Harrisons Principles of Internal Medicine Self-Assessment and Board Review 18th Ed.

SECTION XI. Neurologic Disorders

ANSWERS

XI-1. The answer is D. (Chap. 366) Channelopathies, disorders of ion channels that lead to disease, are a growing mechanism to explain a number of neurologic diseases. Most are caused by a mutation in the ion channel gene or by autoimmune alteration of ion channel proteins. Some forms of epilepsy, including benign neonatal familial convulsions and generalized epilepsy with febrile convulsions, are associated with genetic abnormalities of sodium or potassium channels. Familial hemiplegic migraines are associated with genetic abnormalities in sodium and calcium channels. Spinocerebellar ataxia and other ataxias are associated with genetic abnormalities in potassium or calcium channels. Lambert-Eaton syndrome is an example of autoimmune-related abnormalities in calcium channel function. Parkinson’s disease is the classic example of neurotransmitter system–mediated disease.

XI-2. The answer is C. (Chap. 366) Synaptic neurotransmission is the predominant mechanism for neuronal communication. Therefore, it is not surprising that dysfunction with any step in the presynaptic synthesis, vesicular storage, and synaptic cleft release, and receptor binding in the postsynaptic cell may be associated with disease. Neurotransmitters bind to specific receptors that are either ionotropic or metabotropic. Functions related to ionotropic receptors are generally fast (<1 millisecond) and metabotropic receptors are more prolonged. Antibodies to the acetylcholine receptors or motor neuron calcium channels cause myasthenia gravis and Lambert-Eaton syndrome, respectively. Parkinson’s syndrome is related to selective cell death in the nigrostriatal dopamine pathway. Stiff-person syndrome is related to antibodies to glutamic acid decarboxylase, the bio-synthetic pathway for GABA. Orthostatic tachycardia syndrome is related to mutations in the norepinephrine transporter. Abnormalities with serotonin neurotransmitter function are implicated in mood disorders, migraine pain pathways, and somatic pain pathways.

XI-3 and XI-4. The answers are D and D, respectively. (Chap. 367) The ability to perform a thorough neurologic examination is an important skill for all internists to master. A careful neurologic examination can localize the site of the lesion and is important in directing further workup. The components of the neurologic examination include mental status, cranial nerves, motor, sensory, gait, and coordination. 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. In this test, an individual is asked to stand with both arms fully extended and parallel to the floor while closing his or her eyes. If the arms flex at the elbows or fingers or there is pronation of the forearm, this is considered a positive test. Other tests of motor strength include tests of maximal effort in a specific muscle or muscle group. Most commonly this type of strength testing is graded from 0 (no movement) to 5 (full power) with varying degrees of weakness noted against resistance. However, many individuals find it more practical to use qualitative grading of strength, such as paralysis, severe weakness, moderate weakness, mild weakness, or full strength.

Babinski sign is a sign of upper motor neuron disease above the level of the S1 vertebra and is characterized by paradoxical extension of the great toe with fanning and extension of the other toes as well. Dysdiadochokinesis refers to the inability to perform rapid alternating movements and is a sign of cerebellar disease. Lhermitte symptom causes electric shock–like sensations in the extremities associated with neck flexion. 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. If the individual begins to sway or fall, this is considered a positive test and is a sign of abnormal proprioception.

XI-5. The answer is C. (Chap. 367) This patient likely has metastatic disease to the cervical spinal cord. The patient’s symptoms are bilateral with sparing of the cranial nerves and normal mental status, localizing the lesion below the level of the brainstem and cerebrum. The patient demonstrates mixed upper and lower motor neuron signs with decreased sphincter tone and a positive Babinski sign, placing the lesion at the level of the spinal cord. As the weakness is involving both the arms and legs, this would indicate a lesion in the lower cervical or upper thoracic spine. Symptoms of abnormalities at the level of the neuromuscular junction include bilateral weakness that can include the face having normal sensation.

XI-6. The answer is C. (Chap. 368) Appropriate and timely evaluation is needed to determine if a subarachnoid hemorrhage is present as it can be rapidly fatal if undetected. The procedure of choice for initial diagnosis is a CT of the head without IV contrast. On the CT, blood in the subarachnoid space would appear whiter compared to the surrounding brain tissue. The CT of the head is most sensitive when it is performed shortly after the onset of symptoms, but declines over several hours. It can also demonstrate the presence of mass effect and midline shift, factors that increase the severity of the underlying hemorrhage. In the situation where the CT head is negative but clinical suspicion is high, a lumbar puncture can be performed. This may demonstrate increased numbers of red blood cells that do not clear with successive aliquots of cerebrospinal fluid. If the lumbar puncture is performed more than 12 hours after a small subarachnoid hemorrhage, then the red blood cells may begin to decompose, leading to xanthochromia—a yellow to pink coloration of cerebrospinal fluid that can be measured spectrographically. A basic CT of the head with IV contrast is rarely useful in subarachnoid hemorrhage, as the brightness of the contrast material may make it difficult to identify blood in the subarachnoid space. However, a CT angiography that is performed with IV contrast can be useful in identifying the aneurismal vessel leading to the bleeding. Classic angiography is a more direct way to visualize the anatomy of the cranial vasculature and is now often combined with interventional procedures to coiling a bleeding vessel. Transcranial Doppler ultrasound is a test that measures the velocity of blood flow through the cranial vasculature. It is used in some centers following subarachnoid hemorrhage to assess for the development of vasospasm, which can worsen ischemia leading to increased damage to brain tissue following subarachnoid hemorrhage.

XI-7. The answer is E. (Chap. 368) Magnetic resonance imaging (MRI) is generated from the interaction between the hydrogen protons in biologic tissues, the magnetic field, and the radio-frequency (Rf) of waves generated by the coil placed next to the body part of interest. The Rf pulses transiently excite the protons of the body with a subsequent return to the equilibrium energy state, a process known as relaxation. During relaxation, the protons release Rf energy creating an echo that is then transformed via Fourier analysis to generate the MR image. The two relaxation rates that influence the signal intensity of the image are T1 and T2. T1 refers to the time in milliseconds that it takes for 63% of protons to return to their baseline state. T2 relaxation is the time for 63% of protons to become dephased owing to interactions among nearby protons. The intensity of the signal is also influenced by the interval between Rf pulses (TR) and the time between the Rf pulse and the signal reception (TE). T1-weighted images are produced by keeping both TR and TE relatively short, while T2-weighted images require long TR and TE times. Fat and subacute hemorrhages have relatively shorted TR and TE times and thus appear more brightly on T1-weighted images. Structures with more water such as cerebrospinal fluid or edema conversely have long T1 and T2 relaxation times, resulting in higher signal intensity on T2-weighted images. T2 images are also more sensitive for detecting demyelination, infarction, or chronic hemorrhage.

FLAIR stands for fluid-attenuated inversion recovery and is a type of T2-weighted image that suppresses the high-intensity signal of CSF. Because of this, images created by the FLAIR technique are more sensitive to detecting water-containing lesions or edema than the standard spin images.

MR angiography refers to several different techniques that are useful for assessing vascular structures, but does not provide details of the underlying brain parenchyma.

XI-8. The answer is E. (Chap. 368) For many years, MRI imaging was considered the modality of choice for patients with renal insufficiency because it does not lead to acute renal failure. However, gadolinium was recently linked to a rare disorder called nephrogenic systemic fibrosis. This newly described disorder results in widespread fibrosis in skin, skeletal muscle, bone, lungs, pleura, pericardium, myocardium, and many other tissues. Histologically, thickened collagen bundles are seen in the deep dermis of the skin with increased numbers of fibrocytes and elastic fibers. There is no known medical treatment for nephrogenic systemic fibrosis (NSF), although improvement may be seen following kidney transplantation. It has only recently been linked to the receipt of gadolinium-containing contrast agents with a typical onset between 5 and 75 days following administration of the contrast. The incidence of NSF following administration of gadolinium in individuals with a glomerular filtration rate of less than 30 mL/min may be as high as 4% and is thus considered absolutely contraindicated in individuals with severe renal dysfunction.

Pseudohypocalcemia can occur following administration of gadolinium in individuals with renal dysfunction, but not true hypocalcemia. This occurs because of an interaction of the contrast dye with standard colorimetric assays for serum calcium that are commonly used. If ionized calcium is measured it would be normal, often in the face of very low levels of serum calcium.

The other reported complications can be seen following administration of iodinated contrast that is used for CT imaging. The most common complication of CT imaging outside of allergic reactions is the development of worsening renal function or acute renal failure. The risk of this can be minimized if the patient is adequately hydrated. Lactic acidosis is a rare but dreaded side effect of iodinated contrast that has been linked to the coadministration of metformin in diabetic patients. Typically a patient is asked to hold metformin for 48 hours before and after a CT scan. The reason for the development of lactic acidosis is actually related to the development of renal insufficiency and a subsequent buildup of lactic acid. In very rare instances, administration of iodinated contrast can unmask hyperthyroidism.

XI-9. The answer is D. (Chap. e45) While seldom diagnostic, the EEG can often provide clinically useful information in comatose patients. In patients with an altered mental state or some degree of obtundation, the EEG tends to become slower as consciousness is depressed, regardless of the underlying cause. The EEG generally slows in metabolic encephalopathies, and triphasic waves may be present. The findings do not permit differentiation of the underlying metabolic disturbance but help to exclude other encephalopathic processes by indicating the diffuse extent of cerebral dysfunction. As the depth of coma increases, the EEG becomes nonreactive and may show a burst-suppression pattern, with bursts of mixed-frequency activity separated by intervals of relative cerebral inactivity. The EEG is usually normal in patients with locked-in syndrome and helps in distinguishing this disorder from the comatose state with which it is sometimes confused clinically. Epileptiform activity characterized by bursts of abnormal discharges containing spikes or sharp waves may be useful to diagnose and treat nonconvulsive status in a presumed comatose patient. Patients with herpes simplex encephalitis may show a characteristic pattern of focal (often in the temporal regions) or lateralized periodic slow-wave complexes. Periodic lateralizing epileptiform discharges (PLEDs) are commonly found with acute hemispheric pathology such as a hematoma, abscess, or rapidly expanding tumor.

XI-10. The answer is B. (Chap. 369) The International League against Epilepsy (ILAE) Commission on Classification and Terminology, 2005–2009, has provided an updated approach to the classification of seizures. This system is based on the clinical features of seizures and associated electroencephalographic findings. Seizures are classified as focal or generalized. Focal seizures arise from a neuronal network either discretely localized within one cerebral hemisphere or more broadly distributed but still within the hemisphere. They are frequently associated with a structural lesion. Generalized seizures are thought to arise at some point in the brain but immediately and rapidly engage neuronal networks in both cerebral hemispheres. Focal seizures are subdivided into those with or without dyscognitive features depending on the patient’s ability to interact with the environment during an episode. The terms “simple partial seizure” and “complex partial seizure” have been eliminated. Typical absence seizures are characterized by sudden, brief lapses of consciousness without loss of postural control. The seizure typically lasts for only seconds, consciousness returns as suddenly as it was lost, and there is no postictal confusion. Myoclonus is a sudden and brief muscle contraction that may involve one part of the body or the entire body. Although the distinction from other forms of myoclonus (e.g., metabolic, degenerative neurologic disease, anoxic encephalopathy) is imprecise, myoclonic seizures are considered to be true epileptic events since they are caused by cortical dysfunction.

XI-11. The answer is A. (Chap. 369) Mesial temporal lobe epilepsy is the most common epilepsy syndrome associated with focal seizures with dyscognitive features. Patients are unable to respond to verbal or visual commands during the seizure and they often manifest complex automatisms or complex posturing. An aura is common before the seizures. There is postictal memory loss or disorientation. Patients often have a history of febrile seizures or a family history of seizures. MRI will show hippocampal sclerosis, a small temporal lobe, or enlarged temporal horn. Mesial temporal lobe epilepsy is important to recognize as a distinct syndrome because it tends to be refractory to treatment with anticonvulsants but responds extremely well to surgical intervention. Hypothyroidism, herpes virus infection, diabetes, and tuberous sclerosis are not associated with mesial temporal lobe epilepsy.

XI-12. The answer is E. (Chap. 369) Focal seizures without dyscognitive features cause motor, sensory, autonomic, or psychic symptoms without an obvious alteration in consciousness. The phenomenon of abnormal motor movements beginning in a restricted area then progressing to involve a larger area is termed Jacksonian march. The patient is describing Todd’s paralysis, which may take minutes to many hours to return to normal. Although meningitis is a common cause of seizure in young patients, it is unlikely to be the cause in someone who has a known seizure disorder. If his symptoms were to persist beyond many hours, it would be reasonable to investigate a different etiology of his hand weakness with imaging studies. Overt deficits in strength are not compatible with a primary psychiatric disorder. Magnetic resonance angiogram and cerebral angiogram are useful to evaluate for cerebrovascular disorders, but there is no evidence of subarachnoid bleeding or vasculitis.

XI-13. The answer is C. (Chap. 369) Nuchal rigidity and an elevated white blood cell count are very concerning for meningitis as the etiology for this patient, and lumbar puncture must be performed to rule this out. In addition, acute cocaine intoxication is a plausible reason for this new-onset seizure. Figure XI-13 illustrates the evaluation of the adult patient with a seizure. MRI would be indicated if the patient had a negative metabolic and toxicologic screening. Substance abuse counseling, while indicated, is not indicated at this point in his workup since he is postictal. The patient is not having seizures, does not have a known seizure disorder, and has not been treated for the underlying metabolic abnormality, making IV loading with an antiepileptic medication premature at this time.

