Neurology_Adams

Neurology_Adams. Intemperance in the use of alcohol creates many problems in modern society, the importance of which can be judged by the emphasis it has received in contemporary writings, both literary and scientific. These problems may be divided into three categories: psychological, medical, and sociological. The main psychologic issue regards why a person drinks excessively, often with full knowledge that such action will result in physical injury and even death. The medical problem embraces all aspects of alcoholic addiction and habituation as well as the diseases that result from the abuse of alcohol. The sociologic problem encompasses the effects of sustained drinking on the patient’s work, family, and community. Some idea of the enormity of these problems can be gleaned from figures supplied by the United States Department of Health and Human Services, which indicate that up to 40 percent of medical and surgical patients have alcohol-related problems and that these patients account for 15


Neurology_Adams

Neurology_Adams. the United States Department of Health and Human Services, which indicate that up to 40 percent of medical and surgical patients have alcohol-related problems and that these patients account for 15 percent of all healthcare costs. Several surveys have suggested a rate of alcohol dependence of 3 to 5.5 percent of adults. A minimum of 3 percent of deaths in the United States are attributable to alcohol-related causes. More striking, but not at all surprising, is the fact that alcohol intoxication is involved in approximately 45 percent of fatal motor vehicle accidents and 22 percent of boating accidents. It requires little imagination to conceive the havoc wrought by alcohol in terms of suicide, accidents, crime, mental and physical disease, and disruption of family life. Finally, the problems engendered by excessive drinking cannot easily be separated from one another.


Neurology_Adams

Etiology of Alcoholism

Neurology_Adams. Etiology of Alcoholism


Neurology_Adams

Neurology_Adams. The cause of alcoholism as an addiction remains as obscure as it is for other forms of dependence and addiction, although environmental, cultural, and genetic factors are clearly implicated. No single personality type has been shown to predict reliably who will become addicted to alcohol. Similarly, no particular aspect of alcohol metabolism has been found to account for the development of addiction, with the possible exception of aldehyde dehydrogenase (see further on). Some persons drink excessively and become alcoholic in response to a profoundly disturbing personal or family problem, but most do not. Alcoholism may develop in response to a depressive illness, more so in women than in men, but far more often depression is a consequence of drinking. Social and cultural influences are undoubtedly important in the genesis of alcoholism as evidenced, for example, by the remarkably high incidence of alcoholism and drinking problems in the American Indian and Eskimo populations and by


Neurology_Adams

Neurology_Adams. undoubtedly important in the genesis of alcoholism as evidenced, for example, by the remarkably high incidence of alcoholism and drinking problems in the American Indian and Eskimo populations and by the disparity in the prevalence of alcoholism, within a single community, among various ethnic groups. However, no ethnic or racial group and no social or economic class are exempt.


Neurology_Adams

Neurology_Adams. The importance of genetic factors in alcoholism has been amply identified. Goodwin and coworkers studied adopted Danish men whose biologic parents were alcoholic and control subjects whose biologic parents were not alcoholic. All of the subjects had been adopted before the age of 5 weeks and had no knowledge of their biologic parentage. Twenty percent of the offspring of biologic alcoholic parents, but only 5 percent of the control subjects, had become alcoholics by the age of 25 to 29 years. A Swedish adoption study (Bohman) and one in the United States (Cadoret et al) corroborate these findings. Family studies disclose a threeto fourfold increased risk for alcoholism in sons and daughters of alcoholics, and twin studies show a twofold higher concordance rate for alcoholism in monozygotic than in dizygotic pairs. Details of these studies can be found in the comprehensive reviews of the genetics of alcoholism by Grove and Cadoret and by Schuckit and Winokur. The search goes on for a


Neurology_Adams

Neurology_Adams. than in dizygotic pairs. Details of these studies can be found in the comprehensive reviews of the genetics of alcoholism by Grove and Cadoret and by Schuckit and Winokur. The search goes on for a biologic trait, or marker, that would identify those who are genetically vulnerable to the development of alcoholism, but none has proved to be sufficiently practical or sensitive to identify all such persons (Reich).


Neurology_Adams

Neurology_Adams. Pharmacology and Physiology of Alcohol Ethyl alcohol, or ethanol, is the active ingredient in beer, wine, whiskey, gin, vodka, and other alcoholic beverages. The stronger spirits contain enanthic ethers, which provide flavor but have no important pharmacologic properties. In some preparations, impurities such as amyl alcohol (fusel oil) and acetaldehyde act like alcohol but are more toxic.


Neurology_Adams

Neurology_Adams. Alcohol is metabolized chiefly by oxidation, less than 10 percent being excreted chemically unchanged in the urine, perspiration, and breath. The energy liberated by the oxidation of alcohol (7 kcal/g) can be utilized as completely as that derived from the metabolism of other carbohydrates. However, calories from alcohol are empty of nutrients such as proteins and vitamins and cannot be used in the repair of damaged tissue. All ingested alcohol, except that metabolized by alcohol dehydrogenase (ADH) in the stomach wall, is carried by the portal system to the liver. Here several enzyme systems independently oxidize alcohol to acetaldehyde. The most important of these, accounting for 80 to 90 percent of ethanol oxidation in vivo, are ADH and its isoenzymes. This reaction leads to the formation of acetaldehyde and the reduction of nicotinic acid dehydrogenase (NAD) to nicotinamide adenine dinucleotide (NADH). A second pathway of lesser importance involves catalase, which is located in


Neurology_Adams

Neurology_Adams. of acetaldehyde and the reduction of nicotinic acid dehydrogenase (NAD) to nicotinamide adenine dinucleotide (NADH). A second pathway of lesser importance involves catalase, which is located in the peroxisomes and mitochondria; a third uses the “microsomal ethanol oxidizing system” (MEOS), located mainly in the microsomes of the endoplasmic reticulum.


Neurology_Adams

Neurology_Adams. The details of the process by which acetaldehyde is metabolized are still not settled. Most likely it is converted by aldehyde dehydrogenase to acetate. Acetaldehyde has a number of unique biochemical effects that are not produced by alcohol alone. Persons who flush easily after ingestion of alcohol (Chinese, Japanese, and other Asians) differ from “nonflushers” with respect to the metabolism of acetaldehyde rather than to the metabolism of alcohol. The flushing reaction has been traced to a deficiency of aldehyde dehydrogenase activity (Harada et al). The low rate of alcoholism among Asians is said to be related to the flushing reaction (which is, in effect, a modified alcohol–disulfiram reaction; see further on), but this can hardly be the case, as North American Indians, a group with a high incidence of alcoholism, show the same reaction.


Neurology_Adams

Neurology_Adams. A scale relating various degrees of functional impairment to blood alcohol levels in nonhabituated persons was constructed many years ago by Miles. At a blood alcohol level of 30 mg/dL, a mild euphoria was detectable, and at 50 mg/dL, mild incoordination. At 100 mg/dL, ataxia was obvious; at 200 mg/dL, there was confusion and a reduced level of mental activity; at 300 mg/dL, the subjects were stuporous; and a level of 400 mg/dL—accompanied by deep anesthesia—was potentially fatal. These figures are valid provided that the alcohol content in the blood rises steadily over a 2-h period.


Neurology_Adams

Neurology_Adams. For all practical purposes, once the absorption of alcohol has ended and equilibrium has been established with the tissues, ethanol is oxidized at a constant rate, independent of its concentration in the blood (about 150 mg alcohol per kilogram of body weight per hour, or about 1 oz of 90-proof whiskey per hour). Actually, slightly more alcohol is metabolized per hour when the initial concentrations are very high, and repeated ingestion of alcohol may facilitate its metabolism, but these increments are of little clinical significance. In contrast, the rate of oxidation of acetaldehyde does depend on its concentration in the tissues. This fact is of importance in connection with the drug disulfiram (Antabuse), which acts by raising the tissue concentration necessary for the metabolism of a certain amount of acetaldehyde per unit of time. The patient taking both disulfiram and alcohol will accumulate an inordinate amount of acetaldehyde, resulting in nausea, vomiting, and hypotension,


Neurology_Adams

Neurology_Adams. a certain amount of acetaldehyde per unit of time. The patient taking both disulfiram and alcohol will accumulate an inordinate amount of acetaldehyde, resulting in nausea, vomiting, and hypotension, sometimes so pronounced in degree as to be fatal. Certain other drugs—notably the sulfonylureas, metronidazole, and furazolidone—have effects like those of disulfiram but are less potent.


Neurology_Adams

Neurology_Adams. Alcohol acts directly on neuronal membranes in a manner akin to that of the general anesthetics. These agents, as well as barbiturates and benzodiazepines, are lipid-soluble and are thought to dissolve in the cell membranes (in direct relation to the degree of their lipid solubility). With continued ingestion of alcohol, the neuronal membranes ostensibly “rigidify” and become resistant to the fluidizing effect of alcohol (Chin and Goldstein; Harris et al). It is unlikely, however, that these changes in the physical properties of cell membranes are in themselves sufficient to alter cell function. Probably of equal importance are the effects of alcohol on membrane receptor systems that regulate ion channels, particularly chloride and calcium channels. One likely site that relates to the acute intoxicating effects of alcohol is a receptor for the inhibitory neurotransmitter GABA and its associated chloride-ion channel. Benzodiazepine antagonists appear to block the potentiation by


Neurology_Adams

Neurology_Adams. acute intoxicating effects of alcohol is a receptor for the inhibitory neurotransmitter GABA and its associated chloride-ion channel. Benzodiazepine antagonists appear to block the potentiation by alcohol of GABA-induced chloride flux. Like the GABA-chloride channel, the N-methyl-d-aspartate (NMDA) receptors, which transduce signals carried by glutamate (the major excitatory transmitter in the brain), are sensitive to extremely low concentrations of alcohol. There is also evidence that alcohol selectively potentiates serotonin receptor-ion currents, and the activity of this receptor has been implicated in alcoholand drug-seeking behavior and addiction.


Neurology_Adams

Neurology_Adams. The effect of chronic administration of alcohol is to increase the number of neuronal calcium channels in the cell membrane. Moreover, calcium channel blockers, given during chronic administration, prevent both the increase in neuronal calcium channels and the development of tolerance to alcohol (Dolin and Little). The significance of these findings has been demonstrated by Little and colleagues, who showed that calcium channel blockers, given to chronically intoxicated animals after withdrawal, prevent withdrawal convulsions.


