Publications by authors named "William H Theodore"

126 Publications

Safety and Efficacy of Nataluzimab as Adjunctive Therapy for People With Drug-Resistant Epilepsy: A Phase 2 Study.

Neurology 2021 Sep 14. Epub 2021 Sep 14.

Stoke Therapeutics, Bedford, MA; Biogen, Cambridge, MA, at the time of the study.

Objective: To explore efficacy/safety of natalizumab, a humanized monoclonal anti-α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy.

Methods: Participants with ≥6 seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed.

Results: Of 32 and 34 participants dosed in the natalizumab 300 mg and placebo groups, 30 (94%) and 31 (91%) completed the placebo-controlled treatment period, respectively (one participant was randomized to receive natalizumab but not dosed due to IV complications). Estimated relative change in seizure frequency of natalizumab over placebo was -14.4% (95% CI -46.1% to 36.1%, = 0.51). The proportion of participants with ≥50% reduction from baseline in seizure frequency was 31.3% for natalizumab and 17.6% for placebo (odds ratio 2.09, 95% CI 0.64-6.85, = 0.22). Adverse events (AEs) were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo.

Conclusions: Although the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted.

Classification Of Evidence: This study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab.
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http://dx.doi.org/10.1212/WNL.0000000000012766DOI Listing
September 2021

Human herpesvirus 6 and epilepsy.

Epilepsia Open 2021 Jul 29. Epub 2021 Jul 29.

Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

We investigated the association between human herpesvirus 6 (HHV-6) and mesial temporal sclerosis (MTS) in 87 patients who had surgery for drug-resistant epilepsy. Fifty-four had MTS, 22 focal cortical dysplasia (FCD), four tumors, three vascular malformations, and three a history of encephalitis. We extracted DNA from fresh brain tissue immediately after surgery and performed viral detection with quantitative real-time polymerase chain reaction (PCR) or digital droplet PCR specific for HHV-6A and HHV-6B. Tissue was studied with standard clinical techniques, including hematoxylin and eosin, glial fibrillary acidic protein, and NeuN stains. Twenty-nine of 54 patients with MTS, six of 23 with focal cortical dysplasia (FCD), and one of three with a history of encephalitis were positive for HHV-6 (P < .02). Febrile seizure history was not associated with HHV-6 detection. Patients with MTS had significantly lower seizure onset age than those with other pathologies. Thirteen patients had positron emission tomography with [11C]PBR28, a marker for reactive astrocytes and activated microglia; there was a trend for HHV-6-positive patients to have higher binding in their seizure foci, suggesting inflammation. Our study supports a potential role for HHV-6 in the etiology of MTS.
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http://dx.doi.org/10.1002/epi4.12531DOI Listing
July 2021

Differential activation of neuroinflammatory pathways in children with seizures: A cross-sectional study.

Seizure 2021 Oct 31;91:150-158. Epub 2021 May 31.

Division of Neuroimmunology and Neurovirology, NINDS, NIH, Bethesda, MD, United States.

Purpose: Inflammation plays a crucial role in epileptogenesis. We analyzed inflammatory cytokines in plasma and saliva from children with seizures and healthy controls and measured their associations with HHV6 and EBV infection.

Methods: We analyzed plasma from 36 children within 24 h of seizures (cases) and 43 healthy controls and saliva from 44 cases and 44 controls with a multiplex immunoassay. Saliva from all controls and 65 cases and blood from 26 controls and 35 cases were also analyzed by PCR for viral DNA. Primary outcome was cytokine levels in cases vs. controls. Secondary outcomes included detection of HHV-6 and EBV viral DNA in cases vs. controls and viral loads in cases vs. controls. Statistical analysis included the Wilcoxon Rank Sum test, Fisher's exact test, ANOVA, and Spearman correlation.

Results: Compared to controls, patients had higher levels of CCL11 (p = 0.0018), CCL26 (p<0.001), IL10 (p = 0.044), IL6 (p<0.001), IL8 (p = 0.018), and MIP1β (p = 0.0012). CCL11 was higher with 3 or more seizures (p = 0.01), seizures longer than 10 min (p = 0.001), and when EEG showed focal slowing (p = 0.02). In saliva, febrile seizures had higher levels of IL-1β (n = 7, p = 0.04) and new onset seizures had higher IL-6 (n = 15, p = 0.02). Plasma and saliva cytokine levels did not show a correlation. The frequency of HHV-6 and EBV detection was similar across groups and not different than controls. We found no correlation between viral load and cytokine levels.

Conclusions: We showed differential activation of neuroinflammatory pathways in plasma from different seizure etiologies compared to controls, unrelated to viral infection.
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http://dx.doi.org/10.1016/j.seizure.2021.05.022DOI Listing
October 2021

A Randomized Controlled Trial of SGS-742, a γ-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency.

J Child Neurol 2021 May 20:8830738211012804. Epub 2021 May 20.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, 35053National Institutes of Health (NIH), Bethesda, MD, USA.

We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 ( = .09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency.Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://clinicaltrials.gov/ct2/show/NCT02019667.
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http://dx.doi.org/10.1177/08830738211012804DOI Listing
May 2021

Identification of clinically relevant biomarkers of epileptogenesis - a strategic roadmap.

Nat Rev Neurol 2021 Apr 16;17(4):231-242. Epub 2021 Feb 16.

Department of Pharmacology & Toxicology and Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, USA.

Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research.
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http://dx.doi.org/10.1038/s41582-021-00461-4DOI Listing
April 2021

Distinguishing type II focal cortical dysplasias from normal cortex: A novel normative modeling approach.

Neuroimage Clin 2021 19;30:102565. Epub 2021 Jan 19.

EEG Section, Office of the Clinical Director, NINDS, National Institutes of Health, United States. Electronic address:

Objective: Focal cortical dysplasias (FCDs) are a common cause of apparently non-lesional drug-resistant focal epilepsy. Visual detection of subtle FCDs on MRI is clinically important and often challenging. In this study, we implement a set of 3D local image filters adapted from computer vision applications to characterize the appearance of normal cortex surrounding the gray-white junction. We create a normative model to serve as the basis for a novel multivariate constrained outlier approach to automated FCD detection.

Methods: Standardized MPRAGE, T and FLAIR MR images were obtained in 15 patients with radiologically or histologically diagnosed FCDs and 30 healthy volunteers. Multiscale 3D local image filters were computed for each MR contrast then sampled onto the gray-white junction surface. Using an iterative Gaussianization procedure, we created a normative model of cortical variability in healthy volunteers, allowing for identification of outlier regions and estimates of similarity in normal cortex and FCD lesions. We used a constrained outlier approach following local normalization to automatically detect FCD lesions based on projection onto the mean FCD feature vector.

Results: FCDs as well as some normal cortical regions such as primary sensorimotor and paralimbic regions appear as outliers. Regions such as the paralimbic regions and the anterior insula have similar features to FCDs. Our constrained outlier approach allows for automated FCD detection with 80% sensitivity and 70% specificity.

Significance: A normative model using multiscale local image filters can be used to describe the normal cortical variability. Although FCDs appear similar to some cortical regions such as the anterior insula and paralimbic cortices, they can be identified using a constrained outlier detection approach. Our method for detecting outliers and estimating similarity is generic and could be extended to identification of other types of lesions or atypical cortical areas.
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http://dx.doi.org/10.1016/j.nicl.2021.102565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887437PMC
July 2021

Epilepsy in the Hippocratic collection: Seizures and syndromes.

Epilepsy Behav 2021 02 10;115:107704. Epub 2021 Jan 10.

Clinical Epilepsy Section, NINDS NIH Building 10 Room 7D-43, Bethesda, MD 20892, USA. Electronic address:

Despite extensive scholarship, several questions on the view of seizures and epilepsy in the Hippocratic collection have not been answered. The book 'On the Sacred Disease' contains descriptions of focal and generalized tonic-clonic seizures, understands the stigma attached to epilepsy, its association with depression, and probably describes auras. Remarkably, the collection presents a physiologic theory of 'mental' disease. Other parts of the collection suggest recognition of syndromes such as childhood febrile seizures. Non-motor seizures are not clearly described. There may be a distinction between 'acute symptomatic' and recurrent seizures or 'epilepsy.' Analysis of the relative occurrence of terms related to 'epilepsy' or 'spasms' in an online text collection shows a significant difference: 'epilepsy' terms are more frequent when seizures are described alone, while 'spasm' terms are more frequent in the context of systemic diseases or injuries. This dichotomy suggests, in contrast to previous accounts, possible understanding of the distinction between 'idiopathic' and 'symptomatic' seizure disorders.
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http://dx.doi.org/10.1016/j.yebeh.2020.107704DOI Listing
February 2021

HHV-6 and hippocampal volume in patients with mesial temporal sclerosis.

Ann Clin Transl Neurol 2020 09 17;7(9):1674-1680. Epub 2020 Aug 17.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.

Objective: To study the effects of human herpes virus 6 (HHV-6) on the hippocampal volume in patients with mesial temporal sclerosis (MTS).

Background: HHV-6 may play an etiologic role in MTS. Previous studies found a possible association with febrile status epilepticus. Several investigators have reported a higher prevalence of HHV-6 in MTS resections compared to other epilepsy etiologies.

Design/methods: We used FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volumes ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real-time PCR specific for HHV-6A and HHV-6B. For 16 patients, viral DNA detection was performed using digital droplet PCR specific for HHV-6A and HHV-6B.

Results: Twenty-two patients were positive (14 of 25 tested with real-time PCR, and 8 of 16 with digital droplet PCR), 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.

Interpretation: Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other etiologies.
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http://dx.doi.org/10.1002/acn3.51152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480901PMC
September 2020

Evaluating the impact of antiretroviral and antiseizure medication interactions on treatment effectiveness among outpatient clinic attendees with HIV in Zambia.

Epilepsia 2020 12 21;61(12):2705-2711. Epub 2020 Oct 21.

Department of Neurology, University of Rochester, Rochester, NY, USA.

Objective: Interactions between enzyme-inducing anti-seizure medications (EI-ASMs) and antiretroviral drugs (ARVs) can lead to decreased ARV levels and may increase the likelihood of viral resistance. We conducted a study to determine if co-usage of ARVs and EI-ASMs is associated with ARV-resistant human immunodeficiency virus (HIV) among people living with HIV in Zambia.

Methods: Eligible participants were ≥18 years of age and concurrently taking ASMs and ARVs for at least 1 month of the prior 6-month period. Data were obtained regarding medication and HIV history. CD4 counts, plasma viral loads (pVLs), and HIV genotype and resistance profile in participants with a pVL >1000 copies/mL were obtained. Pearson's test of independence was used to determine whether treatment with EI-ASM was associated with pVL >1000/mL copies.

