Alcohol and the Nervous System

Keywords

alcoholic dementia, Wernicke–Korsakoff, alcoholic cerebellar degeneration, alcoholic neuropathy, alcoholic myopathy

Who could have foretold, from the structure of the brain, that wine could derange its functions? Hippocrates

Alcohol is the most commonly used recreational psychoactive substance worldwide. While moderate drinking can be beneficial to health, excessive use can result in serious medical disorders. Excessive alcohol consumption has been implicated in diseases affecting virtually every level of the neuraxis ( Fig. 33-1 ). Despite its protean nature, alcoholic neurologic disease often involves select anatomic structures or cell populations, suggesting that multiple, discrete pathophysiologic processes are involved.

Alcohol Intoxication and Withdrawal

Intoxication

In nonalcoholics, early signs of intoxication occur at blood alcohol concentrations less than 50 mg/dl (11 mmol/L) and include relaxation, loss of social inhibitions, increased talking, and impairment in some skilled tasks. Ataxia, nystagmus, slurred speech, impaired judgment, and changes in mood and behavior generally occur at blood alcohol levels above 100 mg/dl (22 mmol/L) and are followed by findings of central nervous system depression as blood levels increase. Blood levels above 300 mg/dl (65 mmol/L) can lead to coma, hyporeflexia, respiratory compromise, and hypotension. Although the behavioral effects of alcohol generally correlate with blood concentrations, tolerance may occur rapidly and greatly modify the clinical response to a specific blood level. Acute tolerance develops even during a single bout of drinking, and can cause the drinker to become sober at blood alcohol concentrations higher than those at which intoxication previously developed. In chronic alcoholics, the degree of tolerance can be extensive, permitting sobriety at blood concentrations above 120 mg/dl and survival above 700 mg/dl.

Minor Withdrawal Syndrome

Characteristic symptoms of alcohol withdrawal follow abrupt cessation of drinking. Tremulousness is the most common early symptom, becoming most marked 24 to 36 hours after the last drink. The tremor is generalized, resembles an accentuated physiologic tremor, and is accompanied by signs of autonomic hyperactivity such as increased arousal, tachycardia, flushing, and hyperreflexia. These signs are associated with elevated blood and urinary catecholamine levels and increased levels of catecholamine metabolites in the cerebrospinal fluid (CSF).

Withdrawal Seizures

Seizures may occur shortly after chronic ethanol intake is discontinued. Alcohol withdrawal seizures are usually associated with a history of daily alcohol consumption, but briefer drinking sprees may also culminate in seizures following cessation. Generalized tonic-clonic seizures are most common; focal seizures suggest an etiology other than alcohol withdrawal, although alcohol can lower the seizure threshold in a patient otherwise predisposed to focal seizures. The majority of seizures occur 6 to 48 hours after cessation of drinking. Approximately 60 percent of patients have more than one seizure, but usually less than four, over a period of less than 12 hours. Among patients undergoing withdrawal, status epilepticus is unusual, but among patients with status epilepticus, alcohol withdrawal is responsible in approximately 9 to 25 percent.

In patients with repeated seizures, benzodiazepines (e.g., diazepam, chlordiazepoxide, and lorazepam) prevent seizure recurrence, but the evidence is not adequate to support the use of non-benzodiazepine anticonvulsants. Status epilepticus that is suspected to be due to alcohol withdrawal is a medical emergency and should be treated with anticonvulsants in the same fashion as status epilepticus due to any other etiology, beginning with doses of benzodiazepines. It is important to recognize that alcoholics are at risk of a variety of other treatable conditions that may cause status epilepticus, including occult head trauma, meningitis, hypoglycemia, hyponatremia, and other drug ingestions.

