Evaluation and treatment of drug-resistant epilepsy

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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 the functional anatomy of language and memory activation, cerebral metabolism, blood flow, binding to neurotransmitter receptors, deposition of inflammatory markers, alterations in blood-brain barrier permeability and structure. Presurgical language assessment can help minimize damage to eloquent cortex during resective epilepsy surgery. Two methods for language mapping are functional MRI and direct cortical stimulation (DCS) of implanted subdural electrodes. We compared fMRI results to DCS to optimize non-invasive language localization and assess its validity. We studied 19 patients referred for presurgical evaluation of drug-resistant epilepsy. Patients completed 4 language tasks during preoperative fMRI. After subdural electrode implantation, we used DCS to localize language areas. For each stimulation site, we determined whether electrode pairs intersected with significant fMRI activity clusters for each language task. Sensitivity and specificity depended on electrode ROI radii and statistical thresholding. For patients with at least one language positive stimulation site, an auditory description task provided the best tradeoff between sensitivity and specificity. For patients with no language positive stimulation sites, fMRI was a dependable method of ruling out language areas. 17 patients subsequently had temporal lobectomy. Four had postoperative language decline one year after surgery. Two of four had overlap of fMRI activated voxels, language positive electrodes in basal temporal regions (within 1cm), and resection. Two had overlap with fMRI activated voxels but not language positive electrodes. Patients who experienced language decline tended to have more fMRI activated voxels overlapping the resection than patients who did not. Age of seizure onset, resection side, resection type (standard anterior temporal lobectomy, amygdalohippocampectomy, or topectomy), resection volume, or seizure outcome at one year did not predict language decline. Language localization overlap of fMRI and direct cortical stimulation in resection influences postoperative language performance. Our preliminary study suggests fMRI may be more sensitive and less specific than direct cortical stimulation in predicting postoperative language outcome. fMRI and direct cortical stimulation together may predict postoperative language outcome after epilepsy surgery better than either test alone. Language fMRI is an effective tool for determining language lateralization prior to electrode implantation, and is especially useful for excluding unexpected critical language areas. In an additional study Using fMRI, we found a significant negative relationship between resected volume of the voxels within the top 10% of fMRI activation and BNT score change, with or without controlling for other potential factors, including resection volume, language LI, resection side dominance, and brain shrinkage after surgery. The amount of resected top 10% activation accounted for 20-25% of the variance in language naming ability decline. In a prospective case series, 17 patients with drug-resistant epilepsy had intracranial monitoring and resection from 2012 to 2016 with 1-year follow-up. All patients completed preoperative language fMRI, mapping with DCS of subdural electrodes, pre- and postoperative neuropsychological testing for language function, and resection. Changes in language function before and after surgery were assessed. fMRI activation and DCS electrodes in the resection were evaluated as potential predictors of language decline. Four of 17 patients (12 female; median range age, 43 23-59 years) experienced postoperative language decline 1 year after surgery. Two of 4 patients had overlap of fMRI activation, language-positive electrodes in basal temporal regions (within 1 cm), and resection. Two had overlap between resection volume and fMRI activation, but not DCS. fMRI demonstrated 100% sensitivity and 46% specificity for outcome compared to DCS (50% and 85%, respectively). When fMRI and DCS language findings were concordant, the combined tests showed 100% sensitivity and 75% specificity for language outcome. Seizure-onset age, resection side, type, volume, or 1 year seizure outcome did not predict language decline. Language localization overlap of fMRI and direct cortical stimulation in the resection influences postoperative language performance. Our preliminary study suggests that fMRI may be more sensitive and less specific than direct cortical stimulation. Together they may predict outcome better than either test alone. In order to investigate alternative methods for preoperative language localization, we compared resting state (RS) functional connectivity and task-based fMRI to lateralize language dominance in 30 epilepsy patients (mean age = 33; SD = 11; 12 female), a measure used for presurgical planning. Language laterality index (LI) was calculated from task fMRI in frontal, temporal, and frontal + temporal regional masks using LI bootstrap method from SPM12. RS language LI was assessed using two novel methods of calculating RS language LI from bilateral Broca's area seed based connectivity maps across regional masks and multiple thresholds (p < .05, p < .01, p < .001, top 10% connections). We compared LI from task and RS fMRI continuous values and dominance classifications. We found significant positive correlations between task LI and RS LI when functional connectivity thresholds were set to the top 10% of connections. Concordance of dominance classifications ranged from 20% to 30% for the intrahemispheric resting state LI method and 50% to 63% for the resting state LI intra- minus interhemispheric difference method. Approximately 40% of patients left dominant on task showed RS bilateral dominance. There was no difference in LI concordance between patients with right-sided and left-sided resections. Early seizure onset (<6 years old) was not associated with atypical language dominance during task-based or RS fMRI. While a relationship between task LI and RS LI exists in patients with epilepsy, language dominance is less lateralized on RS than task fMRI. Concordance of language dominance classifications between task and resting state fMRI depends on brain regions surveyed and RS LI calculation method. Human herpes virus 6 (HHV-6) is a potential cause of temporal lobe epilepsy with mesial temporal sclerosis (TLE-MTS). In 87 patients who had resections for focal epilepsy, we used real time quantitative PCR and digital droplet PCR to detect HHV6 in surgical specimens. Viral DNA was isolated from fresh brain tissue. Patients with MTS were significantly more likely to have actively replicating HHV6 than those with other etiologies such as focal cortical dysplasia. We studied effects of HHV-6 using FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with TLE-MTS. Twenty-two patients were positive and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results. Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other TLE-MTS etiologies.