Results: Of 50 participants, 41 (82%) were taking carbamazepine (37 on monotherapy), and all had stable regimens in the prior 6 months. Among the 13 ARV regimens used, 68% had a tenofovir/lamivudine backbone. The majority (94%) were on a stable ARV regimen for >6 months. Median CD4 nadir was 205 cells/mm (interquartile range [IQR] 88-389), and 60% of participants had commenced ARV treatment before advanced disease occurred. Mean CD4 count at enrollment was 464 cells/mm (SD 226.3). Seven participants (14%) had a CD4 count <200 cells/mm . Four (8%) had a pVL >1000 copies/mL; all were on carbamazepine. Three participants with elevated pVL had a CD4 count <200 cells/mm . None had documented adherence concerns by providers; however, two had events concerning for clinical failure. HIV genotype testing showed mutations in three participants. Carbamazepine was not found to correlate with elevated pVL (P = .58).

Significance: EI-ASMs are commonly used in sub-Saharan Africa. Despite concurrent use of EI-ASMs and ARVs, the majority of participants showed CD4 counts >200 cells/mm and were virally suppressed. Carbamazepine was not associated with an increased risk of virological failure or ARV-resistant HIV.
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http://dx.doi.org/10.1111/epi.16723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725895PMC
December 2020

Language lateralization from task-based and resting state functional MRI in patients with epilepsy.

Hum Brain Mapp 2020 08 24;41(11):3133-3146. Epub 2020 Apr 24.

National Institute of Neurological Disorders and Stroke, Clinical Epilepsy Section, Bethesda, Maryland, USA.

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.
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http://dx.doi.org/10.1002/hbm.25003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336139PMC
August 2020

Individualizing the definition of seizure clusters based on temporal clustering analysis.

Epilepsy Res 2020 07 9;163:106330. Epub 2020 Apr 9.

Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States.

Objective: Seizure clusters are often encountered in people with poorly controlled epilepsy. Detection of seizure clusters is currently based on simple clinical rules, such as two seizures separated by four or fewer hours or multiple seizures in 24 h. Current definitions fail to distinguish between statistically significant clusters and those that may result from natural variation in the person's seizures. Ability to systematically define when a seizure cluster is significant for the individual carries major implications for treatment. However, there is no uniform consensus on how to define seizure clusters. This study proposes a principled statistical approach to defining seizure clusters that addresses these issues.

Methods: A total of 533,968 clinical seizures from 1,748 people with epilepsy in the Seizure Tracker™ seizure diary database were used for algorithm development. We propose an algorithm for automated individualized seizure cluster identification combining cumulative sum change-point analysis with bootstrapping and aberration detection, which provides a new approach to personalized seizure cluster identification at user-specified levels of clinical significance. We develop a standalone user interface to make the proposed algorithm accessible for real-time seizure cluster identification (ClusterCalc™). Clinical impact of systematizing cluster identification is demonstrated by comparing empirically-defined clusters to those identified by routine seizure cluster definitions. We also demonstrate use of the Hurst exponent as a standardized measure of seizure clustering for comparison of seizure clustering burden within or across patients.

Results: Seizure clustering was present in 26.7 % (95 % CI, 24.5-28.7 %) of people with epilepsy. Empirical tables were provided for standardizing inter- and intra-patient comparisons of seizure cluster tendency. Using the proposed algorithm, we found that 37.7-59.4 % of seizures identified as clusters based on routine definitions had high probability of occurring by chance. Several clusters identified by the algorithm were missed by conventional definitions. The utility of the ClusterCalc algorithm for individualized seizure cluster detection is demonstrated.

Significance: This study proposes a principled statistical approach to individualized seizure cluster identification and demonstrates potential for real-time clinical usage through ClusterCalc. Using this approach accounts for individual variations in baseline seizure frequency and evaluates statistical significance. This new definition has the potential to improve individualized epilepsy treatment by systematizing identification of unrecognized seizure clusters and preventing unnecessary intervention for random events previously considered clusters.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106330DOI Listing
July 2020

Prospective validation study of an epilepsy seizure risk system for outpatient evaluation.

Epilepsia 2020 01 2;61(1):29-38. Epub 2019 Dec 2.

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.

Objective: We conducted clinical testing of an automated Bayesian machine learning algorithm (Epilepsy Seizure Assessment Tool [EpiSAT]) for outpatient seizure risk assessment using seizure counting data, and validated performance against specialized epilepsy clinician experts.

Methods: We conducted a prospective longitudinal study of EpiSAT performance against 24 specialized clinician experts at three tertiary referral epilepsy centers in the United States. Accuracy, interrater reliability, and intra-rater reliability of EpiSAT for correctly identifying changes in seizure risk (improvements, worsening, or no change) were evaluated using 120 seizures from four synthetic seizure diaries (seizure risk known) and 120 seizures from four real seizure diaries (seizure risk unknown). The proportion of observed agreement between EpiSAT and clinicians was evaluated to assess compatibility of EpiSAT with clinical decision patterns by epilepsy experts.

