Severe Communication Delays Are Independent of Seizure Burden and Persist Despite Contemporary Treatments in SCN1A+ Dravet Syndrome: Insights from the ENVISION Natural History Study.

Abstract

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. 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 (BSID-III) and the parent-reported Vineland Adaptive Behavior Scales 3rd Edition (VABS-III). We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (youngest), 2:1-3:6 years:months (middle) and 3:7-5:0 years:months (oldest). Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range: 0.0-24.0), with 54/58 (93.1%) followed for at least 6 months and 51/58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [min-max]: 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [0.0-2647.0] 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 0.52, P=0.024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize the optimal therapeutic window to prevent language/communication delay is before 3 years of age.