Wernicke-Korsakoff Syndrome: Diagnosis and Pathogenesis
Abstract and Commentary
By Louise M. Klebanoff, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Klebanoff reports no financial relationships relevant to this field of study.
Synopsis: Wernicke-Korsakoff syndrome, consisting of the triad of mental status changes, ocular motility abnormalities, and ataxia, in the setting of thiamine deficiency, remains a clinical diagnosis.
Source: Wijnia JW, Oudman E. Biomarkers of delirium as a clue to diagnosis and
pathogenesis of Wernicke-Korsakoff syndrome. Eur J Neurol 2013;20:1531-1538
Wernicke-korsakoff syndrome is an example of delirium-related cognitive impairment, with an initial state of delirium subsequently progressing to chronic cognitive impairment. This neuro-psychiatric syndrome, caused by thiamine deficiency, is characterized by acute mental status changes, ocular motility abnormalities, and ataxia. In autopsy-confirmed cases, mental status changes are reported in 82% of cases. However, the complete triad of mental status changes, ocular motility abnormalities, and ataxia is present in only 16%. The diagnosis can be missed due to the lack of the clinical triad as well as the difficulty in distinguishing this acute encephalopathy from other causes of encephalopathy, including the delirium associated with alcohol withdrawal. In developed countries, the vast majority of cases of thiamine deficiency are associated with alcohol abuse.
Wernicke's encephalopathy is due to brain lesions caused by high metabolic demands on already depleted vitamin B1 (thiamine) stores. In neuronal and glial cells, thiamine is converted to thiamine pyrophosphate, which is necessary for several biochemical pathways in the brain. With thiamine deficiency, the earliest biochemical change is a decrease in a-ketoglutarate-dehydrogenase activity (a-KGDH) in astrocytes. Activated microglia is a pathological feature of thiamine deficiency and, based on rat models, has been suggested as a contributing cause of the neurological impairment seen in this condition. Thiamine deficiency can lead directly to cellular energy deficit, focal acidosis, regional increase in glutamate, and ultimately cell damage and death. In the early phase of the condition, these deficits are potentially reversible if the thiamine deficit is corrected. For this reason, early identification of Wernicke's encephalopathy can allow for correction of thiamine deficiency and prevention of cell death and ultimately cognitive impairment.
In an effort to identify the main biomarkers of delirium in Wernicke-Korsakoff syndrome and related conditions, the authors reviewed articles describing possible underlying causal mechanisms in delirium and alcohol withdrawal delirium published between January 1997 and December 2012. From an initial pool of 1400 articles, they identified five studies related to delirium with alcohol withdrawal and another 22 studies related to delirium of other causes.
Several potential biomarkers showed strong relationships with delirium. Lower cerebrospinal fluid levels of neuronal-specific enolase, an enolase-isoenzyme normally present in neuronal and neuroendocrine tissue, were associated with the occurrence of delirium. Higher median levels of S100B were found in blood samples of patients following an episode of delirium when compared with levels taken during delirium or in patients without delirium. Catecholamine metabolites were found to be elevated in certain patients with delirium. Mean homovanillic acid levels were higher in Alzheimer's patients with delirium when compared with age- and gender-matched non-delirious controls. Plasma levels of MHPG were found to be higher preoperatively in patients who subsequently developed postoperative delirium when compared to those who did not. Patients with delirium demonstrated higher levels of cerebrospinal fluid lactate when compared to patients with dementia. Tissue counts of CD68-positive cells and of human leukocyte antigen DR-positive cells, which in postmortem studies are markers of microglial activation, were found to be significantly elevated in delirious patients when compared with controls.
When focusing exclusively on delirium in Wernicke-Korsakoff syndrome, the potential biomarkers were further reduced. Only brain tissue cells counts of CD68-positive cells in an animal model of Wernicke-Korsakoff syndrome, high cerebrospinal fluid lactate levels in six children with Wernicke's encephalopathy, and low MHPG concentrations in patients with long-standing Korsakoff syndrome could be identified.
It remains undetermined if these biomarkers provide an objective measure of disease pathophysiology in delirious patients. They may reflect an underlying general medical condition, a non-specific state of increased arousal, or other traits that may increase the risk of developing delirium but are not necessarily causative.
Delirium is a common neurological syndrome; however, the pathophysiology of underlying biomechanisms of delirium remains poorly understood. Wernicke-Korsakoff syndrome represents a unique form of delirium, progressing to chronic cognitive impairment if the underlying thiamine deficiency is not corrected. Microglial proliferation caused by thiamine deficiency is a possible underlying pathological mechanism.
Due to the difficulty in diagnosing the condition, identification of biomarkers could enhance early diagnosis and increase the potential for therapeutic intervention. Although the biomarkers identified may have an association with delirium, evidence for causality is lacking. Additional investigation, including prospective and longitudinal studies of patients with thiamine deficiency and Wernicke-Korsakoff syndrome, is needed.