, Volume 78, Issue 13, pp 1321–1337 | Cite as

Pharmacotherapy for Focal Seizures in Children and Adolescents

  • Clare E. Stevens
  • Carl E. StafstromEmail author
Review Article


Focal-onset seizures are among the most common forms of seizures in children and adolescents and can be caused by a wide diversity of acquired or genetic etiologies. Despite the increasing array of antiseizure drugs available, treatment of focal-onset seizures in this population remains problematic, with as many as one-third of children having seizures refractory to medications. This review discusses contemporary concepts in focal seizure classification and pathophysiology and describes the antiseizure medications most commonly chosen for this age group. As antiseizure drug efficacy is comparable in children and adults, here we focus on pharmacokinetic aspects, drug–drug interactions, and side effect profiles. Finally, we provide some suggestions for choosing the optimal medication for the appropriate patient.



This work involved no funding source. The authors declare no conflicts of interest.

Compliance with Ethical Standards


This work involved no funding source.

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshé SL, Nordli D, Plouin P, Scheffer IE. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51(4):676–85.PubMedCrossRefGoogle Scholar
  2. 2.
    Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshé SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512–21.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Fisher RS. The new classification of seizures by the International League Against Epilepsy 2017. Curr Neurol Neurosci Rep. 2017;17(6):48. Scholar
  4. 4.
    Stafstrom CE. Recognizing seizures and epilepsy: insights from pathophysiology. In: Miller JW, Goodkin HP, editors. epilepsy. West Sussex: Wiley Blackwell; 2014. p. 3–9.Google Scholar
  5. 5.
    Stafstrom CE, Rho JM. Neurophysiology of seizures and epilepsy. In: Swaiman KF, Ashwal S, Ferriero DM, Schor NF, Finkel RS, Gropman AL, Pearl PL, Shevell MI, editors. Swaiman’s pediatric neurology: principles and practice. 6th ed. Edinburgh: Elsevier; 2017. p. 506–12.CrossRefGoogle Scholar
  6. 6.
    Spencer SS. Neural networks in human epilepsy: evidence of and implications for treatment. Epilepsia. 2002;43:219–27.PubMedCrossRefGoogle Scholar
  7. 7.
    Tankus A. Exploring human epileptic activity at the single-neuron level. Epilepsy Behav. 2016;58:11–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Truccolo W, Donoghue JA, Hochberg LR, Eskandar EN, Madsen JR, Anderson WS, Brown EN, Halgren E, Cash SS. Single-neuron dynamics in human focal epilepsy. Nat Neurosci. 2011;14(5):635–41.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Smith EH, Schevon CA. Toward a mechanistic understanding of epileptic networks. Curr Neurol Neurosci Rep. 2016;16:97.PubMedCrossRefGoogle Scholar
  10. 10.
    Dunne J, Rodriguez WJ, Murphy MD, Beasley BN, Burckart GJ, Filie JD, Lewis LL, Sachs HC, Sheridan PH, Starke P, Yao LP. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5):e1242–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Rosati A, Ilvento L, Lucenteforte E, Pugi A, Crescioli G, McGreevy KS, Virgili G, Mugelli A, De Masi S, Guerrini R. Comparative efficacy of antiepileptic drugs in children and adolescents: a network meta-analysis. Epilepsia. 2018;59(2):297–314.PubMedCrossRefGoogle Scholar
  12. 12.
    Pellock JM, Arzimanoglou A, D’Cruz O, Holmes GL, Nordli D, Shinnar S, Pediatric Epilepsy Academic Consortium for Extrapolation. Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥ 2 years old: the case for disease similarity. Epilepsia. 2017;58(10):1686–96.PubMedCrossRefGoogle Scholar
  13. 13.
    Pellock JM, Carman WJ, Thyagarajan V, Daniels T, Morris DL, D’Cruz O. Efficacy of antiepileptic drugs in adults predicts efficacy in children: a systematic review. Neurology. 2012;79(14):1482–9.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Mohd-Tahir NA, Li SC. Meta-analyses of newer antiepileptic drugs as adjunct for treatment of focal epilepsy in children. Epilepsy Res. 2018;139:113–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Arya R, Glauser TA. Pharmacotherapy of focal epilepsy in children: a systematic review of approved agents. CNS Drugs. 2013;27(4):273–86.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Nabulsi M, Mikati MA. Clinical trials versus anecdotal reports. In: Duchowny M, Cross JH, Arzimanoglou A, editors. Pediatric epilepsy. New York: McGraw Hill; 2013. p. 391–405.Google Scholar
  17. 17.
    Mudigoudar B, Weatherspoon S, Wheless JW. Emerging antiepileptic drugs for severe pediatric epilepsies. Semin Pediatr Neurol. 2016;23(2):167–79.CrossRefPubMedGoogle Scholar
  18. 18.
