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To evaluate safety and tolerability of long-term treatment with diazepam nasal spray (Valtoco) for seizure clusters in patients aged six to 17 years.The study enrolled patients aged six to 65 years with frequent seizure clusters. Age- and weight-based doses of diazepam nasal spray were administered; second doses were permitted if needed. Safety assessments included treatment-emergent adverse events (TEAEs).Of 163 treated patients, 45 (27.6%) were aged six to 11 years and 33 (20.2%) were aged 12 to 17 years. Mean doses per month were 2.1 in the 6 to 11 subgroup and 2.4 in the 12 to 17 subgroup. Of 1634 seizure clusters in pediatric patients, 186 (11.4%) required a second dose of diazepam nasal spray within 24 hours of the first dose. Similar proportions of TEAEs and serious TEAEs were reported in 6 to 11 (91.1%, 40.0%) and 12 to 17 subgroups (81.8%, 30.3%), respectively. No serious TEAEs were considered treatment related, and no patients discontinued because of TEAEs. Treatment-related TEAEs were more frequent in the 12 to 17 subgroup; only epistaxis and somnolence occurred in two or more patients overall. TEAE rates were similar across subgroups that received concomitant clobazam (90.0%), received prior diazepam rectal gel (90.9%), and were administered less than two versus greater than or equal to two doses per month (87.2% for both) of diazepam nasal spray. Most survey respondents (88%) were satisfied or very satisfied with treatment.In this long-term safety analysis in pediatric patients with seizure clusters, repeated doses of diazepam nasal spray demonstrated a safety profile consistent across subgroups. These data support the dosing guidelines for diazepam nasal spray according to age and weight for pediatric patients.

The safety of transcranial magnetic stimulation (TMS) has been previously evaluated in healthy volunteers and clinical adult populations. We sought to fill the gap in safety of TMS functional mapping in a clinical, predominately pediatric cohort.In a retrospective chart review, we assessed TMS motor and language mapping studies in persons with epilepsy or brain tumor for adverse events and safety of TMS, and in patients with cranial metal.Out of 500 TMS sessions attempted in 429 individual patients (51% males, 82% ≤ 18 y), seizures occurred in 29 sessions (5.8%) during or after TMS with semiology consistent with their typical presentation and 53 patients (10.6%) experienced pain during stimulation. TMS was completed safely in 276 patients with cranial metal.Most TMS-related adverse events were benign and transient; the most serious safety events were seizures that could not be conclusively attributed to TMS. However, useful mapping results were obtained in almost all patients. Presence of cranial metal did not adversely affect TMS mapping. We show that TMS functional mapping is safe in a largely pediatric clinical cohort.This study demonstrates the safety of TMS functional mapping in patients with refractory epilepsy, brain tumor or cranial metal and fills a gap in knowledge for TMS safety in pediatric clinical population.

Following approval by the US Food and Drug Administration (FDA) in late 2019, cenobamate (Xcopri) has been utilized to treat adults with focal seizures. Based on its robust efficacy from the phase 2 trials, we began using cenobamate in our adolescent and young adult patients whose seizures were not controlled with previously available options. This study expanded its real-world application to this cohort with focal epilepsy and a history of drug-related rash.We conducted a retrospective study of our patients exposed to cenobamate (n = 45). We evaluated dosage and serum levels, efficacy, drug interactions, and adverse effects.After gradually increasing cenobamate to clinical effect using the FDA-approved dosing protocol, 60% (n = 22) of patients were responders. Adolescents were treated with an average daily dose of 204.0 mg, and adults with 223.4 mg cenobamate, and had serum levels of 20.5 μg/mL and 26.7 μg/mL, respectively. The side effect profile observed was similar to that seen in the phase 2/3 registry trials. Importantly, patients with a prior history of rash to other medications or antiseizure medications (n = 5) experienced no rashes related to cenobamate.This real-world study supports the findings of prior controlled studies regarding the efficacy of cenobamate as a treatment for focal seizures in adolescents and suggests that patients with a history of rash may benefit from this medication.

