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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.

Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

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.

Pharmacoresistant seizures occur in nearly one-third of people with epilepsy. Medial temporal lobe and lesional epilepsy are the most favorable surgically remediable epileptic syndromes. Successful surgery may render the patient seizure-free, reduce antiseizure drug(s) adverse effects, improve quality of life, and decrease mortality. Surgical management should not be considered a procedure of "last resort." Despite the results of randomized controlled trials, surgery remains an underutilized treatment modality for patients with drug-resistant epilepsy (DRE). Important disparities affect patient referral and selection for surgical treatment. This article discusses the advances in surgical treatment of DRE in adults with focal seizures.

From April 1, 2011, through September 30, 2011, Neurology ® received 2,167 new and 643 revised manuscripts. During this interval, 3,909 peer reviews were received (compared to 3,758 during the same period in 2010), with the average turnaround time after assignment being 8.5 days. Average time from submission to first decision for papers chosen for review remained at 33 days. Limitations in the number of pages we can publish allow us to accept only a minority of papers submitted. Your specific comments regarding the uniqueness of study populations, novel methods, studies that are especially educational, or new strategies for diagnosing and treating neurologic disease are appreciated; these comments help us immeasurably when we make final decisions regarding which articles we believe will most benefit our authors and readers, as well as improve patient care. Manuscripts for the Resident & Fellow Section of Neurology are often submitted by trainees who have less experience in preparing articles for publication, and it is the goal of the Section to help these junior authors improve their clinical and scientific writing abilities. We especially appreciate the constructive feedback provided by reviewers of these manuscripts. We recently posted an Information for Reviewers (IFR) link on www.neurology.org. Click on this link for information on expectations of reviewers regarding confidentiality, timeliness, and reviewer conflicts of interest. The IFR also provides instructions for formatting the comments to editors and authors in order to make communication with authors most effective. In appreciation of your dedication to Neurology , we offer an hour of CME credit, if requested, for each manuscript you review for the Journal (maximum of 15 credits per year as determined by ACCME). To receive credit, it should be evident that the reviewer has read and understood the content of the manuscript, accompanying figures and tables, supplementary …

OBJECTIVE: Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. METHODS: We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. RESULTS: A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. SIGNIFICANCE: Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.

Objective To evaluate the presence of tau deposition and pathologic features of chronic traumatic encephalopathy (CTE) in young adult patients treated with focal cortical resections for drug‐resistant epilepsy. Methods Sixty consecutive patients who had undergone surgical treatment for drug‐resistant focal epilepsy between 18 and 45 years of age were identified (2010‐2017). Medical records were reviewed to determine clinical factors, including history of head trauma, age at seizure onset, age at surgical resection, seizure type(s) and frequency, imaging findings, and surgical outcome. All formalin‐fixed, paraffin‐embedded blocks from the surgical specimens from each subject were sectioned and stained with hematoxylin and eosin and antibodies to tau (Thermo Fisher Scientific Clone AT8), and examined blindly for tau pathology, including lesions characteristic of CTE. Results The median age at resection was 29.5 years (range = 19‐45). A history of head trauma was reported in 19 patients. Although none of the patients had pathological findings characteristic of CTE, 23 patients (38%) demonstrated tau‐immunoreactive lesions, including neurites, neurofibrillary pretangles, neurofibrillary tangles, subpial tau, and/or glial tau. In 4 of the 23 patients (7% of the cohort; 17% of those with tau pathology), substantial tau burden was identified. Three of these 4 patients had no significant history of head trauma; 1 patient had multiple sports‐related concussions. No specific clinical factors correlated with the presence of tau pathology. Significance Tau‐immunoreactive lesions were found in 38% of 60 patients who underwent a focal cortical resection for drug‐resistant focal epilepsy. Diagnostic features of CTE were not detected in any patient; however, the pathological evaluation for CTE was limited to a surgical specimen. The prominent and excessive tau deposition in 23 patients (38%) is abnormal in this age group and warrants further investigation.

In this case series, we describe a novel observation in which 4 patients with acute ischemic stroke secondary to large vessel occlusion and no history of seizure present with focal seizure activity localizable to a chronic, contralateral infarct. The explanation for this phenomenon is unknown but may be due to a combination of effects involving disrupted interhemispheric inhibitory connections and epileptogenic changes involving chronically infarcted tissue.