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FIGURE XI-13

XI-14. The answer is B. (Chap. 369) Optimal medical therapy for epilepsy depends on the underlying cause, type of seizure, and patient factors. The goal is to prevent seizures and minimize the side effects of therapy. The minimal effective dose is determined by trial and error. In choosing medical therapies, drug interactions are a key consideration. Certain medications, such as tricyclic antidepressants, may lower the seizure threshold and should be avoided. Patients who respond well to medical therapy and have completely controlled seizures are good candidates for the discontinuation of therapy, with about 70% of children and 60% of adults being able to discontinue therapy eventually. Patient factors that aid in this include complete medical control of seizures for 1–5 years, a normal neurologic examination, a normal EEG, and single seizure type. On the other end of the spectrum, about 20% of these patients are completely refractory to medical therapy and should be considered for surgical therapy. In the best examples, such as mesial temporal sclerosis, resection of the temporal lobe may result in about 70% of these patients becoming seizure-free and an additional 15–25% having a significant reduction in the incidence of seizures. In patients with epilepsy other considerations are critical. Psychosocial sequelae such as depression, anxiety, and behavior problems may occur. Approximately 20% of epileptic patients have depression, with their suicide rate being higher than that of age-matched controls. There is an impact on the ability to drive, perform certain jobs, and function in social situations. Furthermore, there is a two- to threefold increase in mortality for patients with epilepsy compared with age-matched controls. Although most of the increased mortality results from the underlying etiology of epilepsy, a significant number of these patients die from accidents, status epilepticus, and a syndrome known as sudden unexpected death in epileptic patients (SUDEP). A recent meta-analysis demonstrated that treatment of patients with refractory seizures with an antiepileptic drug could reduce the frequency of SUDEP (Lancet Neurol 2011;10:961).

XI-15. The answer is D. (Chap. 369) Adolescence and early adulthood mark the period where idiopathic or genetic epilepsy syndromes become less common and seizures due to acquired central nervous system (CNS) lesions become more common. The most common causes of seizures in the young adults are head trauma, CNS infections, brain tumors, congenital CNS lesions, illicit drug use, or alcohol withdrawal. Fever rarely causes seizure in patients older than 12 years. Amyloid angiopathy and uremia are more common in older adults.

XI-16. The answer is A. (Chap. 369) Status epilepticus refers to continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal period. The duration of seizure activity sufficient to meet the definition of status epilepticus has traditionally been specified as 15–30 minutes. Generalized convulsive status epilepticus (GCSE) is typically when seizures last beyond 5 minutes. GCSE is an emergency and must be treated immediately, since cardiorespiratory dysfunction, hyperthermia, and metabolic derangements can develop as a consequence of prolonged seizures, and these can lead to irreversible neuronal injury. Furthermore, CNS injury can occur even when the patient is paralyzed with neuromuscular blockade but continues to have electrographic seizures. The most common causes of GCSE are anticonvulsant withdrawal or noncompliance, metabolic disturbances, drug toxicity, CNS infection, CNS tumors, refractory epilepsy, and head trauma. 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 dilation. In such cases, the EEG may be the only method of establishing the diagnosis. Thus, if the patient stops having overt seizures yet remains comatose, an EEG should be performed to rule out ongoing status epilepticus. The first steps in the management of a patient in GCSE are to attend to any acute cardiorespiratory problems or hyperthermia, perform a brief medical and neurologic examination, establish venous access, and send samples for laboratory studies to identify metabolic abnormalities. Anticonvulsant therapy should then begin without delay; a treatment approach is shown in Figure XI-16. Carbamazepine is a first-line therapy for focal seizures.

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FIGURE XI-16

XI-17. The answer is A. (Chap. 370) Cardioembolism accounts for up to 20% of all ischemic strokes. Stroke caused by heart disease is due to thrombotic material forming on the atrial or ventricular wall or the left heart valves. If the thrombus lyses quickly, only a transient ischemic attack may develop. If the arterial occlusion lasts longer, brain tissue may die and a stroke will occur. Emboli from the heart most often lodge in the middle cerebral artery (MCA), the posterior cerebral artery (PCA), or one of their branches. Atrial fibrillation is the most common cause of cerebral embolism overall. Other significant causes of cardioembolic stroke include myocardial infarction, prosthetic valves, rheumatic heart disease, and dilated cardiomyopathy. Furthermore, paradoxical embolization may occur when an atrial septal defect or a patent foramen ovale exists. This may be detected by bubble-contrast echocardiography. Bacterial endocarditis may cause septic emboli if the vegetation is on the left side of the heart or if there is a paradoxical source.

XI-18. The answer is D. (Chap. 370) Nonrheumatic atrial fibrillation is the most common cause of cerebral embolism overall. The presumed stroke mechanism is thrombus formation in the fibrillating atrium or atrial appendage. The average annual risk of stroke is around 5%. However, the risk varies with the following factors: age, hypertension, left ventricular function, prior embolism, diabetes, and thyroid function. The risk of stroke can be estimated by calculating the CHADS2 score (see Table XI-18). Patients younger than 60 years of age without structural heart disease or without one of these risk factors have a very low annual risk of cardioembolism of less than 0.5%. Therefore, it is recommended that these patients only take aspirin daily for stroke prevention. Older patients with numerous risk factors may have annual stroke risks of 10–15% and must take a vitamin K antagonist indefinitely. Cardioversion is indicated for symptomatic patients who want an initial opportunity to remain in sinus rhythm. However, studies have shown that there is an increased stroke risk for weeks to months after a successful cardioversion, and these patients must remain on anticoagulation for a long period. Patients who do not respond to cardioversion and do not want catheter ablation have mortality and morbidity with rate control and anticoagulation similar to those of patients who opt for cardioversion. Low-molecular-weight heparin may be used as a bridge to vitamin K–antagonist therapy and may facilitate outpatient anticoagulation in selected patients.

TABLE XI-18 Recommendations on Chronic Use of Antithrombotics for Various Cardiac Conditions

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XI-19. The answer is E. (Chap. 370) Numerous studies have identified key risk factors for ischemic stroke. Old age, family history, diabetes, hypertension, tobacco smoking, and cholesterol are all risk factors for atherosclerosis and therefore stroke. Hypertension 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. The overall relative risk reduction of nonfatal stroke is about 25–30% across most large clinical trials. The “true” absolute benefit is dependent on the individual patient’s risk; therefore, patients with a low risk for stroke (e.g., younger patients with minimal cardiovascular risk factors) may have a relative risk reduction with antiplatelet therapy but a meaningless “benefit.” Numerous studies have shown the benefit of statin therapy in the reduction of stroke risk even in the absence of hypercholesterolemia. Anticoagulation is the treatment of choice to prevent stroke in patients with atrial fibrillation and other potential causes of cardiocerebral emboli. However, data do not support the use of long-term vitamin K antagonists for preventing atherothrombotic stroke for either intracranial or extracranial cerebrovascular disease. The WARSS study found no benefit of warfarin (INR 1.4–2.8) over aspirin 325 mg for secondary prevention of stroke but did find a slightly higher bleeding rate in the warfarin group. A recent European study confirmed this finding. The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study demonstrated no benefit of warfarin (INR 2–3) over aspirin in patients with symptomatic intracranial atherosclerosis, and also found higher rates of bleeding complications.

XI-20. The answer is C. (Chap. 370) Once the diagnosis of stroke is made, a brain imaging study is necessary to determine if the cause of stroke is ischemia or hemorrhage (Figure XI-20). There are no clinical findings that definitively distinguish ischemia from hemorrhage. If the stroke is ischemic, administration of recombinant tissue plasminogen activator (rtPA) or endovascular mechanical thrombectomy may be beneficial in restoring cerebral perfusion. Medical management to reduce the risk of complications becomes the next priority, followed by plans for secondary prevention. For ischemic stroke, several strategies can reduce the risk of subsequent stroke in all patients, while other strategies are effective for patients with specific causes of stroke such as cardiac embolus and carotid atherosclerosis. For hemorrhagic stroke, aneurysmal subarachnoid hemorrhage (SAH) and hypertensive intracranial hemorrhage are two important causes. The National Institute of Neurological Disorders and Stroke (NINDS) recombinant TPA (rtPA) Stroke Study showed a clear benefit for IV rtPA in selected patients with acute stroke. The NINDS study used IV rtPA (0.9 mg/kg to a 90-mg max; 10% as a bolus, then the remainder over 60 minutes) versus placebo in patients with ischemic stroke within 3 hours of onset. Subsequent studies using different dosing and timing ranges have not been as positive. rtPA is being reviewed for approval in the 3- to 4.5-hour window in Europe, but is only approved for 0–3 hours in the United States and Canada. Use of IV rtPA is considered a central component in primary stroke centers as the first treatment proven to improve clinical outcomes in ischemic stroke and is cost-effective and cost saving. Because collateral blood flow within the ischemic brain is blood pressure dependent, there is controversy about whether blood pressure should be lowered acutely. Blood pressure should be lowered if there is malignant hypertension or concomitant myocardial ischemia or if blood pressure is above 185/110 mmHg and thrombolytic therapy is anticipated. When faced with the competing demands of myocardium and brain, lowering the heart rate with a β1-adrenergic blocker (such as esmolol) can be a first step to decreasing cardiac work and maintaining blood pressure. Endovascular mechanical thrombectomy has recently shown promise as an alternative or adjunctive treatment of acute stroke in patients who are ineligible for, or have contraindications to, thrombolytics or in those who have failed to have vascular recanalization with IV thrombolytics. Studies have shown excellent acute and chronic recanalization rates and the FDA has approved some devices for intracerebral use. Hypothermia is a powerful neuroprotective treatment in patients with cardiac arrest and is neuroprotective in animal models of stroke, but it has not been adequately studied in patients with ischemic stroke.

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FIGURE XI-20

XI-21. The answer is B. (Chap. 371) Approximately 10% of all persons over the age of 70 have significant memory loss, and in more than half the cause is Alzheimer’s disease (AD). AD can occur in any decade of adulthood, but it is the most common cause of dementia in the elderly. AD most often presents with an insidious onset of memory loss followed by a slowly progressive dementia over several years. Pathologically, atrophy is distributed throughout the medial temporal lobes, as well as lateral and medial parietal lobes and lateral frontal cortex. Microscopically, there are neurofibrillary tangles composed of hyperphosphorylated tau filaments, and accumulation of amyloid in blood vessel walls in the cortex and leptomeninges. The cognitive changes of AD tend to follow a characteristic pattern beginning with memory impairment and spreading to language and visuospatial deficits. Yet approximately 20% of patients with AD present with nonmemory complaints such as word-finding, organizational, or navigational difficulty. In the early stages of the disease, the memory loss may go unrecognized or be ascribed to benign forgetfulness. Slowly the cognitive problems begin to interfere with daily activities, such as keeping track of finances, following instructions on the job, driving, shopping, and housekeeping. Some patients are unaware of these difficulties (anosognosia), while others remain acutely attuned to their deficits. Social 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. Word-finding difficulties and circumlocution may be a problem even when formal testing demonstrates intact naming and fluency. Visuospatial deficits begin to interfere with dressing, eating, or even walking, and patients fail to solve simple puzzles or copy geometric figures. Simple calculations and clock reading become difficult in parallel. Loss of judgment and reasoning is inevitable. Delusions are common and usually simple, with common themes of theft, infidelity, or misidentification. In end-stage AD, patients become rigid, mute, incontinent, and bedridden. Hyperactive tendon reflexes and myoclonic jerks may occur spontaneously or in response to physical or auditory stimulation. Generalized seizures may also occur. Often death results from malnutrition, secondary infections, pulmonary emboli, heart disease, or, most commonly, aspiration. The typical duration of AD is 8–10 years, but the course can range from 1 to 25 years. For unknown reasons, some AD patients show a steady decline in function, while others have prolonged plateaus without major deterioration.

XI-22. The answer is D. (Chap. 370) There is currently no robust or curative medical therapy for Alzheimer’s disease (AD). The acetylcholinesterase inhibitors donepezil, rivastigmine, and galantamine, as well as the NMDA receptor antagonist memantine are FDA approved for treatment of AD. Double-blind, placebo-controlled crossover studies with these agents have shown improved caregiver ratings of patients’ functioning with an apparent decreased rate of decline in cognitive test scores over periods of up to 3 years. The average patient on an anticholinesterase compound maintains his or her MMSE score for close to a year, whereas a placebo-treated patient declines 2–3 points over the same time period. Memantine, used in conjunction with cholinesterase inhibitors or by itself, slows cognitive deterioration and decreases caregiver burden for patients with moderate to severe AD but is not approved for mild AD. Each of these compounds has only modest efficacy for AD. Some studies have suggested a protective effect of estrogen replacement in women. However, a prospective study of a estrogen-progesterone combination increased the prevalence of AD in previously asymptomatic women. A randomized, double-blind, placebo-controlled trial of an extract of Ginkgo biloba found modest improvement in cognitive function in subjects with AD and vascular dementia. Unfortunately, a comprehensive 6-year multi-center prevention study using Ginkgo biloba found no slowing of progression to dementia in the treated group. Experimental studies are investigating chemical or vaccination strategies to interfere or inhibit amyloid protein deposition. Retrospective studies suggest a beneficial role of statins in the development of dementia. Mild to moderate depression is common in the early stages of AD and may respond to antidepressants or cholinesterase inhibitors. Newer-generation antipsychotics (risperidone, quetiapine, olanzapine) in low doses may benefit neuropsychiatric symptoms. Medications with strong anticholinergic effects should be vigilantly avoided, including prescription and over-the-counter sleep aids (e.g., diphenhydramine) or incontinence therapies (e.g., oxybutynin).

