondary rashes are relatively common. +• F. +tularensis is a Tier 1 select agent, and its possession and shipment are tightly restricted. +• Surgical therapy is limited to drainage of suppurated nodes or of empyemas. +TABLE 160-1  Characterization of Francisella Species +FEATURE +F. +TULARENSIS SUBSPECIES +F. +PHILOMIRAGIAF. +*Variable or delayed. +†Using Kovacs test; negative using cytochrome-oxidase test. +Data from Huber B, Escudero R, Busse HJ, et al. +Description of Francisella hispaniensis sp. +nov., isolated from +human blood, reclassification of Francisella novicida (Larson et al. +1955) Olsufiev et al. +1959 as Francisella tularensis +subsp. +novicida comb. +nov. +and emended description of the genus Francisella. +Int J Syst Evol Microbiol. +2010;60(pt +8):1887-1896; Petersen JM, Schriefer ME, Araj GF. +Francisella and Brucella. +In: Versalovic J, Carroll KC, Funke G, +et al, eds. +Manual of Clinical Microbiology. +Vol 1. +10th ed. +Washington, DC: ASM Press; 2011:751-769; Sjöstedt +AB. +Francisella. +In: Brenner DJ, Krieg NR, Staley JT, et al, eds. +Bergey’s Manual of Systematic Bacteriology. +Vol 2. +2nd ed. +New York: Springer-Verlag; 2005:200-210; and Escudero R, Elia M, Saez-Nieto JA, et al. +Clin Microbiol Infect. +2010;16:1026-1030. +S tandard precautions for handling contaminated secretions are adequate. +tularensis. +FIGURE  160-1 Examples of primary lesions seen in ulceroglandular tularemia. +B, Papule undergoing central necrosis with desquamation on +the thigh of a middle-aged man. +The nodes coalesced, suppurated, and required drainage after 3 days of gentamicin therapy. +Cultures +of the ulcer and node drainage both grew F. +tularensis. +(A and C courtesy Dr. +Joseph A. +John W. +King, +Louisiana State University Health Sciences Center, Shreveport, LA; and E courtesy Dr. +This patient remained +symptomatic for more than 3 months. +(From Penn RL, Kinasewitz GT. +Factors associated with +a poor outcome in tularemia. +Arch Intern Med. +In adults with normal renal function, once-daily administration of gentamicin also +is acceptable. +†A ciprofloxacin dose of 750 mg twice daily also has been used in some reports. +335 +161  Pasteurella Species +John J. +multocida +  Subspecies multocida +  Subspecies septicum +  Subspecies gallicida +P. +canis +P. +dagmatis +P. +stomatis +Pasteurella-related Species +P. +aerogenes +P. +bettyae +P. +caballi +P. +pneumotropica +Data fr om Versalovic J, Carroll KC, Jorgensen JH, et al, eds. +Manual of Clinical Microbiology, 10th ed. +Washington,  +DC: ASM Press; 2011:574-587. +337 +162  Yersinia Species (Including Plague) +Paul S. +Mead +DEFINITION +• Three human pathogens: Yersinia enterocolitica, Y. +pseudotuberculosis, Y. +pestis usually found within distinct ecologic foci +• Y. +enterocolitica, Y. +pestis, Y. +pseudotuberculosis), Salmonella- +Shigella media (Y. +enterocolitica, Y. +enterocolitica, Y. +†Ciprofloxacin has not been approved by the U.S. +Food and Drug Administration (FDA) for this indication. +Modified from Inglesby TV, Dennis DT, Henderson DA, et al. +Plague as a biological weapon: medical and public +health management. +Working Group on Civilian Biodefense. +JAMA. +2000;283:2281-2290. +339 +163  Bordetella pertussis +Valerie Waters and Scott A. +• Peaks o f disease continue to occur every 3 to 5 years. +MICROBIOLOGY +• Bordetella s pecies a re small gram-negative coccobacilli; growth is fastidious. +• Filamentous hemagglutinin and fimbriae are two major adhesins. +• Newer p olymerase chain reaction assays are more sensitive for detection of B. +pertussis a nd +are t he p rocedure of choice. +• Antibodies to B. +pertussis PT c an be used for diagnosis. +• Direct fl uorescent antibody is available but not recommended. +Azithromycin is recommended for infants younger than 1 month +of a ge. +• Supportive care is paramount in management of pertussis, especially in infants. +341 +164  Rat-Bite Fever: Streptobacillus +moniliformis and Spirillum minus +Ronald G. +DIAGNOSIS +• S. +S. +minus is di agnosed by clinical presentation plus direct visualization +or x enodiagnosis. +THERAPY +• Penicillin is the treatment of choice for both types of rat-bite fever. +342 +165  Legionnaires’ Disease and +Pontiac Fever +Paul H. +Edelstein and Craig R. +b acteria, most commonly L. +pneumophila. +t hat r esolves spontaneously. +• Legionellosis includes Legionnaires’ disease, Pontiac fever, and extrapulmonary Legionella +spp. +inf ection not associated with pneumonia. +b ac- +teria, a nd p ossibly by microaspirating Legionella s pp.–containing water. +• Optimal bacterial growth requires specialized media that contain cysteine and iron. +PREVENTION +• No vaccine is available. +• Proper environmental design and maintenance reduce disease risk. +344 +166  Capnocytophaga +J. +• Mortality rate is low (<5%) w ith a ppropriate treatment. +• Reported mortality rates range from 20% to 33%. +MICROBIOLOGY +• Bacilli a re gram negative with tapered ends. +DIAGNOSIS +• Is hi story compatible with Capnocytophaga inf ection (dog bite)? +• Acquired drug resistance has been reported in some isolates. +• Use ra pid testing methods to decrease time to diagnosis. +346 +167  Bartonella, Including +Cat-Scratch Disease +Tejal N. +Gandhi, Leonard N. +Slater, David F. +Welch, +and Jane E. +henselae: c at-scratch disease (CSD): self-limited regional lymphadenopathy +• B. +quintana: t rench f ever: usually a self-limited febrile illness +• B. +quintana: b acillary a ngiomatosis (cutaneous, subcutaneous, osseous) +• B. +quintana +• Avoid c at scratches, bites, licks, and cat fleas to reduce risk of B. +EPIDEMIOLOGY +• Donovanosis is largely confined to discrete geographic areas of the tropics. +• Donovanosis is sexually transmitted but of low infectivity. +• Treatment should be continued until complete epithelialization has occurred. +349 +169  Other Gram-Negative +and Gram-Variable Bacilli +James P. +Steinberg and Eileen M. +• The t axonomy of many of these organisms has been and continues to be in a state of flux. +Epidemiology +• Some o f these gram-negative bacilli are ubiquitous in the environment. +Microbiology +• Many o f these organisms are fastidious and difficult to grow. +351 +170  Syphilis (Treponema pallidum) +Justin D. +Radolf, Edmund C. +Tramont, and Juan C. +MICROBIOLOGY +• T. +Treponema carateum c auses p inta. +• Humans are the only natural hosts for T. +pallidum s ubsp. +pallidum. +• T. +• T. +DIAGNOSIS +• Because T. +• Serodiagnosis of syphilis involves two types of serologic tests: nontreponemal and trepone- +mal. +pallidum p roteins. +Treponemal tests remain reactive for life. +• Doxycycline is the preferred alternative for nonpregnant, penicillin-allergic patients. +• Penicillin-allergic pregnant females should be desensitized. +• Early identification and treatment of gestational syphilis prevents congenital infection. +353 +171  Endemic Treponematoses +Edward W. +Hook III +DEFINITION +• The en demic treponematoses include yaws, endemic syphilis, and pinta. +EPIDEMIOLOGY +• The en demic treponematoses are spread only from human to human by direct contact. +Over the past 2 decades, yaws rates have increased worldwide. +Endemic +syphilis a nd pinta remain very uncommon. +PREVENTION +• Yaws a ppears to be amenable to mass therapy as a control and prevention measure. +354 +172  Leptospira Species (Leptospirosis) +David A. +Haake and Paul N. +EPIDEMIOLOGY +• Leptospirosis is a zoonosis of global distribution. +DIAGNOSIS +• Clinical diagnosis requires a high index of suspicion based on epidemiologic exposure. +• The signs and symptoms of early leptospirosis are nonspecific. +For mild disease, doxycycline, amoxicillin, or oral ampicillin is recom- +mended. +For more severe disease, intravenous ceftriaxone, ampicillin, or penicillin is used. +noguchii Panama, Pomona +L. +borgpetersenii Ballum, Hardjo, Javanica +L. +santarosai Bataviae +L. +kirschneri Bim, Bulgarica, Grippotyphosa, Cynopteri +L. +weilii Celledoni, Sarmin +L. +alexanderi Manhao 3 +L. +alstonii Sichuan +L. +meyeri Sofia +L. +wolffii Khorat +L. +kmetyi Manilae +L. +wolbachii Nonpathogen +L. +biflexa Nonpathogen +L. +vanthielii Nonpathogen +L. +terpstrae Nonpathogen +L. +yanagawae Nonpathogen +L. +idonii Nonpathogen +L. +inadai Indeterminate +L. +fainei Indeterminate +L. +broomii Indeterminate +L. +Horton +DEFINITION +• Relapsing fever is caused by spirochetes of the Borrelia g enus. +• The i llness is characterized by relapsing fevers with spirochetes evident on a blood smear. +ORGANISM +• Borrelia s pecies a re divided between B. +• The r elapsing fever species are divided between the louse-borne and tick-borne