Neuropediatrics 2021; 52(02): 073-083
DOI: 10.1055/s-0040-1721702
Review Article

Recent Advances in the Diagnosis and Treatment of Neonatal Seizures

1   Child Neurology Section, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
› Author Affiliations
Funding The author received no financial support for the research, authorship, and/or publication of this article.

Abstract

Seizures are the most common neurological emergency in the neonates, and this age group has the highest incidence of seizures compared with any other period of life. The author provides a narrative review of recent advances in the genetics of neonatal epilepsies, new neonatal seizure classification system, diagnostics, and treatment of neonatal seizures based on a comprehensive literature review (MEDLINE using PubMED and OvidSP vendors with appropriate keywords to incorporate recent evidence), personal practice, and experience. Knowledge regarding various systemic and postzygotic genetic mutations responsible for neonatal epilepsy has been exploded in recent times, as well as better delineation of clinical phenotypes associated with rare neonatal epilepsies. An International League Against Epilepsy task force on neonatal seizure has proposed a new neonatal seizure classification system and also evaluated the specificity of semiological features related to particular etiology. Although continuous video electroencephalogram (EEG) is the gold standard for monitoring neonatal seizures, amplitude-integrated EEGs have gained significant popularity in resource-limited settings. There is tremendous progress in the automated seizure detection algorithm, including the availability of a fully convolutional neural network using artificial machine learning (deep learning). There is a substantial need for ongoing research and clinical trials to understand optimal medication selection (first line, second line, and third line) for neonatal seizures, treatment duration of antiepileptic drugs after cessation of seizures, and strategies to improve neuromorbidities such as cerebral palsy, epilepsy, and developmental impairments. Although in recent times, levetiracetam use has been significantly increased for neonatal seizures, a multicenter, randomized, blinded, controlled phase IIb trial confirmed the superiority of phenobarbital over levetiracetam in the acute suppression of neonatal seizures. While there is no single best choice available for the management of neonatal seizures, institutional guidelines should be formed based on a consensus of local experts to mitigate wide variability in the treatment and to facilitate early diagnosis and treatment.

Disclosures

The author declares no potential conflicts of interest with respect to the research, authorship, and publication of this article.