    McTague A, Martland T, Appleton R. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev. 2018;1:CD001905.Google Scholar
  19. 19.
    Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, Williamson PD, Treiman DM, McNamara JO, McCutchen CB. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med. 1985;313:145–51.PubMedCrossRefGoogle Scholar
  20. 20.
    Brodie MJ, Kwan P. Current position of phenobarbital in epilepsy and its future. Epilepsia. 2012;53(Suppl 8):40–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Taylor S, Tudur Smith C, Williamson PR, Marson AG. Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev. 2003;2:CD002217.Google Scholar
  22. 22.
    De Silva M, MacArdle B, McGowan M, Hughes E, Stewart J, Neville BG, Johnson AL, Reynolds EH. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine or sodium valproate for newly diagnosed childhood epilepsy. Lancet. 1996;347:709–13.PubMedCrossRefGoogle Scholar
  23. 23.
    Pal DK, Das T, Chaudhury G, Johnson AL, Neville BG. Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India. Lancet. 1998;351:19–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, Paneth N, Minnigh B, Alvin J. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341(7):485–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Olson RW. Phenobarbital and other barbiturates: mechanism of action. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 489–95.Google Scholar
  26. 26.
    Wolf SM, Forsythe A. Behavior disturbance, phenobarbital, and febrile seizures. Pediatrics. 1978;61:728–31.PubMedGoogle Scholar
  27. 27.
    Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. J Perinatol. 2013;33(11):841–6.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Donovan MD, Griffin BT, Kharoshankaya L, Cryan JF, Boylan GB. Pharmacotherapy for neonatal seizures: current knowledge and future perspectives. Drugs. 2016;76(6):647–61.PubMedCrossRefGoogle Scholar
  29. 29.
    Johannessen SI. Pharmacokinetics of antiepileptic drugs and their clinical significance. Behav Neurol. 1990;3(Suppl. 1):1–11.PubMedGoogle Scholar
  30. 30.
    Pitlick W, Painter M, Pippenger C. Phenobarbital pharmacokinetics in neonates. Clin Pharmacol Ther. 1978;23:346–50.PubMedCrossRefGoogle Scholar
  31. 31.
    Dodson WE, Bourgeois BFD. Pharmacology and therapeutic aspects of antiepileptic drugs in pediatrics. J Child Neurol. 1994;9:281–7.CrossRefGoogle Scholar
  32. 32.
    Conway JE, Morita DA, Glauser TA. Phenytoin and fosphenytoin. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 6th ed. Philadelphia: Wolters Kluwer; 2015. p. 691–704.Google Scholar
  33. 33.
    Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev 2004;3:CD004218.Google Scholar
  34. 34.
    Thomas P, Valton L, Genton P. Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy. Brain. 2006;129(Pt 5):1281–92.PubMedCrossRefGoogle Scholar
  35. 35.
    Privitera M. Clinical rules for phenytoin dosing. Ann Pharmacother. 1993;27:1169–73.PubMedCrossRefGoogle Scholar
  36. 36.
    van der Weide J, Steijns LS, van Weelden MJ, de Haan K. The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics. 2001;11(4):287–91.PubMedCrossRefGoogle Scholar
  37. 37.
    Johannessen SI, Ben-Menachem E. Management of focal-onset seizures: an update on drug treatment. Drugs. 2006;66(13):1701–25.PubMedCrossRefGoogle Scholar
  38. 38.
    Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, Leppik IE, Tomson T, Perucca E. 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
  39. 39.
    Rasmussen S, Kristensen M. Choreoathetosis during phenytoin treatment. Acta Med Scand. 1977;201:239–44.PubMedCrossRefGoogle Scholar
  40. 40.
    Stern JM, Perucca E, Browne TR. Phenytoin, fosphenytoin and other hydantoins. In: Engel Jr J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 1609–27.Google Scholar
  41. 41.
    Tudur Smith C, Marson AG, Williamson PR. Carbamazepine versus phenobarbitone monotherapy for epilepsy. Cochrane Database Syst Rev. 2003;(1):CD001904.Google Scholar
  42. 42.
    Chadwick DW, Anhut H, Greiner MJ, Alexander J, Murray GH, Garofalo EA, Pierce MW. A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International Gabapentin Monotherapy Study Group 945-77. Neurology. 1998;51:1282–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Gamble CL, Williamson PR, Marson AG. Lamotrigine versus carbamazepine monotherapy for epilepsy. Cochrane Database Syst Rev. 2006;CD001031.Google Scholar
  44. 44.
    Vajda FJ, Eadie MJ. The clinical pharmacology of traditional antiepileptic drugs. Epileptic Disord. 2014;16(4):395–408.PubMedGoogle Scholar
  45. 45.
    Guerreiro CAM, Guerreiro MM, Mintzer S. Carbamazepine, oxcarbazepine, and eslicarbazepine. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 6th ed. Philadelphia: Wolters Kluwer; 2015. p. 615–25.Google Scholar
  46. 46.
