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Background and ObjectivesTo explore efficacy/safety of natalizumab, a humanized monoclonal anti–α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy.MethodsParticipants 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.ResultsOf 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% confidence interval [CI] –46.1%–36.1%; p = 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; p = 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo.DiscussionAlthough 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.Trial Registration InformationThe ClinicalTrials.gov registration number is NCT03283371.Classification of EvidenceThis 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.

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

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.

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 HIV among people living with HIV in Zambia. METHODS: Eligible participants were ≥18 years of age, concurrently taking ASMs and ARVs for at least 1 month of the prior 6-month period. Data was obtained regarding medication and HIV history. CD4 counts, plasma viral loads (pVL), 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 on carbamazepine (37 on monotherapy), all had stable regimens in the prior 6 months. Among the 13 ARV regimens used, 68% had a TDF/3TC backbone. The majority (94%) were on a stable ARV regimen for > 6 months. Median CD4 nadir was 205 (IQR 88–389) cells/mm3, and 60% of participants had commenced ARVs treatment before advanced disease occurred. Mean CD4 count at enrollment was 464 cells/mm(3) (SD 226.3). Seven participants (14%) had a CD4 count1000 copies/mL, all were on carbamazepine. Three participants with elevated pVL had a CD4 count < 200 cells/mm(3). None had documented adherence concerns by providers; however, 2 had events concerning for clinical failure. HIV genotype testing showed mutations in 3 participants. Carbamazepine was not found to correlate with elevated pVL (p=0.58). 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/mm3 and were virally suppressed. Carbamazepine was not associated with an increased risk of virological failure or ARV-resistant HIV.

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 ( P = .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

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.

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.

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.

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.

Summary 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.

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.

Highlights • Multiscale image filters provide a good representation of local cortical appearance. • Most FCD lesions and some normal cortical regions appear as outliers in our model. • FCDs appear similar to the anterior insula and some paralimbic cortical regions. • Our constrained outlier detection approach allows for automated FCD detection., 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, T2 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.

Carefully selected patients with drug-resistant epilepsy may be candidates for resective surgery. Neuroimaging, including positron emission tomography (PET), magnetic resonance imaging (MRI), and ictal single-photon emission computed tomography (SPECT), are important clinical tools for presurgical seizure focus localization. MRI is an essential part of evaluation for patients with epilepsy. Structural studies may show focal abnormalities such as mesial temporal sclerosis or focal cortical dysplasia, which are the pathological substrates of seizure initiation. Functional localization data from arterial spin labeling for cerebral blood flow and spike-triggered or resting-state signal acquisition are potentially valuable as well. PET and SPECT usually only are performed for patients being considered for surgery. PET may show decreased interictal glucose metabolism in the epileptogenic zone. PET may also contribute to understanding the pathophysiology of epilepsy through the use of ligands for neurotransmitter receptors and neuroinflammation. Reduced benzodiazepine receptor binding may have occasional clinical relevance. Ictal SPECT may show increased blood flow if the tracer is injected soon after seizure onset, particularly if an interictal scan is subtracted and the image co-registered with structural MRI. When interpreting imaging in epilepsy, it is important to consider the clinical context, ictal semiology, and electrographic studies.

Background: Experimental and clinical findings suggest a crucial role of inflammation in epileptogenesis. We aimed to analyze levels of inflammatory cytokines in plasma and saliva from children with acute seizures and healthy controls and measure their associations with HHV6 and EBV infection. Methods: We analyzed plasma from 36 children within 24 hours of acute 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 ddPCR for viral DNA. Statistical analysis included Wilcoxon Rank Sum test, Fisher’s exact test, ANOVA and Spearman correlation. Results: Compared to controls, children with breakthrough seizures (n=18) had higher levels of CCL11 (p

Summary 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 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

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 (Cmax ); 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 Cmax 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.

Summary 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.

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".

Objective Presurgical language assessment can help minimize damage to eloquent cortex during resective epilepsy surgery. Two methods for presurgical language mapping are functional MRI (fMRI) and direct cortical stimulation (DCS) of implanted subdural electrodes. We compared fMRI results to DCS to help optimize noninvasive language localization and assess its validity. Methods We studied 19 patients referred for presurgical evaluation of drug-resistant epilepsy. Patients completed four language tasks during preoperative fMRI. After subdural electrode implantation, we used DCS to localize language areas. For each stimulation site, we determined whether language positive electrode pairs intersected with significant fMRI activity clusters for language tasks. Results Sensitivity and specificity depended on electrode region of interest radii and statistical thresholding. For patients with at least one language positive stimulation site, an auditory description decision task provided the best trade-off between sensitivity and specificity. For patients with no language positive stimulation sites, fMRI was a dependable method of excluding eloquent language processing. Interpretation Language fMRI is an effective tool for determining language lateralization before electrode implantation and is especially useful for excluding unexpected critical language areas. It can help guide subdural electrode implantation and narrow the search for eloquent cortical areas by DCS. Ann Neurol 2017;81:526-537.

