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Early-onset epilepsy is associated with a high risk of developing drug-resistant epilepsy (DRE), often manifesting as developmental and epileptic encephalopathies (DEEs). This study aimed to characterize the incidence, syndromes, comorbidities, and etiology of early-onset DRE in Estonia. This study is a continuation of our earlier nationwide, population-based investigation and included all children with early-onset epilepsy (seizure onset before two years) who developed drug resistance in Estonia between 2013 and 2017 ( = 37). Cases were identified at the country's only two pediatric neurology departments, ensuring nationwide coverage. Clinical data, electroencephalography, neuroimaging, genetic investigations (chromosomal microarray, single-gene tests, gene panels, exome/genome sequencing), and etiology were analyzed overall and by epilepsy type or syndrome. A total of 37 children with early-onset DRE were included. The incidence of early-onset DRE was 26.5 per 100,000 person-years, peaking in the first year of life (36.1). Drug resistance developed in 43% within six months and 65% within one year. DEEs accounted for 76% of cases, most commonly infantile epileptic spasms syndrome (IESS/West syndrome, 35%). Structural abnormalities were observed in 49% of cases (50% of DEEs), most commonly congenital brain malformations (22%). Pathogenic genetic findings were identified in 41% overall (43% of DEEs). The etiology was established in 78% of children with DRE. Among DEEs, it was found in all Dravet syndrome patients (100%) and 62% of those with IESS/West syndrome. Global developmental delay/intellectual disability occurred in 86%, and motor impairment in 46%. Early-onset DRE, often presenting as DEE, has high incidence, progresses rapidly to drug resistance, and causes substantial comorbidities.