Sullivan, Joseph

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 .

Abstract Objective We analyzed the long‐term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open‐label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults. Methods Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment‐emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent‐to‐treat (mITT) population. Post hoc analyses compared effectiveness in patients on concomitant stiripentol (STP) vs those not taking STP, and assessed safety (TEAEs) and effectiveness (Clinical Global Impression‐Improvement [CGI‐I] scale ratings) in patients enrolled as adults. Results A total of 374 patients, including 45 adults, received ≥1 FFA dose. Median FFA exposure was 824 days (range, 7–1280). TEAEs occurring in ≥10% of patients were pyrexia, nasopharyngitis, decreased appetite, seizure, decreased blood glucose, diarrhea, abnormal echocardiography (only physiologic regurgitation), upper respiratory tract infection, influenza, vomiting, and ear infection; no valvular heart disease or pulmonary arterial hypertension was observed over the OLE. In the mITT population ( n = 324), median percentage change in MCSF from baseline to EOS was −66.8% ( p < .001). The post hoc analyses of MCSF change from baseline to EOS in patients on concomitant STP ( n = 75) was −36.2% vs −71.6% in those not on concomitant STP ( n = 234) ( p < .0001). In adult patients, 29 of 41 (70.7%) and 29 of 42 patients (69.1%) demonstrated clinically meaningful improvement on CGI‐I at last visit as rated by caregivers and investigators, respectively. Significance Our OLE study of FFA in patients with DS confirmed previous positive findings and extended the exposure up to 3.5 years. No new or unexpected safety signals were observed and FFA demonstrated sustained and clinically meaningful reduction in MCSF.

AbstractObjectivesCorpus callosotomy (CC) is used to reduce seizures, primarily in patients with generalized drug‐resistant epilepsy (DRE). The invasive nature of the procedure contributes to underutilization despite its potential superiority to other palliative procedures. The goal of this study was to use a multi‐institutional epilepsy surgery database to characterize the use of CC across participating centers.MethodsData were acquired from the Pediatric Epilepsy Research Consortium (PERC) Surgery Database, a prospective observational study collecting data on children 0–18 years referred for surgical evaluation of DRE across 22 U.S. pediatric epilepsy centers. Patient, epilepsy, and surgical characteristics were collected across multiple CC modalities. Outcomes and complications were recorded and analyzed statistically.ResultsEighty‐three patients undergoing 85 CC procedures at 14 participating epilepsy centers met inclusion criteria. Mean age at seizure onset was 2.3 years (0–9.4); mean age for Phase I evaluation and surgical intervention were 9.45 (.1–20) and 10.46 (.2–20.6) years, respectively. Generalized seizure types were the most common (59%). Complete CC was performed in 88%. The majority of CC procedures (57%) were via open craniotomy, followed by laser interstitial thermal therapy (LiTT) (20%) and mini‐craniotomy/endoscopic (mc/e) (22%). Mean operative times were significantly longer for LiTT, whereas mean estimated blood loss was greater in open cases. Complications occurred in 11 cases (13%) and differed significantly between surgical techniques (p < .001). There was no statistically significant difference in length of postoperative stay across approaches. Mean follow‐up was 12.8 months (range 1–39). Favorable Engel outcomes were experienced by 37 (78.7%) of the patients who underwent craniotomy, 10 (58.8%) with LiTT, and 12 (63.2%) with mc/e; these differences were not statistically significant.SignificanceCC is an effective surgical modality for children with DRE. Regardless of surgical modality, complication rates are acceptable and seizure outcomes generally favorable. Newer, less‐invasive, surgical approaches may lead to increased adoption of this efficacious therapeutic option for pediatric DRE.

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.