    Bertilsson L. Clinical pharmacokinetics of carbamazepine. Clin Pharmacokinet. 1978;3(2):128–43.PubMedCrossRefGoogle Scholar
  47. 47.
    Tolou-Ghamari Z, Zare M, Habibabadi JM, Najafi MR. A quick review of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012. J Res Med Sci. 2013;18(Suppl 1):S81–5.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Marson AG, Williamson PR, Clough H, Hutton JL, Chadwick DW, Epilepsy Monotherapy Trial Group. Carbamazepine versus valproate monotherapy for epilepsy: a meta-analysis. Epilepsia. 2002;43:505–13.PubMedCrossRefGoogle Scholar
  49. 49.
    Löscher W. Valproic acid: mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 767–79.Google Scholar
  50. 50.
    Jeavons PM. Non-dose-related side effects of valproate. Epilepsia. 1984;25(Suppl. 1):18–23.Google Scholar
  51. 51.
    Isojarvi JI, Tauboll E, Herzog AG. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs. 2005;19:207–23.PubMedCrossRefGoogle Scholar
  52. 52.
    Dreifuss FE, Langer DH, Moline KA, Maxwell JE. Valproic acid hepatic fatalities II: US experience since 1984. Neurology. 1989;39(2 Pt 1):201–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Cramer JA, Mattson RH, Bennett DM, Swick CT. Variable free and total valproic acid concentrations in sole- and multi-drug therapy. Ther Drug Monit. 1986;8:411–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Pt II. Phenytoin, carbamazepine, sulthiame, lamotrigine, vigabatrin, oxcarbazepine and felbamate. Clin Pharmacokinet. 1995;29:341–69.PubMedCrossRefGoogle Scholar
  55. 55.
    Gunes A, Bilir E, Zengil H, Babaoglu MO, Bozkurt A, Yasar U. Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients. Basic Clin Pharmacol Toxicol. 2007;100(6):383–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol. 2006;61(3):246–55.PubMedCrossRefGoogle Scholar
  57. 57.
    Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol. 2006;6:108–13.PubMedCrossRefGoogle Scholar
  58. 58.
    Cooper TE, Wiffen PJ, Heathcote LC, Clinch J, Howard R, Krane E, Lord SM, Sethna N, Schechter N, Wood C. Antiepileptic drugs for chronic non-cancer pain in children and adolescents. Cochrane Database Syst Rev. 2017;(8):CD012536.Google Scholar
  59. 59.
    Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, Garofalo E. gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multi-centre, double-blind, placebo-controlled study, Gabapentin Paediatric Study Group. Epilepsia. 1999;40:1147–54.PubMedCrossRefGoogle Scholar
  60. 60.
    Yamauchi T, Kaneko S, Yagi K, Sase S. Treatment of partial seizures with gabapentin: double-blind, placebo-controlled, parallel-group study. Psychiatry Clin Neurosci. 2006;60:507–15.PubMedCrossRefGoogle Scholar
  61. 61.
    Korn-Merker E, Borusiak P, Boenigk HE. Gabapentin in childhood epilepsy: a prospective evaluation of efficacy and safety. Epilepsy Res. 2000;38:27–32.PubMedCrossRefGoogle Scholar
  62. 62.
    Al-Bachari S, Pulman J, Hutton JL, Marson AG. Gabapentin add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev. 2013;(7):CD001415.Google Scholar
  63. 63.
    Richens A. Clinical pharmacokinetics of gabapentin. In: Chadwick D, editor. New trends in epilepsy management: the role of gabapentin. London: Royal Society of Medicine Services; 1993. p. 41–6.Google Scholar
  64. 64.
    Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Shi LL, Dong J, Ni H, Geng J, Wu T. Felbamate as an add-on therapy for refractory partial epilepsy. Cochrane Database Syst Rev. 2017;7:CD008295.Google Scholar
  66. 66.
    The felbamate study group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med. 1993;328:29–33.CrossRefGoogle Scholar
  67. 67.
    Faught E, et al. Felbamate monotherapy for partial-onset seizures: an active-control trial. Neurology. 1993;43:688–92.PubMedCrossRefGoogle Scholar
  68. 68.
    Kuo EC, Lin B-J, Chang HR. Use-dependent inhibition of the NMDA currents by felbamate: a gating modifier with selective binding to the desensitized channels. Mol Pharmacol. 2004;65:370–80.PubMedCrossRefGoogle Scholar
  69. 69.
    Sachdeo R, Kramer LD, Rosenberg A, Sachdeo S. Felbamate monotherapy: controlled trial in patients with partial onset seizures. Ann Neurol. 1992;32:386–92.PubMedCrossRefGoogle Scholar
  70. 70.
