Pediatric Drugs

, Volume 15, Issue 1, pp 9–18 | Cite as

Clinical Management of Seizures in Newborns

Diagnosis and Treatment
  • Linda G. M. van RooijEmail author
  • Marcel P. H. van den Broek
  • Carin M. A. Rademaker
  • Linda S. de Vries
Therapy in Practice


Neonatal seizures can be classified as tonic, clonic, myoclonic, and subtle. A clinical diagnosis is not easy as seizures are usually subtle in neonates. In the majority of newborn infants seizures are subclinical. On the other hand, not all abnormal movements identified by clinicians as clinical seizures are accompanied by electroencephalographic seizure discharges in the EEG. Precise incidence is difficult to delineate and depends on study population and criteria used for diagnosis of seizures. Controversy exists as to whether neonatal seizures themselves cause damage to the developing brain, or if the damage is primarily due to the underlying cause of the seizures. As a result of this controversy there is ongoing discussion whether all seizures (both clinical and subclinical) should be treated. In addition, when (sub)clinical seizures are treated, there is no consensus about the most appropriate treatment for neonatal seizures and how to assess the efficacy of treatment.

Current therapeutic options to treat neonatal seizures (i.e. primarily first-generation antiepileptic drugs [AEDs]) are relatively ineffective. In practice, phenobarbital still remains the drug of first choice for EEG confirmed or suspected seizures. Benzodiazepines are also used in (phenobarbital) refractory cases. Several (small) studies indicate that lidocaine is an effective drug for refractory seizures as second- or third-line treatment. Although data are scarce, some AEDs with a wide acceptance in adult and pediatric neurology practice are being used to treat neonatal seizures (i.e. second-generation AEDs). These drugs are chemically different from all first-generation AEDs and they have an effect on other pathways so they provide new pharmacological targets for controlling seizures in newborns. Levetiracetam, topiramate, felbamate, bumetanide, lamotrigine and vigabatrin are examples of these second-generation AEDs.

There is an urgent need for prospective, randomized, controlled trials to assess the efficacy and safety of these second-generation AEDs in neonates.

The aim of this review is to provide an overview of the current knowledge of diagnosis, the effect on brain injury, and the treatment of neonatal seizures.


Lamotrigine Phenobarbital Topiramate Levetiracetam Vigabatrin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Linda van Rooij and Marcel van den Broek contributed equally to this article. No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Volpe JJ. Neurology of the newborn. 5th ed. Philadelphia: Saunders Elsevier; 2008.Google Scholar
  2. 2.
    Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr. 1999;134(1):71–5.PubMedCrossRefGoogle Scholar
  3. 3.
    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(7):e133–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Hoffmann GF, Schmitt B, Windfuhr M, et al. Pyridoxal 5′-phosphate may be curative in early-onset epileptic encephalopathy. J Inherit Metab Dis. 2007;30(1):96–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Lanska MJ, Lanska DJ, Baumann RJ, et al. A population-based study of neonatal seizures in Fayette County, Kentucky. Neurology. 1995;45(4):724–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Saliba RM, Annegers JF, Waller DK, et al. Incidence of neonatal seizures in Harris County, Texas, 1992–1994. Am J Epidemiol. 1999;150(7):763–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Boylan GB, Rennie JM, Pressler RM, et al. Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed. 2002;86(3):F165–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Clancy RR, Legido A, Lewis D. Occult neonatal seizures. Epilepsia. 1988;29(3):256–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology. 1987;37(12):1837–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Scher MS, Alvin J, Gaus L, et al. Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use. Pediatr Neurol. 2003;28(4):277–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Glass HC, Sullivan JE. Neonatal seizures. Curr Treat Options Neurol. 2009;11(6):405–13.PubMedCrossRefGoogle Scholar
  12. 12.
    Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev 2004; (4): CD004218.Google Scholar
  13. 13.
    Vento M, de Vries LS, Alberola A, et al. Approach to seizures in the neonatal period: a European perspective. Acta Paediatr. 2010;99(4):497–501.PubMedCrossRefGoogle Scholar
  14. 14.
    Volpe JJ. Neonatal seizures: current concepts and revised classification. Pediatrics. 1989;84(3):422–8.PubMedGoogle Scholar
  15. 15.
