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Epilepsy is increasingly considered a disorder of brain networks. Studying these networks with functional connectivity can help identify hubs that facilitate the spread of epileptiform activity. Surgical resection of these hubs may lead patients who suffer from drug-resistant epilepsy to seizure freedom. Here, we aim to map non-invasively epileptogenic networks, through the virtual implantation of sensors estimated with electric and magnetic source imaging, in patients with drug-resistant epilepsy. We hypothesize that highly connected hubs identified non-invasively with source imaging can predict the epileptogenic zone and the surgical outcome better than spikes localized with conventional source localization methods (dipoles). We retrospectively analysed simultaneous high-density electroencephalography (EEG) and magnetoencephalography data recorded from 37 children and young adults with drug-resistant epilepsy who underwent neurosurgery. Using source imaging, we estimated virtual sensors at locations where intracranial EEG contacts were placed. On data with and without spikes, we computed undirected functional connectivity between sensors/contacts using amplitude envelope correlation and phase locking value for physiologically relevant frequency bands. From each functional connectivity matrix, we generated an undirected network containing the strongest connections within sensors/contacts using the minimum spanning tree. For each sensor/contact, we computed graph centrality measures. We compared functional connectivity and their derived graph centrality of sensors/contacts inside resection for good (n = 22, ILAE I) and poor (n = 15, ILAE II–VI) outcome patients, tested their ability to predict the epileptogenic zone in good-outcome patients, examined the association between highly connected hubs removal and surgical outcome and performed leave-one-out cross-validation to support their prognostic value. We also compared the predictive values of functional connectivity with those of dipoles. Finally, we tested the reliability of virtual sensor measures via Spearman’s correlation with intracranial EEG at population- and patient-level. We observed higher functional connectivity inside than outside resection (P < 0.05, Wilcoxon signed-rank test) for good-outcome patients, on data with and without spikes across different bands for intracranial EEG and electric/magnetic source imaging and few differences for poor-outcome patients. These functional connectivity measures were predictive of both the epileptogenic zone and outcome (positive and negative predictive values ≥55%, validated using leave-one-out cross-validation) outperforming dipoles on spikes. Significant correlations were found between source imaging and intracranial EEG measures (0.4 ≤ rho ≤ 0.9, P < 0.05). Our findings suggest that virtual implantation of sensors through source imaging can non-invasively identify highly connected hubs in patients with drug-resistant epilepsy, even in the absence of frank epileptiform activity. Surgical resection of these hubs predicts outcome better than dipoles.

Vaccination against the SARS-CoV-2 virus is a primary tool to combat the COVID-19 pandemic. However, vaccination is a common seizure trigger in individuals with Dravet syndrome (DS). Information surrounding COVID-19 vaccine side effects in patients with DS would aid caregivers and providers in decisions for and management of COVID-19 vaccination.A survey was emailed to the Dravet Syndrome Foundation's Family Network and posted to the Dravet ParentCaregiver Support Group on Facebook between May and August 2021. Deidentified information obtained included demographics and vaccination status for individuals with DS. Vaccine type, side effects, preventative measures, and changes in seizure activity following COVID-19 vaccination were recorded. For unvaccinated individuals, caregivers were asked about intent to vaccinate and reasons for their decision.Of 278 survey responses, 120 represented vaccinated individuals with DS (median age = 19.5 years), with 50% reporting no side effects from COVID-19 vaccination. Increased seizures following COVID-19 vaccination were reported in 16 individuals, but none had status epilepticus. Of the 158 individuals who had not received a COVID-19 vaccination, 37 were older than 12 years (i.e., eligible at time of study), and only six of these caregivers indicated intent to seek vaccination. The remaining 121 responses were caregivers to children younger than 12 years, 60 of whom indicated they would not seek COVID-19 vaccination when their child with DS became eligible. Reasons for vaccine hesitancy were fear of increased seizure activity and concerns about vaccine safety.These results indicate COVID-19 vaccination is well tolerated by individuals with DS. One main reason for vaccine hesitancy was fear of increased seizure activity, which occurred in only 13% of vaccinated individuals, and none had status epilepticus. This study provides critical and reassuring insights for caregivers and health care providers making decisions about the safety of COVID-19 vaccinations for individuals with DS.

