Research Interests:
Research Interests:
CLN3 disease is a pediatric neurodegenerative condition wherein seizures are common. The most common disease‐causing variant is an ~1‐kb deletion in CLN3. We investigated seizure phenotype in relation to genotype and to adaptive behavior,... more
CLN3 disease is a pediatric neurodegenerative condition wherein seizures are common. The most common disease‐causing variant is an ~1‐kb deletion in CLN3. We investigated seizure phenotype in relation to genotype and to adaptive behavior, MR spectroscopy and CSF biochemical markers in a CLN3 cohort. We performed seizure phenotyping using clinical history, EEG, and the Unified Batten Disease Rating Scale (UBDRS) seizure score. We assessed correlations of seizure severity with disease severity (UBDRS capability), adaptive behavior composite score (ABC; Vineland‐3), glutamate+glutamine+GABA and N‐acetylaspartate+N‐acetylaspartyl glutamate (MR spectroscopy), and CSF neurofilament light chain (NEFL) levels. In 20 participants, median age was 10.7 years (IQR = 7.8). Eighteen completed baseline EEG; 12 had a 1‐year follow‐up. Seizures were reported in 14 (8 1‐kb deletion homozygotes), with median age at onset of 10.0 (IQR = 6.8). Epileptiform discharges were noted in 15 (9 homozygotes). Bilateral tonic clonic (n = 11) and nonmotor seizures (n = 7) were most common. UBDRS seizure score correlated with age (rp = 0.50; [0.08,0.77]; P = .02), UBDRS capability (rp = −0.57; [−0.81,−0.17]; P = .009) and ABC (rp = −0.66; [−0.85,−0.31]; P = .001) scores, glutamate+glutamine+GABA (rp = −0.54; [−0.80,−0.11]; P = .02) and N‐acetylaspartate+N‐acetylaspartyl glutamate (rp = −0.54; [−0.80,−0.11]; P = .02), and CSF NEFL (rp = 0.65; [0.29,0.85]; P = .002) levels. After controlling for age, correlations with ABC and CSF NEFL remained significant. In our CLN3 cohort, seizures and epileptiform discharges were frequent and often started by age 10 years without significant difference between genotypes. ABC and CSF NEFL correlate with UBDRS seizure score, reflecting the role of seizures in the neurodegenerative process. Longitudinal evaluations in a larger cohort are needed to confirm these findings.
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Research Interests:
Objective: To study the association between HHV-6 viruses and hippocampal volumes in patients with mesial temporal sclerosis (MTS). Background: Human herpes virus 6 (HHV-6) may play an etiologic role in mesial temporal lobe epilepsy and... more
Objective: To study the association between HHV-6 viruses and hippocampal volumes in patients with mesial temporal sclerosis (MTS). Background: Human herpes virus 6 (HHV-6) may play an etiologic role in mesial temporal lobe epilepsy and MTS. Previous studies found an association with febrile status epilepticus. We have reported higher prevalence of HHV-6 in MTS compared to other epilepsy etiologies. Design/Methods: We studied prospectively 34 patients referred to the Clinical Epilepsy Section, NINDS, NIH for evaluation of intractable epilepsy, with ictal video-EEG monitoring, 1.5-T or 3T GE Signa MRI with FLAIR, T1- and T2- weighted images, and 3-D SPGR or MP-RAGE. An investigator blinded to other data manually traced hippocampi manually on each slice, before assembly into three- dimensional volumes. The main study outcome measure was the hippocampal volume asymmetry index (AI) ipsilateral and contralateral to the seizure focus compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue. For 25 patients, viral detection was performed using quantitative real time PCR specific for HHV-6A and HHV-6B. For nine patients, viral DNA detection was performed using digital droplet PCR (DdPCR) specific for HHV-6A and HHV-6B. DdPCR is a highly sensitive and precise novel PCR technology that enables absolute quantification of target DNA molecules. Statistical analysis was performed with SPSS. Results: HHV-6B was detected in 16 of 25 patients studied with real time PCR. Among 9 studied with DdPCR, one had HHV-6A, two HHV-6B, and two both viruses. HHV-6-negative patients had significantly greater AI and lower ipsilateral volume than HHV-6 positive patients (p<0.001). On ANOVA including epilepsy duration, HHV-6 status retained a significant effect on AI (p<0.01). Conclusion: Our data suggest multiple potential etiologies for MTS. HHV6 may have a protective effect on hippocampal volume. Study Supported By: Division of Intramural Research NINDS NIH Disclosure: Dr. Theodore has received personal compensation in an editorial capacity for Epilepsy Research. Dr. Theodore holds stock and/or stock options in General Electric. Dr. Leibovitch has nothing to disclose. Dr. Billioux has nothing to disclose. Dr. Germayen has nothing to disclose. Dr. Kalikhman has nothing to disclose. Dr. Inati has nothing to disclose. Dr. Heiss has nothing to disclose. Dr. Zaghloul has nothing to disclose. Dr. Jacobson has nothing to disclose.