XI-23. The answer is D. (Chap. 370) All the choices given in the question are causes of or may be associated with dementia. Binswanger’s disease, the cause of which is unknown, often occurs in patients with long-standing hypertension and/or atherosclerosis; it is associated with diffuse subcortical white matter damage and has a subacute insidious course. Alzheimer’s disease, the most common cause of dementia, is also slowly progressive and can be confirmed at autopsy by the presence of amyloid plaques and neurofibrillary tangles. Creutzfeldt-Jakob disease, a prion disease, is associated with a rapidly progressive dementia, myoclonus, rigidity, a characteristic EEG pattern, and death within 1–2 years of onset. Vitamin B12 deficiency, which often is seen in the setting of chronic alcoholism, most commonly produces a myelopathy that results in loss of vibration and joint position sense, and brisk deep tendon reflexes (dorsal column and lateral corticospinal tract dysfunction). This combination of pathologic abnormalities in the setting of vitamin B12 deficiency is also called subacute combined degeneration. Vitamin B12 deficiency may also lead to a subcortical type of dementia. Recent studies have demonstrated that elevated levels of MMA, which is a more sensitive measure of vitamin B12 deficiency, may increase the risk of cognitive decline in elderly patients. The therapeutic implications of this finding are not yet clear but emphasize the importance of adequate vitamin B12 intake. Multi-infarct dementia, as in this case, presents with a history of sudden stepwise declines in function associated with the accumulation of bilateral focal neurologic deficits. Brain imaging demonstrates multiple areas of stroke.

XI-24. The answer is D. (Chap. 370) The differential diagnosis of Parkinson’s disease is broad, and the disease can be difficult to diagnose, with an estimated misdiagnosis of 10–25% even by experienced physicians. This patient exhibits several atypical features that should alert the physician to search for alternative diagnoses. These include early age of onset, prominent orthostasis, autonomic symptoms of flushing and diaphoresis, and failure to respond to dopaminergic agents. In addition, recurrent urinary tract infections should prompt an evaluation for urinary retention due to autonomic dysfunction in this patient. These symptoms are most consistent with multiple system atrophy with parkinsonian features (MSA-p). The average age of onset is 50 years, and these individuals more frequently present with bilateral, symmetric tremor and more prominent spasticity than those with Parkinson’s disease. Orthostasis and autonomic symptoms are typically prominent. On MRI, one would expect to find volume loss and T2-hyperintensity in the area of the putamen, globus pallidus, and white matter. On pathologic examination, α-synuclein–positive inclusions would be seen in the affected areas. Median survival after diagnosis is 6–9 years. Dopaminergic agents are not helpful in the treatment of this disorder and are usually associated with drug-induced dyskinesias of the face and neck, rather than the limbs and trunk. Corticobasal degeneration is a sporadic tauopathy that presents in the sixth to seventh decades. In contrast to Parkinson’s disease, this disorder is frequently associated with myoclonic jerks and involuntary purposeful movements of a limb. Its progressive nature leads to spastic paraplegia. Diffuse Lewy body disease has prominent dementia with parkinsonian features. Neuropsychiatric complaints including paranoia, delusions, and personality changes are more common than in Parkinson’s disease. Drug-induced Parkinson’s disease is not seen with nitrofurantoin, and the patient has no history of illicit drugs such as MTPT, which could cause Parkinson’s disease. Finally, this is unlikely to be inadequately treated Parkinson’s disease because one would expect at least an initial improvement on dopaminergic agents.

XI-25. The answer is C. (Chap. 370) Therapy for Parkinson’s disease should be initiated when symptoms interfere with the patient’s quality of life. Choice of initial drug therapy is usually with dopamine agonists, levodopa, or MAO inhibitors. The initial choice in most individuals is a dopamine agonist (pramipexole, ropinirole, rotigotine), and monotherapy with dopamine agonists usually controls motor symptoms for several years before levodopa therapy becomes necessary. Over this period, escalating doses are frequently required, and side effects may be limiting. It is thought that dopamine agonists delay the onset of dyskinesias and on-off motor symptoms such as freezing. By 5 years, over half of individuals will require levodopa to control motor symptoms. Levodopa remains the most effective therapy for the motor symptoms of Parkinson’s disease, but once levodopa is started, dyskinesias and on-off motor fluctuations become more common. MAO inhibitors (selegiline, rasagiline) work by decreasing the postsynaptic breakdown of dopamine. As monotherapy, these agents have only small effects and are most often used as adjuncts to levodopa. Surgical procedures such as pallidotomy and deep-brain stimulation are reserved for advanced Parkinson’s disease with intractable tremor or drug-induced motor fluctuations or dyskinesias. In this setting, deep-brain stimulation can alleviate disabling symptoms.

XI-26. The answer is D. (Chap. 370) Restless legs syndrome (RLS) is a neurologic disorder that affects approximately 10% of the adult population, causing significant morbidity in some. It is rare in Asians. The four core symptoms required for diagnosis are as follows: an urge to move the legs, usually caused or accompanied by an unpleasant sensation in the legs; symptoms begin or worsen with rest; partial or complete relief by movement; worsening during the evening or night. Symptoms most commonly begin in the legs, but can spread to or even begin in the upper limbs. In about 80% of patients, RLS is associated with periodic leg movements (PLMs) during sleep and occasionally while awake. These involuntary movements are usually brief, lasting no more than a few seconds, and recur every 5–90 seconds. The restlessness and PLMs are a major cause of sleep disturbance in patients, leading to poor-quality sleep and daytime sleepiness. Primary RLS is genetic, and several loci have been found with an autosomal dominant pattern of inheritance, although penetrance may be variable. The mean age of onset in genetic forms is 27 years, although pediatric cases are recognized. The severity of symptoms is variable. Secondary RLS may be associated with pregnancy or a range of underlying disorders, including anemia, ferritin deficiency, renal failure, and peripheral neuropathy. The pathogenesis probably involves disordered dopamine function, which may be peripheral or central, in association with an abnormality of iron metabolism. Diagnosis is made on clinical grounds but can be supported by polysomnography and the demonstration of PLMs. The neurologic examination is normal. Secondary RLS should be excluded, and ferritin levels, glucose, and renal function should be measured. Most RLS sufferers have mild symptoms that do not require specific treatment. If symptoms are intrusive, low doses of dopamine (pramipexole, ropinirole) may be administered before bedtime. Levodopa can be effective but is frequently associated with augmentation (spread and worsening of restlessness and its appearance earlier in the day) or rebound (reappearance sometimes with worsening of symptoms at a time compatible with the drug’s short half-life). Other drugs that can be effective include anticonvulsants, analgesics, and even opiates. Management of secondary RLS should be directed to correcting the underlying disorder.

XI-27. The answer is E. (Chap. 374) The combination of upper and lower motor neuron findings is highly suggestive of ALS. Indolent presentation is typical and many patients receive alternative diagnoses before defining ALS. There is currently no curative therapy for ALS; therefore, treatable causes of motor nerve dysfunction should be ruled out. Compression of the cervical spinal cord or cervicomedullary junction from tumors in the cervical regions or at the foramen magnum or from cervical spondylosis with osteophytes projecting into the vertebral canal can produce weakness, wasting, and fasciculations in the upper limbs and spasticity in the legs, closely resembling ALS. Absence of pain or of sensory changes, normal bowel and bladder function, normal roentgenographic studies of the spine, and normal cerebrospinal fluid (CSF) all favor ALS. Another important entity in the differential diagnosis of ALS is multifocal motor neuropathy with conduction block (MMCB). In this disorder, remarkably focal blocks in conduction regionally and chronically disrupt lower motor neuron function. Many cases have elevated serum titers of mono- and polyclonal antibodies to ganglioside GM1; it is hypothesized that the antibodies produce selective, focal, paranodal demyelination of motor neurons. MMCB is not typically associated with corticospinal signs. In contrast with ALS, MMCB may respond dramatically to therapy such as IV immunoglobulin or chemotherapy; it is thus imperative that MMCB be excluded when considering a diagnosis of ALS. A diffuse, lower motor axonal neuropathy mimicking ALS sometimes evolves in association with hematopoietic disorders such as lymphoma or multiple myeloma. Lyme disease may also cause an axonal, lower motor neuropathy, although typically with intense proximal limb pain and a CSF pleocytosis.

Other treatable disorders that occasionally mimic ALS are chronic lead poisoning and thyrotoxicosis. Vitamin C deficiency may cause myalgias in addition to fatigue, lethargy, and skin findings, but motor neuron findings are not typical.

XI-28. The answer is E. (Chap. 375) Postural orthostatic tachycardia syndrome is characterized by symptomatic orthostatic intolerance and either an increase in heart rate to more than 120 beats/min or an increase of 30 beats/min with standing that subsides on sitting or lying down. There is no orthostatic hypotension. Women are affected approximately five times more often than men, and most develop the syndrome between the ages of 15 and 50. Approximately half of affected patients report an antecedent viral infection. Lightheadedness, weakness, and blurred vision combined with symptoms of autonomic over activity (palpitations, tremulousness, nausea) are common. Recurrent, unexplained episodes of dysautonomia and fatigue also occur. The pathogenesis is unclear in most cases; hypovolemia, deconditioning, venous pooling, impaired brainstem regulation, or adrenergic receptor supersensitivity may play a role. Although up to 80% of patients improve, only about 25% eventually resume their usual daily activities (including exercise and sports). Expansion of fluid volume and postural training are initial approaches to treatment. If these approaches are inadequate, then midodrine, fludrocortisone, phenobarbital, beta blockers, or cloni-dine may provide some benefit. Reconditioning and a sustained exercise program are very important. All of the other listed choices are associated with orthostatic hypotension.

XI-29. The answer is D. (Chap. 375) Complex regional pain syndrome (CRPS) types I and II are the terms that have replaced reflex sympathetic dystrophy (RSD) or causalgia because of the absence of a proven causative role for the autonomic nervous system. CRPS type I is a regional pain syndrome that usually develops after tissue trauma. Examples of associated trauma include myocardial infarction, minor shoulder or limb injury, and stroke. Allodynia, hyperpathia, and spontaneous pain occur. The symptoms are unrelated to the severity of the initial trauma and are not confined to the distribution of a single peripheral nerve. CRPS type II is a regional pain syndrome that develops after injury to a specific peripheral nerve, usually a major nerve trunk. Spontaneous pain initially develops within the territory of the affected nerve but eventually may spread outside the nerve distribution. Pain is the primary clinical feature of CRPS. Vasomotor dysfunction, sudomotor abnormalities, or focal edema may occur alone or in combination but must be present for diagnosis. Localized sweating and changes in blood flow may produce temperature differences between affected and unaffected limbs. CRPS type I has classically been divided into three clinical phases but is now considered to be more variable. Phase I consists of pain and swelling in the distal extremity occurring within weeks to 3 months after the precipitating event. 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. After an additional 3–6 months (phase III), atrophy of the skin and subcutaneous tissue plus flexion contractures complete the clinical picture. A variety of surgical and medical treatments have been developed for CRPS, with conflicting reports of efficacy. Clinical trials suggest that early mobilization with physical therapy or a brief course of glucocorticoids may be helpful for CRPS type I. Other medical treatments include the use of adrenergic blockers, nonsteroidal anti-inflammatory drugs, calcium channel blockers, phenytoin, opioids, and calcitonin. Stellate ganglion blockade is a commonly used invasive technique that often provides temporary pain relief, but the efficacy of repetitive blocks is uncertain.

XI-30. The answer is F. (Chap. 376) Trigeminal neuralgia is a clinical diagnosis based entirely on patient history. The disorder is characterized by paroxysms of excruciating pain in the lips, gums, cheeks, and chin that resolves over seconds to minutes. It is caused by ectopic action potentials in afferent pain fibers of the fifth cranial nerve, due either to nerve compression or other causes of demyelination. 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 syndrome. Elevated ESR is associated with temporal arteritis, a vasculitis associated with jaw claudication, unilateral vision loss, and symptoms of polymyalgia rheumatica. Trigeminal neuralgia is specifically notable for a lack of sensory findings on examination, unless the diagnosis is made in conjunction with another disorder such as a midbrain mass lesion or aneurysm. Deep-seated facial and head pain is more commonly a feature of migraine headache, dental pathology, or sinus disease. First-line therapy is with carbamazepine, not gabapentin. It should be started and increased gradually until pain symptoms subside; 50–75% of patients will respond to this therapy. If treatment is effective, it is continued for 1 month then tapered.

