Epileptic encephalopathies refers to a group of disorders where cognitive and behavioral deterioration occurs as a direct consequence of frequent seizures and epileptiform discharge, and is not solely due to the underlying cause of the seizures. Most of them have a poor motor and cognitive prognosis [1]. Few of these are treatable; e.g., pyridoxine dependency, folinic acid responsive seizures, biotinidase deficiency, glucose transporter-1 deficiency syndrome and creatine deficiency syndrome. Most recommendations advise use of these drugs/strategies for managing these children where obvious cause like perinatal insult is not evident [1,2].

In this group of epileptic encephalopathies, broad spectrum anti-epileptic drugs such as sodium valproate (once inborn errors of metabolism are ruled out), phenobarbitone, benzodiazepines and levetiracetam are preferred. At the same time, we tend to avoid sodium channel blockers like phenytoin and carbamazepine among these group of patients. However, there are conditions like KCNQ2 encephalopathy and SCN2A encephalopathy that present with refractory focal and generalized clonic/ tonic seizures starting in the first few weeks of life along with developmental arrest, and may have burst suppression pattern on EEG [3,4]. Mutations in these genes usually present as benign familial neonatal seizures which are self limiting or get easily controlled with one anti-epileptic drug but some children may present with features of an epileptic encephalopathy. These conditions respond dramatically to sodium channel blockers like phenytoin, carbamazepine, lacosamide, mexiltine and lignocaine [3-5]. Owing to apprehension of apparent clinical worsening, there is trend towards avoiding phenytoin among children with epileptic encephalopathy and there is good chance that we miss many of cases of treatable KCNQ2 and SCN2A encephalopathies.

We managed three infants with epileptic encephalopathy with normal neuroimaging who had seizures (10-50 per day) starting in the first month of life. These babies had failed trial of pyridoxine, pyridoxal phosphate, steroids, folinic acid, ketogenic diet and anti-epileptic drugs like levetiracetam, clonazepam, phenobarbitone, topiramate, and sodium valproate. Phenytoin dramatically controlled the seizures and reversed the encephalopathy. EEG also normalized in two weeks. Next generation sequencing (NGS) for epilepsy panel revealed pathogenic mutation in KCNQ2 gene (autosomal dominant) in two babies [heterozygous missense in exon 15 at c.1657C>T (p.Arg553Trp) in one and in exon 3 at c.440C>A (p.Ala147Asp) in the other baby, and SCN2A (autosomal dominant) in one [heterozygous missense in exon 7 at c.794T>C (p.Ile265Thr)] baby. The babies with KCNQ2 genes had a likely pathogenic mutation and hence parental testing was not advised, whereas the results of parental testing of the child with SCN2A mutation which was a variant of unknown significance is awaited. The follow-up of these babies for 6 months showed good control of seizures with occasional fever-triggered seizures and near normal development.

In developing countries like India, epileptic encephalopathies secondary to perinatal insults are common and in these conditions the diagnosis is suggested by history and imaging findings. Here we avoid sodium channel blockers like phenytoin and carbamazepine as they aggravate myoclonic seizures and spasms seen in these children. However, in epileptic encephalopathies without an obvious cause, therapeutic trial with pyridoxine, pyridoxal phosphate, biotin, and folinic acid is always warranted pending the results of next generation sequencing. Based on our observations, we propose to add sodium channel blockers to this armamentarium of potential therapeutic drugs, pending the genetic testing results.

1. Vigevano F,　Arzimanoglou A,　Plouin P,　Specchio N. Therapeutic approach to epileptic encephalopathies. Epilepsia.　2013;54:45-50.

2. Wilmshurst JM,　Gaillard WD,　Vinayan KP,　Tsuchida TN,　Plouin P,　Van Bogaert P, et al. Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia.　2015;56:1185-97.

3. Pisano T,　Numis AL,　Heavin SB,　Weckhuysen S,　Angriman M,　Suls A, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia.　2015;56:685-91.

4. Wolff M,　Johannesen KM,　Hedrich UBS,　Masnada S,　Rubboli G,　Gardella E, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain.　2017;140:1316-36.

5. Foster LA,　Johnson MR,　MacDonald JT,　Karachunski PI,　Henry TR,　Nascene DR, et al. Infantile epileptic encephalopathy associated with SCN2A mutation responsive to oral mexiletine. Pediatr Neurol.　2017; 66:108-11.