The objective of this study was to describe serological association of musicogenic epilepsy and to evaluate clinical features and outcomes of seropositive cases. Through retrospective chart review, musicogenic epilepsy patients were identified. Among 16 musicogenic epilepsy patients, nine underwent autoantibody evaluations and all had high-titer glutamic acid decarboxylase 65-immunoglobulin G (GAD65-IgG; >20 nmol·L-1 , serum, normal ≤ .02 nmol·L-1 , eight women). Median GAD65-IgG serum titer was 294 nmol·L-1 (20.3-3005 nmol·L-1 ), and median cerebrospinal fluid titer (n = 4) was 14.7 nmol·L-1 . All patients had temporal lobe epilepsy, and bitemporal epileptiform abnormalities were common. Right temporal lobe seizures were most frequently captured when seizures were induced by music on electroencephalogram (3/4; 75%). Intravenous (IV) methylprednisolone and/or IV Ig (IVIG) was utilized in four patients, with one having greater than 50% reduction. Rituximab (n = 2) and mycophenolate (n = 1) were ineffective. Two patients underwent right temporal lobe resections but continued to have seizures. Vagus nerve stimulation was effective at reducing seizures in one patient by 50%, and an additional patient was seizure-free by avoiding provoking music. Right temporal lobe epilepsy was more common among patients with musicogenic epilepsy when compared to nonmusicogenic GAD65 epilepsies (n = 71, 89% vs. 47%, p = .03). GAD65-IgG should be tested in patients with musicogenic epilepsy, given implications for management and screening for comorbid autoimmune conditions.

Infrequent seizures can pose a treatment dilemma. Selected patients with a history of 1–2 seizure(s) may be a candidate for observation without antiseizure medication (ASM), especially if recurrence is rare or inter-seizure interval is widely spaced. The putative beneficial effects of ASM are often dependent upon a patient’s seizure type, desire to begin ASM, and lifestyle or occupation. Some epilepsy syndromes have limited likelihood of recurrence and typically do not require treatment after a first seizure. Even patients with seizures that are either poorly substantiated by historical recount, those potentially provoked, or when the patient desires to defer ASM can delay initial treatment despite risk. Treatment-emergent adverse effects including memory loss, gait unsteadiness and altered balance, and metabolic bone disease may be subtle and develop over time. Informed consent, close observation, and seizure precautions should be maintained. In contrast those patients with convulsions, high-risk occupations, and anticipatory anxiety for impending seizures should be recommended to pursue treatment despite infrequent seizures. While some seizure disorders may have a benign clinical course over years, the risks of ASM must be balanced against the risks of breakthrough seizures. Ultimately, the care and management of the patient with seizures are to minimize adverse effects of therapy while promoting a risk-free lifestyle without limitations.

Selected patients with a history of head trauma may have isolated or recurrent seizure activity. Seizures may occur in the setting of an acute traumatic brain injury, i.e., post-traumatic seizures, or 1 week or longer from the head trauma, i.e., post-traumatic epilepsy (PTE). Several clinical risk factors may be associated with an increased risk of PTE including severe head trauma with dural penetration, intracerebral hemorrhage, and need for operative intervention; combat or military-related traumatic brain injuries; and acute post-traumatic seizures. The prophylactic use of antiseizure drugs (ASDs) is controversial. ASD may reduce the presence of early post-traumatic seizures, but are not effective prophylactically in preventing PTE. Ultimately, the care and management of the patient with traumatic brain injury and seizures is to render the patient seizure-free and minimize the adverse effects of therapy.

Patients with a seizure disorder receive antiseizure medication (ASM) and may experience idiosyncratic or dose-related treatment-emergent adverse effects. One important concern associated with ASM use is metabolic bone disease. Selected medical therapies have an increased incidence for bone health issues and may predispose to fractures. The combination of a gait disorder, balance issues, and falling also needs to be considered in individuals with metabolic bone disease. All patients receiving long-term antiseizure medications, regardless of diagnosis or seizure classification, need to have periodic evaluation for bone health.

Intracranial EEG is considered when seizures are non-localized during a non-invasive evaluation or when discordant information exists or confirmation of the seizure-onset zone residing in non-eloquent cortex is necessary prior to proceeding to epilepsy surgery. Intracranial EEG is a valuable tool for defining the seizure-onset zone; however, it is a procedure that carries risk and as such should only be used when necessary for localization and definition of the seizure focus.

