OBJECTIVE:To assess the efficacy and safety of fenfluramine in patients with Dravet syndrome (DS) stratified by age, number of previously attempted antiseizure medications (ASMs), and SCN1A pathogenic variant status. METHODS:In this post hoc analysis, data from three randomized controlled trials (RCTs) in patients with DS (2-18 years) were pooled and stratified by age (<4; ≥4 years), number of previous ASMs (1-3; 4-6; ≥7), and SCN1A pathogenic variant status (SCN1A+; SCN1A-). Stratified groups were assessed and compared with the pooled placebo group (change in monthly convulsive seizure frequency [MCSF], longest convulsive seizure-free interval, and Clinical Global Impression-Improvement [CGI-I] scale scores rated by parents/caregivers and investigators), and safety (treatment-emergent adverse events [TEAEs]: frequency, days to onset, and proportion resolved). RESULTS:Among 348 patients included in the RCTs, 216 were randomized to fenfluramine (0.7 mg/kg/day, n = 88; 0.4 mg/kg/day [with stiripentol], n = 43; 0.2 mg/kg/day, n = 85) and 132 to placebo. Compared with placebo, fenfluramine treatment (all doses combined) resulted in greater MCSF reductions, greater increases in longest convulsive seizure-free intervals, and a higher proportion of parents/caregivers and investigators reporting clinically meaningful improvement ("Much Improved", "Very Much Improved") on CGI-I scores across all stratified groups. CGI-I scores were consistent across fenfluramine doses in most stratified groups, but patients with the fewest number of previous ASMs had the greatest frequency of clinically meaningful improvement on investigator-rated CGI-I scores. Safety outcomes were similar across all strata. Most TEAEs resolved by end-of-study. SIGNIFICANCE:Fenfluramine treatment was associated with improved seizure outcomes and global functioning compared with placebo regardless of age, number of previous ASMs, and SCN1A status in patients with DS. Fenfluramine was well-tolerated; no new safety signals were identified. Further studies with larger sample sizes (including adults) and a priori inferential analyses of stratified groups are warranted. PLAIN LANGUAGE SUMMARY:Patients with Dravet syndrome struggle with seizures and everyday life. In three studies, patients aged 2-18 years received fenfluramine or placebo (sugar pill). Fenfluramine lowered seizures without many side effects. Researchers combined results from these studies to see how fenfluramine worked in different patient groups based on age, number of previous medications, and a gene called SCN1A. They looked at seizure reduction and whether doctors felt patients had improved. In all groups, fenfluramine worked better than placebo, with similar side effects. Researchers believe fenfluramine helped these patients, but some groups were small, so these results need to be confirmed.

OBJECTIVE:Dravet syndrome (DS) is the prototypic developmental and epileptic encephalopathy, characterized by drug-resistant seizures, developmental slowing, and many other morbidities. Detailed characterization of behavioral phenotypes and social-emotional skill development are limited. METHODS:We prospectively assessed behavioral and social-emotional problems in the ENVISION natural history study (NCT04537832) of children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at <5 years of age. Assessments every 3 months for up to 2 years included the Child Behavior Checklist (CBCL), Strengths and Difficulties Questionnaire (SDQ), Brief Infant-Toddler Social and Emotional Assessment (BITSEA), and Vineland Adaptive Behavior Scales, 3rd Edition (VABS-3). RESULTS:Fifty-eight children with DS enrolled at 16 sites worldwide. Problematic behaviors-inattention, aggressive or oppositional behaviors, and withdrawn and autistic behaviors-began before age 3 years, became more evident with age, and were clinically significant in many children by age 3-4 years. CBCL Total, Externalizing, and Internalizing Problems T-scores rose by approximately 3 points per year, and BITSEA Problem scale scores increased by 2.3 points annually (p = .002). SDQ Hyperactivity scores worsened over time (p = .013), whereas emotional difficulties remained stable. VABS-3 Socialization domain scores, which were already more than 1 SD below the normative mean at baseline, decreased further, particularly in younger participants. Correlation analyses showed that poorer communication abilities were associated with increased problematic behaviors (R = -.55 for CBCL Total Problems and VABS-3 Communication scores). Mixed-effects modeling identified age as the strongest predictor of worsening behavioral outcomes. SIGNIFICANCE:We found that behavioral and social-emotional problems are inherent components of DS that present in toddlerhood and worsen throughout early childhood. This highlights the need to diagnose and manage these issues early. Targeted therapy may alleviate the wide-ranging morbidities that are intrinsic to DS, including the social-emotional and behavior problems that frequently emerge.

