Neurologic Complications of Alcoholism

Allison L. Weathers

key points

The potential neurologic consequences of chronic alcoholism are wide ranging with potential involvement of both the central nervous system and peripheral nervous system.
Wernicke encephalopathy is a neurologic emergency, whose diagnosis and the decision to treat should be based on the clinical picture alone. This diagnosis should be considered in all high-risk patients.
In addition to the more commonly occurring neurologic complications of alcoholism such as hepatic encephalopathy and Wernicke encephalopathy, more rare manifestations such as pancreatic encephalopathy, pellagra encephalopathy, and Marchiafava-Bignami disease may occur and should be considered in the differential of an alcoholic patient with mental status changes.

Ethanol is one of the most commonly abused substances in the United States. Chronic alcoholism results in substantial health consequences for those who suffer from this disease and overall impacts our medical resources to a significant degree. The potential neurologic complications of chronic alcoholism are broad, with both the central nervous system (CNS) and peripheral nervous system (PNS) possible targets of the adverse effects of chronic alcohol abuse. This chapter will cover these potential complications ranging from those that may be considered acute neurologic emergencies, such as Wernicke encep ha lopathy, to more chronic, insidious processes such as alcoholic neuropathy. Internists, family medicine practitioners, and emergency department physicians are usually well versed in the potential neurologic complications of acute alcohol intoxication and withdrawal and their management, often more so than neurologists. Therefore, this chapter will focus solely on the neurologic manifestations of chronic alcohol abuse.

WERNICKE ENCEPHALOPATHY

Though Wernicke encephalopathy is not one of the most common neurologic manifestations of alcoholism, its potential for devastating neurologic consequences and ultimately death if unrecognized and untreated makes it one of the most significant possible complications of alcohol abuse. It is now recognized that a number of clinical scenarios may result in Wernicke encephalopathy; however, chronic alcohol use remains one of the most common causes of thiamine deficiency and therefore is still the underlying cause in the majority of cases. In this patient population, the onset of Wernicke encephalopathy is especially likely to occur during concurrent febrile illnesses, during or following treatment of delirium tremens, during detoxification, with the administration of glucose (often as a component of intravenous fluids), or during refeeding after prolonged starvation. The unifying feature of all of these circumstances is that they result in increased metabolic demand or stress. Physicians who care for alcoholic patients need to be cognizant of these inciting factors and aware of the wide range of clinical features of this illness.

Although the triad of mental status changes, ophthalmoplegia, and ataxia is wellrecognized as the classic clinical picture of Wernicke encephalopathy, in actuality the full triad occurs in relatively few patients. Mental status and personality changes, including insomnia, lethargy, anxiety, apprehension, apathy, confusion, memory loss, and difficulty with concentration, are frequently the initial symptoms. Ocular symptoms, including wavering of vision, double vision (diplopia), and photophobia, may precede the mental status changes, and nystagmus may be the initial neurologic finding on exam. Lateral rectus palsies, conjugate gaze palsy, complete ophthalmoplegia, pupillary abnormalities, and ptosis are not as frequently seen. Ataxia may also be a presenting sign, but occurs less commonly than mental status changes and eye signs. If untreated, the neurologic symptoms and signs will progress with increasingly severe confusion, confabulation, hallucinations, and ultimately coma and death are possible outcomes. Though rare, patients may present in coma without focal neurologic signs, mimicking other metabolic encephalopathies, and patients may also present with systemic signs including hypotension, hypothermia, and tachycardia.

Although controversy exists surrounding the pathophysiology of many of the neurologic complications of alcoholism, specifically whether they are due to the direct toxic effects of alcohol and its metabolites or to superimposed nutritional and vitamin deficiencies. Wernicke encephalopathy is known to be the result of thiamine deficiency. Thiamine deficiency is common in this population for a number of reasons including decreased gastrointestinal (GI) absorption of thiamine both by chronic alcohol use and by the concurrent use of alcohol with thiamine administration, decreased thiamine storage in the liver, impaired transformation of thiamine into its active form, and independently decreased absorption due to malnutrition. Thiamine deficiency can occur within weeks without continued dietary (or supplemental) intake, and symptoms can start within a few weeks of the onset of the deficient state.