Tolerance is a known consideration for maintenance use of benzodiazepines and other antiseizure drugs; however, clinical experience suggests that tolerance may not be anticipated with long-term intermittent use of benzodiazepines as rescue therapy. Diazepam nasal spray (Valtoco®) is a proprietary intranasal formulation approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Reported here are exploratory analyses investigating whether there was evidence of development of tolerance in an interim analysis of a long-term, phase 3, open-label safety study of diazepam nasal spray.Patients and care partners were trained to administer 5, 10, 15, or 20 mg of diazepam nasal spray (age- and weight-based dosing), with a second dose administered 4-12 hours later if needed. A series of analyses were performed to assess evidence of tolerance using 2 equal, adjacent time periods and data for each patient to compare the proportion of events for which second doses of diazepam nasal spray (as a proxy for effectiveness) were administered in period 1 compared with period 2.A total of 175 patients were enrolled at interim cutoff, and 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. For 73.4% of patients, duration of exposure to diazepam nasal spray was ≥12 months. A total of 191 analyses were conducted; the proportion of analyses in which second doses in period 2 were lower than in period 1 was 72.8%. Only 5 analyses showed nominally statistically significant changes (P 0.05); this is fewer than expected by chance, and these differences were not directionally consistent. There was no safety signal with continued use.These analyses found no statistical evidence of tolerance with the use of diazepam nasal spray over time based on use of a second dose in an initial period of the study compared with a subsequent period for each patient. These results are in agreement with prior studies of benzodiazepine rescue therapy.

Background and purpose The aim of this study was to evaluate the quality of smartphone videos (SVs) of neurologic events in adult epilepsy outpatients. The use of home video recording in patients with neurological disease states is increasing. Experts interpretation of outpatient smartphone videos of seizures and neurological events has demonstrated similar diagnostic accuracy to inpatient video-electroencephalography (EEG) monitoring. Methods A prospective, multicenter cohort study was conducted to evaluate SV quality in patients with paroxysmal neurologic events from August 15, 2015 through August 31, 2018. Epileptic seizures (ESs), psychogenic nonepileptic attacks (PNEAs), and physiologic nonepileptic events (PhysNEEs) were confirmed by video-EEG monitoring. Experts and senior neurology residents blindly viewed cloud-based SVs without clinical information. Quality ratings with regard to technical and operator-driven metrics were provided in responses to a survey. Results Forty-four patients (31 women, age 45.1 years [r = 20-82]) were included and 530 SVs were viewed by a mean of seven experts and six residents; one video per patient was reviewed for a mean of 133.8 s (r = 9-543). In all, 30 patients had PNEAs, 11 had ESs, and three had PhysNEEs. Quality was suitable in 70.8% of SVs (375/530 total views), with 36/44 (81.8%) patient SVs rated as adequate by the majority of reviewers. Accuracy improved with the presence of convulsive features from 72.4% to 98.2% in ESs and from 71.1% to 95.7% in PNEAs. An accurate diagnosis was given by all reviewers (100%) in 11/44 SVs (all PNEAs). Audio was rated as good by 86.2% of reviewers for these SVs compared with 75.4% for the remaining SVs (p = 0.01). Lighting was better in SVs associated with high accuracy (p = 0.06), but clarity was not (p = 0.59). Poor video quality yielded unknown diagnoses in 24.2% of the SVs reviewed. Features hindering diagnosis were limited interactivity, restricted field of view and short video duration. Conclusions Smartphone video quality is adequate for clinical interpretation in the majority of patients with paroxysmal neurologic events. Quality can be optimized by encouraging interactivity with the patient, adequate duration of the SV, and enlarged field of view during videography. Quality limitations were primarily operational though accuracy remained for SV review of ESs and PNEAs.

Pharmacoresistant seizures occur in nearly one-third of people with epilepsy. Medial temporal lobe and lesional epilepsy are the most favorable surgically remediable epileptic syndromes. Successful surgery may render the patient seizure-free, reduce antiseizure drug(s) adverse effects, improve quality of life, and decrease mortality. Surgical management should not be considered a procedure of "last resort." Despite the results of randomized controlled trials, surgery remains an underutilized treatment modality for patients with drug-resistant epilepsy (DRE). Important disparities affect patient referral and selection for surgical treatment. This article discusses the advances in surgical treatment of DRE in adults with focal seizures.