Neurology_Adams

Neurology_Adams. The molecular mechanisms involved in alcohol intoxication and tolerance are obviously more complex than the foregoing remarks would indicate (see reviews by Charness and by Samson and Harris). There is now a vast literature on this subject, much of it contradictory, and a unified concept of the role of neurotransmitters and their receptors and modulators in the production of alcohol intoxication and tolerance has yet to emerge. The part played by internal cellular messengers, which have attracted much attention in the field of addiction, is also currently under investigation.


Neurology_Adams

Neurology_Adams. Alcohol tolerance A scale of blood concentrations such as the one previously described has virtually no value in the chronic alcoholic patient, as it does not take into account the phenomenon of tolerance. It is common knowledge that a habituated person can drink more and show fewer effects than the moderate drinker or abstainer. This phenomenon accounts for the surprisingly large amounts of alcohol that the chronic drinker can consume without showing significant signs of drunkenness. Sober-appearing alcoholics may have blood alcohol levels of 400 to 500 mg/dL. This aspect of tolerance must be considered in judging the significance of a single estimation of the blood alcohol concentration as an index of functional capacity. The mechanisms that underlie tolerance and addiction are just beginning to be understood. There is little evidence that an enhanced rate of alcohol metabolism can adequately account for the degree of tolerance observed in alcoholics. An increase of neuronal


Neurology_Adams

Neurology_Adams. beginning to be understood. There is little evidence that an enhanced rate of alcohol metabolism can adequately account for the degree of tolerance observed in alcoholics. An increase of neuronal adaptation to alcohol is a more likely explanation. Theoretically, the factors that are operative in this adaptation are the increasing resistance of neuronal membranes to the effects of alcohol and an increase in the number of neuronal calcium channels in the cell membrane.


Neurology_Adams

Clinical Effects of Alcohol on the

Neurology_Adams. Clinical Effects of Alcohol on the


Neurology_Adams

Neurology_Adams. Alcohol functions as a central nervous system (CNS) depressant. Some of the early effects of alcohol, such as garrulousness, aggressiveness, excessive activity, and increased electrical excitability of the cerebral cortex—all of them suggestive of cerebral stimulation—are thought to be caused by the inhibition of certain subcortical structures (possibly the high brainstem reticular formation) that ordinarily modulate cerebrocortical activity. Similarly, the initial hyperactivity of tendon reflexes may represent a transitory escape of spinal motor neurons from higher inhibitory centers. With increasing amounts of alcohol, however, the depressant action involves the cortical as well as other brainstem and spinal neurons. All motor functions—whether the simple maintenance of a standing posture, the control of speech and eye movements, or highly organized and complex motor skills—are adversely affected by alcohol. The movements involved in these acts are not only slower than normal but


Neurology_Adams

Neurology_Adams. the control of speech and eye movements, or highly organized and complex motor skills—are adversely affected by alcohol. The movements involved in these acts are not only slower than normal but also more inaccurate and random in character and therefore less well adapted to the accomplishment of specific ends.


Neurology_Adams

Neurology_Adams. Alcohol also impairs the efficiency of mental function by interfering with the speed of perception and the ability to persist in mental processing. The learning process is slowed and rendered less effective. Facility in forming associations, whether of words or of figures, and the ability to focus, sustain attention, and concentrate are reduced. Finally, alcohol impairs the faculties of judgment and discrimination and, all in all, the ability to think and reason clearly. A number of neurologic disorders are characteristically associated with alcoholism. The factor common to all of them, of course, is the abuse of alcohol, but the mechanism by which alcohol produces its effects varies widely from one group of disorders to another and in many cases, the essential problem is one of nutritional deficiency as discussed in the preceding chapter. The classification that follows is based for the most part on known mechanisms.


Neurology_Adams

Neurology_Adams. I. Alcohol intoxication—drunkenness, coma, paradoxical excitement (“pathologic intoxication”), “blackouts” II. Abstinence or withdrawal syndrome—tremulousness, hallucinosis, seizures, delirium tremens III. Nutritional diseases of the nervous system accompanying alcoholism (see Chap. 40) A. Wernicke-Korsakoff syndrome B. Polyneuropathy C. Optic neuropathy (“tobacco-alcohol amblyopia”) D. Pellagra IV. Diseases of uncertain pathogenesis associated with alcoholism A. Cerebellar degeneration B. Marchiafava-Bignami disease C. Central pontine myelinolysis D. “Alcoholic” myopathy and cardiomyopathy E. Alcoholic dementia F. Cerebral atrophy V. Fetal alcohol syndrome VI. Neurologic disorders resulting from cirrhosis and portal–systemic shunts (see Chap. 39) A. Hepatic stupor and coma B. Chronic hepatocerebral degeneration VII. Traumatic brain lesions acquired during intoxication—subdural hematoma, cerebral contusion


Neurology_Adams

Neurology_Adams. A. Hepatic stupor and coma B. Chronic hepatocerebral degeneration VII. Traumatic brain lesions acquired during intoxication—subdural hematoma, cerebral contusion The usual manifestations of alcohol intoxication are so commonplace that they require little elaboration. They consist of varying degrees of exhilaration and excitement, loss of restraint, irregularity of behavior, loquacity and slurred speech, incoordination of movement and gait, irritability, drowsiness, and, in advanced cases, sleepiness, stupor, and coma. There are several complicated types of alcohol intoxication, which are considered below.


Neurology_Adams

Neurology_Adams. As has been indicated, the symptoms of alcoholic intoxication are the result of the depressant action of alcohol on cerebral and spinal neurons. In this respect, alcohol acts on nerve cells in a manner akin to the general anesthetics and can cause coma. Unlike the anesthetics, however, the margin between the dose of alcohol that produces surgical anesthesia and that which dangerously depresses respiration is a narrow one, a fact that adds an element of urgency to the diagnosis and treatment of alcoholic coma. One must also be alert to the possibility that other sedative-hypnotic drugs may have potentiated the depressant effects of alcohol. Another treacherous situation is that of traumatic brain injury that is complicated by intoxication, a circumstance that is prone to misinterpretation because of uncertainty as to the main cause of stupor or coma.


Neurology_Adams

Neurology_Adams. Despite what has been said earlier, on rare occasions, alcohol has an exclusively excitatory rather than a sedative effect. This reaction has been referred to in the past as pathologic, or complicated, intoxication and as acute alcoholic paranoid state. Because all forms of intoxication are pathologic, atypical intoxication or idiosyncratic alcohol intoxication are more appropriate designations, nevertheless, the term pathologic intoxication is still used. The boundaries of this syndrome have never been clearly drawn. In the past, variant forms of delirium tremens and epileptic phenomena, as well as psychopathic and criminal behavior, were indiscriminately included. Now the term is generally used to designate an outburst of blind fury with assaultive and destructive behavior. Often the patient is subdued only with difficulty. The attack terminates with deep sleep, which occurs spontaneously or in response to parenteral sedation; on awakening, the patient has no memory of the episode.


Neurology_Adams

Neurology_Adams. is subdued only with difficulty. The attack terminates with deep sleep, which occurs spontaneously or in response to parenteral sedation; on awakening, the patient has no memory of the episode. Lesser degrees are also known wherein the patient, after several drinks, repeatedly commits gross social indiscretions. Allegedly this reaction may follow the ingestion of a small amount of alcohol, but in some of the patients we have observed the amount has often been substantial. Unlike the usual forms of alcohol intoxication and withdrawal, the atypical form has not been produced in experimental subjects, and the diagnosis depends upon the aforementioned arbitrary criteria.


Neurology_Adams

Neurology_Adams. Pathologic intoxication has been ascribed to many factors, but there are no meaningful data to support any of them. However, an analogy may be drawn between pathologic intoxication and the paradoxical reaction that occasionally follows the administration of barbiturates or other sedative drugs. The few patients we have seen, mostly young men of college age or slightly older, have been docile and seemingly well adjusted when not drinking. Usually, they have avoided alcohol after a first episode of this sort, but there have been exceptions.


Neurology_Adams

Neurology_Adams. The main disorders to be distinguished from pathologic intoxication are temporal lobe seizures that occasionally take the form of outbursts of rage and violence and the explosive episodes that characterize the behavior of certain sociopaths. The diagnosis in these cases may be difficult and depends on eliciting the other manifestations of temporal lobe epilepsy or sociopathy. Pathologic intoxication may require the use of restraints and the parenteral administration of diazepam (5 to 10 mg) or haloperidol (2 to 5 mg), repeated once after 30 to 40 min if necessary.


Neurology_Adams

Neurology_Adams. In the language of the alcoholic, the term blackout refers to an interval of time, during a period of severe intoxication, for which the patient later has no memory—even though the state of consciousness, as observed by others, was not grossly altered during that interval. However, a systematic assessment of mental function during the amnesic period has usually not been made. A few observations indicate that it is short-term (retentive) memory rather than immediate or long-term memory that is impaired; this feature and the subsequent amnesia for the episode are vaguely reminiscent of the disorder known as transient global amnesia (see Chap. 20) but without the incessant repetitive questioning and competence in nonmemory mental activities that characterize the latter.


Neurology_Adams

Neurology_Adams. Blackouts may occur at any time in the course of alcoholism, even during the first drinking experience, and they certainly have happened in persons who never became alcoholic. The salient facts are that there is a degree of intoxication that interferes with the registration of events and the formation of memories during the period of intoxication and that the amount of alcohol consumed in moderate social drinking will only rarely produce this effect. Treatment of Severe Alcohol Intoxication


Neurology_Adams

Neurology_Adams. Treatment of Severe Alcohol Intoxication Coma caused by alcohol intoxication represents a medical emergency. The main objective of treatment is to prevent aspiration and respiratory depression. One would like to lower the blood alcohol level as rapidly as possible. The previously favored administration of fructose or of insulin and glucose for this purpose is now known to be of little value. Analeptic drugs such as amphetamine and various mixtures of caffeine and picrotoxin are antagonistic to alcohol only insofar as they are overall nervous system excitants, but they do not hasten the oxidation of alcohol and are not clinically useful. The use of hemodialysis should be considered in comatose patients with extremely high blood alcohol concentrations (>500 mg/dL), particularly if accompanied by acidosis, and in those who have concurrently ingested methanol or ethylene glycol or some other dialyzable drug. Methyl, Amyl, and Isopropyl Alcohols and Ethylene Glycol


Neurology_Adams

Neurology_Adams. Methyl, Amyl, and Isopropyl Alcohols and Ethylene Glycol Poisoning with alcohols other than ethyl alcohol is a rare but catastrophic occurrence. Amyl alcohol (fusel oil) and isopropyl alcohol are used as industrial solvents and in the manufacture of varnishes, lacquers, and pharmaceuticals; in addition, isopropyl alcohol is readily available as a rubbing alcohol. Intoxication may follow the ingestion of these alcohols or inhalation of their vapors. The effects of both are much like those of ethyl alcohol, but more toxic. They also have in common the generation of acidosis, usually with an anion gap, and if a sample of serum is obtained soon after the ingestion, an osmolar gap that represents the molecules of the circulating alcohol is seen.