species. +DIAGNOSIS +• Spirochetes can be seen on the peripheral blood smear during febrile periods. +THERAPY +• Doxycycline or penicillin is effective treatment. +PREVENTION +• Postexposure therapy with doxycycline is preventive. +357 +174  Lyme Disease (Lyme Borreliosis) +Due to Borrelia burgdorferi +Allen C. +• The di sease occurs in parts of North America, Europe, and Asia. +• The p eak onset of early infection is in the summer months. +burgdorferi in t he g eneral sense). +• The h uman infection is caused primarily by three pathogenic species: B. +burgdorferi s ensu +stricto (B. +DIAGNOSIS +• Culture of B. +358 +175  Clostridium difficile Infection +Dale N. +Gerding and Vincent B. +EPIDEMIOLOGY +• C. +Patients are exposed to and +ingest C. +• Recurrence of diarrhea after treatment occurs in 25% of patients and requires re-treatment. +MICROBIOLOGY +• C. +• The m ajority of strains produce both toxins A and B. +• Some s trains of C. +difficile o rganism or +its t oxin g enes or detects C. +difficile t oxin u sing an enzyme immunoassay or cell cytotoxin +assay. +Bleach is used in the environment to eradicate +spores. +difficile. +360 +176  Tetanus (Clostridium tetani) +Aimee Hodowanec and Thomas P. +• Tetanus i s divided into four clinical types: generalized, localized, cephalic, a nd neonatal. +EPIDEMIOLOGY +• Acute in jury and injection drug use are risk factors for tetanus. +• Tetanus i s rare in developed countries due to the availability of effective vaccines. +MICROBIOLOGY +• C. +tetani is an o bligately anaerobic bacillus. +• Tetanus produces two toxins: tetanospasmin and tetanolysin. +DIAGNOSIS +• Diagnosis of tetanus relies on history and examination findings. +• Culturing C. +tetani is diffic ult a nd not helpful. +THERAPY +• The a irway must be secured at the time of presentation. +• Benzodiazepines provide the mainstay of symptomatic therapy. +• Antibiotic therapy with metronidazole (Flagyl) may improve outcomes. +PREVENTION +• All c hildren should be vaccinated against tetanus through DTaP vaccine series. +• Adults s hould receive a tetanus booster (Td) every 10 years. +One of the Td doses should be +replaced w ith Tdap. +Patients with serious contaminated wounds should also receive HTIG. +361 +177  Botulism (Clostridium botulinum) +Aimee Hodowanec and Thomas P. +Bleck +DEFINITION +• Botulism is a toxin-mediated paralytic illness caused by Clostridium botulinum. +EPIDEMIOLOGY +• Foodborne botulism occurs in outbreaks, whereas other forms are sporadic. +• Foodborne botulism is associated with home-canned or fermented foods. +• Infant botulism historically is associated with honey ingestion. +• Wound botulism is associated with injection drug use of “black-tar” heroin. +• Botulism is a potential bioterrorism agent deployed by aerosol or ingestion. +MICROBIOLOGY +• C. +botulinum is a gram-positive, strictly anaerobic bacillus that forms a subterminal spore. +• C. +botulinum produces seven distinct toxins, designated types A through G. +• Mouse bioassay is the gold standard for botulinum toxin. +• Characteristic electrophysiologic study findings are suggestive of botulism. +THERAPY +• Supportive care remains the mainstay of botulism treatment. +• Heptavalent botulinum antitoxin is available for noninfant botulism in the United States. +PREVENTION +• Proper food preparation prevents foodborne botulism. +• There is no currently available vaccine. +362 +178  Gas Gangrene and Other +Clostridium-Associated Diseases +Andrew B. +Onderdonk and Wendy S. +Garrett +CHARACTERISTICS OF CLOSTRIDIUM SPP. +Full-blown sepsis with hypotension, renal failure, +and metabolic acidosis occurs rapidly. +FOOD POISONING CAUSED BY CLOSTRIDIUM PERFRINGENS +• C. +Risk factors include +hemodialysis, intestinal malignancy, and inflammatory bowel disease. +perfringens accounts for 50%. +C. +perfringens +and C. +sordellii can be isolated from postpartum and postabortion infections. +perfringens accounting for the majority. +perfringens ST, C + − Yes Yes No +C. +ramosum T − − No Yes No +C. +septicum ST − − No Yes No +C. +sordellii ST + − No Yes No +C. +bifermentans ST + − No Yes No +C. +tertium T − − No Yes No +C. +sphenoides ST − − No Yes No +C. +baratii ST − − No Yes No +C. +novyi ST + + No Yes No +C. +histolyticum ST − − No Yes No +Intoxications +C. +difficile ST − − Yes Yes No +C. +botulinum ST, T − + No Yes Yes +C. +tetani T − − No Yes Yes +C, centrally; ST, subterminally; T, terminally. +Garrett and Andrew B. +Onderdonk +DEFINITION +• Bacteroides, Porphyromonas, Prevotella, and Fusobacterium spp. +account for the majority of +infections caused by anaerobic gram-negative rods. +Bilophila and Sutterella spp. +also cause +human infections, although they are less frequently encountered. +MICROBIOLOGY +• The organisms are obligately anaerobic, gram-negative, non–spore-forming rods. +Members +of this group can be proteolytic, saccharolytic, or both. +Some species produce catalase and +superoxide dismutase in low concentrations. +THERAPY +• Treatment is directed by culture and sensitivity test results (see Table 179-1). +365 +180  Mycobacterium tuberculosis +Daniel W. +Fitzgerald, Timothy R. +Sterling, +and David W. +Haas +MICROBIOLOGY +• Humans are the only reservoir for Mycobacterium tuberculosis. +• Visible g rowth takes 3 to 8 weeks on solid media. +• An es timated 10,000 organisms/mL are required for sputum smear positivity. +• Incomplete necrosis produces cheesy, acellular material (i.e., caseous necrosis). +• Pulmonary cavities contain huge numbers of organisms. +EPIDEMIOLOGY +• M. +• Almost a ll infections are due to inhalation of droplet nuclei. +• Greatest case rates are in countries heavily affected by AIDS. +• Drug r esistance can be primary or secondary. +• Transmission of XDR-TB is of immense concern. +IMMUNOLOGY AND PATHOGENESIS +• Infection requires a cellular immune response. +• Granulomas form when antigen load is small and tissue hypersensitivity is high. +• Age infl uences likelihood and pattern of disease. +TUBERCULIN SKIN TESTING AND INTERFERON-γ +RELEASE ASSAYS +• To det ect latent M. +tuberculosis inf ection, a positive skin test is defined by induration. +• Interferon-γ release assays may be used instead of skin testing. +DIAGNOSIS +• Culture is the gold standard. +• Liquid broth cultures require 1 to 3 weeks to detect organisms. +• Nucleic acid amplification tests have sensitivities and specificities that approach culture. +• Three sputum specimens increase sensitivity. +• Pulmonary tuberculosis can occur in persons with normal chest radiographs. +• At least 6 months of therapy is usually required. +• Directly observed therapy is crucial. +• Susceptibility testing is important to guide therapy. +• With appropriate chemotherapy, patients become noninfectious within 2 weeks. +• Treatment of XDR-TB is usually associated with poor outcomes. +• Bedaquiline is a recently approved drug for MDR-TB. +For adults weighing more than 50 kg, the dose of both drugs is 900 mg +once a week. +PREVENTION +• Case finding and treatment is the most effective method of tuberculosis control. +N95 masks are used for health care +workers. +‡Five-day-a-week administration is always given by directly observed therapy. +§Not recommended for HIV-infected patients with CD4+ cell counts <100 cells/mm3. +Modified from Centers for Disease Control and Prevention. +Treatment of tuberculosis. +American Thoracic Society, +CDC and Infectious Diseases Society of America. +MMWR Recomm Rep. +2003;52(RR-11):1-88. +Overdose may be +fatal. +Aluminum-containing antacids +reduce absorption. +Pyridoxine (vitamin B6) +may decrease peripheral neuritis and CNS +effects. +CDC no longer recommends +routine monitoring tests. +However, many clinicians +continue to order baseline +CBC, platelets, hepatic +enzymes. +Repeat if baseline +abnormal, risk factors for +hepatitis or symptoms of +adverse reactions. +Interaction with many drugs leads to +decreased levels of one or both. +May +make glucose control more difficult in +diabetics. +Contraindicated for patients +taking PIs and some NNRTIs. +Women on +birth control pills need a barrier method +while on rifampin. +Treat increased uric acid only if +symptomatic. +Most common reason for +TB patients experiencing GI upset. +Tablets: 100 mg and +400 mg +Optic neuritis may be unilateral; check +each eye separately. +Not recommended +for children too young to monitor vision +unless drug resistant. +Use lowest possible +dose in range (except for drug-resistant +patients). +EMB should be discontinued +immediately and permanently for any +signs of visual toxicity. +With +increased rifabutin levels, severe arthralgias, +uveitis, leukopenia