Vigabatrin (
Sabril) is a
gamma-aminobutyric acid-
transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of
drug-resistant or uncontrolled
epilepsy but is known to cause microscopic vacuolation (intramyelinic
edema) in the brains of treated rats, mice, and dogs. The effects of high oral doses (300 mg/kg/day) of
vigabatrin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28.
Emesis, loose 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 more 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 severity between 8 and 12 wk, and were reversible upon cessation of dosing. Inhibition of brain
GABA-T and elevation of brain
GABA were noted after 1 wk of treatment. During the course of treatment
vigabatrin ranged 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
vigabatrin-induced microvacuolation is unknown, the results of the study demonstrated that
GABA-T inhibition with subsequent
GABA elevation occurred within the first week of treatment and was followed by the onset of detectable microvacuolation several weeks later.