Abstracts

RATIONALE: Topiramate is the most potent on a molar basis of the newer antiepileptic drugs that increase GABA in humans. This study is designed to assess the effects of the first dose of topiramate on brain GABA metabolism of patients with complex partial seizures. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cm3 volume centered in the occipital cortex using proton spectroscopy with a 2.1 Tesla magnetic resonance spectrometer and an 8-cm surface coil. Four patients (two women) were studied serially after the first, oral dose (100 mg) of topiramate. RESULTS: The first dose of topiramate increased brain GABA within 30 minutes. By two hours GABA was increased by 0.8 mM (95% CI 0.7 - 0.9) to 1.6 mM (95% CI 1.5 - 1.7). Brain GABA remained elevated for at least 24 hours (1.5 mM, 95% CI 1.4 -1.6). Homocarnosine was unchanged at two hours. By 24 hours homocarnosine increased by 0.07 mM (95% CI 0.03 - 0.11) to 0.40 mM (95% CI 0.33 - 0.46). Homocarnosine synthesis is limited by the low concentration of histidine in human brain. Pyrrolidinone was unchanged at two hours, but increased by 0.04 mM (95% CI 0.01 - 0.07) to 0.34 mM (95% CI 0.32 - 0.35) by 24 hours. CONCLUSIONS: Low dose topiramate promptly increases brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the effects of increased homocarnosine and pyrrolidinone within 24 hours. The beneficial effects of low dose topiramate, under 100 mg daily, may be attributed to the increase in GABA, homocarnsoine, or pyrrolidinone. Once-a-day dosing should be sufficient. Support: We thank our patients for donating their time. Salary support was provided by Yale University, Department of Veterans Affairs, and NIH-NINDS grants NS32518 and NS06208. Ortho-McNeill provided topiramate.