Cascino, Gregory D.

Abstract 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.

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.

AbstractObjectiveCurrent diazepam nasal spray labeling requires waiting 4 h before administering a second dose. The objective of the current analyses was to examine safety and pharmacokinetic profiles of second doses of diazepam nasal spray given 0−4 h after the first dose.MethodsTwo datasets were analyzed. The first, a long‐term, repeat‐dose safety study of diazepam nasal spray, compared rates of treatment‐emergent adverse events (TEAEs), serious TEAEs, and treatment‐related TEAEs for patients receiving ≥1 second dose ≤4 h versus all second doses >4 h after the first. The second was a population pharmacokinetic analysis using data from three phase 1 studies to model drug exposure when a second dose of diazepam nasal spray was administered across multiple time points (1 min−4 h) following the first dose.ResultsIn the repeat‐dose safety study, a second dose of diazepam nasal spray was administered ≤24 h after the first to treat 485 seizure clusters in 79 patients. Rates of TEAEs were similar between patients receiving ≥1 second dose in ≤4 h (89.5%, n = 38) compared with >4–24 h only (80.5%, n = 41). The most common treatment‐related TEAEs were associated with nasal discomfort, which was mild or moderate and transient. There were no reports of respiratory or cardiac depression. The pharmacokinetic simulations of second doses predicted comparable elevations of plasma diazepam concentrations with administrations across a range of intervals after the first dose (1 min−4 h).SignificanceThese data indicate that the safety and pharmacokinetic profiles of a second dose of diazepam nasal spray administered within 4 h of the first dose are consistent with those associated with current labeling. This is potentially important for patients with seizure clusters who have a recurrent seizure within 4 h of first treatment and might benefit from immediate retreatment to reduce the risk of progression to status epilepticus.

Abstract Objective 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. Methods Seizures and doses were recorded in diaries. Results 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). Significance 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.

Abstract Objective A Phase 3 open‐label safety study (NCT02721069) evaluated long‐term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters. Methods Patients were 6–65 years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12 months, with study visits at Day 30 and every 60 days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment‐emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded. Results Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was ≥12 months for 81.6% of patients. There was one death (sudden unexpected death in epilepsy) and one withdrawal owing to a TEAE (major depression), both considered unlikely to be related to treatment. Diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with 485 clusters treated with a second dose within 24 h; 53.4% of patients had monthly average usage of one to two doses, 41.7% two to five doses, and 4.9% more than five doses. No serious TEAEs were considered to be treatment related. TEAEs possibly or probably related to treatment ( n = 30) were most commonly nasal discomfort (6.1%); headache (2.5%); and dysgeusia, epistaxis, and somnolence (1.8% each). Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis. Significance In this large open‐label safety study, the safety profile of diazepam nasal spray was consistent with the established profile of rectal diazepam, and the high retention rate supports effectiveness in this population. A second dose was used in only 12.6% of seizure clusters.

AbstractObjectiveNeed 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.MethodsThis 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 (<2, moderate frequency; 2‐5, high frequency; >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.ResultsOf 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.SignificanceFrequency of dosing diazepam nasal spray had little impact on the safety/tolerability profile across a range of <2 to >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.

Abstract 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.

AbstractThe 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.

Abstract 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.