Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Etiology and prognosis of neonatal seizures

Renee Shellhaas, MD, MS
Section Editors
Douglas R Nordli, Jr, MD
Joseph A Garcia-Prats, MD
Deputy Editor
April F Eichler, MD, MPH


Identifying the etiology of seizures is a primary clinical objective in the management of neonatal seizures. Accurate determination of the cause can lead to etiology-specific therapy and may limit central nervous system (CNS) dysfunction that would otherwise occur if the underlying condition is left untreated. Treatment of the underlying cause of seizures may also be necessary to control the seizures themselves.

While there has been much discussion of the potential adverse effect of seizures on the immature brain, the most likely overriding factors that affect long-term outcome are the etiology of the seizures and the degree and distribution of brain injury caused by the underlying disturbance.

This topic review will discuss neonatal seizures in terms of their etiologies and will focus on acute symptomatic seizures. The much less common neonatal epilepsy syndromes are discussed separately. (See "Neonatal epilepsy syndromes".)

The clinical features, diagnosis, etiologic evaluation, and treatment of neonatal seizure are reviewed separately. (See "Clinical features, evaluation, and diagnosis of neonatal seizures" and "Treatment of neonatal seizures".)


Almost all neonatal seizures may be categorized as "symptomatic" seizures, occurring as a consequence of a specific identifiable etiology (table 1) [1]. Such seizures are considered acute and reactive and are therefore distinct from neonatal epilepsy. (See 'Acute symptomatic seizures' below.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Aug 22, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Mizrahi EM, Watanabe K. Symptomatic neonatal seizures. In: Epileptic syndromes in infancy, childhood and adolescence, 3rd, Roger J, Bureau M, Dravet CH, et al. (Eds), John Libbey, 2002. p.15.
  2. Proposal for classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1985; 26:268.
  3. Wolfe P. International classification of the epilepsies. In: Epilepsy: A Comprehensive Textbook, Engel J Jr, Pedley TA. (Eds), Lippincott-Raven, Philadelphia 1997. p.773.
  4. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989; 30:389.
  5. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 51:676.
  6. Mizrahi EM, Kellaway P. Diagnosis and Management of Neonatal Seizures, Lippincott-Raven, Philadelphia 1998. p.181.
  7. Co JP, Elia M, Engel J Jr, et al. Proposal of an algorithm for diagnosis and treatment of neonatal seizures in developing countries. Epilepsia 2007; 48:1158.
  8. Chapman KE, Mizrahi EM, Clancy, RR. Neonatal seizures. In: Wyllie's Treatment of Epilepsy: Principles and Practice, 5th, Lippincott, Williams & Wilkens, Philadelphia.
  9. Glass HC, Shellhaas RA, Wusthoff CJ, et al. Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. J Pediatr 2016; 174:98.
  10. Lynch NE, Stevenson NJ, Livingstone V, et al. The temporal evolution of electrographic seizure burden in neonatal hypoxic ischemic encephalopathy. Epilepsia 2012; 53:549.
  11. Nelson KB, Leviton A. How much of neonatal encephalopathy is due to birth asphyxia? Am J Dis Child 1991; 145:1325.
  12. Paneth N. The causes of cerebral palsy. Recent evidence. Clin Invest Med 1993; 16:95.
  13. Leviton A, Nelson KB. Problems with definitions and classifications of newborn encephalopathy. Pediatr Neurol 1992; 8:85.
  14. Perlman JM. Intrapartum hypoxic-ischemic cerebral injury and subsequent cerebral palsy: medicolegal issues. Pediatrics 1997; 99:851.
  15. Glass HC, Wusthoff CJ, Shellhaas RA, et al. Risk factors for EEG seizures in neonates treated with hypothermia: a multicenter cohort study. Neurology 2014; 82:1239.
  16. Wusthoff CJ, Dlugos DJ, Gutierrez-Colina A, et al. Electrographic seizures during therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy. J Child Neurol 2011; 26:724.
