Abstract
Children with epilepsy and developmental impairment encompass two groups: developmental and epileptic encephalopathy (DEE) and intellectual disability and epilepsy (ID+E). In both of these disorders the underlying aetiology causes seizures and neurodevelopmental abnormalities. In DEE, the frequent seizures and/or epileptiform activity additionally impact directly on development.
Approximately 1 in 2,000 children develop a DEE in the first 2 years of life. There is little epidemiological data regarding children who develop DEE after this age, or for children that develop ID+E at any age. The incidence of many epilepsy syndromes in these children is also poorly described.
The aetiology of DEE and ID+E is heterogeneous. If no environmental cause is evident, they are largely thought to be genetic disorders; however, half remain undiagnosed even after genomic sequencing. Genetic diagnosis is critical, and has both personal and clinical utility. It enables accurate reproductive and prognostic counselling, and can direct targeted therapies.
This population-based study aimed to discover the cumulative incidence of DEE and ID+E in children presenting prior to their 16th birthday, as well as the cumulative incidence of specific epilepsy syndromes found in these disorders. The two groups were compared in terms of cognitive development, epilepsy resolution, and mortality. A second focus was determining the underlying genetic aetiology, using a range of modalities including whole genome sequencing.
Children with epilepsy born 2000-2016 in the Wellington region of New Zealand were identified using centralised EEG records. Epilepsy phenotype was determined by interview and/or review of the medical records. 235 children were identified; two-thirds had a DEE and one-third ID+E. On 31/12/16, the point prevalence of DEE or ID+E was 175/100,000 children (95% confidence interval [CI] 149-203; DEE 112 and ID+E 63 per 100,000 children). Cumulative incidence by 16 years of DEE was 169/100,000 children (CI 144-199) and of ID+E was 125/100,000 (CI 95.4-165).
At the end of follow-up (median 7.9 years), 14% of children with DEE had normal cognition; however, children with DEE were more likely than those with ID+E to have a severe/profound intellectual disability (ID). Younger age at seizure onset was associated with more severe ID in children with DEEs but not those with ID+E. 5-year seizure freedom was achieved in 27% of children with DEE but 59% of children with ID+E.
Thirty-nine percent of the cohort had an identified genetic aetiology, 31% structural, 3% metabolic, and 2% infectious. 11% had an acquired condition. Diagnostic yield from genetic testing was higher in children whose epilepsy began in infancy than in those aged 1-4 years, but did not decline appreciably in older children.
This population-based study showed that epilepsy in children with DEE and ID+E frequently begins beyond the first few years of life. The finding of a DEE in 1 in 590 children is significantly higher than in previous reports. Though genetic findings differed in children with DEE and ID+E, the results indicated that the same approach to genetic testing should be taken for both groups, and that genomic sequencing is currently the single test most likely to result in a diagnosis.