Pathophysiology of cerebellar dysfunction in the Wernicke-Korsakoff syndrome

Abstract

Cerebellar ataxia is a common presenting sign in the Wernicke-Korsakoff syndrome (WKS). Recovery from ataxia following thiamine treatment is rarely complete, suggesting the existence of both a reversible ('biochemical') lesion as well as irreversible, neuropathological damage. Cerebellar pathology in WKS includes severe loss of Purkinje cells in superior cerebellar vermis as well as neuronal loss from the granular layer. In addition, damage to inferior olivary nucleus could result in loss of climbing fibre input to cerebellum in this condition. Experiments using an animal model of WKS, the pyrithiamine-treated rat, reveal selective reversible decreases of α-ketoglutarate dehydrogenase (αKGDH) in cerebellum. Decreased enzyme activities are associated with decreased cerebellar content of GABA and aspartate. Thiamine reversal of neurological symptoms results in normalization of cerebellar enzyme activities and GABA content suggesting that reduced activities of αKGDH constitute 'the biochemical lesion' in these animals. Possible mechanisms implicated in neuronal cell death in cerebellum include impaired cellular energy metabolism, focal lactic acidosis and excitotoxic damage resulting from excess glutamate release mediated by N- methyl-D-aspartate (NMDA) receptors. Similar mechanisms could be involved in the reversible and irreversible neurological symptoms of WKS in humans.