Publication History

Received: 12 June 2020

Accepted: 16 September 2020

Article published online:
08 December 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Volpe JJ. Neurology of the newborn E-book. Philadelphia, PA: Elsevier Health Sciences; 2008
  • 2 Shellhaas RA, Chang T, Tsuchida T. et al. The American Clinical Neurophysiology Society's guideline on continuous electroencephalography monitoring in neonates. J Clin Neurophysiol 2011; 28 (06) 611-617
  • 3 Pisani F, Barilli AL, Sisti L, Bevilacqua G, Seri S. Preterm infants with video-EEG confirmed seizures: outcome at 30 months of age. Brain Dev 2008; 30 (01) 20-30
  • 4 Pisani F, Cerminara C, Fusco C, Sisti L. Neonatal status epilepticus vs recurrent neonatal seizures: clinical findings and outcome. Neurology 2007; 69 (23) 2177-2185
  • 5 Berry K, Pesko MF, Hesdorffer DC, Shellhaas RA, Seirup JK, Grinspan ZM. An evaluation of national birth certificate data for neonatal seizure epidemiology. Epilepsia 2017; 58 (03) 446-455
  • 6 Shellhaas RA, Wusthoff CJ, Tsuchida TN. et al; Neonatal Seizure Registry. Profile of neonatal epilepsies: characteristics of a prospective US cohort. Neurology 2017; 89 (09) 893-899
  • 7 Glass HC, Shellhaas RA, Wusthoff CJ. et al; Neonatal Seizure Registry Study Group. Contemporary profile of seizures in neonates: a prospective cohort study. J Pediatr 2016; 174: 98-103.e1
  • 8 Olson HE, Kelly M, LaCoursiere CM. et al. Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. Ann Neurol 2017; 81 (03) 419-429
  • 9 Berg AT, Coryell J, Saneto RP. et al. Early-life epilepsies and the emerging role of genetic testing. JAMA Pediatr 2017; 171 (09) 863-871
  • 10 Weckhuysen S, Mandelstam S, Suls A. et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012; 71 (01) 15-25
  • 11 Pisano T, Numis AL, Heavin SB. et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 2015; 56 (05) 685-691
  • 12 Mikati MA, Jiang YH, Carboni M. et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol 2015; 78 (06) 995-999
  • 13 Hardies K, de Kovel CG, Weckhuysen S. et al; Autosomal Recessive Working Group of the EuroEPINOMICS RES Consortium. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain 2015; 138 (Pt 11): 3238-3250
  • 14 Pressler RM, Cilio MR, Mizrahi EM. et al. The ILAE Classification of Seizures & the Epilepsies: Modification for Seizures in the Neonate. Proposal from the ILAE Task Force on Neonatal Seizures. Flower Mound, TX: ILAE; 2017
  • 15 Nunes ML, Yozawitz EG, Zuberi S. et al; Task Force on Neonatal Seizures, ILAE Commission on Classification & Terminology. Neonatal seizures: is there a relationship between ictal electroclinical features and etiology? A critical appraisal based on a systematic literature review. Epilepsia Open 2019; 4 (01) 10-29
  • 16 Glass HC, Shellhaas RA, Tsuchida TN. et al; Neonatal Seizure Registry study group. Seizures in preterm neonates: a multicenter observational cohort study. Pediatr Neurol 2017; 72: 19-24
  • 17 Wietstock SO, Bonifacio SL, Sullivan JE, Nash KB, Glass HC. Continuous video electroencephalographic (EEG) monitoring for electrographic seizure diagnosis in neonates: a single-center study. J Child Neurol 2016; 31 (03) 328-332
  • 18 Rakshasbhuvankar A, Paul S, Nagarajan L, Ghosh S, Rao S. Amplitude-integrated EEG for detection of neonatal seizures: a systematic review. Seizure 2015; 33: 90-98
  • 19 Rakshasbhuvankar A, Rao S, Palumbo L, Ghosh S, Nagarajan L. Amplitude integrated electroencephalography compared with conventional video EEG for neonatal seizure detection: a diagnostic accuracy study. J Child Neurol 2017; 32 (09) 815-822
  • 20 Temko A, Lightbody G. Detecting neonatal seizures with computer algorithms. J Clin Neurophysiol 2016; 33 (05) 394-402
  • 21 Mathieson SR, Stevenson NJ, Low E. et al. Validation of an automated seizure detection algorithm for term neonates. Clin Neurophysiol 2016; 127 (01) 156-168
  • 22 O'Shea A, Lightbody G, Boylan G, Temko A. Neonatal seizure detection from raw multi-channel EEG using a fully convolutional architecture. Neural Netw 2019
  • 23 Barnette AR, Horbar JD, Soll RF. et al. Neuroimaging in the evaluation of neonatal encephalopathy. Pediatrics 2014; 133 (06) e1508-e1517
  • 24 Osmond E, Billetop A, Jary S, Likeman M, Thoresen M, Luyt K. Neonatal seizures: magnetic resonance imaging adds value in the diagnosis and prediction of neurodisability. Acta Paediatr 2014; 103 (08) 820-826
