Seizure worsening and sodium‐channel blockers in <scp> <i>HCN1</i> </scp> ‐related epilepsies: A case series

This study describes seven children with HCN1-related epilepsies, a rare condition, whose seizures became worse after treatment with a group of antiseizure medicines called sodium-channel blockers. These medicines, which include phenytoin, lamotrigine, lacosamide, and oxcarbazepine, are commonly used to treat epilepsy. In contrast, sodium-channel blockers used in people with HCN1-related epilepsy associated with increased seizure frequency, and in some cases severe and prolonged seizure episodes known as status epilepticus. Importantly, in all cases seizure burden improved after sodium-channel blockers were stopped. HCN1 is a gene that encodes an ion channel that helps regulate electrical activity in the brain. Changes (variants) in this gene can disrupt normal brain signalling and cause epilepsy ranging from mild forms to severe developmental and epileptic encephalopathies (a group of rare, neurological disorders where frequent, drug-resistant seizures and abnormal brain activity cause developmental delays or regression). In this case series, all patients carried HCN1 variants associated with increased channel activity, known as gain-of-function effects. The findings support previous laboratory studies showing that sodium-channel–blocking medicines may worsen brain hyperexcitability in HCN1-related epilepsy. Although this study included a small, intentionally selected group of patients, the consistent pattern observed across different countries and clinical settings suggests that this is a meaningful and clinically important adverse drug response.