Early sodium channel blocker use improves seizures and neurodevelopment in KCNQ2 -related disorders

Abstract Background Pathogenic KCNQ2 variants are the most common genetic cause of neonatal-onset epilepsies, with phenotypes ranging from self-limited (familial) neonatal epilepsy (SeL(F)NE) to severe developmental and epileptic encephalopathy (KCNQ2-DEE). Sodium channel blockers (SCBs) have shown promise for seizure control in these disorders, but their impact on neurodevelopmental outcomes and possible relationship with timing of initiation remain incompletely understood. Methods We leveraged a large, multicentre international cohort comprising 282 individuals with KCNQ2 pathogenic variants to retrospectively assess the effectiveness of antiseizure medications (ASMs), particularly SCBs, on seizure control and neurodevelopment. Individuals were grouped according to the predicted variant-specific functional effects: loss-of-function (LOF) variants known to be associated with SeL(F)NE or DEE respectively, and gain-of-function (GOF) variants. Epilepsy course, ASM effectiveness, and neurodevelopmental milestones were systematically collected and analysed. Results SCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2 -DEE, early SCB initiation within the first month of life was associated with significantly more favourable neurodevelopmental trajectories, including higher rates of achievement of major motor milestones. Early seizure freedom itself was a strong predictor of improved neurodevelopment, with the positive effect of SCBs likely mediated by their ability to control seizures. However, considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation. Variant severity and possible genetic modifiers likely contribute to this heterogeneity, underscoring the need for precision therapies beyond nonspecific ASM approaches. Conclusion Our results strongly support the use of SCBs as first-line therapy in (LOF) KCNQ2 -DEE and SeL(F)NE due to their high effectiveness. Moreover, SCBs appear most beneficial when initiated during the neonatal period, with earlier treatment linked to earlier seizure offset and better developmental outcomes. These results highlight the importance of early genetic diagnosis and timely SCB therapy, and support CBZ or OXC as first-line agents. We however emphasise that early treatment is not universally transformative, and further work, including exploration of targeted therapies but also standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.