Neurology_Adams

Neurology_Adams. Methyl alcohol (methanol, wood alcohol) is a component of antifreeze and many combustibles and is used in the manufacture of formaldehyde, as an industrial solvent, and as an adulterant of alcoholic beverages, the latter being the most common source of methyl alcohol intoxication. The oxidation of methyl alcohol to formaldehyde and formic acid proceeds relatively slowly; thus, signs of intoxication do not appear for several hours or may be delayed for a day or longer. Many of the toxic effects are like those of ethyl alcohol, but in addition severe methyl alcohol poisoning may produce serious degrees of acidosis (with an anion gap). The characteristic features of this intoxication, however, are damage to retinal ganglion cells—giving rise to scotomata and varying degrees of blindness, dilated unreactive pupils, and retinal edema—and bilateral degeneration of the putamens, readily visible on brain scans. Survivors may be left blind or, less often, with putamenal necrosis and dystonia


Neurology_Adams

Neurology_Adams. unreactive pupils, and retinal edema—and bilateral degeneration of the putamens, readily visible on brain scans. Survivors may be left blind or, less often, with putamenal necrosis and dystonia or parkinsonism (McLean et al). The most important aspect of treatment is the intravenous administration of large amounts of sodium bicarbonate to reverse acidosis. Hemodialysis and 4-methylpyrazole (see later) may be useful adjuncts because of the slow rate of oxidation of methanol.


Neurology_Adams

Neurology_Adams. Ethylene glycol, an aliphatic alcohol, is a commonly used industrial solvent and the major constituent of antifreeze. In the latter form, it is sometimes consumed by alcoholics (5,000 cases of poisoning annually in the


Neurology_Adams

Neurology_Adams. United States) and in suicide attempts with disastrous results. At first the patient merely appears drunk, but after a period of 4 to 12 h, hyperventilation and severe metabolic acidosis develop, followed by confusion, convulsions, coma, and renal failure and death in rapid succession. Cerebrospinal fluid lymphocytosis is a common but not invariable feature. The metabolic acidosis is a result of the conversion of ethylene glycol by ADH into glycolic acid, thus producing an anion gap that reflects the presence of this additional substance in the blood. (The anion gap has been defined in different ways, but the most convenient is the difference between the positive ion Na+ and the sum of negative ions, Cl− plus HCO3− [venous CO2 is used for the latter]; a value greater than 12 is considered a gap.) The cause of the renal toxicity is less clear—probably it is a result of the formation of oxalate from glycolate and the deposition of oxalate crystals in renal tubules. (One of our recent


Neurology_Adams

Neurology_Adams. a gap.) The cause of the renal toxicity is less clear—probably it is a result of the formation of oxalate from glycolate and the deposition of oxalate crystals in renal tubules. (One of our recent patients had hippurate crystals in the urine, a finding that is more characteristic of toluene ingestions.) These crystals appear in the urine and sometimes in the cerebrospinal fluid and aid in diagnosis.


Neurology_Adams

Neurology_Adams. Treatment of Nonethanol Alcohol Intoxication


Neurology_Adams

Neurology_Adams. The treatment of ethylene glycol poisoning has, until relatively recently, consisted of hemodialysis and the intravenous infusion of sodium bicarbonate and ethanol, the latter serving as a competitive substrate for ADH. However, the use of ethanol in this regimen is problematic. Baud and colleagues, and more recently Brent and colleagues and Jacobsen, have advocated the use of intravenous 4- methylpyrazole (fomepizole), which is a far more effective inhibitor of ADH than is alcohol. They recommend this form of treatment for methanol poisoning as well. Information from the American Academy of Toxicology is cited in a review of the use of fomepizole by Brent, which is recommended to the interested reader. Generally, for either methanol or ethylene glycol, a plasma level of the alcohol above 20 mg/dL, or above 10 mg/dL when combined with an osmolal gap over 10 is considered appropriate to institute the drug. In the case of ethylene glycol, oxaluria and acidosis are additional factors


Neurology_Adams

Neurology_Adams. 20 mg/dL, or above 10 mg/dL when combined with an osmolal gap over 10 is considered appropriate to institute the drug. In the case of ethylene glycol, oxaluria and acidosis are additional factors that may precipitate treatment. Dialysis remains an essential therapy if cerebral and renal damage is not too advanced.


Neurology_Adams

Neurology_Adams. Some patients who recover from the acute renal and metabolic effects are left with multiple cranial nerve defects, particularly of the seventh and eighth nerves. The latter abnormalities develop 6 to 18 days after the ingestion of ethylene glycol and have been attributed to the deposition of oxalate crystals along the cisternal portions of the affected nerves (Spillane et al). The Alcohol Abstinence, or Withdrawal, Syndrome


Neurology_Adams

Neurology_Adams. The Alcohol Abstinence, or Withdrawal, Syndrome This is the well-known symptom complex of tremulousness, hallucinations, seizures, confusion, and psychomotor and autonomic overactivity. Although a sustained period of chronic inebriation is the most obvious factor in the causation of these symptoms, they become manifest only after a period of relative or absolute abstinence from alcohol—hence the designation abstinence, or withdrawal, syndrome. Figure 41-1 illustrates this concept. Each of the major manifestations of the withdrawal syndrome may occur in more or less pure form and are so described below, but usually they occur in combination. Major withdrawal symptoms are observed mainly in the binge, or periodic, drinker, although the steady drinker is not immune if for some reason he stops drinking, such as during a hospital admission for surgery or a medical illness. The full syndrome, depicted further on, is called delirium tremens.


Neurology_Adams

Neurology_Adams. The most common single manifestation of the abstinence syndrome is tremulousness, often referred to as “the shakes” or “the jitters,” combined with general irritability and gastrointestinal symptoms, particularly nausea and vomiting. These symptoms first appear after several days of drinking, usually in the morning after a night’s abstinence. The patient “quiets his nerves” with a few drinks and is then able to drink for the rest of the day without undue distress. The symptoms return on successive mornings with increasing severity. The symptoms then become augmented, reaching their peak intensity 24 to 36 h after the complete cessation of drinking. Generalized tremor is the most obvious feature. It is of fast frequency (6 to 8 Hz), slightly irregular, and variable in severity, tending to diminish when the patient is in quiet surroundings and to increase with motor activity or emotional stress. The tremor may be so violent that the patient cannot stand without help, speak clearly, or


Neurology_Adams

Neurology_Adams. diminish when the patient is in quiet surroundings and to increase with motor activity or emotional stress. The tremor may be so violent that the patient cannot stand without help, speak clearly, or eat without assistance. Sometimes there is little objective evidence of tremor, and the patient complains only of being “shaky inside.”


Neurology_Adams

Neurology_Adams. Within a few days, flushed facies, anorexia, tachycardia, and tremor characteristic of the mild withdrawal syndrome subside to a large extent, but overalertness, tendency to startle easily, and jerkiness of movement may persist for a week or longer. Feelings of uneasiness may not leave the patient completely for 10 to 14 days. According to Porjesz and Begleiter, certain electrophysiologic abnormalities (diminished amplitudes of sensory evoked potentials and prolonged latencies and conduction velocities of auditory brainstem potentials) remain altered long after the clinical abnormalities have subsided.


Neurology_Adams

Neurology_Adams. Symptoms of disordered perception occur in about one-quarter of withdrawing hospitalized tremulous patients. The patient may complain of “bad dreams”—nightmarish episodes associated with disturbed sleep—which he finds difficult to separate from real experience. Sounds and shadows may be misinterpreted, or familiar objects may be distorted and assume unreal forms (illusions). There may also be more overt hallucinations, which are purely visual in type, mixed visual and auditory, tactile, or olfactory, in this order of frequency. There is little evidence to support the popular belief that certain visual hallucinations (bugs, pink elephants) are specific to alcoholism. Actually, the hallucinations comprise the full range of visual experience. They are more often animate than inanimate; persons or animals may appear singly or in panoramas, shrunken or enlarged, natural and pleasant, or distorted, hideous, and frightening. The hallucinosis may be an isolated phenomenon lasting for a few


Neurology_Adams

Neurology_Adams. or animals may appear singly or in panoramas, shrunken or enlarged, natural and pleasant, or distorted, hideous, and frightening. The hallucinosis may be an isolated phenomenon lasting for a few hours, and it may later be attended by other withdrawal signs.


Neurology_Adams

Neurology_Adams. A special type of alcoholic psychosis consisting of a more or less pure auditory hallucinosis has been recognized for many years. Kraepelin referred to it as the “hallucinatory insanity of drunkards,” or “alcoholic mania.” A report of 75 such cases was made by Victor and Hope. The central feature of the illness, in the beginning, is the occurrence of auditory hallucinations despite an otherwise clear sensorium during the withdrawal period; that is, the patients are not disoriented or obtunded, and they have an intact memory. The hallucinations may take the form of unstructured sounds such as buzzing, ringing, gunshots, or clicking (the elementary hallucinations of Bleuler), or they may have a musical quality, like a low-pitched hum or chant. The most common hallucinations, however, are human voices. When the voices can be identified, they are often attributed to the patient’s family, friends, or neighbors—rarely to God, radio, or television. The voices may be addressed directly to the


Neurology_Adams

Neurology_Adams. voices. When the voices can be identified, they are often attributed to the patient’s family, friends, or neighbors—rarely to God, radio, or television. The voices may be addressed directly to the patient, but more frequently, they discuss him in the third person. In the majority of cases, the voices are maligning, reproachful, or threatening in nature and are disturbing to the patient; a significant proportion, however, are not unpleasant and leave the patient undisturbed. To the patient, the voices are clearly audible and intensely real, and they tend to be exteriorized; that is, they come from behind a radiator or door, from the corridor, or through a wall, window, or floor. Another feature of auditory hallucinosis is that the patient’s response is more or less understandable in light of the hallucinatory content. The patient may call on the police for protection or erect a barricade against invaders; he may even attempt suicide to avoid what the voices threaten. The hallucinations


Neurology_Adams

Neurology_Adams. the hallucinatory content. The patient may call on the police for protection or erect a barricade against invaders; he may even attempt suicide to avoid what the voices threaten. The hallucinations are most prominent during the night, and their duration varies greatly: they may be momentary, or they may recur intermittently for days on end and, in exceptional instances, for weeks or months.