    Danner R, Shewmon DA, Sherman MP. Seizures in an atelencephalic infant. Is the cortex essential for neonatal seizures? Arch Neurol. 1985;42(10):1014–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341(7):485–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Clancy RR. Prolonged electroencephalogram monitoring for seizures and their treatment. Clin Perinatol. 2006;33(3):649–65. vi.PubMedCrossRefGoogle Scholar
  18. 18.
    Lombroso CT, Holmes G. Value of the EEG in neonatal seizures. J Epilepsy. 1993;1(6):39–70.CrossRefGoogle Scholar
  19. 19.
    Clancy RR. The contribution of EEG to the understanding of neonatal seizures. Epilepsia. 1996;37(Suppl. 1):S52–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Khan O, Chang E, Cipriani C, et al. Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol. 2011;44(4):265–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Patrizi S, Holmes GL, Orzalesi M, et al. Neonatal seizures: characteristics of EEG ictal activity in preterm and fullterm infants. Brain Dev. 2003;25(6):427–37.PubMedCrossRefGoogle Scholar
  22. 22.
    Shellhaas RA, Clancy RR. Characterization of neonatal seizures by conventional EEG and single-channel EEG. Clin Neurophysiol. 2007;118(10):2156–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Clancy RR, Legido A. The exact ictal and interictal duration of electroencephalographic neonatal seizures. Epilepsia. 1987;28(5):537–41.PubMedCrossRefGoogle Scholar
  24. 24.
    McBride MC, Laroia N, Guillet R. Electrographic seizures in neonates correlate with poor neurodevelopmental outcome. Neurology. 2000;55(4):506–13.PubMedCrossRefGoogle Scholar
  25. 25.
    Oliveira AJ, Nunes ML, Haertel LM, et al. Duration of rhythmic EEG patterns in neonates: new evidence for clinical and prognostic significance of brief rhythmic discharges. Clin Neurophysiol. 2000;111(9):1646–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Scher MS, Hamid MY, Steppe DA, et al. Ictal and interictal electrographic seizure durations in preterm and term neonates. Epilepsia. 1993;34(2):284–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Shewmon DA. What is a neonatal seizure? Problems in definition and quantification for investigative and clinical purposes. J Clin Neurophysiol. 1990;7(3):315–68.PubMedCrossRefGoogle Scholar
  28. 28.
    Murray DM, Boylan GB, Ali I, et al. Defining the gap between electrographic seizure burden, clinical expression, and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 2008;93(3):F187–91.Google Scholar
  29. 29.
    Maynard D, Prior PF, Scott DF. Device for continuous monitoring of cerebral activity in resuscitated patients. BMJ. 1969;4(682):545–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Hellstrom-Westas L, Rosen I. Continuous brain-function monitoring: state of the art in clinical practice. Semin Fetal Neonatal Med. 2006;11(6):503–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Toet MC, van Rooij LG, de Vries LS. The use of amplitude integrated electroencephalography for assessing neonatal neurologic injury. Clin Perinatol. 2008;35(4):665–78.PubMedCrossRefGoogle Scholar
  32. 32.
    Hellstrom-Westas L, Rosen I. Amplitude-integrated electroencephalogram in newborn infants for clinical and research purposes. Acta Paediatr. 2002;91(10):1028–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Spitzmiller RE, Phillips T, Meinzen-Derr J, et al. Amplitude-integrated EEG is useful in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischemic encephalopathy: a meta-analysis. J Child Neurol. 2007;22(9):1069–78.PubMedCrossRefGoogle Scholar
  34. 34.
    Hellstrom-Westas L, Rosen I, Swenningsen NW. Silent seizures in sick infants in early life: diagnosis by continuous cerebral function monitoring. Acta Paediatr Scand. 1985;74(5):741–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Toet MC, van der Meij W, de Vries LS, et al. Comparison between simultaneously recorded amplitude integrated electroencephalogram (cerebral function monitor) and standard electroencephalogram in neonates. Pediatrics. 2002;109(5):772–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Shany E, Khvatskin S, Golan A, et al. Amplitude-integrated electroencephalography: a tool for monitoring silent seizures in neonates. Pediatr Neurol. 2006;34(3):194–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Shah DK, Mackay MT, Lavery S, et al. Accuracy of bedside electroencephalographic monitoring in comparison with simultaneous continuous conventional electroencephalography for seizure detection in term infants. Pediatrics. 2008;121(6):1146–54.PubMedCrossRefGoogle Scholar
  38. 38.