    Pellock JM. Felbamate in epilepsy therapy: evaluating the risks. Drug Saf. 1999;21:225–39.PubMedCrossRefGoogle Scholar
  71. 71.
    Pellock JM, Brodie MJ. Felbamate: 1997 update. Epilepsia. 1997;38:1261–4.PubMedCrossRefGoogle Scholar
  72. 72.
    Felbamate Faught E. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 6th ed. Philadelphia: Wolters Kluwer; 2015. p. 641–6.Google Scholar
  73. 73.
    Leppik IE, Wolff DL. The place of felbamate in the treatment of epilepsy. CNS Drugs. 1995;4:294–301.CrossRefGoogle Scholar
  74. 74.
    Brodie MJ, Chadwick DW, Anhut H, Otte A, Messmer SL, Maton S, Sauermann W, Murray G, Garofalo EA, Gabapentin Study Group 945-212. Gabapentin versus lamotrigine monotherapy: a double-blind, placebo-controlled comparison in newly diagnosed epilepsy. Epilepsia. 2002;43:993–1000.PubMedCrossRefGoogle Scholar
  75. 75.
    Steinhoff BJ, Ueberall MA, Siemes H, Kurlemann G, Schmitz B, Bergmann L. The LAM-SAFE Study: lamotrigine versus carbamazepine or valproic acid in newly diagnosed focal and generalized epilepsies in adolescents and adults. Seizure. 2005;14:597–605.PubMedCrossRefGoogle Scholar
  76. 76.
    Kaminow L, Schimschock JR, Hammer AE, Vuong A. Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy. Epilepsy Behavior. 2003;4:659–66.PubMedCrossRefGoogle Scholar
  77. 77.
    Duchowny M, et al. A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children: lamictal Pediatric Partial Seizure Study Group. Neurology. 1999;53:1724–31.PubMedCrossRefGoogle Scholar
  78. 78.
    Marson AG, Al-Kharusi AA, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR, SANAD Study group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369:1000–15.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Campos MS, Ayres LR, Morelo MR, Marques FA, Pereira LR. Efficacy and tolerability of antiepileptic drugs in patients with focal epilepsy: systematic review and network meta-analyses. Pharmacotherapy. 2016;36(12):1255–71.PubMedCrossRefGoogle Scholar
  80. 80.
    Gidal BE, Stern JM. Lamotrigine. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 6th ed. Philadelphia: Wolters Kluwer; 2015. p. 663–70.Google Scholar
  81. 81.
    Auvin S. Treatment of myoclonic seizures in patients with juvenile myoclonic epilepsy. Neuropsychiatr Dis Treat. 2007;3(6):729–34.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Coulter DA. Antiepileptic drug cellular mechanisms of action: where does lamotrigine fit in? J Child Neurol. 1997;12(Suppl. 1):S2–9.PubMedCrossRefGoogle Scholar
  83. 83.
    FDA Drug Safety Communication: FDA warns of serious immune system reaction with seizure and mental health medicine lamotrigine (Lamictal). U.S. Food and Drug Administration. Accessed 25 Apr 2018.
  84. 84.
    Goa KL, Ross SR, Chrisp P. Lamotrigine. A review of its pharmacological properties and clinical efficacy in epilepsy. Drugs. 1993;46(1):152–76.PubMedCrossRefGoogle Scholar
  85. 85.
    Kaufman KR, Gerner R. Lamotrigine toxicity secondary to sertraline. Seizure. 1998;7:163–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Arroyo S, Dodson WE, Privitera MD, Glauser TA, Naritoku DK, Dlugos DJ, Wang S, Schwabe SK. Twyman RE; EPMN-106/INT-28 Investigators. Randomized dose-controlled study of topiramate as first-line therapy in epilepsy. Acta Neurol Scand. 2005;112:214–22.PubMedCrossRefGoogle Scholar
  87. 87.
    Elterman RD, Glauser TA, Wyllie E, Reife R, Wu SC, Pedger G. A double-blind randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children: topiramate YTC Study Group. Neurology. 1999;52:1330–7.CrossRefGoogle Scholar
  88. 88.
    Mikaeloff Y, de Saint-Martin A, Mancini J, Peudenier S, Pedespan JM, Vallée L, Motte J, Bourgeois M, Arzimanoglou A, Dulac O, Chiron C. Topiramate: efficacy and tolerability in children according to epilepsy syndromes. Epilepsy Res. 2003;53:225–32.PubMedCrossRefGoogle Scholar
  89. 89.
    Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000;41(Suppl. 1):S3–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Langtry HD, Gillis JC, Davis R. Topiramate: a review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of epilepsy. Drugs. 1997;54:752–73.PubMedCrossRefGoogle Scholar
  91. 91.