Results: EpiSAT exhibited substantial observed agreement (75.4%) with clinicians for assessing seizure risk. The mean accuracy of epilepsy providers for correctly assessing seizure risk was 74.7%. EpiSAT accurately identified seizure risk in 87.5% of seizure diary entries, corresponding to a significant improvement of 17.4% (P = .002). Clinicians exhibited low-to-moderate interrater reliability for seizure risk assessment (Krippendorff's α = 0.46) with good intrarater reliability across a 4- to 12-week evaluation period (Scott's π = 0.89).

Significance: These results validate the ability of EpiSAT to yield objective clinical recommendations on seizure risk which follow decision patterns similar to those from specialized epilepsy providers, but with improved accuracy and reproducibility. This algorithm may serve as a useful clinical decision support system for quantitative analysis of clinical seizure frequency in clinical epilepsy practice.
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http://dx.doi.org/10.1111/epi.16397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980278PMC
January 2020

The seizure onset zone drives state-dependent epileptiform activity in susceptible brain regions.

Clin Neurophysiol 2019 09 2;130(9):1628-1641. Epub 2019 Jul 2.

Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address:

Objective: Due to variability in the patterns of propagation of interictal epileptiform discharges (IEDs), qualitative definition of the irritative zone has been challenging. Here, we introduce a quantitative approach toward exploration of the dynamics of IED propagation within the irritative zone.

Methods: We examined intracranial EEG (iEEG) in nine participants undergoing invasive monitoring for seizure localization. We used an automated IED detector and a community detection algorithm to identify populations of electrodes exhibiting IED activity that co-occur in time, and to group these electrodes into communities.

Results: Within our algorithmically-identified communities, IED activity in the seizure onset zone (SOZ) tended to lead IED activity in other functionally coupled brain regions. The tendency of pathological activity to arise in the SOZ, and to spread to non-SOZ tissues, was greater in the asleep state.

Conclusions: IED activity, and, by extension, the variability observed between the asleep and awake states, is propagated from a core seizure focus to nearby less pathological brain regions.

Significance: Using an unsupervised, computational approach, we show that the spread of IED activity through the epilepsy network varies with physiologic state.
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http://dx.doi.org/10.1016/j.clinph.2019.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730646PMC
September 2019

Neuroinflammation in neocortical epilepsy measured by PET imaging of translocator protein.

Epilepsia 2019 06 30;60(6):1248-1254. Epub 2019 May 30.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

Objectives: Neuroinflammation, implicated in epilepsy, can be imaged in humans with positron emission tomography (PET) ligands for translocator protein 18 kDa (TSPO). Previous studies in patients with temporal lobe epilepsy and mesial temporal sclerosis found increased [11C]PBR28 uptake ipsilateral to seizure foci. Neocortical foci present more difficult localization problems and more variable underlying pathology.

Methods: We studied 11 patients with neocortical seizure foci using [11C]PBR28 or [11C] N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA) 713, and 31 healthy volunteers. Seizure foci were identified with structural magnetic resonance imaging (MRI) and ictal video-electroencephalography (EEG) monitoring. Six patients had surgical resections; five had focal cortical dysplasia type 2A or B and one microdysgenesis. Brain regions were delineated using FreeSurfer and T1-weighted MRI. We measured brain radioligand uptake (standardized uptake values [SUVs]) in ipsilateral and contralateral regions, to compare calculated asymmetry indices [AIs; 200% *(ipsilateral - contralateral)/(ipsilateral + contralateral)] between epilepsy patients and controls, as well as absolute [11C]PBR28 binding as the ratio of distribution volume to free fraction (V /f ) in 9 patients (5 high affinity and 4 medium affinity binders) and 11 age-matched volunteers (5 high-affinity and 6 medium affinity) who had metabolite-corrected arterial input functions measured.

Results: Nine of 11 patients had AIs exceeding control mean 95% confidence intervals in at least one region consistent with the seizure focus. Three of the nine had normal MRI. There was a nonsignificant trend for patients to have higher binding than volunteers both ipsilateral and contralateral to the focus in the group that had absolute binding measured.

Significance: Our study demonstrates the presence of focal and distributed inflammation in neocortical epilepsy. There may be a role for TSPO PET for evaluation of patients with suspected neocortical seizure foci, particularly when other imaging modalities are unrevealing. However, a complex method, inherent variability, and increased binding in regions outside seizure foci will limit applicability.
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http://dx.doi.org/10.1111/epi.15967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268896PMC
June 2019

Recommendations for the use of structural magnetic resonance imaging in the care of patients with epilepsy: A consensus report from the International League Against Epilepsy Neuroimaging Task Force.

Epilepsia 2019 06 28;60(6):1054-1068. Epub 2019 May 28.

Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and treatment of epilepsy, particularly when surgery is being considered. Despite previous recommendations and guidelines, practices for the use of MRI are variable worldwide and may not harness the full potential of recent technological advances for the benefit of people with epilepsy. The International League Against Epilepsy Diagnostic Methods Commission has thus charged the 2013-2017 Neuroimaging Task Force to develop a set of recommendations addressing the following questions: (1) Who should have an MRI? (2) What are the minimum requirements for an MRI epilepsy protocol? (3) How should magnetic resonance (MR) images be evaluated? (4) How to optimize lesion detection? These recommendations target clinicians in established epilepsy centers and neurologists in general/district hospitals. They endorse routine structural imaging in new onset generalized and focal epilepsy alike and describe the range of situations when detailed assessment is indicated. The Neuroimaging Task Force identified a set of sequences, with three-dimensional acquisitions at its core, the harmonized neuroimaging of epilepsy structural sequences-HARNESS-MRI protocol. As these sequences are available on most MR scanners, the HARNESS-MRI protocol is generalizable, regardless of the clinical setting and country. The Neuroimaging Task Force also endorses the use of computer-aided image postprocessing methods to provide an objective account of an individual's brain anatomy and pathology. By discussing the breadth and depth of scope of MRI, this report emphasizes the unique role of this noninvasive investigation in the care of people with epilepsy.
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http://dx.doi.org/10.1111/epi.15612DOI Listing
June 2019

Infection with HHV-6 and its role in epilepsy.

