The effect of vigabatrin (gamma-vinyl GABA) on cerebral blood flow and metabolism

Objective: To investigate the effect of vigabatrin(VGB; gamma-vinyl gamma-a minobutyric acid [GABA]), a selective irreversible GABA-transaminase inhibi tor, on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flo w (CBF) measured with F-18-fluorodeoxyglucose (EDG) PET and O-15 water PET. Background: Antiepileptic drugs (AEDs) reduce CMRGlc to varying degrees. P henobarbital causes a mean decrease of 30 to 40%. Phenytoin, carbamazepine (CBZ), and valproate (VPA) cause milder reductions in CMRGlc. The combinati on of VPA with CBZ results in a greater decrease than either drug alone. Th e effect of novel AEDs on both CBF and CMRGlc has not been studied extensiv ely. Methods: Fourteen patients with refractory complex partial seizures on CBZ monotherapy for 4 weeks were included in the study. All patients had b aseline F-18-FDG and O-15 water PET studies followed by double-blind random ization to placebo (PLC) or VGB while on continuous CBZ treatment. PET scan s were repeated after an interval of 2 months on target dose of VGB (50 mg/ kg) or PLC. Quantitative PET data analysis was performed using a region of interest template. Significance was tested with the Wilcoxon rank sum test. Results: No statistically significant difference in age, duration of epile psy, or CZ levels was observed in the two patient groups. VGB reduced globa l CMRGlc by 8.1 +/- 6.5% and global CBF by 13.1 +/- 10.4%. The change in CM RGlc was different in patients taking VGB compared with those on PLC (p < 0 .04). VGB patients showed regional decreases in both CMRGlc and CBF, partic ularly in temporal lobes. CSF total GABA increased in the VGB patient group (1.48 +/- 1.06 versus 4.03 +/- 4.19 nm/mL). The increase differed from the PLC group (p < 0.03). We found a strong relation between decreased total C SF GABA and increased CMRGlc in the VGB patient group (R-2 = 0.82, p < 0.01 ). Conclusions: Vigabatrin (VGB) causes mild reductions in both cerebral bl ood flow (CBP) and cerebral metabolic rate for glucose (CMRGlc) in contrast to other drugs such as barbiturates, which are direct agonists at the gamm a-aminobutyric acid-benzodiazepine receptor complex. Conventional AEDs depr ess CBF and CMRGlc to a greater degree than does VGB. The relatively mild r eduction could be due to pre- as well as postsynaptic effects or a use-depe ndent mechanism.