    Biton V, Edwards KR, Montouris GD, Sackellares JC, Harden CL, Kamin M, Topiramate TPS-TR Study Group. Topiramate titration and tolerability. Ann Pharmacother. 2001;35:173–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Rosenfeld WE. Topiramate. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 6th ed. Philadelphia: Wolters Kluwer; 2015. p. 712–25.Google Scholar
  93. 93.
    Doose DR, Wang S-S, Padmanabhan M, Schwabe S, Jacobs D, Bialer M. Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Epilepsia. 2003;44:540–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, Lu Z, N159 Study Group. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology. 2006;66:1654–60.PubMedCrossRefGoogle Scholar
  95. 95.
    Glauser TA, Pellock JM, Bebin EM, Fountain NB, Ritter FJ, Jensen CM, Shields WD. Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial. Epilepsia. 2002;43:518–24.PubMedCrossRefGoogle Scholar
  96. 96.
    Klitgaard H. Levetiracetam: the preclinical profile of a new class of antiepileptic drugs. Epilepsia. 2001;42(Suppl. 4):13–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Deshpande LS, Delorenzo RJ. Mechanisms of levetiracetam in the control of status epilepticus and epilepsy. Front Neurol. 2014;31(5):11. Scholar
  98. 98.
    Egunsola O, Choonara I, Sammons HM, Whitehouse WP. Safety of antiepileptic drugs in children and young people: a prospective cohort study. Seizure. 2018;56:20–5.PubMedCrossRefGoogle Scholar
  99. 99.
    Harden C. Safety profile of levetiracetam. Epilepsia. 2001;42(Suppl. 4):36–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Major P, Greenberg E, Khan A, Thiele EA. Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: preliminary results. Epilepsy Behav. 2008;13(3):557–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Schmutz M, Brugger F, Gentsch C, McLean MJ, Olpe HR. Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action. Epilepsia. 1994;35(Suppl. 5):S47–50.PubMedCrossRefGoogle Scholar
  102. 102.
    Beydoun A, Sachdeo RC, Rosenfeld WE, Krauss GL, Sessler N, Mesenbrink P, Kramer L, D’Souza J. Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, double-blind, clinical trial. Neurology. 2000;54(12):245–51.CrossRefGoogle Scholar
  103. 103.
    Pina-Garza JE, Espinoza R, Nordli D, Bennett DA, Spirito S, Stites TE, Tang D, Sturm Y. Oxcarbazepine adjunctive therapy in infants and young children with partial seizures. Neurology. 2005;65:1370–5.PubMedCrossRefGoogle Scholar
  104. 104.
    Geng H, Wang C. Efficacy and safety of oxcarbazepine in the treatment of children with epilepsy: a meta-analysis of randomized controlled trials. Neuropsychiatr Dis Treat. 2017;13:685–95.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Gelisse P, Genton P, Kuate C, Pesenti A, Baldy-Moulinier M, Crespel A. Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies. Epilepsia. 2004;45(10):1282–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Coppola G, Franzoni E, Verrotti A, Garone C, Sarajlija J, Operto FF, Pascotto A. Levetiracetam or oxcarbazepine as monotherapy in newly diagnosed benign epilepsy of childhood with centrotemporal spikes (BECTS): an open-label, parallel group trial. Brain Dev. 2007;29(5):281–4.PubMedCrossRefGoogle Scholar
  107. 107.
    Chapman K, Holland K, Erenberg G. Seizure exacerbation associated with oxcarbazepine in idiopathic focal epilepsy of childhood. Neurology. 2003;61(7):1012–3.PubMedCrossRefGoogle Scholar
  108. 108.
    Shorvon S. Oxcarbazepine: a review. Seizure. 2000;9:75–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Dong X, Leppik I, White J, Rarick J. Hyponatremia from oxcarbazepine and carbamazepine. Neurology. 2005;65:1976–8.PubMedCrossRefGoogle Scholar
  110. 110.
    Larkin JG, McKee PJ, Forrest G, Beastall GH, Park BK, Lowrie JI, Lloyd P, Brodie MJ. Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects. Br J Clin Pharmacol. 1991;31:65–71.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Guerrini R, Rosati A, Bradshaw K, Giorgi L. Adjunctive zonisamide therapy in the long-term treatment of children with partial epilepsy: results of an open-label extension study of a phase III, randomized, double-blind, placebo-controlled trial. Epilepsia. 2014;55(4):568–78.PubMedCrossRefGoogle Scholar
  112. 112.
    Welty TE. Zonisamide. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 6th ed. Philadelphia: Wolters Kluwer; 2015. p. 740–6.Google Scholar
  113. 113.
    Glauser TA, Pellock JM. Zonisamide in pediatric epilepsy: review of the Japanese experience. J Child Neurol. 2002;17(2):87–96.PubMedCrossRefGoogle Scholar
  114. 114.
    Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs. Focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet. 1996;31(1):29–46.PubMedCrossRefGoogle Scholar
  115. 115.