Epilepsy Res 2019 07 29;153:34-39. Epub 2019 Mar 29.

Center for Neuroscience, Children's National Medical Center, George Washington University, 111 Michigan Ave NW, Washington, DC 20010, USA.

Infection with Human Herpesvirus-6 (HHV-6) has been associated with different epilepsy syndromes, including febrile seizures and status epilepticus, acute symptomatic seizures secondary to encephalitis and temporal lobe epilepsy. This neurotropic DNA virus is ubiquitous and primary infection occurs in up to 80% of children by age two years. While two viral variants have been identified, HHV-6B is the one that has been primarily linked to disease in humans, including epilepsy. After initial viremia, the virus can establish chronic latency in brain tissue, peripherally in tonsils and salivary glands and infect several different cell lines by binding to the complement regulator CD-46. In this review we will focus on discussing the evidence linking HHV-6 infection to different epilepsy syndromes and analyzing proposed pathogenic mechanisms.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.03.016DOI Listing
July 2019

Functional MRI and direct cortical stimulation: Prediction of postoperative language decline.

Epilepsia 2019 03 11;60(3):560-570. Epub 2019 Feb 11.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

Objective: To assess the ability of functional MRI (fMRI) to predict postoperative language decline compared to direct cortical stimulation (DCS) in epilepsy surgery patients.

Methods: In this 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.

Results: 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.

Significance: 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.
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http://dx.doi.org/10.1111/epi.14666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467056PMC
March 2019

fMRI prediction of naming change after adult temporal lobe epilepsy surgery: Activation matters.

Epilepsia 2019 03 11;60(3):527-538. Epub 2019 Feb 11.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

Objective: We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability.

Method: Thirty-five adults (mean age 37.5 ± 10.9 years, 13 male) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative MRI tissue map comparison. This mask provided the following: (a) resection volume; (b) overlap between resection and preoperative activation; and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance.

Results: Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjusted r = 0.28, P = 0.012). The percentage of top 10% fMRI activation resected (P = 0.017) was the most significant contributor. Other factors in the model included WA LI, ASO, volume of WA resected, and WA LI absolute value (extent of laterality).

Significance: Resection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection.
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http://dx.doi.org/10.1111/epi.14656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401285PMC
March 2019

The Feasibility and Impact of the EMOVE Intervention on Self-efficacy and Outcome Expectations for Exercise in Epilepsy.

J Neurosci Nurs 2019 Apr;51(2):95-100

Questions or comments about this article may be directed to Irene H. Dustin, PhD CRNP, at She is a Senior Nurse Consultant, National Institutes of Health, Bethesda, MD. Barbara Resnick, PhD CRNP FAAN FAANP, is Professor, University of Maryland, Baltimore, Baltimore, MD. Elizabeth Galik, PhD CRNP FAAN FAANP, is Professor, University of Maryland, Baltimore, Baltimore, MD. N. Jennifer Klinedinst, PhD MPH MSN FAHA, is Assistant Professor, University of Maryland, Baltimore, Baltimore, MD. Kathleen Michael, PhD CRRN, is Associate Professor, University of Maryland, Baltimore, Baltimore, MD. Edythe Wiggs, PhD, is Clinical Neuropsychologist, National Institutes of Health, Bethesda, MD. William H. Theodore, MD, is Chief, Clinical Epilepsy Section, National Institutes of Health, Bethesda, MD.

The purpose of this pilot study was to evaluate the feasibility of the self-efficacy based Epilepsy-Motivate and Outcome Expectations for Vigorous Exercise (EMOVE) intervention and report on the preliminary efficacy of this intervention aimed at improving exercise behaviors in adults with epilepsy. Methods: A single-group, repeated-measures design was used in 30 outpatients. Data were collected at baseline and 12 weeks after the intervention. Participant outcomes included Self-Efficacy and Outcome Expectations for Exercise in Epilepsy, Beck Depression Inventory-II, Quality of Life in Epilepsy Inventory-31, seizure frequency, average daily steps, and body mass index. Daily number of steps was measured using a wrist-worn activity monitor. Feasibility data were assessed using evidence of treatment fidelity including intervention delivery, receipt, and enactment. Results: Participants were single (63%), white (53%), female (63%), had a mean (SD) age of 46.7 (13) years (range, 26-68 years), had low levels of self-efficacy (mean, 5.10; range, 0-10) and high outcome expectations (mean, 3.90; range, 0-5), took under the recommended 10 000 steps per day (mean, 5107), and had an average of 6 seizures per month. Postintervention testing showed statistical improvement in depressive symptoms (mean [SD], 9.95 [9.47]; P < .05). There were no significant differences found for the other study outcomes. Our study showed the EMOVE intervention was feasible. Study participants had improved depressive symptoms. Future research should focus on increasing the sample size, improving exercise performance through group or individualized exercise sessions, and adding a control group to better evaluate the relationship between the intervention and improved depressive symptoms.
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http://dx.doi.org/10.1097/JNN.0000000000000425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399022PMC
April 2019

Mortality & recurrent seizure risk after new-onset seizure in HIV-positive Zambian adults.