An exploratory analysis from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray for acute treatment of seizure clusters assessed the use of a second dose up to 24 hours after the initial dose and effectiveness in potentially reducing the number of seizures.Seizures and doses were recorded in diaries.Of 175 patients enrolled, 163 received ≥1 dose of diazepam nasal spray and were included in the safety population; those patients received a total of 4390 doses for a total of 3853 seizure clusters. Less than half of these patients used a second dose a least once during the study (79 patients [48.5%]), with a total of 485 second doses for seizure clusters (12.6% of all seizure clusters). Among these 79 patients, 33 (41.8%) used only one second dose during the study (range: 1-82). The proportion of seizure clusters treated with a second dose over time was consistently low across 24 h: 0-4 h, 152 (3.9%); 4-6 h, 72 (1.9%); 6-8 h, 39 (1.0%); 8-12 h, 55 (1.4%); 12-16 h, 42 (1.1%); 16-20 h, 42 (1.1%); 20-24 h, 83 (2.2%). Rates of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs occurring within 1 day of a second dose were low (15.2% and 5.1%, respectively).Patients with epilepsy may experience seizure clusters lasting up to 24 hours, and little is known about the effectiveness of rescue therapies for that duration. The current labeling of the US Food and Drug Administration (FDA)-approved outpatient treatments for seizure clusters (rectal diazepam, intranasal midazolam, and diazepam nasal spray) allows for a second dose, if needed, for control. These findings support the safety profile of second doses, and the low use supports the effectiveness of diazepam nasal spray across 24 hours.

Clinical studies of rescue medications for seizure clusters are limited and are designed to satisfy regulatory requirements, which may not fully consider the needs of the diverse patient population that experiences seizure clusters or utilize rescue medication. The purpose of this narrative review is to examine the factors that contribute to, or may influence the quality of, seizure cluster research with a goal of improving clinical practice. We address five areas of unmet needs and provide advice for how they could enhance future trials of seizure cluster treatments. The topics addressed in this article are: (1) unaddressed end points to pursue in future studies, (2) roles for devices to enhance rescue medication clinical development programs, (3) tools to study seizure cluster prediction and prevention, (4) the value of other designs for seizure cluster studies, and (5) unique challenges of future trial paradigms for seizure clusters. By focusing on novel end points and technologies with value to patients, caregivers, and clinicians, data obtained from future studies can benefit the diverse patient population that experiences seizure clusters, providing more effective, appropriate care as well as alleviating demands on health care resources.

Objective Need for rescue therapy differs among patients with seizure clusters. Diazepam nasal spray is approved to treat seizure clusters in patients with epilepsy ≥6 years of age. This analysis used interim data from a phase 3 safety study to assess safety profile and effectiveness of diazepam nasal spray using average number of doses/month as a proxy measurement. Methods This phase 3, open‐label, repeat‐dose, safety study of diazepam nasal spray enrolled patients (6‐65 years) with epilepsy and need of benzodiazepine rescue. Patients were stratified by average number of doses/month (5, very‐high frequency). Safety was evaluated based on treatment‐emergent adverse events (TEAEs), assessed nasal irritation, and olfaction. The proportion of treatments given as a second dose was used as an exploratory proxy for effectiveness. Results Of 175 enrolled patients (data cutoff, October 31, 2019), 158 received ≥1 dose of diazepam nasal spray. Frequency of use was moderate in 43.7% of patients, high in 50.6% of patients, and very high in 5.7% of patients. Patients treated 3397 seizure episodes (moderate frequency, 14.2%; high frequency, 59.9%; very high frequency, 25.8%). Nasal discomfort was the most common treatment‐related TEAE in all groups. No notable changes in nasal irritation or olfaction were observed. Second doses represented only 2.5%, 7.5%, and 17.2% of all doses in the moderate‐, high‐, and very‐high‐frequency groups, respectively. Overall retention rate was 82.9%, without an observed relationship to frequency of use. Significance Frequency of dosing diazepam nasal spray had little impact on the safety/tolerability profile across a range of 5 doses/month. Effectiveness was suggested for all dosing frequencies by the high proportion of seizure clusters not treated with a second dose. These results support the utility, safety profile, and effectiveness of diazepam nasal spray across frequencies of seizure cluster burden.

