Abstracts

Pediatric epilepsy due to areas of focal cortical dysplasia is often intractable to anticonvulsant treatment. Many of the medications used unsuccessfully in treating this disorder, such as barbiturates, benzodiazepines, ACTH, and topiramate, are thought to exert at least a portion of their action through enhancement of inhibitory neurotransmission via GABA-A receptors. In the present study, GABA-A receptor properties in resected epileptogenic brain tissue from four children with intractable epilepsy and focal cortical dysplasia were measured to determine if this clinical resistance to pharmacologic treatment correlates with alterations in receptor responsiveness to these agents., Operative resection of the epileptogenic zones was performed, with pathologic diagnoses of focal cortical dysplasia type 2A. Portions of the epileptogenic cortex were flash frozen at the time of surgery and maintained at -80[deg] C until use. The tissue was homogenized and subjected to a series of centrifugation steps to isolate the membrane fraction. This fraction was resuspended and injected into Xenopus oocytes, resulting in incorporation of brain membrane vesicles into the oocyte cellular membrane. Two-electrode voltage clamp analysis was performed 18-72 hours after injection, at which time GABA-A receptor currents were easily measured., Functional characterization of GABA-A receptor properties was performed, including agonist potency, current-voltage relationship, current rundown, and responses to benzodiazepines, barbiturates, neurosteroids, topiramate, and zinc. Results from epileptic cortex were compared with those from non-epileptic autopsy and surgical control samples. Experimentally determined receptor properties were correlated with patient age and clinical characteristics., These studies of GABA-A receptor function in children with intractable epilepsy due to focal cortical dysplasia provide valuable insight into the mechanisms of anticonvulsant resistance in this disorder., (Supported by NIH NINDS K08 NS52454.)