  17. Kirton A, Armstrong-Wells J, Chang T, et al. Symptomatic neonatal arterial ischemic stroke: the International Pediatric Stroke Study. Pediatrics 2011; 128:e1402.
  18. Clancy RR, Sharif U, Ichord R, et al. Electrographic neonatal seizures after infant heart surgery. Epilepsia 2005; 46:84.
  19. Andropoulos DB, Mizrahi EM, Hrachovy RA, et al. Electroencephalographic seizures after neonatal cardiac surgery with high-flow cardiopulmonary bypass. Anesth Analg 2010; 110:1680.
  20. Gaynor JW, Jarvik GP, Gerdes M, et al. Postoperative electroencephalographic seizures are associated with deficits in executive function and social behaviors at 4 years of age following cardiac surgery in infancy. J Thorac Cardiovasc Surg 2013; 146:132.
  21. Bellinger DC, Wypij D, Rivkin MJ, et al. Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure: neuropsychological assessment and structural brain imaging. Circulation 2011; 124:1361.
  22. Verboon-Maciolek MA, Groenendaal F, Hahn CD, et al. Human parechovirus causes encephalitis with white matter injury in neonates. Ann Neurol 2008; 64:266.
  23. Dhamija R, Patterson MC, Wirrell EC. Epilepsy in children--when should we think neurometabolic disease? J Child Neurol 2012; 27:663.
  24. Ficicioglu C, Bearden D. Isolated neonatal seizures: when to suspect inborn errors of metabolism. Pediatr Neurol 2011; 45:283.
  25. Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 2006; 12:307.
  26. Mills PB, Footitt EJ, Mills KA, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain 2010; 133:2148.
  27. Mefford HC, Zemel M, Geraghty E, et al. Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. Neurology 2015; 85:756.
  28. van Karnebeek CD, Tiebout SA, Niermeijer J, et al. Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum. Pediatr Neurol 2016; 59:6.
  29. Mills PB, Camuzeaux SS, Footitt EJ, et al. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain 2014; 137:1350.
  30. Plecko B, Paul K, Mills P, et al. Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology 2014; 82:1425.
  31. Guerin A, Aziz AS, Mutch C, et al. Pyridox(am)ine-5-Phosphate Oxidase Deficiency Treatable Cause of Neonatal Epileptic Encephalopathy With Burst Suppression: Case Report and Review of the Literature. J Child Neurol 2015; 30:1218.
  32. Basura GJ, Hagland SP, Wiltse AM, Gospe SM Jr. Clinical features and the management of pyridoxine-dependent and pyridoxine-responsive seizures: review of 63 North American cases submitted to a patient registry. Eur J Pediatr 2009; 168:697.
  33. Schmitt B, Baumgartner M, Mills PB, et al. Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency. Dev Med Child Neurol 2010; 52:e133.
  34. Bok LA, Halbertsma FJ, Houterman S, et al. Long-term outcome in pyridoxine-dependent epilepsy. Dev Med Child Neurol 2012; 54:849.
  35. Stockler S, Plecko B, Gospe SM Jr, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 2011; 104:48.
  36. Pérez B, Gutiérrez-Solana LG, Verdú A, et al. Clinical, biochemical, and molecular studies in pyridoxine-dependent epilepsy. Antisense therapy as possible new therapeutic option. Epilepsia 2013; 54:239.
  37. Proudfoot M, Jardine P, Straukiene A, et al. Long-Term Follow-up of a Successfully Treated Case of Congenital Pyridoxine-Dependent Epilepsy. JIMD Rep 2013; 10:103.
  38. Gallagher RC, Van Hove JL, Scharer G, et al. Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol 2009; 65:550.
  39. Schwarz G. Molybdenum cofactor biosynthesis and deficiency. Cell Mol Life Sci 2005; 62:2792.
  40. Reiss J, Hahnewald R. Molybdenum cofactor deficiency: Mutations in GPHN, MOCS1, and MOCS2. Hum Mutat 2011; 32:10.
  41. 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; 386:1955.