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Background Jeavons syndrome is an underreported epileptic syndrome characterized by eyelid myoclonia, eyelid closure-induced seizures or electroencephalography paroxysms, and photosensitivity. Drug-resistant epilepsy is common, but the prognostic factors and clinical course leading to drug resistance have not been well characterized. Methods We identified 30 patients who met the diagnostic criteria of Jeavons syndrome at a single institution between January 1, 2000 and December 15, 2016. Criteria for Jeavons syndrome included all of the following: (1) eyelid myoclonia with or without absences, (2) eye–closure-induced seizures or electroencephalography paroxysms, and (3) seizure onset after 12 months of age. We reviewed and described the epilepsy history, antiepileptic drug trials, and response to treatments. Results Mean age at seizure onset was 7.3 years, and 80% were female. Absence seizures (63%) and generalized tonic-clonic seizures (23%) were most common at onset. Diagnosis was delayed by an average of 9.6 years. After a median follow-up of two years, 80% of patients had drug resistant epilepsy and 70% experienced generalized tonic-clonic seizures. Generalized tonic-clonic seizures and seizure types other than absence seizures increased the risk of drug-resistant epilepsy (P values 0.049 and 0.03, respectively). Valproic acid, lamotrigine, ethosuximide, and levetiracetam were the most effective in reducing seizures by more than 50%. Conclusions The diagnosis of Jeavons syndrome is often delayed. Generalized tonic-clonic seizures and seizure types other than absence seizures may be predictors of drug-resistant epilepsy among patients with Jeavons syndrome.

OBJECTIVEEpilepsy surgery is effective for lesional epilepsy, but it can be associated with significant morbidity when seizures originate from eloquent cortex that is resected. Here, the objective was to describe chronic subthreshold cortical stimulation and evaluate its early surgical safety profile in adult patients with epilepsy originating from seizure foci in cortex that is not amenable to resection.METHODSAdult patients with focal drug-resistant epilepsy underwent intracranial electroencephalography monitoring for evaluation of resection. Those with seizure foci in eloquent cortex were not candidates for resection and were offered a short therapeutic trial of continuous subthreshold cortical stimulation via intracranial monitoring electrodes. After a successful trial, electrodes were explanted and permanent stimulation hardware was implanted.RESULTSTen patients (6 males) who underwent chronic subthreshold cortical stimulation between 2014 and 2016 were included. Based on radiographic imaging, intracranial pathologies included cortical dysplasia (n = 3), encephalomalacia (n = 3), cortical tubers (n = 1), Rasmussen encephalitis (n = 1), and linear migrational anomaly (n = 1). The duration of intracranial monitoring ranged from 3 to 20 days. All patients experienced an uneventful postoperative course and were discharged home with a median length of stay of 10 days. No postoperative surgical complications developed (median follow-up length 7.7 months). Seizure severity and seizure frequency improved in all patients.CONCLUSIONSThe authors’ institutional experience with this small group shows that chronic subthreshold cortical stimulation can be safely and effectively performed in appropriately selected patients without postoperative complications. Future investigation will provide further insight to recently published results regarding mechanism and efficacy of this novel and promising intervention.

ObjectiveTo determine the occurrence of chronic traumatic encephalopathy (CTE) in young adult patients undergoing epilepsy surgery.MethodsTen patients who underwent epilepsy surgery were randomly selected for this retrospective study. The patients were 18–45 years of age, had preoperative neuropsychological evaluation, and had 1 year postoperative follow-up. Microscopic sections from resections were evaluated for the presence of CTE with standard stains and antibodies to tau (clone AT8).ResultsThe median age at resection was 32.5 years (range 23–43) and the median duration of seizures was 23.5 years (range 3–28). Eight had a history of head injury. Preoperative neuropsychological testing showed mild to moderate cognitive impairment in 8 patients (80%). Pathologic examination in one patient showed focal sparse tau-immunoreactive lesions along descending rami and cortical gyral depths of the resected frontal lobe. Nine patients had no evidence of CTE. All focal cortical resections showed variable subpial and subcortical gliosis commonly identified in patients with chronic seizure disorders.ConclusionsThe present small retrospective observational study suggests that CTE may occur, but appears uncommon, in young adult patients undergoing surgical treatment for drug-resistant focal epilepsy. The significance of these findings requires further investigation to define the relative importance of tau accumulation in younger adult patients with drug-resistant focal epilepsy and cognitive decline.

Summary Two patients who shared similar presenting clinical features of anterograde and retrograde autobiographical amnesia typical of transient epileptic amnesia (TEA) underwent prolonged video electroencephalogram (VEEG) monitoring and were found to have sleep-activated epileptiform activity and frequent subclinical bitemporal seizures predominantly during sleep. Case one is a 59 year old woman whose presenting complaint was memory impairment. Over 18 months, she had three distinct eight hour long episodes of confusion and disorientation with persistent anterograde and retrograde autobiographical amnesia. VEEG recorded frequent interictal bitemporal sharp waves confined to sleep, and 14 subclinical seizures, also mostly during sleep. Case two is a 50 year old woman with known focal epilepsy also presented with memory complaints. Over the course of one year, she had two discrete two hour long episodes of amnesia, with ongoing anterograde and retrograde autobiographical amnesia. VEEG recorded independent bitemporal sharp waves, and 14 subclinical seizures during sleep and drowsiness. Memory impairment improved in both patients with successful treatment of their seizures. While the etiology of accelerated long term forgetting (ALF) and remote memory impairment (RMI) in transient epileptic amnesia (TEA) is unknown, these cases suggest frequent sleep-related seizures may contribute, and highlight the importance of video-EEG monitoring. This article is protected by copyright. All rights reserved.