  • 25 Rincon SP, Blitstein MB, Caruso PA, González RG, Thibert RL, Ratai EM. The use of magnetic resonance spectroscopy in the evaluation of pediatric patients with seizures. Pediatr Neurol 2016; 58: 57-66
  • 26 Weeke LC, Groenendaal F, Mudigonda K. et al. A novel magnetic resonance imaging score predicts neurodevelopmental outcome after perinatal asphyxia and therapeutic hypothermia. J Pediatr 2018; 192: 33-40.e2
  • 27 Czech T, Pardo AC. Utility of rapid sequence magnetic resonance imaging in guiding management of patients with neonatal seizures. Pediatr Neurol 2019
  • 28 Rennie JM, de Vries LS, Blennow M. et al. Characterisation of neonatal seizures and their treatment using continuous EEG monitoring: a multicentre experience. Arch Dis Child Fetal Neonatal Ed 2019; 104 (05) F493-F501
  • 29 Harris ML, Malloy KM, Lawson SN, Rose RS, Buss WF, Mietzsch U. Standardized treatment of neonatal status epilepticus improves outcome. J Child Neurol 2016; 31 (14) 1546-1554
  • 30 Boylan GB, Rennie JM, Chorley G. et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology 2004; 62 (03) 486-488
  • 31 Painter MJ, Scher MS, Stein AD. et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999; 341 (07) 485-489
  • 32 Sharpe C, Reiner GE, Davis SL. et al. Neolev2 Investigators. Levetiracetam versus phenobarbital for neonatal seizures: a randomized controlled trial. Pediatrics 2020; 145 (06) e20193182
  • 33 Pressler RM, Boylan GB, Marlow N. et al; NEonatal seizure treatment with Medication Off-patent (NEMO) consortium. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol 2015; 14 (05) 469-477
  • 34 Dwivedi D, Lin N, Venkatesan C, Kline-Fath B, Holland K, Schapiro M. Clinical, neuroimaging, and electrographic predictors of phenobarbital failure in newborns with hypoxic ischemic encephalopathy and seizures. J Child Neurol 2019; 34 (08) 458-463
  • 35 Rao LM, Hussain SA, Zaki T. et al. A comparison of levetiracetam and phenobarbital for the treatment of neonatal seizures associated with hypoxic-ischemic encephalopathy. Epilepsy Behav 2018; 88: 212-217
  • 36 Falsaperla R, Vitaliti G, Mauceri L. et al. Levetiracetam in neonatal seizures as first-line treatment: a prospective study. J Pediatr Neurosci 2017; 12 (01) 24-28
  • 37 Gowda VK, Romana A, Shivanna NH, Benakappa N, Benakappa A. Levetiracetam versus phenobarbitone in neonatal seizures - a randomized controlled trial. Indian Pediatr 2019; 56 (08) 643-646
  • 38 Han JY, Moon CJ, Youn YA, Sung IK, Lee IG. Efficacy of levetiracetam for neonatal seizures in preterm infants. BMC Pediatr 2018; 18 (01) 131
  • 39 Khan O, Cipriani C, Wright C, Crisp E, Kirmani B. Role of intravenous levetiracetam for acute seizure management in preterm neonates. Pediatr Neurol 2013; 49 (05) 340-343
  • 40 Kreimer AM, Littrell RA, Gibson JB, Leung NR. Effectiveness of levetiracetam as a first-line anticonvulsant for neonatal seizures. J Pediatr Pharmacol Ther 2019; 24 (04) 320-326
  • 41 Liu BK, Jiang L, Li XJ, Hong SQ, Chen W, Hu Y. Efficacy and safety of levetiracetam in the off-label treatment of neonatal seizures. Int J Neurosci 2019; •••: 1-7
  • 42 Lloreda-García JM, Fernández-Fructuoso JR, Gómez-Santos E, García-González A, Leante-Castellanos JL. Use of levetiracetam in neonatal seizures [in Spanish]. An Pediatr (Barc) 2017; 86 (05) 286-288
  • 43 Mollamohammadi M, Amirhoseini ZS, Saadati A, Pirzadeh Z, Hassan Amouzadeh M. Oral levetiracetam as add-on therapy in refractory neonatal seizures. Iran J Child Neurol 2018; 12 (04) 103-110
  • 44 Neininger MP, Ullmann M, Dahse AJ. et al. Use of levetiracetam in neonates in clinical practice: a retrospective study at a German university hospital. Neuropediatrics 2015; 46 (05) 329-334
  • 45 Rakshasbhuvankar A, Rao S, Kohan R, Simmer K, Nagarajan L. Intravenous levetiracetam for treatment of neonatal seizures. J Clin Neurosci 2013; 20 (08) 1165-1167
  • 46 Sedighi M, Asadi F, Moradian N, Vakiliamini M, Moradian M. Efficacy and safety of levetiracetam in the management of seizures in neonates. Neurosciences (Riyadh) 2016; 21 (03) 232-235
  • 47 Venkatesan C, Young S, Schapiro M, Thomas C. Levetiracetam for the treatment of seizures in neonatal hypoxic ischemic encephalopathy. J Child Neurol 2017; 32 (02) 210-214
  • 48 Yau ML, Fung EL, Ng PC. Response of levetiracetam in neonatal seizures. World J Clin Pediatr 2015; 4 (03) 45-49
