Ineffective quinidine therapy in early onset epileptic encephalopathy with KCNT1 mutation

Ineffective Quinidine Therapy in Early Onset Epileptic Encephalopathy With KCNT1 Mutation Pin Fee Chong, MD, Ryoko Nakamura, MD, Hirotomo Saitsu, MD, PhD, Naomichi Matsumoto, MD, PhD, and Ryutaro Kira, MD, PhD Bearden et al reported an impressive antiepileptic effect of quinidine on 1 patient initiated at 25 months with KCNT1 (c.1283G>A; p.Arg428Gly, R428Q) mutation diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). R428Q was proven to be a gain-of-function pathogenic KCNT1 mutation, with an increase of current observed in electrophysiological study. The reported patient was completely seizure free and showed improved psychomotor development. Due to the promising effect, we started the therapy on an unclassified early onset epileptic encephalopathy patient who had the same R428Q mutation. The patient is currently a 6-year-old male who was born at term with no family history of neurologic disorders. He was brought to us at 6 weeks of life with seizures characterized by a brief episode of staring and right hemiclonic seizures. Interictal electroencephalogram (EEG) showed multifocal sharp waves, and ictal EEG at 3 months displayed rhythmic delta-wave activity in bilateral occipital areas. Intracranial magnetic resonance imaging was normal at 1 month. At 4 years, whole exome sequencing revealed a heterozygous de novo KCNT1 R428Q mutation by a previously published method (Patient 11). Seizure control was refractory to multiple antiepileptic drugs, with seizure frequency peaking at 200 times/day. Ketogenic diet and vagal nerve stimulation reduced the seizure frequency to half. He was bedridden with poor neurodevelopment. Quinidine therapy was started at 5 years. The dose was titrated slowly, adjusted by monitoring the trough serum levels of quinidine at the range of 1.5 to 3.0 lg/ml. The patient was monitored for side effects, and no major adverse event was noted. Frequency of daily seizures was recorded, with monthly seizure frequency before and after quinidine therapy presented in the Figure. Contrary to expectations, quinidine was ineffective in seizure reduction. Seizure frequency per month after quinidine therapy was 103 6 27.7, compared to 106 6 13.3 for the same period before. In a recent literature concerning KCNT1-positive epilepsies, whereas quinidine showed 80% seizure reduction in one 3-year-old EIMFS patient (K629N), it was ineffective in an 11-year-old patient with unclassified epilepsy (Y796H). Therapy initiation at a later age and electroclinical syndrome other than EIFMS are possible reasons for poor response to quinidine in our case. Earlier