    Navakatikyan MA, Colditz PB, Burke CJ, et al. Seizure detection algorithm for neonates based on wave-sequence analysis. Clin Neurophysiol. 2006;117(6):1190–203.PubMedCrossRefGoogle Scholar
  39. 39.
    Lavery S, Shah DK, Hunt RW, et al. Single versus bihemispheric amplitude-integrated electroencephalography in relation to cerebral injury and outcome in the term encephalopathic infant. J Paediatr Child Health. 2008;44(5):285–90.PubMedCrossRefGoogle Scholar
  40. 40.
    Rennie JM, Chorley G, Boylan GB, et al. Non-expert use of the cerebral function monitor for neonatal seizure detection. Arch Dis Child Fetal Neonatal Ed. 2004;89(1):F37–40.PubMedCrossRefGoogle Scholar
  41. 41.
    Hellstrom-Westas L. Comparison between tape-recorded and amplitude-integrated EEG monitoring in sick newborn infants. Acta Paediatr. 1992;81(10):812–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Shellhaas RA, Soaita AI, Clancy RR. Sensitivity of amplitude-integrated electroencephalography for neonatal seizure detection. Pediatrics. 2007;120(4):770–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Silverstein FS, Jensen FE. Neonatal seizures. Ann Neurol. 2007;62(2):112–20.PubMedCrossRefGoogle Scholar
  44. 44.
    Levene M. The clinical conundrum of neonatal seizures. Arch Dis Child Fetal Neonatal Ed. 2002;86(2):F75–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. 2002;58(4):542–8.PubMedCrossRefGoogle Scholar
  46. 46.
    van Rooij LG, Toet MC, van Huffelen AC, et al. Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics. 2010;125(2):e358–66.PubMedCrossRefGoogle Scholar
  47. 47.
    Wusthoff CJ, Dlugos DJ, Gutierrez-Colina A, et al. Electrographic seizures during therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy. J Child Neurol. 2011;26(6):724–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Glass HC, Nash KB, Bonifacio SL, et al. Seizures and magnetic resonance imaging-detected brain injury in newborns cooled for hypoxic-ischemic encephalopathy. J Pediatr. 2011;159(5):731–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA. 2002;99(23):15089–94.PubMedCrossRefGoogle Scholar
  50. 50.
    Bittigau P, Sifringer M, Ikonomidou C. Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci. 2003;993:103–14.PubMedCrossRefGoogle Scholar
  51. 51.
    Ikonomidou C, Bittigau P, Koch C, et al. Neurotransmitters and apoptosis in the developing brain. Biochem Pharmacol. 2001;62(4):401–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Clancy RR. The newborn drug development initiative workshop: summary proceedings from the neurology group on neonatal seizures. Clin Ther. 2006;28(9):1342–52.PubMedCrossRefGoogle Scholar
  53. 53.
    Bartha AI, Shen J, Katz KH, et al. Neonatal seizures: multicenter variability in current treatment practices. Pediatr Neurol. 2007;37(2):85–90.PubMedCrossRefGoogle Scholar
  54. 54.
    Carmo KB, Barr P. Drug treatment of neonatal seizures by neonatologists and paediatric neurologists. J Paediatr Child Health. 2005;41(7):313–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Glier C, Dzietko M, Bittigau P, et al. Therapeutic doses of topiramate are not toxic to the developing rat brain. Exp Neurol. 2004;187(2):403–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Gilman JT, Gal P, Duchowny MS, et al. Rapid sequential phenobarbital treatment of neonatal seizures. Pediatrics. 1989;83(5):674–8.PubMedGoogle Scholar
  57. 57.
    Van Orman CB, Darwish HZ. Efficacy of phenobarbital in neonatal seizures. Can J Neurol Sci. 1985;12(2):95–9.PubMedGoogle Scholar
  58. 58.
    Painter MJ, Pippenger C, MacDonald H, et al. Phenobarbital and diphenylhydantoin levels in neonates with seizures. J Pediatr. 1978;92(2):315–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Barks JD, Liu YQ, Shangguan Y, et al. Phenobarbital augments hypothermic neuroprotection. Pediatr Res. 2010;67(5):532–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Grasela TH Jr, Donn SM. Neonatal population pharmacokinetics of phenobarbital derived from routine clinical data. Dev Pharmacol Ther. 1985;8(6):374–83.PubMedGoogle Scholar
  61. 61.
