Epilcpsia, zyxwvutsrqponmlk 40(7):958-964, zyxwvutsrqponm 1999 Lippincott Williamb zyxwvutsrqponm & Wilkina, lnc., Philadelphia zyxwvutsrq 0 International League Against Epilepsy Clinical Research Acute Effects of Vigabatrin on Brain GABA and Homocarnosine in Patients with Complex Partial Seizures Ognen A. C. Petroff, *Fahmeed Hyder, Theresa Collins, Richard H. Mattson, and "Douglas L. Rothman zyxwv Departments of Neurology and *Diagnostic Radiology, Yule University, New Haven, Connecticut, zyx U.S.A. Summary: Purpose: The acute, subacute, and chronic effects of vigabatrin (VGB) were studied in patients with refractory complex partial seizures. VGB increases human brain y-ami- nobutyric acid (GABA) and the related metabolites, homocar- nosine and 2-pyrrolidinone. Methods: In vivo measurements of GABA and homocarno- sine were made of a 14-cc volume in the occipital cortex by using ' H spectroscopy with a 2. I-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (three women) were studied serially during the initiation and mainte- nance of VGB as adjunct therapy. Results: The first, 3 g dose of VGB increased brain GABA by 2.0 pmol/g within 81 min of oral administration. After 2 h, median edited GABA remained essentially the same for 2 days. The response to the second, 3-g dose of VGB given at 48 h was considerably less than that to the first dose, with a median increase of 0.5 kmol/g within 72 min. After 2-3 months, re- challenging patients taking 1.5-g VGB twice daily with 6 g increased GABA by 0.4 pmollg within 87 min. Homocarnosine increased more gradually than GABA to above-normal levels after a week of VGB therapy. Conclusions: VGB promptly elevates brain GABA and pre- sumably offers partial protection against further seizures within hours of the first oral dose. Once-a-day dosing is sufficient to increase GABA. Patients may be expected to experience the effects of increased homocarnosine within 1 week. Key Words: Vigabatrin-y-Aminobutyric acid-Homocarno- sine-Human epilepsy-'H nuclear magnetic resonance spec- troscopy. Vigabatrin (VGB) is a selective y-aminobutyric acid (GABA)-transaminase (GABA-T) inhibitor, synthesized as a rational approach to antiepileptic drug (AED) therapy (1,2). The drug binds to neuronal and glial GABA-T with high affinity and irreversibly inhibits the enzyme, markedly increasing GABA concentrations (3- 6). Neuronal GABA-T is more sensitive to VGB than astrocytic transaminase. A high-affinity, active uptake system demonstrated in cultured rodent neurons, but not astrocytes, accounts for part of the difference (3). Both synaptic and total GABA are increased (5). The time course of seizure protection after acute administration of VGB is closely related to the increase in synaptosomal GABA concentration (2-5). The nonvesicular release of GABA, another protective mechanism, is postulated to suppress the evolution and spread of seizure activity, Accepted December 7, 1998. Address correspondence and reprint requests to Dr. 0. A. C. Petroff at Department of Neilrology, Yale University, 333 Cedar Street, New Haven, CT 06520-8018, U.S.A. being augmented by the VGB-induced increase in cyto- solic GABA (7-9). Vigabatrin was shown to be a safe and effective AED in several human studies (10-15). The drug is well ab- sorbed irrespective of food intake (I 6). Vigabatrin has a serum half-life of 5-7 h and virtually no binding to se- rum proteins. It is 70% excreted by the kidney with no active metabolites (17). Human cerebrospinal fluid (CSF) VGB concentrations increase linearly with daily dose to 6 g (18). In patients with epilepsy, Ben Men- achem et al. (19) found a single oral 50-mg/kg dose of VGB given to patients with epilepsy achieved peak se- rum levels in <1 h (0.5 mM) and CSF level (12 pM) in zy 4 h. Total GABA, homocarnosine, and free GABA lev- els increased within 6 h and remained elevated in the CSF for >1 week. Petroff et al. (20) reported that brain GABA, measured by nuclear magnetic resonance spec- troscopy, increased rapidly within 2 h and remained the same for 24 h after a single, 50-mgkg oral dose of VGB. Mean GABA levels declined over 1 week. The rate of synthesis by glutamic acid decarboxylase 958