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We report the case of a multifocal dysembryoplastic neuroepithelial tumor (DNT) in a 7-year-old girl with local tumor regrowth 6 years later. The tumor was localized in the right parietal lobe extending from the cortex into the... more
We report the case of a multifocal dysembryoplastic neuroepithelial tumor (DNT) in a 7-year-old girl with local tumor regrowth 6 years later. The tumor was localized in the right parietal lobe extending from the cortex into the periventricular white matter. After subtotal resection of a histopathologically confirmed DNT we observed unexpected tumor progression in long-term follow-up. Therefore, a second surgery was performed when the patient was 14 years of age. In neuropathological examination of the second specimen the tumor showed an increased cellularity and pleomorphism, microvascular proliferations, an elevated proliferative activity (MIB1-index focally up to 10%) and cellular atypia not typical for WHO grade I DNT. Furthermore, MRI studies showed additional supratentorial and infratentorial lesions which remained stable over years and are also well consistent with DNTs. Thus, an unusual form of a DNT with multifocal lesions, local regrowth and morphological transformation is supposed.
Research Interests:
CLN3 disease is a pediatric neurodegenerative condition wherein seizures are common. The most common disease‐causing variant is an ~1‐kb deletion in CLN3. We investigated seizure phenotype in relation to genotype and to adaptive behavior,... more
CLN3 disease is a pediatric neurodegenerative condition wherein seizures are common. The most common disease‐causing variant is an ~1‐kb deletion in CLN3. We investigated seizure phenotype in relation to genotype and to adaptive behavior, MR spectroscopy and CSF biochemical markers in a CLN3 cohort. We performed seizure phenotyping using clinical history, EEG, and the Unified Batten Disease Rating Scale (UBDRS) seizure score. We assessed correlations of seizure severity with disease severity (UBDRS capability), adaptive behavior composite score (ABC; Vineland‐3), glutamate+glutamine+GABA and N‐acetylaspartate+N‐acetylaspartyl glutamate (MR spectroscopy), and CSF neurofilament light chain (NEFL) levels. In 20 participants, median age was 10.7 years (IQR = 7.8). Eighteen completed baseline EEG; 12 had a 1‐year follow‐up. Seizures were reported in 14 (8 1‐kb deletion homozygotes), with median age at onset of 10.0 (IQR = 6.8). Epileptiform discharges were noted in 15 (9 homozygotes). Bilateral tonic clonic (n = 11) and nonmotor seizures (n = 7) were most common. UBDRS seizure score correlated with age (rp = 0.50; [0.08,0.77]; P = .02), UBDRS capability (rp = −0.57; [−0.81,−0.17]; P = .009) and ABC (rp = −0.66; [−0.85,−0.31]; P = .001) scores, glutamate+glutamine+GABA (rp = −0.54; [−0.80,−0.11]; P = .02) and N‐acetylaspartate+N‐acetylaspartyl glutamate (rp = −0.54; [−0.80,−0.11]; P = .02), and CSF NEFL (rp = 0.65; [0.29,0.85]; P = .002) levels. After controlling for age, correlations with ABC and CSF NEFL remained significant. In our CLN3 cohort, seizures and epileptiform discharges were frequent and often started by age 10 years without significant difference between genotypes. ABC and CSF NEFL correlate with UBDRS seizure score, reflecting the role of seizures in the neurodegenerative process. Longitudinal evaluations in a larger cohort are needed to confirm these findings.