  42. Wilcken B. Treatments for rare diseases: molybdenum cofactor deficiency. Lancet 2015; 386:1924.
  43. Veldman A, Santamaria-Araujo JA, Sollazzo S, et al. Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics 2010; 125:e1249.
  44. Hitzert MM, Bos AF, Bergman KA, et al. Favorable outcome in a newborn with molybdenum cofactor type A deficiency treated with cPMP. Pediatrics 2012; 130:e1005.
  45. Ohtahara S, Ohstsuka Y, Yamatogi Y, et al.. Early-infantile epileptic encephalopathy with supression-bursts. In: Epileptic Syndromes in Infancy, Childhood and Adolescence, 4th, Roger J, Bureau M, Dravet CH, et al. (Eds), John Libbey & Company, 2005. p.25.
  46. Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neurophysiol 2003; 20:398.
  47. Plouin P, Anderson VE. Benign familial and non-familial neonatal seizures. In: Epileptic Syndromes in Infancy, Childhood and Adolescence, Roger J, Bureau M, Dravet CH, et al. (Eds), John Libbey & Company, 2005. p.3.
  48. Quattlebaum TG. Benign familial convulsions in the neonatal period and early infancy. J Pediatr 1979; 95:257.
  49. Ronen GM, Rosales TO, Connolly M, et al. Seizure characteristics in chromosome 20 benign familial neonatal convulsions. Neurology 1993; 43:1355.
  50. Mizrahi EM, Clancy RR. Neonatal seizures: early-onset seizure syndromes and their consequences for development. Ment Retard Dev Disabil Res Rev 2000; 6:229.
  51. Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006; 117:1270.
  52. Maartens IA, Wassenberg T, Buijs J, et al. Neurodevelopmental outcome in full-term newborns with refractory neonatal seizures. Acta Paediatr 2012; 101:e173.
  53. Ortibus EL, Sum JM, Hahn JS. Predictive value of EEG for outcome and epilepsy following neonatal seizures. Electroencephalogr Clin Neurophysiol 1996; 98:175.
  54. Blume WT, Lüders HO, Mizrahi E, et al. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 2001; 42:1212.
  55. Brunquell PJ, Glennon CM, DiMario FJ Jr, et al. Prediction of outcome based on clinical seizure type in newborn infants. J Pediatr 2002; 140:707.
  56. Ronen GM, Buckley D, Penney S, Streiner DL. Long-term prognosis in children with neonatal seizures: a population-based study. Neurology 2007; 69:1816.
  57. Mizrahi EM, Clancy RR, Dunn JK, et al. Neurological impairment, developmental delay and postnatal seizures 2 years after EEG-video documented seizures in near-term and term neonates: a report of the clinical research centers for neonatal seizures. Epilepsia 2001; 42(Supplement 7):102.
  58. Davis AS, Hintz SR, Van Meurs KP, et al. Seizures in extremely low birth weight infants are associated with adverse outcome. J Pediatr 2010; 157:720.
  59. Uria-Avellanal C, Marlow N, Rennie JM. Outcome following neonatal seizures. Semin Fetal Neonatal Med 2013; 18:224.
  60. Garfinkle J, Shevell MI. Cerebral palsy, developmental delay, and epilepsy after neonatal seizures. Pediatr Neurol 2011; 44:88.
  61. Ellenberg JH, Hirtz DG, Nelson KB. Age at onset of seizures in young children. Ann Neurol 1984; 15:127.
  62. Bye AM, Cunningham CA, Chee KY, Flanagan D. Outcome of neonates with electrographically identified seizures, or at risk of seizures. Pediatr Neurol 1997; 16:225.
  63. Scher MS, Aso K, Beggarly ME, et al. Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993; 91:128.
  64. Clancy RR, Legido A. Postnatal epilepsy after EEG-confirmed neonatal seizures. Epilepsia 1991; 32:69.
  65. Pisani F, Cerminara C, Fusco C, Sisti L. Neonatal status epilepticus vs recurrent neonatal seizures: clinical findings and outcome. Neurology 2007; 69:2177.
  66. Watanabe K, Miura K, Natsume J, et al. Epilepsies of neonatal onset: seizure type and evolution. Dev Med Child Neurol 1999; 41:318.