occur. +Baseline hepatic enzymes. +Capsules: 150 mg Patients on methadone may need an +increased dose to avoid opiate +withdrawal. +Interaction with many drugs +leads to decreased levels of one or both. +May make glucose control more difficult +in diabetics. +Women on birth control pills +need to use a barrier method while on +rifabutin. +In combination with NNRTIs or PIs, +dosages change significantly. +Overdose may be +fatal. +Aluminum-containing antacids +reduce absorption. +Pyridoxine (vitamin B6) +may decrease peripheral neuritis and CNS +effects. +CDC no longer recommends +routine monitoring tests. +However, many clinicians +continue to order baseline +CBC, platelets, hepatic +enzymes. +Repeat if baseline +abnormal, risk factors for +hepatitis or symptoms of +adverse reactions. +Interaction with many drugs leads to +decreased levels of one or both. +May +make glucose control more difficult in +diabetics. +Contraindicated for patients +taking PIs and some NNRTIs. +Women on +birth control pills need a barrier method +while on rifampin. +Treat increased uric acid only if +symptomatic. +Most common reason for +TB patients experiencing GI upset. +Tablets: 100 mg and +400 mg +Optic neuritis may be unilateral; check +each eye separately. +Not recommended +for children too young to monitor vision +unless drug resistant. +Use lowest possible +dose in range (except for drug-resistant +patients). +EMB should be discontinued +immediately and permanently for any +signs of visual toxicity. +With +increased rifabutin levels, severe arthralgias, +uveitis, leukopenia occur. +Baseline hepatic enzymes. +Capsules: 150 mg Patients on methadone may need an +increased dose to avoid opiate +withdrawal. +Interaction with many drugs +leads to decreased levels of one or both. +May make glucose control more difficult +in diabetics. +Women on birth control pills +need to use a barrier method while on +rifabutin. +In combination with NNRTIs or PIs, +dosages change significantly. +Baseline hepatic enzymes, +CBC, and platelets. +Administered +once weekly with INH +during the continuation +phase of treatment. +See drug interactions with rifampin. +†In 2003, the CDC recommended dosing based on weight ranges for PZA and EMB. +Modified from the 2007 Maryland Guidelines for Prevention and Treatment of Tuberculosis. +Available at http://phpa.dhmh.maryland.gov/OIDPCS/CTBCP/CTBCPDocuments/tbguidelines.pdf. +Renault and Joel D. +• Clinical manifestations vary significantly, depending on the subtype of disease. +• Peripheral sensory nerve damage (mediated directly by M. +372 +Part +  +II +  Infectious +  +Diseases +  +and +  +their +  +Etiologic +  +Agents +• M. +Alternative +agents include ofloxacin, minocycline, and clarithromycin. +• Recommended treatment courses vary based on subtype of disease and resources available. +Although both the WHO and NHDP recommend multiple drug therapy, the U.S. +• Choice of therapy for reversal reactions should be made based on the severity of disease. +Multiple drug therapy should always be +continued in patients presenting with reactions. +373 +182  Mycobacterium avium Complex +Fred M. +Gordin and C. +Robert Horsburgh, Jr. +• MAC is found in water, soil, and animals but not spread from person to person. +• The source from which patients acquire the disease is usually unknown. +• MAC causes pulmonary disease, lymphadenitis, and disseminated disease. +• Lymphadenitis is mostly in children younger than 5 years of age. +It can closely mimic tuberculosis. +Diagnosis requires a triad of clinical symptoms, radiographic abnormalities, and culture. +• Lymphadenitis is usually cervicofacial, unilateral, and painless. +Diagnosis is via lymph node +aspiration or excision. +• Disseminated disease is usually accompanied by fever, weight loss, and night sweats. +Diagnosis is made in more than 90% of patients by blood cultures for M. +avium complex +(MAC). +More advanced disease may require the addition +of aminoglycosides, usually amikacin. +These +individuals should have antiretroviral therapy initiated after 2 to 4 weeks. +Immune reconstitution inflammatory syndrome +may complicate recovery. +This can be stopped once sustained +CD4+ cell counts above 100/mm3 have occurred. +*Oral dosing unless otherwise indicated. +Am J Respir Crit Care Med. +2007;175:367-416. +Brown-Elliott and Richard J. +Wallace, Jr. +• NTM in clude pathogens and nonpathogens. +MICROBIOLOGY +• Acid-fast bacilli (AFB) stain poorly with Gram staining. +• They r equire 7 to 10 days to reach mature growth. +• Most s pecies except M. +DIAGNOSIS +Pulmonary +• Signs a nd symptoms of NTM lung disease are variable and nonspecific. +Less frequently malaise, dyspnea, fever, hemoptysis, and weight loss +may o ccur. +• Follow t he American Thoracic Society guidelines for diagnosis. +• High-resolution chest computed tomography is useful. +• Routine chest radiographs are recommended. +• Single p ositive sputum cultures are not definitive for NTM disease. +• Expert consultation is required for patients with infrequently encountered species of NTM. +dep ending on the site of infection. +abscessus or M. +abscessus s ubsp. +massiliense. +• Antimicrobial therapy alone is generally unsuccessful for microbiologic eradication of +M. +abscessus. +abscessus. +The role of inhaled amikacin is not yet +established. +• Patients with M. +• Macrolides may not be useful for isolates of M. +abscessus (b ut n ot M. +• Other a ntimicrobials are often useful for species other than M. +• Rifampin, rifabutin, ethambutol, and isoniazid are not effective. +• Other a ntimicrobials often useful for species of the M. +fortuitum g roup a re minocycline, +doxycycline, TMP-SMX, quinolones, linezolid, and, for M. +chelonae, t obramycin. +Intermediately Growing Mycobacteria +• M. +marinum is f ound on skin and in soft tissue infections (usually hands). +• Patients are generally treated for 12 months of culture negativity. +PREVENTION +• No e vidence of person-to-person spread of NTM exists. +• Tap (h ousehold) water is considered the major reservoir for most common NTM species. +• Biofilms may render NTM less susceptible to disinfectants and antimicrobials. +• Public h ealth concerns are increasing. +378 +184  Nocardia Species +Tania C. +Sorrell, David H. +Mitchell, Jonathan R. +Iredell, +and Sharon C-A. +asteroides co mplex. +• Infection arises by direct inoculation through the skin or by inhalation. +• Mycetomas from Nocardia s pecies, m ost often caused by N. +brasiliensis, a ffect imm unocom- +petent h osts in tropical countries. +cyriacigeorgica, N. +nova, or +N. +farcinica. +Isolated CNS lesions also occur and their presentation can be insidious. +Modified acid-fast stain of sputum or pus is helpful in suggesting the diagnosis. +Growth of +Nocardia s pecies m ay take 48 hours to several weeks but usually 3 to 5 days. +• Prolonged therapy is necessary to prevent relapse. +TABLE 184-1  Antimicrobial Susceptibility of Selected Nocardia Species +N. +cyriacigeorgicaN. +farcinicaN. +nova complexN. +transvalensis complexN. +Data taken from multiple published sources. +380 +185  Agents of Actinomycosis +Thomas A. +Patterson +DEFINITION +• Aspergillosis is caused by species of the mold Aspergillus. +MICROBIOLOGY +• Culture-based diagnosis is useful to establish the specific diagnosis. +• Molecular analysis is required to establish species-level identity. +DIAGNOSIS +• Proven infection is established by culture of the organism. +• Serial assessment of biomarkers may be useful for measuring response to therapy. +THERAPY +• Voriconazole is recommended for primary therapy in most patients (see Table 186-3). +• The r isk-benefit ratio of prophylaxis in individual patients at risk should be considered. +Clin Infect Dis. +2010;50:1091-1100. +Neofytos D, Treadway S, Ostrander D, et al. +Transpl Infect Dis. +2013;15: +233-242. +Steinbach WJ, Marr KA, Anaissie EJ, et al. +Clinical epidemiology of 960 patients with invasive aspergillosis from +the PATH Alliance registry. +J Infect. +2012;65:453-464. +Pappas PG, Alexander BD, Andes DR, et al. +Clin Infect Dis. +2010;50: +1101-1111. +Singh N, Paterson DL. +Aspergillus infections in transplant recipients. +Clin Microbiol Rev. +2005;18:44-69. +Neofytos D, Fishman JA, Horn D, et al. +Transpl Infect Dis. +2010;12:220-229. +Baddley JW, Andes DR, Marr KA, et al. +Factors associated with mortality in transplant patients with invasive asper- +gillosis. +Clin Infect Dis. +2010;50:1559-1567. +Invasive aspergillosis: disease spectrum, treatment practices, and +outcomes. +I3 Aspergillus Study Group. +Medicine (Baltimore). +2000;79:250-260. +Alastruey-Izquierdo