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. We used PET with [18F]trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide ([18F]FCWAY), a 5-HT1A receptor antagonist, to study 22 patients with TLE and 10 controls. In patients, [18F]fluorodeoxyglucose scans also were performed. An automated magnetic resonance-based partial volume correction (PVC) algorithm was applied. Psychiatric symptoms were assessed with the Beck Depression Inventory Scale. Results. Before PVC, significant (uncorrected P<0.05) reductions of [18F]FCWAY binding potential (BP) were detected in both mesial and lateral temporal structures, mainly ipsilateral to the seizure focus, in the insula, and in the raphe. Group differences were maximal in ipsilateral mesial temporal regions (corrected P<0.05). After PVC, differences in mesial, but not lateral, temporal structures and in the insula remained highly significant (corrected P<0.05). Significant (uncorrected P<0.05) BP reductions were also detected in TLE patients with normal MR images (n=6), in mesial temporal structures. After PVC, asymmetries in BP remained significantly greater than for glucose metabolism in hippocampus and parahippocampus. There was a significant inverse relation between the Beck Depression score and the ipsilateral hippocampal BP, both before and after PVC. Conclusion. Our study shows that in TLE patients reductions of 5-HT1A receptor binding in mesial temporal structures and insula are still significant after PVC. In contrast, partial volume effects may be an important contributor to 5-HT1A receptor binding reductions in lateral temporal lobe. Reduction of 5-HT1A receptors in the ipsilateral hippocampus may contribute to depressive symptoms in TLE patients. Hypothalamic hamartomas (HH) have been associated with uncontrolled seizures, and aggressive therapy including surgery is often recommended. However, some patients, particularly those with other findings associated with Pallister-Hall syndrome (PHS), have a more benign course. Methods: Thirty-seven of 40 PHS and 16 of 16 patients with isolated HH had a lesion confirmed on MRI. Records for all patients were reviewed for the following information: presence of seizures, age at seizure onset, seizure type, seizure frequency, and number of antiepileptic medications at the time of evaluation, past antiepileptic medications, MRI characteristics of the HH, presence of endocrine dysfunction, and presence of developmental and behavioral problems. Results: All isolated HH patients had a history of seizures, compared to13 of 40 PHS patients (all PHS patients with seizures had hamartomas). In isolated HH, seizures started earlier in life, occurred more frequently, and were harder to control than in patients with PHS. Isolated HH patients were more likely to have behavioral and developmental problems than PHS patients. The T2 signal of the hamartoma was isointense to gray matter in the majority of PHS patients, but showed a significant increase in all but one patient with isolated HH. Conclusion: Patients with isolated HH have a distinct clinical phenotype, showing more severe seizures and neurological dysfunction, HH showing increased T2 signal, and are more likely to have precocious puberty. In contrast, PHS patients usually have well-controlled seizures, and other endocrine disturbances than precocious puberty. Patients presenting with HH with or without seizures should be evaluated carefully for other clinical manifestations of PHS, particularly before surgery is considered. To assess long-term outcome after temporal lobectomy, we obtained information from 48 patients and families traced though the NIH Medical Records Department, Social Security, National Death Indices, and other sources. Preoperative evaluation, limited by current standards, was based mainly on interictal surface EEG. After mean 29.9 year follow-up, 24 were seizure-free, and 10 had died. Early seizure recurrence and invasive EEG studies predicted worse long-term outcome. Glutamatergic receptors may play a significant role in epileptogenesis in the amygdala. The role of GluR receptor subtypes has not been elucidated. Agents such as kainic acid (KA) activate multiple glutamatergic receptors. Preliminary studies with amygdalar infusion of the specific KAr GluR5 agonist ATPA ((RS-2-amino-3-(3-hydroxy-5-tert-butylisoxazole-4-yl)propanoic acid) led to prolonged limbic seizures (10 mins ? 4hrs ) monitored behaviorally (Racine stages 1 ? 5 ) and by EEG, suggesting that the KAr GluR5 receptor subtype could mediate ictal activity. In order to evaluate the physiologic effects of specific GluR5 activation, we used KA, AMPA and ATPA, and functional MRI to map the cerebral blood flow (CBF) response to seizures induced by amygdalar injection in rats. METHODS: Rats were anesthetized with ketamine / xylazine and MR-compatible cannula was placed stereotactically in basolateral amygdala. After several days rest, they were intubated under isoflurane anesthesia. Body core temperature was maintained at 37 degrees with a heated water pad. Lines were placed in femoral artery to monitor blood pressure, and femoral vein for drug and fluid administration. Blood gas was analyzed at frequent intervals. MRI was performed on a horizontal 7T Bruker Avance scanner using a 72mm diameter transmit-receive coil. A 2mm axial slice containing the cannula was scanned for 10 minutes before and for approximately two hours after 10 nanomoles (5uL) infusion of each convulsant. Regional cerebral perfusion was measured using arterial spin labeling techniques. MRI parameters: matrix size : 64x64, TR : 2 s, TE: 6.5 ms, 2 ms labeling pulse with power of 81 mG/cm. Field of View= 3.2 cm, Time per scan : 4.5 min. T2 weighted and Diffusion weighted images (in read) were acquired for five 1mm slices centered around the cannula. Parameters: 128x128, TR = 3000 ms, TE = 10 (T2) and 20 ms, (DWI), ? = 20 ms, FOV = 3.2 cm. RESULTS: After infusion of each EAA, CBF increased rapidly throughout the brain, reaching a peak of 250-350% of baseline levels at approximately 20 minutes. Activation was bilateral, and involved neocortical and basal ganglia regions as well as hippocampus and amygdala, suggesting secondary generalization of seizure activity. There was no significant difference in the degree of activation among the three drugs, although the time course varied from agent to agent. Normal saline did not affect CBF. None of the drug infusions led any significant changes in vital signs. CONCLUSION: Focal Amgydalar infusion of glutamatergic agonists leads to rapid widespread bilateral cerebral activation. Selective GluR5 activation is sufficient to produce this response. The pattern of activation is unlikely to have been due to physical diffusion of the infused agent.