Dr. Jasper R. Daube died on April 17, 2020. Dr. Daube was born in 1936 in Uetersen, Germany, and emigrated to the United States as a child with his family. He grew up in the Chicago suburbs before attending college at Princeton University where he earned his Bachelor of Arts in Biology in 1957. He graduated from the University of Rochester, School of Medicine, earning his MD and master's degree in neuroanatomy. Following medical school, he completed his neurology residency at the University of Wisconsin. Subsequently, he fulfilled 2 years of service in the US Army where he was stationed at Camp Zama, Japan. While stationed in Japan, he met a lovely nurse, Cynthia Sokol, who would become his wife and love of his life. Together, they would raise 2 children, Christopher and Lizabeth.

Objective To assess relative rates and clinical features of patients with genetic generalized epilepsy (GGE), focal epilepsy (FE), and developmental encephalopathic epilepsy (DEE) in the North American SUDEP Registry (NASR). Methods We identified all adjudicated definite, definite plus, and probable sudden unexpected death in epilepsy (SUDEP) cases (n = 262) and determined epilepsy type (GGE, FE, or DEE) from medical record review including history, imaging and EEG results, genetics, and next-of-kin interviews. Results Of the 262 SUDEP cases, 41 occurred in GGE, 95 in FE, 24 in DEE, and 102 were unclassifiable. GGE cases comprised 26% of NASR cases with an epilepsy syndrome diagnosis. The relative frequency of FE:GGE was slightly lower (2.3:1) than in population cohorts (2.1–6:1). Compared to patients with FE, patients with GGE had similar (1) ages at death and epilepsy onset and rates of (2) terminal and historical antiseizure medication adherence; (3) abnormal cardiac pathology; (4) illicit drug/alcohol use histories; and (5) sleep state when SUDEP occurred. Conclusions GGE cases were relatively overrepresented in NASR. Because GGEs are less often treatment-resistant than FE or DEE, seizure type rather than frequency may be critical. Many people with GGE predominantly have generalized tonic-clonic seizures (GTCS) when they have uncontrolled or breakthrough seizures, whereas patients with FE more commonly experience milder seizures. Future mechanistic SUDEP studies should assess primary and focal-to-bilateral GTCS to identify potential differences in postictal autonomic and arousal disorders and to determine the differential role that lifestyle factors have on breakthrough seizures and seizure types in GGE vs FE to effectively target SUDEP mechanisms and prevention.

The choice of subdural grid (SDG) or stereoelectroencephalography (sEEG) for patients with epilepsy can be complex and in some cases overlap. Comparing postoperative pain and narcotics consumption with SDG or sEEG can help develop an intracranial monitoring strategy.A retrospective study was performed for adult patients undergoing SDG or sEEG monitoring. Numeric Rating Scale (NRS) was used for pain assessment. Types and dosage of the opioids were calculated by converting into milligram morphine equivalents (MME). Narcotic consumption was analyzed at the following three time periods: I. the first 24 h of implantation; II. from the second postimplantation day to the day of explantation; and III. the days following electrode removal to discharge.Forty-two patients who underwent SDG and 31 patients who underwent sEEG implantation were analyzed. After implantation, average NRS was 3.7 for SDG and 2.2 for sEEG (P .001). After explantation, the NRS was 3.5 for SDG and 1.4 in sEEG (P .001). Sixty percent of SDG patients and 13% of sEEG patients used more than one opioid in period III (P .001). The SDG group had a significantly higher MME throughout the three periods compared with the sEEG group: period I: 448 (SDG) vs. 205 (sEEG) mg, P = .002; period II: 377 (SDG) vs. 102 (sEEG) mg, P .001; and period III: 328 (SDG) vs. 75 (sEEG) mg; P = .002. Patients with the larger SDG implantation had the higher NRS (P = .03) and the higher MME at period I (P = .019). There was no correlation between the number of depth electrodes and pain control in patients with sEEG.Patients undergoing sEEG had significantly less pain and required fewer opiates compared with patients with SDG. These differences in perioperative pain may be a consideration when choosing between these two invasive monitoring options.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published

