Harrison Neurology in Clinical Medicine Second Edition

SECTION V Psychiatric Disorders682 produce characteristic signs of schizophrenia in normal newer “atypical” agents exert some degree of D2 recep- individuals; cycloserine, an NMDA receptor agonist, can tor blockade. All neuroleptics induce expression of the decrease the negative symptoms of psychosis. immediate-early gene c-fos in the nucleus accumbens, a dopaminergic site connecting prefrontal and limbic cor- Treatment: tices. The clinical efficacy of newer atypical neuroleptics, SCHIZOPHRENIA however, may involve NMDA receptor blockade, α1- and Antipsychotic agents (Table 49-14) are the cornerstone α2-noradrenergic activity, altering the relationship of acute and maintenance treatment of schizophrenia between 5HT2 and D2 receptor activity, as well as faster and are effective in the treatment of hallucinations, dissociation of D2 binding and effects on neuroplasticity. delusions and thought disorders, regardless of etiology. The mechanism of action involves, at least in part, bind- Conventional neuroleptics differ in their potency and ing to dopamine D2/D3 receptors in the ventral striatum; side-effect profile. Older agents, such as chlorpromazine the clinical potencies of traditional antipsychotic drugs and thioridazine, are more sedating and anticholinergic parallel their affinities for the D2 receptor, and even the and more likely to cause orthostatic hypotension, while higher potency antipsychotics, such as haloperidol, per- phenazine, and thiothixene, are more likely to induce TABLE 49-14 ANTIPSYCHOTIC AGENTS NAME USUAL PO SIDE EFFECTS SEDATION COMMENTS DAILY DOSE, mg EPSEs usually not prominent; can cause anticholinergic First-Generation Antipsychotics delirium in elderly patients Low-potency 100–1000 Anticholinergic effects; +++ Requires weekly WBC for Chlorpromazine orthostasis; photosensitivity; first 6 months, then biweekly (Thorazine) cholestasis; QT prolongation ++ if stable Thioridazine (Mellaril) 100–600 Agranulocytosis (1%); weight ++ Well tolerated by most Clozapine (Clozaril) 150–600 gain; seizures; drooling; patients hyperthermia ++ Mid-potency 2–50 Fewer anticholinergic side ++ Little weight gain Trifluoperazine effects; fewer EPSEs than 0 (Stelazine) with higher potency agents. 0/+ Often prescribed in doses that are too high; long-acting Perphenazine (Trilafon) 4–64 Frequent EPSEs 0/+ injectable forms of haloperidol Loxapine (Loxitane) 30–100 Frequent EPSEs 0/+ and fluphenazine available Molindone (Moban) 30–100 High-potency No anticholinergic side Requires slow titration; EPSEs Haloperidol (Haldol) .5–20 effects; EPSEs often observed with doses >6 mg qd prominent Fluphenazine (Prolixin) 1–20 Mild prolactin elevation Thiothixene (Navane) 2–50 Frequent EPSEs Bid dosing Frequent EPSEs Minimal weight gain; increases Second-Generation Antipsychotics QT interval Risperidone (Risperdal) 2–8 Orthostasis + Mixed agonist/antagonist Olanzapine (Zyprexa) 10–30 Weight gain ++ Quetiapine (Seroquel) 350–800 Sedation; weight gain; +++ anxiety Ziprasidone (Geodon) 120–200 Orthostatic hypotension +/++ Aripiprazole (Abilify) 10–30 Nausea, anxiety, insomnia 0/+ Note: EPSEs, extrapyramidal side effects; WBC, white blood count.

extrapyramidal side effects. The model first-generation improvement, but a prolonged delay in response in 683 antipsychotic agent is clozapine, a dibenzodiazepine some cases necessitates a 6- to 9-month trial for maxi- that has a greater potency in blocking the 5HT2 than the mal benefit to occur. CHAPTER 49 Mental Disorders D2 receptor and a much higher affinity for the D4 than the D2 receptor. Its principal disadvantage is a risk of Antipsychotic medications can cause a broad range of blood dyscrasias. Unlike other antipsychotics, clozapine side effects, including lethargy, weight gain, postural does not cause a rise in prolactin level. Approximately hypotension, constipation, and dry mouth. Extrapyramidal 30% of patients who do not benefit from conventional symptoms such as dystonia, akathisia, and akinesia are antipsychotic agents will have a better response to this also frequent with first-generation agents and may con- drug, which also has a demonstrated superiority to tribute to poor adherence if not specifically addressed. other antipsychotic agents in preventing suicide; how- Anticholinergic and parkinsonian symptoms respond well ever, its side-effect profile makes it most appropriate for to trihexyphenidyl, 2 mg bid, or benztropine mesylate, treatment-resistant cases. Risperidone, a benzisoxazole 1–2 mg bid. Akathisia may respond to beta blockers. In derivative, is more potent at 5HT2 than D2 receptor sites, rare cases, more serious and occasionally life-threatening like clozapine, but it also exerts significant α2 antago- side effects may emerge, including ventricular arrhyth- nism, a property that may contribute to its perceived mias, gastrointestinal obstruction, retinal pigmentation, ability to improve mood and increase motor activity. obstructive jaundice, and neuroleptic malignant syn- Risperidone is not as effective as clozapine in treat- drome (characterized by hyperthermia, autonomic dys- ment-resistant cases but does not carry a risk of blood function, muscular rigidity, and elevated creatine phos- dyscrasias. Olanzapine is similar neurochemically to phokinase levels). The most serious adverse effects of clozapine but has a significant risk of inducing weight clozapine are agranulocytosis, which has an incidence of gain. Quetiapine is distinct in having a weak D2 effect 1%, and induction of seizures, which has an incidence but potent α1 and histamine blockade. Ziprasidone of 10%. Weekly white blood cell counts are required, par- causes minimal weight gain and is unlikely to increase ticularly during the first 3 months of treatment. prolactin but may increase QT prolongation. Aripiprazole also has little risk of weight gain or prolactin increase The risk of type 2 diabetes mellitus appears to be but may increase anxiety, nausea, and insomnia as a increased in schizophrenia, and second-generation agents result of its partial agonist properties. as a group produce greater adverse effects on glucose regulation, independent of effects on obesity, than tradi- Antipsychotic agents are effective in 70% of patients tional agents. Clozapine, olanzapine, and quetiapine seem presenting with a first episode. Improvement may be more likely to cause hyperglycemia, weight gain, and observed within hours or days, but full remission usually hypertriglyceridemia than other atypical antipsychotic requires 6–8 weeks. The choice of agent depends princi- drugs. Close monitoring of plasma glucose and lipid levels pally on the side-effect profile and cost of treatment or are indicated with the use of these agents. on a past personal or family history of a favorable response to the drug in question. Atypical agents A serious side effect of long-term use of first genera- appear to be more effective in treating negative symp- tion antipsychotic agents is tardive dyskinesia, character- toms and improving cognitive function. An equivalent ized by repetitive, involuntary, and potentially irreversible treatment response can usually be achieved with rela- movements of the tongue and lips (bucco-linguo- tively low doses of any drug selected, i.e., 4–6 mg/d of masticatory triad), and, in approximately one-half of cases, haloperidol, 10–15 mg of olanzapine, or 4–6 mg/d of choreoathetosis. Tardive dyskinesia has an incidence of risperidone. Doses in this range result in >80% D2 recep- 2–4% per year of exposure, and a prevalence of 20% in tor blockade, and there is little evidence that higher chronically treated patients.The prevalence increases with doses increase either the rapidity or degree of response. age, total dose, and duration of drug administration. The Maintenance treatment requires careful attention to the risk associated with second-generation agents appears to possibility of relapse and monitoring for the develop- be much lower. The cause may involve formation of free ment of a movement disorder. Intermittent drug treat- radicals and perhaps mitochondrial energy failure. Vita- ment is less effective than regular dosing, but gradual min E may reduce abnormal involuntary movements if dose reduction is likely to improve social functioning in given early in the syndrome. many schizophrenic patients who have been main- tained at high doses. If medications are completely The CATIE study, a large scale investigation of the discontinued, however, the relapse rate is 60% within effectiveness of antipsychotic agents in “real world” 6 months. Long-acting injectable preparations (risperi- patients, revealed a high rate of discontinuation of treat- done) are considered when noncompliance with oral ment over 18 months. Olanzapine showed greater effec- therapy leads to relapses. In treatment-resistant tiveness than quetiapine, risperidone, perphenazine, or patients, a transition to clozapine usually results in rapid ziprasidone but also a higher discontinuation rate due to weight gain and metabolic effects. Surprisingly, per- phenazine, a first-generation agent, showed little evi- dence of inferiority to newer drugs. A recent long-term

SECTION V Psychiatric Disorders684 study of schizophrenic patients transitioning from older total number of homeless individuals in the United States range from 800,000–2 million, one-third of to newer-generation antipsychotics did not demon- whom qualify as having a serious mental disorder. Poor strate any effect on mortality. hygiene and nutrition, substance abuse, psychiatric ill- ness, physical trauma, and exposure to the elements Drug treatment of schizophrenia is by itself insuffi- combine to make the provision of medical care chal- cient. Educational efforts directed toward families and lenging. Only a minority of these individuals receive relevant community resources have proved to be neces- formal mental health care; the main points of contact are sary to maintain stability and optimize outcome. A treat- outpatient medical clinics and emergency departments. ment model involving a multidisciplinary case-manage- Primary care settings represent a critical site in which ment team that seeks out and closely follows the patient housing needs, treatment of substance dependence, and in the community has proved particularly effective. evaluation and treatment of psychiatric illness can most efficiently take place. Successful intervention is depen- ASSESSMENT AND EVALUATION dent on breaking down traditional administrative OF VIOLENCE barriers to health care and recognizing the physical con- straints and emotional costs imposed by homelessness. Primary care physicians may encounter situations in Simplifying health care instructions and follow-up, which family, domestic, or societal violence is discovered allowing frequent visits, and dispensing medications in or suspected. Such an awareness can carry legal and limited amounts that require ongoing contact are possi- moral obligations; many state laws mandate reporting of ble techniques for establishing a successful therapeutic child, spousal, and elder abuse. Physicians are frequently relationship. the first point of contact for both victim and abuser. Approximately 2 million older Americans and 1.5 mil- FURTHER READINGS lion U.S. children are thought to experience some form of physical maltreatment each year. Spousal abuse is AMERICAN PSYCHIATRIC ASSOCIATION: American Psychiatric Associ- thought to be even more prevalent. An interview study ation Practice Guidelines for the Treatment of Psychiatric Disor- of 24,000 women in 10 countries found a lifetime ders: Compendium 2006.Washington, DC,APA Press, 2006 prevalence of physical or sexual violence that ranged from 15–71%; these individuals are more likely to suffer CIPRIANI A et al: Comparative efficacy and acceptability of 12 new- from depression, anxiety, somatization disorder, and sub- generation antidepressants: A multiple-treatments meta-analysis. stance abuse and to have attempted suicide. In addition, Lancet 373:746, 2009 abused individuals frequently express low self-esteem, vague somatic symptomatology, social isolation, and a GALE C, DAVIDSON O: Generalised anxiety disorder. BMJ 334:579, passive feeling of loss of control. Although it is essential 2007 to treat these elements in the victim, the first obligation is to ensure that the perpetrator has taken responsibility LESPERANCE F et al: Effects of citalopram and interpersonal psy- for preventing any further violence. Substance abuse chotherapy on depression in patients with coronary artery dis- and/or dependence and serious mental illness in the ease: The Canadian Cardiac Randomized Evaluation of Antide- abuser may contribute to the risk of harm and require pressant and Psychotherapy Efficacy (CREATE) trial. JAMA direct intervention. Depending on the situation, law 297:367, 2007 enforcement agencies, community resources such as support groups and shelters, and individual and family MALLET L et al:Treatment of subthalamic nucleus stimulation in severe counseling can be appropriate components of a treat- obsessive–compulsive disorder. N Engl J Med 359:2121, 2008 ment plan. A safety plan should be formulated with the victim, in addition to providing information about MAURER D, Colt R: An evidence-based approach to the manage- abuse, its likelihood of recurrence, and its tendency to ment of depression. Prim Care 33:923, 2007 increase in severity and frequency. Antianxiety and anti- depressant medications may sometimes be useful in MITCHELL AJ et al: Clinical diagnosis of depression in primary care: treating the acute symptoms, but only if independent A meta-analysis. Lancet 374:609, 2009 evidence for an appropriate psychiatric diagnosis exists. RAY WA et al: Atypical antipsychotic drugs and the risk of sudden MENTAL HEALTH PROBLEMS cardiac death. N Engl J Med 360:225, 2009 IN THE HOMELESS ROBINSON RG et al: Escitalopram and problem-solving therapy for There is a high prevalence of mental disorders and sub- prevention of post-stroke depression. JAMA 299:2391, 2008 stance abuse among homeless and impoverished individ- uals. Depending on the definition used, estimates of the SACHS GS et al: Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 356:1711, 2007 SCHANZER B et al: Homelessness, health status, and health care use. Am J Public Health 97:464, 2007 STEIN DJ et al: Post-traumatic stress disorder: Medicine and politics. Lancet 369:139, 2007 TIIHONEN J et al: Eleven-year follow-up of mortality in patients with schizophrenia: A population-based cohort study (FIN11 study). Lancet 374:620, 2009 TYLEE A, WALTERS P: Underrecognition of anxiety and mood disor- ders in primary care: Why does the problem exist and what can be done? J Clin Psychiatry 68(Suppl 2):27, 2007 WHOOLEY MA et al: Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease. JAMA 300:2379, 2008

SECTION VI ALCOHOLISM AND DRUG DEPENDENCY

CHAPTER 50 ALCOHOL AND ALCOHOLISM Marc A. Schuckit Pharmacology and Nutritional Impact of Ethanol . . . . . . . . . . 686 Other Effects of Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690 Behavioral Effects, Tolerance, and Dependence . . . . . . . . . . 687 ■ Alcoholism (Alcohol Abuse or Dependence) . . . . . . . . . . . . . 690 ■ The Effects of Ethanol on Organ Systems . . . . . . . . . . . . . . . 688 Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688 Definitions and Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . 690 The Gastrointestinal System . . . . . . . . . . . . . . . . . . . . . . . . . 689 Genetics of Alcoholism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689 Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691 Hematopoietic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689 Identification of the Alcoholic and Intervention . . . . . . . . . . . . 691 Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689 The Alcohol Withdrawal Syndrome . . . . . . . . . . . . . . . . . . . . 692 Genitourinary System Changes, Sexual Functioning, ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695 and Fetal Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690 Alcohol, a drug, is consumed at some time by up to about 0.02 g/dL resulting from the ingestion of one 80% of the population. At low doses alcohol can have typical drink. In round figures, 340 mL (12 oz) of beer, some beneficial effects such as decreased rates of 115 mL (4 oz) of nonfortified wine, and 43 mL (1.5 oz) myocardial infarction, stroke, gallstones, and possibly (a shot) of 80-proof beverage such as whisky, gin, or vascular and Alzheimer’s dementias. However, the con- vodka each contain ~10–15 g of ethanol; 0.5 L (1 pint) sumption of more than two standard drinks per day of 80-proof beverage contains ~160 g (about 16 stan- increases the risk for health problems in many organ dard drinks), and 1 L of wine contains ~80 g of ethanol. systems. Heavy repetitive drinking, as is seen in alcohol These beverages also have additional components, called abuse and dependence, cuts short the life span by an congeners, that affect the taste and effects; congeners estimated decade in both genders, all cultural groups, include low-molecular-weight alcohols (e.g., methanol and all socioeconomic strata. Unless an individual stops and butanol), aldehydes, esters, histamine, phenols, tan- drinking, a diagnosis of alcohol dependence carries a nins, iron, lead, and cobalt. Such congeners might also ≥80% risk for continued severe problems over the next contribute to the adverse health consequences associated 5 years. In addition, even relatively low doses of alcohol with heavy drinking. can adversely affect many preexisting disease states and alter the effectiveness or blood levels of most over-the- Ethanol is a central nervous system (CNS) depressant counter and prescribed medications. that decreases neuronal activity, although some behav- ioral stimulation is observed at low blood levels. This PHARMACOLOGY AND NUTRITIONAL drug has cross-tolerance with other depressants, includ- IMPACT OF ETHANOL ing benzodiazepines and barbiturates, and all produce similar behavioral alterations. Alcohol is absorbed from Ethanol is a weakly charged molecule that moves easily mucous membranes of the mouth and esophagus (in through cell membranes, rapidly equilibrating between small amounts), from the stomach and large bowel (in mod- blood and tissues. The level of alcohol in the blood is est amounts), and from the proximal portion of the small expressed as milligrams or grams of ethanol per deciliter intestine (the major site). (e.g., 100 mg/dL or 0.10 g/dL), with blood values of The rate of absorption is increased by rapid gastric emptying (as can be induced by carbonated beverages); 686

by the absence of proteins, fats, or carbohydrates (which lactate, and a β-hydroxybutyrate/lactate ratio of between 687CHAPTER 50 Alcohol and Alcoholism interfere with absorption); by the absence of congeners; 2:1 and 9:1 (with normal being 1:1). and by dilution to a modest percentage of ethanol (max- imum at ~20% by volume). BEHAVIORAL EFFECTS, TOLERANCE, AND DEPENDENCE Between 2% (at low blood alcohol concentrations) and 10% (at high blood alcohol concentrations) of The acute effects of a drug depend on many factors. ethanol is excreted directly through the lungs, urine, or These include the dose, the rate of increase in plasma, the sweat, but the greater part is metabolized to acetaldehyde, concomitant presence of other drugs, and the past expe- primarily in the liver. The most important pathway rience with the agent. With alcohol, an additional factor occurs in the cell cytosol where alcohol dehydrogenase is whether blood alcohol levels are rising or falling; the (ADH) produces acetaldehyde, which is then rapidly effects are more intense during the former period. destroyed by aldehyde dehydrogenase (ALDH) in the cytosol and mitochondria (Fig. 50-1). A second path- “Legal intoxication” in the United States requires a way in the microsomes of the smooth endoplasmic blood alcohol concentration of at least 0.08–0.10 g/dL, reticulum (the microsomal ethanol-oxidizing system, or while levels of 0.04 or even lower are cited in some other MEOS), is responsible for ≥10% of ethanol oxidation at countries. However, behavioral, psychomotor, and cogni- high blood alcohol concentrations. tive changes are seen at levels as low as 0.02–0.03 g/dL (i.e., after one to two drinks) (Table 50-1). Deep but While alcohol supplies calories (a drink contains disturbed sleep can be seen at twice the legal intoxication ~300 kJ, or 70–100 kcal), these are devoid of nutrients level, and death can occur with levels between 0.30 and such as minerals, proteins, and vitamins. Alcohol can 0.40 g/dL. Beverage alcohol is probably responsible for also interfere with absorption of vitamins in the small more overdose deaths than any other drug. intestine and decreases their storage in the liver with modest effects on folate (folacin or folic acid), pyridox- The intoxicating effects of alcohol reflect the actions ine (B6), thiamine (B1), nicotinic acid (niacin, B3), and of this drug on a wide range of neurotransmitters, recep- vitamin A. tors, and transporters. Most prominently, alcohol acutely enhances actions at γ-aminobutyric acid A (GABAA) An ethanol load in a fasting, healthy individual is receptors and inhibits N-methyl-D-aspartate (NMDA) likely to produce transient hypoglycemia within 6–36 h, receptors. There are also effects on adenosine, with an secondary to the acute actions of ethanol on gluconeo- inhibition of uptake of this transmitter, and a transloca- genesis. This can temporarily result in abnormal glucose tion of the cyclic AMP–dependent protein kinase cat- tolerance tests (with a resulting erroneous diagnosis of alytic subunit from the cytoplasm to the nucleus. Alcohol diabetes mellitus) until the alcoholic has abstained for also affects opioid systems and cannabinol receptors, 2–4 weeks. Alcohol ketoacidosis, probably reflecting a enhances activity of the dopamine-rich reward system, decrease in fatty acid oxidation coupled with poor diet increases serotonin actions, and directly or indirectly or recurrent vomiting, can be misdiagnosed as diabetic affects most other neurochemical systems. As with most ketosis. With the former, patients show an increase in depressants, neurons adapt quickly to these actions, and serum ketones along with a mild increase in glucose but tolerance to many effects develops; after repeated expo- a large anion gap, a mild to moderate increase in serum sure, abrupt decreases in blood alcohol levels are likely to produce physiologic changes that are opposite to the 20% MEOS Acetaldehyde Ethanol TABLE 50-1 Alcohol Acetaldehyde EFFECTS OF BLOOD ALCOHOL LEVELS IN THE ABSENCE OF TOLERANCE 80% Aldehyde dehydrogenase dehydrogenase Acetyl CoA BLOOD USUAL EFFECT LEVEL, g/dL Acetate 0.02 Decreased inhibitions, a slight feeling of intoxication Citric acid 0.08 Decrease in complex cognitive functions cycle and motor performance 0.20 Obvious slurred speech, motor incoordina- Fatty acids tion, irritability, and poor judgment 0.30 Light coma and depressed vital signs CO2 + Water 0.40 Death FIGURE 50-1 The metabolism of alcohol. MEOS, microsomal ethanol- oxidizing system.

SECTION VI Alcoholism and Drug Dependency688 acute effects of this drug (i.e., withdrawal). The presence Alcohol relaxes muscles in the pharynx, which can cause of tolerance and/or withdrawal characterizes physical snoring and exacerbate sleep apnea; symptoms of the dependence. latter occur in 75% of alcoholic men >60 years. Another Tolerance is a complex phenomenon involving at common consequence of alcohol use is impaired judg- least three types of compensatory mechanisms. (1) After ment and coordination, increasing the risk of accidents 1–2 weeks of daily drinking, metabolic or pharmacokinetic and injury; 40% of drinkers in the United States have at tolerance can be seen, with up to a 30% increase in the some time driven while intoxicated. Heavy drinking can rate of hepatic ethanol metabolism.This alteration disap- also be associated with headache, thirst, nausea, vomit- pears almost as rapidly as it develops. (2) Cellular or phar- ing, and fatigue the following day, a hangover syndrome macodynamic tolerance develops through neurochemical that is responsible for significant financial losses in most changes that maintain relatively normal physiologic work environments. functioning despite the presence of alcohol. Subsequent decreases in blood levels contribute to symptoms of The effect of alcohol on the nervous system is even withdrawal. (3) Individuals learn to adapt their behavior more pronounced among alcohol-dependent individu- so that they can function better than expected under als. Chronic high doses cause peripheral neuropathy in influence of the drug (behavioral tolerance). 5–15% of alcoholics: similar to diabetes, patients experi- The cellular changes caused by chronic ethanol expo- ence bilateral limb numbness, tingling, and paresthesias, sure may not resolve for several weeks or longer following all of which are more pronounced distally. Approxi- cessation of drinking.The resulting withdrawal syndrome mately 1% of alcoholics develop cerebellar degeneration is most intense during the first 5 days, but some symp- or atrophy. This is a syndrome of progressive unsteady toms (e.g., disturbed sleep and anxiety) can take up to stance and gait often accompanied by mild nystagmus; 4–6 months to resolve. neuroimaging studies reveal atrophy of the cerebellar vermis. Fortunately, very few alcoholics (perhaps as few THE EFFECTS OF ETHANOL as 1 in 500) develop Wernicke’s (ophthalmoparesis, ataxia, ON ORGAN SYSTEMS and encephalopathy) and Korsakoff’s (retrograde and anterograde amnesia) syndromes. These occur as the result Although one to two drinks per day in an otherwise of thiamine deficiency, especially in predisposed indi- healthy and nonpregnant individual can have some ben- viduals, e.g., those with transketolase deficiency. Alco- eficial cardiovascular effects, at higher doses alcohol is holics can manifest cognitive problems lasting for weeks to toxic to most organ systems. Knowledge about the dele- months after an alcoholic binge. Brain atrophy, evident terious effects of alcohol helps the physician to identify as ventricular enlargement and widened cortical sulci alcoholic patients and provides information that can be on MRI and CT scans, occurs in ~50% of chronic used to help motivate patients to abstain. The informa- alcoholics; these changes are often reversible if absti- tion offered here generally applies to all, regardless of nence is maintained. There is no single alcoholic age or gender, although some differences apply. It is dementia syndrome; rather, this label is used to describe important to remember that the typical white- or blue- patients who have apparently irreversible cognitive collar alcoholic often functions at a fairly high level for changes (possibly from diverse causes) in the context of years, holding a job and maintaining ties with friends and chronic alcoholism. relatives who may be unaware of the severity of the drink- ing problem. Not everyone develops each of the problems As many as two-thirds of alcohol-dependent individ- described below. uals meet the criteria for a psychiatric syndrome in the Fourth Diagnostic and Statistical Manual of Mental NERVOUS SYSTEM Disorders, (DSM-IV) of the American Psychiatric Asso- ciation (Chap. 49). One-half of these relate to a preexist- Approximately 35% of drinkers (and a much higher per- ing antisocial personality manifesting as impulsivity and centage of alcoholics) experience a blackout, an episode disinhibition.The lifetime risk is 3% in males, and ≥80% of temporary anterograde amnesia, in which the person of such individuals demonstrate alcohol and/or drug forgets all or part of what occurred during a drinking dependence. Another common comorbidity occurs with evening. Another common problem, one seen after as dependence on illicit substances. The remaining third of few as several drinks, is disturbed sleep. Although alcohol alcoholics with psychiatric syndromes have preexisting might initially help a person to fall asleep, it disrupts conditions such as schizophrenia or manic depressive disease sleep throughout the rest of the night. The stages of and anxiety disorders such as panic disorder.The reasons for sleep are also altered, and time spent in rapid eye move- the comorbidities of alcoholism with independent psychi- ment (REM) and deep sleep is reduced. Patients may atric disorders are not known, but they might represent experience prominent and sometimes disturbing dreams. an overlap in genetic vulnerabilities, impaired judgment resulting from the independent psychiatric condition, or an attempt to use alcohol to alleviate some of the symptoms of the disorder or side effects of medications.

