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

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OBJECTIVE: Dravet 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. METHODS: The 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). RESULTS: Fifty-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.

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