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Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment‐resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. Methods ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants ( SCN1A + DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent‐reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6–2:0 years:months (Y:M; youngest), 2:1–3:6 Y:M (middle), and 3:7–5:0 Y:M (oldest). Results Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow‐up was 17.5 months (range = .0–24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum–maximum] = 1.0 in the youngest [1.0–70.0] and middle [1.0–242.0] age groups and 4.5 [.0–2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. Significance In infants and young children with SCN1A + DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

AbstractObjectiveThis study was undertaken to evaluate the long‐term safety and effectiveness of fenfluramine in patients with Lennox–Gastaut syndrome (LGS).MethodsEligible patients with LGS who completed a 14‐week phase 3 randomized clinical trial enrolled in an open‐label extension (OLE; NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3‐month intervals. The protocol‐specified treatment duration was 12 months, but COVID‐19‐related delays resulted in 142 patients completing their final visit after 12 months.ResultsAs of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2–4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was −28.6% over the entire OLE (n = 241) and −50.5% at Month 15 (n = 142,p < .0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was −45.9% (n = 192,p = .0038). Generalized tonic–clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p < .0001,n = 106) and 35.8% (p < .0001,n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%–44.1%,n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%–41.8%,n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment‐emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed.SignificancePatients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long‐term. Fenfluramine may provide an important long‐term treatment option for LGS.

Dravet syndrome (DS) is a drug-resistant, early-onset, developmental and epileptic encephalopathy where there have been many recently approved therapies with many more in development. With the availability of more syndrome specific treatment options coupled with an earlier diagnosis, DS is well-positioned to be an example of how a precise syndromic diagnosis can guide treatment choices and improve overall outcomes and also allow for the development of potential disease modifying therapies to address more than just seizures. In this review we summarize the current state of DS approved therapies and those that are in various stages of development.

Abstract Objective This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently approved, DS‐specific therapies and emerging disease‐modifying treatments. Methods A core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease‐modifying therapies) and nominated the 31‐member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS. Results There was strong consensus that infants 2–15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first‐ to third‐line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease‐modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians. Significance This International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease‐modifying therapies.

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

AbstractIntroductionA wearable cardioverter defibrillator (WCD) is indicated in appropriate patients to reduce the risk for sudden cardiac death. Challenges for patients wearing a WCD have been frequent false shock alarms primarily due to electrocardiogram noise and wear discomfort. The objective of this study was to test a contemporary WCD designed for reduced false shock alarms and improved comfort.MethodsOne hundred and thirty patients with left ventricular ejection fraction ≤40% and an active implantable cardioverter defibrillator (ICD) were fitted with the ASSURE WCD (Kestra Medical Technologies) and followed for 30 days. WCD detection was enabled and shock alarm markers recorded, but shocks and shock alarms were disabled. All WCD episodes and ICD ventricular tachycardia/ventricular fibrillation (VT/VF) episodes were adjudicated. The primary endpoint was the false‐positive shock alarm rate with a performance goal of 1 every 3.4 days (0.29 per patient‐day).ResultsOf 163 WCD episodes, 4 were VT/VF and 159 non‐VT/VF (121 rhythms with noise, 32 uncertain with noise, 6 atrial flutter without noise). Only three false‐positive shock alarm markers were recorded; one false‐positive shock alarm every 1333 patient‐days (0.00075 per patient‐day, 95% confidence interval: 0.00015–0.00361; p < .001). No ICD recorded VT/VF episodes meeting WCD detection criteria (≥170 bpm for ≥20 s) were missed by the WCD during 3501 patient‐days of use. Median wear was 31.0 days (interquartile range [IQR] 2.0) and median daily use 23.0 h (IQR 1.7). Adverse events were mostly mild: skin irritation (19.4%) and musculoskeletal discomfort (8.5%).ConclusionThe ASSURE WCD demonstrated a low false‐positive shock alarm rate, low patient‐reported discomfort, and no serious adverse events.