Early sodium channel blocker initiation is associated with better outcomes in KCNQ2 disorders.

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. We leveraged a large, multicentre international cohort comprising 282 individuals with pathogenic KCNQ2 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, including time-to-event and adjusted outcome analyses. SCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, time-to-event analyses showed that early SCB initiation (≤1 month) was associated with earlier seizure offset. Early SCB initiation was also associated with significantly more favourable neurodevelopmental outcomes, including higher rates of attaining major motor milestones. This association remained significant after adjustment for seizure control by 1 month and total ASM burden. Considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation, suggesting that variant severity and additional genetic or biological modifiers contribute to outcome heterogeneity.Our results support the use of SCBs, particularly CBZ and OXC, as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE. Earlier SCB initiation was associated with earlier seizure offset and more favourable developmental outcomes, underscoring the importance of early genetic diagnosis and timely SCB therapy. We however emphasise that early treatment is not universally transformative and further prospective work, including exploration of targeted therapies and standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.

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PubMed
Published
2026-08-18
DOI
https://doi.org/10.1093/brain/awag277
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Epilepsy research and treatment
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article
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article

Early sodium channel blocker initiation is associated with better outcomes in KCNQ2 disorders.

Béatrice Desnous, Trine Bjørg Hammer, Mathieu Kuchenbuch, Claire Bar et al.
PubMed
Epilepsy research and treatment
article

Early sodium channel blocker initiation is associated with better outcomes in KCNQ2 disorders.

Béatrice Desnous, Trine Bjørg Hammer, Mathieu Kuchenbuch, Claire Bar, Marta Pietruszka, Magdalena Krygier, Jérémie Lefranc, Patrick Van Bogaert, Nathalie Villeneuve, Carmen Fons, Raluca Ioana Teleanu, Charissa Millevert, Laurence Chaton, Maurizio Taglialatela, Dídac Casas‐Alba, Annie Ting Gee Chiu, Edward C. Cooper, Laura Licchetta, Samuel Dahan, C. Hachon Le Camus, Safa Mete Dağdaş, Caroline Perriard, Megan Hairabedian, Silvia Napuri, Anne Lepine, Johannes Lemke, Dorothée Ville, Eugenia Roza, Steffen Syrbe, Mathieu Milh, Maria Mazurkiewicz-Bełdzińska, Bénédicte Héron, Pinar Gencpinar, Duccio M Cordelli, Laurent Villard, Sarah Weckhuysen, Gaëtan Lesca, Ingrid E Scheffer, Francesca Bisulli, Cyril Mignot, Anne de Saint Martin, Blandine Dozieres, Stéphane Auvin
article en

Abstract

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. We leveraged a large, multicentre international cohort comprising 282 individuals with pathogenic KCNQ2 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, including time-to-event and adjusted outcome analyses. SCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, time-to-event analyses showed that early SCB initiation (≤1 month) was associated with earlier seizure offset. Early SCB initiation was also associated with significantly more favourable neurodevelopmental outcomes, including higher rates of attaining major motor milestones. This association remained significant after adjustment for seizure control by 1 month and total ASM burden. Considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation, suggesting that variant severity and additional genetic or biological modifiers contribute to outcome heterogeneity.Our results support the use of SCBs, particularly CBZ and OXC, as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE. Earlier SCB initiation was associated with earlier seizure offset and more favourable developmental outcomes, underscoring the importance of early genetic diagnosis and timely SCB therapy. We however emphasise that early treatment is not universally transformative and further prospective work, including exploration of targeted therapies and standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.

PubMed
Université Claude Bernard Lyon 1 (FR), Centre National de la Recherche Scientifique (FR), Hospital Sant Joan de Déu Barcelona (ES), Royal Children's Hospital (AU), Izmir University (TR), University of Antwerp (BE), Université de Bordeaux (FR), Inserm (FR), Carol Davila University of Medicine and Pharmacy (RO), Délégation Paris 7 (FR), Baylor College of Medicine (US), Institut Universitaire de France (FR), Université Paris Cité (FR), Aix-Marseille Université (FR), Heidelberg University (DE), Université de Lille (FR), Izmir Kâtip Çelebi University (TR), University Hospital Heidelberg (DE), Copenhagen University Hospital (DK), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Toulouse (FR), Université Rennes 2 (FR), Sorbonne Université (FR), Hôpital Femme Mère Enfant (FR), Hôpital Armand-Trousseau (FR), Assistance Publique Hôpitaux de Marseille (FR), Lille’s Cardiology Hospital (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), Hospices Civils de Lyon (FR), Antwerp University Hospital (BE), Hôpital Saint-André (FR), Federico II University Hospital (IT), Institute of Neurological Sciences (IT), Pitié-Salpêtrière Hospital (FR), Institut NeuroMyoGène (FR), Hôpital Robert-Debré (FR), Sant Joan de Déu Research Foundation (ES), VIB-UAntwerp Center for Molecular Neurology (BE), Centre Hospitalier Régional Universitaire de Brest (FR), Hôpital Sainte-Marguerite (FR), Spitalul Clinic Dr. Victor Babes (RO), Fondation Lenval (FR), Epilepsy Action (GB), Centre d’Immunologie de Marseille-Luminy (FR), Murdoch Children's Research Institute (AU), Centre Hospitalier Universitaire de Rennes (FR), Epilepsy Foundation (AU), Hôpital de la Timone (FR), Austin Health (AU), Hôpital Civil, Strasbourg (FR), Université d'Angers (FR), Université de Rennes (FR), Université de Strasbourg (FR), University of Naples Federico II (IT), Gdańsk Medical University (PL), Leipzig University (DE), University of Bologna (IT), HCL Technologies (India) (IN)
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