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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 322-337 |
| Number of pages | 16 |
| Journal | Epilepsia |
| Volume | 65 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2024 |
Funding
The ENVISION study was sponsored by Encoded Therapeutics. The authors thank the children with DS and their families, without whom this study would not have been possible. We also thank the health care professionals who participated in the ENVISION study, and Drs. Elsa Shapiro, Rebecca Shaffer, and Susan Waisbren for data interpretation support. We thank Dr. Jacqueline French and the Epilepsy Study Consortium for their support during the conduct of the study. We thank the Encoded Clinical Operations team, Shawn Jones, Sarah Christensen, Caroline Daniels, Katherine Schloetter, and Judy Ho. We also thank Laurie LaRusso, MS, ELS, of Chestnut Medical Communications for editorial support for the manuscript and FourWave Medical Communications for figure layout and editorial support. M.S.P. has received support for speaking engagements from Zogenix/UCB, NobelPharma, and Marinus; for consulting from Zogenix/UCB, Biocodex, Stoke Therapeutics, Marinus, Bright Minds, Eisai, Jazz Pharmaceuticals, and Neurelis; and for research (paid to institution) from Zogenix/UCB, Stoke Therapeutics, Encoded Therapeutics, Neurocrine, and Takeda Pharmaceutical Company. I.E.S. has received support for serving on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, RogCon, Takeda Pharmaceutical Company, UCB, Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, LivaNova, Nutricia, Zuellig Pharma, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, BioMarin, Encoded Therapeutics, and Eisai; has served as an investigator for Anavex Life Sciences, Cerecin, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder, Epygenyx, ES Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceutical Company, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, and Zynerba; has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics, and Biohaven Pharmaceuticals; and is a nonexecutive director of Bellberry and a director of the Australian Academy of Health and Medical Sciences and the Australian Council of Learned Academies. She may accrue future revenue on pending patent WO61/010176 (filed 2008): Therapeutic Compound; has a patent for testing held by Bionomics and licensed to various diagnostic companies; and has a patent Molecular Diagnostic/Theranostic Target for Benign Familial Infantile Epilepsy (BFIE) [PRRT2] 2011904493 & 2 012 900 190 and PCT/AU2012/001321 (TECH ID:2012–009). J.S. has received support for contracted research from Zogenix, UCB, Stoke Therapeutics, Bio‐Pharm Solutions, Encoded Therapeutics, Xenon Pharmaceuticals, Neurocrine Biosciences, and Takeda Pharmaceutical Company; for consulting from Epilepsy Study Consortium, Greenwich Biosciences, Epygenix Therapeutics, Marinus Pharmaceuticals, Bright Minds, Longboard, Praxis, CAMP4, Rapport, Locanabio, Ceribell, and Cerecin; and for participation on a data safety monitoring board for NeuroPace. He holds restricted stock units in Epygenix Therapeutics. He serves as a board member and Medical Advisory Board member for the Dravet Syndrome Foundation and as Chair of the Scientific Advisory Board for PCDH19 Alliance. A.B. has received honoraria for presenting at educational events, serving on advisory boards, and consultancy work for Biocodex, Jazz/GW Pharmaceuticals, Encoded Therapeutics, Stoke Therapeutics, Nutricia, and UCB/Zogenix. S.B. has received speaking honoraria from Jazz Pharmaceuticals and has served as a paid consultant on advisory boards for Biocodex and UCB. J.W.W. has received grant support from Shainberg Foundation, TSC Alliance, Neuro Event Labs, NIH, Envision, Xenon, Stoke Therapeutics, Neurelis, Marinus, Epiwatch, UCB, Longboard, SKLSI, and Biohaven; support for speaker's bureau from LivaNova, Eisai, Supernus, Jazz Pharmaceuticals, UCB, Neurelis, BioMarin, SKLSI, and Azurity; and consulting fees from Jazz Pharmaceuticals, Neurelis, Marinus, BioMarin Consultant, and Azurity. L.L. has served as a consultant for Biocodex and participated in research that includes the following: GW Pharma, Zogenix, Biocodex, Stoke Therapeutics, Encoded Therapeutics, Epygenix therapeutics, Xenon, Praxis, Neurocrine, and Ovid Therapeutics. A.D.P. has received institutional research support from Encoded, Stoke Therapeutics, NIH, and PCORI. D.D. has received salary support for research from the Epilepsy Study Consortium and the Pediatric Epilepsy Research Foundation and is an investigator on research grants awarded to his institution from Encoded Therapeutics. K.G.K. has received research funding from Zogenix, Encoded, Eisai, and West Pharmaceuticals; has participated on data and safety monitoring boards for GW Pharmaceuticals and Epygenix; and has received consulting fees from BioMarin, Zogenix, Encoded, Eisai, Stoke Therapeutics, and Biocodex. M.L. is a paid consultant for Jazz Pharmaceuticals. E.S. is a consultant for Neurelis, GW Pharmaceuticals, Encoded Pharmaceuticals, Aquestive, and UCB and a speaker for Neurelis, GW Pharmaceuticals, Lundbeck, Eisai, Aquestive, UCB, and Novartis. D.L. has received consulting fees from Encoded. E.W. has received support for serving on data and safety monitoring boards for Acadia, Amicus, Neurocrine, Longboard, and Encoded; she has also received funding to her institution as a site investigator for Stoke Therapeutics, Marinus, and Takeda Pharmaceutical Company. S.Z. has received research support from Epilepsy Research UK, Dravet Syndrome UK, Scottish Government Digital Health & Care, Chief Scientists Office Scotland, Biocodex, Jazz Pharmaceuticals, UCB Pharma, Stoke Therapeutics, and Encoded Therapeutics for departmental investigator initiated studies; support for commercial research trials and natural history studies conducted by Research & Innovation, NHS Greater Glasgow & Clyde for UCB Pharma, GW Pharma, Stoke Therapeutics, and Encoded Therapeutics; and honoraria for educational symposia, consultancy work, and advisory boards from Zogenix/UCB, GW/Jazz Pharmaceuticals, and Encoded Therapeutics. M.W. has served as a paid consultant for Autism Speaks. P.O. is a consultant for Encoded Therapeutics. B.M. is employed by SSI Strategy and has received consulting fees from Encoded Therapeutics. M.M., E.J., M.C.V., N.H., J.S.G., and S.R. are employees of Encoded Therapeutics. None of the other authors have any conflict of interest to disclose. SCN1A
Keywords
- Dravet syndrome
- ENVISION
- communication/language delays
- developmental and epileptic encephalopathy
- natural history study
ASJC Scopus subject areas
- Clinical Neurology
- Neurology