Neurology_Adams

Neurology_Adams. While hallucinating, most patients have no appreciation of the unreality of their hallucinations. With improvement, the patient begins to question the inauthenticity and may be reluctant to talk about them and may even question his own sanity. Full recovery is characterized by the realization that the voices were imaginary and by the ability to recall, sometimes with remarkable clarity, some of the abnormal thought content of the psychotic episode.


Neurology_Adams

Neurology_Adams. A unique feature of this alcoholic psychosis is its evolution, in a small proportion of the patients, to a state of chronic auditory hallucinosis. The chronic disorder begins like the acute one, but after a short period, perhaps a week or two, the symptomatology begins to change. The patient becomes quiet and resigned, even though the hallucinations remain threatening and derogatory. Ideas of reference and influence and other poorly systematized paranoid delusions become prominent. At this stage the illness may be mistaken for paranoid schizophrenia and indeed was so identified by Bleuler. There are, however, important differences between the two disorders: the alcoholic illness develops in close relation to a drinking bout and the past history rarely reveals schizoid personality traits. Moreover, alcoholic patients with hallucinosis are not distinguished by a high incidence of schizophrenia within their families (Schuckit and Winokur; Scott), and a large number of such patients, whom


Neurology_Adams

Neurology_Adams. alcoholic patients with hallucinosis are not distinguished by a high incidence of schizophrenia within their families (Schuckit and Winokur; Scott), and a large number of such patients, whom our colleagues Victor and Adams evaluated long after their acute attacks, did not show signs of schizophrenia. There is some evidence that repeated attacks of acute auditory hallucinosis render the patient more susceptible to the chronic state.


Neurology_Adams

Neurology_Adams. In the setting of alcohol withdrawal either as relative or absolute abstinence following a period of chronic inebriation, convulsive seizures are common. More than 90 percent of withdrawal seizures occur during the 7to 48-h period following the cessation of drinking, with a peak incidence between 13 and 24 h. During the period of seizure activity, the EEG is usually abnormal, but it reverts to normal in a matter of days, even though the patient may go on to develop delirium tremens. During the period of seizure activity and for days afterward, the patient is unusually sensitive to stroboscopic stimulation; almost half the patients respond with generalized myoclonus or a convulsive seizure (photoparoxysmal response).


Neurology_Adams

Neurology_Adams. Seizures occurring in the abstinence period have a number of other distinctive features. There may be only a single seizure, but in the majority of cases the seizures occur in bursts of 2 to 6 over a day, occasionally even more; only 2 percent of patients studied by Victor (1968) developed status epilepticus. The seizures are generalized and convulsive. Focal seizures should always suggest the presence of a focal brain lesion (most often traumatic) in addition to the effects of alcohol. Twenty-eight percent of Victor’s patients with generalized withdrawal seizures went on to develop delirium tremens (see Victor, Adams and Collins, the percentage has been less in other series); almost invariably, the seizures preceded the delirium. The postictal confusional state may blend imperceptibly with the onset of the delirium, or the postictal state may have cleared over several hours or even a day or longer before the delirium sets in. Seizures of this type typically occur in a patient whose


Neurology_Adams

Neurology_Adams. the onset of the delirium, or the postictal state may have cleared over several hours or even a day or longer before the delirium sets in. Seizures of this type typically occur in a patient whose drinking history has extended over a period of many years and must be distinguished from other forms of seizures that have their onset in adult life. The term rum fits, or whiskey fits—the names sometimes used by alcoholics—is reserved for seizures with the attributes described here. This serves to distinguish them from seizures that occur in the interdrinking period, long after withdrawal has been accomplished.


Neurology_Adams

Neurology_Adams. It is important to note that the common idiopathic or posttraumatic forms of epilepsy are also influenced by alcohol. In these types of epilepsy, a seizure or seizures may be precipitated by only a short period of drinking (e.g., a weekend, or even one evening of heavy social drinking); perhaps unsurprisingly in these circumstances, the seizures occur not when the patient is intoxicated but usually the morning after, in the “sobering-up” period. Except for the transient dysrhythmia in the withdrawal period, the incidence of EEG abnormalities in patients who have had rum fits is no greater than in normal persons, in sharp contrast to the EEGs of nonalcoholic patients with recurrent seizures. Treatment and Prevention of Withdrawal Seizures


Neurology_Adams

Neurology_Adams. Most patients during withdrawal do not require antiepileptic drugs, as the entire episode of seizure activity—whether a single seizure or a brief flurry of seizures—may have terminated before the patient is brought to medical attention. The parenteral administration of diazepam or sodium phenobarbital early in the withdrawal period does, however, prevent withdrawal fits in patients with a previous history of this disorder, as well as in those who might be expected to develop seizures on withdrawal of alcohol. This approach has been supported by the observations of D’Onofrio and colleagues that intravenous lorazepam (2 mg in 2 mL of normal saline) was highly effective in preventing recurrent seizures after a first seizure in the same withdrawal period. Only 3 of 100 patients so treated had a second seizure within 48 h, compared to 21 of 86 untreated patients. The long-term administration of anticonvulsants is neither necessary nor practical: if such patients remain abstinent, they will


Neurology_Adams

Neurology_Adams. a second seizure within 48 h, compared to 21 of 86 untreated patients. The long-term administration of anticonvulsants is neither necessary nor practical: if such patients remain abstinent, they will be free of seizures; if they resume drinking, they often abandon their medications. Furthermore, it is not certain that continued administration of anticonvulsants dependably prevents abstinence seizures. The rare instances of status epilepticus should be managed like status of any other type (see Chap. 15). In alcoholics with a history of idiopathic or posttraumatic epilepsy, the goal of treatment should be abstinence from alcohol, because of the tendency of even short periods of drinking to precipitate seizures. Such patients need to be maintained on anticonvulsant drugs.


Neurology_Adams

Neurology_Adams. This is the most dramatic and grave of all the acute alcoholic illnesses. It is characterized by profound confusion, delusions, vivid hallucinations, tremor, agitation, and sleeplessness, as well as by the signs of increased autonomic nervous system activity—that is, dilated pupils, fever, tachycardia, and profuse perspiration. The clinical features of delirium are presented in detail in Chap. 19 as they relate to delirium tremens (DTs) and to other illnesses that simulate it.


Neurology_Adams

Neurology_Adams. Delirium tremens develops in one of several settings. The patient, an excessive and steady drinker for many years, may have been admitted to the hospital for an unrelated illness, accident, or operation and, after 2 to 4 days, occasionally even later, becomes delirious. Or, following a prolonged drinking binge, the patient may have experienced several days of tremulousness and hallucinosis or one or more seizures and may even be recovering from these symptoms when delirium tremens develops, rather abruptly as a rule. As to the frequency of delirium tremens, Foy and Kay reported an incidence of 0.65 percent of all patients admitted for other reasons to a large general hospital. Among 200 consecutive alcoholics admitted to a city hospital,


Neurology_Adams

Neurology_Adams. Ferguson and colleagues reported that 24 percent developed delirium tremens; of these, 8 percent died—figures that are considerably higher than those recorded in our hospitals (see below). Of course, the reported incidence of delirium tremens will vary greatly, depending on the population served by a particular hospital.


Neurology_Adams

Neurology_Adams. In the majority of cases, delirium tremens is benign and short-lived, ending as abruptly as it begins. Consumed by relentless activity and wakefulness for several days, the patient falls into a deep sleep and then awakens lucid, quiet, and exhausted, with virtually no memory of the events of the delirious period. Less commonly, the delirious state subsides gradually with intermittent episodes of recurrence. In either event, when delirium tremens occurs as a single episode, the duration is 72 h or less in more than 80 percent of cases. Less frequently still, there may be one or more relapses, several episodes of delirium of varying severity being separated by intervals of relative lucidity—the entire process lasting for several days or occasionally for as long as 4 to 5 weeks.


Neurology_Adams

Neurology_Adams. In the past, approximately 15 percent of cases of delirium tremens ended fatally, but the figure now is closer to 5 percent. In many of the fatal cases there is an associated infectious illness or injury, but in others, no complicating illness is discernible. Many of the patients die in a state of hyperthermia; in some, death comes so suddenly that the nature of the terminal events cannot be determined. Reports of series of cases with a negligible mortality rate in delirium tremens can usually be traced to a failure to distinguish between delirium tremens and the minor forms of the withdrawal syndrome, which are far more common and practically never fatal. We make note here of our experience with delirium following the withdrawal of barbiturates (Romero et al), which is almost identical to the DTs, including the abrupt cessation of symptoms, as discussed in the section on “Barbiturate Abstinence, or Withdrawal, Syndrome” further on.


Neurology_Adams

Neurology_Adams. There are also alcohol withdrawal states, closely related to delirium tremens and about as frequent, in which one facet of the delirium tremens complex assumes prominence, to the virtual exclusion of the other symptoms. The patient may simply exhibit a transient state of quiet confusion, agitation, or peculiar behavior lasting several days or weeks. Or there may be a vivid hallucinatory–delusional state and abnormal behavior consistent with the patient’s false beliefs. Unlike typical delirium tremens, the atypical states usually present as a single circumscribed episode without recurrences, are only rarely preceded by seizures, and do not end fatally.


