Cognitive stagnation and executive function deficits in young children with SCN1A+ Dravet syndrome: Detailed characterization of onset, progression, and impact in the ENVISION natural history study.

objectiveDravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug-resistant seizures and developmental slowing. Although cognitive and executive function deficits have been described, their early trajectory is not well understood.

methodsThe prospective ENVISION natural history study (NCT04537832) assessed cognitive, executive, and adaptive function in children younger than 5 years of age with SCN1A+ DS every 6 months for up to 2 years using Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III), Wechsler Preschool & Primary Scale of Intelligence, 4th Edition (WPPSI-IV), Vineland Adaptive Behavior Scales, 3rd Edition (VABS-3), Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P), and Pediatric Evaluation of Disability Inventory (PEDI).

resultsFifty-eight children were enrolled, with 47% younger than age 2 years. At least 80% of children did not achieve age-appropriate milestones. Mean BSID-III Cognitive raw scores increased minimally, with age-equivalent gains of only 3 months over 1.5 years. Mean Cognitive Composite scores declined significantly by Month 12 (from 81.6 to 72.2; change: -11.0, 95% confidence interval [CI]: -15.3 to -6.8), signaling a widening gap compared with neurotypical development. Executive function worsened, with mean BRIEF-P Global Executive Composite T-scores increasing by 3.2 points/year. For some participants, scores were 5 standard deviations (SD) above the normative mean, reflecting abilities profoundly below age expectations (bottom .00003% of the population). Adaptive functioning worsened, with mean VABS-3 Adaptive Behavior Composite decreasing from 78.7 to 68.1 over 1.5 years (change: -9.0, 95% CI: -11.9 to -6.1) and greater decline among children <2 years at enrollment, with scores decreasing by ~15 points (1 SD). Over half of children >3 years could not remove clothing independently; and when placed on a toilet, 48% could not use it. SIGNIFICANCE: Infants and young children with SCN1A+ DS show significant and progressive developmental slowing across several domains, highlighting urgent need for therapies to mitigate the devastating impact on individuals and families.