Objective Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness. Methods A long‐term, phase 3, open‐label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen. Results Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6–65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no‐benzodiazepine group. Findings were similar in a sub‐analysis of patients who were (n = 44) or were not (n = 75) taking clobazam. Significance This analysis of patients from a long‐term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub‐analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use.

Resection of an epileptogenic focus improves seizure control in patients with drug-resistant epilepsy. There is little data available on usefulness of epilepsy surgery in childhood cancer survivors with drug-resistant epilepsy. To learn about seizure outcome after epilepsy surgery in childhood cancer survivors, we retrospectively reviewed charts of 42 children who were referred to an epilepsy center for surgical evaluation. Sixteen children (38%) were offered epilepsy surgery and 10 consented. Seizure outcome was classified based on International League Against Epilepsy outcome scale. All 10 children were having multiple seizures a month on therapeutic doses of three antiepilepsy drugs (AEDs). At a median follow-up of 5.6 years after epilepsy surgery, three children had class 1 outcome (no seizures), four had class 3 outcome (1–3 seizure days/year), and three had class 4 outcome (≥ 50% reduction in seizure frequency). One child was off AEDs, seven were on a single AED, and two were on three AEDs at their last follow-up. Epilepsy surgery had low morbidity and improved seizure control in childhood cancer survivors with drug-resistant epilepsy. Childhood cancer survivors with drug-resistant epilepsy should be referred to an epilepsy center for a higher level of care.

Introduction: Patients with epilepsy may experience seizure clusters (SCs), which are considered a medical emergency requiring immediate treatment. Besides seizures and seizure-related injuries, pa...

Introduction: Despite US FDA approval of cannabidiol (CBD) liquid (Epidiolex®), patients with epilepsy still supplement prescription treatments with dispensary CBD. This study aimed to evaluate therapeutic effectiveness of dispensary CBD. Methods: We retrospectively collected dosage information, CBD serum levels, efficacy, and adverse effects from patient charts (children, adolescents, adults) (n = 18). Results: All 18 patients showed no clinical benefit from dispensary CBD as detectable serum levels never reached a therapeutic range of 150 ng/mL (6 patients had barely detectable levels that were below laboratory reporting thresholds). Minute levels of tetrahydrocannabinol (THC) were found in 3 patients, and moderate levels were found in 1 patient. Conclusion: Dispensary CBD failed to reach effective therapeutic levels in all of these patients. The presence of THC demonstrates the current lack of regulation of dispensary CBD. Anecdotal reports of clinical effectiveness should be considered an effect of concomitant prescription antiseizure medications and not dispensary CBD.