Neurology_Adams

Neurology_Adams. Pathologic examination is singularly unrevealing in patients with delirium tremens. Cerebral edema been absent in the authors’ pathologic material except when shock or hypoxia had occurred terminally. There have been no significant microscopic changes in the brain, which is what one might expect in a disease that is essentially reversible. The EEG findings have been discussed in relation to withdrawal seizures. Pathogenesis of the Tremulous-Hallucinatory-Delirious Disorders


Neurology_Adams

Neurology_Adams. Pathogenesis of the Tremulous-Hallucinatory-Delirious Disorders Prior to 1950, it was the common belief that these symptoms represented the most severe forms of alcohol intoxication—an idea that fails to satisfy the simplest clinical logic. The symptoms of toxicity—consisting of slurred speech, uninhibited behavior, staggering gait, stupor, and coma—are in themselves distinctive and, in a sense, the opposite of the symptom complex of tremor, fits, and delirium. It is evident, from observations in both humans and experimental animals, that the most important and the one obligate factor in the genesis of delirium tremens and related disorders is the withdrawal of alcohol following a period of sustained chronic intoxication. Furthermore, the emergence of withdrawal symptoms depends on a rapid decline in the blood alcohol level from a previously higher level and not necessarily upon the complete disappearance of alcohol from the blood.


Neurology_Adams

Neurology_Adams. The mechanisms by which the withdrawal of alcohol produces symptoms are incompletely understood. In all but the mildest cases, the early phase of alcohol withdrawal is attended by a drop in serum magnesium concentration and a rise in arterial pH—the latter on the basis of respiratory alkalosis (Wolfe and Victor). Possibly the compounded effect of these two factors, both of which are associated with hyperexcitability of the nervous system, is responsible in part for seizures and for other symptoms that characterize the early phase of withdrawal. However, these factors alone are not explanatory. The molecular mechanisms that are thought to be operative in the genesis of alcohol tolerance and withdrawal have been mentioned earlier. The GABA-ergic system has been most strongly implicated, in part because the receptors for this inhibitory transmitter are downregulated by chronic alcohol use, but the situation is not nearly so simple, insofar as the excitatory glutaminergic system is also


Neurology_Adams

Neurology_Adams. part because the receptors for this inhibitory transmitter are downregulated by chronic alcohol use, but the situation is not nearly so simple, insofar as the excitatory glutaminergic system is also inhibited by alcohol.


Neurology_Adams

Neurology_Adams. Laboratory findings Rarely, blood glucose is seriously depressed in the alcohol withdrawal states. Ketoacidosis with normal blood glucose is another infrequent finding. Disturbances of electrolytes are of varying frequency and significance. Serum sodium levels are altered infrequently and are more often increased than decreased. The same is true for chloride and phosphate. Serum calcium and potassium are lowered in about one-quarter of patients. Most patients show some degree of hypomagnesemia, low Pco2, and high arterial pH—abnormalities that are probably important in the pathogenesis of withdrawal symptoms (see later). Abnormalities of the CSF occur unpredictably (it is usually normal), as do changes on brain imaging studies; they may indicate the presence of some medical or surgical complication. Enlargement of the third and lateral ventricles is a common finding (see later). The MRI is normal unless there is an incipient Wernicke disease, in which case lesions in the


Neurology_Adams

Neurology_Adams. surgical complication. Enlargement of the third and lateral ventricles is a common finding (see later). The MRI is normal unless there is an incipient Wernicke disease, in which case lesions in the periaqueductal region and hypothalamus may be evident, as described in the previous chapter.


Neurology_Adams

Neurology_Adams. Treatment of Delirium Tremens and Minor Withdrawal Symptoms (See Chap. 19)


Neurology_Adams

Neurology_Adams. The treatment of delirium tremens begins with a search for associated injuries (particularly head injury with cerebral lacerations or subdural hematoma), infections (pneumonia or meningitis), pancreatitis, and liver disease. Because of the frequency and seriousness of these complications, chest films and head imaging should be obtained in most instances, and lumbar puncture should be performed if there is suspicion of meningitis. In severe forms of delirium tremens, the temperature, pulse, and blood pressure should be measured at frequent intervals in anticipation of peripheral circulatory collapse and hyperthermia, which, added to the effects of injury and infection, are the usual causes of death in this disease. In the case of hypotension, one must act quickly, using intravenous fluids and, if called for, vasopressor drugs. The occurrence of hyperthermia demands the use of a cooling mattress or evaporative cooling in addition to specific treatment for any infection that may be


Neurology_Adams

Neurology_Adams. and, if called for, vasopressor drugs. The occurrence of hyperthermia demands the use of a cooling mattress or evaporative cooling in addition to specific treatment for any infection that may be present.


Neurology_Adams

Neurology_Adams. An additional important element in treatment is the correction of fluid and electrolyte imbalance, particularly hypokalemia and hypomagnesemia. Severe degrees of agitation and perspiration may require the administration of up to 5 L of fluid daily, of which at least 1,500 to 2,000 mL should be normal saline. The specific electrolytes and the amounts that must be administered are governed by the laboratory values for these electrolytes. If the serum sodium is extremely low, one must be cautious in raising the level lest a central pontine myelinolysis be induced (see Chap. 39). In the rare case of hypoglycemia, the administration of glucose is an urgent matter. Patients who present with severe alcoholic ketoacidosis and normal or only slightly elevated blood glucose concentrations usually recover promptly, without the use of insulin.


Neurology_Adams

Neurology_Adams. It must be emphasized, as it was in Chap. 40, that a special danger attends the use of glucose solutions in alcoholic patients. The administration of intravenous glucose may serve to consume the last available reserves of thiamine and precipitate Wernicke disease. Typically, these patients have subsisted on a diet disproportionately high in carbohydrate (in addition to alcohol, which is metabolized entirely as carbohydrate) and low in thiamine, and their body stores of B vitamins may have been further reduced by gastroenteritis and diarrhea. For this reason it is good practice to add B vitamins, specifically thiamine (which may also be supplemented by intramuscular injection), in all cases requiring parenterally administered glucose—even though the alcoholic disorder under treatment, for example, delirium tremens, is not primarily caused by vitamin deficiency.


Neurology_Adams

Neurology_Adams. With respect to the use of medications to treat the withdrawal syndromes, it is important to distinguish between mild symptoms, which are essentially benign and responsive to practically any sedative drug, and full-blown delirium tremens. There is no certain way to predict whether a patient with the early signs of withdrawal will progress to delirium tremens. In the latter state, the object of therapy is to blunt the psychomotor and autonomic overactivity, prevent exhaustion, and facilitate the administration of parenteral fluid and nursing care; one should not attempt to suppress agitation “at all costs,” as doing so requires an amount of drug that might depress respiratory drive.


Neurology_Adams

Neurology_Adams. A wide variety of drugs are effective in controlling withdrawal symptoms. The more popular ones have been chlordiazepoxide (Librium), diazepam (Valium), and the ancillary medications, clonidine and beta-adrenergic blockers, and a number of both older and newer anticonvulsant drugs such as gabapentin, which may reduce the requirement for sedative drugs. There is little to choose among the primary sedative drugs in respect to their therapeutic efficacy. More importantly, there are few data to indicate that any one of them can prevent hallucinosis or delirium tremens, or shorten the duration, or alter the mortality rate of the latter disorder (Kaim et al). A contemporary summary of the medication management of withdrawal has been given by Kosten and O’Connor. In general, phenothiazine drugs should be avoided because they may reduce the threshold to seizures. Probably, the use of any of the diazepine medications is as effective as a single dose of lorazepam in prophylactically suppressing


Neurology_Adams

Neurology_Adams. be avoided because they may reduce the threshold to seizures. Probably, the use of any of the diazepine medications is as effective as a single dose of lorazepam in prophylactically suppressing seizures (see earlier discussion).


Neurology_Adams

Neurology_Adams. If parenteral medication is necessary, we still prefer 10 mg of diazepam or chlordiazepoxide given intravenously and repeated once or twice at 20to 30-min intervals until the patient is calm but awake; we also favor midazolam in closely controlled circumstances when hyperactivity and hallucinosis are extreme. Beta-adrenergic-blocking agents, such as propranolol, labetalol, and atenolol, are helpful in reducing heart rate, blood pressure, and the tremor to some extent. Lofexidine, an alpha2-agonist that blocks autonomic outflow centrally, and clonidine may be similarly effective in reducing the severity of withdrawal symptoms, but clinical trials have given conflicting results for lofexidine and they are not recommended as the sole treatments. Corticosteroids have no place in the treatment of the withdrawal syndrome and more potent agents such as propofol are usually not necessary. Wernicke-Korsakoff Syndrome and Alcoholic–Nutritional Diseases (See Chap. 40)


Neurology_Adams

Neurology_Adams. Wernicke-Korsakoff Syndrome and Alcoholic–Nutritional Diseases (See Chap. 40) Alcoholism provides the ideal setting for the development of nutritional diseases of the nervous system. Although only a small proportion of alcoholics develop nutritional diseases, the overall number of these diseases is substantial because of the frequency of alcoholism. The importance of the alcohol-induced deficiency diseases relates to the fact that they are preventable and, if neglected, may lead to permanent disability. These illnesses, particularly the Wernicke-Korsakoff syndrome, are discussed fully in Chap. 40. Contrary to popular opinion with regard to the prevention of Wernicke disease, the content of B vitamins in American beer and other liquors is so low as to have little nutritional value (Davidson). Disorders of Uncertain Pathogenesis Associated With Alcoholism


Neurology_Adams

Neurology_Adams. Disorders of Uncertain Pathogenesis Associated With Alcoholism Also discussed in Chap. 40 are alcoholic cerebellar degeneration and Marchiafava-Bignami disease. The former is almost certainly of nutritional origin; in the latter a nutritional–metabolic etiology seems likely but has not been established. Central pontine myelinolysis, although frequently observed in alcoholics, is more appropriately considered with the acquired metabolic disorders, usually the too rapid correction of hyponatremia (see Chap. 39). Certain disorders of skeletal and cardiac muscle associated with alcoholism (acute alcoholic myopathy and cardiomyopathy) are described in Chap. 45, with the myopathies caused by drugs and toxins. There remain to be discussed several diverse disorders that have been attributed to alcoholism but whose causal relationship to alcohol abuse, nutritional deficiency, or some other relevant factor is not clear.


