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. We used two measures of depressive symptoms, the state-related Beck Depression Inventory (BDI), and the trait-related Structured Clinical Interview for Depression (SCID). 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 18FFCWAY, 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 18FFCWAY V/f1 values, where V= volume of distribution, and f1 = the tracer plasm free fraction. In the first study, there was a significant inverse relation between ipsilateral hippocampal V/f1 and the BDI. For contralateral hippocampus, there was a non-significant trend. Patients with BDI > 20 had significantly lower ipsilateral hippocampal V/f1 than patients in the low and medium groups. There was no significant effect of the presence of mesial temporal sclerosis, focus laterality or gender on the BDI. These factors had been associated with depression in epilepsy in previous studies. ? ? In our second study, in addition to decreased 5-HT1A receptor binding in the epileptic focus itself, comorbid MDD life-time trait as measured by the SCID was associated with a significantly more pronounced reduction in 5-HT1A receptor binding in TLE patients, extending into non-lesional limbic brain areas outside the epileptic focus. Again, 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 1.8 18FDG-PET scans over 3.0 1 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 but did not predict fluctuation in 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 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 14 of 23 patients with MTS/MTLE, in contrast to none of 15 with other syndromes. MTS has been related to glutamate transporter dysfunction, and our preliminary results suggest a potential etiology for MTS.? ? To investigate whether there is down-regulation of the GABA(a) receptor in human patients with SSADH deficiency, we investigated benzodiazepine receptor (BZPR) binding using 11C flumazenil (FMZ) and PET. FMZ binding was measured in 6 patients with SSADH deficiency, 10 unaffected parents (obligate heterozygotes) and 6 healthy controls. A bolus dose of 1mg/kg of dexmedetomidine, a selective alpha-2 adrenergic agonist that does not appear to have GABAergic effects, infused over 10 min, was followed by a continuous infusion. Data analysis was performed using a reference region compartmental model, with time-activity curve from pons as the input function. Relative parametric binding potential (BP2) was derived, with MRI-based pixel by pixel partial volume correction, in regions of interest drawn on co-registered MRI. The results showed that in amygdala, hippocampus, cerebellar vermis, frontal, parietal, and occipital cortex, patients with SSADH deficiency had significant reductions in FMZ BP compared to parents and controls. There were no differences between controls and parents in any cortical region. In thalamus, there was a non-significant trend for parents to have values intermediate between patients and controls. There was no effect of gender. ? ? Studies with TMS showed increased cortical excitability in these patients. Our results suggest that high endogenous brain GABA levels in SSADH deficiency down-regulate GABA(a)-BZPR binding site availability, and may explain the increased cortical excitability and seizure activity.
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