A, Mellado E, Cuenca-Estrella M. +Ann N Y Acad Sci. +2012;1273:18-24. +Balajee SA, Kano R, Baddley JW, et al. +J Clin Microbiol. +2009;47:3138-3141. +Sutton DA, Fothergill AW, Rinaldi MG, eds. +Guide to Clinically Significant Fungi. +Baltimore: Williams & Wilkins; +1998. +Some experts advise +oral dosing as 4 mg/kg +(PO) q12h. +Kontoyiannis and Russell E. +• Conidiobolus coronatus a nd Conidiobolus incongruus c ause co nidiobolomycosis. +Basidiobolus +ranarum c auses b asidiobolomycosis. +Cultures have a poor sensitivity. +TREATMENT +• Lipid f ormulations of amphotericin B are the drug of choice. +Some patients can then be +transitioned to oral posaconazole if absorption is adequate. +386 +188  Sporothrix schenckii +John H. +Rex and Pablo C. +Secondary lesions along lymphangitic channels are +characteristic. +Biopsy will show pyogranulomas without visible organisms; culture will be +positive. +• The m ost common extracutaneous form is osteoarticular. +Pulmonary disease (usually cavi- +tary) a nd m eningeal disease are also well described. +• Serodiagnostic methods remain experimental. +• Itraconazole is also active in extracutaneous disease, but extended therapy may be required. +In diffic ult s ettings, amphotericin B is also employed. +387 +189  Agents of Chromoblastomycosis +Duane R. +MICROBIOLOGY +• M. +• N. +• Culture of causative agent from grains can better direct selection of antimicrobial therapy. +THERAPY +• Small lesions may be treated successfully with surgical excision alone. +• Actinomycetoma is typically treated with medical therapy alone. +• Eumycetoma commonly requires combined medical and surgical therapy. +• No sin gle therapy has proved most effective for either form of mycetoma. +• Most ac tinomycetoma regimens include parenteral aminoglycosides and oral sulfa drugs. +PREVENTION +• No vaccine is available. +• Use o f f ootwear and proper protective clothing should protect against this infection. +390 +191  Cryptococcosis (Cryptococcus +neoformans and +Cryptococcus gattii) +John R. +TAXONOMY +• There are 19 cryptococcal species with two major pathogenic species, C. +neoformans and +C. +gattii. +• At present, the following taxonomic divisions have been proposed: Cryptococcus neoformans +var. +grubii (serotype A), with three genotypes (VNI, VNII, VNB); Cryptococcus neoformans +var. +neoformans (serotypes A and D) found in pigeon guano to rotting trees +• C. +• Other sites with unique considerations are the skin, prostate, peritoneum, and eye. +• Cryptococci can infect any organ of the human body. +• Direct antifungal drug resistance uncommonly arises during therapy. +Finally, a suppressive phase is begun with fluco- +nazole 200 mg once daily. +*Immunosuppressive therapy may account for the predisposition. +†Diabetes mellitus has historically been considered a risk factor for cryptococcal infection. +Modified from Casadevall A, Perfect JR. +Cryptococcus neoformans. +Washington, DC: ASM Press; 1998:410. +Cryptococcus neoformans. +Washington, DC: ASM Press; 1998:409. +393 +192  Histoplasma capsulatum +(Histoplasmosis) +George S. +Deepe, Jr. +• Indigenous cases have been reported worldwide. +• The fungus thrives in decaying bird guano (starlings and blackbirds) and bat guano. +MICROBIOLOGY +• The fungus exists in the mycelial form in nature. +• The mycelia produce two sizes of conidia—micro and macro. +• Conversion to the yeast phase is driven by temperature. +DIAGNOSIS +• Serology is useful for all but AIDS patients. +Complement-fixation titers of 1 : 32 or greater +are indicative of active disease. +The presence of the H immunodiffusion band signifies active +disease. +An M band does not discriminate between current or remote infection. +It is also useful for following response to therapy. +• Tissue and buffy coat examination is useful for detecting the organism. +• See Table 192-1 for diagnostic tests. +Moderate to severe As above. +Serum or urine antigen, or both, also may  +be positive in up to 70%. +Bronchoalveolar fluid  +antigen may be useful. +Culture of bronchoalveolar  +lavage fluid and silver stain of concentrated lavage  +fluid. +Sputum culture. +Chronic cavitary H and M bands and complement fixation. +Culture   +of br onchoalveolar lavage fluid and silver stain of  +concentrated lavage fluid. +Sputum cultures. +Disseminated +Acute Serum or urine antigen, or both. +H and M bands and  +complement fixation. +These are not useful in AIDS  +patients. +Examination of the buffy coat for yeast cells  +in phagocytes. +Biopsy of bone marrow or liver with  +silver stain and culture. +Blood culture. +Chronic Serum or urine antigen, or both. +H and M bands and  +complement fixation. +Biopsy of tissue with silver stain  +and cultur e. +Central nervous system Serum or urine antigen, or both. +CSF antigen. +Culture  +of CSF. +H and M bands and complement fixation are  +not as useful. +Mediastinal +Lymphadenitis H and M bands and complement fixation. +Granuloma H and M bands and complement fixation. +Fibrosis H and M bands and complement fixation. +Rheumatologic Arthralgias H and M bands and complement fixation. +Pericarditis H and M bands and complement fixation. +Endocarditis/Endovascular H and M bands and complement fixation. +Serum or  +urine antigen, or both. +Culture and silver stain of  +valve. +AIDS, acquired immunodeficiency syndrome; CSF, cerebrospinal fluid. +For childr en, itraconazole 5-10 mg/kg or deoxycholate  +amphotericin B, 1 mg/kg daily. +Total  +duration = 3 mo. +Serum levels should be  +monitored to ensure adequate concentrations. +Mediastinal +Lymphadenitis No tr eatment. +If symptomatic (e.g., dysphagia), itraconazole  +200 mg twice daily for 12 wk. +Corticosteroids (60 mg with a  +rapid taper) may be used to diminish lymph node size. +Granuloma Same as lymphadenitis. +Corticosteroids are not necessary. +Fibrosis Surgical intervention with stents. +Antifungals are not useful. +Rheumatologic Arthralgias, etc. +Nonsteroidals +Pericarditis Nonsteroidals or corticosteroids. +Data fr om Wheat LJ, Freifeld AG, Kleiman MB, et al. +Clin Infect Dis. +2007;45: +807-825. +396 +193  Blastomycosis +Robert W. +Bradsher, Jr. +Brain abscess or meningitis Amphotericin B as above until improved. +*Total duration of therapy at least 6 months. +398 +194  Coccidioidomycosis +(Coccidioides Species) +John N. +EPIDEMIOLOGY +• Coccidioidomycosis is endemic to arid regions of the Western Hemisphere. +• Approximately 150,000 new U.S. +infections occur annually with 60% originating in Arizona +and 30% in California. +Of these, 50,000 produce significant illness. +• Patients with diabetes are more likely to suffer pulmonary complications. +• Dissemination is frequent in patients with impaired cellular immunity. +immitis. +immitis p redominantly found in California +and C. +posadasii in a ll o ther endemic regions. +• On m ost laboratory media, growth by apical mycelial elongation is visible within a week. +Sequence a nalysis indicates that Coccidioides is an a scomycete. +Treatment would normally be continued for at least 1 +year. +• In s ome patients, surgery is essential in addition to antifungal drugs to control infection. +This treatment is lifelong for all patients. +Patients who develop +hydrocephalus usually require the placement of an internal ventricular shunt. +PREVENTION +• A p reventive vaccine for coccidioidomycosis is not available. +400 +195  Dermatophytosis (Ringworm) +and Other Superficial Mycoses +Roderick J. +Other superficial infections are +caused by Candida and Malassezia spp. +or less common organisms (e.g., Piedraia). +Less commonly, other +mold fungi (e.g., Scytalidium) are implicated. +DIAGNOSIS +• Direct microscopy of the skin and culture is diagnostic. +Molecular diagnostic techniques are +in development. +THERAPY +• Topical treatments include azole antifungal agents and terbinafine. +Selenium sulfide and zinc +pyrithione have specific activity against Malassezia. +A new species, Paracoccidioides lutzii, +has been recognized within P. +brasiliensis and also causes paracoccidioidomycosis. +• Paracoccidioides spp. +are thermally dimorphic fungi, identified by multiple-budding yeast +cells (pilot’s wheel). +• These fungi exhibit slow mycelial growth for more than 20 days at 22° to 24° C. +The yeast +form appears ±10 days at 36° to 37° C. +• Direct microscopy and histopathology allow prompt diagnosis. +• These fungi are restricted to Latin American countries in unknown habitats. +• The largest endemic areas are found in Brazil. +• Most patients are males and work (or have worked) in agriculture within the endemic areas. +Multiple skin and mucosal lesions occur in half of the