Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

Abstract

Vigabatrin (Sabril®) is a γ-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 fomix, 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.

The Potential for Vigabatrin‐Induced Intramyelinic Edema in Humans

“…This time frame is consistent with the earliest histologic IME lesions detected in serial pathologic studies (17). All treated dogs showed EP changes by week 14 of treatment, with the magnitude of latency increase from baseline ranging from 14.2 to 45.9%.…”

“…Animal studies raised an additional concern. Prolonged administration of high doses of VGB produced intramyelinic edema (TME) in the brains of mice, rats, and dogs (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Understandably, careful surveillance for VGB-induced TME in humans has been a primary objective during the drugdevelopment process.…”

Visual field constriction

“…30,31 In contrast, TGB did not influence GABA-T activity or GABA concentration and did not appear to accumulate in the retina. [34][35][36] However, this neuropathologic profile is not extrapolated to humans. The recognized pharmacologic effects of TGB are directly related to drug concentration, 19 whereas those of VGB extend beyond the pharmacokinetic profile.…”

Vigabatrin in Childhood Epilepsy: A 5-Year Follow-Up Study

“…They can be shown by microscopy (9,24) or by quantitative MRI T-2 relaxometry (12); however, comparative human studies have all been negative (13, 21). In agreement with these pathological Endings, reversible prolongation of central conduction time in somato-sensory evoked potentials was shown in dogs (1).…”