Neurology_Adams

Neurology_Adams. The term alcoholic dementia is used widely and often indiscriminately to designate a presumably distinctive form of dementia that is attributable to the chronic, direct effects of alcohol on the brain. Unfortunately, a syndrome subsumed under the title of alcoholic dementia and its many synonyms that appear in the older literature (alcoholic deteriorated state, chronic alcoholic psychosis, chronic or organic brain syndrome due to alcohol) has never been delineated satisfactorily, either clinically or pathologically. In the Comprehensive Textbook of Psychiatry, it has been defined as “a gradual disintegration of personality structure, with emotional lability, loss of control, and dementia” (Sadock and Sadock). Purported examples of this state show a remarkably diverse group of symptoms, including jealousy and suspiciousness; coarsening of moral fiber and other personality and behavioral disorders; deterioration of work performance, personal care, and living habits; and disorientation,


Neurology_Adams

Neurology_Adams. jealousy and suspiciousness; coarsening of moral fiber and other personality and behavioral disorders; deterioration of work performance, personal care, and living habits; and disorientation, impaired judgment, and defects of intellectual function, particularly of memory.


Neurology_Adams

Neurology_Adams. There have been many attempts to redefine alcoholic dementia. Cutting, as well as Lishman, expressed the view that the term Korsakoff psychosis should be limited to patients with a fairly pure disorder of memory of acute onset and that patients with more global symptoms of intellectual deterioration, of gradual evolution, be considered to have alcoholic dementia. These are rather weak diagnostic criteria. As pointed out in Chap. 40, Korsakoff psychosis may have an insidious onset and gradual progression, and patients with this disorder, in addition to an amnesic defect, characteristically show disturbances of cognitive functions that depend little or not at all on memory. More importantly, in none of the patients designated by these authors as having alcoholic dementia was there a neuropathologic examination, without which the clinical assessment must remain arbitrary and imprecise.


Neurology_Adams

Neurology_Adams. The pathologic changes that purportedly underlie primary alcoholic dementia are even less precisely defined than the clinical syndrome. Courville, whose writings have been quoted most frequently in this respect, described a series of cerebral cortical changes that he attributed to the toxic effects of alcohol. Some of them turn out on close inspection to be quite nonspecific, reflecting nothing more than the effects of aging or the insignificant artifacts of tissue fixation and staining. Harper and Blumbergs, and subsequently Harper and Kril, reported that the mean brain weight is decreased in alcoholics and the pericerebral space is increased in volume—findings that do no more than confirm the brain shrinkage that is readily demonstrable by brain imaging studies in many alcoholics and is to some extent reversible with sustained abstinence (see later).


Neurology_Adams

Neurology_Adams. The majority of cases that come to autopsy with the label of alcoholic dementia prove simply to have the lesions of the Wernicke-Korsakoff syndrome. Traumatic lesions of varying degrees of severity are commonly added. Other cases show the lesions of Marchiafava-Bignami disease, hepatic encephalopathy, subdural hematomas, or an unrelated communicating hydrocephalus, Alzheimer disease, ischemic necrosis, or some other disease quite unrelated to alcoholism. Practically always in our material, the clinical state can be accounted for by one or a combination of these disease processes and there has been no need to invoke a hypothetical toxic effect of alcohol on the brain. This has also been the experience of Torvik and associates; with a few exceptions, such as coincidental Alzheimer disease, all their cases that had been diagnosed as having alcoholic dementia turned out, on neuropathologic examination, to have the chronic lesions of Wernicke-Korsakoff disease.


Neurology_Adams

Neurology_Adams. In brief, the most serious flaw in the concept of a primary alcoholic dementia is that it lacks a distinctive, well-defined pathology. Until such time as the morphologic basis is established, its status must remain ambiguous. A more detailed discussion of this subject and of so-called alcoholic cerebral atrophy can be found in the review by Victor (1994).


Neurology_Adams

Neurology_Adams. Alcoholic cerebral atrophy likewise does not constitute a well-defined entity. The concept was the product originally of pneumoencephalographic studies. Relatively young alcoholics, some with and some without symptoms of cerebral disease were often found to have enlarged cerebral ventricles and widened sulci, mainly of the frontal lobes (see, e.g., reports of Brewer and Perrett and of Haug). Similar findings have been reported in brain imaging studies of chronic alcoholics (see review by Carlen et al). The clinical correlates of these radiologic findings are unclear. Wilkinson demonstrated that in clinically normal alcoholics, the radiologic measures of “brain atrophy” were age related; once the age factor was removed, the imaging findings in these subjects did not differ significantly from those in nonalcoholic controls. However, from the studies by Harper and Blumbergs (1982) and Harper and Kril (1985) it may indeed be the case that chronic exposure to alcohol induces cerebral


Neurology_Adams

Neurology_Adams. from those in nonalcoholic controls. However, from the studies by Harper and Blumbergs (1982) and Harper and Kril (1985) it may indeed be the case that chronic exposure to alcohol induces cerebral atrophy, but this requires confirmation. The idea of alcoholic atrophy is open to criticism mainly on the grounds that dilated ventricles have in fact been reversible to a considerable extent when abstinence is maintained (Carlen et al; Lishman; Zipursky et al; Schroth et al).


Neurology_Adams

Neurology_Adams. That parental alcoholism may have an adverse effect on the offspring has been a recurrent theme in medical writings. Probably the first allusion to such a relationship was that of Sullivan in 1899, who reported that the mortality among the children of drunken mothers was more than two times greater than that among children of nondrinking women of “similar stock.” This increased mortality was attributed by Sullivan and later by Haggard and Jellinek to postnatal influences such as poor nutrition and a chaotic home environment, rather than to the intrauterine effects of alcohol. The idea that maternal alcoholism could damage the fetus was generally rejected and relegated to the category of superstitions about alcoholism or the claims of temperance ideologues.


Neurology_Adams

Neurology_Adams. In the late 1960s, the effects of alcohol abuse on the fetus were rediscovered, so to speak. Lemoine and associates in France, and then Ulleland and Jones and Smith in the United States, described a distinctive pattern of abnormalities in infants born of severely alcoholic mothers. They stated that the affected infants are small in length in comparison to weight, and most of them fall below the third percentile for head circumference. They are distinguished also by the presence of short palpebral fissures (shortened distance between inner and outer canthi) and epicanthal folds; maxillary hypoplasia, micrognathia, indistinct philtrum, and thin upper lip; and longitudinally oriented palmar creases, flexion deformities of the fingers, and a limited range of motion of other joints. Minor anomalies (usually spontaneously closing cardiac septal defects), anomalous external genitalia, and cleft lip and palate are much more frequent than in the general population. All of these features have


Neurology_Adams

Neurology_Adams. (usually spontaneously closing cardiac septal defects), anomalous external genitalia, and cleft lip and palate are much more frequent than in the general population. All of these features have similarities to the syndrome described in a proportion of infants whose mothers had taken anticonvulsants during pregnancy, the “fetal anticonvulsant (antiepileptic) syndrome” (see Chap. 15). The newborn infants suck and sleep poorly, and many of them are irritable, restless, hyperactive, and tremulous; these last symptoms resemble those of alcohol withdrawal except that they persist.


Neurology_Adams

Neurology_Adams. The first long-term study of children with what has come to be called fetal alcohol syndrome (FAS) was reported by Jones and coworkers. Among 23 infants born to alcoholic mothers, there was a neonatal mortality of 17 percent; among the infants who survived the neonatal period, almost half failed to achieve normal weight, length, and head circumference or remained mentally retarded to a varying degree, even under optimal environmental conditions. Several large groups of severely affected children have now been observed for 20 years or longer (see Streissguth). Distractibility, inattentiveness, hyperactivity, and impairment of fine motor coordination are prominent features in early childhood. Most such children fall into the category of attention-deficit hyperactivity disorder. Slow growth of head circumference is a consistent finding throughout infancy and childhood. The physical stigmata of the syndrome become less distinctive after puberty, but practically all adolescents are left


Neurology_Adams

Neurology_Adams. of head circumference is a consistent finding throughout infancy and childhood. The physical stigmata of the syndrome become less distinctive after puberty, but practically all adolescents are left with some degree of mental retardation and behavioral abnormalities.


Neurology_Adams

Neurology_Adams. The pathologic changes that underlie the syndrome have been studied in a small number of cases and no uniform change has emerged. Of some interest are observations such as those of Ikonomidu and coworkers that demonstrate a profound effect of alcohol exposure on the deletion of millions of neurons in the developing rat brain by a mechanism of apoptosis. The main vulnerability occurs during periods of synaptogenesis, which in humans extends from the sixth month of gestation onward.


Neurology_Adams

Neurology_Adams. It is noteworthy that infants born to nonalcoholic mothers who had been subjected to severe dietary deprivation during pregnancy (during World War II) were small and often premature, but these infants did not show the pattern of malformations that characterizes FAS. Alcohol readily crosses the placenta in humans and animals; in the mouse, rat, chick, miniature swine, and beagle dog, alcohol has been shown to have both embryotoxic and teratogenic effects. Thus, the evidence to date favors a toxic effect of alcohol, although a possible toxic effect of acetaldehyde and smoking and a possible contributory role for nutritional deficiency have not been totally excluded.


Neurology_Adams

Neurology_Adams. Unequivocal cases of FAS observed to date have occurred only in infants born to severely alcoholic mothers (many of them with delirium tremens and liver disease) who continued to drink heavily throughout pregnancy. It is important to state that a relationship to lesser degrees of alcohol intake is far less secure. Data derived from the collaborative study sponsored by the National Institutes of Health indicate that about one-third of the offspring of women who are heavy drinkers have FAS. Abel and Sokol have estimated that the worldwide incidence of FAS is 1.9 per 1,000 live births and have pronounced it the leading known cause of mental retardation in the western world. The degree of maternal alcoholism that is necessary to produce the syndrome and the critical stage in gestation during which it occurs are still vague. The various teratogenic effects described earlier are estimated to occur in the embryonic period, that is, in the first 2 months of fetal life. Other nonteratogenic


Neurology_Adams

Neurology_Adams. which it occurs are still vague. The various teratogenic effects described earlier are estimated to occur in the embryonic period, that is, in the first 2 months of fetal life. Other nonteratogenic effects appear to be related to periods during gestation when the fetus is exposed to particularly high alcohol levels.


Neurology_Adams

Neurology_Adams. A comprehensive and not outdated account of alcohol-related birth defects and the controversial issues surrounding this subject is contained in a special issue of Alcohol Health and Research World, published by the National Institutes of Health (Vol. 18, 1994). Neurologic Complications of Alcoholic Cirrhosis and Portal–Systemic Shunts This category of alcoholic disease is discussed in Chap. 39, in connection with the acquired metabolic disorders of the nervous system. Treatment of Alcohol Dependence


Neurology_Adams

Neurology_Adams. This category of alcoholic disease is discussed in Chap. 39, in connection with the acquired metabolic disorders of the nervous system. Treatment of Alcohol Dependence Following recovery from the acute medical and neurologic complications of alcoholism, the patient still must face the underlying problem of alcohol dependence. To treat only the medical complications and leave the management of the drinking problem to the patient alone is shortsighted. Almost always, drinking is resumed, with a predictable recurrence of medical illness. For this reason, the medical profession must be prepared to deal with the addiction or at least to initiate treatment.