Background:Perampanel (PER) is effective in treating focal and generalised seizures. The PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) Extension study was a large, pooled analysis of PER clinical practice studies that assessed the effectiveness and safety/tolerability of PER in over 6800 people with epilepsy. Objectives:To determine clinical factors associated with PER retention, response, seizure freedom and tolerability when used in clinical practice. Design:An exploratory post hoc analysis of data from all individuals included in PERMIT Extension. Methods:Univariate and multivariable logistic regression analyses were performed to identify baseline factors associated with retention rate, responder rate (⩾50% seizure frequency reduction), seizure freedom rate (no seizures since at least the previous visit) and incidence of adverse events (AEs). Results:A total of 6822 people with epilepsy treated with PER were included. Baseline factors associated with retention were absence of psychiatric comorbidity (odds ratio [95% confidence interval], 1.99 [1.403-2.825]; p < 0.001), fewer focal seizures (1.01 [1.004-1.014]; p < 0.001) and fewer previous antiseizure medications (ASMs; 1.06 [1.013-1.119]; p = 0.013). Factors associated with response were absence of focal seizures (2.12 [1.532-2.924]; p < 0.001), fewer previous ASMs (1.19 [1.136-1.250]; p < 0.001) and absence of concomitant sodium channel blocker (SCB) ASM(s) (1.96 [1.455-2.628]; p < 0.001). Factors associated with seizure freedom were fewer total seizures (1.04 [1.020-1.061]; p < 0.001), absence of focal seizures (3.45 [2.387-4.979]; p < 0.001), fewer previous ASMs (1.11 [1.028-1.205]; p = 0.008), absence of concomitant SCB ASM(s) (1.46 [1.051-2.028]; p = 0.024) and absence of concomitant gamma-aminobutyric acid (GABA)-ergic ASM(s) (2.08 [1.266-3.412]; p = 0.004). Factors associated with occurrence of AEs were older age (1.01 [1.006-1.015]; p < 0.001), longer epilepsy duration (1.01 [1.010-1.012]; p = 0.044), presence of psychiatric comorbidity (1.74 [1.469-2.062]; p < 0.001) and greater number of previous ASMs (1.09 [1.069-1.119]; p < 0.001). Conclusion:This study identified clinical factors associated with PER's real-world effectiveness and tolerability, which may help inform treatment decisions in clinical practice.

PURPOSE:Combined malonic and methylmalonic acidemia (CMAMMA) is a rare genetic disorder caused by biallelic variants in the acyl-CoA synthetase family member 3 (ACSF3) gene (Witkowski et al., 2011) and is associated with elevated levels of malonic acid (MA) and methylmalonic acid (MMA) in urine (Sloan et al., 2011). CMAMMA is generally considered a benign disorder, with recent descriptions of potential neuropsychiatric symptoms in children (Levtova et al., 2019). We expand the phenotype by describing a case of severe developmental and epileptic encephalopathy with a CMAMMA-associated Lennox-Gastaut Syndrome (LGS) phenotype and comorbid neuropsychiatric abnormalities. METHODS AND RESULTS:An 8-year-old boy with CMAMMA, referred to our clinic's neurogenetic center, presented with refractory epilepsy and severe neurobehavioral symptoms. His epilepsy consisted of tonic, atonic, and generalized tonic-clonic seizures with electroclinical features consistent with LGS. The patient had comorbid autism, aggression, and intellectual disability with a history of developmental regression. Genetic testing confirmed pathogenic biallelic ACSF3 variants, and urine organic acid testing showed elevated levels of MA and MMA in urine. CONCLUSION:This case suggests that CMAMMA can lead to severe epilepsy and a neuropsychiatric phenotype, expanding the clinical spectrum of the disorder.