The active form of thiamine, thiamine diphosphate, plays a critical role in three different enzyme pathways, which in turn are vital to a number of biologic functions, such as the synthesis of neurotransmitters, the maintenance of myelin sheaths, the production of energy through lipid and glucose metabolism, and branched-chain amino acid production. As a consequence, thiamine deficiency results in cerebral energy deficits, focal lactic acidosis, glutamate-mediated excitotoxicity, blood-brain barrier breakdown, and free radical formation, which in turn are thought to result in the pathologic changes seen in Wernicke encephalopathy, and therefore the clinical picture.

It is possible to measure thiamine levels, as well as to assess thiamine status through the
measurement of red blood cell transketolase; however, these studies, though they may identify at-risk patients, are not diagnostic, may not be available emergently, and should not be relied on to make treatment decisions. This holds true for other adjunctive studies such as magnetic resonance imaging (MRI) and lumbar puncture. Although MRI may show signal abnormalities, usually in the medial thalami, mammillary bodies, and certain regions of the midbrain in acute cases, these findings will not be seen in all patients. Cerebrospinal fluid (CSF) studies are often normal.

▪SPECIAL CLINICAL POINT: Wernicke encephalopathy is a neurologic emergency, whose diagnosis, and therefore the decision to treat, should be based on the clinical picture alone.

Although the need for thiamine replacement in these patients is clear, exact treatment recommendations cannot be made on the basis of the literature. Treatment should be given in parental form in all cases due to the known decreased absorption from the GI tract in alcoholic patients, and alcoholic patients require higher doses than do those with other underlying etiologies for the same reasons that this population is more often deficient. Alcoholic patients may require several hundred milligrams of parental thiamine given up to twice daily for several days. Magnesium is a required cofactor in the metabolism of thiamine and is frequently a codeficiency in alcoholics. It should be replenished as well in deficient patients to ensure response to treatment. Although parenteral thiamine is thought to have a good safety profile, anaphylaxis is a possible reaction and treatment should only be given in a setting where cardiopulmonary resuscitation and epinephrine are available emergently.

Generally, the response to adequate treatment is fairly rapid, with the eye movement abnormalities improving first and resolving within days, followed by the cognitive deficits and ataxia within weeks to months. A potential consequence of inadequate and of course a complete lack of treatment is Wernicke- Korsakoff syndrome. Patients with this chronic amnestic condition will have severe anterograde amnesia with retrograde amnesia for the months to years prior to the onset of the illness. Confabulation is a common associated finding in patients with this severe amnestic syndrome.

Given the potential for a devastating neurologic outcome, Wernicke encephalopathy is a neurologic emergency and treatment should not be delayed.

▪ SPECIAL CLINICAL POINT: As treatment is generally well tolerated and the risk of missing the diagnosis is so great, the diagnosis of Wernicke encephalopathy should be considered in all high-risk patients, including those with hepatic encephalopathy, those with encephalopathy secondary to head trauma, and those with any one of the possible presenting clinical symptoms, particularly when the patient presents acutely intoxicated.

PELLAGRA ENCEPHALOPATHY

As with Wernicke encephalopathy, although a number of medical conditions may predispose patients to pellagra, chronic alcoholism has long been known to be the chief underlying condition; both for cases in nonendemic areas at the height of the epidemic in the mid-20th century and today, despite the enrichment of bread and flour by niacin. Although vitamin enrichment did greatly reduce the incidence of this disease, it still persists, especially in malnourished, indigent alcoholics, and therefore pellagra encephalopathy should still be considered a potential neurologic complication of alcoholism.

In addition to being associated strongly with chronic alcoholism and the result of a vitamin deficiency, pellagra shares other characteristics with Wernicke encephalopathy, including the fact that the diagnosis is coupled to a classic triad of clinical symptoms that does not actually occur in the majority of patients. In this case, the triad is dermatitis, diarrhea, and dementia, also known as “the three Ds” of pellagra.”
Dementia” is often a late characteristic with mild cognitive and personality changes occurring early in the disease course. These include fatigue, insomnia, anorexia, apprehension, anxiety, depression, mania, apathy, and mood lability. Headache, mild memory loss, and vertigo may also be early neurologic manifestations of this illness. With disease progression, both the psychiatric and neurologic symptoms and signs will often increase in severity. Patients may develop acute psychosis, paranoid delusions, and hallucinations, and most will develop confusion with disorientation and fluctuations in their level of consciousness. Neurologic examination may reveal spastic weakness, extrapyramidal signs, hyperreflexia, Babinski sign, myoclonus, gait abnormalities, gegenhalten tone, tremor, dysphagia, and bowel and bladder incontinence. Seizures may occur. The neuropsychiatric manifestations of pellagra may occur in isolation, often making it hard to distinguish pellagra encephalopathy from other encephalopathies seen in alcoholic patients, such as delirium tremens.

