Alcohol and the Nervous System

Intoxication

In persons who drink alcohol infrequently, 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 central nervous system depression as blood levels increase. Amnesia for all or part of a drinking episode (“blackout”) may occur without loss of consciousness at blood levels above 140 mg/dL. Blood levels above 300 mg/dL (65 mmol/L) can produce coma, hyporeflexia, respiratory compromise, and hypotension. Although the behavioral effects of alcohol generally correlate with blood concentrations, tolerance can 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 be unaffected at blood alcohol concentrations higher than those at which intoxication previously developed. In people who drink heavily, the degree of tolerance can be extensive, permitting sobriety at blood concentrations above 120 mg/dL and survival above 700 mg/dL.

Alcohol Withdrawal Syndromes

In approximately 8 percent of people hospitalized for alcohol use disorder, characteristic signs of alcohol withdrawal syndrome follow 1 to 3 days after abrupt cessation of heavy drinking. Generalized tremor is a common early sign and resembles an accentuated physiologic tremor. It is often accompanied by insomnia, headache, and autonomic hyperactivity with increased arousal, tachycardia, diaphoresis, and flushing. These signs usually begin within 8 hours after cessation of drinking, peak at 72 hours, and resolve after 5 to 7 days.

Seizures may also occur shortly after chronic drinking 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. Status epilepticus may occur in up to 5 percent. More than half of withdrawal seizures are associated with underlying epilepsy, structural brain lesions, or concurrent use of other drugs.

In patients with repeated seizures in the setting of alcohol withdrawal, benzodiazepines (e.g., diazepam, chlordiazepoxide, and lorazepam) prevent seizure recurrence, but the evidence is not adequate to support the use of nonbenzodiazepine 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 for a variety of other treatable conditions that may cause status epilepticus, including occult head trauma, meningitis, hypoglycemia, hyponatremia, and other drug ingestions.

Approximately 20 percent of patients become delirious 2 to 5 days after signs of alcohol withdrawal begin, and in 3 to 5 percent of patients hospitalized for alcohol withdrawal, the syndrome of delirium tremens develops with marked confusion, hallucinations, tremor, hyperpyrexia, and sympathetic hyperactivity. The risk of developing 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, thrombocytopenia, and findings of tachycardia (≥100 bpm), ataxia, and polyneuropathy on admission. The major threat to life is from associated illnesses or injuries, hyperthermia, dehydration, hypotension, arrythmias, and complications of seizures. Although initial studies reported mortality rates as high as 15 percent, rates with current methods of detection and 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. Three treatment approaches have been described. The loading dose approach uses high doses of a long-acting benzodiazepine (e.g., 10 to 20 mg of diazepam every 1 to 2 hours) until the patient is sedated and then allows for tapering through endogenous clearance mechanisms. However, because high doses may cause respiratory depression, vital signs must be carefully monitored with each loading dose to avoid benzodiazepine toxicity, especially in patients with liver disease. In the second approach repeated fixed doses at regular intervals are administered; this strategy can be particularly useful when it is difficult to assess and monitor progression of withdrawal signs. A dose of 5 to 20 mg of diazepam can be given 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, with a ceiling dose of about 60 mg of diazepam per day. After the patient is stable for 2 to 3 days, the benzodiazepine can be slowly tapered over 7 to 10 days. In elderly patients or those with liver disease, repeated administration of shorter-acting benzodiazepines such as oxazepam or lorazepam may be safer. A third approach is symptom-guided by monitoring instruments such as the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), which is a 10-item scale that can be administered at the bedside within 5 minutes. Using a CIWA-Ar score of at least 8 as a cutoff, treatment begins with diazepam (5 to 10 mg) followed by hourly assessment and repeated dosing until the score is less than 8. Thereafter, assessments can be made every 4 to 8 hours to determine the need for repeated dosing. All treatment methods have similar efficacy, but the loading-dose and the symptom-guided approaches may be faster and use less drug than the repeated fixed-dose method, resulting in less sedation and less risk of respiratory depression.

Patients refractory to benzodiazepines may respond to addition of a different class of sedative-hypnotic (e.g., barbiturates 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, lowers seizure threshold, 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.

Alcohol-Related Dementia

People with severe alcohol use disorder can suffer 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 and signal abnormalities in several subcortical structures, including the corpus callosum, pons, cerebellar hemispheres, and vermis. These regions are less affected in patients with uncomplicated alcohol use disorder 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.

Wernicke Encephalopathy

Wernicke encephalopathy is an acute disorder manifested by the classic triad of nystagmus and ophthalmoplegia, gait ataxia, and an acute confusional state. However because not all patients exhibit the complete triad and because the diagnosis can be difficult to distinguish from drunkenness and other causes of confusion, it is missed in 75 to 80 percent of cases. To avoid underdiagnosis, one should consider Wernicke encephalopathy when two of the following four signs are present: dietary deficiency, oculomotor abnormalities, cerebellar dysfunction, and either an altered mental state or memory impairment. 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. Magnetic resonance imaging (MRI) and sensitive measures of serum thiamine can improve diagnostic accuracy but should not delay treatment. 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.

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. Alcohol use disorder is the most frequent predisposing factor. However, persistent vomiting due to a variety of causes such as starvation, malignancy or other chronic systemic diseases, and other mainly surgical causes of malabsorption has also been implicated, as described in Chapter 13 .

The link between malnutrition and Wernicke encephalopathy is a deficiency of vitamin B ₁ (thiamine). In people with chronic alcohol use disorder, decreased dietary intake of thiamine may be compounded by alcohol-induced defects in intestinal absorption, metabolism, and hepatic storage of thiamine. 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. Metabolic impairment in glucose utilization, impaired amino acid transport and resultant excitotoxicity, impaired ion transport, acidosis from increased lactate production, and mitochondrial dysfunction with resultant oxidative stress and blood–brain barrier disruption have all been implicated in pathogenesis. Variant forms of transketolase and thiamine transport genes could provide a basis for the preferential vulnerability of certain patients to develop Wernicke encephalopathy.

Treatment of Wernicke encephalopathy is by repletion of thiamine. Patients should be hospitalized and receive 200 to 500 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 or concurrent with 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 about 17 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.