Long‐term outcomes of a cohort of patients with pharmacoresistant neonatal epilepsy and negative brain MRI

Objective Neonatal seizures initiate the onset of epilepsy in less than 20% of cases. Establishing accurate and prompt diagnosis for precision medicine, offering tailored care, and informing families about neurodevelopmental prognosis represents a significant challenge. We aim to describe the natural history of drug‐resistant epilepsy and negative brain MRI with neonatal onset, and to identify predictors of neurodevelopmental outcomes. Methods We retrospectively analyzed demographic, clinical, electroencephalogram (EEG), and genetic data from neonates with epilepsy onset before 1 month of age, with no provoked cause, and a normal brain MRI, followed at a tertiary center from 2000 to 2020. Neonates with self‐limited epilepsy (SLE) or those responding to phenobarbital without later epilepsy were excluded. Results Among 56 patients, 60% had a genetic etiology (KCNQ2, STXBP1, KCNT1, others). Most (96%) developed intellectual disability (ID); moderate ID without cerebral palsy (CP) was recorded in 11, and profound intellectual and multiple disabilities (PIMD) in 42. Only two patients had a favorable neurodevelopmental outcome without intellectual disability. An abnormal neurological exam at epilepsy onset was the sole risk factor for future PIMD. Significance Neonatal‐onset pharmacoresistant epilepsies with a normal brain MRI are predominantly monogenic and lead to poor neurodevelopmental outcomes. An abnormal initial neurodevelopmental assessment predicts future PIMD. Plain Language Summary Our study found that epilepsy starting in the neonatal period is often linked to a strong genetic component. The prognosis is generally poor, with frequent neurodevelopmental delays. An abnormal neurological examination during the neonatal period is a predictor of worse outcomes.