The “dermatitis” of pellagra is classically a symmetric, sharply demarcated, erythematous, photosensitive rash that occurs is sun-exposed areas in the spring and summer, including the face, dorsal surfaces of the hands and arms, and the front of the neck. Other dermatologic manifestations of this disease may occur, including desquamation of the skin, thickening, mild hyperpigmentation, and eczema-like lesions. The classic rash may not develop in patients who are not exposed to sunlight. The potential GI manifestations are also broad, and in addition to diarrhea include abdominal pain, nausea and vomiting, steatorrhea, and constipation. Stomatitis and glossitis are common clinical features.

Pellagra is the result of niacin deficiency or of a deficiency of tryptophan, the essential amino acid that is the precursor of niacin. Niacin, through the enzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), plays a crucial role in multiple oxidation-reduction reactions in the body, including glycolysis and fat synthesis. Multiple other vitamins are essential for the synthesis of niacin from tryptophan, including thiamine, riboflavin, and pyridoxine, and a codeficiency of protein or of one of these other vitamins is likely needed for the development of the disease. As chronic alcoholics often will be overall malnourished with deficiencies in more than one vitamin, this population is especially predisposed to the development of pellagra.

Niacin deficiency can be assessed in the laboratory, both by the direct blood levels of niacin and tryptophan and by the urinary metabolites of niacin-dependent pathways, but these tests are not routinely available or have low specificity or poor reliability.

▪ SPECIAL CLINICAL POINT: As with Wernicke encephalopathy, pellagra encephalopathy remains a clinical diagnosis that can be confirmed by clinical improvement with replacement therapy.

Pellagra differs from Wernicke encephalopathy in that large oral doses of niacin and a diet enriched in niacin and protein is sufficient for treatment. Niacinamide is frequently used due to its improved adverse effect profile compared to niacin, including less GI effects and less vasoactive properties (less flushing); however, both are U.S. Food and Drug Administration (FDA) approved for the treatment of pellagra. Adequate replacement of the other B vitamins is necessary due to both the frequently associated codeficiencies of these vitamins and to the requirements for them in niacin metabolism. Magnesium may be required, if found to be deficient.

Though relatively rare, pellagra did not disappear with the end of the epidemic in the mid-20th century. Pellagra encephalopathy often responds rapidly and completely to treatment, especially when treatment is started early in the course of the illness, and has a very high mortality rate when untreated. For all of these reasons, it must be considered in the differential diagnosis

of the encephalopathic alcoholic patient and the diagnosis should not be discarded on the basis of the absence of GI and dermatologic manifestations.

METABOLIC ENCEPHALOPATHIES

Hepatic Encephalopathy

Alcohol abuse is a very common cause of cirrhosis and therefore a common etiology of hepatic encephalopathy associated with cirrhosis with portal hypertension or portosystemic shunts. The potential clinical findings of hepatic encephalopathy are broad and may range from the subtle personality changes and cognitive deficits detectable only on formal neuropsychiatric testing found in minimal hepatic encephalopathy, to coma. The degree of severity of the encephalopathy is characterized by the level of consciousness, intellectual function, and the extent of personality and behavioral changes. With progression of the disease course, patients will usually have worsening of all of these individual components.

The impairment in level of consciousness will advance from mild fatigue or insomnia to lethargy to somnolence and then on to coma. Diminished attention span may progress to mild disorientation, amnesia, and mild confusion, and then further to marked cognitive impairment. Mild irritability and depression will evolve to clear personality changes with inappropriate behavior, followed by paranoid ideations and hallucinations. Finally, while a slight tremor or incoordination may be the only motor findings in the early stage of hepatic encephalopathy, examination will often evolve to show dysarthria, hyporeflexia, and ataxia, and in later stages hyperreflexia, weakness, nystagmus, Babinski sign, clonus, and rigidity are all possible. In late-stage hepatic encephalopathy, opisthotonus and posturing may be associated with the comatose state. Asterixis, a well-recognized feature of hepatic encephalopathy, is a prominent feature of the middle stages of the disease process. Although this is the usual course of disease progression, patients may have swift progression between stages, with rapid evolution to coma. Though not an absolute, patients often demonstrate other findings consistent with liver disease, such as ascites, jaundice, and spider angiomas.