Delirium Tremens

Approximately 20 percent of patients become delirious 2 to 5 days after ethanol withdrawal, and in up to one-half of these patients the syndrome of delirium tremens may develop, with marked confusion, hallucinations, tremor, hyperpyrexia, and sympathetic hyperactivity. The risk of development of delirium tremens is higher in alcoholics with heavy daily alcohol intake, prior alcohol withdrawal seizures or delirium, decreased serum chloride and potassium concentrations, elevated serum levels of alanine aminotransferase and γ-glutamyltransferase, and findings of tachycardia (≥100 bpm), ataxia, and poly- neuropathy on admission. The major threat to life is from associated illnesses or injuries, hyperthermia, dehydration, and hypotension. Although initial studies reported mortality rates as high as 15 percent, rates with current treatment have declined to 1 percent or less. A variety of sedatives, anticonvulsants, sympatholytics, and neuroleptics have been administered to patients with alcohol-withdrawal delirium, usually in uncontrolled trials. Several double-blind studies have suggested that benzodiazepines are effective in controlling the symptoms of alcohol withdrawal. Benzodiazepines and barbiturates are better than neuroleptics in reducing mortality from the delirium associated with alcohol withdrawal and should be used preferentially.

The dose of medication required to control alcohol-withdrawal symptoms can vary greatly among different patients and over time in the same patient. A typical regimen is to administer 5 to 10 mg of diazepam intravenously every 5 to 10 minutes until the patient is lightly somnolent, followed by 5 to 20 mg every few hours as needed to control delirium and agitation. Shorter-acting benzodiazepines such as oxazepam or lorazepam may be safer in patients with liver disease. Patients refractory to benzodiazepines may respond to addition of a different class of sedative-hypnotic (e.g., barbituates or propofol). Neuroleptics, such as haloperidol, are reserved for severe agitation as adjunctive therapy. Fluid and electrolyte abnormalities can be severe and require prompt therapy. Dehydration accompanying delirium tremens may require replacement of up to 4 to 10 liters of fluid during the first 24 hours. Hypomagnesemia is common and should be treated with magnesium sulfate (e.g., 1 g intravenously every 6 hours during the first day in patients with adequate renal function). Potassium should be included in intravenous solutions because hypokalemia may be exacerbated by glucose administration, leading to cardiac arrhythmias.

Disorders of Cognition

More than 10 percent of patients with alcohol use disorders develop cognitive dysfunction. The pathogenic mechanisms are often multiple and include the neurotoxic effects of ethanol, nutritional deficiencies, and electrolyte disturbances. Several alcohol-related clinical syndromes with cognitive dysfunction as the predominant feature are described in this section.

Alcoholic Dementia

Alcohol-induced dementia is a recognized form of substance-induced dementia. It presents in the context of chronic, excessive alcohol use and is characterized by progressive memory impairment along with aphasia, agnosia, apraxia, or impaired executive function that persists beyond periods of intoxication or withdrawal and cannot be attributed to other causes. Heavy alcohol use can result in brain atrophy with neuronal loss in the frontal cortex, hypothalamus, and cerebellum; a reduction in the size of cell bodies and dendritic arbors in layer III pyramidal neurons of the superior frontal gyrus and motor cortices; and white matter loss, particularly in the hippocampus, corpus callosum, and cerebellum. With several years of abstinence, cognitive function can improve.

Brain imaging studies have shown widespread volume loss affecting cortical gray and white matter. In addition, magnetic resonance imaging (MRI) studies show signal abnormalities in several subcortical structures, including the corpus callosum, pons, cerebellar hemispheres, and vermis. These regions are less affected in patients with uncomplicated alcoholism free of alcohol-associated electrolyte and nutritional disturbances. White matter abnormalities may be observed with greater sensitivity and detail using diffusion tensor imaging. These imaging and neuropsychiatric abnormalities are partly reversible during abstinence. Volume loss and recovery during abstinence may reflect changes in brain water, but longitudinal studies using MR spectroscopy have shown increases in N -acetyl aspartate and phospholipids in certain brain regions, suggesting actual recovery of neurons and white matter during abstinence.

