Imaging tryptophan metabolism in children with epilepsy

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DESCRIPTION (provided by applicant): Approximately 0.5% to 1.0% of the population suffers from epilepsy. Fifteen to 20% of these individuals have seizures which cannot be controlled with anticonvulsants. Epilepsy is particularly devastating in children, in whom recurrent prolonged seizures may result in impaired cognitive development. The major goal of this proposal is to provide improved preoperative localization of epileptogenic brain tissue in children with medically uncontrolled neocortical epilepsy who are being treated with surgical resection of the epileptic focus. The central hypothesis of this proposal is that abnormalities in brain tryptophan metabolism via the serotonin and/or kynurenine pathways contribute to the pathophysiology and localization of neocortical epilepsy. Brain tryptophan metabolism will be measured in vivo in drug-resistant epilepsy patients using the tracer alpha [C-11 ]methyl-L-tryptophan (AMT) with positron emission tomography (PET). Our preliminary data show increased AMT accumulation in epileptogenic cortex in approximately one-half of patients assessed for epilepsy surgery. The focus of increased AMT uptake is typically much smaller than the large areas of hypometabolism seen on glucose metabolism PET scanning. In the present grant application, we propose to confirm and extend these findings by comparing AMT PET results to quantitative electrophysiological measures obtained during presurgical evaluation. In order to better understand the pathophysiology underlying altered AMT uptake by epileptic brain tissue, we will perform biochemical measurements in the tissue which is surgically resected for control of intractable epilepsy. Three specific aims will be addressed: 1. To determine the extent to which AMT PET and glucose metabolism PET regions of abnormality localize neocortical epileptogenic regions defined by subdural electrode recordings in both lesional and nonlesional neocortical epilepsy. 2. To determine whether resection of cortex with increased AMT uptake is related to outcome of epilepsy surgery. 3. To determine the underlying biochemical mechanism for the observed focal increases in cortical AMT uptake in patients with epilepsy. Our research will contribute to a better understanding of the pathophysiology and improve localization of focal epilepsy.