Intractable epilepsy is a devastating condition: infants and children with recurrent and prolonged seizures not controlled by anticonvulsants have a poor prognosis for cognitive function. In spite of advances in noninvasive localization of epileptic foci in children being evaluated for surgical resection, there remains a large number of intractable epileptics in whom [F-18]fluorodeoxyglucose (FDG) positron emission tomography (PET) and CT/MRI fail to identify the epileptic focus. For these patients, preoperative evaluation is invasive and costly, requiring chronic intracranial EEG monitoring for seizure onset localization. The major goal of the proposed studies is to provide improved nonivasive localization of epileptogenic brain tissue in children with medically uncontrolled epilepsy who are being evaluated for surgical treatment. We will evaluate the utility of PET imaging of the GABA/benzodiazepine receptor complex with [C-11]flumazenil (FMZ) in 3 groups of children with refractory seizures in whom CT/MRI and FDG PET fail to provide optimum identification of the epileptic focus. We will study patients with extratemporal lobe epilepsy with either no or subtle defects on FDG PET and normal CT/MRI (Group I), children with bilateral or multifocal abnormalities on FDG PET, normal CT/MRI, but EEG and seizure semiology suggesting unilateral seizure onset (Group II), and children who have previously undergone cortical resection for control of epilepsy but continue to have uncontrolled seizure (Group III). Patients will be referred from Children's Hospital of Michigan and Minnesota Epilepsy Group. Cortical regions with abnormal FDG and FMZ PET findings will be compared with EEG data from subdural electrodes to determine the accuracy of FMZ in delineating regions of seizure onset. Postsurgical seizure outcome using PET-guided placement of subdural electrodes will be compared to outcome data from a control group , obtained from Boston Children's Hospital and Miami Children's Hospital, where PET data are not used for identification of the epileptic brain region. In addition, in vitro [H-3] FMZ binding will be measured with quantitative autoradiography in resected brain tissue and compared to subdural EEG data and in vivo FMZ binding measurements. Our studies are designed to further reduce the necessity for intracranial EEG monitoring in children being evaluated for epilepsy surgery and to increase understanding of the basic mechanisms of epileptogenesis.
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