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

From the Clinical Epilepsy Section (Drs. Spanaki and Siegel, S. Fazilat, and Drs. Dean, Liow, Gaillard, and Theodore), Epilepsy Research Branch, and the Biometry and Field Studies Branch (Dr. Kopylev), NIH/NINDS, Bethesda, MD; Department of Clinical Neuroscience (Dr. Ben-Menachem), University of Goteborg, Sweden; and Children’s National Medical Center (Dr. Gaillard), Washington, DC.

Address correspondence and reprint requests to Dr. William H. Theodore, NIH/NINDS/ERB, Bldg. 10, Room 5N-250, 10 Center Dr., MSC 1408, Bethesda, MD 20892-1408.

OBJECTIVE: To investigate the effect of vigabatrin (VGB; -vinyl -aminobutyric acid [GABA]), a selective irreversible GABA-transaminase inhibitor, on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF) measured with ¹⁸F-fluorodeoxyglucose (FDG) PET and ¹⁵O water PET.

BACKGROUND: Antiepileptic drugs (AEDs) reduce CMRGlc to varying degrees. Phenobarbital causes a mean decrease of 30 to 40%. Phenytoin, carbamazepine (CBZ), and valproate (VPA) cause milder reductions in CMRGlc. The combination of VPA with CBZ results in a greater decrease than either drug alone. The effect of novel AEDs on both CBF and CMRGlc has not been studied extensively.

METHODS: Fourteen patients with refractory complex partial seizures on CBZ monotherapy for 4 weeks were included in the study. All patients had baseline ¹⁸F-FDG and ¹⁵O water PET studies followed by double-blind randomization to placebo (PLC) or VGB while on continuous CBZ treatment. PET scans 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 epilepsy, or CBZ levels was observed in the two patient groups. VGB reduced global CMRGlc by 8.1 ± 6.5% and global CBF by 13.1 ± 10.4%. The change in CMRGlc was different in patients taking VGB compared with those on PLC (p < 0.04). VGB patients showed regional decreases in both CMRGlc and CBF, particularly 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 CSF GABA and increased CMRGlc in the VGB patient group (R² = 0.82, p < 0.01).

CONCLUSIONS: Vigabatrin (VGB) causes mild reductions in both cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMRGlc) in contrast to other drugs such as barbiturates, which are direct agonists at the -aminobutyric acid–benzodiazepine receptor complex. Conventional AEDs depress CBF and CMRGlc to a greater degree than does VGB. The relatively mild reduction could be due to pre- as well as postsynaptic effects or a use-dependent mechanism.

Key words: Epilepsy—PET—Vigabatrin—GABA—Cerebral metabolism—Cerebral blood flow.

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