XI-31. The answer is C. (Chap. 376) Trigeminal neuralgia is a clinical diagnosis based entirely on patient history, and as such should be treated once a patient presents with the virtually pathognomonic complaints of paroxysms of excruciating pain in the lips, gums, cheeks, and chin that resolve over seconds to minutes. Carbamazepine is first-line therapy. Oxcarbazepine likely has equivalent efficacy to carbamazepine with less toxicity. Lamotrigine, orphenytoin, and baclofen are other potential therapeutic options. Surgical approaches, such as radiofrequency thermal rhizotomy, gamma-knife radiosurgery, and microvascular decompression, should be considered only when medical options fail. Steroids have no therapeutic role, as trigeminal neuralgia is not an inflammatory condition. Neuroimaging is not indicated, unless other clinical features or a focal neurologic deficit elicited on history or physical examination suggest another possible diagnosis such as intracranial mass or multiple sclerosis.

XI-32. The answer is D. (Chap. 376) Brief paroxysms of severe, sharp pains in the face without demonstrable lesions in the jaw, teeth, or sinuses are called tic douloureux, or trigeminal neuralgia. The pain may be brought on by stimuli applied to the face, lips, or tongue or by certain movements of those structures. Aneurysms, neurofibromas, and meningiomas impinging on the fifth cranial nerve at any point during its course typically present with trigeminal neuropathy, which will cause sensory loss on the face, weakness of the jaw muscles, or both; neither symptom is demonstrable in this patient. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that may present with bulbar motor findings but sensory findings (in the absence of muscle spasms) are uncommon.

XI-33. The answer is C. (Chap. 377) The MRI shows an infiltrated and collapsed second thoracic vertebral body with posterior displacement and compression of the upper thoracic spinal cord due to metastatic breast cancer. The low-intensity bone marrow signal in panel A of Figure XI-33 signifies replacement by tumor. When a patient presents with possible myelopathy, the first priority is to distinguish between a compressive or noncompressive etiology. The common causes of compressive myelopathy are tumor, epidural abscess or hematoma, herniated disk, or vertebral pathology. Epidural compression due to malignancy or abscess often causes warning signs of neck or back pain, bladder disturbances, and sensory symptoms that precede the development of paralysis. MRI is the optimal diagnostic modality to image the spinal cord. In adults, most neoplasms are epidural in origin, resulting from metastases to the adjacent spinal bones. The propensity of solid tumors to metastasize to the vertebral column probably reflects the high proportion of bone marrow located in the axial skeleton. Almost any malignant tumor can metastasize to the spinal column, with breast, lung, prostate, kidney, lymphoma, and plasma cell dyscrasia occurring particularly frequently. The thoracic spinal column is most commonly involved; exceptions are metastases from prostate and ovarian cancer, which occur disproportionately in the sacral and lumbar vertebrae, probably resulting from spread through Batson’s plexus, a network of veins along the anterior epidural space. Retroperitoneal neoplasms (especially lymphomas or sarcomas) enter the spinal canal through the intervertebral foramens and produce radicular pain with signs of root weakness prior to cord compression. Pain is usually the initial symptom of spinal metastasis and characteristically awakens patients at night. A recent onset of persistent back pain, particularly if in the thoracic spine (which is uncommonly involved by spondylosis), should prompt consideration of vertebral metastasis. Infections of the spinal column (osteomyelitis and related disorders) are distinctive in that, unlike tumor, they may cross the disk space to involve the adjacent vertebral body. Management of cord compression includes glucocorticoids to reduce cord edema, local radiotherapy (initiated as early as possible) to the symptomatic lesion, and specific therapy for the underlying tumor type. Spinal epidural abscess presents as a clinical triad of midline dorsal pain, fever, and progressive limb weakness. Risk factors include an impaired immune status (diabetes mellitus, renal failure, alcoholism, malignancy), IV drug abuse, and infections of the skin or other tissues. Two-thirds of epidural infections result from hematogenous spread of bacteria from the skin (furunculosis), soft tissue (pharyngeal or dental abscesses), or deep viscera (bacterial endocarditis). Hemorrhage into the epidural (or subdural) space causes acute focal or radicular pain followed by variable signs of a spinal cord or conus medullaris disorder. Therapeutic anticoagulation, trauma, tumor, or blood dyscrasias are predisposing conditions. Hemorrhage into the substance of the spinal cord is a rare result of trauma, intraparenchymal vascular malformation, vasculitis due to polyarteritis nodosa or systemic lupus erythematosus (SLE), bleeding disorders, or a spinal cord neoplasm. Hematomyelia presents as an acute, painful transverse myelopathy.

XI-34. The answer is B. (Chap. 377) This patient has a history and examination consistent with a myelopathy. The rapidity of onset and the lack of other antecedent symptoms (e.g., pain) make a noncompressive etiology most likely. An MRI is the initial test of choice and will easily identify a structural lesion such as a neoplasm or subluxation. Noncompressive myelopathies result from five basic causes: spinal cord infarction; systemic disorders such as vasculitis, systemic lupus erythematosus (SLE), and sarcoidosis; infections (particularly viral); demyelinating disease such as multiple sclerosis; and idiopathic. Therefore, serologies for antinuclear antibodies, viral serologies such as HIV and HTLV-I, and lumbar puncture are all indicated. Because the clinical scenario is consistent with a myelopathy, an electromyogram is not indicated.

XI-35. The answer is A. (Chap. 377) Syringomyelia is a developmental, slowly enlarging cavitary expansion of the cervical cord that produces a progressive myelopathy. Symptoms typically begin in adolescence or early adulthood. They may undergo spontaneous arrest after several years. More than half are associated with Chiari malformations. Acquired cavitations of the spinal cord are referred to as syrinx cavities. They may result from trauma, myelitis, infection, or tumor. The classic presentation is that of a central cord syndrome with sensory loss of pain and temperature sensation, and weakness of the upper extremities. Vibration and position sensation are typically preserved. Muscle wasting in the lower neck, shoulders, arms, and hands with asymmetric or absent reflexes reflects extension of the cavity to the anterior horns. With progression, spasticity and weakness of the lower extremities, and bladder and bowel dysfunction may occur. MRI scans are the diagnostic modality of choice. Surgical therapy is generally unsatisfactory. Syringomyelia associated with Chiari malformations may require extensive decompressions of the posterior fossa. Direct decompression of the cavity is of debatable benefit. Syringomyelia secondary to trauma or infection is treated with decompression and a drainage procedure, with a shunt often inserted that drains into the subarachnoid space. Although relief may occur, recurrence is common.

XI-36. The answer is A. (Chap. 378) Concussions result from blunt head trauma that causes anterior-posterior movement of the brain within the skull. Transient loss of consciousness is common, as are confusion and amnesia. Many patients do not lose consciousness but feel dazed, stunned, or confused. A brief period of both retrograde and anterograde amnesia is characteristic of concussion and it recedes rapidly in alert patients. Head imaging is typically normal. Postconcussive syndrome is a constellation of symptoms including fatigue, headache, dizziness, and difficulty concentrating that follows a concussion. The patient described fits this diagnosis; strict diagnostic criteria do not exist. Typically patients will improve over a 6- to 12-month period. Patients who were energetic and highly functioning prior to their trauma have an excellent prognosis. 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.

XI-37. The answer is D. (Chap. 378) The head CT (Figure XI-37) shows chronic bilateral subdural hematomas of varying age. The collections began as acute hematomas and have become hypodense in comparison to the adjacent brain. Some areas of resolving blood are contained in the more recently formed collection on the left. Acute hematomas (which would be as bright as the resolving blood shown in arrows) become hypodense in comparison with adjacent brain after approximately 2 months. During the isodense phase (2–6 weeks after injury), they may be difficult to discern. Chronic subdural hematoma may present without a history of trauma or injury in 20–30% of patients. Headache is common. Other symptoms may be vague, as in this case, or there may be focal signs including hemiparesis mimicking stroke. Underlying cortical damage may serve as a seizure focus. In relatively asymptomatic patients with small hematomas, observation and serial imaging may be reasonable; however, surgical evacuation is often necessary for large or symptomatic chronic hematomas.

XI-38. The answer is D. (Chap. 378) Hemorrhages beneath the dural layer (subdural) or between the skull and the dura (epidural) are common sequelae of head trauma. They can be life-threatening, and prompt evaluation and management are imperative. Several clinical features allow these conditions to be distinguished from one another. Acute subdural hematomas typically arise from venous sources, often the bridging veins located immediately under the dura mater. As the brain volume decreases with age, traction on these venous structures increases and even minor head trauma in the elderly can lead to a subdural hematoma. A “lucid interval” of several minutes to hours before coma supervenes is most characteristic of epidural hemorrhage, but it is still uncommon, and epidural hemorrhage is not the only cause of this temporal sequence. Subdural bleeding is typically slower than epidural bleeding due to their different sources. Small subdural bleeds are asymptomatic and often do not require evacuation. Epidural hematomas, on the other hand, can arise quickly and typically represent arterial bleeding. A lacerated middle meningeal artery from an overlying skull fracture often causes these. A rapid increase in intracranial pressure from these bleeds can necessitate arterial ligation or emergent craniotomy. Most patients with epidural bleeding are unconscious when first evaluated; a “lucid interval” can occasionally be seen.

XI-39. The answer is D. (Chap. 379) Distinguishing CNS toxoplasmosis from primary CNS lymphoma in a patient with HIV infection is often difficult. The standard approach in a neurologically stable patient is to treat the patient for toxoplasmosis for 2–3 weeks then repeat neuroimaging. If the imaging shows clear improvement, continue antibiotics. If there is no response to therapy after 2 weeks, therapy does not need to be continued and a stereotactic brain biopsy is indicated. In this immunocompromised patient who has not responded to treatment for CNS toxoplasmosis, a positive CNS EBV DNA would be diagnostic of CNS lymphoma. Whole-brain radiation therapy is part of the treatment for CNS lymphoma, which is not yet diagnosed in this patient, and should not be instituted empirically. Treatments directed at viral infections of the CNS or CNS lymphomas are not indicated at this time since a diagnosis is still yet to be made. In the absence of a change in neurologic status or evidence of mass effect on CT, there is no indication for dexamethasone. Of note, the incidence of primary CNS lymphoma appears to be increasing in immunocompetent individuals for unclear reasons.

XI-40. The answer is A. (Chap. 379) Endocrine dysfunction resulting in hypopituitarism frequently follows exposure of the hypothalamus or pituitary gland to therapeutic radiation. Growth hormone is the most sensitive to the damaging effects of WBRT, and thyroid-stimulating hormone is the least sensitive. ACTH, prolactin, and gonadotropins have an intermediate sensitivity. Other complications of radiation therapy to the brain include acute radiation injury manifest by headache, sleepiness, and worsening of preexisting neurologic defects. 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 responsive. Late delayed radiation injury occurs more than 4 months after therapy, typically 8–24 months. There may be dementia, gait apraxia, focal necrosis (after focal irradiation), or the development of secondary malignancies.

XI-41. The answer is D. (Chap. 379) The postgadolinium MRI shows multiple meningiomas along the falx and left parietal cortex. Meningiomas derive from the cells that give rise to the arachnoid granulations. They are now the most common primary brain tumor, accounting for approximately 32% of the total, and occur more commonly in women than men. They are usually benign (WHO classification grade 1) and attached to the dura. They rarely invade the brain. Meningiomas are diagnosed with increasing frequency as more people undergo neuroimaging studies for various indications. Their incidence increases with age, and they are more common in patients with a history of cranial irradiation. They are most commonly located over the cerebral convexities, especially adjacent to the sagittal sinus, but can also occur in the skull base and along the dorsum of the spinal cord. Many meningiomas are found incidentally following neuroimaging for unrelated reasons. They can also present with headaches, seizures, or focal neurologic deficits. On imaging studies they have a characteristic appearance usually consisting of a partially calcified, densely enhancing extra-axial tumor arising from the dura. The main differential diagnosis of meningioma is a dural metastasis. Total surgical resection of a meningioma is curative. Low-grade astrocytoma and high-grade astrocytoma (glioblastoma) often infiltrate into adjacent brain and rarely have the clear margins seen in Figure XI-41. Oligodendroma comprise approximately 15% of all gliomas and show calcification in roughly 30% of cases. They have a more benign course and are more responsive than other gliomas to cytotoxic therapy. For low-grade oligodendromas, the median survival is 7–8 years. Brain abscess will have distinctive ring-enhancing features with a capsule, will often have mass effect, and will have evidence of inflammation on MRI scanning.

XI-42. The answer is D. (Chap. 380) The onset of multiple sclerosis (MS) may be abrupt or insidious. Symptoms may be severe or seem so trivial that a patient may not seek medical attention for months or years. Indeed, at autopsy, approximately 0.1% of individuals who were asymptomatic during life will be found, unexpectedly, to have pathologic evidence of MS. Similarly, in the modern era, an MRI scan obtained for an unrelated reason may show evidence of asymptomatic MS. Symptoms of MS are extremely varied and depend on the location and severity of lesions within the CNS (see Table XI-42). 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.

