SCN1A-related Dravet syndrome : Vaccinations and seizure precipitants in disease course and diagnosis

Febrile seizures are well known adverse events following childhood vaccinations. If a seizure following vaccination is the first of an evolving epilepsy syndrome, the vaccination might be misinterpreted as the primary cause of the epilepsy. Dravet syndrome (formerly known as severe myoclonic epilepsy of infancy, or SMEI) is a rare epilepsy syndrome with seizure onset in the first year of life often triggered by fever or vaccinations, in a previously healthy child. In the second year or later, multiple seizure types develop and neurodevelopment slows down. In the majority of patients the syndrome is caused by spontaneous, heterozygous mutations in the SCN1A gene. The aim of the studies in this thesis was to further delineate the relationship with vaccinations, and specify the role of seizure precipitants in SCN1A-related Dravet syndrome. The prevalence of Dravet syndrome was studied among 1,269 children reported at the RIVM with seizures following vaccination in the first two years of life, and estimated to be at least 1.2%. Of all reported seizures following vaccinations in the first year of life, 2.5% were due to Dravet syndrome. For 2.6% of the 1,269 reported children with seizures following vaccination, this seizure marked the onset of epilepsy. Of them, 13% already had encephalopathy prior to seizure onset, 52% developed epileptic encephalopathy thereafter, and 35% had benign epilepsy. Of the children with a (supposed) epileptic encephalopathy, two-thirds had SCN1A-related Dravet syndrome. Overall, underlying causes had been identified in 65% of children. In 77 children with Dravet syndrome, the effect of vaccination-associated seizure onset on disease course and the risk of subsequent seizures after vaccinations were studied. The age at first seizure was younger in the 21% of children with a vaccination-associated seizure onset, but children with and without vaccination-associated seizure onset did not differ in age at first non-vaccination-associated seizure, age at first report of developmental delay, or cognitive outcome. After seizure onset, the risk of a seizure within 24 hours following an acellular pertussis combination vaccination was 9%, significantly lower than the 37% risk after whole-cell pertussis vaccines. Within the risk period of 5-12 days following mumps-measles-rubella vaccination, self-controlled case series analysis showed a 2.3-fold increased incidence rate of seizures. The importance of seizure precipitants in Dravet syndrome, other than vaccinations, was studied with a questionnaire answered by parents of 71 patients with Dravet syndrome. Fever, a cold, a bath, acute stress and physical exercise were reported as seizure precipitants in more than half of the patients. Seizure precipitating effects of visual stimuli were noted in 65% of 53 patients with Dravet syndrome, by re-evaluation of EEGs, data retrieval from medical files and use of parental questionnaires. The last part of the thesis is on the diagnostic process that was studied in a cohort of patients with SCN1A-related Dravet syndrome. The age at clinical diagnosis of Dravet syndrome decreased significantly after introduction of SCN1A analysis in the Netherlands. Use of contra-indicated antiepileptic drugs had occurred in 87% of patients and decreased with a shorter diagnostic interval and later birth year