Objective To assess the retention rate, efficacy, safety, and dosing of perampanel administered to patients with epilepsy during routine clinical care in the retrospective phase IV, PROVE Study (NCT03208660). Methods Exposure, efficacy, and safety data were obtained from the medical records of patients initiating perampanel after January 1, 2014, across 29 US study sites. The cutoff date for this interim analysis was October 10, 2018. The primary efficacy endpoint was retention rate. Secondary efficacy endpoints included median percent changes in seizure frequency, seizure‐freedom rate, and overall investigator impression of seizure effect. Results All enrolled patients (N = 1121) received perampanel. Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 16.6 (14.7) months; overall mean (SD) daily perampanel dose was 5.7 (2.7) mg. Perampanel uptitration occurred weekly (21.1%), biweekly (23.8%), every 3 weeks (1.5%), other (43.3%), and unknown (10.3%). Across the Safety Analysis Set (N = 1121), retention rate on perampanel at 24 months was 49.5% (n = 319/645). At 12 months, the median reduction in seizure frequency per 28 days from baseline in the small number of patients for whom data were available was 75.0% (n = 85), and 30/85 (35.3%) patients were seizure free. Based on investigator impression at the end of treatment, improvement, no change (ie, stable), or worsening of seizures was reported in 54.3%, 33.7%, and 12.0% of patients, respectively. Treatment‐emergent adverse events occurred in 500 (44.6%) patients; the most common were dizziness (9.2%), aggression (5.4%), and irritability (4.5%). Serious treatment‐emergent adverse events occurred in 32 (2.9%) patients. Significance Favorable retention and sustained efficacy were demonstrated for ≥12 months following initiation of perampanel during routine clinical care in patients with epilepsy.

Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration's (FDA's) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries. As there are key differences in clinical evidence of perampanel as adjunctive therapy vs monotherapy, we review the clinical outcomes of perampanel when administered as primary or secondary monotherapy. Eight publications reporting the efficacy and safety outcomes of perampanel monotherapy in clinical trial and real-world settings were selected during our literature search and are included; these comprise three Eisai-sponsored studies in patients with epilepsy: one prospective, open-label, Phase III clinical trial of patients with newly diagnosed epilepsy (Study 342 [FREEDOM]) and two retrospective, real-world Phase IV studies of patients with epilepsy who received perampanel during routine clinical care (Studies 504 and 506 [PROVE]); and five retrospective, real-world studies in patients with epilepsy who were prescribed perampanel during routine clinical care. Results from these studies demonstrated that seizure freedom may be achieved following treatment with perampanel monotherapy (either primary or secondary), with favorable retention rates and safety profiles. Overall, the clinical evidence supports the use of perampanel monotherapy both in newly diagnosed patients and in those who have been unable to control their seizures with other ASMs.

International audience; Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.

Objective Localization of epileptic seizures, usually characterized by abnormal hypersynchronous wave patterns from the cortex, remains elusive. We present a novel, robust method for automatic localization of seizures on the scalp from clinical electroencephalogram (EEG) data. Methods Seizure patient EEG data was decomposed via the Hilbert Transform and processed through the following methodology: sorting the analytic amplitude (AA) in the time instance, locating the maximum amplitude within the vector of channels, cross-correlating amplitude values in the time index with the channel vector. The channel with highest AA value in time was located. Results Our approach provides an automated way to isolate the epi-genesis of seizure events with 93.3% precision and 100% sensitivity. The method differentiates seizure-related neural activity from other common EEG noise artifacts (e.g., blinks, myogenic noise). Conclusions We evaluated performance characteristics of our source location methodology utilizing both phase and energy of EEG signals from patients who exhibited seizure events. Feasibility of the new algorithm is demonstrated and confirmed. Significance The proposed method contributes to high-performance scalp localization for seizure events that is more straightforward and less computationally intensive than other methods (e.g., inverse source modeling). Ultimately, it may aid clinicians in providing improved patient diagnosis.

Background Neuronal ceroid lipofuscinosis type 2 or CLN2 disease is a rare, autosomal recessive, neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 deficiency. Cerliponase alfa, a recombinant human tripeptidyl peptidase 1 enzyme, is the first and only approved treatment for CLN2 disease and the first approved enzyme replacement therapy administered via intracerebroventricular infusion. Methods A meeting of health care professionals from US institutions with experience in cerliponase alfa treatment of children with CLN2 disease was held in November 2018. Key common practices were identified, and later refined during the drafting of this article, that facilitate safe chronic administration of cerliponase alfa. Results Key practices include developing a multidisciplinary team of clinicians, pharmacists, and coordinators, and institution-specific processes. Infection risk may be reduced through strict aseptic techniques and minimizing connections and disconnections during infusion. The impact of intracerebroventricular device design on port needle stability during extended intracerebroventricular infusion is a critical consideration in device selection. Monitoring for central nervous system infection is performed at each patient contact, but with flexibility in the degree of monitoring. Although few institutions had experienced positive cerebrospinal fluid test results, the response to a positive cerebrospinal fluid culture should be determined on a case-by-case basis, and the intracerebroventricular device should be removed if cerebrospinal fluid infection is confirmed. Conclusions The key common practices and flexible practices used by institutions with cerliponase alfa experience may assist other institutions in process development. Continued sharing of experiences will be essential for developing standards and patient care guidelines.