    Hachad H, Ragueneau-Majlessi I, Levy RH. New antiepileptic drugs: review on drug interactions. Ther Drug Monit. 2002;24(1):91–103.PubMedCrossRefGoogle Scholar
  116. 116.
    Schulze-Bonhage A. Pharmacokinetic and pharmacodynamic profile of pregabalin and its role in the treatment of epilepsy. Expert Opin Drug Metab Toxicol. 2013;9(1):105–15.PubMedCrossRefGoogle Scholar
  117. 117.
    Brodie MJ. Pregabalin as adjunctive therapy for partial seizures. Epilepsia. 2004;45(suppl 6):19–27.PubMedCrossRefGoogle Scholar
  118. 118.
    Perucca P, Dopp JM. Gabapentin and pregabalin. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 6th ed. Philadelphia: Wolters Kluwer; 2015. p. 647–57.Google Scholar
  119. 119.
    Warner G, Figgitt DP. Pregabalin: as adjunctive treatment of partial seizures. CNS Drugs. 2005;19:265–72.PubMedCrossRefGoogle Scholar
  120. 120.
    Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45(Suppl. 6):13–8.PubMedCrossRefGoogle Scholar
  121. 121.
    Ortiz de la Rosa JS, Ladino LD, Rodríguez PJ, Rueda MC, Polanía JP, Castañeda AC. Efficacy of lacosamide in children and adolescents with drug-resistant epilepsy and refractory status epilepticus: a systematic review. Seizure. 2018;56:34–40.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Errington AC, Stöhr T, Heers C, Lees G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol. 2008;73(1):157–69.PubMedCrossRefGoogle Scholar
  123. 123.
    Kim JS, Kim H, Lim BC, Chae JH, Choi J, Kim KJ, Hwang YS, Hwang H. Lacosamide as an adjunctive therapy in pediatric patients with refractory focal epilepsy. Brain Dev. 2014;36(6):510–5.PubMedCrossRefGoogle Scholar
  124. 124.
    Brandt C, Heile A, Potschka H, Stoehr T, Löscher W. Effects of the novel antiepileptic drug lacosamide on the development of amygdala kindling in rats. Epilepsia. 2006;47(11):1803–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Rosenfeld W, Fountain NB, Kaubrys G, Ben-Menachem E, McShea C, Isojarvi J, Doty P, SP615 Study Investigators. Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years. Epilepsy Behav. 2014;41:164–70.PubMedCrossRefGoogle Scholar
  126. 126.
    Cawello W, Stockis A, Andreas JO, Dimova S. Advances in epilepsy treatment: lacosamide pharmacokinetic profile. Ann N Y Acad Sci. 2014;1329:18–32.PubMedCrossRefGoogle Scholar
  127. 127.
    de Biase S, Valente M, Gigli GL, Merlino G. Pharmacokinetic drug evaluation of lacosamide for the treatment of partial-onset seizures. Expert Opin Drug Metab Toxicol. 2017;13(9):997–1005.PubMedCrossRefGoogle Scholar
  128. 128.
    Doty P, Rudd GD, Stoehr T, Thomas D. Lacosamide. Neurotherapeutics. 2007;4(1):145–8.PubMedCrossRefGoogle Scholar
  129. 129.
    Cawello W. Clinical pharmacokinetic and pharmacodynamic profile of lacosamide. Clin Pharmacokinet. 2015;54(9):901–14.PubMedCrossRefGoogle Scholar
  130. 130.
    Cross SA, Curran MP. Lacosamide: in partial-onset seizures. Drugs. 2009;69(4):449–59.PubMedCrossRefGoogle Scholar
  131. 131.
    Coppola G, Besag F, Cusmai R, Dulac O, Kluger G, Moavero R, Nabbout R, Nikanorova M, Pisani F, Verrotti A, von Stülpnagel C, Curatolo P. Current role of rufinamide in the treatment of childhood epilepsy: literature review and treatment guidelines. Eur J Paediatr Neurol. 2014;18(6):685–90.PubMedCrossRefGoogle Scholar
  132. 132.
    Cusmai R, Verrotti A, Moavero R, Curatolo P, Battaglia D, Matricardi S, Spalice A, Vigevano F, Pruna D, Parisi P, D’Aniello A, Di Gennaro G, Coppola G. Rufinamide for the treatment of refractory epilepsy secondary to neuronal migration disorders. Epilepsy Res. 2014;108(3):542–6.PubMedCrossRefGoogle Scholar
  133. 133.
    Wheless JW, Vazquez B. Rufinamide: a novel broad-spectrum antiepileptic drug. Epilepsy Curr. 2010;10(1):1–6.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Wier HA, Cerna A, So TY. Rufinamide for pediatric patients with Lennox-Gastaut syndrome: a comprehensive overview. Paediatr Drugs. 2011;13(2):97–106.PubMedCrossRefGoogle Scholar
  135. 135.