cases. +Adrenal lesions with adrenal insufficiency are +common. +Lack of physicians’ awareness is a problem. +• Lung imaging studies are essential in adult patients. +Healing by fibrosis creates serious +complications. +• In tissues, granuloma formation is an important clue to diagnosis. +Budding yeast cells are +found in lesions. +• Serology shows that anti–P. +brasiliensis antibodies are detectable in most patients. +Quantitative +tests allow treatment follow-up. +Antigen determination also is useful in certain patients. +• Human immunodeficiency virus comorbidity is uncommon. +This should be followed by oral medications. +• Regular follow-up observations (clinical, laboratory oriented) are mandatory. +*Shown only with the aim of guiding therapy. +404 +197  Uncommon Fungi +and Related Species +Duane R. +boydii (Scedosporium apiospermum) is a g roup of at least five species. +• Identification is typically made by identification of microscopic structures from culture. +Diagnosis +• Diagnosis is made by culture recovery from infected site. +• Because P. +boydii m ay co lonize airways, sputum cultures may not reflect infection. +Therapy +• Voriconazole is likely the most effective agent. +• S. +prolificans m ay c ause onychomycosis and infections of the eye and wounds. +Epidemiology +• Disseminated infection commonly occurs in the severely immunocompromised. +• Localized infection occurs in immunocompetent individuals after trauma. +• The o rganism can be found in soil and colonizing the respiratory tract. +Microbiology +• Identification is made by culture. +Diagnosis +• Diagnosis is made by culture recovery from the infected site. +• Because S. +prolificans m ay co lonize airways, sputum cultures may not reflect infection. +Therapy +• No eff ective therapy. +Consider voriconazole with amphotericin B. +Epidemiology +• Infection is commonly acquired from minor trauma or inhalation. +• Fungi a re found in soil, organic material, plants, and air. +• They m ay be spread through contaminated products (e.g., injectable steroids). +• Cell wa lls may appear dark brown or golden on histopathology (hematoxylin and eosin). +Use o f a F ontana-Masson stain may allow easier identification of these fungi. +solani is t he m ost common pathogen, although other species may also cause infection. +• Fusarium p roduces b anana- (or crescent)-shaped multicellular macroconidia in culture. +• Recovery from neutropenia is essential in response to therapy of disseminated infection. +• Amphotericin B or voriconazole is suggested. +TRICHOSPORON SPP. +asahii. +Therapy +• Corticosteroids appear to be useful. +wickerhamii or P. +zopfii. +• Unicellular algae lack chlorophyll. +• Prototheca s pp. +g row on fungal culture media with yeastlike colonial morphology. +• Microscopic appearance in tissue is diagnostic. +Diagnosis +• Recovery of algae in culture is diagnostic. +• Yeast b iochemical panels commonly identify Prototheca. +Diagnosis +• Recovery of the organism from culture is diagnostic. +• Local s erologic testing may be available. +Therapy +• Can p erform surgical resection or amputation. +• No s atisfactory medical therapy is known. +• Doxycycline, minocycline, tigecycline, linezolid, and macrolides have activity in vitro. +Walzer, A. +George Smulian, and Robert F. +Miller* +DEFINITION +• Pneumocystis spp. +EPIDEMIOLOGY +• Infection is acquired by inhalation of the cyst form of the organism. +• Primary infection occurs in the first 2 years of life in most people. +• Environmental factors influence PCP hospitalizations. +• Colonization is common, associated with obstructive airway disease. +• Several alternative regimens are available depending on the severity of PCP. +• Prednisone is mainly indicated for HIV-positive patients. +• Alternative regimens are available. +412 +199  Microsporidiosis +Louis M. +Weiss +DEFINITION +• Microsporidia are obligate eukaryotic intracellular pathogens related to fungi. +• Taxonomy of the phylum is based on ultrastructural descriptions of the spores and life cycle. +• Molecular phylogeny, based on rRNA sequences, is also utilized for classification. +• Microsporidiosis occurs in both immunocompromised and immune-competent hosts. +• These p athogens can be transmitted by food or water and are likely zoonotic. +• Species-specific diagnosis is useful for guiding treatment. +• Topical f umagillin is useful for microsporidian keratoconjunctivitis. +histolytica, +which is the cause of amebic colitis, liver abscess, and, rarely, brain abscess; E. +moshkovskii, +which causes diarrhea; and E. +dispar, which is nonpathogenic. +• Most infections are in impoverished communities in the developing world. +• Amebic liver and brain abscess occur 90% of the time in young men. +• E. +histolytica is a common cause of diarrhea in returning international travelers. +MICROBIOLOGY +• Cyst form is infectious, environmentally stable, and resistant to chlorination. +• Trophozoite is the tissue-invasive stage. +PREVENTION +• Prevention is accomplished by sanitation and clean water. +• Vaccine is under development. +Nitazoxanide  +may be effective therapy as well, but clinical experience is limited. +†Drug of choice for treatment of amebic liver abscess. +‡Amebic colitis may necessitate antiparasitic treatment plus surgical treatment. +Modified from Haque R, Huston CD, Hughes M, et al. +Current concepts: amebiasis. +N Engl J Med. +2003;348: +1565-1573. +415 +201  Free-Living Amebae +Anita A. +Koshy, Brian G. +The trophozoite stages of these organisms feed on bac- +teria a nd de bris in the environment. +• Acanthamoeba s pp. +a re u biquitous members of the environment and are found worldwide +in s oil a nd f resh water. +CLINICAL MANIFESTATIONS AND DIAGNOSIS +• N. +The disease is nearly +always fa tal. +• The cer ebrospinal fluid (CSF) profile of patients with N. +Motile +trophozoites can sometimes be seen on wet mount of the CSF. +• Neuroimaging studies in patients with PAM are usually nonspecific. +• Acanthamoeba s pp. +a nd B. +The case-fatality rate for these infections is also high. +• Acanthamoeba s pp. +a nd B. +mandrillaris c an in volve other sites (lungs, sinuses, adrenals, and +skin). +• Acanthamoeba s pp. +• Treatment for N. +However, the +most effic acious regimen is not currently known. +• B. +However, the most efficacious regimen is not currently +known. +• Surgical débridement may play an adjunctive role in the management of both forms of GAE. +417 +202  Malaria (Plasmodium Species) +Rick M. +Fairhurst* and Thomas E. +Wellems +DEFINITION +• The history of travel and exposure in a malaria-endemic area is typical. +• Malaria is transmitted by the bite of a female Anopheles mosquito. +MICROBIOLOGY +• Plasmodia are parasitic protozoa of the Apicomplexa phylum. +• Rapid diagnostic tests are available (e.g., BinaxNOW in the United States). +• Uncomplicated malaria due to: +• Chloroquine-sensitive P. +vivax, P. +ovale, +P. +malariae, and P. +falciparum (most areas of the world) or chloroquine-resistant +P. +418 +Part +  +II +  Infectious +  +Diseases +  +and +  +their +  +Etiologic +  +Agents +• Prevent relapsing P. +vivax a nd P. +DIAGNOSIS +• Giemsa s tain, culture, and polymerase chain reaction assay are performed. +TREATMENT +• Treatment of skin lesions includes topical, oral, and systemic regimens. +MICROBIOLOGY +• T. +• T. +• Infection with T. +cruzi in humans is lifelong. +• The infection is not endemic in any of the Caribbean islands. +• About 8 million persons are chronically infected with T. +An estimated 300,000 +immigrants with Chagas’ disease currently live in the United States. +• Chronic cardiac Chagas’ disease typically involves rhythm disturbances and cardiomyopathy. +• Gastrointestinal problems can include megaesophagus and megacolon. +• Immunosuppression of persons who harbor T. +cruzi chronically can result in life-threatening +reactivation of the infection. +*All material in this chapter is in the public domain, with the exception of borrowed figures. +• Chronic T. +THERAPY +• Nifurtimox and benznidazole are the only two drugs available for treating T. +cruzi inf ections +(available f rom the Centers for Disease Control and Prevention Drug Service). +PREVENTION +• No vaccine or prophylactic drugs are available for reducing transmission of T. +cruzi. +422 +205  Agents of African +Trypanosomiasis +(Sleeping Sickness) +Louis V. +The flies become infected when they take a blood meal from an infected mammal. +• HAT is much less of a problem today than in the past. +Fewer than 10,000 new cases are +reported annually to the World Health Organization. +CLINICAL MANIFESTATIONS +• Two clinical stages exist. +Stage 