Background: Recurrent and prolonged seizures are harmful for the developing brain, emphasizing the importance of early seizure recognition and effective therapy. Amplitude-integrated electroencephalography (aEEG) has become a valuable tool to diagnose epileptic seizures, and, in parallel, genetic etiologies are increasingly being recognized, changing the paradigm of the workup and management of neonatal seizures. Objective: To report the ictal aEEG pattern in neonates with KCNQ2-related epilepsy. Subjects and Methods: In this multicenter descriptive study, clinical data and aEEG findings of 9 newborns with KCNQ2 mutations are reported. Results: Refractory seizures occurred in the early neonatal period with similar seizure type, including tonic features, apnea, and desaturation. A distinct aEEG seizure pattern, consisting of a sudden rise of the lower and upper margin of the aEEG, followed by a marked depression of the aEEG amplitude, was found in 8 of the 9 patients. Prompt recognition of this pattern led to early treatment with carbamazepine in the 2 most recent cases. Conclusion: Early recognition of the electroclinical phenotype by using aEEG may direct genetic testing and a precision medicine approach with sodium channel blockers in neonates with KCNQ2 mutations.

Murray DM, Boylan GB, Ali I, Ryan C, Murphy BP, Connolly S: Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 2008;93:F187-F191.
Boylan GB, Stevenson NJ, Vanhatalo S: Monitoring neonatal seizures. Semin Fetal Neonatal Med 2013;18:202-208.
de Vries LS, Hellström-Westas L: Role of cerebral function monitoring in the newborn. Arch Dis Child Fetal Neonatal Ed 2005;90:F201-F207.
Vasudevan C, Levene M: Epidemiology and aetiology of neonatal seizures. Semin Fetal Neonatal Med 2013;18:185-191.
Weeke CL, Brilstra E, Braun KP, Zonneveld-Huijssoon E, Salomons G, Koeleman BP, Gassen KL, Straaten HL, Craiu D, de Vries LS: Punctate white matter lesions associated with SLC13A5 mutations. Eur J Paediatr Neurol 2017;21:396-403.
Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK: A potassium channel mutation in neonatal human epilepsy. Science 1998;279:403-406.
Weckhuysen S, Mandelstam S, Suls A, Audenaert D, Deconinck T, Claes LR, Deprez L, Smets K, Hristova D, Yordanova I, Jordanova A, Ceulemans B, Jansen A, Hasaerts D, Roelens F, Lagae L, Yendle S, Stanley T, Heron SE, Mulley JC, Berkovic SF, Scheffer IE, de Jonghe P: KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012;71:15-25.
Kato M, Yamagata T, Kubota M, Arai H, Yamashita S, Nakagawa T, Fujii T, Sugai K, Imai K, Uster T, Chitayat D, Weiss S, Kashii H, Kusano R, Matsumoto A, Nakamura K, Oyazato Y, Maeno M, Nishiyama K, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Saito K, Hayasaka K, Matsumoto N, Saitsu H: Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia 2013;54:1282-1287.
Milh M, Boutry-Kryza N, Sutera-Sardo J, Mignot C, Auvin S, Lacoste C, Villeneuve N, Roubertie A, Heron B, Carneiro M, Kaminska A, Altuzarra C, Blanchard G, Ville D, Barthez MA, Heron D, Gras D, Afenjar A, Dorison N, Doummar D, Billette de Villemeur T, An I, Jacquette A, Charles P, Perrier J, Isidor B, Vercueil L, Chabrol B, Badens C, Lesca G, Villard L: Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2. Orphanet J Rare Dis 2013;8:80.
Sands TT, Balestri M, Bellini G, Mulkey SB, Danhaive O, Bakken EH, Taglialatela M, Oldham MS, Vigevano F, Holmes GL, Cilio MR: Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia 2016;57:2019-2030.
Numis AL, Angriman M, Sullivan JE, Lewis AJ, Striano P, Nabbout R, Cilio MR: KCNQ2 encephalopathy: delineation of the electroclinical phenotype and treatment response. Neurology 2014;82:368-370.
Weckhuysen S, Ivanovic V, Hendrickx R, Van Coster R, Hjalgrim H, Møller R, Grønborg S, Schoonjans AS, Ceulemans B, Heavin SB, Eltze C, Horvath R, Casara G, Pisano T, Giordano L, Rostasy K, Haberlandt E, Albrecht B, Bevot A, Benkel I, Syrbe S, Sheidley B, Guerrini R, Poduri A, Lemke JR, Mandelstam S, Scheffer I, Angriman M, Striano P, Marini C, Suls A, De Jonghe P; KCNQ2 Study Group: Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 2013;81:1697-1703.
Pisano T, Numis AL, Heavin SB, Weckhuysen S, Angriman M, Suls A, Podesta B, Thibert RL, Shapiro KA, Guerrini R, Scheffer IE, Marini C, Cilio MR: Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 2015;56:685-691.