OBJECTIVE:Benzodiazepine immediate-use seizure medications (ISMs; also called rescue therapies) are used to treat seizure clusters/acute repetitive seizures in patients with epilepsy. In the United States, diazepam nasal spray is an approved ISM for patients ≥2 years of age. The primary objective was to assess diazepam nasal spray pharmacokinetics (PK) in patients 2-5 years of age; safety and tolerability were secondary objectives. METHODS:This Phase 1/2a, open-label, single-dose, PK study with a 180-day open-label safety period enrolled patients with epilepsy 2-5 years of age. Diazepam nasal spray (0.5-mg/kg per diazepam rectal gel dosing) was administered by a medical professional, followed by PK sampling. During the safety period, caregivers administered diazepam nasal spray as needed for frequent or acute repetitive seizures. Seizures and dosing were recorded in a diary. Study visits included safety evaluations. Use of second doses was a proxy for effectiveness. RESULTS:Thirty-six patients were enrolled, with 35 in the PK population. PK parameters and modeling were comparable to older children and adults, confirming that diazepam nasal spray was readily absorbed and supporting the adequacy of the 0.5-mg/kg dose for this age group. In the open-label period, second doses within 24 h of the initial dose were administered for 16.3% of seizure events (37/227), indicating that a second dose was not used for most seizure events (83.7%). Treatment-related treatment-emergent adverse events occurred in seven patients (19.4%); all were mild except one (moderate). There was one report each of respiratory depression and respiratory distress; neither was treatment related. SIGNIFICANCE:This study characterizes the PK of diazepam in patients 2-5 years of age and reports a safety profile consistent with older patients. Results demonstrate that the diazepam nasal spray drug-device combination is appropriate for drug delivery and absorption in these patients.

BACKGROUND:People with epilepsy (PWE) may experience seizure clusters, broadly defined as ≥2 seizures that occur in close proximity. In epilepsy monitoring units (EMUs), seizure clusters can spontaneously occur during long-term videoelectroencephalogram monitoring (LTVEM) or as a result of antiseizure medication dose adjustments. In this survey, we examined the experiences and practices of expert clinicians with seizure clusters in EMUs. METHODS:A 55-item survey was sent to members of an Epilepsy Education Council who are epilepsy experts. Items described experiences, treatment practices, and negative outcomes with seizure clusters in EMUs. RESULTS:Of the 15 experts (aged 43-77 y), 14 are physicians and 1 is an advanced practice provider; 14 work at level 4 epilepsy centers. The definition of seizure cluster varied across experts, from 2 seizures in 1 hour to 3 seizures over 24 hours. Twelve experts prescribe immediate-use rescue medication (RM) during EMU stay, usually a benzodiazepine. An intranasal route is preferred by 11 if intravenous access is unavailable. Nine experts have had a presurgical evaluation compromised owing to seizure clusters during LTVEM, and 12 have cared for PWE who required transfer to a higher-level care (eg, intensive care unit) owing to seizure clusters. Thirteen experts indicated they would follow expert consensus recommendations for immediate-use RMs in the EMU if available. CONCLUSIONS:In the EMU, seizure clusters may compromise presurgical evaluations and require higher levels of care. Consensus recommendations are needed to guide patient-specific treatment practices before, during, and after EMU admission.

OBJECTIVE:Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug-resistant seizures and developmental slowing. Although cognitive and executive function deficits have been described, their early trajectory is not well understood. METHODS:The prospective ENVISION natural history study (NCT04537832) assessed cognitive, executive, and adaptive function in children younger than 5 years of age with SCN1A+ DS every 6 months for up to 2 years using Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III), Wechsler Preschool & Primary Scale of Intelligence, 4th Edition (WPPSI-IV), Vineland Adaptive Behavior Scales, 3rd Edition (VABS-3), Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P), and Pediatric Evaluation of Disability Inventory (PEDI). RESULTS:Fifty-eight children were enrolled, with 47% younger than age 2 years. At least 80% of children did not achieve age-appropriate milestones. Mean BSID-III Cognitive raw scores increased minimally, with age-equivalent gains of only 3 months over 1.5 years. Mean Cognitive Composite scores declined significantly by Month 12 (from 81.6 to 72.2; change: -11.0, 95% confidence interval [CI]: -15.3 to -6.8), signaling a widening gap compared with neurotypical development. Executive function worsened, with mean BRIEF-P Global Executive Composite T-scores increasing by 3.2 points/year. For some participants, scores were 5 standard deviations (SD) above the normative mean, reflecting abilities profoundly below age expectations (bottom .00003% of the population). Adaptive functioning worsened, with mean VABS-3 Adaptive Behavior Composite decreasing from 78.7 to 68.1 over 1.5 years (change: -9.0, 95% CI: -11.9 to -6.1) and greater decline among children <2 years at enrollment, with scores decreasing by ~15 points (1 SD). Over half of children >3 years could not remove clothing independently; and when placed on a toilet, 48% could not use it. SIGNIFICANCE:Infants and young children with SCN1A+ DS show significant and progressive developmental slowing across several domains, highlighting urgent need for therapies to mitigate the devastating impact on individuals and families.