Pellagra

Endemic pellagra, which results from deficiency of nicotinic acid (niacin) or its amino acid precursor tryptophan, is uncommon in developed countries because of fortification of processed foods with niacin (vitamin B ₃). However, alcoholic pellagra is an underappreciated cause of confusion and delirium in malnourished alcoholics. Neuropathologic changes are most prominent in neurons of the pons and deep cerebellar nuclei, though neurons elsewhere are also involved. Affected neurons show chromatolysis, appearing swollen and rounded, with eccentric nuclei and loss of Nissl substance. Systemic manifestations of pellagra include diarrhea, glossitis, anemia, and erythematous cutaneous lesions that appear in sun-exposed areas. Although pellagra was named for the characteristic skin lesions, they are not always present. Early mental symptoms of irritability, depression, fatigue, insomnia, and inability to concentrate are nonspecific and suggest a psychiatric disorder. However, the later development of confusion, hallucinosis, or paranoid ideation confirms the presence of an encephalopathy, and is usually accompanied by spastic weakness and extensor plantar responses. Tremor, rigidity, polyneuropathy, optic neuritis, and deafness may also be present. Pellagra responds readily to administration of niacin, although cerebral symptoms may not be completely reversible. Further details are given in Chapter 15 .

Marchiafava–Bignami Disease

Marchiafava–Bignami disease is a rare disorder characterized by destruction of myelin mainly in the corpus callosum and anterior commissure. Exceptionally, lesions extend laterally to involve the centrum semiovale, and in some instances the middle cerebellar peduncles are demyelinated. Neurons in layer III of the cerebral cortex may be replaced by gliosis, possibly owing to disruption of involved callosal fibers. The disease is usually diagnosed postmortem because the clinical signs are nonspecific, although MRI has made diagnosis more feasible during life. Most patients are alcoholics of long standing and many have associated malnutrition or liver disease, although the disease has appeared in a few nondrinkers. The etiology is not known.

Patients may present acutely with seizures and coma often accompanied by signs of upper motor neuron dysfunction, or alternatively they may follow a subacute course with gait disturbance, dysarthria, hyperreflexia, cognitive impairment, neuropsychiatric symptoms, and signs of interhemispheric disconnection. Brain MRI demonstrates T2-hyperintense swelling of the corpus callosum, followed later in the course by callosal atrophy along with cortical and subcortical atrophy. T1-weighted images may show hypointense necrotic lesions of the corpus callosum. Motor deficits, such as pyramidal tract signs and gait disturbances, tend to recover with abstinence from alcohol and improved nutrition, but many patients show residual cognitive impairment and a disconnection syndrome. Patients who develop coma carry the greatest risk of serious disability or death, whereas those with little impairment in consciousness may recover with only mild disability.

Hepatocerebral Disorders

Severe alcoholism can cause hepatic cirrhosis with portocaval shunting and hepatic insufficiency, leading to serious secondary neurologic disorders. In its mildest, covert form, hepatic encephalopathy presents with a normal neurologic examination and deficits apparent only on psychometric testing, termed “minimal hepatic encephalopathy.” Overt hepatic encephalopathy presents as a confusional state with deficits in awareness, attention, and calculation ability or, in severe cases, somnolence, stupor, and coma. The pathogenesis and treatment of hepatic encephalopathy are discussed in Chapter 12 .

Acquired (non-Wilsonian) hepatocerebral degeneration is a less common disorder that can accompany advanced liver disease and is characterized by parkinsonism, ataxia and, in some patients, dystonia, chorea, and orobuccolingual dyskinesia. Cognitive dysfunction is common but is not always present. Occasional patients show signs of a myelopathy with corticospinal tract signs. Acquired hepato- cerebral degeneration begins insidiously after many weeks or years of hepatic dysfunction and is usually progressive, with episodes of stability or spontaneous remissions and relapses. It is characterized by neuropathologic lesions that resemble those found in Wilson disease with diffuse, patchy necrosis and microcavitation at the junction of cerebral gray and white matter, and a loss of neurons and myelinated fibers in the basal ganglia and cerebellum. Protoplasmic type II (Alzheimer) astrocytes are increased in number, and Opalski cells may be present.