    Jung MJ, Lippert B, Metcalf BW, Böhlen P, Schechter PJ. gamma-Vinyl GABA (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T: effects on brain GABA metabolism in mice. J Neurochem. 1977;29(5):797–802.PubMedCrossRefGoogle Scholar
  136. 136.
    French JA, Mosier M, Walker S, Sommerville K, Sussman N. A double-blind, placebo-controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures. Vigabatrin Protocol 024 Investigative Cohort. Neurology. 1996;46(1):54–61.PubMedCrossRefGoogle Scholar
  137. 137.
    Greiner HM, Lynch ER, Fordyce S, Agricola K, Tudor C, Franz DN, Krueger DA. Vigabatrin for childhood partial-onset epilepsies. Pediatr Neurol. 2012;46(2):83–8.PubMedCrossRefGoogle Scholar
  138. 138.
    Hemming K, Maguire MJ, Hutton JL, Marson AG. Vigabatrin for refractory partial epilepsy. Cochrane Database Syst Rev. 2013;1:CD007302.Google Scholar
  139. 139.
    Lortie A, Plouin P, Chiron C, Delalande O, Dulac O. Characteristics of epilepsy in focal cortical dysplasia in infancy. Epilepsy Res. 2002;51:133–45.PubMedCrossRefGoogle Scholar
  140. 140.
    Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia. 1997;38:1270–4.PubMedCrossRefGoogle Scholar
  141. 141.
    Tartara A, Manni R, Galimberti CA, Hardenberg J, Orwin J, Perucca E. Vigabatrin in the treatment of epilepsy: a double-blind placebo-controlled study. Epilepsia. 1986;27:717–23.PubMedCrossRefGoogle Scholar
  142. 142.
    Fecarotta C, Sergott RC. Vigabatrin-associated visual field loss. Int Ophthalmol Clin. 2012;52(3):87–94.PubMedCrossRefGoogle Scholar
  143. 143.
    Hussain K, Walsh TJ, Chazen JL. Brain MRI findings with vigabatrin therapy: case report and literature review. Clin Imaging. 2016;40(1):180–2.PubMedCrossRefGoogle Scholar
  144. 144.
    Schechter PJ. Clinical pharmacology of vigabatrin. Br J Clin Pharmacol. 1989;27:S19–22.CrossRefGoogle Scholar
  145. 145.
    Shorvon SD. The use of clobazam, midazolam and nitrazepam in epilepsy. Epilepsia. 1998;39(Suppl 1):S15–23.CrossRefGoogle Scholar
  146. 146.
    Canadian Study Group for Childhood Epilepsy. Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy. Epilepsia. 1998;39:952–9.CrossRefGoogle Scholar
  147. 147.
    Kaushal S, Rani A, Chopra SC, Singh G. Safety and efficacy of clobazam versus phenytoin-sodium in the antiepileptic drug treatment of solitary cysticercus granulomas. Neurol India. 2006;54:157–60.PubMedGoogle Scholar
  148. 148.
    Sankar R. GABA(A) receptor physiology and its relationship to the mechanism of action of the 1,5-benzodiazepine clobazam. CNS Drugs. 2012;26(3):229–44.CrossRefGoogle Scholar
  149. 149.
    Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia. 2013;54:11–27.PubMedCrossRefGoogle Scholar
  150. 150.
    Hermann R, Knebel NG, Niebch G, Richards L, Borlak J, Locher M. Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects. Eur J Clin Pharmacol. 2003;58:795–802.PubMedCrossRefGoogle Scholar
  151. 151.
    Stephen J, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents. CNS Drugs. 2011;25:89–107.PubMedCrossRefGoogle Scholar
  152. 152.
    Mathias SV, Abou-Khalil BW. Ezogabine skin discoloration is reversible after discontinuation. Epilepsy Behav Case Rep. 2017;7:61–3.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr. 2011;11(2):56–63.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    De Liso P, Moavero R, Coppola G, Curatolo P, Cusmai R, De Sarro G, Franzoni E, Vigevano F, Verrotti A. Current role of perampanel in pediatric epilepsy. Ital J Pediatr. 2017;43(1):51. Scholar
  155. 155.
    Tsai JJ, Wu T, Leung H, Desudchit T, Tiamkao S, Lim KS, Dash A. Perampanel, an AMPA receptor antagonist: from clinical research to practice in clinical settings. Acta Neurol Scand. 2018;137(4):378–91.PubMedCrossRefGoogle Scholar
  156. 156.
    Patsalos PN. The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist. Epilepsia. 2015;56:12–27.PubMedCrossRefGoogle Scholar
  157. 157.
    Ben-Menachem E, Gabbai AA, Hufnagel A, Maia J, Almeida L, Soares-da-Silva P. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89(2–3):278–85.PubMedCrossRefGoogle Scholar
  158. 158.