Many psychiatric syndromes can be seen temporarily CANCER 689 during heavy drinking and subsequent withdrawal.These include an intense sadness lasting for days to weeks in Drinking as few as 1.5 drinks per day increases a the midst of heavy drinking seen in 40% of alcoholics woman’s risk of breast cancer 1.4-fold. For both gen- (alcohol-induced mood disorder); temporary severe ders, four drinks per day increases the risk for oral and anxiety in 10–30% of alcoholics, often beginning during esophageal cancers approximately threefold and rectal alcohol withdrawal, and which can persist for a month cancers by a factor of 1.5; seven to eight or more drinks or more after cessation of drinking (alcohol-induced anx- per day enhances approximately fivefold the risks for iety disorder); and auditory hallucinations and/or paranoid many cancers. delusions in a person who is alert and oriented, seen in 3–5% of alcoholics (alcohol-induced psychotic disorder). HEMATOPOIETIC SYSTEM CHAPTER 50 Alcohol and Alcoholism Treatment of all forms of alcohol-induced psy- Ethanol causes an increase in red blood cell size [mean chopathology includes helping patients achieve absti- corpuscular volume, (MCV)], which reflects its effects nence and offering supportive care, as well as reassurance on stem cells. If heavy drinking is accompanied by folic and “talk therapy” such as cognitive-behavioral approaches. acid deficiency, there can also be hypersegmented neu- However, with the exception of short-term antipsychotics trophils, reticulocytopenia, and a hyperplastic bone mar- for substance-induced psychosis, substance-induced psychi- row; if malnutrition is present, sideroblastic changes can atric conditions only rarely require medications. Recovery be observed. Chronic heavy drinking can decrease pro- is likely within several days to 4 weeks of abstinence. A duction of white blood cells, decrease granulocyte mobility history of alcohol intake is an important consideration in and adherence, and impair delayed-hypersensitivity any patient with one of these psychiatric symptoms. responses to novel antigens (with a possible false-negative tuberculin skin test). Finally, many alcoholics have mild The distinction between long-term, independent thrombocytopenia, which usually resolves within a week psychiatric conditions and temporary alcohol-induced of abstinence unless there is hepatic cirrhosis or con- syndromes is important because their prognoses and gestive splenomegaly. optimal treatments are quite different. Independent syn- dromes can be recognized because they often began CARDIOVASCULAR SYSTEM before the alcohol dependence and/or remain after a period of a month or more of abstinence. Acutely, ethanol decreases myocardial contractility and causes peripheral vasodilation, with a resulting mild THE GASTROINTESTINAL SYSTEM decrease in blood pressure and a compensatory increase in cardiac output. Exercise-induced increases in cardiac Esophagus and Stomach oxygen consumption are higher after alcohol intake. These acute effects have little clinical significance for the Alcohol intake can result in inflammation of the esopha- average healthy drinker but can be problematic in men gus and stomach causing epigastric distress and gastroin- and women with persisting cardiac disease. testinal bleeding. Alcohol is one of the most common causes of hemorrhagic gastritis. Violent vomiting can The consumption of three or more drinks per day produce severe bleeding through a Mallory-Weiss lesion, results in a dose-dependent increase in blood pressure, a longitudinal tear in the mucosa at the gastroe- which returns to normal within weeks of abstinence. sophageal junction. Thus, heavy drinking is an important factor in mild to moderate hypertension. Chronic heavy drinkers have a Pancreas and Liver sixfold increased risk for coronary artery disease as well as an increased risk for cardiomyopathy. Symptoms range The incidence of acute pancreatitis (~25 per 1000 per from unexplained arrhythmias in the presence of left year) is almost threefold higher in alcoholics than in the ventricular impairment to heart failure with dilation of general population, accounting for an estimated 10% or all four heart chambers and hypocontractility of heart more of the total cases. Alcohol impairs gluconeogenesis muscle. Perhaps one-third of cases of cardiomyopathy in the liver, resulting in a fall in the amount of glucose are alcohol-induced. Mural thrombi can form in the left produced from glycogen, increased lactate production, atrium or ventricle, while heart enlargement >25% can and decreased oxidation of fatty acids. This contributes cause mitral regurgitation. Atrial or ventricular arrhyth- to an increase in fat accumulation in liver cells. In mias, especially paroxysmal tachycardia, can also occur healthy individuals these changes are reversible, but with after a drinking binge in individuals showing no other repeated exposure to ethanol, more severe changes in evidence of heart disease—a syndrome known as the the liver occur, including alcohol-induced hepatitis, “holiday heart.”This condition is observed transiently in perivenular sclerosis, and cirrhosis, with the latter the majority of alcoholics entering treatment. observed in an estimated 15% of alcoholics.

SECTION VI Alcoholism and Drug Dependency690 Chronic intake of modest doses of alcohol can have and enhanced secretion at falling blood alcohol concen- some beneficial effects.A maximum of one to two drinks trations (with the final result that most alcoholics are per day may decrease the risk for cardiovascular death, likely to be slightly overhydrated); a modest and perhaps through an increase in high-density lipoprotein reversible decrease in serum thyroxine (T4); and a more (HDL) cholesterol or changes in clotting mechanisms. In marked decrease in serum triiodothyronine (T3). Hor- one large national study, cardiovascular mortality was mone irregularities should be reevaluated after a month reduced by 30–40% among individuals reporting one or of abstinence. more drinks daily compared to nondrinkers, with overall mortality lowest among those consuming approximately ALCOHOLISM (ALCOHOL ABUSE one drink per day. Recent data have also corroborated OR DEPENDENCE) that regular light drinking decreases the risk for ischemic, but not hemorrhagic, stroke. Because many drinkers occasionally imbibe to excess, temporary alcohol-related pathology is common in GENITOURINARY SYSTEM CHANGES, nonalcoholics, especially those in the late teens to the SEXUAL FUNCTIONING, AND FETAL late twenties. When repeated problems in multiple life DEVELOPMENT areas develop, the individual is likely to meet criteria for alcohol abuse or dependence. Acutely, modest ethanol doses (e.g., blood alcohol con- centrations of 0.06 gm/dL) can increase sexual drive but DEFINITIONS AND EPIDEMIOLOGY also decrease erectile capacity in men. Even in the absence of liver impairment, a significant minority of Alcohol dependence is defined in DSM-IV as repeated chronic alcoholic men show irreversible testicular atro- alcohol-related difficulties in at least three of seven areas phy with shrinkage of the seminiferous tubules, decreases of functioning that cluster together over a 12-month in ejaculate volume, and a lower sperm count. period. Two of these seven items, tolerance and with- drawal, may have special importance as they are associated The repeated ingestion of high doses of ethanol by with a more severe clinical course. Alcohol dependence women can result in amenorrhea, a decrease in ovarian is seen in all countries where alcohol is available and occurs size, absence of corpora lutea with associated infertility, in men and women from all socioeconomic strata and and an increased risk of spontaneous abortion. Heavy all racial backgrounds. The diagnosis of alcohol depen- drinking during pregnancy results in the rapid placental dence predicts a course of recurrent problems with the transfer of both ethanol and acetaldehyde, which may use of alcohol and the consequent shortening of the life have serious consequences for fetal development. The span by a decade on average. fetal alcohol syndrome can include any of the following: facial changes with epicanthal eye folds; poorly formed Alcohol abuse is defined as repetitive problems with ear concha; small teeth with faulty enamel; cardiac atrial alcohol in any one of four life areas—social, interper- or ventricular septal defects; an aberrant palmar crease and sonal, legal, and occupational—or repeated use in haz- limitation in joint movement; and microcephaly with ardous situations such as driving while intoxicated. If an mental retardation. The amount of ethanol required and individual is not alcohol dependent, he or she still may the time of vulnerability during pregnancy have not be given a diagnosis of alcohol abuse. been defined, making it advisable for pregnant women to abstain completely. The lifetime risk for alcohol dependence in most western countries is about 10–15% for men and 5–8% OTHER EFFECTS OF ETHANOL for women. Rates are generally similar in the United States, Canada, Germany, Australia, and England; rates Between one-half and two-thirds of alcoholics have tend to be lower in most Mediterranean countries, such skeletal muscle weakness caused by acute alcoholic myopa- as Italy, Greece, and Israel, and may be higher in Ireland, thy, a condition that improves but which might not fully France, and Scandinavia. Even higher rates have been remit with abstinence. Effects of repeated heavy drink- reported for several native cultures including Native ing on the skeletal system include changes in calcium Americans, Eskimos, Maori groups, and aboriginal metabolism, lower bone density, and decreased growth tribes of Australia. These differences reflect both cul- in the epiphyses, leading to an increased risk for frac- tural and genetic influences, as described later in the tures and osteonecrosis of the femoral head. Hormonal chapter.When alcohol abuse is also considered, the rates changes include an increase in cortisol levels, which can of alcohol use disorders increase. In western countries, remain elevated during heavy drinking; inhibition of the typical alcoholic does not fulfill the common stereo- vasopressin secretion at rising blood alcohol concentrations type of a “skid-row” denizen but is more often a blue- or white-collar worker or homemaker. The lifetime

risk for alcoholism among physicians is similar to that with the leading causes of death, in decreasing order, the 691CHAPTER 50 Alcohol and Alcoholism of the general population. result of heart disease, cancer, accidents, and suicide. GENETICS OF ALCOHOLISM IDENTIFICATION OF THE ALCOHOLIC AND INTERVENTION Several separate and distinct characteristics appear to contribute to the risk. For example, some families carry Even in affluent areas ~20% of patients have an alcohol a risk for both alcoholism and drug dependence associ- use disorder. It is important to pay attention to the ated with the characteristic of high levels of impulsivity, alcohol-related symptoms and signs as well as laboratory as can be seen in the antisocial personality disorder. In tests that are likely to be abnormal in the context of reg- other families, the risk for both alcohol and drug depen- ular consumption of six to eight or more drinks per day. dence may relate to a genetic vulnerability to schizo- The two blood tests with ≥70% sensitivity and speci- phrenia, panic disorder, or manic depressive disease. A ficity for heavy alcohol consumption are γ-glutamyl third and different mechanism increases only the alco- transferase (GGT) (>35 units) and carbohydrate-deficient holism risk (e.g., in some offspring of alcoholics and transferrin (CDT) (>20 units/L); the combination of the Native Americans) through a low response to alcohol two is likely to be more accurate than either alone. and subsequent drinking higher doses to achieve the Physicians should consider using these tests to screen all desired effects. The relatively low response to alcohol patients as indicators of possible alcoholism. These sero- contributes to attitudes and drinking patterns that logic markers of heavy drinking can also be useful in increase the risk for alcohol-related problems and alco- monitoring abstinence, as they are likely to return holism. By contrast, a decreased risk for heavy drinking toward normal within several weeks of the cessation of can result from a more intense response to alcohol, as drinking; thus, increases in values of as little as 10% are seen in approximately one-half of Asian men and likely to indicate a resumption of heavy alcohol intake. women. This is due primarily to a mutation that causes Other blood tests that can be useful in identifying indi- the production of an inactive form of the enzyme viduals consuming six or more standard drinks per day ALDH, which results in higher levels of acetaldehyde include high-normal MCVs (≥91 μm3) and serum uric following alcohol ingestion. acid (>416 mol/L, or 7 mg/dL). Physical signs and symptoms that can be useful in identifying alcoholism NATURAL HISTORY include mild and fluctuating hypertension, repeated infections such as pneumonia, and otherwise unex- Although the age of the first drink is similar in alco- plained cardiac arrhythmias. Other disorders suggestive holics and nonalcoholics, earlier onset of regular drink- of dependence include cancer of the head and neck, ing and drunkenness is associated with a higher risk for esophagus, or stomach as well as cirrhosis, unexplained later problems. By the early to mid-twenties, most non- hepatitis, pancreatitis, bilateral parotid gland swelling, and alcoholic men and women moderate their drinking peripheral neuropathy. (perhaps learning from minor problems), whereas alco- holics are likely to escalate their patterns of drinking The clinical diagnosis of alcohol abuse or dependence despite difficulties. The first major life problem from ultimately rests on the documentation of a pattern of alcohol often appears in the early to mid-twenties. repeated difficulties associated with alcohol use; the def- Once established, the course of alcoholism is likely to inition is not based on the quantity and frequency of be one of exacerbations and remissions. As a rule, there alcohol consumption. Thus, in screening it is important is little difficulty in stopping alcohol use when prob- to probe for life problems and then attempt to tie in use lems develop, and this step is often followed by days to of alcohol or another substance. Information regarding months of abstinence and then a period of carefully marital or job problems, legal difficulties, histories of controlled drinking. Unless abstinence is maintained, accidents, medical problems, evidence of tolerance, etc., however, these phases almost inevitably give way to are important. While all physicians should be able to escalations in alcohol intake and subsequent problems. take the time needed to gather such information, some The course is not hopeless; following treatment, standardized questionnaires can be helpful, including the between one-half and two-thirds of alcoholics maintain 10-item Alcohol Use Disorder Screening Test (AUDIT) abstinence for years, and often permanently. Even with- (Table 50-2). However, these are only screening tools, out formal treatment or self-help groups there is at least and a careful face-to-face interview is still required for a a 20% chance of spontaneous remission with long-term meaningful diagnosis. abstinence. However, should the alcoholic continue to drink, the life span is shortened by 10–15 years on average, After alcoholism is identified, the diagnosis must be shared with the patient as part of an intervention. The presenting complaint can be used as an entrée to the alcohol problem. For instance, the patient with insomnia

692 TABLE 50-2 reminder. Motivational interviewing uses the clinician’s level of concern and understanding of the need for THE ALCOHOL USE DISORDERS IDENTIFICATION patients to progress through their own stages of enhanced TEST (AUDIT)a understanding of their problems to optimize their ability to alter their drinking behaviors. ITEM 5-POINT SCALE (LEAST TO MOST) The process of intervention is rarely accomplished in one session. Multiple sessions to explain the prob- SECTION VI Alcoholism and Drug Dependency 1. How often do you have a drink Never (0) to 4+ per lem, the optimal treatments, and the benefits of making containing alcohol? week (4) certain lifestyle changes are often required. For the 1 or 2 (0) to 10+ (4) person who refuses to stop drinking at the first inter- 2. How many drinks containing alco- vention, a logical step is to “keep the door open,” hol do you have on a typical day? Never (0) to daily establishing future meetings so that help is available as or almost daily (4) problems escalate. In the meantime the family may 3. How often do you have six or Never (0) to daily benefit from counseling or referral to self-help groups more drinks on one occasion? or almost daily (4) such as Al-Anon (the Alcoholics Anonymous group for family members) and Alateen (for teenage children of 4. How often during the last year Never (0) to daily alcoholics). have you found that you were or almost daily (4) not able to stop drinking once THE ALCOHOL WITHDRAWAL SYNDROME you had started? Never (0) to daily or almost daily (4) Once the brain has been repeatedly exposed to high 5. How often during the last year doses of alcohol, any sudden decrease in intake can pro- have you failed to do what was Never (0) to daily duce withdrawal symptoms, many of which are the normally expected from you or almost daily (4) opposite of those produced by intoxication. Features because of drinking? include tremor of the hands (shakes or jitters); agitation Never (0) to daily and anxiety; autonomic nervous system overactivity 6. How often during the last year or almost daily (4) including an increase in pulse, respiratory rate, and body have you needed a first drink in temperature; and insomnia, sometimes accompanied by the morning to get yourself going No (0) to yes, dur- frightening dreams. Because alcohol has a short half-life, after a heavy drinking session? ing the last year (4) these withdrawal symptoms generally begin within 5–10 h No (0) to yes, dur- of decreasing ethanol intake, peak in intensity on day 7. How often during the last year ing the last year (4) 2 or 3, and improve by day 4 or 5. Anxiety, insomnia, have you had a feeling of guilt or and mild levels of autonomic dysfunction may persist to remorse after drinking? some degree for 4–6 months as a protracted abstinence syndrome, which may contribute to the tendency to 8. How often during the last year return to drinking. have you been unable to remem- ber what happened the night At some point in their lives, between 2 and 5% of before because you had been alcoholics experience withdrawal seizures, often within drinking? 48 h of stopping drinking. These rare events usually involve a single generalized seizure, and electroen- 9. Have you or someone else been cephalographic abnormalities generally return to normal injured as a result of your drinking? within several days. 10. Has a relative, friend, doctor or The term delirium tremens (DTs) refers to an uncom- other health worker been con- mon state of intense acute withdrawal that includes delir- cerned about your drinking or sug- ium (mental confusion, agitation, and fluctuating levels of gested that you should cut down? consciousness) associated with a tremor and autonomic overactivity (e.g., marked increases in pulse, blood pres- Note: a The AUDIT is scored by simply summing the values associ- sure, and respirations). Fortunately, this serious and ated with the endorsed response. potentially life-threatening complication of alcohol with- Source: Adapted from DF Reinert, GP Allen: Alcoholism: Clinical drawal is seen in <5% of alcohol-dependent individuals; & Experimental Research 26:272, 2002, and from MA Schuckit, the chance of DTs during any single withdrawal is <1%. 2006. DTs are most likely to develop in patients with con- comitant severe medical disorders and can usually be or hypertension can be told that these are clinically avoided by identifying and treating the underlying med- important problems which, in conjunction with other ical conditions. physical findings and laboratory tests, indicate that alcohol is increasing the risk for further medical and psychologi- cal problems. The physician should share information about the course of alcoholism and explore possible avenues of addressing the problem. This process can be carried out by any physician or other health care provider. Sev- eral protocols, categorized as brief interventions and motivational interviewing, are available for health care workers to follow. The technique of brief interventions has been shown to be effective in decreasing alcohol use and problems when instituted as two 15-min ses- sions 1 month apart, along with a telephone follow-up

Treatment: can be controlled by administering any drug of this 693 ALCOHOL-RELATED CONDITIONS class in doses that decrease the agitation, and gradu- ally taper the dose over 3–5 days. While most CNS CHAPTER 50 Alcohol and Alcoholism ACUTE INTOXICATION The first priority is to depressants are effective, benzodiazepines (Chap. 49) assess vital signs and manage respiratory depression, have the highest margin of safety and lowest cost and cardiac arrhythmia, or blood pressure instability, if pre- are, therefore, the preferred class of drugs. Benzodi- sent. The possibility of intoxication with other drugs azepines with short half-lives are especially useful for should be considered, and blood and urine samples are patients with serious liver impairment or evidence of obtained to screen for opioids or other CNS depressants preexisting encephalopathy or brain damage. However, such as benzodiazepines or barbiturates. Other medical short-acting benzodiazepines such as lorazepam can conditions that must be considered include hypoglycemia, produce rapidly changing drug blood levels and must hepatic failure, or diabetic ketoacidosis. be given every 4 h to avoid abrupt fluctuations that may increase the risk for seizures. Therefore, most clini- Patients who are medically stable should be placed cians use drugs with longer half-lives, such as diazepam in a quiet environment. If recumbent, patients should lie or chlordiazepoxide, administering enough drug on on their side to minimize the risk of aspiration. When the day 1 to alleviate most of the symptoms of withdrawal intoxicated person is aggressive or violent, hospital pro- (e.g., the tremor and elevated pulse) and then gradually cedures should be followed, including planning for the decreasing the dose over a period of 3–5 days. The possibility of a show of force with an intervention team. approach is flexible; the dose is increased if signs of In the context of aggressiveness, patients should be withdrawal escalate, and the medication is withheld if reminded in a clear and nonthreatening way that the the patient is sleeping or shows signs of increasing staff wants to help them to feel better and to avoid orthostatic hypotension. The average patient requires problems. If the aggressive behavior continues, rela- 25–50 mg of chlordiazepoxide or 10 mg of diazepam tively low doses of a short-acting benzodiazepine such given PO every 4–6 h on the first day. as lorazepam (e.g., 1–2 mg PO or IV) may be used and can be repeated as needed, but care must be taken so Treatment of the patient with DTs can be challeng- that the addition of this second CNS depressant does ing, and the condition is likely to run a course of 3–5 not destabilize vital signs or worsen confusion. An alter- days regardless of the therapy employed. The focus of native approach is to use an antipsychotic medication care is to identify and correct medical problems and to (e.g., 0.5–5 mg of haloperidol PO or IM every 4-8 h if control behavior and prevent injuries. Many clinicians needed), but this has the potential danger of lowering recommend the use of high doses of a benzodiazepine the seizure threshold. Two other medications useful for (as much as 800 mg/d of chlordiazepoxide has been agitation are ziprasidone (10 mg IM every 2 h as needed, reported), a treatment that will decrease agitation and up to 40 mg) and olanzapine (2.5–10 mg IM repeated at raise the seizure threshold but probably does little to 2 h and 6 h, if needed). If aggression escalates, the improve the confusion. Other clinicians recommend patient might require a short-term admission to a locked the use of antipsychotic medications, such as haloperi- ward, where medications can be used more safely and dol, ziprasidone, or olanzapine as discussed above, vital signs more closely monitored. although these drugs have not been directly evaluated for DTs. Antipsychotics are less likely to exacerbate WITHDRAWAL The first step is to perform a thor- confusion but may increase the risk of seizures; they ough physical examination in all alcoholics who are have no place in the treatment of mild withdrawal considering stopping drinking, including a search for symptoms. evidence of liver failure, gastrointestinal bleeding, car- diac arrhythmia, infection, and glucose or electrolyte Generalized withdrawal seizures rarely require imbalance. aggressive pharmacologic intervention beyond that given to the usual patient undergoing withdrawal, i.e., The second step is to offer reassurance that the acute adequate doses of benzodiazepines. There is little evi- withdrawal is short lived and to offer adequate nutrition dence that anticonvulsants such as phenytoin or and rest. All patients should be given oral multiple B vit- gabapentin are effective in drug-withdrawal seizures, amins, including 50–100 mg of thiamine daily for a week and the risk of seizures has usually passed by the or more. Because most alcoholics who enter withdrawal time effective drug levels are reached. The rare patient are either normally hydrated or mildly overhydrated, IV with status epilepticus must be treated aggressively fluids should be avoided unless there is evidence of sig- (Chap. 20). nificant recent bleeding, vomiting, or diarrhea. Medica- tions can usually be administered orally. While alcohol withdrawal is often treated in a hospi- tal, efforts at reducing costs have resulted in the devel- The third step in treatment is to recognize that most opment of outpatient detoxification for relatively mild withdrawal symptoms are caused by the rapid removal abstinence syndromes. This is appropriate for patients in of a CNS depressant, in this case, alcohol. The symptoms