1 (hemolymphatic disease) is characterized by fever, adenopa- +thy, and headache. +• Untreated HAT almost inevitably ends in death. +*All material in this chapter is in the public domain, with the exception of borrowed figures. +• A defini tive diagnosis of African trypanosomiasis requires demonstration of the parasite. +• Toxicity of the drugs used to treat HAT is a major problem. +424 +206  Toxoplasma gondii +José G. +Montoya, John C. +Boothroyd, +and Joseph A. +Less commonly, there is congenital transmission or trans­ +plantation of an infected organ. +Retinochoroiditis can occur after congenital infection or recently acquired +infection. +MICROBIOLOGY +• Toxoplasma organisms are exclusively intracellular. +The sexual phase occurs in felines. +Excreted oocysts require 1 to 5 days to become infectious. +Tachyzoites actively replicate in +essentially all cell types. +Tissue cysts with intracystic bradyzoites maintain organism viability +during latent infection. +• Multiple strains are identified by genotyping. +• HIV­infected patients usually present with focal neurologic symptoms. +• Immunodeficient patients present with encephalopathy, seizures, pneumonia, and fever. +Diagnosis i s based on positive PCR or histopathology. +High +relapse ra te occurs without ART and maintenance therapy. +Food +and Dr ug A dministration) until delivery. +Before 14 to 18 weeks of +gestation, g ive no pyrimethamine or leucovorin. +TMP­SMX, one double­strength tablet every +3 d ays, c an prevent relapse. +F or HSCT recipients, start TMP­SMX after engraftment. +426 +207  Giardia lamblia +David R. +Hill and Theodore E. +EPIDEMIOLOGY +• Giardia is one of the most widely distributed enteric parasites. +• In low-income countries, Giardia infects nearly all children by the age of 10 years. +Animals typically +harbor other assemblages. +• Stool examination for ova and parasites is the traditional method of diagnosis. +Polymerase chain reaction assay is becoming more widely used +and can identify the assemblage. +THERAPY +• Tinidazole is the drug of choice, taken in a single dose (see Table 207-1). +• Alternatives are metronidazole, nitazoxanide, and albendazole. +• Potential adverse events associated with treatment should be discussed with the patient. +• Treatment during pregnancy requires special considerations. +• Post-Giardia lactose intolerance should be considered if treatment appears to fail. +Food and Drug Administration; NC, not categorized. +†Not an FDA-approved indication. +‡No longer produced in the United States; may be obtained from some compounding pharmacies. +428 +208  Trichomonas vaginalis +Jane R. +Schwebke +MICROBIOLOGY AND EPIDEMIOLOGY +• Trichomonas vaginalis is a fl agellated parasite. +• Infection is through sexual transmission. +• Susceptibility to human immunodeficiency virus (HIV) infection may be increased. +• Gold s tandard for diagnosis is nucleic acid amplification testing. +THERAPY +• Metronidazole is the usual therapy. +• Resistance to metronidazole may occur. +• Tinidazole may be more effective. +PREVENTION +• Sexual p artners should be treated. +• Condoms prevent infection. +429 +209  Babesia Species +Jeffrey A. +Gelfand and Edouard G. +• B. +Transplacental transmission is rare. +DIAGNOSIS +• Fever is the salient symptom. +Chills and sweats are common. +Less frequent symptoms include +headache, myalgia, anorexia, arthralgia, and nausea. +• Diagnosis is made on Giemsa-stained thin blood smears. +Trophozoites often appear as rings. +Tetrads of merozoites are pathognomonic. +Serology confirms the +diagnosis. +Thrombocytopenia and elevated liver enzyme values are common. +THERAPY (SEE TABLE 209-1) +• Mild B. +Symptoms should be expected to abate within 48 hours and to resolve within +3 months. +• Severe B. +microti illness requires hospitalization. +Despite therapy, half of +hospitalized patients develop complications and about 10% die. +PREVENTION +• No vaccine is available. +Individuals at risk should avoid highly endemic areas. +IV, intravenously; PO, orally; RBC, red blood cell. +*Treatment for 7 to 10 days, but duration may vary. +With this regimen, symptoms and parasitemia resolve faster. +431 +210  Cryptosporidiosis +(Cryptosporidium Species) +A. +Clinton White, Jr. +DEFINITION +• Cryptosporidiosis is caused by infection with oocysts of Cryptosporidium s pecies. +• The m ajor species, Cryptosporidium hominis, p rimarily infects humans. +• Zoonotic species, including Cryptosporidium parvum, a re a lso co mmon in humans. +MICROBIOLOGY +• Cryptosporidium s pecies a re apicocomplexan protozoan parasites. +CLINICAL MANIFESTATIONS +• Most p atients present with diarrhea that is frequently prolonged. +PREVENTION +• Water t reatment and hand hygiene are key measures to prevent infection. +Suh, Phyllis Kozarsky, and Jay S. +• Contaminated food and water are primary sources. +• Oocysts can survive in environment for months but must sporulate to become infective. +• Oocysts in stool may be visualized using modified acid-fast stain. +• Multiple stool examinations may be required. +• Sarcocystis suihominis and Sarcocystis hominis are the main causes of human disease. +Diagnosis +• Infection is generally asymptomatic. +• Sporocysts or oocysts may be visible in stool; muscle biopsy may be required. +Therapy +• None; albendazole has been used. +• Cysts in contaminated food or water are infective. +Diagnosis +• The infection is generally asymptomatic; occasionally a diarrheal illness is reported. +• Trophozoites are visible in stool. +Therapy +• Tetracycline, metronidazole, or iodoquinol is used (see Table 211-3). +• Microscopic diagnosis is challenging; trichrome stain is the most sensitive. +• Polymerase chain reaction assay is more sensitive and specific but not widely available. +Therapy +• Therapy is often unsatisfactory. +• Trimethoprim-sulfamethoxazole, metronidazole, or iodoquinol is used (see Table 211-4). +*Drugs are listed in order of preference. +†One DS tablet contains 160 mg trimethoprim/800 mg sulfamethoxazole. +*Drugs are listed in order of preference. +†One DS tablet contains 160 mg trimethoprim/800 mg sulfamethoxazole. +*Drugs are listed in order of preference. +*Drugs are listed in order of preference. +†One DS tablet contains 160 mg trimethoprim/800 mg sulfamethoxazole. +435 +I  Diseases Due to Toxic Algae +212  Human Illness Associated  +with Harmful Algal Blooms +J. +Glenn Morris, Jr. +212-1). +DIAGNOSIS +• Diagnosis is based on clinical presentation (see Table 212-1). +THERAPY +• Therapy is supportive. +PREVENTION +• Prevention is based on avoidance of fish or shellfish that contain toxins. +Microcystins (??) +Pfiesteria- +associated +syndrome +Pfiesteria spp. +coast. +(From U.S. +• Ascaris and Trichuris (whipworm) are acquired by ingestion of contaminated soil. +• Strongyloides and hookworms (Ancylostoma, Necator) are acquired by exposure to larvae in +soil. +The duration of infection is the lifespan +of adult worms, usually less than a few years. +• Pinworms are common in all parts of the world, particularly in children. +†Drug of choice. +THERAPY +• Anthelmintic drugs are available for many infections. +Corticosteroids and mebendazole are sometimes utilized in severe disease. +• Diethylcarbamazine is also used to treat tropical pulmonary eosinophilia and loiasis. +• Ivermectin is used to treat onchocerciasis. +440 +215  Trematodes (Schistosomes and +Liver, Intestinal, and Lung Flukes) +James H. +†Not available or limited availability. +‡Alternative drug. +Food and Drug +Administration. +¶Limited data. +King and Jessica K. +• Hymenolepis nana is the most common tapeworm worldwide and transmitted person to +person. +• Taenia saginata (beef tapeworm) occurs in cattle-breeding areas of the world. +MICROBIOLOGY +• Mature tapeworms reside in intestines of carnivorous animals. +• Echinococcosis is diagnosed by typical scan imagery and supported by serology. +THERAPY +• Mainstay of therapy for intestinal tapeworms is praziquantel or niclosamide. +• Neurocysticercosis therapy depends on the location and stage of the cyst. +• Livestock at market or slaughterhouse should be screened for cysts. +• Dogs s hould be screened and treated to eliminate Echinococcus granulosus. +• Prolonged freezing or thorough cooking will kill cysts in tissue. +Treatment +• Most patients recover without therapy. +Retinal detachment may also occur. +There +is no specific therapy. +446 +K  Ectoparasitic Diseases +218  Lice (Pediculosis) +James H. +capitis or corporis a nd +Phthirus pubis. +• Head lice afflict millions of people annually, mostly school-aged children. +B. +• Pharmacotherapy should begin with the least toxic