We describe an 11-year-old female who presented with severe hypersomnolence after receiving 1 week of modest doses of clobazam (CLB). In reviewing the above case, we considered that the hypersomnolence could be related to a pharmacodynamic, pharmacokinetic, or pharmacogenomic issue associated with CLB or to a combination of these factors. Although serum concentrations of CLB and its active metabolite are sensitive to factors that affect cytochrome-dependent metabolism, drug-drug interactions were omitted as a cause of the hypersomnolence. Subsequent DNA analysis of the cytochrome P450 2C19 gene revealed the patient as *2/*2 genotype with poor metabolizer enzyme activity. Because genetic testing of all patients treated with CLB is currently not practical, CLB dose/concentration ratios and pharmacokinetic drug-drug interaction impact models may be indicated. Genetic testing should be considered when an adverse effect suggests the possibility of a polymorphism important to drug metabolism.

Focal epilepsy originates within networks in one hemisphere. However, previous studies have investigated network topologies for the entire brain. In this study, magnetoencephalography (MEG) was used to investigate functional intra‐hemispheric networks of healthy controls (HCs) and patients with left‐ or right‐hemispheric temporal lobe or temporal plus extra‐temporal lobe epilepsy. 22 HCs, 25 left patients (LPs), and 16 right patients (RPs) were enrolled. The debiased weighted phase lag index was used to calculate functional connectivity between 246 brain regions in six frequency bands. Global efficiency, characteristic path length, and transitivity were computed for left and right intra‐hemispheric networks. The right global graph measures (GGMs) in the theta band were significantly different (p

Transcranial magnetic stimulation (TMS) is a newer noninvasive language mapping tool that is safe and well-tolerated by children. We examined the accuracy of TMS-derived language maps in a clinical cohort by comparing it against functional magnetic resonance imaging (MRI)–derived language map. The number of TMS-induced speech disruptions and the volume of activation during functional MRI tasks were localized to Brodmann areas for each modality in 40 patients with epilepsy or brain tumor. We examined the concordance between TMS- and functional MRI–derived language maps by deriving statistical performance metrics for TMS including sensitivity, specificity, accuracy, and diagnostic odds ratio. Brodmann areas 6, 44, and 9 in the frontal lobe and 22 and 40 in the temporal lobe were the most commonly identified language areas by both modalities. Overall accuracy of TMS compared to functional MRI in localizing language cortex was 71%, with a diagnostic odds ratio of 1.27 and higher sensitivity when identifying left hemisphere regions. TMS was more accurate in determining the dominant hemisphere for language with a diagnostic odds ratio of 6. This study is the first to examine the accuracy of the whole brain language map derived by TMS in the largest cohort examined to date. While this comparison against functional MRI confirmed that TMS reliably localizes cortical areas that are not essential for speech function, it demonstrated only slight concordance between TMS- and functional MRI–derived language areas. That the localization of specific language cortices by TMS demonstrated low accuracy reveals a potential need to use concordant tasks between the modalities and other avenues for further optimization of TMS parameters.