Neurology_Adams

Neurology_Adams. The problem of excessive drinking is formidable but not nearly as hopeless as it is generally made out to be (see review of O’Connor and Schottenfeld). A common misconception among physicians is that specialized training in psychiatry and an inordinately large amount of time are required to deal with the addictive drinker. Actually, a successful program of treatment can be initiated by any interested physician, using the standard techniques of history taking, establishing rapport with the patient, and setting up a schedule of frequent visits, although not necessarily for prolonged periods. Our position on this matter was reinforced by a controlled study of problem drinkers in whom treatment was equally successful whether carried out by general practitioners or by specialists (Drummond et al). O’Connor and Schottenfeld summarize the various approaches to the patient who has a drinking problem but is not yet alcohol dependent. They favor brief and focused interventions that point out


Neurology_Adams

Neurology_Adams. al). O’Connor and Schottenfeld summarize the various approaches to the patient who has a drinking problem but is not yet alcohol dependent. They favor brief and focused interventions that point out the problem in unambiguous terms and offer empathetic advice; the physician is often the central person in this interaction.


Neurology_Adams

Neurology_Adams. It appears that the requisite for successful treatment is total abstinence from alcohol; for all practical purposes, this represents the only permanent solution. There are alcohol addicts who have been able to reduce their intake of alcohol and eventually to drink in moderation, but they represent only a small proportion of the addicted population. Alcoholic patients must be made fully aware of the medical and social consequences of continued drinking. They must also be made to understand that because of some constitutional peculiarity (like that of the diabetic, who cannot handle sugar) they are incapable of drinking in moderation. These facts should be presented in much the same way as one would explain the essential features of any other disease; there is nothing to be gained from adopting a punitive or moralizing attitude. Yet patients should not be given the idea that they are in no way to blame for their illness; there appears to be an advantage in making them feel that they are


Neurology_Adams

Neurology_Adams. a punitive or moralizing attitude. Yet patients should not be given the idea that they are in no way to blame for their illness; there appears to be an advantage in making them feel that they are responsible for doing something about their drinking.


Neurology_Adams

Neurology_Adams. A number of methods have proved valuable in the shortand long-term management of alcoholic patients. The more important of these are admission to a detoxification or special hospital unit, rehabilitative therapy, aversion treatment, the use of disulfiram (Antabuse), and the participation in self-help organizations for recovery from alcoholism. Detoxification clinics and special hospital units for the treatment of alcoholism are now widely available. The physician should be aware of the community resources available for the management of this problem and should be prepared to take advantage of them in appropriate cases. Most inpatient programs include individual and group counseling, didactics about the illness and recovery, and family intervention. Outpatient treatment (of individuals or groups) is widely available, either from specialized facilities or from specialized therapists in general mental health facilities; family counseling is usually offered as well and is often


Neurology_Adams

Neurology_Adams. or groups) is widely available, either from specialized facilities or from specialized therapists in general mental health facilities; family counseling is usually offered as well and is often beneficial. Most professional alcoholism treatment in the United States includes an introduction to the methods and utilization of Alcoholics Anonymous (AA; see below).


Neurology_Adams

Neurology_Adams. Disulfiram, less used in recent years, interferes with the metabolism of alcohol, so that a patient who takes both alcohol and disulfiram accumulates an inordinate amount of acetaldehyde in the tissues, resulting in nausea, vomiting, and hypotension, sometimes pronounced in degree. It is no longer considered necessary to demonstrate these effects to patients; it is sufficient to warn them of the severe reactions that may result if they drink while they have the drug in their bodies.


Neurology_Adams

Neurology_Adams. The opioid antagonist naltrexone (50 mg/d orally) or a long-acting injectable formulation has also been used for this purpose, with overall favorable results in numerous trials. The depot injectable form has the advantage of improving compliance in this population that is difficult to treat and to retain in clinical trials. The relevant trials and clinical implementation of naltrexone for alcohol dependence are summarized by Anton (2008). In Europe, modest success has been achieved with the GABA and glutamate modulator acamprosate (2,000 mg daily), but this drug is not yet available in the United States and some trials have shown it to be ineffective. Putatively, a novel approach has been to block the addicting effects of alcohol on the mesolimbic dopaminergic system by the use of anticonvulsants such as topiramate. Johnson and colleagues were able to demonstrate a reduction in alcoholic intake in patients taking this drug, in comparison to placebo, albeit over only a 12-week period.


Neurology_Adams

Neurology_Adams. such as topiramate. Johnson and colleagues were able to demonstrate a reduction in alcoholic intake in patients taking this drug, in comparison to placebo, albeit over only a 12-week period. The use of these medications and the possible reasons for conflicting results between studies are given in a review by Swift. A complex randomized trial conducted by Anton and colleagues (2006) compared naltrexone, cognitive-behavioral therapy, and both, and found that abstinence was most likely, in the short period of 4 months, with the drug alone or when combined with the psychologic therapy; those who received the cognitive therapy but neither naltrexone or a placebo pill did somewhat worse.


Neurology_Adams

Neurology_Adams. Treatment with disulfiram is instituted only after the patient has been sober for several days, preferably longer. It should never be given to patients with cardiac or advanced liver disease. Should the patient drink while taking disulfiram, the ensuing reaction is usually severe enough to require medical attention, and a protracted spree can thus be prevented. Disulfiram may cause a polyneuropathy if continued over months or years, but this is a rare complication.


Neurology_Adams

Neurology_Adams. Alcoholics Anonymous, an informal fellowship of recovering alcoholics, has proven to be the single most effective force in the rehabilitation of alcoholic patients. The philosophy of this organization is embodied in its “12 Steps,” a series of principles for sober living that guide the patient to recovery. The AA approach stresses in particular the practice of making restitution, the necessity to help other alcoholics, trust in a higher power, the group confessional, and the belief that the alcoholic alone is powerless over alcohol. Although accurate statistics are lacking, it is said that about one-third of the members who express more than a passing interest in the program attain a state of long-sustained or permanent sobriety. The methods used by AA are not acceptable to every patient, but most who persist in its activities appear to benefit; in particular, the physician should not accept a patient’s initial negative reaction as reason to abandon AA as a mode of treatment.


Neurology_Adams

Neurology_Adams. Finally, it should be noted that alcoholism is very frequently associated with psychiatric disease of other types, particularly sociopathy and affective illness (the term dual diagnosis is used by psychiatrists to denote this combination of psychopathologies). In the latter case, the prevailing mood is far more often one of depression than of mania and is more often encountered in women, who are more apt to drink under these conditions than are men. In these circumstances, expert psychiatric help should be sought, preferably from someone who is also familiar with addictive diseases. Attempts are being made to treat alcohol addiction with invasive methods such as deep brain stimulation of various sites but these can only be considered experimental. The role of physicians in caring for patients with alcohol problems has been outlined by several governmental agencies and is summarized in the review article by O’Connor and Schottenfeld.


Neurology_Adams

Neurology_Adams. The opiates, or opioids, strictly speaking, include all the naturally occurring alkaloids in opium, which is prepared from the seed capsules of the poppy Papaver somniferum. For clinical purposes, the term opiate refers only to the alkaloids that have a high degree of analgesic activity, that is, morphine. The terms opioid and narcotic-analgesic designate drugs with actions similar to those of morphine. Compounds that are chemical modifications of morphine include diacetylmorphine, or heroin, hydromorphone (Dilaudid), codeine, hydrocodone, oxycodone (OxyContin), and from the Victorian era and later, laudanum and paregoric. A second class of opioids comprises the purely synthetic analgesics: meperidine (Demerol) and its congeners, notably fentanyl, methadone, levorphanol, propoxyphene (Darvon), loperamide (the active ingredient in Imodium), and diphenoxylate (the main component of Lomotil). The synthetic analgesics are similar to the opiates in both their pharmacologic effects and


Neurology_Adams

Neurology_Adams. (Darvon), loperamide (the active ingredient in Imodium), and diphenoxylate (the main component of Lomotil). The synthetic analgesics are similar to the opiates in both their pharmacologic effects and patterns of abuse, the differences being mainly quantitative.


Neurology_Adams

Neurology_Adams. Opioids activate G-coupled transmembrane receptors, meaning they influence neuronal activity through the intermediate of cAMP; the receptor types are denominated as mu, delta, and kappa. An understanding of the clinical effects of opioids is clarified by the knowledge that these receptors are concentrated in the thalamus and dorsal root ganglia (mu receptors, pain), amygdala (affect) and brainstem raphe (alertness), and Edinger-Westphal nuclei (pupillary miosis). Receptors in the brainstem, also of the mu type, are involved in modulating respiratory responses to hypoxia and hypercarbia (respiratory suppression). Receptors are also widely distributed in neural components of other organs, particularly the gastrointestinal tract, accounting for the constipation that is an effect of the administration of this class of drugs. The clinical effects of the opioids are considered from two points of view: acute poisoning and addiction.


Neurology_Adams

Neurology_Adams. The clinical effects of the opioids are considered from two points of view: acute poisoning and addiction. Because of the common, and particularly the illicit, use of opioids, poisoning is a frequent occurrence. This happens also as a result of ingestion or injection accidentally or with suicidal intent, errors in the calculation of dosage, the use of a substitute or contaminated street product, or unusual sensitivity. Children exhibit an increased susceptibility to opioids, so that relatively small doses may prove toxic. This is true also of adults with myxedema, Addison disease, chronic liver disease, and pneumonia. Acute poisoning may also occur in persons who are unaware that opioids available from illicit sources vary greatly in potency and that tolerance for opioids declines quickly after the withdrawal of the drug; upon resumption of the habit, a formerly well-tolerated dose can be fatal.