Acquired hepatocerebral degeneration is thought to result from central nervous system exposure to neurotoxic substances present in the portal circulation, such as ammonia, aromatic amino acids, and metals. A role for manganese in particular is supported by elevated serum and CSF manganese levels and by pallidal hyperintensities on T1-weighted MRI images of patients with severe liver disease, reminiscent of findings in occupational manganese toxicity. Dopaminergic drugs may reduce parkinsonian symptoms, although less effectively than in patients with Parkinson disease. Death usually occurs as a complication of advanced liver disease or intercurrent infection.

Wernicke Encephalopathy

Wernicke encephalopathy is an acute disorder manifested by nystagmus, ophthalmoplegia, gait ataxia, and an acute confusional state. Neuropathologic findings include neuronal loss, demyelination, glial and vascular proliferation, hemorrhage, and necrosis, particularly affecting the anterior and mediodorsal thalamus, mammillary bodies, basal forebrain, raphe nuclei, and cerebellar vermis. An underlying disorder that predisposes to malnutrition appears to be common to all cases. Alcoholism is the most frequent predisposing factor, but persistent vomiting due to a variety of causes, starvation, and malignancy or other chronic systemic diseases, and other causes of malabsorption have also been implicated. A detailed account of its clinical features is provided in Chapter 13 .

The link between malnutrition and Wernicke encephalopathy is a deficiency of vitamin B ₁(thiamine). With chronic alcoholism, decreased dietary intake of thiamine may be compounded by alcohol-induced defects in intestinal absorption, metabolism, and hepatic storage of thiamine. However, the manner in which thiamine depletion produces neurologic dysfunction is unknown. Thiamine pyrophosphate is a required cofactor for at least four enzymes involved in intermediary metabolism: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, transketolase, and branched-chain α-ketoacid dehydrogenase. Variant forms of transketolase and thiamine transport genes could provide a basis for the preferential vulnerability of certain alcoholic patients to develop Wernicke encephalopathy.

The diagnosis of Wernicke encephalopathy has historically been made by the presence of the clinical triad of ophthalmoplegia, ataxia, and confusion. In patients who present with this triad, the differential diagnosis includes sedative drug intoxication and structural lesions of the posterior fossa. In the absence of overt ocular signs in patients with confusion or ataxia, the differential diagnosis includes ethanol intoxication and encephalopathy due to other causes such as hepatic insufficiency or infection.

Over the past 20 years, careful neuropathologic studies have raised concern that reliance on this classic clinical triad has led to underdiagnosis, resulting in establishment of modified diagnostic criteria that have been validated at autopsy. These criteria require two of the following four signs to be present for diagnosis: dietary deficiency, oculomotor abnormalities, cerebellar dysfunction, and either an altered mental state or memory impairment. Application of these criteria leads to nearly 100 percent diagnostic specificity, while greatly improving sensitivity to 85 percent from only 22 percent using the classic clinical triad.

In addition to modified clinical criteria, the advent of MRI and sensitive measures for serum thiamine have also served to improve diagnostic accuracy. The most characteristic MRI findings are of cytotoxic and vasogenic edema involving the thalamus, hypothalamus, and brainstem, appearing as symmetric signal intensities on T2-weighted images of medial thalamic nuclei, periventricular gray matter, midbrain tectum, and the mammillary bodies. Less common are symmetric alterations in the cerebellum, dentate nuclei, cranial nerve nuclei, caudate, splenium of the corpus callosum, and cerebral cortex.

Treatment of Wernicke encephalopathy is by repletion of thiamine. Patients should be hospitalized and receive 200 mg of thiamine intravenously three times daily for several days until there is no further improvement in signs and symptoms. It is important that thiamine replacement is started prior to administering glucose, to avoid worsening the encephalopathy. Improvement with therapy is considered evidence of correct diagnosis. Acute, reversible MRI abnormalities have also been described, and may be helpful in confirming the diagnosis in mild cases or those with atypical clinical features. Detection of a low blood thiamine level may also be useful; current guidelines recommend that total blood thiamine levels be sent at first diagnosis, immediately before beginning thiamine replacement.