SECTION VI Alcoholism and Drug Dependency694 good physical condition who demonstrate mild signs of Whether the treatment begins in an inpatient or an outpatient setting, subsequent outpatient contact withdrawal despite low blood alcohol concentrations should be maintained for a minimum of 6 months and and for those without prior history of DTs or withdrawal preferably a full year after abstinence is achieved. Coun- seizures. Such individuals still require a careful physical seling with an individual physician or through groups examination, appropriate blood tests, and vitamin sup- focuses on day-to-day living, emphasizing areas of plementation. Benzodiazepines can be given in a 1- to improved functioning in the absence of alcohol (i.e., 2-day supply to be administered to the patient by a why it is a good idea to continue to abstain) and help- spouse or other family member four times a day. ing the patient to manage free time without alcohol, Patients are asked to return daily for evaluation of vital develop a nondrinking peer group, and handle stresses signs and to come to the emergency room if signs and on the job. symptoms of withdrawal escalate. The physician serves an important role in identifying REHABILITATION OF ALCOHOLICS After the alcoholic, diagnosing and treating associated med- completing alcoholic rehabilitation, ≥60% of alcoholics, ical or psychiatric syndromes, overseeing detoxification, especially middle class patients, maintain abstinence for referring the patient to rehabilitation programs, and at least a year, and many achieve lifetime sobriety. providing counseling. Physicians are also responsible for selecting which (if any) medication might be appropri- The core of treatment begins with helping patients ate during alcoholism rehabilitation. Patients often com- recognize the need to change, while working with them plain of continuing sleep problems or anxiety when to alter their behaviors to enhance compliance. Thera- acute withdrawal treatment is over, problems that may peutic maneuvers fall into several general categories, be a component of protracted withdrawal. In general, which are applied to all patients regardless of age or hypnotics or antianxiety drugs should be avoided in this ethnic group. The manner in which the treatments are situation. Patients should be reassured that the trouble used should be sensitive to the practices and needs of sleeping is normal after alcohol withdrawal and will specific populations. The first step is to help the alco- improve over the subsequent weeks and months. holic achieve and maintain a high level of motivation Patients should follow a rigid bedtime and awakening toward abstinence. This includes education about alco- schedule and avoid naps or the use of caffeine in the holism and instructions to family and/or friends to stop evenings. The sleep pattern will improve with time, and protecting the patient from problems caused by alco- the patient can avoid the rebound insomnia associated hol. The second step is to help the patient readjust to with most hypnotics and the risk for developing depen- life without alcohol and to reestablish a functional dence on another depressant. Anxiety can be addressed lifestyle through counseling, vocational rehabilitation, by helping the person to gain insight into the tempo- and self-help groups such as Alcoholics Anonymous rary nature of the symptoms and to develop strategies (AA). The third component, called relapse prevention, to achieve relaxation as well as by using forms of cogni- helps the patient to identify situations in which a return tive therapy. to drinking is likely, formulate ways of managing these risks, and develop coping strategies that increase the While the mainstay of alcoholic rehabilitation involves chances of a return to abstinence if a slip occurs. counseling, education, and cognitive approaches, several medications might be useful. The optimal length of time For many patients, especially those who are highly to continue these drugs in the context of a positive motivated and have supportive social systems, treat- response is unclear, but most clinicians would recom- ment can be on an outpatient basis. However, more mend 6–12 months. The first is the opioid-antagonist intense interventions work better than less intensive drug naltrexone, 50–150 mg/d, which has been reported measures, and some alcoholics do not respond to out- to decrease the probability of a return to drinking and to patient approaches. The decision to hospitalize or utilize shorten periods of relapse. Recently a once-per-month residential care can be made if (1) the patient has med- injection of this drug (380 mg) has been developed to ical problems that are difficult to treat outside a hospi- help improve compliance. By blocking opioid receptors, tal; (2) depression, confusion, or psychosis interferes naltrexone may decrease activity in the dopamine- with outpatient care; (3) there is a severe life crisis that rich ventral tegmental reward system, or decrease the makes it difficult to work in an outpatient setting; (4) feeling of pleasure or reward if alcohol is imbibed. outpatient treatment has failed; or (5) the patient lives The improved rate of functioning and abstinence with too far from the treatment center to participate in an this drug is modest. The side effects are relatively few outpatient program. The best predictors of continued at the recommended doses and include gastrointestinal abstinence include evidence of higher levels of life distress. A second medication, acamprosate (Campral), stability (e.g., supportive family and friends) and higher 2 g/d, has been widely tested in patients in the United levels of functioning (e.g., job skills, higher levels of edu- States and Europe; results are generally similar to those cation, and absence of crimes unrelated to alcohol).

reported for naltrexone. This drug inhibits the actions high-risk drinking situations for them (such as the 695 of NMDA receptors and has been hypothesized to act Christmas holiday). Other drugs under investigation for by decreasing mild symptoms of protracted withdrawal. possible use in alcoholism rehabilitation include the CHAPTER 50 Alcohol and Alcoholism There are few side effects, aside from mild gastroin- serotonin antagonist ondansetron; topiramate, an anti- testinal distress. Several long-term trials of combined convulsant with possible effects on dopamine; and the naltrexone and acamprosate using doses similar to cannabinol receptor antagonist ramonibant; at present, those noted above have reported that the combination there are insufficient data to support their use in clini- may be superior to either drug alone, although not all cal settings. studies agree. Additional support for alcoholics and their relatives Disulfiram, an ALDH inhibitor, has been used and friends is available through self-help programs such extensively in the past for treatment of alcoholism. In as AA. These groups, which typically consist of recover- doses of 250 mg/d this drug produces an unpleasant ing alcoholics, offer an effective model of abstinence, (and potentially dangerous) reaction in the presence of provide a sober peer group, and make crisis interven- alcohol, a phenomenon related to rapidly rising blood tion freely available when the urge to drink escalates. levels of the first metabolite of alcohol, acetaldehyde. This can help patients optimize their chances for recov- Few adequate controlled trials have demonstrated a ery, especially when incorporated into a more struc- clear superiority of disulfiram over placebo. Drinking tured treatment milieu. alcohol while taking disulfiram produces a reaction involving an increased pulse, changes in blood pressure, FURTHER READINGS and vomiting and diarrhea. This can be dangerous, especially for patients with heart disease, stroke, dia- ANDERSON P et al: Effectiveness and cost-effectiveness of policies betes mellitus, or hypertension. The drug itself has also and programmes to reduce the harm caused by alcohol. Lancet been reported to carry potential risks of depression, 373:2173, 2009 psychotic symptoms, peripheral neuropathy, and liver damage. Thus, most clinicians reserve this medication CASSWELL S, THAMARANGSI T: Reducing harm from alcohol: Call to for patients who have a clear history of longer-term action. Lancet 373:2247, 2009 abstinence associated with prior use of disulfiram, and for those who might take the drug under the supervi- GELERNTER J et al: Opioid receptor gene (OPRM1, OPRK1, and sion of another individual (such as a spouse), especially OPRD1) variants and response to naltrexone treatment for alco- during discrete periods identified as representing hol dependence: Results from the VA Cooperative Study. Alcohol Clin Exp Res 31:555, 2007 LAWRENCE AJ: Therapeutics for alcoholism: What’s the future? Drug Alcohol Rev 26:3, 2007

CHAPTER 51 OPIOID DRUG ABUSE AND DEPENDENCE Marc A. Schuckit I Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696 I Acute and Chronic Effects of Opioids . . . . . . . . . . . . . . . . . . 697 I Opioid Abuse and Dependence . . . . . . . . . . . . . . . . . . . . . . 698 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701 It is difficult to imagine modern medical practice without of these actions include nalorphine, levallorphan, cycla- the use of opioid analgesics.These drugs have been part of zocine, butorphanol, buprenorphine, and pentazocine, health care since 300 B.C. Opium and codeine were iso- each of which has mixed agonist and antagonist properties, lated in the early nineteenth century, opioid-like substances as well as naloxone, nalmefene, and naltrexone, which produced by the body were recognized in the 1970s, and are pure opiate antagonists. the first endogenous opioid was isolated in 1995.As impor- The availability of relatively specific antagonists has tant as these substances are to modern medicine, opioid drugs have many disadvantages, including overdosage and helped identify at least three receptor subtypes. These dependency; close to 1 million individuals in the United include μ receptors, which influence some of the more States are opioid-dependent. All opioid drugs are capable classic opioid actions such as pain control, reinforcement, of producing a heroin-like intoxication, as well as toler- constipation, hormone levels, and respiration; κ receptors, ance and withdrawal. with possible similar functions along with sedation and effects on hormones; and δ receptors, thought to relate mostly to analgesia, mood, reinforcement, and breathing. PHARMACOLOGY A fourth possible receptor subtype, sensitive to another endogenous peptide, is sometimes called nociceptin or The prototypic opiates, morphine and codeine orphanin and may influence pain. The major features of (3-methoxymorphine), are derived from the juice of the tolerance, dependence, and withdrawal are thought to be poppy Papaver somniferum. The semisynthetic drugs pro- mediated primarily by μ receptors, and these are affected duced from morphine or thebane molecules include by all prescription opioids. hydromorphone, diacetylmorphine (heroin), and oxy- codone. The purely synthetic opioids and their cousins The most rapid and pronounced effects of opioids include meperidine, propoxyphene, diphenoxylate, fentanyl, occur through IV administration, with only slightly less buprenorphine, tramadol, methadone, and pentazocine. efficient absorption after smoking or inhaling the vapor (“chasing the dragon”).The slowest onset and least intense The body’s own endogenous opioid peptides (e.g., effects occur after oral consumption. Most of the metab- enkephalins, endorphins, dynorphins, and others) have olism of opioids occurs in the liver, primarily through distinct distributions in the central nervous system (CNS) conjugation with glucuronic acid, and only small amounts and appear to be natural ligands for opioid receptors. are excreted directly in the urine or feces. The plasma As summarized in Table 51-1, the receptors with which half-lives of these drugs range from 2.5–3 h for mor- opioid peptides interact differentially produce analgesia, phine to >22 h for methadone. respiratory depression, constipation, euphoria, and other actions. Substances capable of antagonizing one or more Street heroin is typically only 5–10% pure and is usually mixed with sugars, quinine, powdered milk, phenacetin, 696

TABLE 51-1 as an antitussive) and respiratory depression, which result 697 ACTIONS OF OPIOID RECEPTORS from a decreased response of the brainstem to carbon dioxide tension, a component of the drug overdose syn- RECEPTOR TYPE ACTIONS drome described below.At even low drug doses, this effect CHAPTER 51 Opioid Drug Abuse and Dependence Mu (μ) (e.g., can be clinically significant for individuals with pulmonary Analgesia, reinforcement euphoria, disease. Aspiration pneumonia is an additional risk. The morphine) cough and appetite suppression, gastrointestinal effects of opioids can include decreased gut decreased respirations, decreased motility (useful in treating diarrhea), nausea, constipation, Kappa (κ) (e.g., GI motility, sedation, hormone and anorexia with weight loss. Cardiovascular changes butorphanol) changes, dopamine and acetyl- following modest doses tend to be relatively mild, with choline release no direct opioid effect on heart rhythm or myocardial Delta (δ) (e.g., Decreased dysphoria, decreased GI contractility, but orthostatic hypotension can occur, etorphine) motility, decreased appetite, probably secondary to histamine release and dilation of decreased respiration, psychotic peripheral vessels. Bacterial endocarditis with septic emboli symptoms, sedation, diuresis, and stroke can occur from contaminated needles. analgesia Opioid Toxicity and Overdosage Hormone changes, appetite suppression, dopamine release High doses of opioids can result in a potentially lethal overdose.This occurs at some point in over half of opioid- Note: GI, gastrointestinal. dependent persons, especially with the more potent drugs such as fentanyl (80–100 times more powerful than caffeine, antipyrine, and strychnine. Unexpected increases morphine).The typical syndrome, which occurs immedi- in the purity of street drugs can cause unintentional lethal ately with IV overdose, includes shallow and slow respira- overdoses. tions, pupillary miosis (with mydriasis once brain anoxia develops), bradycardia, hypothermia, and stupor or coma ACUTE AND CHRONIC EFFECTS (Chap. 14). If not treated rapidly, respiratory depression, OF OPIOIDS cardiorespiratory arrest, and death can ensue. Postmortem examination reveals few specific changes except for diffuse With the exception of overdose and physical depen- cerebral edema. An “allergic-like” reaction to IV heroin, dence, most opioid effects are rapidly reversible. A major perhaps in part related to adulterants, can also occur and is danger, however, comes through the use of contaminated characterized by decreased alertness, frothy pulmonary needles by IV users, which increases the risk of hepatitis edema, and an elevation in the blood eosinophil count. B and C, bacterial endocarditis, and infection with HIV (Chap. 37). Treatment: OPIOID OVERDOSE Effects on Organ Systems The first step in managing overdose is to support vital Euphoria and rewarding effects of opioids are due, at least signs, using intubation if needed. Definitive treatment is in part, to stimulation of dopaminergic pathways origi- the administration of a narcotic antagonist such as nalox- nating in the midbrain and terminating in the nucleus one, 0.4–2 mg IV or IM. A response should occur in 1–2 min, accumbens. Effects on other neurotransmitter systems also but if needed, the dose can be repeated every 2–3 min occur. CNS effects of opioid drugs include nausea and up to 10 mg. With the exception of buprenorphene over- vomiting (medulla), decreased pain perception (spinal cord, doses, a lack of response after 10 mg makes a toxic reac- thalamus, and periaqueductal gray region), and sedation tion due solely to opioids unlikely. It is important to titrate (reticular activating system).The adulterants added to street the dose relative to the patient’s symptoms to amelio- drugs may contribute to nervous system damage, including rate the respiratory depression but not provoke a severe peripheral neuropathy, amblyopia, myelopathy, and leukoen- withdrawal state; the latter cannot be aggressively treated cephalopathy. Acute opioid administration inhibits release until overdose-related vital signs are relatively stable. of some hormones from the hypothalamus, including Because the effects of naloxone diminish within several corticotropin-releasing factor (CRF) and luteinizing hor- hours, the individual must be monitored for at least 24 h mone, with a subsequent reduction in some sex hormones, after a heroin overdose and 72 h after an overdose of a actions that might contribute to a decreased sex drive and longer-acting drug such as methadone. If there is little problems in handling stress. Other hormonal changes response to an opioid antagonist, the possibility of a include a decrease in the release of thyrotropin and increases in prolactin and possibly growth hormone. Acute changes in the respiratory system include a CNS- mediated decrease in the cough reflex (which can be useful

SECTION VI Alcoholism and Drug Dependency698 concomitant overdose with a benzodiazepine should be at ~50%. Specific genes potentially include variations in the α2 subunit of the γ-aminobutyric acid (GABA)-A considered and a challenge with IV flumazenil, 0.2 mg/min receptor; this might affect the risk of abuse or dependence up to a maximum of 3 mg in an hour, might be used. on a wide range of substances through effects on impulsiv- This drug should be administered with caution as it can ity and sensation-seeking. All genetic influences operate precipitate seizures and increase intracranial pressure. in the context of environmental factors as well. Treatment of either the typical or the “allergic” type of Natural History opioid toxic reaction requires continued respiratory sup- port (often with oxygen supplementation and positive- While an opioid use disorder can develop in anyone, at pressure breathing for the “allergic” type of overdose), least three groups are at increased risk for dependence or IV fluids, and pressor agents when needed to support misuse. First, a minority of persons with chronic pain syn- blood pressure. Activated charcoal (e.g., 1 g/kg suspended dromes (e.g., back, joint, and muscle disorders) misuse their in water) should be considered if ingestion of large doses prescribed drugs. If physical dependence is established, of oral opioids is suspected; alternatively, gastric lavage any drop in opioid blood levels can intensify the pain and can be used to remove any remaining drug. Intubation is promote continued drug intake. Physicians can avoid con- often required to prevent aspiration in the stuporous or tributing to physical dependence by helping the patient comatose patient. Cardiac arrhythmias and/or seizures to accept the goal of moderation rather than disappearance may also be part of the opioid toxic reaction, especially of the pain, and to recognize that discomfort may not be with codeine, propoxyphene, or meperidine. completely eliminated.Analgesic medication should be only one component of treatment and should be limited to OPIOID ABUSE AND DEPENDENCE the oral administration of the least potent analgesic that is able to “take the edge off ” the pain (e.g., naproxen or Definition and Epidemiology ibuprofen). Behavior-modification techniques, such as muscle relaxation and meditation, and carefully selected The Fourth Diagnostic and Statistical Manual of Mental exercises should be used as appropriate to help increase Disorders, (DSM-IV) of the American Psychiatric Associ- function and decrease pain. Finally, nonmedicinal approaches, ation defines dependence as repeated use of a drug to the including electrical transcutaneous neurostimulation for point of causing repetitive problems in multiple life areas. muscle and joint disease, may be useful. The definition requires evidence of three or more such problems clustered together within the same 12-month The second group at high risk consists of physicians, period of time, including tolerance, withdrawal, use of nurses, and pharmacists, primarily because of easy access greater amounts of opiates than intended, and use despite to opioids. Physicians may begin use to help with sleep consequences. Patients who do not have dependence but or to reduce stress or physical aches and pains, and then demonstrate repeated opioid-related difficulties with the escalate doses as tolerance develops. Because of the growing law, impaired ability to meet obligations, use in hazardous awareness of these problems, programs have been devel- situations, or continued use despite problems can be labeled oped to identify and aid substance-impaired physicians, as having abuse. providing peer support and education before problems escalate to the point of licensure revocation.All physicians The use of opioids for intoxication is less prevalent are advised never to prescribe opioids for themselves or than the use of alcohol, marijuana, and stimulants such as family members cocaine or amphetamines. A national survey of adoles- cents and young adults published in 2005 reported that The third group is those who buy illicit drugs to get 13.5% of 12th graders (high school seniors) had tried an high.While some of these individuals have severe antisocial opioid outside of a doctor’s prescription, including 1.5% problems, many had a relatively high level of premorbid who had used heroin. Figures for young adults and col- functioning. The typical person begins using opioids lege students were almost 17.6% and 1.9%, respectively. occasionally, often after experimenting with tobacco, In all studies, prevalence rates were only slightly higher in then alcohol, then marijuana, and then brain depressants males than females.The prevalence of opioid dependence or stimulants. Occasional opioid use, or “chipping,” might is estimated as a lifetime risk of about 1%. continue for some time, and some individuals never esca- late their intake to the point of developing dependence. For Genetics others, the frequency of use and quantity needed increase, tolerance develops, excuses are made for associated prob- Genetic factors appear to influence an individual’s specific lems, and a full dependence syndrome appears. risk for opioid dependence as well as a more general vulnerability toward substance-related problems.The pro- Opioid-dependent individuals are not likely to give up portion of the total risk explained by genes is estimated their intake of other drugs.Alcohol may be used to mod- erate withdrawal problems, to enhance the opioid high, and to serve as a substitute when the opioid is not available,

including during methadone or other maintenance or SYMPTOMS OF WITHDRAWAL Withdrawal symp- 699 antagonist treatments. Problematic drinking, including toms (which are generally the opposite of the acute alcohol dependence, is seen in about half of opioid- effects of the drug) include nausea, diarrhea, coughing, CHAPTER 51 Opioid Drug Abuse and Dependence dependent persons. Cocaine appears to be taken for many lacrimation, mydriasis, rhinorrhea, profuse sweating, of the same reasons, and is often administered IV with twitching of muscles, and piloerection (or “goose bumps”) the opioid in a mixture known as a “speedball.” Another as well as mild elevations in body temperature, respiratory relevant class of drugs is the benzodiazepines, taken for a rate, and blood pressure. In addition, diffuse body pain, high or alleviation of withdrawal symptoms, especially insomnia, and yawning occur, along with intense drug among people in methadone maintenance. craving. Withdrawal from opioids with shorter half-lives, such as morphine or heroin, usually causes symptoms Once persistent opioid use is established, severe problems within 8–16 h of the last dose; intensity peaks within are likely to develop. At least 25% of opioid-dependent 36–72 h after discontinuation of the drug; and the acute individuals die within 10–20 years (a mortality rate 15-fold syndrome disappears within 5–8 days. A protracted absti- higher than the general population) from suicide, homi- nence phase of mild moodiness, autonomic dysfunction, cide, accidents, or infectious diseases such as tuberculosis, and changes in pain threshold and sleep patterns may per- hepatitis, or AIDS. The latter has become an epidemic sist for ≥6 months and probably contributes to relapse. For among injection drug users, with as many as 60% of these longer-acting opioids such as methadone or continuous- men and women in some locales carrying the HIV virus release morphine, symptoms may not appear for several (Chap. 37). Although the majority of opioid-dependent days, and may not peak until 7–10 days later. persons experience frequent exacerbations and remissions, it is important to remember that even without treatment TREATMENT OF THE WITHDRAWAL SYN- ~35% achieve long-term, often permanent, abstinence, DROME A thorough physical examination, including especially after 40 years of age.As is true with most drugs an assessment of neurologic function and a search for focal of abuse, a favorable prognosis is associated with a prior and systemic infections, especially abscesses, is essential. history of marital and employment stability and fewer Laboratory testing includes assessment of liver function prior criminal activities unrelated to drugs. and, in IV users, HIV and hepatitis B and C status. Treatment: One treatment approach to withdrawal is to administer OPIOID ABUSE AND DEPENDENCE an opioid (e.g., 10–25 mg of methadone bid) on day 1 to decrease symptoms. After several days of a stabilized drug The first step in treatment is to identify the problem. It is dose, the opioid is then decreased by 10–20% of the important to discard the erroneous stereotype that opioid- original day’s dose each day. However, the use of opioids dependent individuals are unemployed and homeless. for detoxification is proscribed or limited in most states. Abuse or dependence is possible in any patient who Thus, pharmacologic treatments often center on relief demonstrates symptoms of what might be opioid with- of symptoms of diarrhea with loperamide, of “sniffles” drawal; anyone who has a chronic pain syndrome; physi- with decongestants, and pain with nonopioid anal- cians, nurses, and pharmacists or others with easy access to gesics (e.g., ibuprofen). Comfort can be enhanced with opioids; and patients who repeatedly seek out prescrip- administration of the α2-adrenergic agonist clonidine in tion analgesics. Before prescribing an opioid analgesic, it doses up to 0.3 mg given two to four times a day to is important to gather a complete history that elucidates decrease sympathetic nervous system overactivity. Blood patterns of life problems and any history of opioid use. If pressure must be closely monitored. Some clinicians a problem with opioids is suspected, gathering further augment this regimen with low to moderate doses of data from a relative or close friend can be helpful. Addi- benzodiazepines for 2–5 days to decrease agitation and tionally, clinicians should search for physical stigmata of promote sleep. An ultra-rapid detoxification procedure misuse (e.g., needle marks) and, when appropriate, screen using deep sedation and withdrawal precipitated by blood or urine for opioids. naltrexone has been proposed but has many inherent dangers and few, if any, advantages. After identifying opioid dependence, the next step is intervention as described for alcoholism in Chap. 50. REHABILITATION The basic strategy, similar to that Motivational interviewing techniques of empathy, careful for alcoholics, includes detoxification and the establish- listening, presenting options, and gauging the patient’s ment of realistic goals for abstinence and improvement motivational readiness to change are important, as are of life functioning, along with counseling and education efforts to enlist the help of relatives and friends. Ongo- to increase motivation toward abstinence. A long-term ing treatment even after the patient achieves abstinence commitment by the patient to maintain a lifestyle with- is important; this includes offering help in establishing a out illicit substances is essential for preventing relapse. drug-free lifestyle. In most programs, patients are educated about their responsibility for improving their lives, and motivation