Neurology_Adams

Neurology_Adams. Unresponsiveness, shallow respirations, slow respiratory rate (e.g., 2 to 8 per min) or periodic breathing, pinpoint pupils, bradycardia, and hypothermia are the well-recognized clinical manifestations of acute opioid poisoning. In the most advanced stage, the pupils dilate, the skin and mucous membranes become cyanotic, and the circulation fails. Later in the course, pulmonary edema may arise, or aspiration pneumonia may become evident as summarized the review of opioid overdose by Boyer. The immediate cause of death is usually respiratory depression with consequent asphyxia. Patients who suffer a cardiorespiratory arrest are sometimes left with all the known residua of anoxic encephalopathy (see Chap. 39). Mild degrees of intoxication are reflected by anorexia, nausea, vomiting, constipation, and loss of sexual interest. Toxicology screens for opiates may be useful but action must be taken before the results of these tests are completed. Treatment of Overdose


Neurology_Adams

Neurology_Adams. This consists of the support of ventilation and administration of naloxone (Narcan), or the longer-acting nalmefene, both specific antidotes to the opiates and also to the synthetic analgesics. The dose of naloxone in adults is usually 0.4 to 0.5 mg and repeated in larger increments (the second dose is typically 2 mg) every 2 min to a dose of 15 mg intravenously as outlined by Boyer. For children, a higher initial dose of 0.1 mg/kg is recommended. Intranansal preparations of 2 mg and 4 mg are available for emergency treatment but are less consistently effectively than the intravenous preparation. The improvements in circulation and respiration and reversal of miosis are usually dramatic. Failure of naloxone to produce such a response should cast doubt on the diagnosis of opioid intoxication. A narcotic withdrawal response may be seen and can be dramatic and resistant to treatment. If an adequate respiratory and pupillary response to naloxone is obtained, the patient should nonetheless


Neurology_Adams

Neurology_Adams. A narcotic withdrawal response may be seen and can be dramatic and resistant to treatment. If an adequate respiratory and pupillary response to naloxone is obtained, the patient should nonetheless be observed for up to 24 h and further doses of naloxone (50 percent higher than the ones previously found effective) can be given intramuscularly as often as necessary.


Neurology_Adams

Neurology_Adams. Naloxone has less direct effect on consciousness, however, and the patient may remain drowsy for many hours. This is not harmful provided respiration is well maintained. Although nalmefene has a plasma half-life of 11 h, compared to 60 to 90 min for naloxone, it has no clear advantage in emergency practice. Gastric lavage is a useful measure if the drug was taken orally. This procedure may be efficacious many hours after ingestion, as one of the toxic effects of opioids is ileus, which causes some of the drug to be retained in the stomach. Concerns of precipitating opioid withdrawal by giving naloxone are generally unfounded.


Neurology_Adams

Neurology_Adams. Once the patient regains consciousness, complaints such as pruritus, sneezing, tearing, piloerection, diffuse body pains, yawning, and diarrhea may appear. These are the recognizable symptoms of the opioid abstinence, or withdrawal, syndrome described later. Consequently, an antidote must be used with great caution in an addict who has taken an overdose of opioid, because in this circumstance, it may precipitate withdrawal phenomena. Nausea and severe abdominal pain, presumably because of pancreatitis (from spasm of the sphincter of Oddi), are other troublesome symptoms of opiate use or withdrawal. Seizures are rare.


Neurology_Adams

Neurology_Adams. Just 50 years ago there were an estimated 60,000 persons addicted to narcotic drugs in the United States, exclusive of those who were receiving drugs because of incurable painful diseases. This represented a relatively small public health problem in comparison with the abuse of alcohol and barbiturates. Moreover, opioid addiction was of serious proportions in only a few cities—New York, Chicago, Los Angeles, Washington DC, and Detroit. Since the late 1960s, a remarkable increase in opioid addiction has taken place. According to statistics from the Centers for Disease Control and Prevention (CDC), as of 2016, 66 percent of the more than 63,000 drug overdose deaths in the United States involved an opioid (including both prescribed and illicit opioids) and on average, 115 Americans die every day from an opioid overdose. A serial rise in opioid-related deaths is traceable to three trends: increased prescribing of opioids (natural and semisynthetic opioid and methadone) in the 1990s,


Neurology_Adams

Neurology_Adams. every day from an opioid overdose. A serial rise in opioid-related deaths is traceable to three trends: increased prescribing of opioids (natural and semisynthetic opioid and methadone) in the 1990s, increases in overdose deaths involving heroin around 2010, and increases in overdose deaths involving synthetic opioids around 2013. The precise number of opioid addicts is unknown but is estimated by the Drug Enforcement Administration to be well more than 500,000. The problem assumes enormous importance when one recognizes that a significant number of addicts are seropositive for HIV and thus a source of transmission to each other, to newborns and to the nonaddicted population.


Neurology_Adams

Neurology_Adams. A number of factors—socioeconomic, psychologic, and pharmacologic—contribute to the genesis of opioid addiction. The most susceptible to opioid addiction are young men living in economically depressed areas of large cities, but significant numbers of addicts are found in suburbs and in small cities, and among affluent populations as well. The onset of opioid use is often in adolescence; fully two-thirds of addicts start using the drugs before the age of 21. Many have psychiatric disturbances, conduct disorder and sociopathy being the most common (“dual-diagnosis,” in psychiatric jargon) but vulnerability to addiction is not confined to one personality type. Monroe and colleagues, using the Lexington Personality Inventory, examined a group of 837 opioid addicts and found evidence of antisocial personality in 42 percent, emotional disturbance in 29 percent, and thought disorder in 22 percent; only 7 percent were free of such disorders. Association with addicts is an additional


Neurology_Adams

Neurology_Adams. of antisocial personality in 42 percent, emotional disturbance in 29 percent, and thought disorder in 22 percent; only 7 percent were free of such disorders. Association with addicts is an additional explanation for becoming addicted. In this sense, opioid addiction is contagious, and partly as a result of this pattern, opioid addiction has attained epidemic proportions.


Neurology_Adams

Neurology_Adams. Opioid addiction consists of three recognizable phases: (1) intoxication, or “euphoria,” (2) pharmacogenic dependence or drug-seeking behavior (addiction), and (3) the propensity to relapse after a period of abstinence. Some of the symptoms of opioid intoxication have already been considered. In patients with severe pain or pain-anticipatory anxiety, the administration of opioids produces a sense of unusual well-being, a state that has traditionally been referred to as morphine euphoria. It should be emphasized that only a negligible proportion of such persons continue to use opioids habitually after their pain has subsided. The vast majority of potential addicts are not suffering from painful illnesses at the time they initiate opioid use, and the term euphoria is probably not an apt description of the initial effects. These persons, after several repetitions, recognize a “high,” despite the subsequent recurrence of unpleasant, or dysphoric, symptoms (nausea, vomiting, and faintness


Neurology_Adams

Neurology_Adams. of the initial effects. These persons, after several repetitions, recognize a “high,” despite the subsequent recurrence of unpleasant, or dysphoric, symptoms (nausea, vomiting, and faintness as the drug effect wanes).


Neurology_Adams

Neurology_Adams. The pharmacologic (in contrast to psychologic) criteria of addiction, as indicated earlier in regards to alcoholism, are tolerance and physical dependence. The latter refers to the symptoms and signs that become manifest when the drug is withdrawn following a period of continued use. These symptoms and signs constitute a specific clinical state, termed the abstinence or withdrawal syndrome (see later). The mechanisms that underlie the development of tolerance and physical dependence are not fully understood. However, it is known that opioids activate an opioid antinociceptive system (enkephalins, dynorphins, endorphins), which are opioid receptors and are located at many different levels of the nervous system (these were referred to earlier and are described in Chap. 7; see also the review of Fields). The desensitization of opioid receptors, probably mainly the mu type, accounts for tolerance through a mechanism of uncoupling of the receptor from the G-protein complex.


Neurology_Adams

Neurology_Adams. The repeated self-administration of the drug is the most important factor in the genesis of dependence aspect of addiction. Regardless of how one characterizes the state of mind that is produced by episodic exposure to the drug, the individual quickly discovers the need to increase the dose in order to obtain the original effects (tolerance). Although the initial effects may not be fully recaptured, the progressively increasing dose of the drug does relieve the discomfort that arises as the effects of each injection wear off. In this way a new pharmacogenically induced need is developed, and the use of opioids becomes self-perpetuating. At the same time a marked degree of tolerance is produced, so that enormous amounts of drugs, for example, 5,000 mg of morphine daily, can eventually be administered without the development of toxic symptoms. The Opioid Abstinence Syndrome


Neurology_Adams

Neurology_Adams. The Opioid Abstinence Syndrome The intensity of the abstinence or withdrawal syndrome depends on the dose of the drug and the duration of addiction. The onset of abstinence symptoms in relation to the last exposure to the drug, however, is related to the pharmacologic half-life of the agent. With morphine, the majority of individuals receiving 240 mg daily for 30 days or more will show moderately severe abstinence symptoms following withdrawal. Mild signs of opiate abstinence can be precipitated by narcotic antagonists in persons who have taken as little as 15 mg of morphine or an equivalent dose of methadone or heroin for 3 days.


Neurology_Adams

Neurology_Adams. The abstinence syndrome that occurs in the morphine addict may be taken as the prototype. The first 8 to 16 h of abstinence usually pass asymptomatically. At the end of this period, yawning, rhinorrhea, sweating, piloerection, and lacrimation are manifest. Mild at first, these symptoms increase in severity over a period of several hours and then remain constant for several days. The patient may be able to sleep during the early abstinence period but is restless, and thereafter insomnia remains a prominent feature. Dilatation of the pupils, recurring waves of “gooseflesh,” and twitching of the muscles appear. The patient complains of aching in the back, abdomen, and legs and of “hot and cold flashes”; he frequently asks for blankets. At about 36 h the restlessness becomes more severe, and nausea, vomiting, and diarrhea usually develop. Temperature, respiratory rate, and blood pressure are slightly elevated. All these symptoms reach their peak intensity 48 to 72 h after withdrawal and


Neurology_Adams

Neurology_Adams. nausea, vomiting, and diarrhea usually develop. Temperature, respiratory rate, and blood pressure are slightly elevated. All these symptoms reach their peak intensity 48 to 72 h after withdrawal and then gradually subside. The opioid abstinence syndrome is rarely fatal (it is life-threatening only in infants). After 7 to 10 days, the clinical signs of abstinence are no longer evident, although the patient may complain of insomnia, nervousness, weakness, and muscle aches for several more weeks, and small deviations of a number of physiologic variables can be detected with refined techniques for up to 10 months (protracted abstinence).