PURPOSE Transcranial magnetic stimulation (TMS) has recently emerged as a noninvasive alternative to the intracarotid sodium amytal (Wada) procedure for establishing hemispheric dominance (HD) for language. The accuracy of HD determined by TMS was examined by comparing against the HD derived by magnetoencephalography (MEG), a prominent clinical technique with excellent concordance with the Wada procedure. METHODS Sixty-seven patients (54 patients ≤18 years) underwent language mapping with TMS and MEG as part of clinical epilepsy and tumor presurgical assessment. Language was mapped in MEG during an auditory word recognition paradigm, and a laterality index was calculated using the number of dipoles and their spatial extent in the two hemispheres. Transcranial magnetic stimulation language mapping was performed as patients performed a naming task, and TMS-induced speech disruptions were recorded during 5-Hz TMS applied to anterior and posterior language cortices. Transcranial magnetic stimulation laterality index was estimated using the number and type of speech disruption in the language regions of each hemisphere. RESULTS Transcranial magnetic stimulation and MEG estimates of HD were concordant in 42 (63%) patients, resulting in a sensitivity of 74% and a specificity of 72%. The overall accuracy of TMS was 73%, equivalent to an odds ratio of 7.35. CONCLUSIONS In this first large-scale comparative study in a clinical population, we demonstrate that TMS is a safe and reliable noninvasive tool in determining HD for language. Improving the accuracy of TMS by optimizing TMS parameters and improving task choice will further facilitate the use of TMS to characterize language function, especially in pediatrics.

Summary Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre‐KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow‐up, side events, and KDT discontinuation. It has been helpful in outlining a state‐of‐the‐art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

The plasticity of the developing brain can be observed following injury to the motor cortex and/or corticospinal tracts, the most commonly injured brain area in the pre- or peri-natal period. Factors such as the timing of injury, lesion size and lesion location may affect a single hemisphere’s ability to acquire bilateral motor representation. Bilateral motor representation of single hemisphere origin is most likely to occur if brain injury occurs before the age of 2 years; however, the link between injury aetiology, reorganization type and functional outcome is largely understudied. We performed a retrospective review to examine reorganized cortical motor maps identified through transcranial magnetic stimulation in a cohort of 52 patients. Subsequent clinical, anthropometric and demographic information was recorded for each patient. Each patient’s primary hand motor cortex centre of gravity, along with the Euclidian distance between reorganized and normally located motor cortices, was also calculated. The patients were classified into broad groups including reorganization type (inter- and intrahemispheric motor reorganization), age at the time of injury (before 2 years and after 2 years) and injury aetiology (developmental disorders and acquired injuries). All measures were analysed to find commonalities between motor reorganization type and injury aetiology, function and centre of gravity distance. There was a significant effect of injury aetiology on type of motor reorganization (P

Background\ud Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.\ud Methods\ud Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.\ud Results\ud Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.\ud Conclusions\ud Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.

Cortical stimulation mapping is the gold standard for presurgical language mapping; however, it cannot be reliably performed in very young patients. Language mapping using noninvasive modalities is also challenging in very young patients. Although utility of language mapping using power of high-gamma in electrocorticographic recordings was demonstrated in adults and older children, there is a gap of knowledge in the ability of this procedure for localizing language-specific cortex in very young patients. We describe a case of a 2-year-old patient who, to our knowledge, is the youngest person to undergo successful high-gamma electrocorticographic presurgical language mapping for localization of the expressive language cortex (Broca area). The surgical plan was to resect a cortical tuber within the left inferior frontal gyrus and there was a strong concern about postoperative language deficit after resection. Presurgical language mapping using noninvasive modalities were attempted without success. Cortical stimulation mapping was not feasible in this patient. Therefore, high-gamma electrocorticography was the only viable option for language mapping, and it successfully localized the expressive language cortex. The patient underwent surgery for resection of the IFG tuber based on results of high-gamma electrocorticography and had no postoperative language deficit. High-gamma electrocorticography can be used for localizing language-specific cortex, especially Broca’s area, in very young patients.