    Castro C Jr, Hernandez Borges AA, Domenech ME, et al. Midazolam in neonatal seizures with no response to phenobarbital. Neurology. 2005;64(5):876–9.CrossRefGoogle Scholar
  62. 62.
    Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology. 2004;62(3):486–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Shany E, Benzaqen O, Watemberg N. Comparison of continuous drip of midazolam or lidocaine in the treatment of intractable neonatal seizures. J Child Neurol. 2007;22(3):255–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Yamamoto H, Aihara M, Niijima S, et al. Treatments with midazolam and lidocaine for status epilepticus in neonates. Brain Dev. 2007;29(9):559–64.PubMedCrossRefGoogle Scholar
  65. 65.
    van Leuven K, Groenendaal F, Toet MC, et al. Midazolam and amplitude-integrated EEG in asphyxiated full-term neonates. Acta Paediatr. 2004;93(9):1221–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Andre M, Boutroy MJ, Dubruc C, et al. Clonazepam pharmacokinetics and therapeutic efficacy in neonatal seizures. Eur J Clin Pharmacol. 1986;30(5):585–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Hellstrom-Westas L, Westgren U, Rosen I, et al. Lidocaine for treatment of severe seizures in newborn infants: I. Clinical effects and cerebral electrical activity monitoring. Acta Paediatr Scand. 1988;77(1):79–84.PubMedCrossRefGoogle Scholar
  68. 68.
    Rey E, Radvanyi-Bouvet MF, Bodiou C, et al. Intravenous lidocaine in the treatment of convulsions in the neonatal period: monitoring plasma levels. Ther Drug Monit. 1990;12(4):316–20.PubMedCrossRefGoogle Scholar
  69. 69.
    Radvanyi-Bouvet MF, Torricelli A, Rey E, et al. Effects of lidocaine on seizures in the neonatal period: some electroclinical aspects. In: Wasterlain C, Vert P, editors. Neonatal seizures. New York: Raven Press; 1990. p. 277–85.Google Scholar
  70. 70.
    Malingre MM, van Rooij LG, Rademaker CM, et al. Development of an optimal lidocaine infusion strategy for neonatal seizures. Eur J Pediatr. 2006;165(9):598–604.PubMedCrossRefGoogle Scholar
  71. 71.
    van den Broek MP, Huitema AD, van Hasselt JG, et al. Lidocaine (lignocaine) dosing regimen based upon a population pharmacokinetic model for preterm and term neonates with seizures. Clin Pharmacokinet. 2011;50(7):461–9.PubMedCrossRefGoogle Scholar
  72. 72.
    van Rooij LG, Toet MC, Rademaker KM, et al. Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive treatment. Eur J Pediatr. 2004;163(11):637–41.PubMedGoogle Scholar
  73. 73.
    van den Broek MP, Groenendaal F, Egberts AC, et al. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet. 2010;49(5):277–94.PubMedCrossRefGoogle Scholar
  74. 74.
    Silverstein FS, Ferriero DM. Off-label use of antiepileptic drugs for the treatment of neonatal seizures. Pediatr Neurol. 2008;39(2):77–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Manthey D, Asimiadou S, Stefovska V, et al. Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain. Exp Neurol. 2005;193(2):497–503.PubMedCrossRefGoogle Scholar
  76. 76.
    Krief P, Li K, Maytal J. Efficacy of levetiracetam in children with epilepsy younger than 2 years of age. J Child Neurol. 2008;23(5):582–4.PubMedCrossRefGoogle Scholar
  77. 77.
    Meehan AL, Yang X, McAdams BD, et al. A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam. J Neurophysiol. 2011;106(3):1227–39.PubMedCrossRefGoogle Scholar
  78. 78.
    Kuzniecky R, Pan J, Burns A, et al. Levetiracetam has no acute effects on brain gamma-aminobutyric acid levels. Epilepsy Behav. 2008;12(2):242–4.PubMedCrossRefGoogle Scholar
  79. 79.
    Poulain P, Margineanu DG. Levetiracetam opposes the action of GABAA antagonists in hypothalamic neurones. Neuropharmacology. 2002;42(3):346–52.PubMedCrossRefGoogle Scholar
  80. 80.