Research Interests:
Research Interests:
Background: fMRI language tasks readily identify frontal language areas; temporal activation has been less consistent. No studies have compared clinical visual judgment to quantitative region of interest (ROI) analysis.Objective: To... more
Background: fMRI language tasks readily identify frontal language areas; temporal activation has been less consistent. No studies have compared clinical visual judgment to quantitative region of interest (ROI) analysis.Objective: To identify temporal language areas in patients with partial epilepsy using a reading paradigm with clinical and ROI interpretation.Methods: Thirty patients with temporal lobe epilepsy, aged 8 to 56 years, had 1.5-T fMRI. Patients silently named an object described by a sentence compared to a visual control. Data were analyzed with ROI analysis from t-maps. Regional asymmetry indices (AI) were calculated ([L−R]/[L+R]) and language dominance defined as >0.20. t-Maps were visually rated by three readers at three t thresholds. Twenty-one patients had intracarotid amobarbital test (IAT).Results: The fMRI reading task provided evidence of language lateralization in 27 of 30 patients with ROI analysis. Twenty-five were left dominant, two right, one bilateral, ...
Research Interests:
Objective: To study the association between HHV-6 viruses and hippocampal volumes in patients with mesial temporal sclerosis (MTS). Background: Human herpes virus 6 (HHV-6) may play an etiologic role in mesial temporal lobe epilepsy and... more
Objective: To study the association between HHV-6 viruses and hippocampal volumes in patients with mesial temporal sclerosis (MTS). Background: Human herpes virus 6 (HHV-6) may play an etiologic role in mesial temporal lobe epilepsy and MTS. Previous studies found an association with febrile status epilepticus. We have reported higher prevalence of HHV-6 in MTS compared to other epilepsy etiologies. Design/Methods: We studied prospectively 34 patients referred to the Clinical Epilepsy Section, NINDS, NIH for evaluation of intractable epilepsy, with ictal video-EEG monitoring, 1.5-T or 3T GE Signa MRI with FLAIR, T1- and T2- weighted images, and 3-D SPGR or MP-RAGE. An investigator blinded to other data manually traced hippocampi manually on each slice, before assembly into three- dimensional volumes. The main study outcome measure was the hippocampal volume asymmetry index (AI) ipsilateral and contralateral to the seizure focus compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue. For 25 patients, viral detection was performed using quantitative real time PCR specific for HHV-6A and HHV-6B. For nine patients, viral DNA detection was performed using digital droplet PCR (DdPCR) specific for HHV-6A and HHV-6B. DdPCR is a highly sensitive and precise novel PCR technology that enables absolute quantification of target DNA molecules. Statistical analysis was performed with SPSS. Results: HHV-6B was detected in 16 of 25 patients studied with real time PCR. Among 9 studied with DdPCR, one had HHV-6A, two HHV-6B, and two both viruses. HHV-6-negative patients had significantly greater AI and lower ipsilateral volume than HHV-6 positive patients (p<0.001). On ANOVA including epilepsy duration, HHV-6 status retained a significant effect on AI (p<0.01). Conclusion: Our data suggest multiple potential etiologies for MTS. HHV6 may have a protective effect on hippocampal volume. Study Supported By: Division of Intramural Research NINDS NIH Disclosure: Dr. Theodore has received personal compensation in an editorial capacity for Epilepsy Research. Dr. Theodore holds stock and/or stock options in General Electric. Dr. Leibovitch has nothing to disclose. Dr. Billioux has nothing to disclose. Dr. Germayen has nothing to disclose. Dr. Kalikhman has nothing to disclose. Dr. Inati has nothing to disclose. Dr. Heiss has nothing to disclose. Dr. Zaghloul has nothing to disclose. Dr. Jacobson has nothing to disclose.
Research Interests:
We report the case of a multifocal dysembryoplastic neuroepithelial tumor (DNT) in a 7-year-old girl with local tumor regrowth 6 years later. The tumor was localized in the right parietal lobe extending from the cortex into the... more
We report the case of a multifocal dysembryoplastic neuroepithelial tumor (DNT) in a 7-year-old girl with local tumor regrowth 6 years later. The tumor was localized in the right parietal lobe extending from the cortex into the periventricular white matter. After subtotal resection of a histopathologically confirmed DNT we observed unexpected tumor progression in long-term follow-up. Therefore, a second surgery was performed when the patient was 14 years of age. In neuropathological examination of the second specimen the tumor showed an increased cellularity and pleomorphism, microvascular proliferations, an elevated proliferative activity (MIB1-index focally up to 10%) and cellular atypia not typical for WHO grade I DNT. Furthermore, MRI studies showed additional supratentorial and infratentorial lesions which remained stable over years and are also well consistent with DNTs. Thus, an unusual form of a DNT with multifocal lesions, local regrowth and morphological transformation is supposed.
