Pyrithiamine-induced acute thiamine-deficient encephalopathy in the mouse

Abstract

Acute thiamine-deficient encephalopathy was produced in mice by the administration of pyrithiamine in conjuction with a thiamine-deficient diet. Clinically, the encephalopathy occurred abruptly on Day 10, frequently with tonic seizures during which many mice died. The survivors developed peculiar neurological signs manifested by ataxia, rigid tail movement, impaired righting reflex, and the Woolley-White sign. With additional malaise and anorexia, the animals died within 4 days. In the brain, there were symmetrically distributed lesions in the thalamus, tegmentum of the fourth ventricle, mammillary body, and periaqueductal gray matter, in order of incidence of involvement. Histologically, the lesion consisted of petechial hemorrhage and/or edematous necrosis of the brain tissue. Electron microscopically, mild petechial lesions were characterized by intact endothelial cells, intact smooth muscle cells and pericytes, a widened Virchow-Robin space associated with erythrocyte infiltration, and an occasional fibrin or platelet clot in the lumen. Among the brain cells, the astrocytes were most severely damaged, showing edematous swelling at the early stage of the illness and necrosis by cytoplasmic fragmentation in the advanced lesions. Moderate edema was also present in the oligodendroglia. Myelin sheaths were often swollen due to edema which occurred most severely at the inner loop. In spite of marked cytoplasmic edema, neuronal cells showed less degenerative alterations than did the glial cells. These ultrastructural changes are similar to the lesions in diet-induced thiamine deficiency in rats, which have been reported by others. It is concluded that pyrithiamine-induced acute thiamine-deficient encephalopathy is an easily reproducible animal model for the human Wernicke-Korsakoff syndrome.