BMC Neurol 2018 Dec 7;18(1):201. Epub 2018 Dec 7.

Epilepsy Division, Department of Neurology, University of Rochester School of Medicine & Dentistry, 265 Crittenden Blvd, CU420694, Rochester, NY, 14642-0694, USA.

Background: Recurrent seizure risks in HIV-positive people with new-onset seizure are largely unknown, making it challenging to offer optimal recommendations regarding antiepileptic drug (AED) initiation. Existing outcomes data is limited, and risk factor identification requires a diagnostic assessment, which is often unavailable in regions heavily effected by HIV, like sub-Saharan Africa.

Methods: HIV-positive Zambian adults with new-onset seizure were enrolled in a prospective cohort study to determine seizure recurrence and risk factors for recurrence. Seizure etiology was evaluated, and recurrent seizures and medication usage were assessed during clinic visits. Due to unexpectedly high mortality rates, predictors of death were evaluated using proportional hazards with Gray's test to compare cumulative incidence functions for recurrent seizure across groups adjusting for the competing outcome of death.

Results: 95 patients were enrolled (mean age 37 years, 43% female, 83% with Karnofsky > 50) and followed for a mean of 293 days (median 241 (IQR: 29-532)). At presentation, 50 (53%) were in status epilepticus. The majority (91, 85%) had advanced HIV disease and 65 (68%) were not on combined antiretroviral therapy (cART). After extensive workup, seizure etiology remained unknown in 16 (17%). Average time to cART initiation after enrollment was 61 days. During follow up, 37 (39%) died and 23 (24%) had recurrent seizure. Most deaths (25/37, 68%) occurred in the first 60 days post-index seizure. Individuals with advanced HIV were more likely to die (HR: 19.1 [95% CI: 1.1-333.4]) as were those whose seizure etiology remained unknown (HR: 2.2 [95% CI: 1.1-4.4]). Among participants that survived from enrolment to the end of data collection on 10 May 2013 (n = 58), 20 (34%) experienced recurrent seizures.

Conclusions: New-onset seizure among HIV-positive Zambian adults is associated with high mortality despite good functional status prior to presentation. Advanced HIV infection and failure to identify an underlying seizure etiology are associated with greater mortality. Recurrent seizures occur in over a third of survivors within only 2 years of follow-up. This provides evidence to support AED initiation after first seizure in HIV-positive individuals with advanced HIV disease at the time of presentation though the risks of AED-cART interactions remain a concern and warrant further study.
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http://dx.doi.org/10.1186/s12883-018-1205-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284303PMC
December 2018

Convection-Enhanced Delivery of Muscimol in Patients with Drug-Resistant Epilepsy.

Neurosurgery 2019 07;85(1):E4-E15

Electroencephalography Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

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 infusion but was unchanged in all patients during vehicle infusion. Mean beta frequencies did not differ significantly before, during, or after infusion periods. Infused fluid provided insufficient MRI-signal to track infusate distribution. In the 2 yr after standard epilepsy surgery, 1 patient had temporary reduction in seizure frequency and 2 patients were seizure-free.

Conclusion: CED of muscimol into the epileptic focus of patients with DRE did not damage adjacent brain parenchyma or adversely affect seizure surgery outcome. This study did not confirm that intracerebral muscimol infusion effectively suppressed seizures. A surrogate tracer is recommended to track infusion distribution to the epileptic focus and surrounding structures in future studies using CED to suppress the seizure focus.
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http://dx.doi.org/10.1093/neuros/nyy480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704347PMC
July 2019

Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study.

Lancet Neurol 2018 11 12;17(11):977-985. Epub 2018 Sep 12.

Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne, VIC, Australia. Electronic address:

Background: Epilepsy has long been suspected to be governed by cyclic rhythms, with seizure rates rising and falling periodically over weeks, months, or even years. The very long scales of seizure patterns seem to defy natural explanation and have sometimes been attributed to hormonal cycles or environmental factors. This study aimed to quantify the strength and prevalence of seizure cycles at multiple temporal scales across a large cohort of people with epilepsy.

Methods: This retrospective cohort study used the two most comprehensive databases of human seizures (SeizureTracker [USA] and NeuroVista [Melbourne, VIC, Australia]) and analytic techniques from circular statistics to analyse patients with epilepsy for the presence and frequency of multitemporal cycles of seizure activity. NeuroVista patients were selected on the basis of having intractable focal epilepsy; data from patients with at least 30 clinical seizures were used. SeizureTracker participants are self selected and data do not adhere to any specific criteria; we used patients with a minimum of 100 seizures. The presence of seizure cycles over multiple time scales was measured using the mean resultant length (R value). The Rayleigh test and Hodges-Ajne test were used to test for circular uniformity. Monte-Carlo simulations were used to confirm the results of the Rayleigh test for seizure phase.