OBJECTIVE Pediatric stereoelectroencephalography (SEEG) has been increasingly performed in the United States, with published literature being limited primarily to large single-center case series. The purpose of this study was to evaluate the experience of pediatric epilepsy centers, where the technique has been adopted in the last several years, via a multicenter case series studying patient demographics, outcomes, and complications. METHODS A retrospective cohort methodology was used based on the STROBE criteria. ANOVA was used to evaluate for significant differences between the means of continuous variables among centers. Dichotomous outcomes were assessed between centers using a univariate and multivariate logistic regression. RESULTS A total of 170 SEEG insertion procedures were included in the study from 6 different level 4 pediatric epilepsy centers. The mean patient age at time of SEEG insertion was 12.3 ± 4.7 years. There was no significant difference between the mean age at the time of SEEG insertion between centers (p = 0.3). The mean number of SEEG trajectories per patient was 11.3 ± 3.6, with significant variation between centers (p < 0.001). Epileptogenic loci were identified in 84.7% of cases (144/170). Patients in 140 cases (140/170, 82.4%) underwent a follow-up surgical intervention, with 47.1% (66/140) being seizure free at a mean follow-up of 30.6 months. An overall postoperative hemorrhage rate of 5.3% (9/170) was noted, with patients in 4 of these cases (4/170, 2.4%) experiencing a symptomatic hemorrhage and patients in 3 of these cases (3/170, 1.8%) requiring operative evacuation of the hemorrhage. There were no mortalities or long-term complications. CONCLUSIONS As the first multicenter case series in pediatric SEEG, this study has aided in establishing normative practice patterns in the application of a novel surgical technique, provided a framework for anticipated outcomes that is generalizable and useful for patient selection, and allowed for discussion of what is an acceptable complication rate relative to the experiences of multiple institutions.

OBJECTIVE The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications. METHODS We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time-to-nth seizure), using a post hoc time-to-event (TTE) analysis of data from two Phase 3 placebo-controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2-19 years were randomized to placebo or adjunctive fenfluramine (Study 1: .7 mg/kg/day or .2 mg/kg/day; Study 2: .4 mg/kg/day with stiripentol). Data were analyzed by Kaplan-Meier TTE curves and waterfall plots. RESULTS The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7 mg/kg/day, 60%; fenfluramine .2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine .4 mg/kg/day, 58%; placebo, 2%). Median time-to-nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7 mg/kg/day, 13 weeks; .2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine .4 mg/kg/day, 13 weeks; placebo, 5 weeks; p

Objective Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. Methods Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. Results Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. Significance Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

Objective: To qualitatively explore the approach of pediatric epilepsy providers when counseling regarding surgical options for epilepsy, presenting risks and benefits of surgery, overcoming resistance to surgery, and fostering shared decision making with patients and families. Methods: We conducted in-depth interviews with 11 academic clinicians (5- neurologists, 5- epileptologists, 1- neurosurgeon) from a Level 4 pediatric epilepsy center to explore how physicians communicate and pursue surgical decision-making. Results: A blended inductive-deductive analysis revealed three key themes (with subthemes) of presurgical discussions: (1) Candidate selection and initial discussion about epilepsy surgery (neurologists compared to epileptologists, the timing of the discussion, reluctant families) (2) Detailed individualized counseling about epilepsy surgery (shared decision-making [enablers and barriers] and risk-benefit analysis [balancing risks and benefits, statistical benefit estimation, discussion about SUDEP, prognostication about cognitive and behavioral outcomes, risks of surgery]) (3) Tools to improve decision-making (educational interventions for patients and families and provider- and organization-specific interventions). Significance: Presurgical discussions lack uniformity among physicians who treat epilepsy. Despite general interest in collaborative decision-making, experts raised concern about lack of exposure to communication training and clinical tools for optimizing decision-making, a high number of families who do not feel equipped to share the decision making leaving the decision-making entirely to the physician, and paucity of practical resources for individualized risk-benefit counseling. Clinical practice guidelines should be developed to reduce existing practice variations in presurgical counseling. Further consensus is needed about when and how to initiate the conversation about epilepsy surgery, essential components of the discussion, and the utility of various tools to improve the utilization of epilepsy surgery.

Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial Nabbout R, Mistry A, Zuberi S, et al. JAMA Neurol. 2020;77(3):300-308. doi:10.1001/jamaneurol.2019.4113.Importance:Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens.Objective:To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens.Design, Setting, and Participants:This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens.Interventions:Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary.Main Outcomes and Measures:The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline.Results:A total of 115 eligible patients were identified; of these, 87 patients (mean [standard deviation], age 9.1 [4.8] years; 50 [57%] male patients; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43), or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (≥50%) reduction in monthly convulsive seizure frequency versus 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 [44%] patients taking fenfluramine vs 5 [11%] taking placebo), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension.Conclusions and Relevance:Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. Fenfluramine Hydrochloride for the Treatment of Seizures in Dravet Syndrome: A Randomised, Double-Blind, Placebo-Controlled Trial Lagae L, Sullivan J, Knupp K, et al. Lancet. 2019;394(10216):2243-2254. doi:10.1016/s0140-6736(19)32500-0Background:Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterized by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome.Methods:In this randomized, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic–atonic, generalized tonic–clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0.2 mg/kg/d, or fenfluramine 0.7 mg/kg/d, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0.7 mg/kg/d group versus placebo; 0.2 mg/kg/d versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with 2 identical protocols NCT02682927 and NCT02826863.Findings:Between January 15, 2016, and August 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive fenfluramine 0.2 mg/kg/d (39), fenfluramine 0.7 mg/kg/d (40), or placebo (40). During treatment, the median reduction in seizure frequency was 74.9% in the fenfluramine 0.7 mg/kg group (from median 20.7 seizures per 28 days to 4.7 seizures per 28 days), 42.3% in the fenfluramine 0.2 mg/kg group (from median 17.5 seizures per 28 days to 12.6 per 28 days), and 19.2% in the placebo group (from median 27.3 per 28 days to 22.0 per 28 days). The study met its primary efficacy end point, with fenfluramine 0.7 mg/kg/d showing a 62.3% greater reduction in mean MCSF compared with placebo (95% CI, 47.7-72·8, P < .0001); fenfluramine 0.2 mg/kg/d showed a 32.4% reduction in mean MCSF compared with placebo (95% CI, 6.2-52.3, P = .0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension.Interpretation:In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome.Funding:Zogenix.

Objective In selected children with drug-resistant epilepsy (DRE), epilepsy surgery is the most effective treatment option, but unfortunately remains highly underutilized. One of the critical obstacles to pursuing surgical therapy is parents/caregivers’ decision against surgery or to delay the surgery until no other treatment option exists. Understanding caregiver decision-making around epilepsy surgery can improve patient/caregiver experience and satisfaction while facilitating appropriate decision-making that optimizes clinical outcomes. The current review systematically explores the existing evidence on caregiver experience and the decision-making process toward epilepsy surgery. Methods The study was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic literature review. Databases (PubMed Ovid, PubMed Medline, Web of Science, CINHAL, PsycInfo) were systematically searched in February 2021 using a defined search strategy and inclusion/exclusion criteria. Total 1304 articles were screened for titles and abstracts, and 54 full-text articles were retrieved for further assessment. We included 14 articles with critical quality assessment using two different tools for qualitative and questionnaire-based studies. A qualitative content analysis was performed to characterize caregiver experience, perception, and decision-making toward favorable or unfavorable opinions of epilepsy surgery. Results Four concepts generated from the analysis may act as enablers or barriers to decision-making around epilepsy surgery: 1. Access to knowledge and information, 2. Communication and coordination issues, 3. Caregiver's emotional state, and 4. Socioeconomic effects. Subsequently, we provided a narrative synthesis of practice recommendations and a conceptual framework to adopt multi-pronged interventions to overcome identified diverse barriers to effective caregiver decision-making. Conclusion Multiple influences impact how caregivers decide about epilepsy surgery for their children, with no single factor identified as the primary driver for or against surgery. However, limited research has explored these influences. Future studies should focus on quantitatively examining factors to identify significant variables most likely to influence caregiver decision-making, ultimately overcoming barriers that limit utilization of epilepsy surgery as a treatment tool.

Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome Devinsky O, Patel AD, Cross JH, et al; GWPCARE3 Study Group. N Engl J Med. 2018;378:1888-1897.Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2-55 years) who had had 2 or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of 20 mg/kg of body weight (20-mg cannabidiol group) or 10 mg/kg (10-mg cannabidiol group) or matching placebo, administered in 2 equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period.A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percentage reduction from baseline in drop seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group ( P = .005 for the 20-mg cannabidiol group vs placebo group, and P = .002 for the 10-mg cannabidiol group vs placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations.Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 or 20 mg/kg/d to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560.) Long-Term Safety and Treatment Effects of Cannabidiol in Children and Adults With Treatment-Resistant Epilepsies: Expanded Access Program Results Szaflarski JP, Bebin EM, Comi AM, et al; CBD EAP Study Group. Epilepsia. 2018;59(8):1540-1548.Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2 to 10 mg/kg/d, titrated to a maximum dose of 25 to 50 mg/kg/d. Patient visits were every 2 to 4 weeks through 16 weeks and every 2 to 12 weeks thereafter. Efficacy end points included the percentage change from baseline in median monthly convulsive and total seizure frequency and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures versus baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit.Of 607 patients in the safety data set, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. Cannabidiol was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%).Results from this ongoing EAP support previous observational and clinical trial data, showing that add-on CBD may be an efficacious long-term treatment option for TRE. Randomized, Dose-Ranging Safety Trial of Cannabidiol in Dravet Syndrome Devinsky O, Patel AD, Thiele EA, et al; GWPCARE1 Part A Study Group. Neurology. 2018;90(14):e1204-e1211.To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome.Patients aged 4 to 10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, electrocardiograms, adverse events (AEs), seizure frequency, and suicidality.Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose proportional (AUCExposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. Cannabidiol resulted in more AEs than placebo but was generally well tolerated.This study provides class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well tolerated.

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs∗102] and c.920delG [p.Gly307Alafs∗11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

This cohort study of children with newly diagnosed epilepsy assesses patterns of use and diagnostic yield of genetic testing for early-life epilepsies.

Panayiotopoulos syndrome is a common idiopathic benign epilepsy that has a peak age of onset in early childhood. The syndrome is multifocal and shows significant electroencephalogram (EEG) variability, with occipital predominance. Although a benign syndrome often refers to the absence of neurological and neuropsychological deficits, the syndrome has recently been associated with cognitive impairments. Also, despite frequent occipital EEG abnormalities, research regarding the visual functioning of patients is less reported and often contradictory. The purpose of this study was to gain additional knowledge regarding the neurocognitive functioning of patients with Panayiotopoulos syndrome and specifically to address any visual processing deficits associated with the syndrome. Following diagnosis of the syndrome based on typical clinical and electrophysiological criteria, three patients, aged 5, 8, and 10years were referred by epileptologists for neuropsychological evaluation. Neuropsychological findings suggest that the patients had notable impairments on visual memory tasks, especially in comparison with verbal memory. Further, they demonstrated increased difficulty on picture memory suggesting difficulty retaining information from a crowded visual field. Two of the three patients showed weakness in visual processing speed, which may account for weaker retention of complex visual stimuli. Abilities involving attention were normal for all patients, suggesting that inattention is not responsible for these visual deficits. Academically, the patients were weak in numerical operations and spelling, which both rely partially on visual memory and may affect achievement in these areas. Overall, the results suggest that patients with Panayiotopoulos syndrome may have visual processing and visual memory problems that could potentially affect their academic capabilities. Identifying such difficulties may be helpful in creating educational and remedial assistance programs for children with this syndrome, as well as developing appropriate presentation of information to these children in school.

Nearly one third of patients with epilepsy become medically intractable, and the likelihood of achieving seizure freedom decreases with each additional medication trial. For appropriately chosen patients, epilepsy surgery affords the opportunity to achieve seizure freedom and potentially wean off medications. Epilepsy surgery, as with medical management, is not without adverse effects; to counsel patients wisely, practitioners need to understand the advantages and disadvantages of both. Randomized controlled trials in temporal lobe epilepsy reveal that epilepsy surgery achieves superior outcome compared to continued medical management. Although seizure freedom is the ultimate goal of any therapy, it represents a single outcome measure among a variety of other domains that affect patient welfare. It is imperative that providers understand the patient variables that affect these outcome measures and how these measures impact each other. Because the data comparing surgical therapy versus medical management for refractory epilepsy are limited, we review the available evidence comparing outcomes beyond seizure freedom including quality of life, cognition, psychosocial function, mortality, and financial costs.

Extraordinary progress has been made in charting the maturation of hematopoietic cells. However, these charted processes do not necessarily represent obligate pathways to specialized types of lymphocytes. In fact, there is a degree of plasticity associated with primitive progenitors. Moreover, all lymphocytes of a given kind are not necessarily produced through precisely the same sequence of events. Particularly contentious is the nature of cells that seed the thymus, because different progenitors can generate T cells under experimental circumstances. Non-renewing progenitors with a high density of c-Kit in bone marrow are likely to replenish the thymus under normal circumstances and most closely resemble canonical T cell progenitors.

