Wernicke Encephalopathy 

Thiamine (vitamin B-1) deficiency can result in Wernicke encephalopathy, a serious neurologic disorder. Dr Carl Wernicke, a Polish neurologist, described it in 1881 as a triad of acute mental confusion, ataxia, and ophthalmoplegia. Korsakoff amnestic syndrome is a late neuropsychiatric manifestation of Wernicke encephalopathy with memory loss and confabulation; sometimes, the condition is referred to as Wernicke-Korsakoff syndrome or psychosis. (See Clinical.)

In the Western world, thiamine deficiency is characteristically associated with chronic alcoholism, because it affects thiamine uptake and utilization. However, Wernicke encephalopathy may develop in nonalcoholic conditions, such as prolonged starvation, hyperemesis gravidarum, bariatric surgery, and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), and can even develop in healthy infants given the wrong formulas. (See Etiology and History.)^[1]

Frequently unrecognized, Wernicke encephalopathy is more prevalent than commonly supposed. Moreover, epidemics of Wernicke encephalopathy can occur, as evidenced by a report of Israeli infants with infantile thiamine deficiency who were fed formula deficient in thiamine. (See Epidemiology.)^[2]

Complications

Complications of Wernicke encephalopathy may include the following:

• Korsakoff psychosis
• Alcohol withdrawal
• Acute precipitation of Wernicke encephalopathy
• Congestive heart failure
• Gastrointestinal beriberi^[3]
• Lactic acidosis^[4]

In addition, the administration of dextrose in the setting of thiamine deficiency can be harmful because glucose oxidation is a thiamine-intensive process that may drive the insufficient circulating vitamin B-1 intracellularly, thereby precipitating neurologic injury. (See Etiology.)^[2]

Thiamine plays a vital role in the metabolism of carbohydrates. Thiamine is a cofactor for several essential enzymes in the Krebs cycle and the pentose phosphate pathway, including alpha-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and transketolase.^[5] In the setting of thiamine deficiency, thiamine-dependent cellular systems begin to fail, resulting eventually in cell death. Because thiamine-dependent enzymes play an essential role in cerebral energy utilization, thiamine deficiency may propagate brain tissue injury by inhibiting metabolism in brain regions with higher metabolic demands and high thiamine turnover.^[5]

Pyruvate dehydrogenase and alpha-ketoglutarate are essential enzymes in the Krebs cycle, and lack of these enzymes alters cerebral energy utilization. If cells with high metabolic requirements have inadequate stores of thiamine to draw from, energy production drops, and neuronal damage ensues. Increased cell death then feeds the localized vasogenic response.^[6] Additionally, the reduced production of succinate, which plays a role in gamma-aminobutyric acid (GABA) metabolism and the electrical stimulation of neurons, leads to further central nervous system injury.

Increased lactic acid production ensues in the absence of pyruvate dehydrogenase function, as the reduced conversion of pyruvate to acetyl coenzyme A results in less efficient oxidative phosphorylation.^[7]

Thiamine pyrophosphate is also essential for nucleotide synthesis, production of nicotinamide adenine dinucleotide phosphate (NADPH), and maintenance of reduced glutathione within erythrocytes.^[7]

Causes

In the Western world, thiamine deficiency is characteristically associated with chronic alcoholism, because it affects thiamine uptake and utilization.^[1] In long-term alcoholics, malnutrition can reduce intestinal thiamine absorption by 70%, decreasing serum levels of thiamine to between 30% and 98% below the lower level established for normal subjects. Alcohol alone can also decrease thiamine absorption by 50% in one third of patients who are not malnourished.

Wernicke encephalopathy may develop in nonalcoholic conditions, such as prolonged starvation, hyperemesis gravidarum, and bariatric surgery.^[1] The numerous reports of severe thiamine deficiency after obesity surgery have led to the expression "bariatric beriberi.”^[8]

Other, less common etiologies are forced or self-imposed starvation, protein-energy malnutrition resulting from inadequate diet or malabsorption (from sprue), conditions associated with protracted vomiting (eg, hyperemesis gravidarum), chronic renal failure, carbohydrate loading in the presence of marginal thiamine stores (feeding after starvation), bariatric surgery and other gastric bypass surgeries, absence of thiamine from the diet (in the case of infants fed formula without the addition of thiamine), and congenital transketolase function abnormalities.

The most common inciting factor precipitating Wernicke encephalopathy in the setting of thiamine deficiency is infection. Concomitant illnesses, such as pneumonia or even meningitis, do not exclude a co-diagnosis of Wernicke encephalopathy.^[5]

Iatrogenic exacerbation of Wernicke encephalopathy can occur with prolonged glucose or carbohydrate loading in the setting of thiamine deficiency. A single, acute administration of glucose does not appear to cause this effect. Nutritionally deficient patients receiving glucose should also receive thiamine, but urgent administration of glucose should not be delayed pending thiamine administration.^[5]

Occurrence in the United States

Autopsy series identifying typical brainstem lesions of Wernicke encephalopathy have placed the incidence of the condition between 0.8% and 2.8% of the general population. However, the incidence can be as high as 12.5% in a population of alcoholics.^[9] Wernicke encephalopathy has been described in many other situations where nutrition has been compromised. These cases include patients with AIDS, individuals receiving hemodialysis, persons with hyperemesis gravidarum, and patients with malignancy with or without chemotherapy.

International occurrence

Although it may not be diagnosed as frequently in third and fourth world nations, the incidence is probably higher in areas where there is more malnutrition and less vitamin supplementation.

Sex- and age-related demographics

The male-to-female ratio for Wernicke encephalopathy is 1.7:1, likely owing to alcoholism being 3-4 times more frequent in men than in women.

Average age at onset is 50 years. However, Wernicke encephalopathy can occur in small numbers in unusual situations, such as in total parenteral nutrition ̶ dependent patients during a multivitamin shortage, in persons with hyperemesis gravidarum, or in infants who are fed thiamine-deficient infant formula.^[2]

Wernicke encephalopathy is a significantly disabling and potentially lethal condition that can be prevented or reversed if treated early. Administration of thiamine improves the patient’s condition to some degree in almost all cases; however, persistent neurologic dysfunction is common.^[5] Ophthalmoplegia usually resolves briskly; the initial presentation of global confusion often improves within hours or days.

Patients with Wernicke encephalopathy have a significant morbidity and mortality rate, especially if no early signs of neurologic improvement are present after repletion of thiamine. Among patients surviving Wernicke encephalopathy, a percentage will develop Korsakoff psychosis. A significant number of patients with Korsakoff psychosis do not recover and require long-term institutionalization. Only about 20% eventually recover completely during long-term follow-up care.

Typical residual findings from Wernicke encephalopathy include nystagmus, gait ataxia, and Korsakoff syndrome.^[5]

A worse outcome may be expected in late-stage Wernicke encephalopathy, which is associated with elevated spinal fluid protein levels and diffuse slowing of postsynaptic potentials on electroencephalography.^[8]

Studies suggest that up to 80% of patients with Wernicke encephalopathy may not be diagnosed, which makes estimates of mortality rates unreliable.^[10]