SECTION VI Alcoholism and Drug Dependency700 for abstinence is increased by providing information Buprenorphine is available as monotherapy or in combination with the antagonist naltrexone (2–8 mg about the medical and psychological problems that can buprenorphine with 0.5–2 mg naltrexone), which pre- be expected if dependence continues. Patients and fam- cipitates withdrawal if the patient dissolves the pills and ilies are encouraged to establish an opioid-free lifestyle by injects them IV. Buprenorphine has several advantages learning to cope with chronic pain and develop realistic including low overdose danger, potentially easier detox- vocational planning.The dependent person is also advised ification than is seen with methadone, and a probable to establish a drug-free peer group and to participate in ceiling effect in which higher doses do not increase self-help groups such as Narcotics Anonymous or Alco- euphoria. It can also be given in the doctor’s office by holics Anonymous; the latter is appropriate for substance- physicians who have completed a required training pro- dependent persons regardless of their usual drug of gram. While some studies report equal effectiveness of abuse. Another important treatment component is relapse buprenorphine and methadone, others suggest higher prevention aimed at identifying triggers for a return to dropout rates or more concomitant illicit drug use with drugs and developing appropriate coping strategies. buprenorphine compared to methadone. As with all opioids, there is a danger of misuse of this drug. Much of this advice and counseling can be given by the physician or by referring patients to formal drug In the past, the British have used heroin maintenance programs, including methadone maintenance clinics, with goals and guidelines similar to those of current programs using narcotic antagonists, and therapeutic methadone programs. There is no evidence that heroin communities. Long-term follow-up of treated patients maintenance has any advantages over methadone main- indicates that approximately one-third are completely tenance, but the heroin approach increases the risk that drug free, and 60% no longer use opioids. the drug will be sold on the streets. Opioid Maintenance Maintenance programs with Opioid Antagonists The opioid antagonists (e.g., methadone or buprenorphene should be used only in naltrexone) compete with heroin and other opioids at combination with education and counseling. The goal is receptors, reducing the effects of the opioid agonists. to provide a substitute drug that is legally accessible, Administered over long periods with the intention of safer, can be taken orally, and has a relatively long half-life blocking the opioid “high,” these drugs can be useful as so that it can be taken once a day. This can help persons part of an overall treatment approach that includes who have repeatedly failed in drug-free programs to counseling and support. Naltrexone doses of 50 mg/d improve functioning within the family and job, to decrease antagonize 15 mg of heroin for 24 h, and the possibly legal problems, and to improve health. Individuals who more effective higher doses (125–150 mg) block the stay in methadone maintenance are likely to show less effects of 25 mg of IV heroin for up to 3 days. To avoid antisocial behavior and improvement in employment precipitating a withdrawal syndrome, patients must be status. free of opioids for a minimum of 5 days before begin- ning treatment with naltrexone and should first be chal- Methadone is a long-acting opioid optimally dosed at lenged with 0.4 or 0.8 mg of the shorter-acting agent 80–120 mg/d (a goal met through slow, careful increases naloxone to be certain they can tolerate the long-acting over time). This dose is effective in blocking heroin- antagonist. A test dose of 10 mg of naltrexone is then induced euphoria while decreasing craving, thereby given, which can produce withdrawal symptoms in helping patients to maintain abstinence from illegal 0.5–2 h. If none appear, the patient can begin with the opioids. Over three-quarters of patients in well-supervised usual dose of 40–150 mg three times per week. methadone clinics are likely to remain heroin-free for ≥6 months. Methadone is usually administered as an Drug-Free Programs Most opioid-dependent indi- oral liquid given once a day at the program, with week- viduals enter treatment programs that are based primar- end doses taken at home. After a period of maintenance ily on the cognitive behavioral approaches of enhancing (usually 6 months to ≥1 year), the clinician can work to commitment to abstinence, helping individuals to rebuild slowly decrease the dose by ~5% per week. Some indi- their lives without substances, and preventing relapse. viduals, however, are unable to taper off the drug and Whether carried out in inpatient, residential, or outpa- require long-term maintenance. tient settings, patients usually do not receive mainte- nance medications. An alternative medication that has been used for maintenance treatment is buprenorphine, a μ opioid A variation of this approach can be used for persons agonist and antagonist. A dose of 6–12 mg buprenor- who are having problems maintaining a drug-free state. phine is roughly equivalent to 35–60 mg of methadone. Here, the basic elements of treatment are incorporated into Administered either as a sublingual liquid or tablet, long-term (often a year or more) residence in a therapeutic doses can be gradually increased to 8–16 mg/d over the community.The person begins with almost full immersion first 2 months. Doses of 16–32 mg per treatment day may in the environment in which other individuals at various be needed if the drug is given three times per week.

stages of recovery become the primary support group, warrant in the average person. Physicians must be vigi- 701 offering advice and a drug-free atmosphere in which lant regarding their own risk for opioid abuse and depen- the opioid-dependent person progresses through ever- dence, never prescribing these drugs for themselves. For increasing levels of independence, including assuming the nonmedical IV drug–dependent person, all possible a job outside the therapeutic atmosphere. efforts must be made to prevent AIDS, hepatitis, bacterial endocarditis, and other consequences of contaminated As is true for treatments of all substance-use disorders, needles both through methadone maintenance and by it is likely that counseling, behavioral treatments, and considering needle-exchange programs. relatively simple approaches to psychotherapy add sig- nificantly to a positive outcome. Most programs focus FURTHER READINGS CHAPTER 51 Opioid Drug Abuse and Dependence on teaching participants to cope with stress, enhancing their understanding of personality attributes, teaching JOHNSTON LD et al: Monitoring the Future: National Results on Adolescent better cognitive styles, and, through the process of relapse Drug Use: Overview of Key Findings, 2005. Bethesda, MD, National prevention, addressing issues that might contribute to Institute on Drug Abuse increased craving, easy access to drugs, or periods of decreased motivation. A combination of these therapies PASSIK SD: Issues in long-term opioid therapy: unmet needs, risks, with the approaches described above appears to give and solutions. Mayo Clin Proc 84:593, 2009 the best results. SCHUCKIT MA: Drug and Alcohol Abuse: A Clinical Guide to Diagnosis Finally, it is important to discuss prevention. Except for and Treatment, 6th ed. New York, Springer, 2006 the terminally ill, physicians should carefully monitor opi- oid drug use in their patients, keeping doses as low as is STRANG J et al: Does prescribing for opiate addiction change after practical while still controlling pain, and administering national guidelines? Methadone and buprenorphine prescribing opioids over as short a period as the level of pain would to opiate addicts by general practitioners and hospital doctors in England, 1995–2005.Addiction 102(5):761, 2007

CHAPTER 52 COCAINE AND OTHER COMMONLY ABUSED DRUGS Jack H. Mendelson† I Nancy K. Mello I Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702 I Marijuana and Cannabis Compounds . . . . . . . . . . . . . . . . . . 704 I Methamphetamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705 I Lysergic Acid Diethylamide (LSD) . . . . . . . . . . . . . . . . . . . . . 706 I Phencyclidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706 I Polydrug Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707 Initiation and perpetuation of the abuse of cocaine and (the “speedball”) is frequently associated with needle- other psychostimulants are determined by a complex inter- sharing by IV drug users. Intravenous drug abusers continue action between the pharmacologic properties and relative to represent the largest single group of persons with HIV availability of each drug, the personality and expectations infection in several major metropolitan areas in the United of the user, and the environmental context in which the States as well as in urban areas in Scotland, Italy, Spain, drug is used. Polydrug abuse, the concurrent use of several Thailand, and China. drugs with different pharmacologic effects, is increasingly common. Some forms of polydrug abuse, such as the com- COCAINE bined use of heroin and cocaine intravenously, are espe- cially dangerous and remain a major problem in hospital Cocaine is a stimulant and local anesthetic with potent emergency departments. Sometimes one drug is used to vasoconstrictor properties. The leaves of the coca plant enhance the effects of another, as with the combined use (Erythroxylon coca) contain ~0.5–1% cocaine.The drug pro- of benzodiazepines and methadone, or cocaine and heroin duces physiologic and behavioral effects when administered in methadone-maintained patients. PO, intranasally, IV, or via inhalation following pyrolysis (smoking).The reinforcing effects of cocaine appear to be Chronic cocaine and psychostimulant abuse may cause related to activation of dopaminergic neurons in the a number of adverse health consequences, ranging from mesolimbic system. Cocaine increases synaptic concentra- pulmonary disease to reproductive dysfunction. Preexisting tions of the monamine neurotransmitters dopamine, disorders such as hypertension and cardiac disease may be norepinephrine, and serotonin by binding to transporter exacerbated by drug abuse, and the combined use of two proteins in presynaptic neurons and blocking reuptake. or more drugs may accentuate medical complications associated with abuse of one of them.The adverse health Prevalence of Cocaine Use consequences of drug abuse are further complicated by increased vulnerability to infections. Cocaine is widely available throughout the United States, and cocaine abuse occurs in virtually all social and eco- Drug abuse increases the risk of exposure to HIV. nomic strata of society. The prevalence of cocaine abuse Cocaine and psychostimulant abuse contribute to the in the general population has been accompanied by an risk for HIV infection in part by suppression of immune increase in cocaine abuse by heroin-dependent persons, function. In addition, concurrent use of cocaine and opiates †Deceased. 702

including those in methadone maintenance programs. effects of cocaine and to residual contaminants in the 703 CHAPTER 52 Cocaine and Other Commonly Abused Drugs Intravenous cocaine is often used concurrently with IV smoked material. Hepatic necrosis has been reported to heroin. This combination purportedly attenuates the occur following crack/cocaine use. postcocaine “crash” and substitutes a cocaine “high” for the heroin “high” blocked by methadone. Although men and women who abuse cocaine may report that the drug enhances libidinal drive, chronic Acute and Chronic Intoxication cocaine use causes significant loss of libido and adversely affects reproductive function. Impotence and gyneco- There has been an increase in both IV administration and mastia have been observed in male cocaine abusers, and inhalation of pyrolyzed cocaine via smoking. Following these abnormalities often persist for long periods fol- intranasal administration, changes in mood and sensation lowing cessation of drug use.Women who abuse cocaine are perceived within 3–5 min, and peak effects occur at may experience major derangements in menstrual cycle 10–20 min.The effects rarely last more than 1 h. Inhalation function including galactorrhea, amenorrhea, and infer- of pyrolyzed materials includes inhaling crack/cocaine or tility. Chronic cocaine abuse may cause persistent hyper- smoking coca paste, a product made by extracting cocaine prolactinemia as a consequence of disordered dopaminergic preparations with flammable solvents, and cocaine free- inhibition of prolactin secretion by the anterior pitu- base smoking. Free-base cocaine, including the free base itary. Cocaine abuse by pregnant women, particularly prepared with sodium bicarbonate (crack), has become the smoking of crack, has been associated with both an increasingly popular because of the relative high potency increased risk of congenital malformations in the fetus of the compound and its rapid onset of action (8–10 s and perinatal cardiovascular and cerebrovascular disease following smoking). in the mother. However, cocaine abuse per se is proba- bly not the sole cause of these perinatal disorders, since Cocaine produces a brief, dose-related stimulation and many problems associated with maternal cocaine abuse, enhancement of mood and an increase in cardiac rate and including poor nutrition and health care status as well blood pressure. Body temperature usually increases follow- as polydrug abuse, also contribute to the risk for peri- ing cocaine administration, and high doses of cocaine may natal disease. induce lethal pyrexia or hypertension. Because cocaine inhibits reuptake of catecholamines at adrenergic nerve Protracted cocaine abuse may cause paranoid ideation endings, the drug potentiates sympathetic nervous sys- and visual and auditory hallucinations, a state that resem- tem activity. Cocaine has a short plasma half-life of bles alcoholic hallucinosis. Psychological dependence on approximately 45–60 min. Cocaine is metabolized by cocaine, indicated by inability to abstain from frequent plasma esterases, and cocaine metabolites are excreted in compulsive use, has also been reported. Although the urine. The very short duration of the euphorigenic occurrence of withdrawal syndromes involving psychomo- effects of cocaine observed in chronic abusers is proba- tor agitation and autonomic hyperactivity remains contro- bly due to both acute and chronic tolerance. Frequent versial, severe depression (“crashing”) following cocaine self-administration of the drug (two to three times per intoxication may accompany drug withdrawal. hour) is often reported by chronic cocaine abusers. Alcohol is used to modulate both the cocaine high and Treatment: the dysphoria associated with the abrupt disappearance COCAINE OVERDOSE AND CHRONIC of cocaine’s effects. A metabolite of cocaine, cocaethyl- ABUSE ene, has been detected in blood and urine of persons who concurrently abuse alcohol and cocaine. Cocaethylene Treatment of cocaine overdose is a medical emergency induces changes in cardiovascular function similar to that is usually best managed in an intensive care unit. those of cocaine alone, and the pathophysiologic conse- Cocaine toxicity produces a hyperadrenergic state char- quences of alcohol abuse plus cocaine abuse may be acterized by hypertension, tachycardia, tonic-clonic additive when both are used together. seizures, dyspnea, and ventricular arrhythmias. Intra- venous diazepam in doses up to 0.5 mg/kg adminis- The prevalent assumption that cocaine inhalation or IV tered over an 8-h period has been shown to be effective administration is relatively safe is contradicted by reports of for control of seizures. Ventricular arrhythmias have been death from respiratory depression, cardiac arrhythmias, and managed successfully by administration of 0.5–1.0 mg convulsions associated with cocaine use. In addition to of propranolol IV. Because many instances of cocaine- generalized seizures, neurologic complications may include related mortality have been associated with concurrent headache, ischemic or hemorrhagic stroke, or subarachnoid use of other illicit drugs (particularly heroin), the physi- hemorrhage. Disorders of cerebral blood flow and perfu- cian must be prepared to institute effective emergency sion in cocaine-dependent persons have been detected with treatment for multiple drug toxicities. magnetic resonance spectroscopy (MRS) studies. Severe pulmonary disease may develop in individuals who inhale Treatment of chronic cocaine abuse requires the crack cocaine; this effect is attributed both to the direct combined efforts of primary care physicians, psychiatrists,

SECTION VI Alcoholism and Drug Dependency704 and psychosocial care providers. Early abstinence from Prevalence of Use cocaine use is often complicated by symptoms of depres- Marijuana is the most commonly used illegal drug in the sion and guilt, insomnia, and anorexia, which may be as United States. Use is particularly prevalent among adoles- severe as those observed in major affective disorders. cents; studies suggest that ~37% of high school students in Individual and group psychotherapy, family therapy, and the United States have used marijuana. Marijuana is rela- peer group assistance programs are often useful for tively inexpensive and is often considered to be less haz- inducing prolonged remission from drug use. A number ardous than other controlled drugs and substances. Very of medications used for the treatment of various medical potent forms of marijuana (sinsemilla) are now available and psychiatric disorders have been administered to in many communities, and concurrent use of marijuana reduce the duration and severity of cocaine abuse and with crack/cocaine and phencyclidine is increasing. dependence. However, no available medication is both safe and highly effective for either cocaine detoxification Acute and Chronic Intoxication or maintenance of abstinence. Some psychotherapeutic interventions may be effective; however, no specific Acute intoxication from marijuana and cannabis com- form of psychotherapy or behavioral modification is pounds is related to both the dose of THC and the route of uniquely beneficial. administration. THC is absorbed more rapidly from mari- juana smoking than from orally ingested cannabis com- MARIJUANA AND CANNABIS pounds. Acute marijuana intoxication usually consists of COMPOUNDS a subjective perception of relaxation and mild euphoria resembling mild to moderate alcohol intoxication. This Cannabis sativa contains >400 compounds in addition to condition is usually accompanied by some impairment in the psychoactive substance, delta-9-tetrahydrocannabinol thinking, concentration, and perceptual and psychomotor (THC). Marijuana cigarettes are prepared from the leaves function. Higher doses of cannabis may produce behavioral and flowering tops of the plant, and a typical marijuana effects analogous to severe alcohol intoxication. Although cigarette contains 0.5–1 g of plant material. Although the the effects of acute marijuana intoxication are relatively usual THC concentration varies between 10 and 40 mg, benign in normal users, the drug can precipitate severe concentrations >100 mg per cigarette have been detected. emotional disorders in individuals who have antecedent Hashish is prepared from concentrated resin of C. sativa psychotic or neurotic problems.As with other psychoactive and contains a THC concentration of between 8 and compounds, both set (user’s expectations) and setting (envi- 12% percent by weight. “Hash oil,” a lipid-soluble plant ronmental context) are important determinants of the extract, may contain a THC concentration of 25–60% type and severity of behavioral intoxication. and may be added to marijuana or hashish to enhance its THC concentration. Smoking is the most common mode As with abuse of cocaine, opioids, and alcohol, chronic of marijuana or hashish use. During pyrolysis, >150 marijuana abusers may lose interest in common socially compounds in addition to THC are released in the smoke. desirable goals and steadily devote more time to drug Although most of these compounds do not have psychoac- acquisition and use. However, THC does not cause a tive properties, they do have potential physiologic effects. specific and unique “amotivational syndrome.”The range of symptoms sometimes attributed to marijuana use is THC is quickly absorbed from the lungs into blood difficult to distinguish from mild to moderate depression and is then rapidly sequestered in tissues. It is metabo- and the maturational dysfunctions often associated with lized primarily in the liver, where it is converted to protracted adolescence. Chronic marijuana use has also 11-hydroxy-THC, a psychoactive compound, and >20 been reported to increase the risk of psychotic symptoms other metabolites. Many THC metabolites are excreted in individuals with a past history of schizophrenia. Persons through the feces at a rate of clearance that is relatively slow who initiate marijuana smoking before the age of 17 may in comparison to that of most other psychoactive drugs. subsequently develop severe cognitive and neuropsycho- logical disorders, and they may also be at higher risk for Specific cannabinoid receptors (CB1 and CB2) have polydrug and alcohol abuse problems in later life. been identified in the central nervous system, including the spinal cord, and in the peripheral nervous system. Physical Effects High densities of these receptors have been found in the cerebral cortex, basal ganglia, and hippocampus.T and B Conjunctival injection and tachycardia are the most fre- lymphocytes also have cannabinoid receptors, and these quent immediate physical concomitants of smoking appear to mediate anti-inflammatory and immunoregu- marijuana. Tolerance for marijuana-induced tachycardia latory properties of cannabinoids. A naturally occurring develops rapidly among regular users. However, marijuana THC-like ligand has been identified in the nervous sys- smoking may precipitate angina in persons with a history tem, where it is widely distributed. of coronary insufficiency. Exercise-induced angina may be increased after marijuana use to a greater extent than

after tobacco cigarette smoking. Patients with cardiac chemotherapy recipients, appetite-promoting effects in 705 CHAPTER 52 Cocaine and Other Commonly Abused Drugs disease should be strongly advised not to smoke mari- AIDS patients, reduction of intraocular pressure in glau- juana or use cannabis compounds. coma, and reduction of spasticity in multiple sclerosis and other neurologic disorders.With the possible exception of Significant decrements in pulmonary vital capacity have AIDS-related cachexia, none of these attributes of mari- been found in regular daily marijuana smokers. Because juana compounds is clearly superior to other readily marijuana smoking typically involves deep inhalation and available therapies. prolonged retention of marijuana smoke, marijuana smok- ers may develop chronic bronchial irritation. Impairment METHAMPHETAMINE of single-breath carbon monoxide diffusion capacity (DLCO) is greater in persons who smoke both marijuana and Methamphetamine is also referred to as “meth,” “speed,” tobacco than in tobacco smokers. “crank,” “chalk,” “ice,” “glass,” or “crystal.” In the United States, hospital admissions for treatment of methamphet- Although marijuana has also been associated with a amine abuse increased substantially (from 3–8%) between number of other adverse effects, many of these studies 1994 and 2004. This increase occurred despite drug await replication and confirmation.A reported correlation seizures, closures of clandestine laboratories that produce between chronic marijuana use and decreased testosterone methamphetamine illegally, and an increase in metham- levels in males has not been confirmed. Decreased sperm phetamine abuse prevention programs. count and sperm motility and morphologic abnormali- ties of spermatozoa following marijuana use have been Methamphetamine can be self-administered PO or reported. Prospective studies demonstrated a correlation by smoking, snorting, and IV injection. Individuals who between impaired fetal growth and development and heavy abuse or become dependent upon methamphetamine marijuana use during pregnancy. Marijuana has also been report that use of this drug induces feelings of euphoria implicated in derangements of the immune system; in and decreases fatigue associated with difficult life situa- chromosomal abnormalities; and in inhibition of DNA, tions. Adverse consequences of methamphetamine abuse RNA, and protein synthesis; however, these findings have include headache, difficulty concentrating, diminished not been confirmed or related to any specific physiologic appetite, abdominal pain, vomiting or diarrhea, disordered effect in humans. sleep, paranoid or aggressive behavior, and psychosis. Chronic methamphetamine abuse can result in severe Tolerance and Physical Dependence dental caries, described as blackened, rotting, crumbling teeth. Severe, life-threatening methamphetamine toxicity Habitual marijuana users rapidly develop tolerance to the may present as hypertension, cardiac arrhythmia or failure, psychoactive effects of marijuana and often smoke more subarachnoid hemorrhage, ischemic stroke, intracerebral frequently and try to secure more potent cannabis com- hemorrhage, convulsions, or coma. Methamphetamines pounds.Tolerance for the physiologic effects of marijuana increase the release of monoamine neurotransmitters develops at different rates; e.g., tolerance develops rapidly (dopamine, norepinephrine, and serotonin) from presy- for marijuana-induced tachycardia but more slowly for naptic neurons. It is thought that the euphoric and rein- marijuana-induced conjunctival injection. Tolerance for forcing effects of this class of drugs are mediated through both behavioral and physiologic effects of marijuana dopamine and the mesolimbic system, whereas the car- decreases rapidly upon cessation of marijuana use. diovascular effects are related to norepinephrine. MRS studies of the brain suggest that chronic abusers have Withdrawal signs and symptoms have been reported neuronal damage in the frontal areas and basal ganglia. in chronic cannabis users, with the severity of symptoms related to dosage and duration of use. These include Therapy of acute methamphetamine overdose is largely tremor, nystagmus, sweating, nausea, vomiting, diarrhea, symptomatic.Ammonium chloride may be useful to acid- irritability, anorexia, and sleep disturbances. Withdrawal ify the urine and enhance clearance of the drug. Hyperten- signs and symptoms observed in chronic marijuana users sion may respond to sodium nitroprusside or α-adrenergic are usually relatively mild in comparison to those observed antagonists. Sedatives may reduce agitation and other signs in heavy opiate or alcohol users and rarely require medical of central nervous system hyperactivity. Treatment of or pharmacologic intervention. More severe and protracted chronic methamphetamine dependence may be accom- abstinence syndromes may occur after sustained use of high- plished in either an inpatient or outpatient setting using potency cannabis compounds. strategies similar to those described earlier for cocaine abuse. Therapeutic Use of Marijuana MDMA (3,4-methylenedioxymethamphetamine), or Marijuana, administered as cigarettes or as a synthetic oral Ecstasy, is a derivative of methamphetamine. Ecstasy is cannabinoid (dronabinol), has been proposed to have a usually taken PO but may be injected or inhaled; its effects number of medicinal properties that may be clinically use- last for 3–6 h. In addition to amphetamine-like effects, ful in some situations.These include antiemetic effects in