TABLE XI-42 Initial Symptoms of MS

image

XI-43. The answer is D. (Chap. 380) The four clinical types of multiple sclerosis (MS) include relapsing/remitting, secondary progressive, primary progressive, and progressive relapsing. Relapsing/remitting MS (RRMS) accounts for 85% of MS cases at onset and is characterized by discrete attacks that generally evolve over days to weeks (rarely over hours). There is often complete recovery over the ensuing weeks to months. However, when ambulation is severely impaired during an attack, approximately half will fail to improve. Between attacks, patients are neurologically stable. Secondary progressive MS (SPMS) always begins as RRMS. At some point, however, the clinical course changes so that the patient experiences a steady deterioration in function unassociated with acute attacks (which may continue or cease during the progressive phase). SPMS produces a greater amount of fixed neurologic disability than RRMS. For a patient with RRMS, the risk of developing SPMS is approximately 2% each year, meaning that the great majority of RRMS ultimately evolves into SPMS. SPMS appears to represent a late stage of the same underlying illness as RRMS. Primary progressive MS (PPMS) accounts for approximately 15% of cases. These patients do not experience attacks but only a steady functional decline from disease onset. Compared to RRMS, the sex distribution is more even, the disease begins later in life (mean age approximately 40 years), and disability develops faster (at least relative to the onset of the first clinical symptom). 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. Like patients with PPMS, these patients experience a steady deterioration in their condition from disease onset. However, like SPMS patients, they experience occasional attacks superimposed upon their progressive course. Autoimmune autonomic neuropathy is a distinct clinical syndrome not related to MS. It presents with the subacute development of autonomic disturbances with orthostatic hypotension, enteric neuropathy (gastroparesis, ileus, constipation/diarrhea), and cholinergic failure; the latter consists of loss of sweating, sicca complex, and a tonic pupil. Autoantibodies against the ganglionic ACh receptor (A3 AChR) are present in the serum of many patients and are now considered to be diagnostic of this syndrome.

XI-44. The answer is D. (Chap. 381) In a patient with suspected bacterial meningitis empirical therapy should be administered promptly to reduce mortality and morbidity. The decision to obtain an imaging study prior to lumbar puncture (LP) is based on the concern of precipitating herniation in a patient with elevated intracranial pressure or focal CNS lesions. Therefore, patients with the presence of papilledema on physical examination, history of recent head trauma, known or suspected intracranial lesions (immunosuppressed, known malignancy), focal neurologic findings, or depressed level of consciousness should have a head CT or MRI prior to LP. In an immunocompetent patient with no known history of recent head trauma, a normal level of consciousness, and no evidence of papilledema or focal neurologic deficits, it is considered safe to perform LP without prior neuroimaging studies. Kernig’s sign is elicited in a supine patient by flexing the thigh and knee. A positive sign occurs when the patient has head/neck pain when passively straightening the knee. The sensitivity and specificity of this sign (also Brudzinski’s) for bacterial meningitis are unknown, but they imply meningeal irritation, not an intracranial lesion or elevated intracranial pressure. While cerebrospinal fluid cultures may be impacted by administration of antibiotics prior to LP, stains, antigen tests, and polymerase chain reaction tests will not be affected.

XI-45. The answer is B. (Chap. 381) The release of bacterial cell wall components after killing by antibiotics may evoke a marked inflammatory cytokine response in the subarachnoid space. This inflammation may lead to increased damage of the blood-brain barrier and central nervous system damage. Glucocorticoids can blunt this response by inhibiting tumor necrosis factor and interleukin-1. They work best if administered before antibiotics. Clinical trials have demonstrated that dexamethasone, 10 mg IV administered 20 minutes before antibiotics, reduced unfavorable outcomes, including death. The dexamethasone was continued for 4 days. The benefits were most striking in pneumococcal meningitis. Because this is the most common cause of meningitis in the elderly, empirical coverage should include this intervention as well. The efficacy of dexamethasone therapy in preventing neurologic sequelae is different between high- and low-income countries. Randomized trials in low-income countries (sub-Saharan Africa, Southeast Asia) failed to show benefit in subgroups of patients. The lack of efficacy of dexamethasone in these trials has been attributed to late presentation to the hospital with more advanced disease, antibiotic pretreatment, malnutrition, infection with HIV, and treatment of patients with probable, but not microbiologically proven, bacterial meningitis. The results of these clinical trials suggest that patients in sub-Saharan Africa and those in low-income countries with negative CSF Gram stain and culture should not be treated with dexamethasone. Empirical antibiotics in this case should include a third-generation cephalosporin, vancomycin, and ampicillin. However, dexamethasone may decrease vancomycin penetration into the CSF, so its use should be considered carefully in cases where the most likely organism requires vancomycin coverage. Acyclovir or valacyclovir may be used as initial empiric treatment in cases of suspected herpes CNS infection. However, in this case the LP is highly suggestive of acute bacterial infection. Intravenous gamma globulin is used as adjunctive therapy in children with known immunoglobulin deficiency who are at risk of viral meningitis/encephalitis.

XI-46. The answer is D. (Chap. 381) Listeria has become an increasingly important cause of bacterial meningitis in neonates (<1 month of age), pregnant women, individuals more than 60 years old, and immunocompromised individuals. Infection is acquired by eating contaminated foods such as unpasteurized dairy products, coleslaw, milk, soft cheeses, delicatessen meats, and uncooked hot dogs. Ampicillin is the agent most often added to the initial empirical regimen to cover L. monocytogenes.

XI-47. The answer is D. (Chap. 382) Ibuprofen, isoniazid, ciprofloxacin, tolmetin, sulfa-containing medicines, and phenazopyridine have been implicated in drug hypersensitivity leading to meningitis. The cerebrospinal fluid (CSF) will typically show neutrophils, but mononuclear cells or eosinophils are occasionally present. Most causes of chronic (not recurrent) meningitis cause a predominance of mononuclear cells. The differential for chronic meningitis is broad and a diagnosis is often difficult to make. The treating physician needs to consider a diverse array of viral, fungal, bacterial, mycobacterial, helminthic, and protozoal pathogens, both common and exotic, and therefore should obtain a detailed social history and consult an expert in the field. Recurrent meningitis is often due to herpes simplex virus type 2 infection and this should be ruled out, particularly if active genital ulcers develop concurrently. Malignancy, sarcoidosis, and vasculitis are all potential causes, and history, physical examination, and appropriate further testing should dictate the degree to which these possibilities are explored. Medications are often overlooked as a cause of chronic meningitis and should always be carefully considered. When CSF neutrophils predominate after 3 weeks of illness, NocardiaActinomycesBrucella, tuberculosis (<10% of cases), and fungal and noninfectious causes of chronic meningitis should be considered.

XI-48. The answer is E. (Chap. 383) Prions are infectious particles that cause central nervous system degeneration. The human prion diseases described to date include Creutzfeldt-Jacob disease (CJD), kuru, Gerstmann-Straüssler-Scheinker disease, and fatal insomnia. The most common prion disease is sporadic CJD (sCJD), which occurs in a seemingly random pattern in adults in their fifth and sixth decades of life. sCJD accounts for about 85% of cases of CJD and occurs in approximately 1 per 1 million population. Variant CJD (vCJD) results from infection from bovine exposure to tainted beef from cattle with bovine spongiform encephalopathy (BSE). There has been a steady decline of cases of vCJD in Europe over the past decade. Infectious CJD (iCJD) has resulted from injection of tainted human growth hormone, as well as transplant of infected dura mater grafts into humans. Familial CJD (fCJD) is due to germ-line mutations that follow an autosomal dominant inheritance. Kuru is due to infection through ritualistic cannibalism. Gerstmann-Straüssler-Scheinker disease and familial fatal insomnia (FFI) occur as dominantly inherited prion diseases. Sporadic cases of fatal insomnia (sFI) have been described.

XI-49. The answer is B. (Chap. 383) Startle myoclonus is a worrisome sign but is neither sensitive nor specific for CJD, though it is more worrisome if it occurs during sleep. The constellation of dementia, myoclonus, and periodic electrical bursts in an afebrile 60-year-old patient generally indicates CJD. Clinical abnormalities in CJD are confined to the CNS. Lewy body dementia, Alzheimer’s disease, central nervous system infections, and myoclonic epilepsy can all cause myoclonus. Both EEG and MRI can help differentiate CJD from these disorders. The MRI finding of cortical ribboning and intensity in the basal ganglia on fluid-attenuated inversion recovery sequences is characteristic of CJD. EEG is useful if stereotypical periodic bursts every 1–2 seconds are present, but this is seen in only 60% of cases, and other findings may be less specific. Demonstration of specific immunoassays for proteolytic products of disease-causing prion proteins (PrPSc) at brain biopsy may be necessary to confirm diagnosis in some cases. However, these proteins are not uniformly distributed throughout the brain and false-negative biopsies occur. Both surgeons and pathologists must be warned to use standard precautions under these circumstances. 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. This test alone is neither sensitive nor specific, as patients with herpes simplex virus encephalitis, multi-infarct dementia, and stroke may have similar elevations.

XI-50. The answer is A. (Chap. 384) Charcot-Marie-Tooth (CMT) syndrome is the most common type of hereditary neuropathy. CMT is comprised of several similar but genetically distinct conditions with different associated mutations. CMT1 is the most common and is an inherited demyelinating sensorimotor neuropathy. CMT1 affects patients in the first to third decades of life with distal leg weakness, i.e., footdrop. Although patients generally do not complain of sensory symptoms, these can often be elicited on physical examination. Muscle stretch reflexes are unobtainable or reduced throughout and calves are often atrophied, which makes legs appear to have a so-called inverted champagne bottle appearance. Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder characterized by recurrent attacks of pain, weakness, and sensory loss in the distribution of the brachial plexus that often begins in childhood. Hereditary sensory and autonomic neuropathy (HSAN) is a very rare group of hereditary neuropathies in which sensory and autonomic dysfunction predominates over muscle weakness. This would not fit the clinical pattern described here. Guillain-Barré syndrome presents generally acutely with involvement of both proximal and distal weakness and sensory loss. The prolonged symptom period and distribution described here is not typical for Guillain-Barré syndrome. Fabry disease is an X-linked disorder in which men are more commonly affected than women. Patients have angiokeratomas, which are reddish-purple lesions usually found around the umbilicus, scrotum, and inguinal region. Burning pain in the hands and feet often is found in late childhood or early adult life. Patients also have premature atheroscloerosis from the underlying mutation in the alpha-galactosidase gene with accumulation of ceramide in nerves and blood vessels.

XI-51. The answer is F. (Chap. 384) One of the most common side effects of isoniazid treatment is peripheral neuropathy. The elderly, malnourished, and “slow acetylators” are at increased risk for developing the neuropathy. INH inhibits pyridoxal phosphokinase, resulting in pyridoxine (vitamin B6) deficiency and the neuropathy. Prophylactic administration of pyridoxine can prevent the neuropathy from developing. 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 hypothyroidism is present.

XI-52. The answer is C. (Chap. 384) Diabetes mellitus (DM) is the most common cause of peripheral neuropathy in developed countries and is associated with several different types of polyneuropathy including distal symmetric sensory or sensorimotor polyneuropathy, autonomic neuropathy, diabetic neuropathic cachexia, polyradiculoneuropathies, cranial neuropathies, and other mononeuropathies. Risk factors for the development of neuropathy include long-standing and poorly controlled diabetes and the presence of retinopathy or nephropathy. The patient here appears to have diabetic distal symmetric sensory and sensorimotor polyneuropathy (DSPN), which is the most common form of diabetic neuropathy and presents with sensory loss beginning in the toes and gradually progresses over time up the legs and into the fingers and arms. Symptoms also may include tingling, burning, and deep, aching pains. Nerve biopsy, though rarely indicated, often shows axonal degeneration, endothelial hyperplasia, and occasionally perivascular inflammation. Tight glucose control prevents the development of disease but does not reverse established disease. Diabetic autonomic neuropathy is often seen in combination with DSPN and manifests by abnormal sweating, dysfunctional thermoregulation, dry eyes and mouth, postural hypotension, gastrointestinal abnormalities including gastroparesis, and genitourinary dysfunction.

XI-53. The answer is B. (Chap. 384) Peripheral neuropathy is a general term indicating peripheral nerve disorders of any cause. The causes are legion, but peripheral neuropathy can be classified by a number of means: axonal versus demyelinating, mononeuropathy versus polyneuropathy versus mononeuritis multiplex, sensory versus motor, and by the tempo of the onset of symptoms. Mononeuropathy typically results from local compression, trauma, or entrapment of a nerve. Polyneuropathy often results from a more systemic process. The distinction between axonal and demyelinating can often be made only with nerve conduction studies. HIV infection causes a common, distal, symmetric, mainly sensory polyneuropathy. Vitamin B12 deficiency typically causes a sensory neuropathy that predominantly involves the dorsal columns. Hypothyroidism and acromegaly may both cause compression and swelling of nerve fibers, resulting first in sensory symptoms and later in disease with motor symptoms. Critical illness polyneuropathy is predominantly motor in presentation. Patients typically present with weakness that can be profound. These patients may recover over the course of weeks to months. The etiology is unknown, but an association may exist with prolonged immobilization, severity of illness, neuromuscular blockade, and corticosteroids.

XI-54. The answer is B. (Chap. 384) Carpal tunnel syndrome is caused by the entrapment of the median nerve at the wrist. Symptoms begin with paresthesias in the median nerve distribution. With worsening, atrophy and weakness may develop. This condition is most commonly caused by excessive use of the wrist and situations involving repetitive motion. Most cases are idiopathic other than those related to occupational or environmental associations. Less commonly, systemic disease may result in carpal tunnel syndrome related to nerve compression or infiltrative disease. This may be suspected when bilateral disease is apparent. Tenosynovitis with arthritis, as in the case of rheumatoid arthritis, and thickening of the connective tissue, as in the case of amyloid or acromegaly, may cause carpal tunnel syndrome. Other systemic diseases, such as hypothyroidism and diabetes mellitus, are also possible etiologies. Acute or chronic leukemia is not typically associated with carpal tunnel syndrome.