Research Interests:
Background: fMRI language tasks readily identify frontal language areas; temporal activation has been less consistent. No studies have compared clinical visual judgment to quantitative region of interest (ROI) analysis.Objective: To... more
Background: fMRI language tasks readily identify frontal language areas; temporal activation has been less consistent. No studies have compared clinical visual judgment to quantitative region of interest (ROI) analysis.Objective: To identify temporal language areas in patients with partial epilepsy using a reading paradigm with clinical and ROI interpretation.Methods: Thirty patients with temporal lobe epilepsy, aged 8 to 56 years, had 1.5-T fMRI. Patients silently named an object described by a sentence compared to a visual control. Data were analyzed with ROI analysis from t-maps. Regional asymmetry indices (AI) were calculated ([L−R]/[L+R]) and language dominance defined as >0.20. t-Maps were visually rated by three readers at three t thresholds. Twenty-one patients had intracarotid amobarbital test (IAT).Results: The fMRI reading task provided evidence of language lateralization in 27 of 30 patients with ROI analysis. Twenty-five were left dominant, two right, one bilateral, ...
Research Interests:
fMRI language tasks reliably identify language areas in presurgical epilepsy patients, but activation using single paradigms may disagree with the intracarotid amobarbital test (IAT). To determine whether a panel of fMRI tasks targeting... more
fMRI language tasks reliably identify language areas in presurgical epilepsy patients, but activation using single paradigms may disagree with the intracarotid amobarbital test (IAT). To determine whether a panel of fMRI tasks targeting different aspects of language processing increases accuracy in determining hemisphere language dominance. Twenty-six patients age 12 to 56 years, predominantly with temporal lobe epilepsy, were studied using whole-brain 1.5 T fMRI (echo planar imaging, blood oxygenation level-dependent) with three task categories using a block design: verbal fluency, reading comprehension, and auditory comprehension. fMRI t maps were visually rated at three thresholds. All patients had assessment of language lateralization by IAT. fMRI showed left dominance in 21 patients, right dominance in 2, and bilateral activation in 2; raters disagreed over a left vs right bilateral rating in 1 patient. There was full agreement between IAT and fMRI in 21 of 25 patients (IAT failed in 1). In three instances of partial disparity with IAT, the fMRI panel showed consistent findings across raters. Agreement between raters was excellent (partial disagreement in only one patient); the panel of tasks was superior to any single task for interrater agreement (Cramer V 0.93 [range 0.91 to 1.0] vs 0.72 [range 0.60 to 0.86]). A panel of fMRI language paradigms may be more accurate for evaluating partial epilepsy patients than a single task. A panel of tasks reduces the likelihood of nondiagnostic findings, improves interrater reliability, and helps confirm language laterality.
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Research Interests: Cognitive Science, Neurology, Magnetic Resonance Imaging, Epilepsy, Language, and 15 moreAdolescent, Language disorders, Humans, Child, Cerebral Cortex, Female, Male, Neuronal Plasticity, Clinical Sciences, Middle Aged, Adult, Neural pathways, Neurosciences, Functional Laterality, and Language tests
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Research Interests: Psychology, Transcranial Magnetic Stimulation, Epilepsy, Placebo Effect, Treatment Outcome, and 13 moreMedicine, Humans, Placebo, Female, Male, Follow-up studies, Clinical Sciences, Middle Aged, Adult, Randomized Controlled Trial, Retrospective Studies, Chi Square Distribution, and Repetitive transcranial magnetic stimulation
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Research Interests:
Research Interests:
Research Interests: Multiple sclerosis, Health Care, Quality of life, Epilepsy, Medicine, and 15 moreHumans, Clinical research, Developing Country, Health related Quality of Life, Incidence, Epilepsia, Health Status, Clinical Sciences, North America, Prevalence, Public awareness, Access to Care, Neurosciences, Primary Prevention, and General Population
BackgroundPositron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) shows widespread hypometabolism even in temporal lobe epilepsy (TLE) patients with mesial temporal foci. 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)... more
