Old Drug, New Mutation in Neonatal Epileptic Encephalopathies

Introduction: KCNQ2 mutations have been detected as a cause of different “idiopathic” neonatal epileptic encephalopathies and the spectrum comprises variable phenotypes. The successful treatment of the seizures may be challenging: a variety of antiepileptic drugs is often needed.

Cases and Results: Case 1: After uneventful family and pregnancy history, the newborn presented with repetitive partial seizures beginning at the 2nd day after birth. Synchronous to clinical overt seizures with alternating head- and eye-deviation, bedside EEG showed alternating left/right-hemispheric seizure onset and pathological background consistent with the diagnosis of severe migrating partial epilepsy. Treatment with vitamin B6, phenobarbitone, levetiracetam, clobazam, and topiramate showed no effect. Introducing phenytoin led to cessation of clinical overt seizures and marked reduction of epileptic activity in the EEG without any other side effect. Genetic analysis by NGS panel revealed a pathogenic mutation c.578C > T/p.A193V in the KCNQ2 gene. Case 2: The girl presented at the age of 2 hours with frequent partial seizures. Her family history was positive for benign familial neonatal seizures. Interictal EEG did not show specific epileptic discharges. Therapy with carbamazepine, topiramate, and phenobarbital showed no positive effect. At the age of 3 months, adding phenytoin to PHB led to cessation of seizures. Genetic analysis by NGS panel showed also a mutation c.1657C > T/p.R553W in the KCNQ2 gene.

Discussion: Phenytoin was first introduced in the 1930s as an anticonvulsant acting as a blocker of the voltage-dependent neuronal sodium channel. Its use as a second-line drug for neonatal seizures has been limited because of toxicity and pharmocodynamic concerns and newer AED have emerged. Our case observations suggest that it may have a specific therapeutic effect in difficult-to-treat neonatal epileptic encephalopathies associated with KCNQ2 mutations and worth a try in comparable cases.

Keywords: KCNQ2, neonatal epileptic encephalopathies, phenytoin.