OBJECTIVE:Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high seizure burden and mortality risk. Stiripentol, one of the first DS-specific therapies, received FDA approval in 2018 but its real-world use and impact post-approval in the USA remain insufficiently characterized. The STIRUS study aimed to assess treatment patterns, clinical efficacy, and quality of life outcomes associated with stiripentol in a contemporary US cohort. METHODS:STIRUS was a retrospective, multicenter chart review of 98 DS patients who initiated stiripentol after FDA approval and were treated for at least 3 months. Data were collected from 10 USA epilepsy centers on seizure types and frequency, status epilepticus (SE), rescue medication use, emergency room visits, and quality of life, at baseline and during the first and final 3 months on stiripentol. Changes over time were assessed using generalized estimating equation models. RESULTS:Initiation of stiripentol was associated with a significant reduction in bilateral convulsive seizure frequency (OR = 2.16, p < 0.006) and a nearly 50% decrease in SE episodes (OR = 2.9, p < 0.003). Importantly, there was a marked decline in rescue medication use and seizure-related hospital visits: the proportion of patients requiring no rescue medications increased from 23% to over 53%, and those needing frequent emergency interventions dropped from 39% at baseline to 14% during the final 3 months. Quality of life improved in more than half of patients and caregivers. SIGNIFICANCE:The STIRUS study supports the real-world efficacy of stiripentol in reducing seizure burden and healthcare utilization in DS. Despite its demonstrated benefits and approval for use in infants, stiripentol remains underutilized and often introduced late in the treatment course. Early and broader adoption may help improve clinical outcomes and quality of life in this vulnerable population. PLAIN LANGUAGE SUMMARY:The STIRUS study found that stiripentol, an anti-seizure medication specifically approved for Dravet Syndrome, helped reduce seizures and hospital visits for children living with this severe form of epilepsy. Patients had fewer convulsive seizures, needed fewer rescue medicines, and reported better quality of life. Despite these benefits, stiripentol is still not widely used and often started too late in treatment, suggesting earlier use could further improve outcomes.

OBJECTIVE:The drug-resistant epilepsy associated with Lennox-Gastaut syndrome (LGS) has a long-term effect on patients and is difficult to treat with conventional pharmacological and nonpharmacological therapies. Our objective is to demonstrate that adjunctive vagus nerve stimulation (VNS) can help manage the seizures associated with LGS. METHODS:CORE-VNS (NCT03529045) is a prospective, multicenter, multinational observational study to collect data on seizure and nonseizure outcomes following treatment with VNS. Participants were identified as having a documented LGS diagnosis and received initial VNS implants. Baseline seizure frequency data and patient-reported outcome measures were collected at 3, 6, 12, 24, and 36 months. This interim analysis compared baseline data to VNS therapy outcomes at 24 months, and the results are presented here. RESULTS:Sixty participants in the CORE-VNS study had a diagnosis of LGS and received an initial implant of VNS. The population was geographically diverse: 31.7% European, 26.7% from the Americas, and 26.7% from the Western Pacific. The median age at implant was 11.8 years (range = 2.2-47.6), and only 26.7% of those diagnosed with LGS were >18 years of age. Most (70%) of the participants had severe cognitive impairment. The LGS participants failed a median of 6 antiseizure medications, and 83.3% had not undergone epilepsy surgery. The LGS responder rate (≥50% reduction in seizure frequency) at 24 months for focal and generalized seizures was 66.7% and 47.4%, respectively. Some participants (20%, 12/60) experienced a ≥80% reduction in total seizure frequency. VNS was well tolerated, with only 15% (9/60) reporting at least one treatment-emergent adverse event, primarily cough, dysphonia, and oropharyngeal pain. SIGNIFICANCE:LGS participants who received adjunctive VNS therapy to manage seizures were predominantly severely cognitively impaired children. Reductions in seizure frequency, including those with drops, and the sustained nature of the response support VNS as a promising therapy in LGS.