BackgroundPositron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) shows widespread hypometabolism even in temporal lobe epilepsy (TLE) patients with mesial temporal foci. 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY) PET may show more specific 5-HT1A receptor binding reduction in seizure initiation than propagation regions. 18FCWAY PET might be valuable for detecting epileptic foci, and distinguishing mesial from lateral temporal foci in MRI negative TLE patients.MethodsWe performed 18F-FCWAY-PET and 18F-FDG-PET in 12 MRI negative TLE patients who had had either surgery or subdural electrode recording, and 15 healthy volunteers. After partial volume correction for brain atrophy, free fraction-corrected volume of distribution (V/f1) measurement and asymmetry indices (AIs) were computed. We compared 18F-FCWAY-PET and 18F-FDG-PET results with scalp video electroencephalography (EEG), invasive EEG and surgical outcome.ResultsMean 18F-FCWAY V/f1, compared with normal controls, was decreased significantly in fusiform gyrus, hippocampus and parahippocampus ipsilateral to epileptic foci, and AIs significantly greater in hippocampus, parahippocampus, fusiform gyrus, amygdala and inferior temporal regions. Eleven patients had clearly lateralized epileptogenic zones. Nine had congruent, and two non-lateralized, 18F-FCWAY PET. One patient with bitemporal seizure onset had non-lateralized 18F-FCWAY-PET. 18FFDG-PET showed congruent hypometabolism in 7/11 EEG-lateralized patients, bilateral hypometabolic regions in one, contralateral hypometabolism in one, as well as lateralized hypometabolism in the patient with bitemporal subdural seizure onset. Patients with mesial temporal foci tended to have lower superior and mid temporal 18F-FCWAY V/f1 binding AI than those with lateral or diffuse foci.Conclusion18F-FCWAY-PET can detect reduced binding in patients with normal MRI, and may be more accurate than 18F-FDG-PET.
Research Interests: Magnetic Resonance Imaging, Electroencephalography, Adolescent, Positron Emission Tomography, Hippocampus, and 15 moreTemporal Lobe, Brain, Humans, Blood Glucose, Glucose Metabolism, Female, Male, Amygdala, Epilepsia, Clinical Sciences, Serotonin Receptors, Adult, Parahippocampal Gyrus, Neurosciences, and Frontal Lobe
This study investigated whether different brain areas are involved during working memory tasks related to first (L1) and second (L2) languages. Functional magnetic resonance imaging (fMRI) was performed on 24 bilingual native Korean... more
This study investigated whether different brain areas are involved during working memory tasks related to first (L1) and second (L2) languages. Functional magnetic resonance imaging (fMRI) was performed on 24 bilingual native Korean speakers who acquired English as their L2 after the age of 12. Their L2 proficiency ranged from low to moderate. The images were acquired while the participants
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Summary: We studied the effects of valproate (VPA) on local cerebral glucose metabolism (LCMRglc) in eight patients with partial seizure disorders and two with primary generalized epilepsy. Each patient had two positron-emission... more
Summary: We studied the effects of valproate (VPA) on local cerebral glucose metabolism (LCMRglc) in eight patients with partial seizure disorders and two with primary generalized epilepsy. Each patient had two positron-emission tomography (PET) scans with 18 F-2-...
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Research Interests:
Functional magnetic resonance imaging is sensitive to the variation in language network patterns. Large populations are needed to rigorously assess atypical patterns, which, even in neurological populations, are a minority. We studied 220... more
Functional magnetic resonance imaging is sensitive to the variation in language network patterns. Large populations are needed to rigorously assess atypical patterns, which, even in neurological populations, are a minority. We studied 220 patients with focal epilepsy and 118 healthy volunteers who performed an auditory description decision task. We compared a data-driven hierarchical clustering approach to the commonly used a priori laterality index (LI) threshold (LI &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.20 as atypical) to classify language patterns within frontal and temporal regions of interest. We explored (n = 128) whether IQ varied with different language activation patterns. The rate of atypical language among healthy volunteers (2.5%) and patients (24.5%) agreed with previous studies; however, we found 6 patterns of atypical language: a symmetrically bilateral, 2 unilaterally crossed, and 3 right dominant patterns. There was high agreement between classification methods, yet the cluster analysis revealed novel correlations with clinical features. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified an association of handedness with frontal lateralization, early seizure onset with temporal lateralization, and left hemisphere focus with a unilateral right pattern. Intelligence quotient was not significantly different among patterns. Language dominance is a continuum; however, our results demonstrate meaningful thresholds in classifying laterality. Atypical language patterns are less frequent but more variable than typical language patterns, posing challenges for accurate presurgical planning. Language dominance should be assessed on a regional rather than hemispheric basis, and clinical characteristics should inform evaluation of atypical language dominance. Reorganization of language is not uniformly detrimental to language functioning.