    Mazarati AM, Baldwin R, Klitgaard H, et al. Anticonvulsant effects of levetiracetam and levetiracetam–diazepam combinations in experimental status epilepticus. Epilepsy Res. 2004;58(2–3):167–74.PubMedCrossRefGoogle Scholar
  81. 81.
    Merhar SL, Schibler KR, Sherwin CM, et al. Pharmacokinetics of levetiracetam in neonates with seizures. J Pediatr. 2011;159(1):152–4.PubMedCrossRefGoogle Scholar
  82. 82.
    Angehagen M, Ben-Menachem E, Ronnback L, et al. Novel mechanisms of action of three antiepileptic drugs, vigabatrin, tiagabine, and topiramate. Neurochem Res. 2003;28(2):333–40.PubMedCrossRefGoogle Scholar
  83. 83.
    Schubert S, Brandl U, Brodhun M, et al. Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets. Brain Res. 2005;1058(1–2):129–36.PubMedCrossRefGoogle Scholar
  84. 84.
    Zhao Q, Hu Y, Holmes GL. Effect of topiramate on cognitive function and activity level following neonatal seizures. Epilepsy Behav. 2005;6(4):529–36.PubMedCrossRefGoogle Scholar
  85. 85.
    Glass HC, Poulin C, Shevell MI. Topiramate for the treatment of neonatal seizures. Pediatr Neurol. 2011;44(6):439–42.PubMedCrossRefGoogle Scholar
  86. 86.
    Novotny E, Renfroe B, Yardi N, et al. Randomized trial of adjunctive topiramate therapy in infants with refractory partial seizures. Neurology. 2010;74(9):714–20.PubMedCrossRefGoogle Scholar
  87. 87.
    Filippi L, la Marca G, Fiorini P, et al. Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy. Epilepsia. 2009;50(11):2355–61.PubMedCrossRefGoogle Scholar
  88. 88.
    Filippi L, Poggi C, la Marca G, et al. Oral topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia: a safety study. J Pediatr. 2010;157(3):361–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring. ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239–76.PubMedCrossRefGoogle Scholar
  90. 90.
    Rho JM, Donevan SD, Rogawski MA. Mechanism of action of the anticonvulsant felbamate: opposing effects on N-methyl-d-aspartate and gamma-aminobutyric acidA receptors. Ann Neurol. 1994;35(2):229–34.PubMedCrossRefGoogle Scholar
  91. 91.
    Wasterlain CG, Adams LM, Hattori H, et al. Felbamate reduces hypoxic-ischemic brain damage in vivo. Eur J Pharmacol. 1992;212(2–3):275–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Laroia N, Guillet R, McBride M. Felbamate in term infants with hypoxic ischemic encephalopathy. J Pediatr Neurology. 2007;5:301–4.Google Scholar
  93. 93.
    Adusumalli VE, Yang JT, Wong KK, et al. Felbamate pharmacokinetics in the rat, rabbit, and dog. Drug Metab Dispos. 1991;19(6):1116–25.PubMedGoogle Scholar
  94. 94.
    Adusumalli VE, Wichmann JK, Kucharczyk N, et al. Distribution of the anticonvulsant felbamate to cerebrospinal fluid and brain tissue of adult and neonatal rats. Drug Metab Dispos. 1993;21(6):1079–85.PubMedGoogle Scholar
  95. 95.
    Pellock JM. Felbamate in epilepsy therapy: evaluating the risks. Drug Saf. 1999;21(3):225–39.PubMedCrossRefGoogle Scholar
  96. 96.
    Payne JA, Rivera C, Voipio J, et al. Cation-chloride co-transporters in neuronal communication, development and trauma. Trends Neurosci. 2003;26(4):199–206.PubMedCrossRefGoogle Scholar
  97. 97.
    Fukuda A. Diuretic soothes seizures in newborns. Nat Med. 2005;11(11):1153–4.PubMedCrossRefGoogle Scholar
  98. 98.
    Kahle KT, Staley KJ. The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures. Neurosurg Focus. 2008;25(3):E22.PubMedCrossRefGoogle Scholar
  99. 99.
    Dzhala VI, Talos DM, Sdrulla DA, et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005;11(11):1205–13.PubMedCrossRefGoogle Scholar
  100. 100.
