Abstracts

Gabapentin rapidly increases intracellular GABA concentrations in drug-free volunteers and patients with localization-related epilepsies. Daily gabapentin increases GABA, homocarnosine and pyrrolidinone concentrations. Homocarnosine is an inhibitory neuromodulator synthesized from GABA and histidine in a sub-class of GABAergic neurons. Low cortical homocarnosine and GABA levels are associated with poor seizure control with carbamazepine, lamotrigine, phenytoin or valproate. Patients with JME and good seizure control have high homocarnosine, but below normal GABA content. Pyrrolidinone, the internal lactam of GABA, is synthesized by the brain and comprises almost 50% of total GABA in human CSF. Pyrrolidinone and its derivatives (levetiracetam) have anticonvulsant properties. Our objective is to assess the relationship between seizure control and GABA, homocarnosine, and pyrrolidinone content in a group of patients starting gabapentin. Serial measurements of pyrrolidinone, homocarnosine and GABA were made of a 14-cm3 volume centered in the occipital cortex using proton spectroscopy (MRS) with a 2.1-Tesla spectrometer. Ten patients (seven women) with complex partial seizures were invited to participate in this project approved by the Yale University Human Investigations Committee. Serial MRS measurements were obtained before and after starting gabapentin. Information concerning medication use and time since last aura, seizure of any type, major seizure or convulsion were obtained with each set of MRS measurements. A major seizure or convulsion in the three months before a set of MRS measurements is defined as poor seizure control. Median time since the last major seizure or convulsion was considerably longer (7.5 months, 95%CI 4.8-42) during periods of better than poor control (1.4 months, 95%CI 0.4-2.5). Mean GABA content was the same during periods of poor seizure control (1.1 mM, 95%CI 0.8-1.3, n 11) and better control (1.1 mM, 95%CI 0.9-1.3, n 16). Homocarnosine content showed a trend (p [lt] 0.1) toward higher levels with better control (0.6 mM, 95%CI 0.5-0.7) compared with poor control (0.5 mM, 95%CI 0.4 to 0.6). Higher pyrrolidinone content was associated (p [lt] 0.05) with fewer major seizures (0.40 mM, 95%CI 0.36-0.43) than during poor control (0.34 mM, 95%CI 0.28-0.39). Regression analysis, using the logarithm of the time since the last major seizure or convulsion, showed significant positive associations with pyrrolidinone (p [lt] 0.02) and homocarnosine (p [lt] 0.01), but none with cortical GABA content. Low homocarnosine levels are associated with poor seizure control on gabapentin by allowing seizures to spread from the epileptogenic zone. Higher pyrrolidinone and homocarnosine levels are associated with better seizure control, which suggests pyrrolidinone decreases cortical excitability, thereby inhibiting the spread of seizures. (Supported by NIH-NINDS NS6208 and NS32518)