Genetic and immune findings in complex febrile seizures and the epidemiology of Dravet syndrome: A nationwide cohort study.

Abstract

Objectives: To determine what proportion of children presenting with complex febrile seizures (CFS) have an identifiable genetic mutation and/or serum anti-neuronal autoantibody positivity. To calculate the incidence of SCN1A-positive Dravet syndrome in Scotland. Methods: Patients were recruited from all 21 acute paediatric centres in the Scottish National Health Service over three-years (2014-2017). All children aged under three years (<3y) presenting with CFS were eligible. CFS was defined as any of: a cluster of two or more febrile seizures within a 24-hour period; any episode of febrile status epilepticus; two or more prolonged (>10 minute) febrile seizures within any time period. All children <3y presenting with new-onset epilepsy (n=167), afebrile status epilepticus (n= 6), or clusters of afebrile seizures (n=5) were recruited as a comparison group. All recruits had testing on a 104-gene epilepsy panel and serum antibodies to 10 neuronal epitopes (AMPA, CASPR2, GABAa, GABAb, Glycine, LGI1, NMDA, TAG, GAD,V GKC). Results: In 32 months, 70/260 (27%) of total recruited cases fulfilled our criteria for CFS, equal to 7% of total first febrile seizure presentations (400 per year in Scotland). Gene panel testing identified a pathogenic mutation in 6 CFS cases (8.6%). In all 6 the causative gene was SCN1A. A further 4 cases of SCN1A mutation were identified from the cohort presenting with epilepsy without antecedent febrile seizures. 9/10 SCN1A-positive cases had a clinical picture consistent with Dravet syndrome, making the incidence of SCN1A- positive Dravet syndrome in this population 1 in 16,600 live births. Anti-neuronal antibodies were identified in 10% of the CFS cohort, versus 14% of the epilepsy cohort. One of 10 SCN1A-positive patients also had antibodies(GABAa). Conclusion: The only major genetic epilepsy presenting initially with CFS is SCN1A- related. Most SCN1A-related epilepsy cases present initially with febrile seizures, but 40% have initial seizures that are afebrile. The incidence of SCN1A-positive Dravet syndrome is higher than previously reported.