Physiologic And Pharmacologic Studies In Epilepsy

Neurological Disorders And Stroke

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Abstract

Epilepsy is one of the most common neurological disorders, and patients whose seizures are not controlled suffer from many adverse effects. The goal of this study is to investigate the effects of epilepsy on brain structure and function, and to test innovative approaches to treatment when seizures cannot be controlled by currently available approaches. Methods: Patients undergo video-EEG monitoring to determine seizure type and focus localization. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are used to study cerebral metabolism, blood flow, and structure. Antiepileptic drug blood levels are obtained. Recent neuroimaging study findings: Activation of central serotonin (5-HT)1A receptors, found in high density in brainstem raphe, hippocampus and temporal neocortex, exerts an anticonvulsant effect in various experimental seizure models. To test the hypothesis that 5-HT1A receptor binding is reduced in human epileptic foci, we performed PET imaging using the radioligand [18F]FCWAY, a selective 5-HT1A receptor antagonist, in normal controls and patients with temporal lobe epilepsy. We performed MRI and PET using [15O]water and [18F]FCWAY in 10 controls and 12 patients with temporal lobe epilepsy confirmed on ictal Video-EEG; patients also underwent [18F]FDG PET. Using quantitative PET image analysis, we obtained regional values for [18F]FCWAY volume of distribution (V), cerebral blood flow (CBF) and glucose cerebral metabolic rate (CMRglc). We also measured hippocampal volume (HV) with MRI. We compared [18F]FCWAY V PET and MR measures within patients and controls using paired T tests; grouped comparisons were made with two sample T tests. We found lower [18F]FCWAY V ipsilateral than contralateral to the epileptic focus in inferior medial (IMT) and lateral (ILT) temporal regions of most patients(ILT 47.4?6.1 vs. 61.8?6.1, P<0.01; IMT 52?4.6 vs. 67.0?6.0, P<0.01). [18F]FCWAY V was 29% lower in raphe and 34% lower in ipsilateral thalamic region of patients than controls. In ILT, mean [18F]FCWAY V asymmetry index (AI) was significantly greater than mean CBF and mean CMRglc AI. Mean [18F]FCWAY V AI in IMT was greater than mean HV AI, but the difference was not significant. These findings support our hypothesis of reduced 5-HT1A receptor binding in temporal lobe epileptic foci. Refractory partial epilepsy patients often exhibit regional hypometabolism. It is unknown whether the metabolic abnormalities are present at seizure onset or develop over time. We studied forty children within one year of their third unprovoked partial seizure with EEG, MRI, and 18FDG-PET; mean age at seizure onset, 5.8 years (range 0.9-11.9); mean epilepsy duration, 1.1 years (range 0.3-2.3); mean number of seizures 30 (range 3-200). We excluded children with abnormal structural MRI, except four with mesial temporal sclerosis and two with subtle hippocampal dysgenesis. 18FDG-PET was analyzed with a region of interest template. An absolute asymmetry index, |AI|, greater than 0.15 was considered abnormal. We found that 32 children had a presumptive temporal lobe focus; 5 fronto-temporal, and 3 frontal. Mean AI for all regions was not different than from 10 normal young adults, even when children with unlikely temporal focus were excluded. Eight of 40 children (20%) had focal hypometabolism, all restricted to the temporal lobe, especially inferior mesial and inferior lateral regions. Abnormalities were ipsilateral to the presumed temporal lobe ictal focus. There was no association between seizure number and presence or extent of regional metabolic abnormalities. Our results suggest that abnormalities of glucose utilization are less common and profound in children with new onset partial seizures than in adults with chronic partial epilepsy. Although our patients' prognosis is uncertain, resolution of epilepsy after three documented seizures is uncommon. If the subjects develop a higher incidence of hypometabolism in the future with planned follow-up studies, metabolic dysfunction might be related to persistent epilepsy rather than present at seizure onset. Recent transcranial magentic stimulation study: We randomized 24 patients with localization-related epilepsy to blinded active or placebo stimulation. Weekly seizure frequency was compared for 8 weeks before and after one week of 1 hertz TMS for 15 minutes twice daily. When the eight week baseline and post-stimulation periods were compared, active patients had a mean seizure frequency reduction of 0.045 ? 0.13, and sham-stimulated controls -0.004 ? 0.20. Over two weeks, actively treated patients had a mean reduction in weekly seizure frequency of 0.16 ? 0.18, and sham-stimulated controls 0.01 ? 0.24. Neither difference was significant. Current Studies: Imaging: We are extending our FCWAY study to patients with extratemporal foci. These patients often have seizures that are more difficult to localize, and harder to control either medically or surgically, than those originating in mesial temporal foci. We are also studying larger numbers of patients with normal structural MRI, with both FCWAY, and advanced MRI techniques, to determine the incidence of occult abnormalities such as sublte cortical dysplasia. We are continuing our study of the evolution of hypometabolism in children with new onset partial seizures. We hypothesize that the incidence of PET abnormlaities will be increased in children with persistent seizures. We are initiating a study of high field strength MRI in animals with epilepsy evoked by excitatory animo acids. We will perform serial studies of the evolution of the epileptogenic zone to model our human observations. We hypothesize that chronic epileptogenic lesions will depend on specific glutamate receptor subtypes. TMS: We plan to perform a follow-up rTMS therpeutic trial in patients with neocortical foci. Based on our previous results, we think that rTMS is most likely to have a significant therpeutic effect in this patient group, as their epileptogenic zones are closer to the cortical surface, and thus can be exposed to a higher strength magentic field than mesial temporal foci. Publications