pediculicides, such as pyrethrins. +• Topical or oral ivermectin preparations should be reserved for pyrethrin-resistant cases. +448 +219  Scabies +James H. +Diaz +DEFINITION +• Scabies i s an infestation by the itch or scabies mite Sarcoptes scabiei va r. +• Crusted or Norwegian scabies is highly transmissible in the hospital environment. +The entire incubation period from eggs to full-grown mites lasts 14 +to 15 d ays. +• Skin b iopsy may help confirm the diagnosis in atypical cases. +450 +220  Myiasis and Tungiasis +James H. +452 +221  Mites, Including Chiggers +James H. +• Both s crub typhus and rickettsialpox respond to treatment with oral doxycycline. +• There a re no vaccines for scrub typhus or rickettsialpox. +• Weekly doses of 200 mg of doxycycline can prevent O. +tsutsugamushi inf ections in endemic +regions. +453 +222  Ticks, Including Tick Paralysis +James H. +• Gravid t icks may also transmit paralytic salivary toxins during blood-feeding. +• New t ick-transmitted pathogenic species are constantly being described in the United States. +• The t ick-transmitted viral diseases can be managed only supportively. +454 +L  Diseases of Unknown Etiology +223  Kawasaki Disease +Jane C. +Coronary artery aneurysms develop in 25% of +untreated p atients. +EPIDEMIOLOGY +• KD a ffects children of all ethnicities worldwide. +Children of Asian and African-American +descent are disproportionately affected. +There is no evidence for person-to-person transmis- +sion. +T emporospatial clustering of cases has been observed. +ETIOLOGY +• The c ause of KD is unknown. +Coronary artery abnormalities are detected by transthoracic +echocardiography. +PREVENTION +• There i s no known intervention that can prevent KD. +Beekmann and David K. +• The majority of CLABSIs now occur in inpatient wards and outpatient hemodialysis centers. +aureus bacteremias have decreased. +• CLABSIs increasingly are caused by multiresistant gram-negative rods. +DIAGNOSIS +• Clinical markers show a poor correlation with intravenous device–related bacteremia. +• Blood culture results positive for coagulase-negative staphylococci, S. +• Chlorhexidine solutions should be used for skin preparation before catheter insertion. +• Maximal sterile barriers should be used during insertion of CVCs. +These signs +are n either s ensitive nor specific. +Stable oxygenation/ventilator settings +argue a gainst clinically significant disease. +Endotracheal aspirates are therefore +preferred. +Dr ug r esistance is common: 50% of S. +• Risk fac tors for methicillin-resistant S. +TREATMENT +• Initiate b road-spectrum antibiotics as soon as pneumonia is suspected. +Use vancomycin or +linezolid p lus two antipseudomonal agents for empiric therapy. +Consider a loading dose of +vancomycin 25 to 30 mg/kg for seriously ill patients. +Include anaerobic coverage if there is +frank a spiration. +• Narrow t reatment as soon as susceptibilities are available. +Avoid double coverage. +If cultures +are n egative and the patient is improving, trim or stop antibiotics. +• Vancomycin and linezolid are similarly effective for MRSA. +Dose vancomycin 15 to +20 m g/kg e very 8 to 12 hours. +The goal trough is 15 to 20 mg/L. +Daily procalcitonin monitoring can safely shorten the duration of antibiotics. +Vibrating +459 +Chapter 225 +  Nosocomial +  +Pneumonia +mesh p late i s preferred for delivery. +Data are sparse. +PREVENTION +• VAP ra tes are subjective and nonspecific. +Therefore, preferentially select interventions proven +to im prove concrete outcomes. +460 +226  Nosocomial Urinary +Tract Infections +Thomas M. +hospitals each year. +• The duration of catheterization is the most important risk factor for CA-bacteriuria. +• Funguria, mostly candiduria, is reported in 3% to 32% of catheterized patients. +• Recommended treatment duration for CA-UTI ranges from 7 to 21 days, depending on the +severity. +• Asymptomatic nosocomial candiduria rarely requires treatment. +• A closed catheter drainage system is indicated in all catheterized patients. +• Routine use of antimicrobial-coated urinary catheters is not supported by available data. +‡Pregnancy category B—no clear risk to fetus based on animal or human studies, or both. +Modified from Hooton TM. +Clinical practice. +Uncomplicated urinary tract infection. +N Engl J Med. +2012;366: +1028-1037. +462 +227  Health Care–Acquired Hepatitis +Kent A. +EPIDEMIOLOGY +• Transmission between patients and HCWs is rare, but the risk remains. +DIAGNOSIS +• Identification of an outbreak is difficult unless a cluster of cases occurs. +• Most in vestigations are identified in conjunction with public health authorities. +• Use o f a genotype to determine homology is useful in investigation. +• Hepatitis B: Treat all exposed nonimmune persons. +The role +of a ntivirals has not been determined. +Use a similar approach for exposed patients. +• Hepatitis C: Treat only if the exposed person has evidence of acute infection. +Use of currently +approved t herapies has not been studied in this context but is likely effective. +VACCINATION +• Hepatitis A vaccine is not routinely recommended for HCWs. +• Hepatitis B vaccine or formal declination is mandated for HCWs. +• No vaccine is available for HCV. +463 +228  Transfusion- and +Transplantation-Transmitted +Infections +Matthew J. +Kuehnert and Sridhar V. +MANAGEMENT OF FEBRILE NEUTROPENIA (SEE FIGS. +At onset of febrile neutropenia consider: +1. +2. +Type of center: knowledge of epidemiology of infections and susceptibility patterns. +If available, use a risk stratification system. +For antibiotic choice, consider the local resistance patterns. +Perform blood cultures (at least 3) and other cultures from sites of suspected infection. +In any case, use antibiotics active against gram-negatives. +Discontinue anti–gram-positive and antifungal drugs if these infections are not confirmed. +Adjust treatment according to isolated pathogens and the site of infection. +Serum galactomannan testing for 3 consecutive days +3. +4. +Blood cultures +5. +Bur den of illness: no or mild symptoms 5 +2. +No hypotension 5 +3. +No chr onic obstructive pulmonary disease 4 +4. +Solid tumor or no previous fungal infection 4 +5. +No dehydration 3 +6. +Outpatient status 3 +7. +Bur den of illness: moderate symptoms 3 +8. +Patient’ s  age <60 yr 2 +MASCC, Multinational Association for Supportive Care in Cancer. +Points attributed to the variable “burden of illness” are not cumulative. +The maximal theoretical score is therefore  +26. +Low-risk patient: score ≥21. +470 +230  Infections in Recipients +of Hematopoietic Stem +Cell Transplants +Jo-Anne H. +Young and Daniel J. +Palifermin may reduce mucositis. +Acute form usually occurs until day 100. +Chronic form generally occurs later and has features +resembling but distinct from scleroderma. +The risk is higher in the elderly and with grafts +from partially matched donors. +High-dose corticosteroids (and other agents) are used to treat +GVHD. +Alternatives include aerosolized pentamidine, atova- +quone, and dapsone. +• Penicillin VK: prevention against Streptococcus pneumoniae during active chronic GVHD. +Regional penicillin resistance may lead to the use of levofloxacin for this indication. +Entecavir or tenofovir may be substituted for lamivudine. +CMV reactivation might be +delayed, occurring later after +HSCT. +Foscarnet and cidofovir are acceptable alternatives. +Renal dose adjustment is required +for all antiviral agents. +‡Foscarnet, high-dose acyclovir, or valacyclovir are acceptable alternatives. +Renal dose adjustment required for all +antiviral agents. +Infections may also be donor derived. +TYPES OF INFECTIONS +• Bacterial infections are the most frequently occurring infections. +Bacteremia occurs in 5% +to 25% o f t ransplant recipients. +• Fungal infections occur in 0.7% to 23% of patients. +• Cytomegalovirus (CMV) is a major viral infection. +475 +232  Infections in Patients +with Spinal Cord Injury +Rabih O. +PREVALENCE AND ETIOLOGY +• SCI a ffects almost 1 per 1000 persons. +• Causes o f SCI include vehicular accidents, falls, violence, sports, and infection. +• Infection can cause or result from SCI. +• Intermittent catheterization is preferred to indwelling bladder catheters. +• Prevention is ineffective. +PNEUMONIA +• Pneumonia has the highest infection-related mortality. +• It o ccurs mostly in patients with tetraplegia. +INFECTION OF PRESSURE SORES AND BONE +• This di agnosis is very problematic. +• Multidisciplinary management is difficult and requires long and repeated hospital stays. +• These o rganisms are more prevalent in SCI units than in general hospital