Findings: We used data from 12 people from the NeuroVista study (data recorded from June 10, 2010, to Aug 22, 2012) and 1118 patients from the SeizureTracker database (data recorded from Jan 1, 2007, to Oct 19, 2015). At least 891 (80%) of 1118 patients in the SeizureTracker cohort and 11 (92%) of 12 patients in the NeuroVista cohort showed circadian (24 h) modulation of their seizure rates. In the NeuroVista cohort, patient 8 had a significant cycle at precisely 1 week. Two others (patients 1 and 7) also had approximately 1-week cycles. Patients 1 and 4 had 2-week cycles. In the SeizureTracker cohort, between 77 (7%) and 233 (21%) of the 1118 patients showed strong circaseptan (weekly) rhythms, with a clear 7-day period. Between 151 (14%) and 247 (22%) patients had significant seizure cycles that were longer than 3 weeks. Seizure cycles were equally prevalent in men and women, and peak seizure rates were evenly distributed across all days of the week.

Interpretation: Our results suggest that seizure cycles are robust, patient specific, and more widespread than previously understood. They align with the accepted consensus that most epilepsies have some diurnal influence. Variations in seizure rate have important clinical implications. Detection and tracking of seizure cycles on a patient-specific basis should be standard in epilepsy management practices.

Funding: Australian National Health and Medical Research Council.
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http://dx.doi.org/10.1016/S1474-4422(18)30274-6DOI Listing
November 2018

Characteristics of large patient-reported outcomes: Where can one million seizures get us?

Epilepsia Open 2018 09 4;3(3):364-373. Epub 2018 Jul 4.

Department of Neurology Albert Einstein College of Medicine and Montefiore Medical Center Bronx New York U.S.A.

Objective: To analyze data from Seizure Tracker, a large electronic seizure diary, including comparison of seizure characteristics among different etiologies, temporal patterns in seizure fluctuations, and specific triggers.

Methods: Zero-inflated negative binomial mixed-effects models were used to evaluate temporal patterns of seizure events (during the day or week), as well as group differences in monthly seizure frequency between children and adults and between etiologies. The association of long seizures with seizure triggers was evaluated using a mixed-effects logistic model with subject as the random effect. Incidence rate ratios (IRRs) and odds ratios were reported for analyses involving zero-inflated negative binomial and logistic mixed-effects models, respectively.

Results: A total of 1,037,909 seizures were logged by 10,186 subjects (56.7% children) from December 2007 to January 2016. Children had more frequent seizures than adults did (median monthly seizure frequency 3.5 vs. 2.7, IRR 1.26; p < 0.001). Seizures demonstrated a circadian pattern (higher frequency between 07:00 a.m. and 10:00 a.m. and lower overnight), and seizures were reported differentially across the week (seizure rates higher Monday through Friday than Saturday or Sunday). Longer seizures (>5 or >30 min) had a higher proportion of the following triggers when compared with shorter seizures: "Overtired or irregular sleep," "Bright or flashing lights," and "Emotional stress" (p < 0.004).

Significance: This study explored a large cohort of patients with self-reported seizures; strengths and limitations of large seizure diary databases are discussed. The findings in this study are consistent with those of prior work in smaller validated cohorts, suggesting that patient-recorded databases are a valuable resource for epilepsy research, capable of both replication of results and generation of novel hypotheses.
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http://dx.doi.org/10.1002/epi4.12237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119749PMC
September 2018

The expression of inflammatory markers and their potential influence on efflux transporters in drug-resistant mesial temporal lobe epilepsy tissue.

Epilepsia 2018 08 21;59(8):1507-1517. Epub 2018 Jul 21.

Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Objective: 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 samples from people with drug-resistant MTLE.

Methods: Formalin-fixed paraffin-embedded surgical brain tissue was obtained from 33 patients with drug-resistant MTLE. Multiplex immunofluorescence was used to quantify the expression and distribution of COX-1, COX-2, TSPO, P-gp, and BCRP.

Results: COX-1 was expressed in microglia, and COX-2 and TSPO were expressed in microglia and neurons. BCRP density correlated significantly with TSPO density, suggesting a potential relationship between inflammatory markers and efflux transporters.

Significance: To the best of our knowledge, this study is the first to measure the cellular expression of COX-1, COX-2, and TSPO in microglia, astrocytes, and neurons in surgical brain tissue samples from patients with drug-resistant MTLE. Further research is needed to determine the effects of the COX inflammatory pathway in epilepsy, and how it relates to the expression of the ABC transporters P-gp and BCRP.
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http://dx.doi.org/10.1111/epi.14505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356105PMC
August 2018

Generic antiepileptic drugs-Safe or harmful in patients with epilepsy?

Epilepsia 2018 07 12;59(7):1273-1281. Epub 2018 Jun 12.

National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

Generic antiepileptic drugs (AED) are significantly cheaper than brand name drugs, and may reduce overall health care expenditures. Regulatory bodies in Europe and North America require bioequivalence between generic and innovator drugs with regard to area under the plasma concentration-time curve (AUC) and peak plasma concentration (C ); strict cutoff values have been defined. The main issue is if bioequivalence ensures therapeutic equivalence. Are switches from brand to generic, or between generic AEDs entirely safe or potentially harmful in patients with epilepsy? We summarized and evaluated the available evidence from bioequivalence, health care utilization, and clinical studies on safety of generic AEDs. In most cases, variations in AUC and C were negligible when comparing innovator and generic AEDs. Due to interindividual pharmacokinetic and pharmacodynamic variability, measured differences between innovator and generic drugs may be the same as differences between different lots of the same brand. Studies from several countries based on insurance data have reported an increase in health care usage after switch from brand to generic AEDs; switchback rates are significantly higher for AEDs compared to other compounds. Patients may be confused, and nonadherence may increase, when AEDs are switched between manufacturers, perhaps due to changes in medication shape and color. But clinical studies do not report changes in seizure frequency and tolerability attributable to generics. Sufficient evidence indicates that most generics are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. We recommend administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.
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http://dx.doi.org/10.1111/epi.14439DOI Listing
July 2018

Different as night and day: Patterns of isolated seizures, clusters, and status epilepticus.

