Excitotoxic Cytopathology, Progression, and Reversibility of Thiamine Deficiency-induced Diencephalic Lesions

The present study examined the cytopathological changes within diencephalon of a rat model of Wernicke's encephalopathy and determined whether administration of thiamine at various intervals after onset of neurological signs can arrest or reverse the cytopathological process. Electron microscopic examination of the brains from animals sacrificed at four progressively severe stages of pyrithiamine-induced thiamine deficiency (PTD) revealed neurocytopathological changes identical to those that have been described in glutamate-induced excitotoxic lesions. These degenerative changes occurred in gelatinosus (Ge) and anteroventral ventrolateral (AVVL) nuclei at an early symptomatic stage and in the ventroposterolateral (VPL), ventroposteromedial (VPM), and ventrolateral (VL) nuclei at slightly later stages of PTD. Light microscopic evaluation of separate groups of PTD rats administered thiamine at each of the same four neurologic stages and allowed to recover for 1 week demonstrated that thiamine treatment is more effective when administered at earlier stages. However, Ge, AVVL, and VPL nuclei sustain severe damage even when thiamine is administered prior to acute neurologic signs. Furthermore, pathologic changes in the mammillary and several midline intralaminar nuclei begin after thiamine administration and reinstitution of thiamine-replete diet to animals in more severe stages of thiamine deficiency. These and other recent findings suggest that excitotoxic and possibly apoptotic mechanisms may mediate neuronal degeneration in the PTD rat model of Wernicke's encephalopathy, and that multiple factors conducive to excitotoxicity may act in concert to produce this syndrome.