  • 49 McHugh DC, Lancaster S, Manganas LN. A systematic review of the efficacy of levetiracetam in neonatal seizures. Neuropediatrics 2018; 49 (01) 12-17
  • 50 Samanta D. Levetiracetam is still not a first-line treatment in neonatal seizures. Indian Pediatr 2020; 57 (01) 80
  • 51 Kurtom W, Courchia B, Pensirikul A, Sosenko I, Del-Moral T. Lack of response to treatment with levetiracetam in extreme preterm infants with seizures. J Perinatol 2019; 39 (11) 1480-1484
  • 52 Dao K, Giannoni E, Diezi M, Roulet-Perez E, Lebon S. Midazolam as a first-line treatment for neonatal seizures: retrospective study. Pediatr Int (Roma) 2018; 60 (05) 498-500
  • 53 Soul J, Bergin A, Stopp C, Jensen F, Wypij D, Staley K. Multi center, randomized, controlled phase I/II trial of bumetanide for neonatal seizures. 2017 82. 344
  • 54 Samanta D, Garrity L, Arya R. Refractory and super-refractory status epilepticus. Indian Pediatr 2020; 57 (03) 239-253
  • 55 Weeke LC, Toet MC, van Rooij LG. et al. Lidocaine response rate in aEEG-confirmed neonatal seizures: retrospective study of 413 full-term and preterm infants. Epilepsia 2016; 57 (02) 233-242
  • 56 Weeke LC, Schalkwijk S, Toet MC, van Rooij LG, de Vries LS, van den Broek MP. Lidocaine-associated cardiac events in newborns with seizures: incidence, symptoms and contributing factors. Neonatology 2015; 108 (02) 130-136
  • 57 Huntsman RJ, Strueby L, Bingham W. Are ketamine infusions a viable therapeutic option for refractory neonatal seizures?. Pediatr Neurol 2019
  • 58 Samanta D. Ketamine in refractory neonatal seizures. Pediatr Neurol 2020; 106: 76
  • 59 Thompson L, Fecske E, Salim M, Hall A. Use of the ketogenic diet in the neonatal intensive care unit-safety and tolerability. Epilepsia 2017; 58 (02) e36-e39
  • 60 Courchia B, Kurtom W, Pensirikul A, Del-Moral T, Buch M. Topiramate for seizures in preterm infants and the development of necrotizing enterocolitis. Pediatrics 2018; 142 (01) e20173971
  • 61 Shellhaas RA, Chang T, Wusthoff CJ. et al; Neonatal Seizure Registry Study Group. Treatment duration after acute symptomatic seizures in neonates: a multicenter cohort study. J Pediatr 2017; 181: 298-301.e1
  • 62 Dilena R, Striano P, Gennaro E. et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev 2017; 39 (04) 345-348
  • 63 Cornet MC, Sands TT, Cilio MR. Neonatal epilepsies: clinical management. Semin Fetal Neonatal Med 2018; 23 (03) 204-212
  • 64 Schwahn BC, Van Spronsen FJ, Belaidi AA. et al. Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet 2015; 386 (10007): 1955-1963
  • 65 Glass HC, Grinspan ZM, Shellhaas RA. Outcomes after acute symptomatic seizures in neonates. Semin Fetal Neonatal Med 2018; 23 (03) 218-222
  • 66 Pisani F, Facini C, Bianchi E, Giussani G, Piccolo B, Beghi E. Incidence of neonatal seizures, perinatal risk factors for epilepsy and mortality after neonatal seizures in the province of Parma, Italy. Epilepsia 2018; 59 (09) 1764-1773
  • 67 Srinivasakumar P, Zempel J, Wallendorf M, Lawrence R, Inder T, Mathur A. Therapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury. J Pediatr 2013; 163 (02) 465-470
  • 68 Weeke LC, Boylan GB, Pressler RM. et al; NEonatal seizure treatment with Medication Off -patent (NEMO)consortium. Role of EEG background activity, seizure burden and MRI in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischaemic encephalopathy in the era of therapeutic hypothermia. Eur J Paediatr Neurol 2016; 20 (06) 855-864
  • 69 Fitzgerald MP, Massey SL, Fung FW, Kessler SK, Abend NS. High electroencephalographic seizure exposure is associated with unfavorable outcomes in neonates with hypoxic-ischemic encephalopathy. Seizure 2018; 61: 221-226
  • 70 Srinivasakumar P, Zempel J, Trivedi S. et al. Treating EEG seizures in hypoxic ischemic encephalopathy: a randomized controlled trial. Pediatrics 2015; 136 (05) e1302-e1309
  • 71 Sigurdson K, Mitchell B, Liu J. et al. Racial/ethnic disparities in neonatal intensive care: a systematic review. Pediatrics 2019; 144 (02) e20183114
  • 72 Soul JS, Pressler R, Allen M. et al; International Neonatal Consortium. Recommendations for the design of therapeutic trials for neonatal seizures. Pediatr Res 2019; 85 (07) 943-954
  • 73 Hill E, Glass HC, Kelley K. et al. Seizures and antiseizure medications are important to parents of newborns with seizures. Pediatr Neurol 2017; 67: 40-44