XI-55. The answer is B. (Chap. 385) Guillain-Barré syndrome (GBS) is an acute, severe polyradiculoneuropathy that is autoimmune in nature. GBS manifests as rapidly evolving, areflexic motor paralysis with or without sensory disturbance, usually with ascending paralysis developing over several days. Approximately 70% of GBS cases occur 1–3 weeks after an acute infectious process, usually respiratory or gastrointestinal. Twenty to thirty percent of cases in North America, Europe, and Australia are preceded by infection or reinfection with Campylobacter jejuni. Other implicated infections include Epstein-Barr virus, CMV, and Mycoplasma pneumoniaeT. whippelii is the etiologic agent of Whipple’s disease and B. henselae is implicated in cat-scratch fever.

XI-56. The answer is E. (Chap. 386) Myasthenia gravis (MG) is a neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. The primary defect is a decrease in the number of acetylcholine receptors at the neuromuscular junction secondary to autoimmune antibodies. MG is not rare, affecting at least 1 in 7500 individuals. Women are affected more frequently than men. Women typically present in the second and third decades of life, and men present in the fifth and sixth decades. The key features of MG are weakness and fatigability. Clinical features include weakness of the cranial muscles, particularly the eyelids and extraocular muscles. Diplopia and ptosis are common initial complaints. Weakness in chewing is noticeable after prolonged effort. Speech may be affected secondary to weakness of the palate or tongue. Swallowing may result from weakness of the palate, tongue, or pharynx. In the majority of patients the weakness becomes generalized. The diagnosis is suspected after the appearance of the characteristic symptoms and signs. Edrophonium is an acetylcholinesterase inhibitor that allows ACh to interact repeatedly with the limited number of AChRs, producing improvement in the strength of myasthenic muscles. False-positive tests may occur in patients with other neurologic diseases. Electrodiagnostic testing may show evidence of reduction in the amplitude of the evoked muscle action potentials with repeated stimulation. Testing for the specific antibodies to AChR are diagnostic. In addition to anti-AChR antibodies, antibodies to MuSK have been found in some patients with clinical MG. Antibodies to voltage-gated calcium channels are found in patients with the Lambert-Eaton syndrome.

XI-57. The answer is C. (Chap. 386) 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. A CT or MRI of the mediastinum may show enlargement or neoplastic changes in the thymus and is recommended upon diagnosis. Hyperthyroidism occurs in 3–8% of patients with myasthenia gravis and may aggravate weakness. Testing for rheumatoid factor and antinuclear antibodies should also be obtained because of the association of myasthenia gravis to other autoimmune diseases. Due to side effects of immunosuppressive therapy, a thorough evaluation should be undertaken to rule out latent or chronic infections such as tuberculosis. Measurements of ventilatory function are valuable as a baseline because of the frequency and seriousness of respiratory impairment in myasthenic patients, and they can be used as an objective measure of response to therapy.

XI-58. The answer is E. (Chap. 387) All classes of lipid-lowering agents have been implicated in muscle toxicity including fibrates, HMG-CoA reductase inhibitors, niacin, and ezetimibe. Myalgia, malaise, and muscle tenderness are the most common manifestations, and muscle pain may be exacerbated by exercise. Proximal weakness may be found on examination. In severe cases, rhabdomyolysis and myoglobinuria may occur, though most cases are mild. Concomitant use of statins with fibrates and cyclosporine are more likely to cause adverse muscle reactions. Elevated serum CK is often identified, and muscle weakness is evidenced by myopathic EMG studies and myonecrosis on muscle biopsy. Severe myalgias, muscle weakness, and significant elevations in CK (>3 × upper limit of normal) and myoglobinuria are indications for stopping. After cessation, improvement generally occurs after several weeks.

XI-59. The answer is E. (Chap. 387) A number of endocrinologic conditions are associated with myopathy. Both hypo- and hyperthyroidism are associated with proximal muscle weakness. Hypothyroidism is frequently associated with an elevated CK, even with minimal clinical evidence of muscle disease. Thyrotoxic patients may have fasciculations in addition to proximal myopathy, but in contrast to hypothyroid patients, CK is not generally elevated. Hyperparathyroidism is associated with muscle weakness that is generally proximal. Muscle wasting and brisk reflexes are also generally present. Serum CK levels may be normal or slightly elevated. Serum calcium and phosphate levels show no correlation with clinical weakness. Hypoparathyroid patients also often have myopathy due to hypocalcemia. Patients with acromegaly usually have mild proximal weakness without atrophy. The duration of acromegaly, not the serum growth hormone levels, correlate with the degree of myopathy. Diabetes mellitus is a very rare cause of myopathy, generally due to ischemic infarction of muscle and not a primary myopathy. Finally, vitamin D deficiency is associated with muscle weakness, as are glucocorticoid excess states, e.g., Cushing’s disease.

XI-60. The answer is D. (Chap. 387) There are two recognized clinical forms of myotonic dystrophy, both of which are characterized by autosomal dominant inheritance. Myotonic dystrophy 1 (DM1) is the most common form and the most likely disorder in this patient. Characteristic clinical features of this disorder include a “hatchet-faced” appearance, due to wasting of the facial muscles, and weakness of the neck muscles. In contrast to the muscular dystrophies (Becker and Duchenne), distal limb muscle weakness is more common in DM1. Palatal, pharyngeal, and tongue involvement are also common and produce the dysarthric voice that is frequently heard. The failure of relaxation after a forced hand-grip is characteristic of myotonia. Percussion of the thenar eminence can also elicit myotonia. In most individuals, myotonia is present by age 5, but clinical symptoms of weakness that lead to diagnosis may not be present until adulthood. Cardiac conduction abnormalities and heart failure are also common in myotonic dystrophy. Diagnosis can often be made from clinical features alone in an individual with classic symptoms and a positive family history. An electromyogram would confirm myotonia. Genetic testing for DM1 would show a characteristic trinucleotide repeat on chromosome 19. Genetic anticipation occurs with an increasing number of repeats and worsening clinical disease over successive generations. Myotonic dystrophy 2 (DM2) causes primarily proximal muscle weakness and is also known by the name proximal myotonic myopathy (PROMM). Other features of the disease overlap with DM1. Acid maltase deficiency (glucosidase deficiency, or Pompe’s disease) has three recognized forms, only one of which has onset in adulthood. In the adult-onset form, respiratory muscle weakness is prominent and often is the presenting symptom. As stated previously, Becker and Duchenne muscular dystrophies present with primarily proximal muscle weakness and are X-linked recessive disorders. Becker muscular dystrophy presents at a later age than Duchenne muscular dystrophy and has a more prolonged course. Otherwise, their features are similar. Nemaline myopathy is a heterogeneous disorder marked by the threadlike appearance of muscle fibers on biopsy. Nemaline myopathy usually presents in childhood and includes a striking facial appearance similar to that in myotonic dystrophy with a long, narrow face. This disease is inherited in an autosomal dominant fashion.

XI-61. The answer is B. (Chap. 388) When patients present with proximal muscle weakness and myositis, whether polymyositis, dermatomyositis, or inclusion body myositis, the diagnosis is confirmed by analysis of serum muscle enzymes, EMG findings, and muscle biopsy. The most sensitive serum enzyme is creatinine kinase (CK), which can be elevated as much as 50-fold in active disease. CK levels usually parallel disease activity, but can be normal in some patients with inclusion body myositis or dermatomyositis. CK is always elevated in active polymyositis and thus is considered most sensitive. Other enzymes may be elevated as well including glutamic-oxaloacetic transaminase, glutamate pyruvate transaminase, lactate dehydrogenase, and aldolase.

XI-62. The answer is B. (Chap. 388) Various autoantibodies against nuclear antigens, e.g., ANAs, and cytoplasmic antigens are found in up to 20% of patients with inflammatory myopathies. The antibodies to cytoplasmic antigens are directed against ribonucleoproteins involved in protein synthesis (antisynthetases) or translational transport (anti–signal-recognition particles). The antibody directed against the histidyl-transfer RNA synthetase, called anti-Jo-1, accounts for 75% of all the antisynthetases and is clinically useful because up to 80% of patients with this autoantibody will have interstitial lung disease. Patients with anti-Jo-1 may also have Raynaud’s phenomenon, nonerosive arthritis, and the MHC molecules DR3 and DRw52. Interstitial lung disease associated with anti-Jo-1 is often rapidly progressive and fatal, even if treated aggressively with cyclophosphamide or other immunosuppressants.

XI-63. The answer is A. (Chap. 388) Dermatomyositis is associated with malignancy in up to 15% of cases, thus age-appropriate cancer screening is indicated when this diagnosis is made. Exhaustive cancer searches are not recommended, however. Dermatomyositis may be associated occasionally with scleroderma and mixed connective tissue disease, but less frequently with systemic lupus erythematosus, rheumatoid arthritis, or Sjögren’s syndrome, which are more closely associated with polymyositis or inclusion body myositis (IBM). Viruses may be associated with IBM and polymyositis, but are not proven to be associated with dermatomyositis. Parasites and bacteria such as cestodes and nematodes are associated with polymyositis, but not other forms of inflammatory myopathy. Finally, thyroid-stimulating immunoglobulins are not known to be associated with dermatomyositis.

XI-64. The answer is A. (Chap. 388) A common mistake in the management of patients with inflammatory myopathy is to “chase the CK” instead of adjusting therapy based on the clinical response. The goal of therapy is to improve strength. If that goal is being achieved, no augmentation of therapy is necessary. In this case, the plan to switch to long-term maintenance with steroid-sparing immunosuppressants should still be pursued. There have been no controlled studies comparing mycophenolate to methotrexate for long-term use in polymyositis, and in the absence of an adverse reaction to mycophenolate, therapy should not be changed. Despite an elevated CK, patients with polymyositis who are responding to therapy do not need a repeat muscle biopsy.

XI-65. The answer is B. (Chap. e47) The FLAIR MRI shows increased signal bilaterally in the occipital lobes predominantly involving the white matter. This pattern is typical of a hyperperfusion state, in this case secondary to calcineurin-inhibitor toxicity. This clinical-radiographic abnormality was previously described as reversible posterior leukoencephalopathy. However, this characterization is no longer utilized because the syndrome may not be reversible, the territory may not be confined posteriorly, and gray matter may be involved. Hyperperfusion syndrome may be due to a hydrostatic elevation in cerebral capillary pressure or disorders with endothelial dysfunction and capillary leakage. Hydrostatic causes include hypertensive encephalopathy, post–carotid endarterectomy syndrome, (pre)eclampsia, and high-altitude cerebral edema. Endothelial dysfunction causes include calcineurin-inhibitor toxicity, other chemotherapeutic agent toxicity, HELLP syndrome, TTP, SLE, or Wegener’s granulomatosis. The diagnosis is clinical and radiographic. CSF findings are nonspecific. In the case of cyclosporine the syndrome may occur with therapeutic serum levels and sporadically after years of treatment. Acoustic neuroma would present on MRI with a discrete mass. The radiologic and clinical appearance is not consistent with pituitary apoplexy. Post–liver transplant patients are at risk of acute (streptococcal) and chronic (tuberculous) meningitis, but the clinical and radiologic findings in this case would not be typical.

XI-66. The answer is B. (Chap. e47) Acute neurologic events, such as encephalopathy or stroke (often related to intraoperative hypotension or embolism), are common after open heart surgery or coronary artery bypass graft (CABG). Additionally, a chronic syndrome of cognitive impairment is now increasingly recognized after surgery. Small or microemboli during surgery are thought to be the etiology of a hyper- or hypoactive confusional state in the postoperative period. A smaller burden of microemboli may be responsible for the more subtle post–cardiac surgery syndrome characterized by confusion and depressive symptoms as described in this case. Cardiac surgery may also unmask the early manifestations of vascular dementia or Alzheimer’s disease. Off-pump CABG patients have a shorter length of hospital stay and fewer perioperative complications. Recent studies do not confirm the hypothesis that off-pump surgery results in less cognitive impairment than on-pump surgery. Ongoing studies are testing the efficacy of microfilters to capture emboli and reduce CNS complications. Given the temporal relation to CABG surgery and the lack of temporal variability, multiple sclerosis is not likely in this case. Similarly, in the absence of meningitis or encephalitis signs or symptoms, streptococcal or West Nile virus disease is unlikely. vCJD is associated with ingestion of prion-contaminated product. It is characterized by rapidly developing delirium and dementia, often associated with myoclonic jerks.

XI-67. The answer is E. (Chap. e47) 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. Poorly applied leg braces, fibular fracture, tight-fitting stockings, or casts may cause peroneal nerve injury and neuropathy. Patients may present with footdrop (dorsiflexion defect) with weakness of foot eversion. Intact foot inversion at the ankle distinguishes peroneal nerve injury from L5 radiculopathy, which involves the muscles innervated by the tibial nerve. Sensory loss due to peroneal nerve injury involves the lateral aspect of the leg below the knee and the dorsum of the foot. Cauda equina syndrome is caused by compression of the spinal nerve roots of the lumbar plexus usually due to tumor, trauma, or spinal stenosis. It typically presents with weakness of the muscles innervated by the involved nerves, incontinence, and decreased anal sphincter tone. Cauda equina syndrome is usually a medical emergency to avoid permanent functional loss. The femoral nerve branches into anterior and posterior portions in the leg. Injury of the anterior branches may lead to sensory findings in the thigh and muscular findings in the sartorius and the quadriceps. L4 radiculopathy causes symptoms in the anterior thigh and knee extensors (including the patellar reflex).