Background:Previous studies evaluated the disposition of IV phenytoin loading doses and found that obese patients had increased drug distribution into excess body weight, larger volumes of distribution, and longer half-lives when compared to their nonobese counterparts. We assess the safety and efficacy of fosphenytoin loading doses in patients with different body mass indices (BMIs).Methods:A retrospective chart review was conducted in 410 patients who received fosphenytoin. Patients were divided into 2 groups: BMI Results:The median dose of fosphenytoin administered was 19 mg/kg (interquartile range 15–20). The most frequently encountered adverse event was hypotension, which occurred in 39% of the cohort. Using a Bonferroni adjustment for multiple comparisons, there were no differences in adverse events between the 2 groups. The need for additional antiepileptic loading doses was not different between the 2 groups (p = 0.07).Conclusions:The incidence of adverse events and the need for repeat loading antiepileptic medications was similar between the 2 groups. From our findings, the patients in our study did not receive empiric loading dose adjustments and the current method of loading fosphenytoin achieves similar outcomes, regardless of the patient's BMI.

This article discusses structural and functional neuroimaging findings in patients with seizures and epilepsy. The indications for neuroimaging in these patients and the potential diagnostic utility of these studies are presented.Patients presenting with new seizures typically require urgent imaging to rule out a critical underlying cause. MRI is the structural neuroimaging procedure of choice in individuals with epilepsy. Specific epilepsy protocols should be considered to increase the diagnostic yield of neuroimaging in patients with structural lesions associated with focal or generalized seizures. Common epileptogenic pathologic processes include mesial temporal sclerosis, malformations of cortical development, focal encephalomacia, primary brain tumors, vascular malformations, and neurocysticercosis. Functional neuroimaging studies are usually restricted to the evaluation of patients with drug-resistant focal epilepsy who are being considered for surgical treatment.The role of neuroimaging in epilepsy depends on the appropriate clinical indication. In patients without known epilepsy presenting with acute seizures, structural imaging is essential to rule out an underlying etiology (eg, subdural hematoma) that may require a specific therapeutic intervention. In individuals with new or previously uninvestigated epilepsy, MRI serves multiple purposes, including identifying a causative focal lesion and helping to diagnose the epilepsy type. In a significant number of patients with epilepsy, the MRI results are normal or reveal indeterminate findings. For patients with drug-resistant focal epilepsy, functional neuroimaging techniques, such as fludeoxyglucose-positron emission tomography (FDG-PET), ictal single-photon emission computed tomography (SPECT), or functional MRI (fMRI), may assist in surgical planning, especially in patients with MRI-negative epilepsy, whose prognosis for a seizure-free outcome after surgery is worse than for patients with an epileptogenic lesion on structural MRI.

Objective Women with epilepsy (WWE) have lower birth rates than expected. The reasons for this are multifactorial and involve a complex interaction between reproductive endocrine and psychosocial factors. The effect of epilepsy surgery on reproduction in women with drug-resistant focal epilepsy has not previously been studied. Methods Adult women of childbearing age (18–45 years old) with drug-resistant focal epilepsy who had undergone a focal cortical resection between 1997 and 2008 at the Mayo Clinic in Rochester, MN were included in the study. Patients who had a history of hysterectomy or tubal ligation or who were menopausal at the time of surgery were excluded. Data on prior pregnancies and births, epilepsy history, surgical treatment, hormonal dysfunction, and socioeconomic status were obtained using a retrospective chart review. Associations between various clinical and demographic variables with changes in pregnancies and births from pre- to postsurgery were assessed using Chi-square or Fisher's exact test for categorical variables and Wilcoxon rank sum test for continuous variables. All tests were 2-sided, and p-values less than 0.05 were considered statistically significant. All analyses were performed using SAS software version 9.2 (SAS INC, Cary NC). Results One hundred and thirteen women (average age: 30.5 years) were included in the study. Average length of follow-up was 5.7 years (SD-3.90). Sixty-four patients (57.5%) were nulliparous at the time of surgery. Sixty-one patients (54%) had never been married. Average number of pregnancies per patient prior to surgery was 0.93, and average number of births prior to surgery was 0.73. After surgery, a total of 17 women had a total of 35 pregnancies and 25 births. The average number of pregnancies and births after surgery was 1.27 and 0.96, respectively. Infertility was reported in one patient postoperatively. Patients who were younger at the time of surgery experienced a greater change in the number of pregnancies and births after surgery (p = 0.0036 and 0.0060, respectively). Patients who received fewer antiepileptic drug medication trials by the time of surgery also had a greater change in the number of births after surgery (p = 0.0362). Seizure onset localization and lateralization, presurgical seizure frequency, age at seizure onset, duration of epilepsy, and postoperative seizure outcome were not statistically significant factors. Conclusion The present retrospective observational study provides additional evidence for the importance of early surgical treatment in women with drug-resistant focal epilepsy. Patients who had received fewer medications prior to surgery were more likely to experience an increase in births following surgery. The significance of these findings requires further investigation but may support a role for earlier surgical intervention in the management of drug-resistant focal epilepsy.

