Sullivan, Joseph

Abstract Objectives Dravet syndrome (DS) is a drug‐resistant developmental and epileptic encephalopathy, often requiring three or more antiseizure medications (ASMs). Consequently, the therapeutic landscape is highly complex, combining DS‐specific agents (stiripentol, STP; cannabidiol, CBD; fenfluramine, FFA), non‐specific ASMs, and non‐pharmacologic options such as dietary therapy or neuromodulation. In addition, recognition of patients' changing needs across the lifespan, together with the essential contribution of caregiver education to effective treatment oversight—including awareness of potential drug–drug interactions and adverse events—emphasizes the value of an integrated and forward‐looking approach. A consensus initiative was developed to guide clinicians in the management of patients with DS, with a particular focus on STP‐containing regimens. Methods Based on a literature review and clinical vignette discussions, a nominal group of five international DS experts developed 38 statements across six themes: (i) general principles, (ii) guiding physicians to empower families, (iii) STP as add‐on to specific and non‐specific Dravet ASMs, (iv) FFA in regimens containing STP, (v) CBD in regimens containing STP, and (vi) patient follow‐up during treatment initiation. Statements were scored on a 9‐point Likert scale (1 = strongly disagree, 9 = strongly agree) first by the nominal group and then by an international panel of 59 DS clinicians. Consensus was defined as ≥75% rating ≥7 and/or a median ≥8. Results Thirty‐four of the 38 statements (89%) reached consensus among both the nominal group and the international panel; one did not reach consensus in either, and three reached consensus only among the nominal group. Both panels agreed on the importance of involving families in treatment decisions and follow‐up, as well as on key aspects of polytherapy management, including ASM initiation, treatment adjustments, and adverse event management. Significance This international consensus integrates evidence and clinical expertise to establish shared principles that address a long‐standing gap in the polytherapeutic management of Dravet syndrome. Plain Language Summary Dravet syndrome is a rare and severe form of epilepsy that begins in early childhood, with seizures that often persist throughout life. Because the disease is highly drug resistant, most patients are treated with polytherapy, making clinical management complex for clinicians. This consensus brings together published evidence and expert experience to provide practical guidance on the management of polytherapy in Dravet syndrome, supporting clinicians in optimizing patient care.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy. Diagnosis is clinical, but ~90% of patients have pathogenic variants in SCN1A . ATP6V0C has recently been proposed as a novel candidate gene for epilepsy, with or without developmental delay. Here we describe two adult patients with a clinical diagnosis of DS associated with ATP6V0C variants. Methods Patients with developmental and epileptic encephalopathies were evaluated by physicians who are experts in DS, and their clinical diagnosis was correlated with genetic findings. A subgroup of those patients with DS but without known genetic causes were evaluated through gene panels, whole exome sequencing, and chromosome microarray. Phenotype was determined by pediatric and adult chart reviews, interviews, and physical examinations. Results Of 753 patients with DS, two unrelated individuals with classic features of DS during childhood and adulthood were identified with heterozygous de novo missense variants in ATP6V0C (c.319G > C, p.(Gly107Arg) and c.284C > T, p.(Ala95Val), respectively). Both variants were absent in normal populations and computational prediction algorithms suggested deleterious effects on protein structure and/or function. No disease‐causing variants in other genes previously associated with DS were found. Significance Here we describe two adult patients with Dravet‐like syndrome and pathogenic/likely pathogenic variants in ATP6V0C . We propose that abnormal ATP6V0C function can, at the severe end of the clinical spectrum, be associated with Dravet‐like phenotype. This is relevant, as these patients would not qualify for disease‐modifying antisense nucleotide or gene therapies targeting SCN1A .

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.