Extrapolation of efficacy data from adults to children is accepted for focal epilepsy - the antiepileptic drug, lacosamide, has been approved for the treatment of children ≥4 years of age on this basis. Since many small-scale, open-label studies are reported in the literature before approval, a systematic review was conducted to ascertain whether results of these could be used to support extrapolation in epilepsy in the future. In the absence of randomised trials, a second analysis was conducted for reports on lacosamide use in adults with generalized epilepsies. Twenty-seven articles were included in the paediatric qualitative synthesis, and 14 in the adult. Paediatric studies were analysed separately based on seizure type: focal, generalised and mixed. In focal epilepsy, safety and seizure-related findings mirrored those observed in the adult Phase II/III trials, supporting the feasibility of data extrapolation. Few studies reported outcomes in children with epilepsies associated with generalised seizures, and those that included children with different seizure types, mostly did not provide results separately. Lacosamide treatment appeared beneficial for children and adults experiencing tonic-clonic and myoclonic seizures. Reports of seizure aggravation were inconsistent and, in many cases, could not be clearly attributed to lacosamide. Given the absence of sufficient data, evidence for the feasibility of extrapolation was not as clear-cut as it was in focal epilepsy. These results highlight the complexities of conducting trials in the generalised epilepsy setting, and the importance of studies in the real-life setting and of analysing efficacy data per generalized seizure type and syndrome.

Objective To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs). Methods This was a phase III, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov NCT01390220) with patients age ≥12 years on a stable regimen of antiepileptic drugs. Following an in-clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double-blind MDZ-NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours, and time-to-next seizure >10 minutes after double-blind drug administration. Safety was monitored throughout. Results Of 292 patients administered a test dose, 262 patients were randomized, and 201 received double-blind treatment for an SC (n = 134 MDZ-NS, n = 67 placebo, modified intent-to-treat population). A significantly greater proportion of MDZ-NS- than placebo-treated patients achieved treatment success (53.7% vs 34.4%; P = 0.0109). Significantly, fewer MDZ-NS- than placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%; P = 0.0043). Time-to-next seizure analysis showed early separation (within 30 minutes) between MDZ-NS and placebo that was maintained throughout the 24-hour observation period (21% difference at 24 hours; P = 0.0124). Sixteen patients (5.5%) discontinued because of a treatment-emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ-NS and placebo groups, respectively, experienced ≥1 TEAE. Significance MDZ-NS was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing an SC in the outpatient setting and was associated with a favorable safety profile.

Enzyme-inducing antiseizure drugs taken concomitantly with perampanel are known to influence perampanel serum concentrations. In this study, we examined perampanel dosage, serum concentrations, and the effect of concomitant enzyme-inducing antiseizure drugs in children for a 3-year period. A retrospective chart review determined patient age, weight, perampanel serum concentration and prescribed dose, and concomitant drugs. Of 87 patients included in the study, 41 were prescribed an enzyme-inducing antiseizure drug. Although perampanel dosage did not differ between patients prescribed/not prescribed enzyme-inducing antiseizure drugs, serum concentrations were significantly lower in patients taking enzyme-inducing antiseizure drugs (average serum concentration for the enzyme-inducing antiseizure drug group was still above the previously reported efficacious serum concentration of 70 ng/mL). Although perampanel serum concentrations are negatively influenced by enzyme-inducing antiseizure drugs in children, it is likely that efficacy would be improved in patients not concomitantly prescribed enzyme-inducing antiseizure drugs because pediatric perampanel dosing is similar to that reported in prior adult efficacy trials.