Objective: To compare the yield of epileptiform abnormalities on 30-minute recordings with those greater than 45 minutes. Methods: We performed a prospective observational cross-sectional study of all outpatient routine EEGs comparing the rate of interictal epileptiform discharges (IEDs) and clinical events during the initial 30 minutes (routine) with those occurring in the remaining 30–60 minutes (extended). A relative increase of 10% was considered clinically significant. Results: EEGs from 1,803 patients were included; overall EEG duration was 59.4 minutes (SD ±6.5). Of 426 patients with IEDs at any time during the EEG, 81 (19.1%, 95% confidence interval 15.6–23) occurred only after the initial 30 minutes. The rate of late IEDs was not associated with age, indication, IED type, or sleep deprivation. Longer recording times also increased event capture rate by approximately 30%. Conclusions: The yield of IED and event detection is increased in extended outpatient EEGs compared to 30-minute studies.

Importance Misdiagnosis of epilepsy is common. Video electroencephalogram provides a definitive diagnosis but is impractical for many patients referred for evaluation of epilepsy. Objective To evaluate the accuracy of outpatient smartphone videos in epilepsy. Design, Setting, and Participants This prospective, masked, diagnostic accuracy study (the OSmartViE study) took place between August 31, 2015, and August 31, 2018, at 8 academic epilepsy centers in the United States and included a convenience sample of 44 nonconsecutive outpatients who volunteered a smartphone video during evaluation and subsequently underwent video electroencephalogram monitoring. Three epileptologists uploaded videos for physicians from the 8 epilepsy centers to review. Main Outcomes and Measures Measures of performance (accuracy, sensitivity, specificity, positive predictive value, and negative predictive value) for smartphone video–based diagnosis by experts and trainees (the index test) were compared with those for history and physical examination and video electroencephalogram monitoring (the reference standard). Results Forty-four eligible epilepsy clinic outpatients (31 women [70.5%]; mean [range] age, 45.1 [20-82] years) submitted smartphone videos (530 total physician reviews). Final video electroencephalogram diagnoses included 11 epileptic seizures, 30 psychogenic nonepileptic attacks, and 3 physiologic nonepileptic events. Expert interpretation of a smartphone video was accurate in predicting a video electroencephalogram monitoring diagnosis of epileptic seizures 89.1% (95% CI, 84.2%-92.9%) of the time, with a specificity of 93.3% (95% CI, 88.3%-96.6%). Resident responses were less accurate for all metrics involving epileptic seizures and psychogenic nonepileptic attacks, despite greater confidence. Motor signs during events increased accuracy. One-fourth of the smartphone videos were correctly diagnosed by 100% of the reviewing physicians, composed solely of psychogenic attacks. When histories and physical examination results were combined with smartphone videos, correct diagnoses rose from 78.6% to 95.2%. The odds of receiving a correct diagnosis were 5.45 times greater using smartphone video alongside patient history and physical examination results than with history and physical examination alone (95% CI, 1.01-54.3;P = .02). Conclusions and Relevance Outpatient smartphone video review by experts has predictive and additive value for diagnosing epileptic seizures. Smartphone videos may reliably aid psychogenic nonepileptic attacks diagnosis for some people.

OBJECTIVEAlmost 30% of the patients with suspected temporal lobe epilepsy (TLE) have normal results on MRI. Success rates for resection of MRI-negative TLE are less favorable, ranging from 36% to 76%. Herein the authors describe the impact of intraoperative electrocorticography (ECoG) augmented by opioid activation and its effect on postoperative seizure outcome.METHODSAdult and pediatric patients with medically resistant MRI-negative TLE who underwent standardized ECoG at the time of their elective anterior temporal lobectomy (ATL) with amygdalohippocampectomy between 1990 and 2016 were included in this study. Seizure recurrence comprised the primary outcome of interest and was assessed using Kaplan-Meier and multivariable Cox regression analysis plots based on distribution of interictal epileptiform discharges (IEDs) recorded on scalp electroencephalography, baseline and opioid-induced IEDs on ECoG, and extent of resection.RESULTSOf the 1144 ATLs performed at the authors’ institution between 1990 and 2016, 127 (11.1%) patients (81 females) with MRI-negative TLE were eligible for this study. Patients with complete resection of tissue generating IED recorded on intraoperative ECoG were less likely to have seizure recurrence compared to those with incomplete resection on univariate analysis (p < 0.05). No difference was found in seizure recurrence between patients with bilateral independent IEDs and unilateral IEDs (p = 0.15), presence or absence of opioid-induced epileptiform activation (p = 0.61), or completeness of resection of tissue with opioid-induced IEDs on intraoperative ECoG (p = 0.41).CONCLUSIONSThe authors found that incomplete resection of IED-generating tissue on intraoperative ECoG was associated with an increased chance of seizure recurrence. However, they found that induction of epileptiform activity with intraoperative opioid activation did not provide useful intraoperative data predictive of improving operative results for temporal lobectomy in MRI-negative epilepsy.