    Pond BB, Berglund K, Kuner T, et al. The chloride transporter Na(+)-K(+)-Cl− cotransporter isoform-1 contributes to intracellular chloride increases after in vitro ischemia. J Neurosci. 2006;26(5):1396–406.PubMedCrossRefGoogle Scholar
  101. 101.
    Dzhala VI, Brumback AC, Staley KJ. Bumetanide enhances phenobarbital efficacy in a neonatal seizure model. Ann Neurol. 2008;63(2):222–35.PubMedCrossRefGoogle Scholar
  102. 102.
    Choi H, Morrell MJ. Review of lamotrigine and its clinical applications in epilepsy. Expert Opin Pharmacother. 2003;4(2):243–51.PubMedCrossRefGoogle Scholar
  103. 103.
    Messenheimer J. Efficacy and safety of lamotrigine in pediatric patients. J Child Neurol. 2002;17(Suppl. 2):2S34–42.PubMedCrossRefGoogle Scholar
  104. 104.
    Barr PA, Buettiker VE, Antony JH. Efficacy of lamotrigine in refractory neonatal seizures. Pediatr Neurol. 1999;20(2):161–3.PubMedCrossRefGoogle Scholar
  105. 105.
    Messenheimer JA, Giorgi L, Risner ME. The tolerability of lamotrigine in children. Drug Saf. 2000;22(4):303–12.PubMedCrossRefGoogle Scholar
  106. 106.
    Morris RG, Black AB, Harris AL, et al. Lamotrigine and therapeutic drug monitoring: retrospective survey following the introduction of a routine service. Br J Clin Pharmacol. 1998;46(6):547–51.PubMedCrossRefGoogle Scholar
  107. 107.
    Metcalf BW. Inhibitors of GABA metabolism. Biochem Pharmacol. 1979;28(11):1705–12.PubMedCrossRefGoogle Scholar
  108. 108.
    Haegele KD, Schechter PJ. Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S-enantiomer. Clin Pharmacol Ther. 1986;40(5):581–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Baxter PS, Gardner-Medwin D, Barwick DD, et al. Vigabatrin monotherapy in resistant neonatal seizures. Seizure. 1995;4(1):57–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Vauzelle-Kervroedan F, Rey E, Pons G, et al. Pharmacokinetics of the individual enantiomers of vigabatrin in neonates with uncontrolled seizures. Br J Clin Pharmacol. 1996;42(6):779–81.PubMedCrossRefGoogle Scholar
  111. 111.
    Jammoul F, Wang Q, Nabbout R, et al. Taurine deficiency is a cause of vigabatrin-induced retinal phototoxicity. Ann Neurol. 2009;65(1):98–107.PubMedCrossRefGoogle Scholar
  112. 112.
    Wild JM, Chiron C, Ahn H, et al. Visual field loss in patients with refractory partial epilepsy treated with vigabatrin: final results from an open-label, observational, multicentre study. CNS Drugs. 2009;23(11):965–82.PubMedCrossRefGoogle Scholar
  113. 113.
    Herranz JL, Arteaga R, Farr IN, et al. Dose-response study of vigabatrin in children with refractory epilepsy. J Child Neurol 1991; Suppl. 2: S45-51.Google Scholar
  114. 114.
    Porro GL, Wittebol-Post D. Impairment of peripheral vision and its measurement. In: Bax M, Dutton G, editors. Visual impairment in children due to damage in the brain. Cambridge: Mc Keith Press; 2010. p. 85–97.Google Scholar
  115. 115.
    Van den Broek MP, Groenendaal F, Toet MC, et al. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia. Clin Pharmacokinet. 2012;51:671–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Van den Broek MP, Rademaker CM, van Straaten HL, et al. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed (in press).Google Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Linda G. M. van Rooij
    • 1
    Email author
  • Marcel P. H. van den Broek
    • 2
  • Carin M. A. Rademaker
    • 2
  • Linda S. de Vries
    • 1
  1. 1.Department of Neonatology, KE 04.123.1, Wilhelmina Children’s HospitalUniversity Medical Centre UtrechtUtrechtThe Netherlands
  2. 2.Department of Clinical Pharmacy, Wilhelmina Children’s HospitalUniversity Medical Centre UtrechtUtrechtThe Netherlands

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