SECTION VI Alcoholism and Drug Dependency706 MDMA can induce hyperthermia and vivid hallucinations anesthetic. PCP binds to ionotropic N-methyl-D-aspartate and other perceptual distortions. (NMDA) receptors in the nervous system, blocking ion During the past decade, an eighteenfold increase in current through these channels. PCP is easily synthesized; MDMA-related emergency department incidents has been its abusers are primarily young people and polydrug users. reported in the United States. Recent studies have revealed It is used PO, by smoking, or by IV injection. It is also used that MDMA use is associated with cognitive and memory as an adulterant in THC, LSD, amphetamine, or cocaine. impairment and a mild withdrawal syndrome after cessa- The most common street preparation, angel dust, is a tion of use.The long-term consequences of recreational use white granular powder that contains 50–100% of the of MDMA by young persons are poorly understood. drug. Low doses (5 mg) produce agitation, excitement, impaired motor coordination, dysarthria, and analgesia. LYSERGIC ACID DIETHYLAMIDE (LSD) Users may have horizontal or vertical nystagmus, flushing, diaphoresis, and hyperacusis. Behavioral changes include The discovery of the psychedelic effects of LSD in 1947 distortions of body image, disorganization of thinking, and led to an epidemic of LSD abuse during the 1960s. Impo- feelings of estrangement. Higher doses of PCP (5–10 mg) sition of stringent constraints on the manufacture and dis- may produce profuse salivation, vomiting, myoclonus, fever, tribution of LSD (classified as a Schedule I substance by stupor, or coma. PCP doses of ≥10 mg cause convulsions, the U.S. Food and Drug Administration), as well as public opisthotonus, and decerebrate posturing, which may be recognition that psychedelic experiences induced by LSD followed by prolonged coma. were a health hazard, have resulted in a reduction in LSD abuse. LSD still remains popular among adolescents and The diagnosis of PCP overdose is difficult because the young adults, and there are indications that LSD use patient’s initial symptoms may suggest an acute schizo- among young persons has been increasing in some com- phrenic reaction. Confirmation of PCP use is possible by munities in the United States. determination of PCP levels in serum or urine. PCP assays are available at most toxicologic centers. PCP remains in LSD is a very potent drug; oral doses as low as 20 μg urine for 1–5 days following high-dose intake. may induce profound psychological and physiologic effects. Tachycardia, hypertension, pupillary dilation, tremor, and PCP overdose requires life-support measures, includ- hyperpyrexia occur within minutes following oral admin- ing treatment of coma, convulsions, and respiratory istration of 0.5–2 μg/kg. A variety of bizarre and often depression in an intensive care unit. There is no specific conflicting perceptual and mood changes, including visual antidote or antagonist for PCP. PCP excretion from the illusions, synesthesias, and extreme lability of mood, usu- body can be enhanced by gastric lavage and acidification ally occur within 30 min after LSD intake. These effects of urine. Death from PCP overdose may occur as a con- of LSD may persist for 12–18 h, even though the half-life sequence of some combination of pharyngeal hyper- of the drug is only 3 h. secretion, hyperthermia, respiratory depression, severe hypertension, seizures, hypertensive encephalopathy, and Tolerance develops rapidly for LSD-induced changes intracerebral hemorrhage. in psychological function when the drug is used one or more times per day for >4 days. Abrupt abstinence fol- Acute psychosis associated with PCP use should be lowing continued use does not produce withdrawal signs considered a psychiatric emergency since patients may be or symptoms.There have been no clinical reports of death at high risk for suicide or extreme violence toward others. caused by the direct effects of LSD. Phenothiazines should not be used for treatment because these drugs potentiate PCP’s anticholinergic effects. The most frequent acute medical emergency associated Haloperidol (5 mg IM) has been administered on an hourly with LSD use is a panic episode (the “bad trip”), which basis to induce suppression of psychotic behavior. PCP, like may persist up to 24 h. Management of this problem is LSD and mescaline, produces vasospasm of cerebral arteries best accomplished by supportive reassurance (“talking at relatively low doses. Chronic PCP use has been shown down”) and, if necessary, administration of small doses of to induce insomnia, anorexia, severe social and behavioral anxiolytic drugs. Adverse consequences of chronic LSD changes, and, in some cases, chronic schizophrenia. use include enhanced risk for schizophreniform psychosis and derangements in memory function, problem solving, POLYDRUG ABUSE and abstract thinking. Treatment of these disorders is best carried out in specialized psychiatric facilities. Although drug abusers often report a preference for a particular drug, such as alcohol or opiates, the concurrent PHENCYCLIDINE use of other drugs is common. Polydrug abuse often involves substances that may have different pharmacologic Phencyclidine (PCP), a cyclohexylamine derivative, is effects from the preferred drug. For example, concurrent widely used in veterinary medicine to briefly immobilize use of such dissimilar compounds as stimulants and opiates large animals and is sometimes described as a dissociative or stimulants and alcohol is not unusual.The diversity of

reported drug use combinations suggests that achieving detoxification, a process that may be difficult because of 707 some perceptible change in state, rather than any partic- the abuse of several drugs with different pharmacologic ular direction of change (stimulation or sedation), may actions (e.g., alcohol, opiates, and cocaine). Because CHAPTER 52 Cocaine and Other Commonly Abused Drugs be the primary reinforcer in polydrug use and abuse. patients may not recall or may deny simultaneous multi- There is also evidence that intoxication with alcohol or ple drug use, diagnostic evaluation should always opiates is associated with increased tobacco smoking. include urinalysis for qualitative detection of psychoac- There is relatively little systematic information available tive substances and their metabolites. Treatment of about multiple drug abuse interactions. However, the polydrug abuse often requires hospitalization or inpa- combined use of cocaine, heroin, and alcohol increases the tient residential care during detoxification and the initial risk for toxic effects and adverse medical consequences phase of drug abstinence. When possible, specialized over risks associated with use of a single drug. One deter- facilities for the care and treatment of chemically depen- minant of polydrug use patterns is the relative availability dent persons should be used. Outpatient detoxification and cost of the drugs. There are many examples of situa- of polydrug abuse patients is likely to be ineffective and tionally determined drug use patterns. For example, alcohol may be dangerous. abuse, with its attendant medical complications, is one of the most serious problems encountered in former heroin Drug abuse disorders often respond to effective treat- addicts participating in methadone maintenance programs. ment, but episodes of relapse may occur unpredictably. The physician should continue to assist patients during The physician must recognize that perpetuation of relapse and recognize that occasional recurrent drug use polydrug abuse and drug dependence is not necessarily is not unusual in this complex behavioral disorder. a symptom of an underlying emotional disorder. Neither alleviation of anxiety nor reduction of depression accounts FURTHER READINGS for initiation and perpetuation of polydrug abuse. Severe depression and anxiety are as frequently the consequences CAMI J, FARRE M: Mechanisms of disease: Drug addiction. N Engl J of polydrug abuse as they are the antecedents.There is also Med 349:975, 2003 evidence that some of the most adverse consequences of drug use may be reinforcing and contribute to the contin- HABER PS et al: Management of injecting drug users admitted to uation of polydrug abuse. hospital. Lancet 384:1284, 2009 Treatment: MONTOYA ID,VOCCI F: Novel medications to treat addictive disorders. POLYDRUG ABUSE Curr Psychiatry Rep 10:392, 2008 Adequate treatment of polydrug abuse, as well as other TOUMBOUROU JW et al: Interventions to reduce harm associated forms of drug abuse, requires innovative programs of with adolescent substance use. Lancet 369:1391, 2007 intervention. The first step in successful treatment is VOCCI FJ et al: Medication development for addictive disorders: The state of the science.Am J Psychiatry 162:1432, 2005 VOLKOW ND et al: Cocaine cues and dopamine in dorsal striatum: Mechanism of craving in cocaine addiction. J Neurosci 26:6583, 2006

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REVIEW AND SELF-ASSESSMENT∗ Charles Wiener I Gerald Bloomfield I Cynthia D. Brown I Joshua Schiffer I Adam Spivak QUESTIONS DIRECTIONS: Choose the one best response for each 2. (Continued ) question. D. Sumatriptan, 50 mg orally, at the onset of an attack E. Surgical consultation for microvascular decompression 1. Delirium, an acute confusional state, is a common of the trigeminal nerve disorder that remains a major cause of morbidity and mortality in the United States. Which patient is at 3. You are seeing your patient with polymyositis in the highest risk for developing delirium? follow-up. He has been taking prednisone at high doses for 2 months, and you initiated mycophenolate A. A 36-year-old man admitted to the medical ward with mofetil at the last clinic visit for a steroid-sparing a deep venous thrombosis effect. He began a steroid taper 2 weeks ago. His symptoms were predominantly in the lower extrem- B. A 55-year-old man postoperative day 2 from a total ities and face, and he has improved considerably. He colectomy no longer needs a cane and his voice has returned to normal. Laboratory data show a creatine kinase (CK) C. A 68-year-old woman admitted to the intensive care of 1300 U/L, which is unchanged from 2 months unit (ICU) with esophageal rupture ago. What is the most appropriate next step in this patient’s management? D. A 74-year-old woman in the preoperative clinic before hip surgery A. Continue current management B. Continue high-dose steroids with no taper E. An 84-year-old man living in an assisted living facility C. Switch mycophenolate to methotrexate D. Repeat muscle biopsy 2. A 46-year-old man presents for evaluation of severe unilateral headache. He states that he has had episodes 4. A patient complains of numbness in his neck. Over of intermittent headache for the past 3 years. He months, the numbness has become more pronounced describes the headaches as a stabbing pain located near and involves a dense area bilaterally from the sternal his right temple. They occur abruptly and last up to notch to the area behind the ear. On examination, 3 h at a time, during which he feels incapacitated, rat- scalp sensation, cranial nerve function, and upper ing the pain as a 10 out of 10. Most of the time, the extremity motor examination are normal.The patient headaches begin in the early morning hours. When has decreased pain and temperature sensation in the they occur, he finds it impossible to sleep. He feels that distribution of C4.Vibration sense is normal. Cranial rubbing his head improves the pain but has noticed no and caudal to the affected area, sensation is intact. other factors that relieve the pain. Specifically, he has Bladder and anal sphincter function are also normal. had no improvement with acetaminophen, naprosyn, What is the most likely cause of this patient’s neuro- or oxycodone.When the headaches occur, he develops logic disorder? nasal congestion and tearing on the side of the pain. He believes the headaches occur in cycles. He will A. Amyotrophic lateral sclerosis have the headaches almost daily for up to 2 weeks at a B. Disc herniation time, but then have no headaches at all for as long as C. Intramedullary tumor 3 months. He has decided to seek medical advice D. Knife or bullet injury because he is worried about the possibility of a brain E. Neurosyphilis tumor because of the severity of the headaches. He takes no medicines regularly. His vital signs and physi- 5. A 56-year-old man is admitted to the intensive care cal examination are normal.What is the best approach unit with a hypertensive crisis after cocaine use. Ini- to treatment of these headaches? tial blood pressure is 245/132. On physical examina- tion the patient is unresponsive except to painful A. Fluticasone nasal spray and loratadine, 10 mg orally stimuli. He has been intubated for airway protection B. Indomethacin, 25 mg three times daily C. Oxygen at 10–12 L/min by nasal cannula at the onset of an attack ∗Questions and answers were taken from Wiener C, et al (eds). Harrison’s Principles of Internal Medicine Self-Assessment and Board Review, 17th ed. New York: McGraw-Hill, 2008. 709

710 Review and Self-Assessment 5. (Continued ) 8. (Continued ) and is being mechanically ventilated, with a respira- A 33-year-old woman comes to your office for eval- tory rate of 14. His pupils are reactive to light, and uation of a bilateral tingling sensation in the finger- there are normal corneal, cough, and gag reflexes.The tips. She describes the sensation as affecting all the patient has a dense left hemiparesis. When presented fingers on both hands. She has no medical problems with painful stimuli, the patient responds with flexure and takes no medications. She is a vegetarian and is posturing on the right side. Computed tomography visiting the area from San Diego, California. She (CT) reveals a large area of intracranial bleeding in the denies any other symptoms, including headache, right frontoparietal area. Over the next several hours nausea, vomiting, shortness of breath, and urinary the patient deteriorates.The most recent examination frequency. On physical examination the patient has a reveals a blood pressure of 189/100. The patient now normal sensory examination, including reaction to has a dilated pupil on the right side.The patient con- light touch and pinprick and vibratory sensation. tinues to have corneal reflexes. You suspect rising She is able to stand normally with the arms extended intracranial pressure related to the intracranial bleed. and the eyes closed. A cerebellar examination reveals All but which of the following can be done to decrease normal finger-to-nose testing and no dysdiadochoki- the patient’s intracranial pressure? nesis. Her gait is normal, including tandem gait, toe walking, and heel walking. What would you recom- A. Administer intravenous mannitol at a dose of 1 g/kg mend as the next step? body weight A. Blood tests for serum vitamin B12 B. Administer hypertonic fluids to achieve a goal sodium B. Fasting blood glucose level level of 155 to 160 meq/L C. Reassurance D. Serologic testing for syphilis C. Consult neurosurgery for an urgent ventriculostomy. E. Treatment with acetazolamide for altitude sickness D. Initiate intravenous nitroprusside to decrease the mean 9. You are doing rounds and see a patient admitted with arterial pressure to a goal of 100 mmHg weakness. He is a 46-year-old man who noticed the E. Increase the respiratory rate to 30 gradual onset of facial weakness and slurred speech 1 day prior to presentation. At the onset of his symp- 6. For the last 5 weeks a 35-year-old woman has had toms, he also complained of right arm weakness and episodes of intense vertigo that last several hours. double vision. He went to bed and woke up the next Each episode is associated with tinnitus and a sense morning without any residual neurologic deficits. He of fullness in the right ear; during the attacks she came to the emergency department for evaluation. prefers to lie on the left side. Examination during an On examination of the patient on evening rounds, attack shows that she has fine rotary nystagmus that you note 3/5 weakness in the upper and lower is maximal on gaze to the left. There are no ocular extremities, with increasing weakness with exertion. palsies, cranial nerve signs, or long-tract signs. An He has intact phonation and mental status, but you audiogram shows high-tone hearing loss in the right also note a disconjugate gaze. He denies any pain. ear, with recruitment but no tone decay. The most Sensation is intact.What is the most likely location of likely diagnosis in this patient is his neurologic disease? A. labyrinthitis A. Brainstem B. Ménière’s disease B. Muscle C. vertebral-basilar insufficiency C. Neuromuscular junction D. acoustic neuroma D. Peripheral nerve E. multiple sclerosis E. Spinal root 7. Lumbar puncture should be preceded by CT or 10. A 34-year-old woman complains of lower extremity MRI in all of the following subsets of patients sus- weakness for the last 3 days. She has noted progres- pected of having meningitis except those with: sive weakness in the lower extremities with loss of sensation “below the belly button” and inconti- A. depressed consciousness nence. She had had some low-grade fevers for the B. focal neurologic abnormality last week. She denies recent travel. Past medical his- C. known central nervous system (CNS) mass lesion tory is unremarkable. Physical examination is notable D. positive Kernig’s sign for a sensory level at the level of the umbilicus. E. recent head trauma 8. You are a physician practicing in a small community in the Rocky Mountains near Aspen, Colorado.

Review and Self-Assessment 711 10. (Continued ) 12. (Continued ) The lower extremities show +3/5 strength bilaterally, lately; she describes him as very energetic prior to his proximally, and distally. Reflexes, cerebellar examina- concussion. The patient’s physical examination is tion, and mental status are normal. All the following entirely normal except for a somewhat flattened are appropriate steps in evaluating this patient except affect. Which of the following statements regarding A. antinuclear antibodies his condition is true? B. electromyography C. lumbar puncture A. He has an excellent prognosis. D. MRI of the spine B. He meets criteria for postconcussive syndrome and E. viral serologies should improve over 1–2 months. 11. Which clinical signs would you expect in a 53-year- C. He should avoid contact sports for the next month. old man with gait ataxia and these MRI findings D. He is most likely malingering. (see Fig. 11)? E. Low-dose narcotics should be started for headache. FIGURE 11 13. Variant Creutzfeldt-Jakob disease (vCJD) has been diagnosed in which of the following populations? A. Gait instability, urinary incontinence, dementia B. Hypertension, tachycardia, diaphoresis A. Family members with well-defined germ-line muta- C. Migraine headache, limb weakness, breathing difficulties tions leading to autosomal dominant inheritance of a D. Scanning speech, oscillatory tremor of the head, fatal neurodegenerative disease nystagmus B. New Guinea natives practicing cannibalism 12. A 17-year-old adolescent is seen in clinic several C. Patients accidentally inoculated with infected material weeks after he suffered a concussion during a high- during surgical procedures school football game. At the time of the event, para- D. Worldwide, in sporadic cases mostly during the fifth medics reported that he experienced no loss of consciousness but was confused for a period of about and sixth decades of life 10 min. Head imaging was normal. He describes a E. Young adults in Europe thought to have been exposed generalized headache that is present all the time since his trauma, and he occasionally feels dizzy. His to tainted beef products mother is concerned that he is having a hard time concentrating in school and seems depressed to her 14. A 44-year-old man with a history of hypertension and Paget’s disease has had lower back pain for the past 3 months. The pain is worse with standing and improves with sitting. Walking does not necessarily exacerbate his symptoms. He has no leg or buttock pain. On examination, he has mild weakness on the right at the hip flexors, knee extenders, and knee flexors and more distally to the same degree. Reflexes are diminished in the right lower extremity. He has no sensory findings in the lower extremities or in the perineum.What is the most likely diagnosis? A. Intervertebral disk herniation B. Lumbar spinal stenosis C. Metastatic malignancy D. Occlusive aortoiliac atherosclerosis E. Tethered cord syndrome 15. On the neurologic consultation service, you are asked to evaluate a patient with mesial temporal lobe epilepsy syndrome. The patient has a history of intractable complex partial seizures that rarely gener- alize. Her seizures often begin with an aura and commonly manifest as behavioral arrests, complex automatisms, and unilateral posturing. MRI findings include small temporal lobes and a small hippocam- pus with increased signal on T2-weighted sequences.

712 Review and Self-Assessment 15. (Continued ) 20. (Continued ) Which of these additional historic factors are also are getting progressively worse. She has great difficulty likely to be present in this patient? walking from the waiting room to the examination room but is not dizzy while doing so. On further A. History of febrile seizures questioning she denies numbness or tingling. On B. Hypothyroidism physical examination, her cranial nerves are intact, and C. Neurofibromas strength examination shows 5 out of 5 strength in D. Recurring genital ulcers both upper and lower extremities. Reflexes are nor- E. Type 2 diabetes mellitus mal throughout. Light touch sensation is normal, and she is not orthostatic. You order a noncontrast head 16. The patient in the preceding scenario was admitted CT and it is read as normal.Which test is most likely with refractory seizures. You are asked to see the to reveal the correct diagnosis? patient and offer treatment options. What treatment option will be the most efficacious in a patient with A. Cerebrospinal fluid viral polymerase chain reaction mesial temporal lobe epilepsy (MTLE) syndrome? B. Lithium level C. Rapid plasma reagent (RPR) A. Acyclovir D. Serum alcohol level B. Amygdalohippocampectomy E. Vitamin B12 deficiency C. Levetiracetam D. Primidone 21. A 78-year-old woman with a long history of vascu- E. Vagus nerve stimulation lar disease presents after an embolic cerebrovascular accident (CVA) with severe and unrelenting pain on 17. The deep tendon reflex requires all of the following the right side. She describes the pain as burning as if structures to be functional except she had been bathed in acid. Where is the most likely site of the recent embolic CVA? A. a motor neurons B. γ motor neurons A. Frontal lobe C. pyramidal neurons B. Hypothalamus D. spindle afferent neurons C. Pons D. Temporal lobe 18. The most common presenting finding or symptom E. Thalamus of multiple sclerosis is 22. A 34-year-old man presents with complaints of A. internuclear ophthalmoplegia 1 week of dizziness, vertigo, tinnitus, and right-sided B. transverse myelitis gait ataxia. Electronystagmography (calorics) with C. cerebellar ataxia sequential administration of warm and cold water D. optic neuritis into the ear canal is performed. On the left, cold E. urinary retention water causes right-beating nystagmus and warm water causes left-beating nystagmus. On the right ear, there 19. You are evaluating a patient with neck pain and you is no response to the cold caloric. What is the cause suspect cervical degenerative disk disease based on of this patient’s dizziness and vertigo? the history. Based on the most common findings with cervical disk disease, which finding do you A. Acoustic neuroma expect when you examine this patient? B. Aminoglycoside antibiotics C. Cerebellar ischemia A. Biceps weakness D. Otoconia (ear otoliths) B. Decreased light touch sensation in the axilla and 23. A 49-year-old man is admitted to the hospital with a medial arm seizure. He does not have a history of seizures and he C. Decreased pin-prick sensation over the lateral deltoid currently takes no medications. He has AIDS and is D. Weak finger flexors not under any care at this time. His physical exam- ination is most notable for small, shoddy lym- 20. A 64-year-old woman is brought to the emergency phadenopathy in the cervical region. A head CT department by her family with complaint of weak- shows a ring-enhancing lesion in the right temporal ness. The patient reports difficulty walking and fre- lobe, with edema but no mass effect.A lumbar puncture quent falls. She also has blurry vision bilaterally. She denies light headedness or vertigo. These symptoms have been present for at least the past 9 months and

Review and Self-Assessment 713 23. (Continued ) 27. A 49-year-old woman presents for a second opinion shows no white or red blood cells, and the Gram stain regarding symptoms of tremors, difficulty with is negative. His serum Toxoplasma IgG is positive. ambulation, and periodic flushing. Her symptoms Which of the following is the best course of action originally began ~3 years ago. At that time, she was for this patient at this time? hospitalized for a syncopal episode, after which she was told to increase her salt intake. Since then, she A. Biopsy of the central nervous system (CNS) lesion has had progressive motor difficulties including bilat- B. Dexamethasone eral tremors and a stiff slow gait. She also has had C. Search for systemic malignancy several more episodes of syncope. She states that she D. Treatment for CNS toxoplasmosis knows when these syncopal events will occur E. Whole-brain radiation therapy because she feels faint and weak. She has never had an injury from syncope. A final recent symptom has 24. The patient in the preceding scenario returns for been periodic flushing and sweating. A neurologist reevaluation after 2 weeks of appropriate therapy. previously diagnosed her with Parkinson’s disease The CNS lesion has not changed in size, and he has and prescribed therapy with ropinirole. Despite not had any more seizures. All microbiologic cul- increasing doses, she does not feel improved, but tures and viral studies, including Epstein-Barr virus rather has recently noticed uncontrollable move- DNA from the cerebrospinal fluid are negative. ments that she describes at tics of her face. Her only What is the best course of action for this patient at other medical history is recent recurrent urinary this time? tract infections. Her medications are ropinirole, 24 mg daily, and nitrofurantoin, 100 mg daily. She A. Continue treatment for CNS toxoplasmosis reports no history of drug use. On physical examina- B. Dexamethasone tion, her blood pressure is 130/70 mmHg with a C. Intravenous acyclovir heart rate of 78 beats/min while sitting. Upon D. Stereotactic brain biopsy standing, her blood pressure drops to 90/50 mmHg E. Whole-brain radiation therapy with a heart rate of 110 beats/min. Her ocular movements are full and intact. She has recurrent 25. Which of the following statements about syringomyelia motor movements of the right side of her face. Her is true? neurologic examination shows increased muscle tone in the lower extremities with bilateral A. More than half the cases are associated with Chiari 4-Hz tremor. Deep tendon reflexes are brisk and 3+ malformations. in upper and lower extremities. Three beats of myoclonus is present at the ankles bilaterally. She B. Symptoms typically begin in middle age. walks with a spastic gait. Strength is normal. What is C. Vibration and position sensation are usually diminished. the most likely diagnosis? D. Syrinx cavities are always congenital. E. Neurosurgical decompression is usually effective in A. Corticobasal degeneration B. Diffuse Lewy body dementia relieving the symptoms. C. Drug-induced Parkinson’s disease D. Multiple systems atrophy with parkinsonian 26. A 34-year-old woman presents with complaints of weakness and double vision for the last 3 weeks. She features (Shy-Drager syndrome) has also noted a change in her speech, and her E. Parkinson’s disease with inadequate friends tell her that she is “more nasal.” She has noticed decreased exercise tolerance and difficulty treatment lifting objects and getting out of a chair.The patient denies pain. The symptoms are worse at the end of 28. A 68-year-old man is brought to clinic for evalua- the day and with repeated muscle use. You suspect tion by his wife. She has noticed that over past myasthenia gravis. All the following are useful in the 2–3 months he has had increasingly slowed thinking diagnosis of myasthenia gravis except and a change in his personality in that he has become very withdrawn. His only complaint is a mild, but A. acetylcholine receptor (AChR) antibodies persistent, diffuse headache. There is no history of B. edrophonium head trauma, prior neurologic or psychiatric disease, C. electrodiagnostic testing or family history of dementia. Physical examination D. muscle-specific kinase (MuSK) antibodies is only notable for a moderate cognitive deficit with E. voltage-gated calcium channel antibodies a mini-mental examination of 19/30. His head

714 Review and Self-Assessment 28. (Continued ) 30. (Continued ) CT is shown in Fig. 28. What is the most likely addition, he states that his right hand shakes more so diagnosis? than his left, and he is right-handed. He believes it to be worse when not moving but states there are times FIGURE 28 when he spills his morning coffee because of the tremors. He has retired but states he is not able to A. Acute epidural hematoma play tennis and golf any longer because of his motor B. Acute subarachnoid hemorrhage symptoms. He denies syncope or presyncope, diffi- C. Alzheimer’s disease culty swallowing, changes to his voice, or memory D. Chronic subdural hematoma difficulties. His past medical history is significant for E. Normal-pressure hydrocephalus hypertension and hypercholesterolemia. His medica- 29. You are evaluating a patient who has complaint of tions are hydrochlorothiazide, 25 mg daily, ezetimibe, vertigo. The patient complains of seeing the room 10 mg daily, and lovastatin, 40 mg daily. He drinks a spin and feeling faint with certain head movements glass of wine with dinner daily and is a lifelong non- to the left. In your office, you perform provocative smoker. On physical examination, he has masked maneuvers to differentiate the cause of this patient’s facies. His gait shows decreased arm swing with slow vertigo. He has been diagnosed with benign parox- shuffling steps. He turns en bloc. A pill-rolling tremor ysmal positional vertigo (BPPV), but symptoms have is present on the right side. There is cogwheel rigid- remained for many months. Which of the following ity bilaterally. Eye movements are full and intact. findings would be suggestive of a central positional There is no orthostatic hypotension. A brain MRI vertigo? with gadolinium shows no evidence of mass lesions, A. Disappearance of the symptoms with maintenance of hydrocephalus, or vascular disease. You diagnose the patient with Parkinson’s disease. The patient asks the offending position about his prognosis and likelihood of disability. B. Immediate vertigo and nystagmus with head turning to Which of the following is correct about the clinical course and treatment of Parkinson’s disease? the affected side C. Lessening of symptoms with repeated trials A. Early initiation of therapy with levodopa will not affect D. Increased severity of symptoms with provocative testing the risk of a higher likelihood of dyskinesias early in 30. A 65-year-old man presents to your office with com- the disease. plaints of a tremor and progressive gait abnormalities. He states that he first noticed a slowing of his gait B. Early therapy with bilateral deep-brain stimulation of ~6 months ago. He has difficulty rising to a standing the subthalamic nuclei slows progression of Parkinson’s position and states that he shuffles when he walks. In disease. C. Initial treatment with a dopamine agonist such as pramipexole is likely to be effective in controlling his motor symptoms for 1–3 years before the addition of levodopa or another agent is necessary. D. Levodopa should be started immediately to prevent development of disabling rigidity. E. Monotherapy with selegiline, a monoamine oxydase (MAO) inhibitor, causes a marked improvement in tremors in most individuals with Parkinson’s disease. 31. A 74-year-old woman comes to clinic with a com- plaint of muscle weakness. She has bilateral deltoid weakness, which has been present for 4 months. She has myalgias as well throughout the day. Her symp- toms are exacerbated by activity and when she ini- tially lays down to sleep. Neurologic examination shows intact cranial nerves II through XII, except for poor vision due to cataracts. She has hyperesthe- sia in her arms in the area of her deltoids, but other- wise sensation is normal. Deep tendon reflexes are normal. Strength examination shows weakness ini- tially, but it improves with encouragement. Creatine

