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. 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, binding of neurtransmitter receptors, and structure. Antiepileptic drug blood levels are obtained. ? ? Major depressive disorder (MDD) is the most common comorbid psychiatric condition associated with temporal lobe epilepsy (TLE). Preclinical and clinical studies suggest that 5-HT1A receptors play a role in the pathophysiology of both TLE and MDD. There is preliminary evidence for an association between decreased 5-HT1A receptor binding in limbic brain areas and affective symptoms in TLE patients. The objective of this study was to compare 5-HT1A receptor binding between TLE patients with and without MDD, and healthy controls. For the first time, 5-HT1A receptor binding was measured in a sample large enough to permit sensitive comparisons between TLE patients with and without comorbid MDD diagnosed by clinical and structured psychiatric interviews. Thirty-seven patients with TLE and 9 healthy controls participated. Patients with temporal lobe foci confirmed by ictal video-EEG monitoring were recruited from the Clinical Epilepsy Section, NINDS. We performed interictal PET scanning, using [18F]FCWAY, a fluorinated derivative of WAY100635, on a GE Medical Systems Advance scanner with continuous EEG monitoring. 5-HT1A receptor binding was estimated by partial volume-corrected [18F]FCWAY V/f1 values. Results: In addition to decreased 5-HT1A receptor binding in the epileptic focus itself, comorbid MDD was associated with a significantly more pronounced reduction in 5-HT1A receptor binding in TLE patients, extending into in non-lesional limbic brain areas outside the epileptic focus. Focus side and the presence of mesial temporal sclerosis were not associated with the presence of comorbid depression. Reductions in 5-HT1A receptor binding may help elucidate the neurobiological mechanisms underlying the TLE-MDD comorbidity.? ? In order to study the evolution of cerebral glucose metabolism after partial seizure onset in children, and its relation to clinical variables, we studied thirty-eight children, who had 3.4 ?.8 18FDG-PET scans over 3.0 ? 1.3 years starting within a year after their third unprovoked partial seizure. 18FDG-PET was analyzed with a region of interest template to measure normalized metabolism in 12 paired anatomic areas. Scans with absolute asymmetry index, |AI|, greater than 0.13 in at least one cortical region other than the cerebellum were considered abnormal. Standard clinical T1 and T2-weighted MRI (1.5T) scans were obtained. The results showed that patients with initial normal PET (n=28) were significantly more likely to remain in good seizure control than those with abnormal initial PET. Patients with initially normal PET scans that became abnormal had longer epilepsy duration before the first PET scan, but not greater seizure frequency, than those with PET always normal. There was no evidence for progression of hypometabolism. Patients with shorter time since last seizure and higher seizure frequency were more likely to have abnormal PET scans. Six of the seven patients whose PET scans were always abnormal had poor seizure control. Febrile seizure history did not affect PET findings. MRI was strongly predictive of initial PET results (?2 = 13.1; p<0.02) but did not predict fluctuation hypometabolism. A model combining MRI and initial PET was strongly predictive of clinical course. This study shows that initial imaging studies can help predict clinical course for children who have had at least three partial seizures. Serial FDG-PET is affected by seizure frequency and time since last seizure. ? ? Human herpesvirus-6 (HHV-6) is a herpesvirus with 90% seroprevalence that infects and establishes latency in the CNS. Active infection or reactivation of either variant in the brain is associated with neurological disorders including epilepsy, encephalitis and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal sclerosis (MTS), opne of the most common forms of intractable epilepsy, and localized viral antigen to glial fibrillary acidic protein (GFAP) positive glia in the same brain sections. We now report HHV-6B viral DNA detection by TaqMan PCR in brain resections from 9/13 additional patients with MTS and from 0/8 additional patients with non-MTS epilepsy. All brain regions positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. In one patient additional patient who presented initially with typical MTLE but appeared to develop progressive disease, primary astrocytes were isolated and cultured from multiple brain resections and astrocyte purity was defined by GFAP reactivity. Primary astrocyte cultures infected in vitro with HHV-6 showed a marked decrease in glutamate transporter EEAT2 expression. This is the first demonstration of HHV-6 infection detected in vivo and maintained in culture. Overall, we have now detected HHV6B in 13/21 patients with MTS/MTLE, in contrast to 0/15 with other syndromes. MTS has been related to glutamate transporter dysfunction, and our preliminary results suggest a potential etiology for MTS.? ? 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. ? ? 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. After infusion of each EAA, CBF increased rapidly throughout the brain, reaching a peak of 250-350% of baseline levels at approximately 20 minutes. there was no difference among the drugs used, and no effect of saline. This study that GluR5 activation alone is sufficient to cause seizures and increase cerebral blood flow. We are investigating the possibility of using PET-labeled mGluR5 ligands in human studies.
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