Epilepsia 2018 05 23;59(5):e73-e77. Epub 2018 Apr 23.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

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 likely at night compared to SE (OR = 0.85, 95% adjusted CI = 0.79-0.91). ISE was more likely at night compared to CWOS (OR = 1.35, 95% adjusted CI = 1.26-1.44) and CIS (OR = 1.65, 95% adjusted CI = 1.44-1.86). CWOS was more likely during the night compared to CIS (OR = 1.22, 95% adjusted CI = 1.05-1.39). With the exception of SE in children, our data suggest that more severe patterns favor daytime. This suggests distinct day/night preferences for different seizure patterns in children and adults.
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http://dx.doi.org/10.1111/epi.14076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934304PMC
May 2018

Postoperative EEG association with seizure recurrence: Analysis of the NIH epilepsy surgery database.

Epilepsia Open 2018 03 31;3(1):109-112. Epub 2018 Jan 31.

EEG Section NINDS National Institutes of Health Bethesda Maryland U.S.A.

The epilepsy surgery database from 1984 to 2012 at the National Institutes of Health (NIH) was reviewed to determine the association of postoperative electroencephalography (EEG) with seizure recurrence. Eighty-three patients were analyzed, with 41 having at least 5 years of follow-up. The relationship between epileptiform postoperative EEG findings and seizure recurrence at 1, 2, and 5 years was not significant, despite a significant decrease in abnormal EEG recordings after surgery. Clinicians use a variety of tools to predict seizure recurrence following epilepsy surgery to guide medication management and to modulate patient expectations. EEG is but one tool for assessing the likelihood of seizure recurrence following epilepsy surgery.
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http://dx.doi.org/10.1002/epi4.12097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839314PMC
March 2018

Is seizure frequency variance a predictable quantity?

Ann Clin Transl Neurol 2018 02 9;5(2):201-207. Epub 2018 Jan 9.

Clinical Epilepsy Section NINDS, NIH Bethesda Maryland 20892.

Background: 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.

Methods: 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.

Results: A consistent mathematical relationship was observed across datasets. The logarithm of the average seizure count was linearly related to the logarithm of the standard deviation with a high correlation ( > 0.83). The three datasets showed high predictive accuracy for this log-log relationship of 94%, compared with a predictive accuracy of 77% for a traditional prediction scheme. The independent validation set showed that the log-log predicted 94% of the correct ranges while the RR50 predicted 77%.

Conclusion: Reliably predicting seizure frequency variability is straightforward based on knowledge of mean seizure frequency, across several datasets. With further study, this may help to increase the power of RCTs, and guide clinical practice.
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http://dx.doi.org/10.1002/acn3.519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817844PMC
February 2018

A multi-dataset time-reversal approach to clinical trial placebo response and the relationship to natural variability in epilepsy.

Seizure 2017 Dec 23;53:31-36. Epub 2017 Oct 23.

National Institutes of Health, NINDS, United States. Electronic address:

Purpose: Clinical epilepsy drug trials have been measuring increasingly high placebo response rates, up to 40%. This study was designed to examine the relationship between the natural variability in epilepsy, and the placebo response seen in trials. We tested the hypothesis that 'reversing' trial direction, with the baseline period as the treatment observation phase, would reveal effects of natural variability.

Method: Clinical trial simulations were run with time running forward and in reverse. Data sources were: SeizureTracker.com (patient reported diaries), a randomized sham-controlled TMS trial, and chronically implanted intracranial EEG electrodes. Outcomes were 50%-responder rates (RR50) and median percentage change (MPC).

Results: The RR50 results showed evidence that temporal reversal does not prevent large responder rates across datasets. The MPC results negative in the TMS dataset, and positive in the other two.

Conclusions: Typical RR50s of clinical trials can be reproduced using the natural variability of epilepsy as a substrate across multiple datasets. Therefore, the placebo response in epilepsy clinical trials may be attributable almost entirely to this variability, rather than the "placebo effect".
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http://dx.doi.org/10.1016/j.seizure.2017.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722663PMC
December 2017

Monte Carlo simulations of randomized clinical trials in epilepsy.

Ann Clin Transl Neurol 2017 08 24;4(8):544-552. Epub 2017 May 24.

Clinical Epilepsy Section, NINDS National Institutes of Health Bethesda Maryland.

Background: 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.

Methods: 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.

Results: 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. Drug effect size had a major impact on trial efficiency and cost. Dropout did not have a major impact on trial efficiency or cost. Eligibility requirements impacted trial efficiency to a limited extent. Cost was minimized while maintaining statistical integrity with very short RCT durations.

Discussion: This study suggests that RCT parameters can be improved over current practice to reduce costs while maintaining statistical power. In addition, use of a large-scale population dataset in a massively parallel computing analysis allows exploration of the wider parameter space of RCT design prior to running a trial, which could help accelerate drug discovery and approval.
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http://dx.doi.org/10.1002/acn3.426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553226PMC
August 2017
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