Review and Self-Assessment 715 31. (Continued ) 36. A young man with a history of a low-grade astrocy- kinase, erythrocyte sedimentation rate, and C-reactive toma comes into your office with complaints of protein are within normal limits. An MRI of the del- weight gain and low energy. He is status post resec- toid muscles shows joint degeneration and a partial tion of his low-grade astrocytoma and had a course rotator cuff tear on the left. You are considering a of whole-brain radiation therapy (WBRT) 1 year ago. muscle biopsy. What is the biopsy most likely to A laboratory workup reveals a decreased morning show? cortisol level of 1.9 μg/dL. In addition to depressed adrenocorticotropic hormone (ACTH) function, A. Endomysial deposits of amyloid which of the following hormones is most sensitive to B. Necrotic muscle damage from whole-brain radiation therapy? C. Normal muscle D. Scattered inflammatory foci surrounding muscle fibers A. Growth hormone B. Follicle stimulating hormone 32. Which of the following criteria suggests the diagno- C. Prolactin sis of trigeminal neuralgia? D. Thyroid stimulating hormone A. Deep-seated steady facial pain 37. A 29-year-old man being treated for lung cancer B. Elevated erythrocyte sedimentation rate (ESR) comes into your office for an acute visit. He has had C. Known metastatic brain tumor backache for a few weeks that has improved with D. Objective signs of sensory loss on physical examination ibuprofen but has developed right lower abdominal E. None of the above pain and inguinal pain. On physical examination, he has tenderness over the lower thoracic spinous 33. CT scanning is superior to MRI of the back in processes and hyperesthesia in the T11 distribution on which setting? the right. Strength is normal in the upper extremities, but he has symmetric weakness in the lower extremi- A. Delineation of the extent of a syrinx ties with hyperreflexia. He also has decreased sensa- B. Evaluation of old lumbar-spine fracture tion below the T11 distribution symmetrically. What C. Evaluation of paraspinal mass is the next step in the management of this patient? D. Imaging of the lateral recesses of the spinal canal A. Add gabapentin to his pain regimen 34. All the following cause primarily a sensory neuropa- B. Order a paraneoplastic antibody panel thy except C. Start treatment with glucocorticoids D. Order thoracic and lumbar radiographs A. acromegaly B. critical illness 38. A 50-year-old man presents with complaint of weak- C. HIV infection ness. His symptoms began as difficulty with buttoning D. hypothyroidism his shirt and using keys to open doors about 2 years E. vitamin B12 deficiency ago. He was treated empirically with nonsteroidal anti- inflammatory medications for arthritis, but responded 35. A 45-year-old woman presents for evaluation of a only minimally. His symptoms have slowly progressed tingling sensation in her feet that has become more to the point where he has weakness in both hands and apparent over the past 5 months. She states that it feet. He avoids going outside because of frequent falls. currently is causing a painful sensation and is inter- On examination, he has weakness and atrophy of the fering with her sleep at night. On physical examina- foot extensor and finger flexors. Proximal muscle tion, you identify decreased sensation to pinprick strength is normal. Reflexes are normal, and sensation and light touch in her feet extending to her mid-calf is intact. He is able to rise out of a chair, but the area. All of the following laboratory tests may be Romberg test is not able to be performed due to useful in determining the cause of her peripheral weakness once standing. Cranial nerves are intact. neuropathy except Serum creatine kinase is 600 units/L. Complete blood count, differential, electrolytes, and thyroid-stimulating A. blood lead level hormone (TSH) are normal. Based on the clinical pre- B. fasting blood glucose sentation, what is the most likely diagnosis? C. hemoglobin A1C D. rapid plasma reagin for syphilis A. Dermatomyositis E. red blood cell folate levels B. Eosinophilic myofasciitis

716 Review and Self-Assessment 38. (Continued ) 42. A 24-year-old woman seeks evaluation for headaches. She first began having recurrent headaches her senior C. Inclusion body myositis year of high school. The headaches increased in fre- D. Polymyositis quency during college, and she has always attributed E. Hyperthyroidism her headaches to tension. The headaches would be more prominent during times of sleep loss, stress, and in 39. You are conducting research on a cellular model of the perimenstrual period. She states that she expected myasthenia gravis in which you measure features of her headaches to improve now that she has finished the acetylcholine (ACh) neuromuscular junction and college and has a more regular schedule. She works as a its microenvironment. In a patient with untreated financial counselor for a university in the human myasthenia gravis, which of the following do you resources department and denies a large degree of stress expect to find at the neuromuscular junction after in her job. She has had this job for 2 years, but the release of ACh from the presynaptic neuron? headaches continue to disrupt her life. She states the headaches occur about seven times monthly. She esti- A. Decreased levels of ACh-esterase mates that the headaches occur >90% of the time on B. Decreased numbers of available ACh receptors the right side and have a throbbing nature. She has no C. Decreased release of ACh from the presynaptic neuron aura before the onset of a headache but describes occa- D. High numbers of mitochondria in the postsynaptic neuron sional visual disturbance and photophobia during the headache. She also states that she frequently develops 40. You have just admitted a young man with a prior sensitivity of her scalp on the side of the headache with history of seizure disorder who was witnessed to associated paresthesias. She rates the pain as about 7 to have a seizure. His family’s description suggests a 8 out of 10 for a usual headache. On two occasions simple partial seizure involving the left hand that over the past 6 months, she has developed severe ver- spread to involve the entire arm. He did not lose tigo that resolved over the course of several hours in consciousness. He was brought in 2 h after symptom association with a mild headache. She has never had to onset and is currently awake, alert, and oriented. He miss work because of headache, but feels like her pro- has not had any further seizures but has been unable ductivity is limited when she feels unwell. Other trig- to move his left hand since his seizure. His elec- gers for her headaches include red wine and aged trolytes and complete blood count are within nor- cheese, which she has restricted from her diet for this mal limits. A noncontrast CT scan of his head is reason. Ibuprofen, acetaminophen, and naprosyn unremarkable. On examination, sensation is intact in sodium have no effect on the duration of her the affected limb but his strength is 0 out of 5 in the headaches. She is otherwise healthy and denies associ- musculature of the left hand.What is the best course ated rhinorrhea or lacrimation. Her only medication is of action at this time? oral contraceptive pills. Her family history is significant for a maternal aunt with classic migraine headaches A. Cerebral angiogram with aura.The physical examination is normal without B. Lumbar puncture any evidence of neurologic deficits and normal blood C. Magnetic resonance angiogram pressure.What is the most appropriate next step in eval- D. Psychiatric evaluation uation and management of this patient? E. Reassess in a few hours A. Ask the subject to keep a headache diary for the next 41. A 78-year-old man with diabetes mellitus presents 2 months to assess the frequency and severity of with fever, headache and altered sensorium. On phys- headaches and assess for specific triggers. ical exam his temperature is 40.2°C, heart rate is 103 beats/min, blood pressure is 84/52 mmHg. His neck B. Encourage the patient to keep a regular routine is stiff and he has photophobia. His cerebrospinal including consistent sleep-wake cycle and regular exer- fluid (CSF) examination shows 2100 cells/μL, with cise such as yoga. 100% neutrophils, glucose 10 mg/dL, and protein 78 mg/dL. CSF gram stain is negative. Empirical C. Initiate therapy with rizatriptan, 10 mg orally, at onset therapy should include which of the following? of attacks. A. Amphotericin D. Perform an MRI of the brain. B. Dexamethasone after antibiotics E. A, B, and C C. Dexamethasone prior to antibiotics F. All of the above D. Doxycycline E. Piperacillin/tazobactam 43. Which of the following cranial nerve physical exam- ination techniques represents the correct approach to the patient with suspected neurologic disease?

Review and Self-Assessment 717 43. (Continued ) 46. All of the following myopathies would be inherited A. Olfactory nerve:With eyes closed, ask the patient to from the female parent except sniff a pungent stimulus such as ammonia or alcohol. B. Optic nerve: Check visual acuity in both eyes using a A. Becker muscular dystrophy Snellen chart without having the patient use their cor- B. Duchenne muscular dystrophy rective lenses. C. Kearns-Sayre syndrome C. Trigeminal nerve: Examine the motor territories on D. limb-girdle muscular dystrophy each side of the face by testing jaw clench, eyebrow E. myoclonic epilepsy with ragged red fibers (MERFF) elevation and forehead wrinkling. D. Accessory nerve: Check shoulder shrug and head rota- 47. A patient is brought to the emergency room after a tion on each side against resistance. head-on motor vehicle collision. The patient is unre- sponsive even to painful stimuli and is apneic; however, 44. You are going on morning rounds to see a 38-year- he does have a pulse. Which of the following clinical old woman who presented the prior day with findings would exclude a diagnosis of brain death? weakness and double vision. It is reported that on examination at that time she had pronounced A. Bilateral positive Babinski signs weakness in cranial nerves VII and XII. She also had B. Constricted pupils weakness in the extraocular muscles, which is C. Invariant pulse rate described to you as “googly eyes” with repeat exam- D. Positive deep tendon reflexes inations. The patient reports that she has profound E. Presence of diabetes insipidus double vision almost exclusively when she watches television in the evening. On your examination, you 48. A 45-year-old man presents with a daily headache. find no neurologic abnormalities. A head CT is He describes two attacks per day over the last 3 weeks. unremarkable. The patient denies any other past Each attack lasts about 1 h and awakens the patient medical history and has a mini-mental status exami- from sleep. The patient has noted associated tearing nation score of 30/30. What is the next appropriate and reddening of the right eye as well as nasal stuffi- step in the management of this patient? ness. The pain is deep, excruciating, and limited to the right side of the head. The neurologic examina- A. Formal psychiatric evaluation tion is nonfocal. The most likely diagnosis of this B. MRI of the brain patient’s headache is C. Serum anti-acetylcholine receptor antibodies D. Serum lead level A. migraine headache E. Slit-lamp examination B. cluster headache C. tension headache 45. A 37-year-old man is witnessed by his family to have D. brain tumor a generalized tonic-clonic seizure at a party. He does E. giant cell arteritis not have a known seizure disorder. There is no his- tory of head trauma, stroke, or tumor. The patient is 49. A 72-year-old woman presents with recurrent unemployed, married, and takes no medication. Phys- episodes of incapacitating facial pain lasting from ical examination shows no skin abnormalities and no second to minutes and then dissipating.The episodes stigmata of chronic liver or renal disease. The patient occur usually twice per day, usually without warn- is postictal. His neck is difficult to maneuver due to ing, but are also occasionally provoked by brushing stiffness. His white blood cell count is 19,000/μL, of her teeth. On physical examination, she appears hematocrit 36%, and platelets 200,000/μL. Glucose well with normal vital signs. Detailed cranial nerve is 102 mg/dL, sodium 136 meq/ dL, calcium 9.5 examination reveals no sensory or motor abnormali- mg/dL, magnesium 2.2 mg/dL, SGOT 18 U/L, blood- ties.The remainder of her neurologic examination is urea nitrogen 7 mg/dL, and creatinine 0.8 mg/dL. normal.What is the next step in her management? Urine toxicology screen is positive for cocaine metabo- lites. A head CT was negative. Which next step is A. Brain MRI most appropriate in this patient’s management? B. Brain MRI plus carbamazepine therapy C. Carbamazepine therapy A. Electroencephalogram (EEG) D. Glucocorticoid therapy B. Intravenous loading with antiepileptic medication E. Referral to Otolaryngology for surgical cure C. Lumbar puncture D. Magnetic resonance imaging 50. A 26-year-old man presents to the emergency room E. Substance abuse counseling with complaints of weakness and difficulty breathing.

718 Review and Self-Assessment 50. (Continued ) 52. (Continued ) He first noticed a feeling of weakness in his legs with A. Passive dorsiflexion of the foot during the maneuver difficulty climbing the stairs to his third-floor apart- will elicit pain from the contralateral nerve root. ment 5 days ago. Over the ensuing days, his weakness B. The crossed straight leg raise is more specific for disk has progressed such that he feels like he is tripping herniation than the straight leg raise. when he walks on flat surfaces and was unable to C. The reverse straight leg raise is indicative of back pain climb to his apartment yesterday. In addition, he now referred from visceral organs. states that he is having difficulty lifting his arms above D. The straight leg raise test is positive if there is restricted his head to comb his hair and twice dropped a bottle range of motion of the affected limb. of soda on the floor due to a feeling of weakness in his arms. He also states that he feels short of breath, espe- 53. A 37-year-old woman presents with complaints of cially if lying flat. He complains of a tingling in his headache and blurry vision that have been present hands and feet. His past medical history is notable for for a year and are slowly getting worse. As part of sickle cell trait. Three weeks ago, he was treated for her evaluation an MRI is obtained and shown in dehydration in the emergency department for food Fig. 53 below: poisoning with diarrhea, abdominal pain, and low- grade fevers. This resolved within 2 days, and he had FIGURE 53 been feeling in his usual state of health prior to the onset of the current symptoms. He is on no medica- What is the most likely diagnosis in this patient? tion and has no history of illicit drug use. He has no A. Brain abscess recent travel and has not eaten shellfish, honey, or B. Glioblastoma home-canned foods. On physical examination, he C. Low-grade astrocytoma appears breathless, has difficulty completing sentences, D. Meningioma and is using accessory muscles of respiration. His vital E. Oligodendroglioma signs show a respiratory rate of 32 breaths/min, a 54. All but which of the following statements regarding heart rate of 95 beats/min, a blood pressure of 112/76 epilepsy are true? mmHg, and a temperature of 37.6°C. His weight is A. The incidence of suicide is higher in epileptic patients 80 kg. His ocular movements are full.There is no pap- illary dilatation. On pulmonary examination, his than it is in the general population. breath sounds are clear.There is paradoxical motion of B. Mortality is no different in patients with epilepsy than the abdomen with inspiration. Neurologic examina- tion shows 3/5 strength symmetrically in the upper it is in age-matched controls. and lower extremities with absent deep tendon reflexes. C. A majority of patients with epilepsy that is completely Cardiovascular, gastrointestinal, and skin examinations are normal. Arterial blood gases show a pH of 7.55, a controlled with medication eventually will be able to PaCO2 of 28 mmHg, and a PaO2 of 84 mmHg while discontinue therapy and remain seizure free. breathing room air. His vital capacity is 800 mL.What D. Surgery for mesial temporal lobe epilepsy (MTLE) is the most appropriate treatment for this individual? decreases the number of seizures in over 70% of patients. E. Tricyclic antidepressants lower the seizure threshold A. Botulinum antitoxin and may precipitate seizures. B. Intravenous immunoglobulin (IVIg) C. IVIg and mechanical ventilation D. IVIg, mechanical ventilation, and ciprofloxacin E. Plasmapheresis and glucocorticoids 51. The most common cause of a cerebral embolism is A. cardiac prosthetic valves B. rheumatic heart disease C. dilated cardiomyopathy D. endocarditis E. atrial fibrillation 52. When evaluating a patient for low back pain, which statement is true regarding the utility of the straight leg raise test?

Review and Self-Assessment 719 55. A 54-year-old man is referred to your clinic for 56. (Continued ) evaluation of atrial fibrillation. He first noted the A. Acid maltase deficiency (Pompe’s disease) irregular heartbeat 2 weeks ago and presented to his B. Becker muscular dystrophy primary care physician. He denies chest pain, short- C. Duchenne muscular dystrophy ness of breath, nausea, or gastrointestinal symptoms. D. Myotonic dystrophy Past medical history is unremarkable. There is no E. Nemaline myopathy history of hypertension, diabetes, or tobacco use. His medications include metoprolol. The examina- 57. A 20-year-old woman is brought to the emergency tion is notable for a blood pressure of 126/74 department after a witnessed generalized tonic-clonic mmHg and a pulse of 64 beats/min. The jugular seizure. She has no identifying information, and her venous pressure is not elevated. His heart is irregu- past medical history is unknown. What is the most larly irregular, with normal S1 and S2. The lungs likely cause of her seizure? are clear, and there is no peripheral edema. An echocardiogram shows a left atrial size of 3.6 cm. Left A. Amyloid angiopathy ventricular ejection fraction is 60%. There are no B. Fever valvular or structural abnormalities. Which of the C. Genetic disorder following statements regarding his atrial fibrillation D. Illicit drug use and stroke risk is true? E. Uremia A. He requires no antiplatelet therapy or anticoagulation 58. The presence of startle myoclonus in a 60-year-old because the risk of embolism is low. man with rapidly progressive deficits in cortical dys- function is which one of the following? B. Lifetime warfarin therapy is indicated for atrial fibrilla- tion in this situation to reduce the risk of stroke. A. Neither sensitive nor specific for Creutzfeldt-Jacob disease (CJD) but does represent grounds to explore C. He should be admitted to the hospital for intravenous further for this condition with an electroencephalo- heparin and undergo electrical cardioversion; afterward gram (EEG) there is no need for anticoagulation. B. Neither sensitive nor specific for CJD but does repre- D. His risk of an embolic stroke is less than 1%, and he sent grounds to explore further for this condition with should take a daily aspirin. an EEG and brain MRI E. He should be started on subcutaneous low-molecular- C. Sensitive but not specific for CJD and is not enough to weight heparin and transitioned to warfarin. prompt a further workup for this condition unless other clinical criteria are met 56. A 34-year-old woman seeks evaluation for weakness. She has noted tripping when walking, particularly in D. Specific but not sensitive for CJD and should therefore her left foot, for the past 2 years. She recently also prompt immediate referral for brain biopsy to confirm began to drop things, once allowing a full cup of the diagnosis coffee to spill onto her legs. In this setting, she also feels as if the appearance of her face has changed E. Virtually diagnostic for CJD, and further workup over the course of many years, stating that she feels including EEG, brain MRI, and perhaps brain biopsy as if her face is becoming more hollow and elon- serves only a prognostic purpose gated although she hasn’t lost any weight recently. She has not seen a physician in many years and has 59. Which nerve functions are spared in a patient with no past medical history. Her only medications are a ventral cord syndrome due to an anterior spinal cord multivitamin and calcium with vitamin D. Her fam- infarct? ily history is significant for similar symptoms of weakness in her brother who is 2 years older. Her A. Bladder sphincter control mother, who is 58 years old, was diagnosed with B. Motor strength mild weakness after her brother was evaluated, but is C. Pain sensation not symptomatic. On physical examination, the D. Proprioception patient’s face appears long and narrow with wasting E. Tendon reflexes of the temporalis and masseter muscles. Her speech is mildly dysarthric, and the palate is high and 60. A 33-year-old woman presents with complaint of a arched. Strength is 4/5 in the intrinsic muscles of the rash on her chest. She has had a nonpruritic red rash hand, wrist extensors, and ankle dorsiflexors. After on the upper chest for 4 weeks associated with a testing handgrip strength, you notice that there is a raised erythematous rash on her hands. She does not delayed relaxation of the muscles of the hand. What wear V-neck shirts, but the chest rash is in a V-neck is the most likely diagnosis? distribution. Her hands have a scaly reddish-purple eruption, and her finger pads have become thicker

720 Review and Self-Assessment 60. (Continued ) 62. (Continued ) and rougher (see Fig. 60). She also has a slight red notable for distal atrophy below the midcalves and hue on the upper eyelids. for prominent high arches.There is obvious footdrop, What other findings are likely to be present in this and dorsiflexion of the foot is severely diminished patient? bilaterally. You suspect a form of Charcot-Marie- Tooth disease and order nerve conduction studies. FIGURE 60 Which of the following statements about CMT disease is true? A. Delayed relaxation phase of deep tendon reflexes B. Hepatosplenomegaly A. CMT disease is usually a motor neuropathy; sensory fea- C. Muscle weakness tures are rare and should prompt an alternative diagnosis. D. Situs inversus E. Subcutaneous nodules on the back of the forearm B. Immunotherapy with intravenous immune globulin 61. A 65-year-old man presents with severe right-sided and/or plasmapheresis may slow the progression of eye and facial pain, nausea, vomiting, colored halos CMT disease. around lights, and loss of visual acuity. His right eye is quite red, and that pupil is dilated and fixed. C. CMT disease affects approximately 1 in 100,000 Which of the following diagnostic tests would con- individuals. firm the diagnosis? A. CT of the head D. Transmission is most commonly autosomal dominant B. MRI of the head but may be autosomal recessive or X-linked. C. Cerebral angiography D. Tonometry E. The age of this patient at presentation is atypical; E. Slit-lamp examination patients usually present in the fourth and fifth decades 62. A 21-year-old man presents to your clinic with of life. complaint of progressive weakness in the feet for the last 2 years. He describes slowly progressive difficulty 63. Which of the following groups of patients should in lifting his feet off the ground when walking. The receive empirical antibiotic therapy that includes legs have “gotten smaller” in bulk. Past medical his- coverage of Listeria monocytogenes in cases of presumed tory is unremarkable.The family history is significant meningitis? for his father, brother, and paternal grandmother all having similar “weaknesses.” The examination is A. Immunocompromised patients B. Elderly patients C. Infants D. All of the above 64. Which of the following neurologic phenomena is classically associated with herniation of the brain through the foramen magnum? A. Third-nerve compression and ipsilateral papillary dilation B. Catatonia C. “Locked-in” state D. Miotic pupils E. Respiratory arrest 65. A 72-year-old woman presents with brief, intermit- tent excruciating episodes of lancinating pain in the lips, gums, and cheek. These intense spasms of pain may be initiated by touching the lips or moving the tongue. The results of a physical examination are normal. MRI of the head is also normal. The most likely cause of this patient’s pain is A. acoustic neuroma B. meningioma C. temporal lobe epilepsy D. trigeminal neuralgia E. facial nerve palsy

Review and Self-Assessment 721 66. A 38-year-old woman patient with facial and ocular 69. (Continued ) weakness has just been diagnosed with myasthenia A. Factors such as cigarette smoking and hypertension have gravis. You intend to initiate therapy with anti- no modifying risk on the development of ischemic cholinesterase medications and glucocorticoids. All stroke in individuals who have migraine with aura. of the following tests are necessary before instituting B. In both women and men, migraine with aura is this therapy except associated with an increased risk of ischemic stroke. C. Migraines generally persist unchanged in severity A. CT or MRI of the chest throughout life. B. purified protein derivative skin test D. Migraine with or without aura is associated with an C. lumbar puncture increased risk of subclinical posterior circulation D. pulmonary function tests infarction on MRI. E. thyroid-stimulating hormone E. Women on oral contraceptives who have migraines without aura should discontinue these medications 67. A 76-year-old nursing home resident is brought to because of a marked increased risk of ischemic stroke. the local emergency department after falling out of bed.The fall was not witnessed; however, she was sus- 70. A 40-year-old man has recurrent bouts of tinnitus. pected to have hit her head. She is not responsive to Except for a fairly severe upper respiratory tract infec- verbal or light tactile stimuli.At baseline she is able to tion 1 year ago, he has been healthy for all of his life. converse but is frequently disoriented to place and In the last year he has had two self-limited episodes of time. She has a medical history that includes stable tinnitus associated with dizziness and a decrement in coronary disease, mild emphysema, and multi-infarct his hearing. His symptoms are always unilateral on the dementia. Immediately after triage she is taken for a same side and have required him to take off from CT scan of the head. Which of the following is true work for a few days each time. He comes into your regarding head injury and hematomas? office at the outset of his third bout of tinnitus. He has taken meclizine at home with no relief. In your A. More than 80% of patients with subdural hematomas will office, he has tinnitus and vertigo while seated, experience a lucid interval prior to loss of consciousness. which is exacerbated with ambulation. His symp- toms of dizziness are not reproduced with Dix- B. Epidural hematomas generally arise from venous sources. Hallpike maneuvers. Which is the best long-term C. Epidural hematomas are common among the elderly treatment option for the patient at this time? with minor head trauma. A. Diuretic D. Most patients presenting with epidural hematomas are B. Glucocorticoid C. Epley procedure unconscious. D. Metoclopramide E. Subdural hematomas lead to rapid increases in intracra- E. Scopolamine transdermal nial pressure and can require arterial ligation. 71. While you are working in the urgent care center, a babysitter brings in a 7-year-old boy who complains of 68. A 45-year-old man presents with complaint of severe visual changes. He complains of difficulty with blue-yel- right arm pain. He gives a history of having slipped low color discrimination. He has no other past medical on the ice and severely contusing his right shoulder history. On examination, visual acuity in the right eye is approximately 1 month ago. At this time he has sharp 20/60 and in the left eye 20/80. He has blue-yellow knifelike pain in the right arm and forearm. Physical color blindness. He has cerebellar ataxia on neurologic examination reveals a right arm that is more moist examination as well as ophthalmoparesis. His strength is and hairy than the left arm. There is no specific 5 out of 5 in all major muscle groups, and all reflexes are weakness or sensory change. However, the right arm normal except for extensor plantar responses.When the is clearly more edematous than the left, and the skin mother arrives, you find out that many relatives on the appears somewhat atrophic in the affected limb. The father’s side of the family, including the father, have been patient’s pain most likely is due to diagnosed with cerebellar ataxia but she does not know more than that. You decide to perform a funduscopic A. subclavian vein thrombosis examination.What do you expect to find on examina- B. brachial plexus injury tion of this patient’s fundi? C. reflex sympathetic dystrophy D. acromioclavicular separation A. Lipemia retinalis E. cervical radiculopathy B. Normal examination 69. Which of the following statements regarding the long- term outcomes in individuals with severe migraines is true?

