Long-term predictors of developmental outcome and disease burden in SCN1A-positive Dravet syndrome

Abstract

Dravet syndrome is a severe infantile onset developmental and epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. Prospective data on long-term developmental and clinical outcomes are limited; this study seeks to evaluate the clinical course of Dravet syndrome over a 10-year period and identify predictors of developmental outcome. SCN1A mutation-positive Dravet syndrome patients were prospectively followed-up in the United Kingdom from 2010 to 2020. Caregivers completed structured questionnaires on clinical features and disease burden; the Epilepsy & Learning Disability Quality of Life Questionnaire, the Adaptive Behavioural Assessment System-3 and the Sleep Disturbance Scale for Children. 68/113 caregivers (60%) returned posted questionnaires. Developmental outcome worsened at follow-up (4.45 [SD 0.65], profound cognitive impairment) compared to baseline (2.9 [SD 1.1], moderate cognitive impairment, p<0.001), whereas epilepsy severity appeared less severe at 10-year follow-up (p=0.042). Comorbidities were more apparent at 10-year outcome including an increase in autistic features (77% [48/62] vs 30% [17/57], X2=19.9, p<0.001), behavioural problems (81% [46/57] vs 38% [23/60], X2=14.1, p<0.001) and motor/mobility problems (80% [51/64] vs 41% [24/59], X2=16.9, p<0.001). Subgroup analysis demonstrated a more significant rise in comorbidities in younger compared to older patients. Predictors of worse long-term developmental outcome included poorer baseline language ability (p<0.001), more severe baseline epilepsy severity (p=0.003) and a worse SCN1A genetic score (p=0.027). Sudden unexpected death in epilepsy had not been discussed with a medical professional in 35% (24/68) of participants. Over 90% of caregivers reported a negative impact on their own health and career opportunities. Our study identifies important predictors and potential biomarkers of developmental outcome in Dravet syndrome and emphasises the significant caregiver burden of illness. The negative impact of epilepsy severity at baseline on long-term developmental outcomes highlights the importance of implementing early and focused therapies while the potential impact of newer anti-seizure medications requires further study.