Research Interests: Language, Adolescent, Temporal Lobe, Prospective studies, Humans, and 15 moreChild, Female, Male, Young Adult, Clinical Sciences, Middle Aged, Adult, Retrospective Studies, Cross Sectional Studies, Neurosciences, Frontal Lobe, Functional Laterality, Acoustic Stimulation, Psychomotor Performance, and Child preschool
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BACKGROUND Minimally invasive therapies for drug-resistant epilepsy (DRE) have been advocated. A study of convection-enhanced delivery (CED) of muscimol, a GABAA receptor agonist, was previously completed in non-human primates. OBJECTIVE... more
BACKGROUND Minimally invasive therapies for drug-resistant epilepsy (DRE) have been advocated. A study of convection-enhanced delivery (CED) of muscimol, a GABAA receptor agonist, was previously completed in non-human primates. OBJECTIVE To investigate the safety and anti-epileptic effects of intracerebral muscimol infusion into the epileptic focus of patients with DRE. METHODS In this phase 1 clinical trial, 3 adult patients with DRE underwent CED into the seizure focus of artificial CSF vehicle followed by muscimol for 12 to 24 h each using a crossover design. Basic pathophysiology of the epileptic focus was examined by assessing the infusions’ effects on seizure frequency, electroencephalogram (EEG) spike-wave activity, and power-spectral EEG frequency. RESULTS Inter-ictal neurological function remained normal in all patients. Pathological examination of resected specimens showed no infusion-related brain injuries. Seizure frequency decreased in 1 of 3 patients during muscimol in...
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The role of neuroinflammation in mesial temporal lobe epilepsy (MTLE), and how it relates to drug resistance, remains unclear. Expression levels of the inflammatory enzymes cyclooxygenase (COX)-1 and COX-2 have been found to be increased... more
The role of neuroinflammation in mesial temporal lobe epilepsy (MTLE), and how it relates to drug resistance, remains unclear. Expression levels of the inflammatory enzymes cyclooxygenase (COX)-1 and COX-2 have been found to be increased in animal models of epilepsy. Knowing the cellular expression of COX-1 and COX-2 is the key to understanding their functional role; however, only 3 studies have investigated COX-2 expression in epilepsy in humans, and there are no reports on COX-1. In addition, previous studies have shown that certain inflammatory proteins up-regulate ATP binding cassette (ABC) transporter expression (thought to be responsible for drug resistance), but this relationship remains unclear in human tissue. This study sought to measure the expression of COX-1, COX-2, and translocator protein 18 kDa (TSPO, an inflammation biomarker acting as a positive control), as well as ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in brain tissue ...
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Using approximations based on presumed U.S. time zones, we characterized day and nighttime seizure patterns in a patient-reported database, Seizure Tracker. A total of 632 995 seizures (9698 patients) were classified into 4 categories:... more
Using approximations based on presumed U.S. time zones, we characterized day and nighttime seizure patterns in a patient-reported database, Seizure Tracker. A total of 632 995 seizures (9698 patients) were classified into 4 categories: isolated seizure event (ISE), cluster without status epilepticus (CWOS), cluster including status epilepticus (CIS), and status epilepticus (SE). We used a multinomial mixed-effects logistic regression model to calculate odds ratios (ORs) to determine night/day ratios for the difference between seizure patterns: ISE versus SE, ISE versus CWOS, ISE versus CIS, and CWOS versus CIS. Ranges of OR values were reported across cluster definitions. In adults, ISE was more likely at night compared to CWOS (OR = 1.49, 95% adjusted confidence interval [CI] = 1.36-1.63) and to CIS (OR = 1.61, 95% adjusted CI = 1.34-1.88). The ORs for ISE versus SE and CWOS versus SE were not significantly different regardless of cluster definition. In children, ISE was less likel...
