Robertino Dilena1, Pasquale Striano2, Elena Gennaro3, Laura Bassi4, Sara Olivotto5, Laura Tadini6, Fabio Mosca4, Sergio Barbieri6, Federico Zara7, Monica Fumagalli4. 1. Service of Pediatric Epileptology - Unit of Clinical Neurophysiology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: robertino.dilena@policlinico.mi.it. 2. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, Institute "G. Gaslini" University of Genova, Genoa, Italy. 3. Laboratory of Genetics, E.O. Ospedali Galliera, Genova, Italy. 4. NICU, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milan, Italy. 5. Child and Adolescent Neuropsychiatric Service (UONPIA), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 6. Service of Pediatric Epileptology - Unit of Clinical Neurophysiology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. 7. Pediatric Neurology and Muscular Diseases Unit, Laboratory of Neurogenetics, Institute "G. Gaslini", Genoa, Italy.
Abstract
BACKGROUND: Recent clinical evidence supports a targeted therapeutic approach for genetic epileptic encephalopathies based on the molecular dysfunction. PATIENT DESCRIPTION: A 2-day-old male infant presented with epileptic encephalopathy characterized by burst-suppression EEG background and tonic-clonic migrating partial seizures. The condition was refractory to phenobarbital, pyridoxine, pyridoxal phosphate and levetiracetam, but a dramatic response to an intravenous loading dose of phenytoin was documented by video-EEG monitoring. Over weeks phenytoin was successfully switched to carbamazepine to prevent seizure relapses associated with difficulty in maintaining proper blood levels of phenytoin. Genetic analysis identified a novel de novo heterozygous mutation (c.[4633A>G]p.[Met1545Val]) in SCN2A. At two years and three months of age the patient is still seizure-free on carbamazepine, although a developmental delay is evident. CONCLUSIONS: Sodium channel blockers represent the first-line treatment for confirmed or suspected SCN2A-related epileptic encephalopathies. In severe cases with compatible electro-clinical features we propose a treatment algorithm based on a test trial with high dose intravenous phenytoin followed in case of a positive response by carbamazepine, more suitable for long-term maintenance treatment. Because of their rarity, collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate.
BACKGROUND: Recent clinical evidence supports a targeted therapeutic approach for genetic epileptic encephalopathies based on the molecular dysfunction. PATIENT DESCRIPTION: A 2-day-old male infant presented with epileptic encephalopathy characterized by burst-suppression EEG background and tonic-clonic migrating partial seizures. The condition was refractory to phenobarbital, pyridoxine, pyridoxal phosphate and levetiracetam, but a dramatic response to an intravenous loading dose of phenytoin was documented by video-EEG monitoring. Over weeks phenytoin was successfully switched to carbamazepine to prevent seizure relapses associated with difficulty in maintaining proper blood levels of phenytoin. Genetic analysis identified a novel de novo heterozygous mutation (c.[4633A>G]p.[Met1545Val]) in SCN2A. At two years and three months of age the patient is still seizure-free on carbamazepine, although a developmental delay is evident. CONCLUSIONS: Sodium channel blockers represent the first-line treatment for confirmed or suspected SCN2A-related epileptic encephalopathies. In severe cases with compatible electro-clinical features we propose a treatment algorithm based on a test trial with high dose intravenous phenytoin followed in case of a positive response by carbamazepine, more suitable for long-term maintenance treatment. Because of their rarity, collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate.
Authors: Anne T Berg; Jason Coryell; Russell P Saneto; Zachary M Grinspan; John J Alexander; Mariana Kekis; Joseph E Sullivan; Elaine C Wirrell; Renée A Shellhaas; John R Mytinger; William D Gaillard; Eric H Kossoff; Ignacio Valencia; Kelly G Knupp; Courtney Wusthoff; Cynthia Keator; William B Dobyns; Nicole Ryan; Tobias Loddenkemper; Catherine J Chu; Edward J Novotny; Sookyong Koh Journal: JAMA Pediatr Date: 2017-09-01 Impact factor: 16.193