722 Review and Self-Assessment 71. (Continued ) 77. (Continued ) C. Papilledema A. carotid artery stenosis D. Proliferative retinopathy B. hypokalemia E. Retinal pigmentary degeneration D. multiple sclerosis E. myasthenia gravis 72. All the following have been shown to reduce the F. transient ischemic attack risk of atherothrombotic stroke in primary or sec- ondary prevention except 78. You are examining a 78-year-old patient in your clinic who is referred to you for difficulty in walking. A. aspirin During your motor examination with the patient B. blood pressure control lying supine, you place your hands behind one knee C. clopidogrel and rapidly raise the knee off the bed. During the D. statin therapy maneuver, the ankle (of the same leg) is also lifted off E. warfarin the examining table. On repeat examination of the same leg, you find varying levels of resistance, and the 73. All the following are associated with a decreased ankle drags for varying distances before being lifted sense of smell except off the bed. The finding is not seen in the other leg nor in the upper extremities when examining the A. head trauma elbow/wrist. What is the significance of this finding? B. HIV infection C. influenza B infection A. The patient has decreased motor tone, which may be D. Kallmann syndrome indicative of a motor neuron disease. E. parainfluenza virus type 3 infection B. The patient has decreased motor tone related to 74. All the following are side effects of phenytoin except musculoskeletal injury. A. ataxia C. The patient’s paratonia may be a normal B. gum hyperplasia reaction. C. hirsutism D. leukopenia D. The patient’s rigidity is a manifestation of E. lymphadenopathy parkinsonism. 75. All but which of the following statements about 79. Which of the following medicines has been most Becker’s muscular dystrophy are true? commonly implicated in the development of nonin- fectious chronic meningitis? A. The inheritance is X-linked. B. Serum creatinine kinase levels are elevated. A. Acetaminophen C. The underlying genetic defect is in the myosin gene. B. Acyclovir D. Survival is better than it is in patients with Duchenne’s C. β-lactam antibiotics D. Ibuprofen muscular dystrophy (DMD). E. Phenobarbital E. Cardiomyopathy may occur, resulting in heart failure. 80. A 72-year-old right-handed man with a history of 76. You are following a patient who has a ruptured L4- atrial fibrillation and chronic alcoholism is evaluated L5 intervertebral disk with herniation. He has had for dementia. His son gives a history of a stepwise left lower extremity weakness that has been constant decline in the patient’s function over the last 5 years for 6 months. He is still able to perform his daily with the accumulation of mild focal neurologic activities. His pain is intermittent and he uses chronic deficits. On examination he is found to have a narcotics on an as-needed basis.What findings would pseudobulbar affect, mildly increased muscle tone, prompt you to refer this patient for surgery? and brisk deep tendon reflexes in the right upper extremity and an extensor plantar response on the A. Absent deep tendon reflexes on the right left.The history and examination are most consistent B. MRI shows L3-L4 herniation as well with which of the following? C. Nighttime symptoms D. Physical examination demonstrates progressive weakness A. Binswanger’s disease B. Alzheimer’s disease 77. All of the following conditions may cause episodic C. Creutzfeldt-Jakob disease generalized paresis except D. Vitamin B12 deficiency E. Multi-infarct dementia

Review and Self-Assessment 723 81. A 50-year-old man presents with complaints of 81. (Continued ) weakness and numbness in the hands for the last median nerve distribution. All the following are month. He describes paresthesias in the thumb and causes of carpal tunnel syndrome except the index and middle fingers. The symptoms are worse at night. He also describes decreased grip A. amyloidosis strength bilaterally. He works as a mechanical engi- B. chronic lymphocytic leukemia neer. The patient denies fevers, chills, or weight loss. C. diabetes mellitus The examination is notable for atrophy of the thenar D. hypothyroidism eminences bilaterally and decreased sensation in a E. rheumatoid arthritis ANSWERS head for relief, whereas those with migraines tend to remain motionless during attacks. Interestingly, unilateral 1. The answer is C. phonophobia and photophobia can occur with cluster (Chap. 13) Confusion is defined as a mental and behav- headaches but do not with migraines. Treatment of acute ioral state of reduced comprehension, coherence, and attacks of cluster headaches requires a treatment with a capacity to reason. Delirium is used to describe an acute fast onset as the headaches reach peak intensity very confusional state. Delirium often goes unrecognized quickly but are of relatively short duration. High-flow despite clear evidence that it is often a cognitive manifes- oxygen (10–12 L/min for 15–20 min) has been very tation of many medical and neurologic illnesses. Delirium effective in relieving the headaches. Alternatively, subcuta- is a clinical diagnosis that may be hyperactive (e.g., alco- neous or intranasal delivery of sumatriptan will also halt hol withdrawal) or hypoactive (e.g., opiate intoxication). an attack. The oral-route triptan medications are less There is often dramatic fluctuation between states. Delir- effective because of the time to onset of effect is too ium is associated with a substantial mortality with in- great. Preventive treatment may be considered in individ- hospital mortality estimates ranging from 25–33%. Overall uals with prolonged bouts of cluster headaches or chronic estimates of delirium in hospitalized patients range from cluster headaches that occur without a pain-free interval. 15–55% with higher rates in the elderly. Patients in the ICU have especially high rates of delirium, ranging from The other TAC syndromes are paroxysmal hemicra- 70–87%. The clinic setting would represent the lowest nia and short-lasting unilateral neuralgiform headache risk. Postoperative patients, especially status post hip attacks with conjunctival injection and tearing (com- surgery, have an incidence of delirium that is somewhat monly known as SUNCT). Paroxysmal hemicrania is higher than patients admitted to the medical wards. characterized by unilateral severe headaches lasting only 2–45 min but occurring up to five times daily. There is 2. The answer is C. marked autonomic symptoms, and paroxysms of (Chap. 6) This patient is presenting with typical cluster headaches last <3 days. Indomethacin is very effective at headaches, one of the three recognized trigeminal auto- preventing this syndrome. SUNCT is a rare syndrome in nomic cephalgias (TACs). TACs are characterized by which the headaches last <4 min at a time. Diagnosis intense episodes of head pain associated with cranial auto- requires at least 20 attacks. There is no acute treatment of nomic symptoms such as tearing, rhinorrhea, and con- SUNCT because of their short duration, but preventative junctival injection. Because of these associated symptoms, therapy with lamotrigine, topiramate, gabapentin, or car- patients may be misdiagnosed as having sinus headache bamazepine may be effective. due to allergic rhinitis and treated inappropriately with antihistamine and nasal steroids. A typical presentation of 3. The answer is A. cluster headaches is one of episodic severe headaches that (Chap. 44) A common mistake in the management of occur at least once daily at about the same time for a patients with inflammatory myopathy is to “chase the period of 8–10 weeks. An attack usually lasts from 15–180 CK” instead of adjusting therapy based on the clinical minutes, and 50% of headaches will have nocturnal onset. response. The goal of therapy is to improve strength. If Between episodes of headache, the patient is generally that goal is being achieved, no augmentation of therapy is well. The period between headache cycles typically lasts necessary. In this case, the plan to switch to long-term about 1 year. Men are affected three times more com- maintenance with steroid-sparing immunosuppressants monly with cluster headaches than women, and alcohol should still be pursued. There have been no controlled ingestion may trigger cluster headaches. A distinguishing studies comparing mycophenolate to methotrexate for the feature between cluster headaches and migraine long-term use in polymyositis, and in the absence of an headaches is that individuals with cluster headaches tend adverse reaction to mycophenolate, therapy should not be to move about during attacks and frequently rub their

724 Review and Self-Assessment changed. Despite an elevated CK, patients with polymyosi- 6. The answer is B. tis who are responding to therapy do not need a repeat (Chap. 9) The symptoms and signs described in this ques- muscle biopsy. tion are most consistent with Ménière’s disease. In this disorder paroxysmal vertigo resulting from labyrinthine 4. The answer is C. lesions is associated with nausea, vomiting, rotary nystag- (Chap. 10) The central cord syndrome manifests clinically mus, tinnitus, high-tone hearing loss with recruitment, as a sensory disorder as the spinothalamic fibers in the and, most characteristically, fullness in the ear. Labyrinthi- ventral commissure of the spinal cord are disrupted. Der- tis would be an unlikely diagnosis in this case because of matomes above and below the level of the destruction are the hearing loss and multiple episodes. Vertebral-basilar usually spared, creating a “suspended sensory level” on insufficiency and multiple sclerosis typically are associated physical examination. As the lesion grows, corticospinal with brainstem signs. Acoustic neuroma only rarely causes tract or anterior horn involvement can produce weakness vertigo as the initial symptom, and the vertigo it does in the affected myotome. Common causes include cause is mild and intermittent. syringomyelia, intramedullary tumor, and hyperextension in a patient with cervical spondylosis. Tabes dorsalis 7. The answer is D. impairs proprioception and sensation and causes weak- (Chap. 35) In a patient with suspected bacterial meningitis ness. Disc herniation most commonly affects posterior empirical therapy should be administered promptly to cord function and nerve roots. A lateral hemisection syn- reduce mortality and morbidity.The decision to obtain an drome (the Brown-Séquard syndrome) is classically due to imaging study prior to lumbar puncture is based on the penetrating trauma from a knife or bullet injury and pro- concern of precipitating herniation in a patient with ele- duces ipsilateral weakness and contralateral loss of pain vated intracranial pressure or focal CNS lesions.Therefore, and temperature sensation. Amyotrophic lateral sclerosis patients with the presence of papilledema on physical presents with combined upper and lower motor neuron examination, history of recent head trauma, known or sus- findings; sensory deficits are uncommon. pected intracranial lesions (immunosuppressed, known malignancy), focal neurologic findings, or depressed level of 5. The answer is D. consciousness should have a head CT or MRI prior to (Chap. 22) This patient has evidence of increased intracra- lumbar puncture. Kernig’s sign is elicited in a supine patient nial pressure and needs to be managed urgently. A variety by flexing the thigh and knee. A positive sign occurs when of maneuvers may decrease intracranial pressure acutely. the patient has head/neck pain when passively straighten- Hyperventilation causes vasoconstriction, reducing cere- ing the knee.The sensitivity and specificity of this sign (also bral blood volume and decreasing intracranial pressure. Brudzinski’s) for bacterial meningitis are unknown, but However, this can be used only for a short period as the they imply meningeal irritation, not an intracranial lesion decrease in cerebral blood flow is of limited duration. or elevated intracranial pressure. While cerebrospinal fluid Mannitol, an osmotic diuretic, is recommended in cases of cultures may be impacted by administration of antibiotics increased intracranial pressure resulting from cytotoxic prior to lumbar puncture, stains, antigen tests, and poly- edema. Hypotonic fluids should be avoided. Instead, merase chain reaction tests will not be affected. hypertonic saline is given to elevate sodium levels and prevent worsening of edema. A more definitive treatment 8. The answer is C. to decrease intracranial pressure is to have a ventricu- (Chap. 12) The patient’s nonspecific dysesthesia is related lostomy placed by which excessive pressure can be to hyperventilation in response to the patient’s change in relieved by draining cerebrospinal fluid (CSF). Further altitude from sea level to a mountainous area.The normal decreases in mean arterial pressure may worsen the respiratory response to decreased atmospheric oxygen patient’s clinical status. The patient already has had more tension is to increase the respiratory rate.This hyperventi- than a 20% reduction in mean arterial pressure, which is lation causes a mild respiratory alkalosis and is experi- the recommended reduction in cases of hypertensive enced as acral and periorbital dysesthesias. Acetazolamide emergency. In addition, the patient is exhibiting signs is often given to patients who have a past history of alti- of increased intracranial pressure, which indicates that tude sickness manifested as headache, nausea with vomit- cerebral perfusion pressure [mean arterial pressure ing, and in severe cases pulmonary edema. This patient is (MAP)–intracranial pressure (ICP) ] has been lowered. experiencing none of those symptoms, and in fact, dyses- Paradoxically, the patient may need a vasopressor agent to thesias are a common side effect related to treatment with increase MAP and thus improve cerebral perfusion. acetazolamide. No further blood testing is necessary as the Finally, in cases of increased intracranial pressure, nitro- symptoms are not associated with any neurologic abnor- prusside is not a recommended intravenous antihyperten- malities. Diabetes mellitus, vitamin B12 deficiency, and ter- sive agent because it causes arterial vasodilation and may tiary syphilis are all associated with a sensory neuropathy, decrease cerebral perfusion pressure and worsen neuro- which this patient does not demonstrate. logic function.

Review and Self-Assessment 725 9. The answer is C. the skull.Transient loss of consciousness is common, as are (Chap. 1) This patient demonstrates increasing weakness confusion and amnesia. Head imaging is typically normal. with repeated exertion, which is characteristic of neuro- Postconcussive syndrome is a constellation of symptoms muscular junction diseases such as myasthenia gravis. The including fatigue, headache, dizziness, and difficulty con- course can fluctuate over the course of a day, which may centrating that follows a concussion.The patient described explain why his symptoms appear worse at the end of the above fits this diagnosis; strict diagnostic criteria do not day. The absence of any sensory deficit is also characteris- exist. Typically patients will improve over a 6- to 12- tic of a neuromuscular junction disorder. Diseases of the month period. Patients who were energetic and highly muscle usually do not exhibit such a marked difference functioning prior to their trauma have an excellent prog- on the examination over the course of hours. Spinal root nosis. Treatment is aimed at reassurance and relieving disorders are symptomatic in a nerve root distribution, prominent symptoms. Dizziness can be treated with phen- and limb pain is usually a prominent component. Clues to ergan, which acts as a vestibular suppressant. He should a brainstem disease are isolated cranial nerve palsies and avoid contact sports at least until his symptoms resolve. “crossed” weakness and sensory abnormalities of the head and limbs. 13. The answer is E. (Chap. 38) Prions are infectious particles that cause central 10. The answer is B. nervous system degeneration. The human prion diseases (Chap. 30) This patient has a history and examination described to date include Creutzfeldt-Jacob disease, kuru, consistent with a myelopathy. The rapidity of onset and Gerstmann-Straüssler-Scheinker disease, and fatal insom- the lack of other antecedent symptoms (e.g., pain) make a nia. The most common prion disease is sporadic CJD noncompressive etiology most likely. An MRI is the initial (sCJD) which occurs in a seemingly random pattern in test of choice and will easily identify a structural lesion adults in their fifth and sixth decades of life. sCJD such as a neoplasm or subluxation. Non-compressive accounts for about 85% of cases of CJD and occurs in ~1 myelopathies result from five basic causes: spinal cord per 1 million population.Variant CJD (vCJD) results from infarction; systemic disorders such as vasculitis, systemic infection from bovine exposure to tainted beef from cattle lupus erythematosus (SLE), and sarcoidosis; infections with bovine spongiform encephalopathy (BSE). Infectious (particularly viral); demyelinating disease such as multiple CJD (iCJD) has resulted from injection of tainted human sclerosis; and idiopathic. Therefore, serologies for antinu- growth hormone, as well as transplant of infected dura clear antibodies, viral serologies such as HIV and HTLVI, mater grafts into humans. Familial CJD (fCJD) is due to and lumbar puncture are all indicated. Because the clinical germ-line mutations that follow an autosomal dominant scenario is consistent with a myelopathy, an electromyo- inheritance. Kuru is due to infection through ritualistic gram is not indicated. cannibalism. Gerstmann-StraüsslerScheinker disease and familial fatal insomnia (FFI) occur as dominantly inher- 11. The answer is D. ited prion diseases. Sporadic cases of fatal insomnia (sFI) (Chap. 26) This MRI shows cerebellar atrophy consistent have been described. with the diagnosis of spinocerebellar ataxia (SCA). The SCAs are a group of autosomal dominant diseases. SCA1, 14. The answer is B. previously known as olivopontocerebellar atrophy, is a dis- (Chap. 7) Neurogenic claudication (back or leg pain ease of early or middle adult life. Patients develop cerebel- induced by walking or standing and relieved by sitting) is lar ataxia of the trunk and limbs with impairment of the most common symptom of lumbar spinal stenosis. equilibrium and gait, scanning speech, nystagmus, and Unlike vascular claudication, symptoms are provoked by oscillatory tremor of the head and trunk. There may also standing without walking. Symptoms are often not pre- be mild dementia. Cerebellar and brainstem atrophy are sent, and severe findings such as paralysis and urinary evident on MRI. Migraine headache, limb weakness, and incontinence are rare. Lumbar spinal stenosis can be con- breathing difficulties are nonspecific but may be seen in genital or acquired. Acquired factors that contribute to serotonin syndrome or alcohol withdrawal. Gait instabil- spinal stenosis include trauma, osteoporosis, hypoparathy- ity, urinary incontinence, and dementia constitute the roidism, renal osteodystrophy, and Paget’s disease. Teth- clinical triad for normal-pressure hydrocephalus, which ered cord syndrome usually presents as a cauda equina does not have cerebellar atrophy on MRI. Hypertension, disorder (urinary incontinence, perineal anesthesia) in a tachycardia, and diaphoresis may be seen in a patient with young adult. Pain associated with disk herniation is dif- an Arnold-Chiari malformation. MRI will often show ferentiated from spinal stenosis when the pain is made abnormalities in the base of the skull. worse with sitting. Vertebral metastases are a common cause of back pain in patients at risk of common malig- 12. The answer is A. nancies.The pain tends to be constant, dull, unrelieved by (Chap. 31) Concussions result from blunt head trauma that rest, and worst at night. causes anterior-posterior movement of the brain within

726 Review and Self-Assessment 15. The answer is A. deltoid would be mediated by injury to the C5 nerve root. (Chap. 20) Complex partial seizures are characterized by Finger flexors and sensation to the axilla and medial arm focal seizure activity plus impairment of the patient’s abil- are mediated by C8 and T1. (See Table 7-4) ity to maintain contact with the environment. Mesial temporal lobe epilepsy is the most common syndrome 20. The answer is C. associated with complex partial seizures. Patients are (Chap. 26) The patient describes cerebellar ataxia, which is unable to respond to verbal or visual commands during differentiated from ataxia associated with vestibular or the seizure and they often manifest complex automatisms labyrinthine disease by the absence of vertiginous com- or complex posturing. An aura is common before the plaints. True cerebellar ataxia is devoid of vertiginous seizures. There is postictal memory loss or disorientation. symptoms and is clearly an unsteady gait due to imbal- Patients often have a history of febrile seizures or a family ance. CT scanning can miss pathology in the cerebellum history of seizures. MRI will show hippocampal sclerosis, due to the surrounding bony structures. Alcohol intoxica- a small temporal lobe, or enlarged temporal horn. tion, lithium toxicity, and viral cerebritis usually cause Hypothyroidism, herpes virus infection, diabetes, and acute or subacute (days to weeks) cerebellar ataxia. Ter- tuberous sclerosis are not associated with mesial temporal tiary syphilis is a common cause of chronic cerebellar lobe epilepsy. ataxia (months to years). 16. The answer is B. 21. The answer is E. (Chap. 20) MTLE is important to recognize because it (Chap. 12) Thalamic pain syndrome may follow an tends to be refractory to treatment with anticonvulsants embolic or lacunar thalamic infarct if it affects the ventral but responds extremely well to surgical intervention. posterolateral (VPL) nucleus or the adjacent white matter. Primidone is an alternative for treatment of partial and The pain is persistent and severe, affecting only the con- generalized tonic-clonic seizures. Levetiracetam is an tralateral side of the body. Other symptoms that may be alternative for simple partial, complex partial, and secon- associated with thalamic infarcts include hemianesthesia, darily generalized seizures. Vagus nerve stimulation is an hemiataxia, choreoathetoid movements, and athetoid pos- option for patients refractory to antiepileptic medication ture. The eponym applied to this syndrome is Déjerine- with seizures arising from more than one site. Herpes Roussy syndrome. virus infection is not a cause of MTLE. 22. The answer is A. 17. The answer is C. (Chap. 9) In the acute evaluation of vertigo, vestibular func- (Chap. 10) A deep tendon reflex is elicited when a tap on tion tests can help to establish the side of the abnormality a tendon stretches muscle spindles which are chronically and differentiate between central and peripheral etiologies. activated by γ motor neurons. Spindle afferent neurons When performing electronystagmography using cold and directly stimulate a motor neurons in the spinal cord, warm water sequentially, the velocity of the slow-phase of causing a muscle contraction.The reflex arc operates inde- nystagmus is compared from side to side. When warm pendent of upper motor neurons (pyramidal neurons); water at 44°C is infused into an ear, the normal response is however, loss of the inhibitory input from upper motor nystagmus with the fast component toward the infused ear. neurons produces an exaggerated deep tendon reflex. The opposite response occurs when cold water at 30°C is infused; the normal response is nystagmus with the fast 18. The answer is D. component away from the cold water–infused ear.The vol- (Chap. 34) Optic neuritis is the initial symptom in ume of water can be increased if no response occurs with approximately 40% of persons who are eventually diag- the initial attempt. Velocity of the slow phase should be nosed with multiple sclerosis. This rapidly developing similar in patients without vestibular nerve abnormalities. ophthalmologic disorder is associated with partial or total An absence of response to the cold caloric indicates a loss of vision, pain on motion of the involved eye, sco- labyrinth system that is “dead” and nonfunctional, such as toma affecting macular vision, and a variety of other in complete destruction of the neural input with acoustic visual field defects. Ophthalmoscopically visible optic neuroma. Otoconia are not a result of and do not cause papillitis occurs in about half these patients. peripheral nerve dysfunction. The caloric testing is normal in patients with otoconia.The peripheral nerve dysfunction 19. The answer is A. seen with aminoglycoside antibiotics is usually bilateral. (Chap. 7) The most commonly affected nerve roots in cer- Unilateral symptoms should raise the suspicion for an vical disk disease are C7 and C6. As such, common motor anatomic as opposed to a systemic cause of the vertigo. findings include biceps and triceps weakness. Common Labyrinthine ischemia will also manifest as a “dead” sensory findings include abnormal sensation in the thumb labyrinth; however, the patient’s age makes ischemic brain- and fingers (except the little finger), radial hand, and dorsal stem lesions less likely than a schwannoma. forearm. Decreased pin-prick sensation over the lateral