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There is currently no formal method for predicting the range expected in an individual's seizure counts. Having access to such a prediction would be of benefit for developing more efficient clinical trials, but also for improving... more
There is currently no formal method for predicting the range expected in an individual's seizure counts. Having access to such a prediction would be of benefit for developing more efficient clinical trials, but also for improving clinical care in the outpatient setting. Using three independently collected patient diary datasets, we explored the predictability of seizure frequency. Three independent seizure diary databases were explored: SeizureTracker (= 3016), Human Epilepsy Project (= 93), and NeuroVista (= 15). First, the relationship between mean and standard deviation in seizure frequency was assessed. Using that relationship, a prediction for the range of possible seizure frequencies was compared with a traditional prediction scheme commonly used in clinical trials. A validation dataset was obtained from a separate data export of SeizureTracker to further verify the predictions. A consistent mathematical relationship was observed across datasets. The logarithm of the avera...
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Epilepsy can be a devastating disorder. In addition to debilitating seizures, epilepsy can cause cognitive and emotional problems with reduced quality of life. Therefore, the major aim is to prevent the disorder in the first place:... more
Epilepsy can be a devastating disorder. In addition to debilitating seizures, epilepsy can cause cognitive and emotional problems with reduced quality of life. Therefore, the major aim is to prevent the disorder in the first place: identify, detect, and reverse the processes responsible for its onset, and monitor and treat its progression. Epilepsy often occurs following a latent period of months to years (epileptogenesis) as a consequence of a brain insult, such as head trauma, stroke, or status epilepticus. Although this latent period clearly represents a therapeutic window, we are not able to stratify patients at risk for long-term epilepsy, which is prerequisite for preventative clinical trials. Moreover, because of the length of the latent period, an early biomarker for treatment response would be of high value. Finally, mechanistic biomarkers of epileptogenesis may provide more profound insight in the process of disease development.
Research Interests: Magnetic Resonance Imaging, Biomarkers, Epilepsy, Electroencephalography, Brain, and 15 moreHumans, Animals, Risk factors, Astrocytes, Epilepsia, Clinical Sciences, Image Enhancement, Rats, Disease Progression, Risk Factors, Status Epilepticus, Neurosciences, Neurogenic Inflammation, Brain injuries, and proton magnetic resonance spectroscopy
The placebo response in epilepsy randomized clinical trials (RCTs) has recently been shown to largely reflect underlying natural variability in seizure frequency. Based on this observation, we sought to explore the parameter space of RCT... more
The placebo response in epilepsy randomized clinical trials (RCTs) has recently been shown to largely reflect underlying natural variability in seizure frequency. Based on this observation, we sought to explore the parameter space of RCT design to optimize trial efficiency and cost. We used one of the world's largest patient reported seizure diary databases, SeizureTracker.com to derive virtual patients for simulated RCTs. We ran 1000 randomly generated simulated trials using bootstrapping (sampling with replacement) for each unique combination of trial parameters, sweeping a large set of parameters in durations of the baseline and test periods, number of patients, eligibility criteria, drug effect size, and patient dropout. We studied the resulting trial efficiency and cost. A total of 6,732,000 trials were simulated, drawing from 5097 patients in the database. We found that the strongest regression predictors of placebo response were durations of baseline and test periods. Dru...
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Sudden unexplained death in epilepsy (SUDEP) during inpatient electroencephalography (EEG) monitoring has been a rare but potentially preventable event, with associated cardiopulmonary markers. To date, no systematic evaluation of alarm... more
Sudden unexplained death in epilepsy (SUDEP) during inpatient electroencephalography (EEG) monitoring has been a rare but potentially preventable event, with associated cardiopulmonary markers. To date, no systematic evaluation of alarm settings for a continuous pulse oximeter (SpO2 ) has been performed. In addition, evaluation of the interrelationship between the ictal and interictal states for cardiopulmonary measures has not been reported. Patients with epilepsy were monitored using video-EEG, SpO2 , and electrocardiography (ECG). Alarm thresholds were tested systematically, balancing the number of false alarms with true seizure detections. Additional cardiopulmonary patterns were explored using automated ECG analysis software. One hundred ninety-three seizures (32 generalized) were evaluated from 45 patients (7,104 h recorded). Alarm thresholds of 80-86% SpO2 detected 63-73% of all generalized convulsions and 20-28% of all focal seizures (81-94% of generalized and 25-36% of foca...