SummaryObjective It is currently unknown whether knowledge of clinically silent (electrographic) seizures improves the statistical efficiency of clinical trials. Methods Using data obtained from 10 patients with chronically implanted subdural electrodes over an average of 1 year, a Monte Carlo bootstrapping simulation study was performed to estimate the statistical power of running a clinical trial based on (1) patient-reported seizures with intracranial electroencephalogram (icEEG) confirmation, (2) all patient-reported events, or (3) all icEEG-confirmed seizures. A “drug” was modeled as having 10%, 20%, 30%, 40%, and 50% efficacy in 1,000 simulated trials each. Outcomes were represented as percentage of trials that achieved p < 0.05 using Fisher's exact test for 50% responder rates (RR50) and the Wilcoxon rank-sum test for median percentage change (MPC). Results At each simulated drug strength, the MPC method showed higher power than RR50. As drug strength increased, statistical power increased. For all cases except RR50 with drug of 10% efficacy, using patient-reported events (with or without icEEG confirmation) was not as statistically powerful as using all available intracranially confirmed seizures (p < 0.001). Significance With simulation, this study demonstrates that additional accuracy in seizure detection using chronically implanted icEEG improves statistical power of clinical trials. Newer invasive and noninvasive seizure detection devices may have the potential to provide greater statistical efficiency, accelerate drug discovery, and lower trial costs.

Objective:To assess the diagnostic accuracy and prognostic value of functional MRI (fMRI) in determining lateralization and predicting postsurgical language and memory outcomes.Methods: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 Results and recommendations: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 considered for lateralizing memory functions in place of IAP in patients with MTLE (Level C) but is of unclear utility in other epilepsy types (Level U). fMRI of verbal memory or language encoding should be considered for predicting verbal memory outcome (Level B). fMRI using nonverbal memory encoding may be considered for predicting visuospatial memory outcomes (Level C). Presurgical fMRI could be an adequate alternative to IAP memory testing for predicting verbal memory outcome (Level C). Clinicians should carefully advise patients of the risks and benefits of fMRI vs IAP during discussions concerning choice of specific modality in each case.

SummaryObjective 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. Methods 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. Results 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 focal seizures when considering only evaluable data). These same thresholds resulted in 25–146 min between false alarms. The sequential probability of ictal SpO2 revealed a potential common seizure termination pathway of desaturation. A statistical model of corrected QT intervals (QTc), heart rate (HR), and SpO2 revealed close cardiopulmonary coupling ictally. Joint probability maps of QTc and SpO2 demonstrated that many patients had baseline dysfunction in either cardiac, pulmonary, or both domains, and that ictally there was dissociation—some patients exhibited further dysfunction in one or both domains. Significance Optimal selection of continuous pulse oximetry thresholds involves a tradeoff between seizure detection accuracy and false alarm frequency. Alarming at 86% for patients that tend to have fewer false alarms and at 80% for those who have more, would likely result in a reasonable tradeoff. The cardiopulmonary findings may lead to SUDEP biomarkers and early seizure termination therapies.

Purpose There is controversy about relative contributions of ictal scalp video EEG recording (vEEG), routine scalp outpatient interictal EEG (rEEG), intracranial EEG (iEEG) and MRI for predicting seizure-free outcomes after temporal lobectomy. We reviewed NIH experience to determine contributions at specific time points as well as long-term predictive value of standard pre-surgical investigations. Methods Raw data was obtained via retrospective chart review of 151 patients. After exclusions, 118 remained (median 5 years follow-up). MRI-proven mesial temporal sclerosis (MTSr) was considered a separate category for analysis. Logistic regression estimated odds ratios at 6-months, 1-year, and 2 years; proportional hazard models estimated long-term comparisons. Subset analysis of the proportional hazard model was performed including only patients with commonly encountered situations in each of the modalities, to maximize statistical inference. Results Any MRI finding, MRI proven MTS, rEEG, vEEG and iEEG did not predict two-year seizure-free outcome. MTSr was predictive at six months (OR=2.894, p=0. 0466), as were MRI and MTSr at one year (OR=10.4231, p=0. 0144 and OR=3.576, p=0. 0091). Correcting for rEEG and MRI, vEEG failed to predict outcome at 6 months, 1year and 2 years. Proportional hazard analysis including all available follow-up failed to achieve significance for any modality. In the subset analysis of 83 patients with commonly encountered results, vEEG modestly predicted long-term seizure-free outcomes with a proportional hazard ratio of 1.936 (p=0.0304). Conclusions In this study, presurgical tools did not provide unambiguous long-term outcome predictions. Multicenter prospective studies are needed to determine optimal presurgical epilepsy evaluation.

