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.