For drug-resistant epilepsy, nonpharmacologic treatments should be considered early rather than late. Of the nondrug treatments, only resective surgery can be curative. Neurostimulation is palliative, i.e., not expected to achieve a seizure-free outcome. While resective surgery is the goal, other options are necessary because the majority of patients with drug-resistant epilepsy are not surgical candidates, and others have seizures that fail to improve with surgery or have only partial improvement but not seizure freedom. Neurostimulation modalities include vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS), each with its own advantages, disadvantages, and side effects. In most scenarios, determined by noninvasive evaluation, especially EEG and MRI, several strategies are reasonable. For focal epilepsies, the choices are between resective surgery, with or without intracranial EEG, and all three modalities of neurostimulation. In situations where resective surgery is likely to result in seizure freedom, such as mesiotemporal lobe epilepsy or lesional focal epilepsy, resection (standard, laser, or radiofrequency) is preferred. For difficult cases like extratemporal nonlesional epilepsies, neurostimulation offers a less invasive option than resective surgery. For generalized and multifocal epilepsies, VNS is an option, RNS is not, and DBS has only limited evidence. "This article is part of the Supplement issue Neurostimulation for Epilepsy."

Background The effects of statistical testing on the results of multivariate autoregressive (MVAR)-based effective connectivity analysis have not been adequately investigated, and it is still unclear which statistical test can provide the most accurate results. New methods Using simulated and real electrocorticographic (ECoG) data, we investigated the performance of three nonparametric statistical tests – Monte Carlo permutation, bootstrap resampling, and surrogate data method in MVAR-based effective connectivity analysis. Receiver operating characteristic (ROC) analysis and area under the ROC curve (AUC) were used to assess the performance of each statistical test method. In addition, we found optimal p-values for each method based on ROC analysis. Finally, we investigated the application of statistical tests on partial directed coherence analysis of ECoG data collected in a patient with epilepsy. Results The bootstrap statistical test performed more accurately than other methods. The surrogate method slightly outperformed the Monte Carlo permutation method. Optimal p-values of statistical tests depended on signal-to-noise ratio (SNR) of data, and its value increased by reducing SNR of data. By considering the typical SNR range of electrophysiological data, we recommended an optimal p-value range for the application of each statistical test method. Comparison with existing methods Limited studies have investigated the performance of statistical tests for MVAR-based effective connectivity analysis. For the first time, we have investigated the effects of baseline connections on the various performances of statistical tests. Conclusions We recommend utilizing the bootstrap statistical test with p-value between 0.05 and 0.1 for effective connectivity analysis of ECoG data.

Background Ideal rescue treatments for acute treatment of seizure clusters should be easy to administer, so it is important to assess user perceptions of these treatments. Diazepam nasal spray is designed to have a rapid, noninvasive, and socially acceptable route of administration. Patient and caregiver (including care partner) responses to surveys from a phase 3 safety study of diazepam nasal spray are reported. Methods The study enrolled patients aged 6–65 years with seizure clusters. Surveys distributed to patients and caregivers at study end, completion, or discontinuation collected data on comfort using diazepam nasal spray outside the home, timing of administration and return to their usual selves, and comfort of use compared with rectal diazepam. Safety was assessed. Results Of 175 patients enrolled at the October 31, 2019, interim cutoff, 158 received diazepam nasal spray. Sixty-seven (42.4%) patients and 84 (53.2%) caregivers responded to the surveys (including 35 matched pairs). Most patients (78.8%, 52/66) responded that they were very comfortable doing activities outside the home with diazepam nasal spray available; 59.4% of patients returned to their usual selves within an hour of administration. Twenty-seven (40.3%) of these patients reported self-administration, 48% doing so at the first sign of a seizure. Administration of diazepam nasal spray was rated extremely or very easy by 93.8% of caregivers. Safety profile was consistent with diazepam rectal gel; no patient discontinued owing to treatment-emergent adverse events. Nasal discomfort was typically mild and transient. Among patients who had used diazepam rectal gel, most were not at all comfortable using it outside the home (86.7%) or at home (64.5%) compared with diazepam nasal spray, whereas caregivers reported that diazepam rectal gel was not at all easy to use compared with diazepam nasal spray. Conclusions This survey from the phase 3 safety study of diazepam nasal spray shows that patients and caregivers were satisfied with, and more comfortable using, diazepam nasal spray than rectal diazepam in public. NCT02721069.