wards. +• Proper infection control measures reduce both colonization and infection. +476 +233  Infections in the Elderly +Kent B. +Crossley* and Phillip K. +• For nearly all infections, clinical manifestations are more subtle in the elderly. +URINARY TRACT INFECTION +• Asymptomatic bacteriuria should not be treated. +• Symptomatic infection is often caused by organisms other than Escherichia coli. +PNEUMONIA +• Pneumonia is common and often followed by death in the year after a pneumonic illness. +• Management of nursing home–associated pneumonia remains controversial. +• Immunization with influenza and pneumococcal vaccines is of significant but lesser benefit. +BACTEREMIA AND ENDOCARDITIS +• Both are more common in the elderly. +CENTRAL NERVOUS SYSTEM INFECTIONS +• Viral meningitis is uncommon in elderly individuals. +• A high-dose influenza vaccine is available for the elderly. +Recent studies have validated the safety of the vaccine. +477 +234  Infections in Asplenic Patients +Janet R. +• White b lood cell count may be elevated or depressed. +• Cerebrospinal fluid examination may be indicated in severe sepsis. +• Avoid s plenectomy if possible. +• Avoid v ectors that carry the parasites causing malaria, babesiosis, and anaplasmosis. +479 +235  Infections in Injection Drug Users +Donald P. +Levine and Patricia D. +• Infection with Staphylococcus aureus (p articularly community-acquired methicillin-resistant +S. +• Bacterial infection with S. +• Infection with S. +albi- +cans) h ave b een reported. +• Initial empirical therapy should be directed against S. +NONCARDIAC VASCULAR INFECTIONS +• Infection with S. +aureus is t he m ost common etiologic +agent. +• IDUs a re at increased risk for tetanus and wound botulism. +• Intravitreal antimicrobial agents with or without pars plana vitrectomy may be required. +482 +236  Surgical Site Infections and +Antimicrobial Prophylaxis +Thomas R. +• Causative organisms of SSI are predominantly the flora present at the incision site. +• Procedural factors include breaks in sterile technique, operating room ventilation, and traffic. +236-1). +236-2); consider higher dose for obese patients; +redose in prolonged procedures. +• Provide “right” duration of drug: stop once incision closed or by 24 hours at the latest. +SSI SURVEILLANCE +• SSI surveillance requires standardized definitions. +*Likely a surrogate marker for severity of underlying illness and comorbidities. +Modified from Mangram AJ, Horan TC, Pearson ML, et al. +Guideline for prevention of surgical site infection, +1999. +Hospital Infection Control Practices Advisory Committee. +Infect Control Hosp Epidemiol. +1999;20:250-278; +quiz 279-280. +Dynamics of tissue antibiotic con- +centration during the course of a surgical procedure. +A, Data from 2847 elective surgical patients. +B, Data from 3656 cardiac, orthopedic, and gynecologic +surgical patients. +(A from Classen DC, Evans RS, Pestotnik SL, et al. +N Engl J Med. +1992;326:281- +286. +B from Steinberg JP, Braun BI, Hellinger WC, et al. +Ann +Surg. +• The primary insult from a burn is the wound itself. +The total burn size is typi- +cally less than 10% of total body surface area (TBSA) in 72% of cases. +Department of the Army, the U.S. +Department of Defense, or +the federal government. +The author is an employee of the U.S. +government, and this work was performed +as part of official duties. +487 +238  Bites +Ellie J. +C. +Goldstein and Fredrick M. +DIAGNOSIS +• The diagnosis is made by the patient’s reported history of events. +• Plain radiographs should be obtained if there is a high likelihood of bony injury. +THERAPY +• Irrigate wounds with copious amounts of normal saline. +• Cautiously débride devitalized or necrotic tissue. +Follow rabies guidelines for details on management of bites that +carry a risk of rabies. +Culture +Aerobic and anaerobic cultures should be taken from infected wounds. +Irrigation +Copious amounts of normal saline should be used for irrigation. +Débridement +Devitalized or necrotic tissue should be cautiously débrided. +Wound Closure +Primary wound closure is not usually advocated. +For larger wounds, edges may be approximated with +adhesive strips in selected cases. +Immunizations +Provide tetanus and rabies immunization, if indicated. +Elevation +Elevation may be required if any edema is present. +Lack of elevation is a common cause of therapeutic +failure. +Reporting +Reporting the incident to a local health department may be required. +bid, two times a day; PO, orally; qid, four times a day; tid, three times a day. +• Provide t etanus and rabies immunization, as indicated. +TABLE 238-1  Management of Bite Wounds—cont’d +490 +D  Zoonoses +239  Zoonoses +W. +Ian Lipkin +DEFINITION +• A zo onosis is an infectious disease of humans that originates in animals. +DIAGNOSIS +• The m ajority of zoonotic diseases are diagnosed using molecular methods. +Thus, treatment is primarily supportive. +In contrast, many +bacterial zo onoses can be treated with antibiotics. +PREVENTION +• Vaccines are established for only a minority of zoonotic diseases. +491 +E  Protection of Travelers +240  Protection of Travelers +David O. +Ascertain which is best suited to the individual patient and +itinerary. +• E ducate on personal protection against arthropods. +TRAVELER’S DIARRHEA +• R ecommend food and water precautions. +493 +241  Infections in Returning Travelers +David O. +• Is malaria possible? +If there is end-organ damage, initiate empirical therapy. +• Are there localizing findings? +Go to syndromic approach and differential diagnosis. +• Are there no localizing findings? +see Antiretroviral therapy (ART). +aeruginosa, 34t-36t +for pertussis, 339 +for SFG rickettsioses, 258 +for trachoma, 250 +without P. +see Bronchoalveolar lavage (BAL). +see Banna virus (BAV). +Benzathine penicillin +for S. +see Catheter-associated urinary tract infection +(CA-UTI). +see Chronic fatigue syndrome (CFS). +see Cardiovascular implantable +electronic device (CIED) infections. +characteristics of, 362, 363t +other diseases associated with, 362 +Clostridium tetani, 360 +CMV. +see Cytomegalovirus (CMV). +see Coronaviruses (CoVs). +see Colorado tick fever virus (CTFV). +see Epstein-Barr virus (EBV). +see Trematodes. +see Human adenoviruses (HAdVs). +see Human African trypanosomiasis (HAT). +HAV. +see Hepatitis A virus (HAV). +HBoVs. +see Human bocaparvoviruses (HBoVs). +HBV. +see Hepatitis B virus (HBV). +HCMV. +see Human cytomegalovirus (HCMV). +HCV. +see Hepatitis C virus (HCV). +HDV. +see Hepatitis D virus (HDV). +see Hepatitis E virus (HEV). +HGA. +see Human granulocytotropic anaplasmosis +(HGA). +HHV-8. +see Human herpesvirus 8 (HHV-8). +see Human immunodeficiency virus (HIV). +HME. +see Human monocytotropic ehrlichiosis (HME). +hMPV. +see Human metapneumovirus (hMPV). +see Human parechoviruses (HPeVs). +HPV. +see Human papillomavirus (HPV). +HSV. +see Herpes simplex virus (HSV). +HTIG. +see Human tetanus immune globulin (HTIG). +HTLV. +see Human T-lymphotropic virus (HTLV). +see JC virus (JCV). +see Kawasaki disease (KD). +see Kyasanur Forest disease virus (KFDV). +see Kaposi’s sarcoma-associated herpesvirus +(KSHV). +see Lymphocytic choriomeningitis virus (LCMV). +see Lymphogranuloma venereum (LGV). +see Left ventricular assist device +(LVAD) infections. +see Middle East respiratory syndrome (MERS). +see Mother-to-child transmission (MTCT). +see Nucleic acid amplification test (NAAT). +see Pneumocystis pneumonia (PCP). +PCR. +see Polymerase chain reaction (PCR). +see Head lice. +Pediculosis corporis. +see Body lice. +see Parainfluenza viruses (PIV). +see Progressive multifocal leukoencephalopathy +(PML). +see Prosthetic vascular graft infections (PVGIS). +see Rocky Mountain spotted fever (RMSF). +see Respiratory syncytial virus (RSV). +RT-PCR. +see Reverse-transcriptase polymerase chain +reaction (RT-PCR). +hominis, 448 +SARS. +see Severe acute respiratory syndrome (SARS). +see Cestodes. +see Visceral larva migrans. +see Urinary tract infection (UTI). +see Ventilator-assisted pneumonia (VAP). +see Varicella-zoster immune globulin +(VariZIG). +see Vaccinia Immune Globulin Intravenous +(VIGIV). +see Vesicular stomatitis virus (VSV). +Vulvitis, 118 +Vulvovaginal candidiasis, 118 +treatment of, 156t-168t +Vulvovaginitis, 118 +VZV. +see Varicella-zoster virus (VZV); Varicella-zoster +virus (VZV) disease. +see Yellow fever (YF). +Content supplied +by Elsevier, the +world’s leading +provider of health +and science +information. +Start searching with ClinicalKey today! +Visit ClinicalKey.com for more information +and subscription options. +Smarter search. +Faster answers. +