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 patients with depression, some studies have shown altered 5HT transport (5HTT).We used 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) to image 5HTT in a preliminary study in patients with localization-related epilepsy and healthy controls. In controls, DASB binding values were comparable to previously reported studies. We found that DASB binding was 6-28% lower in patients than controls, with the greatest differences in bilateral striatum, thalamus, amygdala and raphe. The difference was present in remote and contralateral regions, as well as in the epileptogenic zone itself. FCWAY binding was 16-34% lower than in controls. There was no clear relationship between FCWAY and DASB binding. Reduction in serotonin transport provides additional evidence to reduced 5HT1A binding in suggesting impaired serontonergic neurotransmission in localization-related epilepsy. ? ? In order to study the value of 18F-FCWAY-PET and 18F-FDG-PET in presurgical evaluation for uncontrolled epilepsy, we scanned 12 MRI negative TLE patients. We compared 18F-FCWAY-PET and 18F-FDG-PET results with scalp video electroencephalography (EEG), invasive EEG and surgical outcome. ? ? 18F-FCWAY binding, compared with normal controls, was decreased significantly in fusiform gyrus, hippocampus and parahippocampus ipsilateral to epileptic foci. 18F-FDG-PET was less senstivie and specific for detection of epileptic foci, particularly when seizure arose from mesial structures. 18F-FCWAY-PET can detect reduced binding in patients with normal MRI, and may be more accurate than 18F-FDG-PET. ? ? 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 the affected SSADH patients, suggesting that reduced GABAergic neurotransmission has physiologic effects that can explain neurologic symptoms.
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