XI-68. The answer is A. (Chap. 389) Chronic fatigue syndrome (CFS) is a disorder characterized by persistent and unexplained fatigue resulting in severe impairment in daily functioning. Besides intense fatigue, most patients with CFS report concomitant symptoms such as pain, cognitive dysfunction, and unrefreshing sleep. Additional symptoms can include headache, sore throat, tender lymph nodes, muscle aches, joint aches, feverishness, difficulty sleeping, psychiatric problems, allergies, and abdominal cramps. Criteria for the diagnosis of CFS have been developed by the U.S. Centers for Disease Control and Prevention (see Table XI-68). CFS is seen worldwide, with adult prevalence rates varying between 0.2% and 0.4%. In the United States, the prevalence is higher in women, members of minority groups (African and Native Americans), and individuals with lower levels of education and occupational status. 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.

TABLE XI-68 Diagnostic Criteria for Chronic Fatigue Syndrome


Characterized by Persistent or Relapsing Unexplained Chronic Fatigue

Fatigue lasts for at least 6 months.

Fatigue is of new or definite onset.

Fatigue is not the result of an organic disease or of continuing exertion.

Fatigue is not alleviated by rest.

Fatigue results in a substantial reduction in previous occupational, educational, social, and personal activities.

Four or more of the following symptoms are concurrently present for 6 months:

Impaired memory or concentration, sore throat, tender cervical or axillary lymph nodes, muscle pain, pain in several joints, new headaches, unrefreshing sleep, or malaise after exertion.

Exclusion Criteria

Medical condition explaining fatigue

Major depressive disorder (psychotic features) or bipolar disorder

Schizophrenia, dementia, or delusional disorder

Anorexia nervosa, bulimia nervosa

Alcohol or substance abuse

Severe obesity (BMI >40)


XI-69. The answer is B. (Chap. 389) Cognitive behavioral therapy (CBT) and graded exercise therapy (GET) have been found to be the only beneficial interventions in chronic fatigue syndrome (CFS). CBT is a psychotherapeutic approach directed at changing condition-related cognitions and behaviors. CBT for CFS aims at changing a patient’s perpetuating factors by exploiting various techniques and components. The intervention, which typically consists of 12–14 sessions spread over 6 months, helps CFS patients gain control over their symptoms. GET is based on the model of deconditioning and exercise intolerance and usually involves a home exercise program that continues for 3–5 months. Walking or cycling is systematically increased, with set target heart rates. Evidence that deconditioning is the basis for symptoms in CFS is lacking, however. The primary component of CBT and GET that results in a reduction in fatigue is a change in the patient’s perception of fatigue and focus on symptoms. CBT is generally the more complex treatment, which might explain why CBT studies tend to yield better improvement rates than GET trials. Not all patients benefit from CBT or GET. Predictors of poor outcome are somatic comorbidity, current disability claims, and severe pain. CBT offered in an early stage of the illness reduces the burden of CFS for the patient as well as society in terms of decreased medical and disability-related costs. Full recovery from untreated CFS is rare: the median annual recovery rate is 5% (range 0–31%) and the improvement rate 39% (range 8–63%). Major depressive disorder, bipolar disorder, eating disorder, and schizophrenia are exclusion criteria for the diagnosis of chronic fatigue syndrome.

XI-70. The answer is D. (Chap. 391) This patient is experiencing her first episode of a panic attack and does not meet the criteria for panic disorder. In this situation, no specific treatment is required. The patient should be reassured in a manner that is empathetic and supportive that she does not have any evidence of a serious medical disorder. Panic attacks are common, with about 1–3% of the population experiencing at least one panic attack. Panic attacks begin abruptly, most commonly without an immediate precipitating cause, and peak in severity over 10 minutes. The symptoms usually subside spontaneously over the course of an hour. Diagnostic criteria for a panic attack include a minimum of four of the following criteria: palpitations or racing heart, sweating, trembling, shortness of breath, feeling of choking, chest pain, nausea or GI distress, dizziness, derealization, fear of losing control, fear of dying, paresthesias, or chills/hot flushes. If a patient subsequently develops panic disorder, a variety of treatment options can be pursued. Panic disorder is marked by at least 1 month of recurrent panic attacks associated with excessive worry about or change in behavior as a result of the attacks. The goals of therapy for panic attacks are to decrease the frequency of attacks and the severity of symptoms during the attack. Antidepressant medications are the cornerstone of therapy with selective serotonin reuptake inhibitors being the most frequently used class of medication. The dose of medication for panic disorder is typically lower than the antidepressant dose. For fluoxetine, this would be 5–10 mg daily. As these medications take 2–6 weeks to become effective, they are often combined with benzodiazepines to be used on an as-needed basis for immediate relief of attacks. Alprazolam and clonazepam are common agents used for panic disorder, although alprazolam may have more associated dependence with the need for escalating doses of medications. In combination with pharmacologic therapy, psychotherapy and education are also useful for the treatment of panic disorder. The therapy often includes breathing techniques, cognitive behavioral therapy, and even homework assignments.

XI-71. The answer is A. (Chap. 391) There are increasing numbers of antidepressant medications available in a variety of classes. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used antidepressant drugs. This class of medications includes fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram. These medications are taken once daily and have side effects including sexual dysfunction, headache, and insomnia. Tricyclic antidepressants were commonly used in past decades for the treatment of depression. However, overdoses can be lethal, and anticholinergic side effects including dry mouth, constipation, and urinary retention can limit the dose. Medications in the tricyclic class of antidepressants include amitriptyline, nortriptyline, imipramine, desipramine, doxepin, and clomipramine. Mixed norepinephrine/serotonin reuptake inhibitors and receptor blockers are a newer class of medications. These medications are increasing in use as they are quite effective and do not have the same frequency of sexual dysfunction. Medications in this class include venlafaxine, desvenlafaxine, duloxetine, and mirtazapine. Monoamine oxidase inhibitors were once a common antidepressant class of medication, but these medications are now only rare used. 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. A final class of antidepressants is called simply mixed action drugs and includes trazodone, bupropion, and nefazodone.

XI-72. The answer is E. (Chap. 391) Post-traumatic stress disorder (PTSD) was only added as a discrete disorder in 1980. The diagnostic criteria for PTSD are long and require that an individual experiences an event where there was an actual or perceived threat of death or serious injury and that the individual’s reaction included intense fear or helplessness. Following the event, the individual continues to re-experience the event and avoids stimuli associated with the trauma. In association with this, there is also often a generalized withdrawal and decrease in responsiveness. At the same time, the patient exhibits an increase in arousal that is often exhibited by insomnia, irritability, hypervigilance, and difficulty concentrating. Treatment of PTSD is almost always multifactorial, including both pharmacotherapy and psychotherapy. It is not uncommon for an individual with PTSD to develop a dependence on drugs or alcohol as an attempt to control the symptoms, and any substance abuse issues need to be treated simultaneously as well. This patient’s treatment would include avoidance of alcohol and intensive substance abuse treatment as needed. Treatment with antidepressant medications can decrease anxiety and avoidance behaviors. Trazodone is often given at night for its sedating properties. Psychotherapeutic strategies include cognitive behavioral therapy to overcome avoidance behaviors as well.

XI-73. The answer is B. (Chap. 391) Fifteen percent of the population will experience at least one episode of major depression over the course of a lifetime, and most episodes of major depression are treated by primary care practitioners. Treatment can be any of a number of medications across a variety of classes. Despite the popularity of newer antidepressants, there is no evidence that these medications are more efficacious than older drugs like tricyclic antidepressants. Indeed, 60–70% of patients will respond to any drug chosen if given in a sufficient dose for 6–8 weeks. Once a patient has been on treatment for about 2 months, the response should be evaluated, and if there has been an insufficient response, a dosage increase should be considered. In this patient, a dosage increase yielded control of depressive symptoms at 4 months. Once control of symptoms has been achieved, the drug should be continued for an additional 6–9 months to prevent relapse. If a patient experiences any additional episodes of major depression, he or she will likely require indefinite maintenance treatment.

XI-74. The answer is A. (Chap. 392) Alcohol is primarily absorbed through the proximal small intestine, but small to moderate amounts can also be absorbed in the mouth, esophagus, stomach, and large intestines. Several factors can increase the rate of absorption. One factor that increases absorption is rapid gastric emptying, which can be induced by concurrent consumption of carbonated beverages. Another factor that increases absorption from the gut to the blood is the ingestion of alcohol in the absence of other calorie sources such as proteins, fat, or carbohydrates. A final factor that can increase absorption is to drink alcohol that is diluted to a modest concentration (~20% or less). At high alcohol concentrations absorption is decreased, although high blood levels may be achieved because the amount of alcohol ingested is high.

XI-75. The answer is C. (Chap. 392) Alcohol has effects on many neurotransmitters in the brain. The predominant effect of alcohol lies in its ability to cause the release of γ-aminobutyric acid (GABA) and acts primarily at the GABAA receptors. GABA is the primary inhibitory neurotransmitter in the brain and is associated with the sedative effects of alcohol. Many other drugs affect the GABA system including benzodiazepines, nonbenzodiazepine sleep aids such as zolpidem, anticonvulsants, and muscle relaxants. The euphoric effects of alcohol consumption are related to increases in dopamine, which is common to all pleasurable activities. The effects on dopamine are thought to be important in alcohol craving and relapse. In addition, alcohol alters opioid receptors and can lead to a release of beta endorphins during acute ingestion. In addition to these effects, alcohol also inhibits postsynaptic N-methyl-D-aspartate excitatory glutamate receptors. Glutamate is the primary excitatory neurotransmitter of the brain, and its inhibition further contributes to the sedative effects of alcohol. Additional important effects on neurotransmitters include increased serotonin activity and decreased nicotinic acetylcholine receptors.

XI-76. The answer is D. (Chap. 392) The acute effects of any drug depend on many factors including amount consumed and absorbed, presence of other drugs, and past experience with the drug. In an individual who is naïve to alcohol, drug levels as low as 0.02 g/dL can lead to a decrease in inhibitions and a slight feeling of intoxication. In the United States, “legal” intoxication occurs at a blood alcohol level of 0.08 g/dL in most states. At this level, decreases in cognitive and motor abilities are seen. Once an alcohol level of 0.20 g/dL is achieved, an individual is obviously impaired with slurred speech, poor judgment, and impaired coordination. Light coma and depression of respiratory rate, blood pressure, and pulse occur at levels of around 0.30 g/dL, and death is likely to occur at levels of 0.40 g/dL. However, in individuals who drink heavily, tolerance begins to develop to alcohol. After a period of 1–2 weeks of daily alcohol consumption, liver metabolism of alcohol increases by as much as 30%, but disappears quite quickly with abstinence. Cellular or pharmacodynamic tolerance also occurs and refers to the neurochemical changes that allow an individual to maintain more normal physiologic functioning despite the presence of alcohol.

XI-77. The answer is C. (Chap. 392) Alcohol abuse is defined as repetitive problems in any one of four life areas that can be attributed to alcohol. The four life areas that can be affected by alcohol include social, interpersonal, legal, or occupational. In addition, an individual who repetitively engages in hazardous behaviors while under the influence of alcohol would be considered to suffer from alcohol abuse. However, this is to be differentiated from alcohol dependence. Alcohol dependence is defined in the DSM-IV as repeated alcohol-related difficulties in three of seven life areas and includes the development of tolerance and dependence. If tolerance or dependence is present, this predicts a more severe clinical course, and the presence of alcohol dependence decreases overall life span by about a decade. Only about 50% of individuals with alcohol abuse will continue to experience similar alcohol-related problems 3–5 years later, and only 10% will go on to develop alcohol dependence. The lifetime risk of alcohol dependence in most Western countries is about 10–15% in men and 5–8% in women. However, there may be higher rates in Ireland, France, and Scandinavian countries. In addition, native cultures appear to be especially susceptible to problems with alcohol dependence. This has been seen in Native Americans, Maoris, and the aboriginal tribes of Australia.

About 60% of the risk for alcohol use disorders is attributed to genetic influences. Children of alcoholics do have a higher risk of alcohol abuse and dependence; however, this risk is about 4 times higher, not 10. Identical twins also exhibit a higher risk of concurrent alcohol abuse and dependence when compared to fraternal twins. The genetic factors that appear to be most strongly linked to alcohol use disorders include genes that are linked to impulsivity, schizophrenia, and bipolar disorder. In addition, genes that affect alcohol metabolism or sensitivity to alcohol also contribute to the genetics of alcoholism. A mutation in aldehyde dehydrogenase that is more common in individuals of Asian descent results in intense flushing when alcohol is consumed and confers a decreased risk of alcohol dependence. Conversely, genetic variants that lead to a low sensitivity to alcohol increase the risk of subsequent alcohol abuse and dependence, as higher and higher doses of alcohol are required to achieve the same effects.