    Almeida L, Minciu I, Nunes T, Butoianu N, Falcão A, Magureanu SA, Soares-da-Silva P. Pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate in children and adolescents with epilepsy. J Clin Pharmacol. 2008;48(8):966–77.PubMedCrossRefGoogle Scholar
  159. 159.
    Soares-da-Silva P, Pires N, Bonifácio MJ, Loureiro AI, Palma N, Wright LC. Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action. Pharmacol Res Perspect. 2015;3(2):e00124. Scholar
  160. 160.
    Klein P, Diaz A, Gasalla T, Whitesides J. A review of the pharmacology and clinical efficacy of brivaracetam. Clin Pharmacol. 2018;10:1–22.PubMedPubMedCentralGoogle Scholar
  161. 161.
    Coppola G, Iapadre G, Operto FF, Verrotti A. New developments in the management of partial-onset epilepsy: role of brivaracetam. Drug Des Devel Ther. 2017;11:643–57.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Stephen LJ, Brodie MJ. Brivaracetam: a novel antiepileptic drug for focal-onset seizures. Ther Adv Neurol Disord. 2017;23(11):1756285617742081. Scholar
  163. 163.
    Coppola G. Treatment of partial seizures in childhood: an overview. CNS Drugs. 2004;18(3):133–56.PubMedCrossRefGoogle Scholar
  164. 164.
    Wheless JW, Clarke DF, Carpenter D. Treatment of pediatric epilepsy: expert opinion, 2005. J Child Neurol. 2005;20(Suppl. 1):S1–56.PubMedCrossRefGoogle Scholar
  165. 165.
    Ben-Menachem E. Weight issues for people with epilepsy—a review. Epilepsia. 2007;48:42–5.PubMedCrossRefGoogle Scholar
  166. 166.
    Gedzelman E, Meador KJ. Antiepileptic drugs in women with epilepsy during pregnancy. Ther Adv Drug Saf. 2012;3(2):71–87.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Leunissen CL, de la Parra NM, Tan IY, Rentmeester TW, Vader CI, Veendrick-Meekes MJ, Aldenkamp AP. Antiepileptic drugs with mood stabilizing properties and their relation with psychotropic drug use in institutionalized epilepsy patients with intellectual disability. Res Dev Disabil. 2011;32(6):2660–8.PubMedCrossRefGoogle Scholar
  168. 168.
    Afra P, Adamolekun B. Update on once-daily zonisamide monotherapy in partial seizures. Neuropsychiatr Dis Treat. 2014;10:493–8.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Purcarin G, Ng Y. Experience in the use of clobazam in the treatment of Lennox-Gastaut syndrome. Ther Adv Neurol Disord. 2014;7(3):169–76.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Anderson GD, Saneto RP. Modified-release formulations of second-generation antiepileptic drugs: pharmacokinetic and clinical aspects. CNS Drugs. 2015;29(8):669–81.PubMedCrossRefGoogle Scholar
  171. 171.
    Jayalakshmi S, Vooturi S, Gupta S, Panigrahi M. Epilepsy surgery in children. Neurol India. 2017;65(3):485–92.PubMedCrossRefGoogle Scholar
  172. 172.
    Varadkar S, Bien CG, Kruse CA, Jensen FE, Bauer J, Pardo CA, Vincent A, Mathern GW, Cross JH. Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol. 2014;13(2):195–205.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Kossoff EH, Vining EP, Pillas DJ, Pyzik PL, Avellino AM, Carson BS, Freeman JM. Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome. Neurology. 2003;61(7):887–90.PubMedCrossRefGoogle Scholar
  174. 174.
    Oliveira TVHF, Francisco AN, Demartini Z Jr, Stebel SL. The role of vagus nerve stimulation in refractory epilepsy. Arq Neuropsiquiatr. 2017;75(9):657–66.PubMedCrossRefGoogle Scholar
  175. 175.
    Rosculet NJ, Stafstrom CE. Neurostimulation techniques for the treatment of epilepsy. J Pediatr Epilepsy. 2017;6:91–6.CrossRefGoogle Scholar
  176. 176.
    Kotagal P. Neurostimulation: vagus nerve stimulation and beyond. Semin Pediatr Neurol. 2011;18(3):186–94.PubMedCrossRefGoogle Scholar
  177. 177.
    Kokoszka MA, Panov F, La Vega-Talbott M, McGoldrick PE, Wolf SM, Ghatan S. Treatment of medically refractory seizures with responsive neurostimulation: 2 pediatric cases. J Neurosurg Pediatr. 2018;21(4):421–7.PubMedCrossRefGoogle Scholar
  178. 178.
    Winesett SP, Bessone SK, Kossoff EH. The ketogenic diet in pharmacoresistant childhood epilepsy. Expert Rev Neurother. 2015;15(6):621–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Division of Pediatric Neurology, Department of Neurology, Johns Hopkins HospitalThe Johns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations