Cognitive and Executive Functioning Difficulties in Young Children with SCN1A+ Dravet Syndrome Participating in the ENVISION Study, an International, Prospective Natural History
Abstract number :
1.193
Submission category :
4. Clinical Epilepsy / 4A. Classification and Syndromes
Year :
2023
Submission ID :
491
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: James Wheless, MD – Le Bonheur Children's Hospital
M. Scott Perry, MD – Cook Children’s Medical Center; Ingrid Scheffer, AO, FAA, FAHMS – University of Melbourne, Austin Health; Joseph Sullivan, MD – University of California at San Francisco; Susana Boronat, MD, PhD – Hospital de la Santa Creu i Sant Pau; Andreas Brunklaus, MD – Royal Hospital for Children; Linda Laux, MD – Ann & Robert H. Lurie Children's Hospital of Chicago; Anup Patel, MD – Nationwide Children’s Hospital; Colin Roberts, MD – Doernbecher Children’s Hospital; Dennis Dlugos, MD, MSCE – Children’s Hospital of Philadelphia; Deborah Holder, MD – Children's Hospital Los Angeles; Kelly Knupp, MD – Children’s Hospital Colorado; Matt Lallas, MD – Nicklaus Children’s Hospital; Steven Phillips, MD – Multicare Health System; Eric Segal, MD – Northeast Regional Epilepsy Group; Dennis Lal, PhD – Cleveland Clinic Lerner Research Institute; Elaine Wirrell, MD – Mayo Clinic; Sameer Zuberi, MD – Royal Hospital for Children; Sarah Christensen, - – Encoded Therapeutics; Jacqueline Gofshteyn, MD – Encoded Therapeutics; Norman Huang, PhD – Encoded Therapeutics; Emma James, PhD – Encoded Therapeutics; Maria Candida Vila, PharmD, PhD – Encoded Therapeutics; Salvador Rico, MD, PhD – Encoded Therapeutics
Rationale:
Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) with frequent seizures and global developmental delay. Substantial differences in cognition and executive functioning are observed between individuals with DS and age-matched children, but limited prospective long-term data characterizing the onset and evolution of these domains at a young age are missing. ENVISION, a prospective observational study, evaluated the course and impact of DS in young children and their families. Here, we present up to 18 months of data focusing on cognition and executive function from the completed study.
Methods:
International, multicenter, longitudinal, prospective study of children with confirmed SCN1A pathogenic variant, aged six months to five years at enrollment, were assessed every three months. Cognitive and executive functions were evaluated using BSID-III, Vineland-III, WPPSI-IV, and BRIEF-P tools.
Results:
Fifty-eight children were enrolled (median age 29 months) with 47% under age two years. Between nominal visits, cognitive raw scores of the BSID-III showed a significant increase only in those < 2 years of age at enrollment. Despite the gains in the < 2 years cohort, a continued decline in normalized scores by two points/year suggests widening cognitive deficits relative to neurotypical peers. WPPSI-IV early setting assessment (FSIQ) showed a marked cognitive slowing between ages 2.5 and 3.5 years, even in higher functioning participants. Adaptive functioning, as measured by the ABC score of the Vineland-III, mirrored these findings; after age three years seven months, all participants showed developmental quotient < 60%. Over an 18-month period, the total cohort age equivalent score only increased by six months. The BRIEF-P showed executive function deficits were evident by age two years and worsened over time, with some children falling five SDs above the normative mean. Emergent metacognition was the most affected domain, followed by inhibitory self-control, with flexibility least affected. Participants aged 2–3.5 years at enrollment consistently scored worse on the emergent metacognition BRIEF-P T-scores, indicating severe deficits in working memory and planning/organizing. No significant differences were noted in BRIEF-P scores between participants with or without tonic/atonic seizures (a potential risk factor for more severe disease).
Conclusions:
Despite modest cognitive gains, cognitive and executive function in children with DS continue to deviate from their neurotypical peers as they age. Executive dysfunction is particularly impacted in areas of working memory, impulsivity, emotional control, and planning. Our findings highlight the urgency for early therapeutic interventions that go beyond seizure control to potentially modify disease progression and prevent or halt cognitive decline in children with DS.
Funding: This study was funded by Encoded Therapeutics.
Clinical Epilepsy