  67. Nunes ML, Martins MP, Barea BM, et al. Neurological outcome of newborns with neonatal seizures: a cohort study in a tertiary university hospital. Arq Neuropsiquiatr 2008; 66:168.
  68. Inoue T, Shimizu M, Hamano S, et al. Epilepsy and West syndrome in neonates with hypoxic-ischemic encephalopathy. Pediatr Int 2014; 56:369.
  69. Thibeault-Eybalin MP, Lortie A, Carmant L. Neonatal seizures: do they damage the brain? Pediatr Neurol 2009; 40:175.
  70. Swann JW. Synaptogenesis and eliptogenesis in developing neural networks. In: Brain Development and Epilepsy, Schwartzkroin PA, Moshe SL, Noebels JL, Swann JW. (Eds), Oxford University, New York 1995. p.195.
  71. Jiang M, Lee CL, Smith KL, Swann JW. Spine loss and other persistent alterations of hippocampal pyramidal cell dendrites in a model of early-onset epilepsy. J Neurosci 1998; 18:8356.
  72. McCabe BK, Silveira DC, Cilio MR, et al. Reduced neurogenesis after neonatal seizures. J Neurosci 2001; 21:2094.
  73. Montgomery EM, Bardgett ME, Lall B, et al. Delayed neuronal loss after administration of intracerebroventricular kainic acid to preweanling rats. Brain Res Dev Brain Res 1999; 112:107.
  74. Holmes GL. The long-term effects of neonatal seizures. Clin Perinatol 2009; 36:901.
  75. Glass HC, Wirrell E. Controversies in neonatal seizure management. J Child Neurol 2009; 24:591.
  76. Glass HC, Glidden D, Jeremy RJ, et al. Clinical Neonatal Seizures are Independently Associated with Outcome in Infants at Risk for Hypoxic-Ischemic Brain Injury. J Pediatr 2009; 155:318.
  77. McBride MC, Laroia N, Guillet R. Electrographic seizures in neonates correlate with poor neurodevelopmental outcome. Neurology 2000; 55:506.
  78. Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002; 58:542.
  79. McInerny TK, Schubert WK. Prognosis of neonatal seizures. Am J Dis Child 1969; 117:261.
  80. Rose AL, Lombroso CT. A study of clinical, pathological, and electroencephalographic features in 137 full-term babies with a long-term follow-up. Pediatrics 1970; 45:404.
  81. Bergman I, Painter MJ, Hirsch RP, et al. Outcome in neonates with convulsions treated in an intensive care unit. Ann Neurol 1983; 14:642.
  82. Lombroso CT. Prognosis in neonatal seizures. Adv Neurol 1983; 34:101.
  83. Mannino FL, Trauner DA. Stroke in neonates. J Pediatr 1983; 102:605.
  84. Clancy R, Malin S, Laraque D, et al. Focal motor seizures heralding stroke in full-term neonates. Am J Dis Child 1985; 139:601.
  85. Kellaway P, Mizrahi EM. Neonatal seizures. In: Epilepsy: Electroclinical Syndromes, Luders H, Lesser RP. (Eds), Springer-Verlag, New York 1987. p.13.
  86. Volpe JJ. Neurology of the Newborn. In: Neonatal Seizures, WB Sanders, Philadelphia 1995. p.172.
  87. Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987; 37:1837.
  88. Pisani F, Copioli C, Di Gioia C, et al. Neonatal seizures: relation of ictal video-electroencephalography (EEG) findings with neurodevelopmental outcome. J Child Neurol 2008; 23:394.
  89. Holmes GL, Lombroso CT. Prognostic value of background patterns in the neonatal EEG. J Clin Neurophysiol 1993; 10:323.
  90. Laroia N, Guillet R, Burchfiel J, McBride MC. EEG background as predictor of electrographic seizures in high-risk neonates. Epilepsia 1998; 39:545.
  91. Thoresen M, Hellström-Westas L, Liu X, de Vries LS. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics 2010; 126:e131.