Hepatic encephalopathy is a clinical diagnosis based on the history and physical examination; however, adjunctive studies may be helpful as supportive evidence. Serum ammonia levels do not clearly correspond to the level of severity of the encephalopathy, though a normal level is not consistent with this diagnosis. Electroencephalogram is useful to rule out underlying seizures, such as in nonconvulsive status epilepticus, a potential mimicker of hepatic (and other) encephalopathies. It will often be abnormal with potential findings including diffuse slowing and triphasic waves. Neuroimaging with computer tomography (CT) or MRI is useful to rule out a structural lesion, but will not confirm the diagnosis. MRI will often show high signal on the T1 images in the globus pallidus, likely due to manganese deposition, but this finding is seen in patients with chronic liver disease and is not in itself specific for the clinical diagnosis of hepatic encephalopathy.

▪ SPECIAL CLINICAL POINT: A triggering clinical event superimposed on chronic underlying liver disease is often responsible for the development of hepatic encephalopathy.

These events include dehydration, GI bleeding, infections, intake of excessive dietary protein, electrolyte abnormalities, surgery, transjugular intrahepatic portosystemic shunt placement, and additional hepatic insults.

▪ SPECIAL CLINICAL POINT: As a result, treatment of hepatic encephalopathy starts with a search for and correction of any triggering factors.

After this initial step, pharmacologic treatment consists of administration of the nonabsorbable disaccharide lactulose and the oral
antibiotic rifaximin, which may be administered in combination. Both act by inhibiting absorption and production of ammonia. Although there is controversy regarding the efficacy of lactulose and it is often not well tolerated by patients given its unavoidable GI effects, its use remains widespread. Rifaximin has improved tolerance over other antibiotics.

Although not as common in chronic alcoholics as hepatic encephalopathy secondary to cirrhosis with portal hypertension or portosystemic shunts, encephalopathy due to fulminant, acute liver failure may occur, most likely due to an acute hepatic insult superimposed on chronic liver disease. This type of hepatic encephalopathy is considered a neurologic emergency due to the frequent occurrence of cerebral edema, which results in increased intracranial pressure. Emergent neurosurgical consultation is indicated in the management of these cases for the placement of an intracranial pressure transducer, as head CT may be unremarkable. Aggressive treatment of this potential complication is necessary.

Acquired Hepatocerebral Degeneration

Acquired (or “non-Wilsonian” to distinguish it from the classic genetic form) hepatocerebral degeneration (AHCD) is a neurodegenerative disease comprising chronic neurologic and psychiatric impairment that occurs as a complication of chronic liver failure and that is unrelated to the underlying cause of liver disease. Its incidence is less than that of hepatic encephalopathy, but it does appear to be an associated process as its onset seems to be related to repeated episodes of hepatic encephalopathy, and especially of hepatic coma. However, this is not an absolute and overt episodes of hepatic encephalopathy do not always precede this illness. There may also be a correlation between the onset of this syndrome with the degree of portosystemic shunting and the ammonia level.

The majority of neurologic symptoms and signs may be classified as extrapyramidal (i.e., secondary to dysfunction of the basal ganglia) including choreoathetosis, tremor, myoclonus of the face and limbs, dystonia, rigidity, and dysarthria. Of the above, tremor, which is often coarse, postural, and kinetic; myoclonus; and mild gait unsteadiness are often the presenting symptoms. Frank ataxia, pyramidal tract signs, and dementia are later signs. A parkinsonian form of AHCD is characterized by the relatively rapid onset of symmetric akinesia, cogwheeling rigidity, and resting tremor in association with a gait disorder, postural instability, and less frequently, focal dystonia. Hepatic myelopathy, also known as portosystemic or postshunt myelopathy, presents with a progressive spastic paraparesis with associated hyperreflexia and minimal sensory involvement.

AHCD differs from Wilson disease by the later age of onset, absence of Kayser-Fleischer rings, and normal copper metabolism. However, a diagnosis of Wilson disease should always be excluded when a diagnosis of AHCD is entertained. Clinical features of cirrhosis including ascites, spider angiomata, palmar erythema, and hypoalbuminemia are often present.

As with hepatic encephalopathy, neuroimaging in patients with AHCD will often reveal hyperintense signal abnormalities on the T1-weighted imaging sequences in the lenticular nuclei, particularly the globus pallidus. These changes correspond to the underlying chronic liver disease and occur regardless of the existence of clinical neurologic impairment consistent with a diagnosis of AHCD.

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