Acute Wernicke-type encephalopathy
This 27-year-old male was hospitalized for abdominal pain and dizziness. He suffered mental status deterioration 4 days after admission. He became unresponsive and MRI showed new areas of T2 FLAIR hyperintensity in the posterior pons, medial thalamus, and bilateral mamillary bodies, while EEG showed diffuse generalized slowing, consistent with brain injury. Thiamine therapy was initiated in response to the typical MRI findings. However, his neurological condition failed to improve. No information was available regarding his history of alcohol consumption. Postmortem examination showed periaqueductal brainstem, medial thalamus, hypothalamus, and mamillary body lesions with a macrophage-rich infiltrate, vascular endothelial proliferation and relative sparing of neuronal structures. The distribution of lesions and their histologic quality is very characteristic of Wernicke encephalopathy.
Wernicke encephalopathy is caused by thiamine (vitamin B1) deficiency. Thiamine is water-soluble and is stored in the heart, kidneys, liver, brain, and muscles. These stores can be depleted within 2-3 weeks in malnourished patients. Neuropsychiatric symptoms can develop if levels of thiamine are reduced below 20% of normal. Thiamine pyrophosphate is a cofactor of enzymes including pyruvate dehydrogenase complex, 2-oxo-glutarate dehydrogenase, and transketolase. These enzymes are involved in glucose, amino acid, nucleic acid, neurotransmitter and myelin metabolism and energy production. Thiamine deficit in the brain leads to cytotoxic edema and astrocyte volume increase within 4 days. After 7 to 10 days, decreased transketolase activity causes endothelial cell dysfunction. Consequently, vasogenic edema and breakdown of blood-brain barrier develop. After 14 days of thiamine deficiency, irreversible structural damage and neuronal necrosis can be seen. Reduction of blood transketolase activity is a sensitive laboratory finding.
Wernicke encephalopathy most commonly occurs in severely malnourished middle-aged alcoholics. The prevalence of Wernicke encephalopathy in patients with alcoholism is approximately 12.5%. Wernicke encephalopathy can also occur in malnourished demented patient and can be associated with gastrointestinal disorders (hyperemesis, gastrectomy, gastric carcinoma), forced starvation, anorexia nervosa, acute pancreatitis, thyrotoxicosis, Crohn disease, other malnutrition settings, and rarely total parenteral nutrition with inadequate vitamin supplementation.
The classic presentation is a triad of ophthalmoplegia (oculomotor paralysis, paralysis of conjugate gaze), ataxia, and mental status changes including withdrawal, apathy, delirium, and confusion. However, less than 20% of the patients present with all three "classical signs". Mental status changes are the most prevalent symptoms. Peripheral neuropathy (a form of beriberi disease) is seen in 80% of patients. Overt heart disease is uncommon, but subtle cardiac abnormalities (tachycardia, dyspnea, hypotension, abnormal electrocardiogram) are common. Patients may also suffer postural hypotension, syncope, and sudden death, probably due to involvement of brainstem cardiorespiratory centers. A high index of suspicion is essential for diagnosis, especially in debilitated patients with unexplained mental confusion. Approximately 60-80% of the cases are not diagnosed during life[8, 9]. Parenteral administration of thiamine causes a rapid reversal of ophthalmoplegia within hours. Recovery from confusion is slower.
The mamillary bodies are involved in all cases and represent the signature pathology. Lesions may also involve areas including the hypothalamus, medial thalamic nuclei, floor of the third ventricle, periaqueductal region, colliculi, nuclei in the pontomedullary tegmentum (particularly the dorsal motor nuclei of the vagus), inferior olives, and cerebral cortex. Midline cerebellar (superior vermis) degeneration is seen in 30 - 50% of patients. The acute lesions can be detected by MRI with high specificity, but with a sensitivity of approximately 50%. EEG, evoked potential, CSF analysis and CT are not useful.
Grossly, the involved regions are slightly shrunken and usually show brown discoloration due to hemosiderin deposition, and there may be petechial hemorrhages. The periventricular and periaqueductal lesions often spare a slender strip of subependymal tissue. In some patients, particularly those with previous treatment, the mamillary bodies may be only mildly discolored and the brain may appear macroscopically normal.
Microscopically, acute lesions are edematous with relative preservation of neurons, variable necrosis and vacuolization, and loss of myelinated fibers. Capillaries may appear strikingly prominent due to endothelial hyperplasia and cuffing by macrophages, but this is not a constant feature. There may be petechial hemorrhages and hemosiderin-laden macrophages. Astrocytes show reactive changes. Chronic lesions usually appear gliotic and slightly spongiotic, with mild loss of neurons, depletion of myelinated fibers, deposition of lipofuscin and scattered hemosiderin-laden macrophages.
Wernicke encephalopathy is sometimes associated with Korsakoff psychosis, which is characterized by retrograde and anterograde amnesia (i.e. impaired recall of events before the onset of illness and of new information), and confabulation. The combination of Korsakoff psychosis with Wernicke encephalopathy is known as Wernicke-Korsakoff syndrome. Intravenous glucose administration may trigger Wernicke-Korsakoff syndrome. Wernicke-Korsakoff syndrome does not respond to thiamine treatment and is usually irreversible. The histologic changes in Wernicke encephalopathy and Wernicke-Korsakoff syndrome are essentially identical. Studies suggest that Korsakoff psychosis occurs in those patients who have lesions involving the medial dorsal (and possibly other medial thalamic) nuclei.
Differential diagnosis of Wernicke encephalopathy includes Leigh syndrome, also known as subacute necrotizing encephalopathy. Leigh syndrome is one of the most frequent phenotypes of mitochondrial disorders. The histopathology and topography of the lesions in Leigh syndrome, especially in the brain stem, is very similar to that of Wernicke-Korsakoff syndrome, except that there is no hemorrhage and the mamillary bodies are not usually affected in Leigh syndrome. Necrosis and/or atrophy of basal ganglia is usually seen. There is also loss of Purkinje cells with torpedo-like expansions of their axons in some cases. Peripheral neuropathy is also seen. Most cases of Leigh syndrome present in infancy or early childhood with hypotonia, developmental regression, ophthalmoplegia, nystagmus, ataxia, optic atrophy, respiratory abnormalities, and failure to thrive. Less frequently, Leigh syndrome presents in late childhood, adolescence, or later. Mean age of death is 5 years. Most cases of Leigh syndrome are caused by autosomal recessive nDNA mutations. A few cases are caused by mtDNA mutations, especially involving the ATP synthase gene. Leigh syndrome is also caused by defects of the pyruvate dehydrogenase complex, which uses thiamine pyrophosphate as a cofactor.
Contributed by Jason Chiang, MD, PhD and Julia Kofler, MD