XI-78. The answer is B. (Chap. 392) Individuals with alcohol dependence are susceptible to alcohol withdrawal when alcohol intake is stopped abruptly. The individual in this case scenario is likely alcohol dependent given his large amount of alcohol intake on a daily basis. Symptoms of alcohol withdrawal can range from mild tremulousness to hallucinations, seizures, or the development of delirium tremens. Other clinical features of alcohol withdrawal include anxiety, insomnia, and autonomic nervous system overactivity manifested as tachycardia, tachypnea, elevated blood pressure, and fever. This patient exhibits symptoms of the more severe delirium tremens, with mental confusion, agitation, and fluctuating levels of consciousness. While minor symptoms of alcohol withdrawal may begin as soon as 5–10 hours after cessation of alcohol intake, the symptoms do not peak for 48–72 hours, putting this patient in the appropriate time frame for alcohol withdrawal.

The best approach for the alcohol-dependent patient who abruptly stops all alcohol intake is to take a prophylactic approach and screen early for symptoms of alcohol withdrawal. Tools such as the Revised Clinical Institute for Withdrawal Assessment for Alcohol (CIWA-Ar) may help clinicians and nurses screen for the early development of symptoms and allow intervention before symptoms escalate. In this setting, most experts recommend the use of oral long-acting benzodiazepines such as chlordiazepoxide or diazepam beginning on the first day. However, in this case, the patient received no such treatment and is now experiencing severe alcohol withdrawal and delirium tremens. Intravenous medications that have a rapid onset of action and can be titrated for more aggressive symptom management are often employed in this setting. Thus, the use of IV lorazepam or diazepam is preferred in this patient. Following an initial bolus, repeated doses can be used in short intervals until the patient is calm but arousable. In some instances a continuous infusion may be required, although bolus dosing is preferred. In the most severe cases, propofol or barbiturates may be required, although the patient would most likely need to be intubated for airway protection with use of these medications.

The other options listed are not appropriate for initial management of this patient. Intravenous fluids and thiamine had been administered since hospital admission. Administration of glucose-containing fluids without thiamine in the alcohol-dependent patient can precipitate Wernicke’s encephalopathy, which would present with ophthalmoparesis, ataxia, and encephalopathy. Given the patient’s fever, an infectious etiology can be considered, and it would be appropriate to perform blood cultures in this patient. However, given the clear symptoms of alcohol withdrawal and lack of necrotizing pancreatitis on CT abdomen, empiric treatment with antibiotics is not required. Likewise, without focal neurologic findings, a head CT would be a low-yield diagnostic procedure that would be difficult to perform in the patient’s current agitated condition and would only delay appropriate therapy. Finally, restraints are best avoided if the patient’s safety can be ensured through the appropriate use of benzodiazepines, as restraints are only likely to make the patient’s agitation worse and may lead to iatrogenic harm. Haloperidol may have some sedative effect on the patient, but could lead to torsades de pointe arrhythmia as this patient is at risk for electrolyte deficiencies from his alcoholism and pancreatitis.

XI-79. The answer is D. (Chap. 392) In individuals recovering from alcoholism several medications may have a modest benefit in increasing abstinence rates. The two medications with the best risk-benefit ratio are acamprosate and naltrexone. Acamprosate inhibits NMDA receptors, decreasing symptoms of prolonged alcohol withdrawal. Naltrexone is an opioid antagonist than can be administered orally or as a monthly injection. It is thought to act by decreasing activity in the dopamine-rich ventral tegmental area of the brainstem and subsequently decreasing the pleasurable feelings associated with alcohol consumption. There is some research to suggest that the use of these medications in combination may be more effective than either one alone. Disulfiram is an aldehyde dehydrogenase inhibitor that has been used for many years in the treatment of alcoholism. However, it is no longer a commonly used drug due to its many side effects and risks associated with treatment. The primary mechanism by which it acts is to create negative effects of vomiting and autonomic nervous system hyperactivity when alcohol is consumed concurrently with use of the medication. As it inhibits an enzyme that is part of the normal metabolism of alcohol, it allows the buildup of acetaldehyde, which creates these symptoms. Because of the autonomic side effects, it is contraindicated in individuals with hypertension, a history of stroke, heart disease, or diabetes mellitus.

XI-80. The answer is E. (Chap. 393) Prescription drug abuse has increased dramatically among all age groups and is strikingly common in teenagers. Since 2007, prescription opiates have passed marijuana as the most common illicit drugs that adolescents initially abuse. This has occurred at the same time as rates of prescription narcotic abuse have increased across all age groups. 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 common prescription narcotics that are abused include morphine and hydrocodone. Among health care professionals, meperidine and fentanyl are more frequently abused.

XI-81. The answer is B. (Chap. 393) Tolerance and withdrawal begin within 6–8 weeks of chronic daily opioid use. Tolerance develops not because of increased metabolism, but through a change in the pharmacodynamics of the drugs, requiring increasing doses to achieve the euphoric effects and prevent withdrawal. With the abrupt cessation of narcotics, acute withdrawal symptoms begin within 8–10 hours after the last dose. While the symptoms of narcotic withdrawal are noxious, they are not life threatening, as is the case with benzodiazepine or barbiturate withdrawal. The primary symptoms of opiate withdrawal are related to over activity of the autonomic nervous system. This manifests as increased lacrimation, rhinorrhea, and sweating. In addition, patients frequently will have diffuse piloerection (chill bumps), giving rise to the term “cold turkey.” As withdrawal symptoms progress, patients appear restless with myalgias, nausea, vomiting, and diarrhea. Hypertension, hyperthermia, and tachypnea can occur as well. Hypotension is not a symptom of opioid withdrawal. A patient with known infection and new-onset hypotension should be evaluated for systemic infection, not withdrawal.

XI-82. The answer is E. (Chap. 393) The patient is presenting with an acute overdose of an unknown quantity of extended-release opioid medications taken with alcohol. When evaluating and treating a patient with an intention overdose, the first priority is to stabilize the patient’s condition. The patient was appropriately given the opiate antagonist naloxone by emergency responders as the patient was near-apneic. In addition, the patient was also appropriately intubated and stabilized for transport to the hospital. In the emergency room, however, the patient remained hypotensive and unresponsive. At this point, the next step in stabilizing the patient is to support the blood pressure with bolus fluid resuscitation, and if the patient fails to respond, IV vasopressors would be required. Given his ongoing unresponsive state and the expected long duration of effect with a sustained-release preparation, it is appropriate to initiate a continuous infusion of naloxone. After a bolus dose, the expected onset of action is 1–2 minutes, but the duration of effect is only a few hours. Some care must be taken when giving naloxone as one only wants to reverse the respiratory and cardiovascular depression associated with the overdose. Particularly in chronic drug abusers, high doses of naloxone can precipitate the distressing symptoms of narcotic withdrawal. When long-acting preparations of opioids are taken, activated charcoal and gastric lavage are appropriate considerations to decrease the absorption of any undigested pills. While the patient is being stabilized from a cardiovascular and respiratory standpoint, it is important that the clinician consider if any other concurrent ingestion may have occurred that would affect the patient’s outcome. As the patient is unable to provide any history and the overdose was not witnessed, one must not focus solely on the opioids. The appropriate approach is to perform a comprehensive toxicology evaluation that should include a urine drug screen, blood alcohol level, and acetaminophen levels, at a minimum. One could also consider sending for levels of aspirin or tricyclic antidepressants.

XI-83. The answer is C. (Chap. 394) Marijuana is the most commonly used illegal drug in the United States with over 6% of all individuals reporting current usage in 2009 (http://www.whitehousedrugpolicy.gov/publications/pdf/nsduh.pdf, accessed July 25, 2011). In part, the prevalence of marijuana use is related to the widespread belief that marijuana is thought to have few negative health effects. Acutely, marijuana causes a sense of relaxation and mild euphoria, not unlike that of alcohol intoxication. In addition, impaired judgment, cognition, and psychomotor performance are seen. Occasionally, acute intoxication can lead to negative emotional responses as well. A consensus about the chronic effects of marijuana usage is not clearly defined. Traditionally, marijuana usage has been linked with an “amotivational syndrome.” While it is true that chronic users of marijuana may lose interest in day-to-day activities and spend more time using the drug, this is certainly not specific for marijuana uses, and a specific “amotivational syndrome” is not defined with chronic marijuana use. Other symptoms that have been attributed to chronic marijuana use that lack good evidence for causation include depression and maturational dysfunction. In individuals with a history of schizophrenia, however, chronic marijuana use has been associated with an increased risk of psychotic symptoms.

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. The chronic effects on lung function are not known, as tobacco products are frequent confounders. Acute decreases in vital capacity and diffusion capacity are seen, but whether this translates into an increased risk of emphysema has not yet been determined. Most studies have not found an association with emphysema. A variety of other adverse physical effects have been described but not confirmed in a systematic fashion. This includes reports of low testosterone levels, decreased sperm count, impaired fetal growth, and chromosomal abnormalities.

Contrary to popular belief, chronic use of marijuana is associated with the development of tolerance as well as a withdrawal syndrome. Signs of physical tolerance include tolerance to the development of tachycardia and conjunctival injection. The psychological tolerance that develops is more prominent and predictable. This occurs rapidly, with individuals often seeking more potent compounds or smoking the drug more frequently. With cessation of marijuana use, a withdrawal syndrome can be demonstrated with irritability, anorexia, and sleep disturbance.

XI-84. The answer is E. (Chap. 395) Approximately 400,000 individuals die yearly in the United States as a result of cigarette smoking, accounting for about 20% of all deaths. While heart disease, lung cancer, and chronic obstructive pulmonary disease are most commonly connected with tobacco-related deaths, multiple cancers have also been associated with cigarette smoking. Of all cancers, cancers of the lung, oropharynx, and larynx have the strongest associations. The relative risk of lung cancer in current male cigarette smokers is as high as 23.3. However, the relative risk of lung cancer is only 12.7 among current female smokers. Other cancers that have been associated with cigarette smoking include esophageal, bladder, kidney, pancreatic, stomach, cervical, and acute myeloid leukemia. Postmenopausal breast cancer is not associated with current cigarette use, although there may be a link with premenopausal breast cancer that has not yet been fully determined.

XI-85. The answer is B. (Chap. 395) Smoking cessation is vitally important in promoting health and preventing adverse outcomes related to cigarette use. However, nicotine is a remarkably addictive substance, and most smokers require several attempts at smoking cessation prior to success. It is estimated that 33% of current smokers attempt to quit each year, with 90% of unassisted attempts at smoking cessation resulting in failure. Even with the appropriate support and best medical treatments available, sustained quit rates of 20–30% are typical. Short counseling sessions by a physician alone do increase quit rates. Therefore, questions about current tobacco use and prior quit attempts should be part of every office visit. Even when patients do not express the desire to stop smoking, they should be encouraged to consider the potential benefits of smoking cessation. As part of counseling, the physician should negotiate a quit date with the patient, typically 2 or 3 weeks after the appointment, and follow-up phone calls may be helpful. However, most often counseling should be combined with pharmacologic interventions to improve quit rates. A variety of options are available, and the most commonly used treatments are nicotine replacement therapy, bupropion, and varenicline. In this patient with a history of depression that is inadequately treated, combined therapy with bupropion and nicotine replacement would have the greatest likelihood of success. Bupropion is an antidepressant medication that has been studied for smoking cessation in randomized clinical trials. Pretreatment with bupropion for 1–2 weeks prior to the quit date increases success. Concomitant use of nicotine replacement therapy can be administered in a variety of forms including patches, gum, lozenges, and nasal or oral inhalers. Some programs advocate combining patches with a more rapidly acting nicotine product that can alleviate acute cravings for nicotine. Varenicline is a recently introduced medication that acts as a partial agonist at the nicotinic acetylcholine receptor. Concomitant nicotine administration is not felt to be helpful. Use of varenicline in this patient is contraindicated given the patient’s history of untreated depression. Varenicline has been associated with severe psychiatric symptoms, and there are reports of suicide that have been related to its use.

XI-86. The answer is D. (Chap. 395) Cigarette smoking is associated with early mortality from a variety of causes including cardiovascular, respiratory, cerebrovascular, and oncologic. It is also associated with increased complications during pregnancy (premature rupture of membranes, placenta previa, abruption placenta), delay in healing of peptic ulcers, osteoporosis, cataracts, macular degeneration, cholecystitis in women, and impotence in men. Children born to smoking mothers are more likely to have preterm delivery, higher perinatal mortality, higher rates of infant respiratory distress, and higher rates of sudden infant death. Moreover, 400,000 individuals die prematurely each year in the United States from cigarette use, representing 1 out of every 5 deaths.

XI-87. The answer is B. (Chap. 395) Smokers regulate their blood levels of nicotine by adjusting the frequency and intensity of their tobacco use. Smokers can compensate for the lower levels of nicotine in low-yield cigarettes by smoking more cigarettes or by adjusting their smoking technique with a deeper inhalation and breath hold. Therefore, smoking low-yield cigarettes is not a reasonable alternative to smoking cessation. Moreover, there is no difference in the harmful physical effects of smoking or in the potential for drug interactions. Finally, although not definitively proven, there is some thought that the rise in adenocarcinoma of the lung over the past 50 years is associated with introduction of the low-tar cigarette and the resultant change in smoking behavior associated with this.