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

ObjectiveWe conducted clinical testing of an automated Bayesian machine learningalgorithm (Epilepsy Seizure Assessment Tool [EpiSAT]) for outpatient seizure risk assessment using seizure counting data, and validated performance against specialized epilepsy clinicianexperts.MethodsWe conducted a prospective longitudinal study of EpiSAT performance against 24 specialized clinician expertsat three tertiary referral epilepsy centers in the United States. Accuracy, interrater reliability, and intra-rater reliability of EpiSATfor correctly identifyingchanges inseizure 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.ResultsEpiSAT 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).SignificanceThese 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.

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(T)/f(P)) 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.

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.

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.

OBJECTIVE: To assess functional MRI’s (fMRI) ability to predict postoperative language decline compared to direct cortical stimulation 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 one-year follow up. All patients completed preoperative language fMRI, mapping with direct cortical stimulation 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 direct cortical stimulation 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 one year after surgery. Two of four patients had overlap of fMRI activation, language positive electrodes in basal temporal regions (within 1cm), and resection. Two had overlap between resection volume and fMRI activation, but not direct cortical stimulation. fMRI demonstrated 100% sensitivity and 46% specificity for outcome compared to direct cortical stimulation (50% and 85%, respectively). When fMRI and direct cortical stimulation language findings were concordant, the combined tests showed 100% sensitivity and 75% specificity for language outcome. Patients with language decline tended to have more fMRI activated voxels overlapping resection (Mann-Whitney test, p=0.068). Seizure onset age, resection side, type, volume, or one 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 fMRI may be more sensitive and less specific than direct cortical stimulation. Together they may predict outcome better than either test alone.

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.

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 r2 = 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.

Location data are becoming easier to obtain and are now bundled with other metadata in a variety of biomedical research applications. At the same time, the level of sophistication required to protect patient privacy is also increasing. In this article, we provide guidance for institutional review boards (IRBs) to make informed decisions about privacy protections in protocols involving location data. We provide an overview of some of the major categories of technical algorithms and medical–legal tools at the disposal of investigators, as well as the shortcomings of each. Although there is no “one size fits all” approach to privacy protection, this article attempts to describe a set of practical considerations that can be used by investigators, journal editors, and IRBs.

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.

Objective Seizure frequency variability is associated with placebo responses in randomized controlled trials (RCT). Increased variability can result in drug misclassification and, hence, decreased statistical power. We investigated a new method that directly incorporated variability into RCT analysis, Z V . Methods Two models were assessed: the traditional 50%-responder rate (RR50), and the variability-corrected score, Z V . Each predicted seizure frequency upper and lower limits using prior seizures. Accuracy was defined as percentage of time-intervals when the observed seizure frequencies were within the predicted limits. First, we tested the Z V method on three datasets (SeizureTracker: n = 3016, Human Epilepsy Project: n = 107, and NeuroVista: n = 15). An additional independent SeizureTracker validation dataset was used to generate a set of 200 simulated trials each for 5 different sample sizes (total N = 100 to 500 by 100), assuming 20% dropout and 30% drug efficacy. “Power” was determined as the percentage of trials successfully distinguishing placebo from drug (p Results Prediction accuracy across datasets was, Z V : 91–100%, RR50: 42–80%. Simulated RCT Z V analysis achieved >90% power at N = 100 per arm while RR50 required N = 200 per arm. Significance Z V may increase the statistical power of an RCT relative to the traditional RR50.

For unknown reasons, placebos reduce seizures in clinical trials in many patients. It is also unclear why some drugs showing statistical superiority to placebo in one trial may fail to do so in another. Using Seizuretracker.com, a patient-centered database of 684,825 seizures, we simulated "placebo" and "drug" trials. These simulations were employed to clarify the sources of placebo effects in epilepsy, and to identify methods of diminishing placebo effects. Simulation 1 included 9 trials with a 6-week baseline and 6-week test period, starting at time 0, 3, 6…24 months. Here, "placebo" reduced seizures regardless of study start time. Regression-to-the-mean persisted only for 3 to 6 months. Simulation 2 comprised a 6-week baseline and then 2 years of follow-up. Seizure frequencies continued to improve throughout follow-up. Although the group improved, individuals switched from improvement to worsening and back. Simulation 3 involved a placebo-controlled "drug" trial, to explore methods of placebo response reduction. An efficacious "drug" failed to demonstrate a significant effect compared with "placebo" (p = 0.12), although modifications either in study start time (p = 0.025) or baseline population reduction (p = 0.0028) allowed the drug to achieve a statistically significant effect compared with placebo. In epilepsy clinical trials, some seizure reduction traditionally attributed to placebo effect may reflect the natural course of the disease itself. Understanding these dynamics will allow future investigations into optimal clinical trial design and may lead to identification of more effective therapies. Ann Neurol 2015;78:329-336.