Review and Self-Assessment 727 23. The answer is D. secondary to trauma or infection is treated with decom- (Chap. 32) This scenario represents a common dilemma in pression and a drainage procedure, with a shunt often the care of patients with HIV infection. The differential inserted that drains into the subarachnoid space. Although diagnosis usually falls between CNS toxoplasmosis or relief may occur, recurrence is common. CNS lymphoma. The standard approach in a neurologi- cally stable patient is to treat the patient for toxoplasmosis 26. The answer is E. for 2–3 weeks then repeat neuroimaging. If the imaging (Chap. 42) Myasthenia gravis (MG) is a neuromuscular dis- shows clear improvement, continue antibiotics. If not, order characterized by weakness and fatigability of skeletal then a stereotactic brain biopsy is indicated. Whole-brain muscles.The primary defect is a decrease in the number of radiation therapy is part of the treatment for CNS lym- acetylcholine receptors at the neuromuscular junction sec- phoma, which is not yet diagnosed in this patient, and ondary to autoimmune antibodies. MG is not rare, affecting should not be instituted empirically. In the absence of at least 1 in 7500 individuals.Women are affected more fre- neurologic collapse, it is reasonable to treat empirically for quently than are men.Women present typically in the sec- toxoplasmosis in such a patient. The leptomeninges are a ond and third decades of life, and men present in the fifth common site for metastases for patients with systemic and sixth decades. The key features of MG are weakness lymphoma and those patients usually have a B cell lym- and fatigability. Clinical features include weakness of the phoma or leukemia. Dexamethasone is indicated for focal cranial muscles, particularly the lids and extraocular mus- CNS lesions with evidence of mass effect or extensive cles. Diplopia and ptosis are common initial complaints. surrounding edema. Weakness in chewing is noticeable after prolonged effort. Speech may be affected secondary to weakness of the palate 24. The answer is D. or tongue weakness. Swallowing may result from weakness (Chap. 32) In this immunocompromised patient who has of the palate, tongue, or pharynx. In the majority of not responded to treatment for CNS toxoplasmosis, a patients the weakness becomes generalized.The diagnosis is positive CNS EBV DNA would be diagnostic of CNS suspected after the appearance of the characteristic symp- lymphoma. However, in the absence of a definitive diag- toms and signs. Edrophonium is an acetylcholinesterase nosis, a biopsy should be pursued for a definitive diagno- inhibitor that allows ACh to interact repeatedly with the sis. If there is no response to therapy after 2 weeks, limited number of AChRs, producing improvement in the therapy does not need to be continued. Treatments strength of myasthenic muscles. False-positive tests may directed at viral infections of the CNS or CNS lym- occur in patients with other neurologic diseases. Electrodi- phomas are not indicated at this time since a diagnosis is agnostic testing may show evidence of reduction in the still yet to be made. In the absence of a change in neuro- amplitude of the evoked muscle action potentials with logic status or evidence of mass effect on CT, there is no repeated stimulation. Testing for the specific antibodies to indication for dexamethasone. AChR are diagnostic. In addition to anti-AChR antibod- ies, antibodies to MuSK have been found in some patients 25. The answer is A. with clinical MG. Antibodies to voltage-gated calcium (Chap. 30) Syringomyelia is a developmental, slowly channels are found in patients with the Lambert-Eaton enlarging cavitary expansion of the cervical cord that pro- syndrome. duces a progressive myelopathy. Symptoms typically begin in adolescence or early adulthood. They may undergo 27. The answer is D. spontaneous arrest after several years. More than half are (Chap. 24) The differential diagnosis of Parkinson’s disease associated with Chiari malformations. Acquired cavitations is broad, and the disease can be difficult to diagnose, with of the spinal cord are referred to as syrinx cavities. They an estimated misdiagnosis of 10–25% even by experi- may result from trauma, myelitis, infection, or tumor. The enced physicians. This patient exhibits several atypical classic presentation is that of a central cord syndrome with features that should alert the physician to search for sensory loss of pain and temperature sensation and weak- alternative diagnoses. These include early age of onset, ness of the upper extremities.Vibration and position sensa- prominent orthostasis, autonomic symptoms of flushing tion are typically preserved. Muscle wasting in the lower and diaphoresis, and failure to respond to dopaminergic neck, shoulders, arms, and hands with asymmetric or agents. In addition, recurrent urinary tract infections absent reflexes reflects extension of the cavity to the ante- should prompt an evaluation for urinary retention due to rior horns.With progression, spasticity and weakness of the autonomic dysfunction in this patient. These symptoms lower extremities and bladder and bowel dysfunction may are most consistent with multiple systems atrophy with occur. MRI scans are the diagnostic modality of choice. parkinsonian features (MSA-p). The average age of onset Surgical therapy is generally unsatisfactory. Syringomyelia is 50 years, and these individuals more frequently present associated with Chiari malformations may require exten- with bilateral, symmetric tremor and more prominent sive decompressions of the posterior fossa. Direct decom- spasticity than those with Parkinson’s disease. Orthostasis pression of the cavity is of debatable benefit. Syringomyelia and autonomic symptoms are typically prominent. On

728 Review and Self-Assessment MRI, one would expect to find volume loss and T2- while the head position is maintained, and repeat trials hyperintensity in the area of the putamen, globus pallidus, lessen the symptoms each time and may extinguish them and white matter. On pathologic examination, a-synuclein- completely. With central causes of vertigo, symptoms are positive inclusions would be seen in the affected areas. often less severe than with peripheral vertigo. Isolated Median survival after diagnosis is 6–9 years. Dopaminer- horizontal nystagmus without a torsional component is gic agents are not helpful in treatment of this disorder and also more suggestive of a central cause of vertigo. are usually associated with drug-induced dyskinesias of the face and neck, rather than the limbs and trunk. Corti- 30. The answer is C. cobasal degeneration is a sporadic tauopathy that presents (Chap. 24) Therapy for Parkinson’s disease should be initi- in the sixth to seventh decades. In contrast to Parkinson’s ated when symptoms interfere with the patient’s quality disease, this disorder is frequently associated with of life. Choice of initial drug therapy is usually with myoclonic jerks and involuntary purposeful movements of dopamine agonists, levodopa, or MAO inhibitors. The a limb. Its progressive nature leads to spastic paraplegia. initial choice in most individuals is a dopamine agonist Diffuse Lewy body disease has prominent dementia with (pramipexole, ropinirole), and monotherapy with dopamine parkinsonian features. Neuropsychiatric complaints agonists usually controls motor symptoms for several years including paranoia, delusions, and personality changes are before levodopa therapy becomes necessary. Over this more common than in Parkinson’s disease. Drug-induced period, escalating doses are frequently required, and side Parkinson’s disease is not seen with nitrofurantoin, and the effects may be limiting. It is thought that dopamine ago- patient has no history of illicit drugs such as MTPT, nists delay the onset of dyskinesias and on-off motor which could cause Parkinson’s disease. Finally, this is symptoms, such as freezing. By 5 years, over one-half of unlikely to be inadequately treated Parkinson’s disease individuals will require levodopa to control motor symp- because one would expect at least an initial improvement toms. Levodopa remains the most effective therapy for the on dopaminergic agents. motor symptoms of Parkinson’s disease, but once lev- odopa is started, dyskinesias and on-off motor fluctuations 28. The answer is D. become more common. MAO inhibitors work by decreas- (Chap. 31) The head CT shows bilateral hypodense fluid ing postsynaptic breakdown of dopamine. As monother- collections in the subdural space. Acute hematomas apy, these agents have only small effects and are most often (which would be as bright as the resolving blood shown used as adjuncts to levodopa. Surgical procedures such as in arrows) become hypodense in comparison with adja- pallidotomy and deep-brain stimulation are reserved for cent brain after ~2 months. During the isodense phase advanced Parkinson’s disease with intractable tremor or (2–6 weeks after injury), they may be difficult to discern. drug-induced motor fluctuations or dyskinesias. In this Chronic subdural hematoma may present without a his- setting, deep-brain stimulation can alleviate disabling tory of trauma or injury in 20–30% of patients. Headache symptoms. is common. Other symptoms may be vague as in this patient, or there may be focal signs including hemiparesis 31. The answer is C. mimicking stroke. Underlying cortical damage may serve (Chap. 44) This patient does not have signs of an inflam- as a seizure focus. In relatively asymptomatic patients with matory myositis. In particular, the “give-away” weakness small hematomas, observation and serial imaging may be and improvement with encouragement suggests that this reasonable; however, surgical evacuation is often necessary patient’s “weakness” may actually be due to muscular for large or symptomatic chronic hematomas. pain. Fibrositis, polymyalgia rheumatica or fibromyalgia may present this way, although the normal erythrocyte 29. The answer is B. sedimentation rate makes polymyalgia rheumatica less (Chap 9) Positional vertigo is precipitated by a recumbent likely. Necrotic muscle can be seen in any of the inflam- head position, either to the right or the left. The benign matory myopathies or necrotizing myositis. Endomysial form that affects the posterior semicircular canal is the deposits of amyloid can be seen in inclusion body myosi- most common and is due to the accumulation of otoco- tis. Scattered inflammatory foci are seen in polymyositis. nia. Central positional vertigo (CPV) is due to lesions of the fourth ventricle and is much less common than 32. The answer is E. BPPV. BPPV can be diagnosed and potentially treated (Chap. 29) Trigeminal neuralgia is a clinical diagnosis based with characteristic maneuvers (i.e., Dix-Hallpike posi- entirely on patient history.The disorder is characterized by tion). With the head supine, the head is turned to the paroxysms of excruciating pain in the lips, gums, cheeks, affected side (left ear down, in this case).Torsional nystag- and chin that resolves over seconds to minutes. It is caused mus and vertigo will result with characteristic eye move- by ectopic action potentials in afferent pain fibers of the ments. In BPPV, the time from assuming head position fifth cranial nerve, due either to nerve compression or and onset of symptoms is 3–40 s, whereas in CPV, the other cause of demyelination. Symptoms are often, but not onset is immediate. With BPPV, symptoms will abate always, elicited by tactile stimuli on the face, tongue or

Review and Self-Assessment 729 lips. An elevated ESR is not part of the clinical syndrome. and time course. Specific features of the history and phys- Elevated ESR is associated with temporal arteritis, a vas- ical examination should lead the clinician toward a possi- culitis associated with jaw claudication, unilateral vision ble diagnosis. For example, lead toxicity is frequently asso- loss, and symptoms of polymyalgia rheumatica. Trigeminal ciated with motor abnormalities in addition to sensory neuralgia is specifically notable for a lack of sensory find- neuropathy. Laboratory examination with specific testing ings on examination, unless the diagnosis comes in con- may be useful in assessing for a variety of etiologies of junction with another disorder such as midbrain mass peripheral neuropathy, including diabetes mellitus, heavy lesion or aneurysm. First-line therapy is with carba- metal toxicity, metabolic abnormalities, vasculitis, and mazepine followed by phenytoin, rather than gabapentin. infections (syphilis, Lyme disease, HIV). Of the choices Deep-seated facial and head pain is more a feature of listed in the question, folate deficiency is not associated migraine headache, dental pathology, or sinus disease. with peripheral neuropathy. 33. The answer is B. 36. The answer is A. (Chap. 7) MRI is the radiologic test of choice for evaluation (Chap. 32) Endocrine dysfunction resulting in hypopitu- of most serious processes involving the spine. However, CT itarism frequently follows exposure of the hypothalamus or scanning is the preferred test when imaging of the bony pituitary gland to therapeutic radiation. Growth hormone structures is most important. In acute processes such as frac- is the most sensitive to the damaging effects of WBRT, and ture or dislocation, MRI may reveal the edema associated thyroid-stimulating hormone is the least sensitive. ACTH, with the acute inflammation, but for more chronic bony prolactin, and gonadotropins have an intermediate sensitiv- conditions, CT scanning is the test of choice. MRI is better ity. Other complications of radiation therapy to the brain than CT scanning for imaging the soft tissues surrounding include acute radiation injury manifest by headache, sleepi- the spine. Imaging the spinal cord itself, in the case of ness, and worsening of preexisting neurologic defects. Early syringomyelia, is also better accomplished with MRI. Simi- delayed radiation injury occurs within the first 4 months larly, MRI is better than CT scanning for imaging the lateral after therapy. It is associated with increased white matter recesses of the spinal cord; however, CTmyelography is pre- signal on MRI and is steroid-responsive. Late delayed radia- ferred over MRI for that indication. tion injury occurs >4 months after therapy, typically 8–24 months.There may be dementia, gait apraxia, focal necrosis 34. The answer is B. (after focal irradiation), or development of secondary (Chap. 40) Peripheral neuropathy is a general term indicat- malignancies. ing peripheral nerve disorders of any cause.The causes are legion, but peripheral neuropathy can be classified by a 37. The answer is C. number of means: axonal versus demyelinating, mononeu- (Chap. 32) Spinal cord compression from solid tumor ropathy versus polyneuropathy versus mononeuritis multi- metastases usually results from growth of a bony vertebral plex, sensory versus motor, and the tempo of the onset of metastasis into the epidural space.The most common pri- symptoms. Mononeuropathy typically results from local mary tumors that metastasize to the bone include lung, compression, trauma, or entrapment of a nerve. Polyneu- breast, and prostate. The thoracic cord is most often ropathy often results from a more systemic process. The involved. Back pain is a prominent symptom in 90% of distinction between axonal and demyelinating can often be patients with vertebral metastases and spinal cord com- made only with nerve conduction studies. HIV infection pression. Concerning features of this patient’s presentation causes a common, distal, symmetric, mainly sensory include the symptoms of radicular injury as well as the polyneuropathy. Vitamin B12 deficiency typically causes a signs of radicular and spinal cord impingement on physi- sensory neuropathy that predominantly involves the dorsal cal examination. Once signs of spinal cord compression columns. Hypothyroidism and acromegaly may both cause develop, they usually progress rapidly and warrant rapid compression and swelling of nerve fibers, resulting first in therapy. Appropriate therapy includes emergent scanning sensory symptoms and later in disease with motor symp- with an MRI as well as immediate glucocorticoids if toms. Critical illness polyneuropathy is predominantly there are signs of spinal cord impingement. Subsequent motor in presentation.These patients may recover over the management will depend on the extent of involvement course of weeks to months. The etiology is unknown, but and the primary tumor. Conservative pain management an association may exist with neuromuscular blockade and measures are not appropriate in this patient since he has corticosteroids. very concerning neurologic findings for spinal cord com- pression and delay will increase the likelihood of irreversible 35. The answer is E. defects. Antibody-mediated paraneoplastic neurologic syn- (Chap. 40) Peripheral neuropathy is a common disorder dromes are unlikely to cause focal findings such as in this affecting 2–8% of the adult population and increasing patient. Radiographs may show bony metastases but will with age. The causes of peripheral neuropathy are myriad not show spinal cord damage. and can be classified by location, fiber type, histopathology,

730 Review and Self-Assessment 38. The answer is C. cytokine response in the subarachnoid space. This inflam- (Chap. 44) The inflammatory myopathies (polymyositis, der- mation may lead to increased damage of the blood brain matomyositis, and inclusion body myositis) are associated barrier and central nervous system damage. Glucocorti- with unique clinical features. Inclusion body myositis is usu- coids can blunt this response by inhibiting tumor necrosis ally seen in patients ≥50 years and initially involves the distal factor and interleukin-1. They work best if administered muscles, especially the foot extensors and finger flexors. before antibiotics. Clinical trials have demonstrated that Atrophy is seen along with weakness as this inflammatory dexamethasone, 10 mg IV administered 20 min before myopathy runs a slowly progressive course, compared to antibiotics, reduced unfavorable outcomes, including polymyositis or dermatomyositis. Polymyositis is a rare disor- death. The dexamethasone was continued for 4 days. The der that usually involves the proximal not distal muscles. It is benefits were most striking in pneumococcal meningitis. a diagnosis of exclusion after a thorough medical examina- Because this is the most common cause of meningitis in tion and muscle biopsy. Dermatomyositis is distinguished by the elderly, empirical coverage should include this inter- the classic heliotrope rash and associated skin findings, vention as well. Empirical antibiotics in this case should which may precede the development of clinical muscular include a third-generation cephalosporin, vancomycin, weakness. Eosinophilic myofasciitis is associated with myal- and ampicillin. However, dexamethasone may decrease gias, skin induration, fatigue, and eosinophilia in the periph- vancomycin penetration into the CSF, so its use should be eral blood as well as in endomysial tissue. Hyperthyroidism considered carefully in cases where the most likely organ- would cause a reduced TSH. It may cause weakness, but is ism requires vancomycin coverage. generally associated with other findings such as tremor, skin changes, and irritability. 42. The answer is E. (Chap. 6) This patient has typical symptoms of migraine 39. The answer is B. headaches without concerning features for an underlying (Chap. 42) In myasthenia gravis, the primary defect is disorder. Specifically, there is no report of worsening decreased number of available ACh receptors in the severity of headaches, fever, intractable vomiting, or postsynaptic neuron at the neuromuscular junction abnormal neurologic examination that would be worri- (NMJ). This occurs as a result of antibody-mediated some for an intracranial process.Vertigo is not an indica- cross-linking of the ACh receptor, which causes tion of a more serious intracranial process, as an estimated increased turnover of ACh receptors, blockage of the 33% of individuals with migraine experience vertigo both active site, and damage to the postsynaptic muscle. The with and without accompanying headache. Therefore, defect is not due to a defect in the release of ACh. Low imaging of the brain is unnecessary in this clinical situa- levels of ACh-esterase would cause increased activation tion. Migraine headaches are the second most common at the NMJ. Finally, the defect in myasthenia gravis headache syndromes after tension headaches and affect occurs at the NMJ, not at nerve synapses. 15% of women and 6% of men. The onset of headaches is usually in late adolescence, with peak prevalence of 40. The answer is E. migraine occurring in the mid-thirties. Migraine (Chap. 20) Simple partial seizures cause motor, sensory, headaches are typically classified as occurring with aura autonomic, or psychic symptoms without an obvious (previously called classic migraine) or without an aura. A alteration in consciousness.The phenomenon of abnormal more simplified diagnostic criterion for migraine has motor movements beginning in a restricted area then been adopted by the International Headache Society. progressing to involve a larger area is termed Jacksonian Migraine is defined as repeated attacks of headache lasting march. The patient is describing Todd’s paralysis, which 4–72 h in individuals with a normal physical examination. may take minutes to many hours to return to normal. To be classified as a migraine, the headaches must fulfill at Although meningitis is a common cause of seizure in least two of the following symptoms: unilateral pain, young patients, it is unlikely to be the cause in someone throbbing quality, aggravation by movement, and moder- who has a known seizure disorder. If his symptoms were ate to severe intensity. At least one additional accompany- to persist beyond many hours, it would be reasonable to ing feature should be present, including either nausea/ investigate a different etiology of his hand weakness with vomiting, phonophobia, or photophobia. Patient educa- imaging studies. Overt deficits in strength are not com- tion and trigger avoidance are important in the manage- patible with a primary psychiatric disorder. Magnetic res- ment of migraine headaches. Migraines can frequently be onance angiogram and cerebral angiogram are useful to controlled, but not eliminated, by lifestyle modifications, evaluate for cerebrovascular disorders, but there is no evi- and it is important to understand an individual’s triggers dence of subarachnoid bleeding or vasculitis. for migraine. A headache diary will help identify patterns of headaches as well as triggers. It will also provide an 41. The answer is C. estimate of headache frequency and severity to aid in (Chap. 35) The release of bacterial cell wall components determining whether prophylactic medication would after killing by antibiotics may evoke a marked inflammatory be required. Other nonpharmacologic treatment of

Review and Self-Assessment 731 migraines includes regular exercise, maintain a regular sleep- for this patient, and lumbar puncture must be performed wake cycle, and stressor avoidance.Yoga, biofeedback, hypno- to rule this out. In addition, acute cocaine intoxication is a sis, and meditation are interventions that may help alleviate plausible reason for this new-onset seizure. Figure 20-2 stress and may have benefit in migraine treatment. Once an illustrates the evaluation of the adult patient with a seizure. acute migraine is experienced, timely treatment is warranted MRI would be indicated if the patient had a negative to decrease the duration of the attack and minimize loss of metabolic and toxicologic screening. Substance abuse productivity. If attacks are mild, analgesics such as nons- counseling, while indicated, is not indicated at this point in teroidal anti-inflammatory drugs or acetaminophen may be his workup since he is postictal. The patient is not having useful. However, the most effective drugs for the treatment of seizures, does not have a known seizure disorder, and has moderate to severe migraines are the 5-hydroxytriptamine not been treated for the underlying metabolic abnormality, agonists—ergotamines and the triptan drugs. Rizatriptan and making intravenous loading with an antiepileptic medica- almotriptan are the most efficacious of the triptan drugs. If tion premature at this time. migraine attacks occur more than five times monthly or are poorly responsive to abortive treatment, additional drug ther- 46. The answer is D. apy for prevention is indicated. (Chap. 43) Becker and Duchenne muscular dystrophy are both X-linked recessive disorders associated with different 43. The answer is D. mutations of the dystrophin gene located on the short arm (Chap. 1) Cranial nerve XI (accessory nerve) is correctly of the X chromosome. This 2000-kb gene is among the paired with the proper examination technique. Testing largest identified human genes. In both Becker and cranial nerve I (olfactory nerve) should be performed Duchenne muscular dystrophy, the most common muta- with a mild stimulus (e.g., coffee or toothpaste) to elimi- tion is a deletion. However, deletions in Becker muscular nate any potential stimulation of pain fibers in the dystrophy do not result in frame-shift mutations, yielding a nasopharynx (trigeminal nerve) by noxious stimuli such as delayed presentation and milder presentation of disease. ammonia or alcohol. When testing visual acuity (cranial Limb-girdle muscular dystrophy designates a clinical syn- nerve II), corrective lenses should be worn by the patient, drome that presents as progressive weakness of pelvic and if necessary.This allows for testing of the neuronal aspects shoulder girdle muscles. There are 12 recognized limb- of vision without confounding by problems within the girdle muscular dystrophies with unique mutations. This lens. It is also important to test each eye individually. The disorder can be inherited in both an autosomal dominant trigeminal (cranial nerve V) is predominantly a sensory or recessive fashion, depending on the mutation present. nerve and has three sensory branches.The motor compo- Kearns-Sayre syndrome and myoclonic epilepsy with nent of the trigeminal nerve predominantly innervates the ragged red fibers (MERFF) are mitochondrial myopathies. masseter muscles used for chewing. Eyebrow elevation Each mitochondrion possesses a DNA genome unique and forehead wrinkling are functions of cranial nerve VII. from the nuclear genome and is inherited primarily from the oocytes, accounting for the maternal inheritance of 44. The answer is C. mitochondrial disorders. Kearns-Sayre syndrome is a mul- (Chap. 42) This patient’s presentation with facial and ocular tisystem disorder with chronic progressive external oph- weakness in a nocturnal pattern is consistent with a typical thalmoplegia (CPEO).Varying degrees of proximal muscle presentation of myasthenia gravis. It is not uncommon for weakness are present. MERFF presents in late childhood symptoms to be mostly nocturnal and be relatively asymp- to adulthood with clinical features of myoclonic epilepsy, tomatic in the early morning hours. Examining these progressive weakness, and cerebellar ataxia. patients in the evening or doing repetitive strength testing may bring out more subtle findings and requires a height- 47. The answer is B. ened index of suspicion. Lead poisoning would be uncom- (Chap. 14) Brain death is defined by the cessation of cere- mon in a woman of this age, and the findings would not bral function while somatic function is maintained by arti- be restricted to the cranial region. Psychiatric diagnoses do ficial means and the heart continues to pump. It is the only not correlate with myasthenia gravis, and repeat examina- type of brain damage that is considered equivalent to tion to corroborate the reported physical examination death. The diagnosis of brain death should be confirmed should be performed first. MRI of the brain is not indi- with the following clinical findings: unresponsiveness to cated at this time as the physical examination findings any stimuli, indicating widespread cortical destruction; point towards a serologic diagnosis. Slit-lamp examination brainstem damage, as evidenced by enlarged or mid-sized is useful for finding abnormalities in the anterior portion pupils without light reaction; absent corneal and of the eye, such as the iris, lens, and cornea. oculovestibular reflexes; and apnea, indicating medullary destruction. The heart rate should be invariant. Because 45. The answer is C. the spinal cord is intact, spinal reflexes may be present.The (Chap. 20) Nuchal rigidity and an elevated white blood presence or absence of the Babinski sign does not con- cell count is very concerning for meningitis as the etiology tribute to the diagnosis of brain death. Central diabetes