We report a patient with Sturge-Weber syndrome without facial angioma, who presented with seizures and normal initial imaging results. The patient experienced several years without seizures before a sudden increase in seizure frequency, followed by an atypical evolution of imaging findings prompting biopsy to establish the diagnosis. This case highlights not only the rare presentation of isolated leptomeningeal angiomatosis, but also the potential for atypical evolution of imaging findings through the course of the disease. We detail the imaging findings of our case and review the potential pathophysiological basis for this appearance. Our experience suggests that repeat imaging is warranted in patients with suspected Sturge-Weber syndrome or those with intractable cryptogenic epilepsy, because some imaging features of Sturge-Weber syndrome may manifest over time.

Amantadine has demonstrated efficacy in small series for absence and myoclonic type seizures. We examined the efficacy of amantadine for treating refractory absence seizures in a cohort of pediatric patients. We retrospectively reviewed medical records for patients with absence seizures treated with amantadine at Cook Children's Medical Center after January 2007. Abstracted data included sex, age at initiation, concomitant antiepileptic drugs, amantadine dosing, and seizure frequency. Outcomes at 3, 6, and 12 months after initiation were categorized as90%, ≥50%, or50% reduction in seizure frequency. Of 13 patients included in the study, many were exposed to multiple antiepileptic drugs (median, 3; range, 1-6). Three were implanted with a vagus nerve stimulator. A response of at least 50% seizure reduction was reported in more than 50% of patients reviewed at 3, 6, and 12 months after initiating treatment. Among responders, a majority had90% reduction in seizure frequency. Amantadine may constitute an efficacious alternative treatment for refractory absence seizures.

Approximately 30% of epilepsy patients are medically intractable. Epilepsy surgery may offer cure or palliation, and neuromodulation and direct drug delivery are being developed as alternatives. Successful treatment requires correct localization of seizure onset zones and understanding surrounding functional cortex to avoid iatrogenic disability. Several neurophysiologic and imaging localization techniques have inherent individual weaknesses which can be overcome by multimodal analysis. We review common noninvasive techniques, then illustrate the value of multimodal analysis to localize seizure onset for targeted treatment.

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred., Author Summary Sensory motor neuropathies are diseases of the peripheral nervous system, involving primarily the nerves which control our muscles. These can result from either genetic or non-genetic causes, with genetic causes usually referred to as Charcot-Marie-Tooth (CMT) disease after the three clinicians who first described the key diagnostic markers. CMT patients lose muscle function, mainly in their arms and legs, with increasing severity during their lives. There are almost two dozen known genes that can mutate to cause CMT, and these fall into a wide variety of biochemical cellular pathways. We identified a group of patients with CMT from a small rural community, with good reason to suspect a genetic basis for their disease. Using high-throughput mapping and DNA sequencing technologies developed as part of the Human Genome Project, we were able to find the likely mutated gene, which was not any of the previously known CMT genes. Based on its sequence, the gene, called LRSAM1, probably plays a role in the correct metabolism of other proteins in the cell. Among the known CMT genes, some are also involved in protein metabolism, suggesting that this is a generally important pathway in the neurons that control muscle activity.

Newer antiepileptic drugs are reported to have better side-effect profiles than traditional antiepileptics, although the evidence to this effect and their efficacy is limited. We compare the efficacy and tolerability of levetiracetam and carbamazepine monotherapy in children with partial epilepsy ≤ 16 years of age. We identified 86 patients (66 levetiracetam, 20 carbamazepine) treated with initial monotherapy for partial epilepsy and followed for ≥ 6 months. Efficacy was based on the number of patients achieving seizure freedom of ≥ 6 months. Tolerability was based on parent-and patient-reported side effects. Forty-eight (73%) subjects on levetiracetam and 13 (65%) subjects on carbamazepine achieved 6 months of seizure freedom. A total of 70% of patients on carbamazepine and 45% of those on levetiracetam had at least 1 adverse event while on monotherapy ( P = .07). Levetiracetam and carbamazepine monotherapy demonstrate similar efficacy for treatment of partial epilepsy and are well tolerated in children.

Summary: Purpose: To describe three cases of refractory status epilepticus (RSE) in children responsive to topiramate (TPM). Methods: Patients with SE refractory to therapeutic doses of at least two antiepileptic medications were given TPM, 10 mg/kg/d, for 2 consecutive days, followed by maintenance doses of 5 mg/kg/d. Results: This protocol has been used in three cases of RSE at our institution. In each case, SE was aborted within 21 h of the initial dose of TPM. Two patients avoided pharmacologic coma, and one was rapidly weaned from continuous benzodiazepine infusion. Conclusions: Our experience indicates that TPM loading can be effective in the treatment of RSE in children.