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Our objective was to develop a generalized linear mixed model for predicting seizure count that is useful in the design and analysis of clinical trials. This model also may benefit the design and interpretation of seizure-recording... more
Our objective was to develop a generalized linear mixed model for predicting seizure count that is useful in the design and analysis of clinical trials. This model also may benefit the design and interpretation of seizure-recording paradigms. Most existing seizure count models do not include children, and there is currently no consensus regarding the most suitable model that can be applied to children and adults. Therefore, an additional objective was to develop a model that accounts for both adult and pediatric epilepsy. Using data from SeizureTracker.com, a patient-reported seizure diary tool with >1.2 million recorded seizures across 8 years, we evaluated the appropriateness of Poisson, negative binomial, zero-inflated negative binomial, and modified negative binomial models for seizure count data based on minimization of the Bayesian information criterion. Generalized linear mixed-effects models were used to account for demographic and etiologic covariates and for autocorrela...
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Objective:To identify the etiology of new-onset seizure in HIV-infected Zambian adults and identify risk factors for seizure recurrence.Methods:A prospective cohort study enrolling HIV-infected adults with new-onset seizure within 2 weeks... more
Objective:To identify the etiology of new-onset seizure in HIV-infected Zambian adults and identify risk factors for seizure recurrence.Methods:A prospective cohort study enrolling HIV-infected adults with new-onset seizure within 2 weeks of index seizure obtained clinical, laboratory, and neuroimaging data to determine seizure etiology. Participants were followed to identify risk factors for seizure recurrence. Risk factors for mortality were examined as mortality rates were unexpectedly high.Results:Eighty-one patients with CSF for analysis were enrolled and followed for a median of 306 days (interquartile range 61–636). Most (91%) were at WHO stage III/IV and 66 (81%) had a pre-seizure Karnofsky score ≥50. Prolonged or multiple seizures occurred in 46 (57%), including 12 (15%) with status epilepticus. Seizure etiologies included CNS opportunistic infections (OI) in 21 (26%), hyponatremia in 23 (28%), and other infections in 8 (10%). OIs included Cryptococcus (17%), JC virus (7%) ...
Research Interests:
Research Interests:
To assess the diagnostic accuracy and prognostic value of functional MRI (fMRI) in determining lateralization and predicting postsurgical language and memory outcomes. An 11-member panel evaluated and rated available evidence according to... more
To assess the diagnostic accuracy and prognostic value of functional MRI (fMRI) in determining lateralization and predicting postsurgical language and memory outcomes. An 11-member panel evaluated and rated available evidence according to the 2004 American Academy of Neurology process. At least 2 panelists reviewed the full text of 172 articles and selected 37 for data extraction. Case reports, reports with <15 cases, meta-analyses, and editorials were excluded. The use of fMRI may be considered an option for lateralizing language functions in place of intracarotid amobarbital procedure (IAP) in patients with medial temporal lobe epilepsy (MTLE; Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C). For patients with temporal neocortical epilepsy or temporal tumors, the evidence is insufficient (Level U). fMRI may be considered to predict postsurgical language deficits after anterior temporal lobe resection (Level C). The use of fMRI may be conside...
Research Interests:
Imaging is pivotal in the evaluation and management of patients with seizure disorders. Elegant structural neuroimaging with magnetic resonance imaging (MRI) may assist in determining the etiology of focal epilepsy and demonstrating the... more
Imaging is pivotal in the evaluation and management of patients with seizure disorders. Elegant structural neuroimaging with magnetic resonance imaging (MRI) may assist in determining the etiology of focal epilepsy and demonstrating the anatomical changes associated with seizure activity. The high diagnostic yield of MRI to identify the common pathological findings in individuals with focal seizures including mesial temporal sclerosis, vascular anomalies, low-grade glial neoplasms and malformations of cortical development has been demonstrated. Positron emission tomography (PET) is the most commonly performed interictal functional neuroimaging technique that may reveal a focal hypometabolic region concordant with seizure onset. Single photon emission computed tomography (SPECT) studies may assist performance of ictal neuroimaging in patients with pharmacoresistant focal epilepsy being considered for neurosurgical treatment. This chapter highlights neuroimaging developments and innovations, and provides a comprehensive overview of the imaging strategies used to improve the care and management of people with epilepsy.