The prognosis of Wernicke encephalopathy depends on the prompt institution of appropriate treatment. The overall mortality rate is 10 to 20 percent. After the institution of treatment, ocular and gaze palsies begin to improve within hours to days, and nystagmus, gait ataxia, and confusion within days to weeks. Long-term sequelae include residual nystagmus or gait ataxia in approximately 60 percent of patients and a chronic memory disorder (Korsakoff amnestic syndrome) in more than 80 percent.

Korsakoff Syndrome

Korsakoff syndrome is a selective disorder of memory that typically arises in chronic alcoholics in the wake of one or more episodes of Wernicke encephalopathy. The distribution of histopathologic lesions is identical to that seen in Wernicke encephalopathy. The main additional behavioral deficits in Korsakoff syndrome are impairment of anterograde episodic memory, with semantic and retrograde memory affected to a lesser extent; in many patients there is also evidence of frontal lobe dysfunction. Both encoding and retrieval of memories are affected. Episodic memory processing requires a network of limbic structures, many of which are damaged in Korsakoff syndrome. Biochemical studies have provided evidence of oxidative stress, glutamate-mediated excitotoxicity, and inflammation in vulnerable brain regions as major mechanisms for brain damage due to thiamine deficiency.

Although a causal relationship between (acute) Wernicke encephalopathy due to thiamine deficiency and (chronic) Korsakoff syndrome is generally assumed, this issue is not completely resolved. Korsakoff syndrome was rarely a consequence of Wernicke encephalopathy in malnourished prisoners of war in the Pacific theater during World War II. A review of cases of nonalcoholic Wernicke encephalopathy found that patients who developed subsequent amnestic syndromes showed a substantial improvement in memory over time compared to alcoholics with Wernicke encephalopathy. This difference in recovery may be due to the duration of malnutrition being briefer in nonalcoholics than is usually the case in chronic alcoholics or alternatively because alcohol itself contributes to development of the syndrome. The latter possibility is supported by the finding that alcoholics who develop Wernicke encephalopathy after a period of vomiting perform better on tests of memory than those without vomiting, possibly because emesis helps to clear alcohol from the body.

The disability afflicting patients with Korsakoff syndrome is one of the most striking in clinical neurology. There is an inability to incorporate new memories (anterograde amnesia) and impaired retrieval of previously established, especially recent, memories (retrograde amnesia). Immediate recall is intact. Patients are typically disoriented to time and place, and hospitalized patients are characteristically unaware of their room numbers or hospital floor, how long they have been in the hospital, what they had for their last meal, or who visited them. At the same time, very distant memories may be preserved in detail; some patients appear to be stuck in time, insisting that the year is one from decades past. Patients with Korsakoff syndrome appear to be unaware of their deficit and commonly attempt to reassure the examiner that nothing is seriously wrong. Confabulation, the invention of material to fill in gaps in memory, is often but not invariably seen. Other aspects of cognitive function may exhibit subtle impairment, but alertness and language are intact.

Patients with Korsakoff syndrome may show evidence of other alcohol-related neurologic disorders. Nystagmus and gait ataxia related to past bouts of Wernicke disease are common, as are signs of a peripheral neuropathy.

Korsakoff syndrome is a clinical diagnosis. This relatively selective memory disorder must be distinguished from the more global cognitive impairment that occurs in dementia due to a variety of causes including alcoholism. The differential diagnosis of a chronic amnestic syndrome resembling Korsakoff syndrome includes pancerebral hypoxia or ischemia, bilateral posterior cerebral artery strokes, herpes simplex virus encephalitis, paraneoplastic limbic encephalitis, and brain tumors in the vicinity of the third ventricle.

Although acute Wernicke encephalopathy should always be treated with thiamine, the effectiveness of thiamine in preventing the subsequent development of the chronic amnestic syndrome is uncertain. Similarly, thiamine has not been shown to be effective for the treatment of established Korsakoff syndrome, although patients with this disorder may improve spontaneously and likely warrant a trial of this treatment, which has few side effects.

Only gold members can continue reading. Log In or Register to continue