SEQUENTIAL NEUROPATHOLOGY OF DOGS TREATED WITH VIGABATRIN, A GABA-TRANSAMINASE INHIBITOR

Vigabatrin (Sabril(R)) is a gamma-aminobutyric acid-transaminase (GABA -T) inhibitor that is effective in the treatment of certain types of d rug-resistant or uncontrolled epilepsy but is known to cause microscop ic vacuolation (intramyelinic edema) in the brains of treated rats, mi ce, and dogs. The effects of high oral doses (300 mg/kg/day) of vigaba trin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28. Emesis, loos e stools, and anorexia and 3 drug-related deaths were observed during the first 4 wk of treatment but were virtually nonexistent thereafter because of adaptation to the drug aided by food supplementation. In mo re sensitive areas of the brain (columns of the fornix, thalamus, and hypothalamus), microscopic quantitative differences between background vacuolation in controls and drug-related vacuolation in treated dogs could be delineated after 4 wk, generally reached highest levels of se verity between 8 and 12 wk, and were reversible upon cessation of dosi ng. Inhibition of brain GABA-T and elevation of brain GABA were noted after 1 wk of treatment. During the course of treatment vigabatrin ran ged between 4-17 nmol/ml (plasma) and 42-1,570 nmol/ml [cerebrospinal fluid (CSF)] while CSF GABA concentrations were 4-32 nmol/ml (treated dogs) and 0. 1-0.6 nmol/ml (control dogs). Although the cause of vigab atrin-induced microvacuolation is unknown, the results of the study de monstrated that GABA-T inhibition with subsequent GABA elevation occur red within the first week of treatment and was followed by the onset o f detectable microvacuolation several weeks later.