BackgroundWe describe the clinical features and outcome in patients with late-onset Lennox-Gastaut syndrome (LGS).MethodsAdult patients evaluated between January 1, 2000, and March 1, 2017, who presented with onset of LGS ≥10 years were identified. Data abstracted included age at seizure onset, seizure types, etiology, treatments, EEG and neuroimaging results, cerebrospinal fluid (CSF) findings, and autoimmune evaluation.ResultsTen patients (8 females) were identified. The mean age at onset of seizures consistent with LGS was 16.5 years (range, 10–32 years). Seizure types included tonic, atonic, and tonic-clonic seizures (all), myoclonic seizures (n = 3), and atypical absence seizures (n = 7). Five patients had normal intellectual function at onset. Prolonged video-EEG monitoring recorded seizures and generalized interictal epileptiform discharges in all. All patients had drug-resistant epilepsy (range of antiseizure drugs tried, 7–16). Two patients had a history of intrathecal methotrexate to treat acute lymphoblastic leukemia. Two patients had malformations of cortical development. CSF analysis (n = 5) showed a mild elevation in the protein level without other abnormalities. Autoantibody determinations in the serum (n = 4) or the CSF (n = 5) and genetic testing (n = 5) were negative. At final follow-up, all but 1 patient was disabled and required a caregiver, and none were driving. One patient died of probable sudden unexpected death in epilepsy (SUDEP).ConclusionsLate-onset LGS represents a rare, treatment-resistant generalized epilepsy that is disabling and may be associated with progressive cognitive impairment. The elevated CSF protein level in our cohort could have been due to high seizure burden but increases the possibility of an inflammatory component to the pathophysiology of this disorder.

OBJECTIVE: We aimed to determine the frequency of probable obstructive sleep apnea (pOSA) in refractory epilepsy monitoring unit inpatients and clinical features associated with pOSA, including risk for Sudden Unexpected Death in Epilepsy (SUDEP). METHODS: We prospectively recruited 49 consecutive adult patients admitted to the Mayo Clinic Epilepsy Monitoring Unit with focal, generalized or unclassified epilepsy syndromes. pOSA was identified using oximetric oxyhemoglobin desaturation index (ODI) and the Sleep Apnea-Sleep Disorders Questionnaire (SA-SDQ) and STOP-BAG screening tools. Revised SUDEP-7 (rSUDEP-7) risk inventory scores were calculated, and epilepsy patients with and without pOSA were compared with Wilcoxon signed rank tests. Correlation and regression analyses were utilized to determine relationships between pOSA and rSUDEP-7 scores. RESULTS: Thirty-five percent of patients had pOSA with a mean ODI of 11.3 ± 5.1/hour (range 5.1–22.8). Patients with pOSA were older, heavier, and more frequently had a focal epilepsy syndrome and longer epilepsy duration, with higher SA-SDQ and STOP-BAG scores (all p

After reading the standard approach to assessment of first unprovoked seizure in an adult in the United States, Brazil, and India (3 very different countries on 3 very different continents), one quickly realizes that there is no standard approach after all.1 Yes, the approach is somewhat “standard” when one considers tertiary care neurology centers (comprehensive epilepsy centers) around the world, but after that, all bets are off. The varying standards around the world toward assessment and management of first unprovoked seizure in an adult underscore the importance of developing and reinforcing the minimum standards that need to be met when evaluating such a patient. All patients warrant an evaluation by a physician, preferably one skilled in neurosciences, a routine awake and sleep EEG (20–40 minute study), and a CT scan. This is the message that needs to go out from organizations such as the World Federation of Neurology, the American Academy of Neurology, and the International League Against Epilepsy to the governments of these diverse countries.

Item does not contain fulltext Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.