Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants

Abstract

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216–263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251–357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139–233), χ2 odds ratio = 1.7 (95% CI 1.3–2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations.

ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions

“…comorbidity, 13 and higher rates of drug resistance 14 and mortality, 15 with up to 50% showing global developmental delay 2 years after presentation. 9 Comorbidities are more frequent among children who develop drug-resistant seizures 14 and those with a high seizure burden. 16,17 Traditionally, syndromes have been defined primarily by electroclinical features; however, in the last two decades, gene discovery in the epilepsies has allowed cohorts of cases with a shared genetic etiology to be studied.…”

“…The incidence of EIDEE is estimated as 10/100 000 live births. 9 Clinical context: This syndrome begins in the early infantile period (range 0-3 months) and affects boys and girls equally. The neurological examination is often severely abnormal, with abnormalities of tone (most frequently central hypotonia), posture, and motor behavior with cortical visual impairment.…”

“…Causative pathogenic gene variants can be identified in more than half of patients with EIDEE. 9,84 The seizure type(s) and EEG with other phenotypic features may predict genotype:…”

Epilepsy Genetics: Advancements in the Field and Impact on Clinical Practice

“…In a recent multi-center study of pediatric epilepsies in Scotland, the overall estimated annual incidence of single-gene epilepsies was 1 per 2120 live births (47.2/100 000) (7). The adjusted incidence of childhood-onset epilepsies in children under 3 years of age in Scotland was 239 per 100 000 live births (20). The proportions of monogenic, polygenic, and complex epilepsies remain unknown.…”

Precision in child neurology: Networks, systems, and technology

“…There may be around 500 genes linked to epilepsy, but in early childhood nine genes account for two-thirds of cases. 3 Until it is standard for large panels, exomes, or genomes to be analysed and reported within a couple of weeks, why not test and report rapidly the 10 to 20 most common and clinically actionable genes and then look at the extremely long list of individually very rare genetic aetiologies? This is adapting systems of gene testing to the needs of the patient.…”