Zara F, Specchio N, Striano P, Robbiano A, Gennaro E, Paravidino R, Vanni N, Beccaria F, Capovilla G, Bianchi A, Caffi L, Cardilli V, Darra F, Bernardina BD, Fusco L, Gaggero R, Giordano L, Guerrini R, Incorpora G, Mastrangelo M, Spaccini L, Laverda AM, Vecchi M, Vanadia F, Veggiotti P, Viri M, Occhi G, Budetta M, Taglialatela M, Coviello DA, Vigevano F, Minetti C: Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia 2013;54:425-436.
Volkers L, Rook MB, Das JH, Verbeuk NE, Groenewegen WA, van Kempem MJ, Lindhout D, Koelemann BP: Functional analysis of novel KCNQ2 mutation found in patients with benign familial neonatal convulsions. Neurosci Lett 2009;462:24-29.
Zhang Y, Kong W, Gao Y, Liu X, Gao K, Xie H, Wu Y, Zhang Y, Wang J, Gao F, Wu X, Jiang Y: Gene mutation analysis in 253 Chinese children with unexplained epilepsy and intellectual/developmental disabilities. PLoS One 2015;10:e0141782.
Milh M, Lacost C, Cacciagli P, Abidi A, Sutera-Sardo L, Tzelepis I, Colin E, Badens C, Afenjar A, Coeslier AD, Dailland T, Lesca G, Philip N, Villard L: Variable clinical expression in patients with mosaicism for KCNQ2 mutations. Am J Med Genet A 2015;167A:2314-2318.
Parrini E, Marini C, Mei D, Galuppi A, Celllini E, Pucatti D, Chiti L, Rutigliano D, Bianchini C, Virdò S, De Vita D, Bigoni S, Barba C, Mari F, Montomoli M, Pisano T, Rosati A, Clinical Study Group, Guerrini R: Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes. Hum Mutat 2017;38:216-225.
Hortigüela M, Fernández-Marmiesse A, Cantarín V, Gouveia S, García-Peñas JJ, Fons C, Fons C, Armstrong J, Barrios D, Díaz-Flores F, Tirado P, Couce ML, Gutiérrez-Solana LG: Clinical and genetic features of 13 Spanish patients with KCNQ2 mutations. J Hum Genet 2016;62:185-189.
Glass HC, Shellhaas RA, Wusthoff CJ, Chang T, Abend NS, Chu CJ, Cilio MR, Glidden DV, Bonifacio SL, Massey S, Tsuchida TN, Silverstein FS, Soul JS; Neonatal Seizure Registry Study Group. Contemporary profile of seizures in neonates: a prospective cohort study. J Pediatr 2016;174:98-103.
Hellström-Westas L, de Vries LS, Rosén I: Atlas of Amplitude-Integrated EEGs in Newborn, ed 2. London, Informa Healthcare, 2008.
van Rooij LGM, van den Broek MPH, Rademaker CMA, de Vries LS: Clinical management of seizures in newborns: diagnosis and treatment. Paediatr Drugs 2013;15:9-18.
Reid ES, Williams H, Stabej PLQ, James C, Ocaka L, Bacchelli C, Footitt EJ, Boyd S, Cleary MA, Mills PB, Clayton PT: Seizures due to a KCNQ2 mutation: treatment with vitamin B6. JIMD Rep 2016;27:79-84.
Weeke LC, Toet MC, van Rooij LG, Groenendaal F, Boylan GB, Pressler RM, Hellström-Westas L, van den Broek MP, de Vries LS: Lidocaine response rate in aEEG-confirmed neonatal seizures: retrospective study of 413 full-term and preterm infants. Epilepsia 2016;57:233-242.
Singh B, Singh P, al Hifzi I, Khan M, Majeed-Saidan M: Treatment of neonatal seizures with carbamazepine. J Child Neurol 1996;11:378-382.
Hoppen T, Elger C, Bartmann P: Carbamazepine in phenobarbital-non responders: experience with ten preterm infants. Eur J Pediatr 2001;160:444-447.
Reif PS, Tsai M-H, Helbig I, Rosenow F, Klein KM: Precision medicine in genetic epilepsies: break of dawn? Expert Rev Neurother 2016;17:381-392.
Striano P, De Jonghe P, Zara F: Genetic epileptic encephalopathies: is all written into the DNA? Epilepsia 2013;54:22-26.
Nardou R, Ferrari DC, Ben-Ari Y: Mechanisms and effects of seizures in the immature brain. Semin Fetal Neonatal Med 2013;18:175-184.
van Rooij LG, Toet MC, van Huffelen AC, Groenendaal F, Laan W, Zecic A, de Haan T, van Straaten IL, Vrancken S, van Wezel G, van der Sluijs J, Ter Horst H, Gavilanes D, Laroche S, Naulaers G, de Vries LS: Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics 2010;125:e358-e66.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.