CNS Drugs

, Volume 27, Issue 4, pp 273–286 | Cite as

Pharmacotherapy of Focal Epilepsy in Children: A Systematic Review of Approved Agents

Systematic Review Article



Partial-onset seizures contribute the bulk of seizure burden in childhood epilepsy. The therapeutic decision making involves consideration of factors specific to drug, patient and socioeconomic situation.


This paper systematically reviews the available efficacy/effectiveness evidence for various anti-epileptic drugs (AED) as monotherapy and adjunctive therapy for partial-onset seizures in children.

Data sources

Relevant randomized clinical trials (RCTs) were identified by a structured PubMed search, supplemented by an additional hand search of reference lists and authors’ files.

Study appraisal and synthesis methods

Eligible studies were reviewed and data extracted into tables. Included RCTs were classified based on accepted published criteria.


Only efficacy and effectiveness outcome measures were evaluated since there is little scientifically rigorous comprehensive AED adverse effects data.


Oxcarbazepine is the only AED with Class I evidence for efficacy/effectiveness as initial monotherapy for partial-onset seizures in children. Carbamazepine, clobazam, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, vigabatrin and zonisamide have, at best, Class III efficacy/effectiveness evidence for monotherapy of partial-onset seizures in children. For adjunctive therapy, gabapentin, lamotrigine, levetiracetam, oxcarbazepine and topiramate have Class I efficacy/effectiveness evidence for treatment of pediatric partial-onset seizures.

Conclusions and implications of key findings

This efficacy/effectiveness analysis must not be used in isolation when selecting therapy. AED selection for a specific child needs to integrate a drug’s efficacy/effectiveness data with its safety and tolerability profile, pharmacokinetic properties, available formulations, and patient specific characteristics. It is critical that physicians and patients incorporate all these relevant variables when choosing AED therapy.



The authors wish to acknowledge the assistance of Lisa C. Garrity, Pharm D; for review and comments on the manuscript. None of the authors received any funding for authorship or publication of this manuscript. R.A. did the literature search, data extraction, data synthesis and wrote the manuscript. T.A.G. provided the concept and overall organization for the review article and edited the manuscript. Both authors approved the final version. Dr. Arya has no conflict of interest to disclose. Dr. Glauser is funded by multiple NIH grants. He has received consulting fees from Supernus, Sunovion, Eisai, UCB, Lundbeck and Questcor, and is on the speakers’ bureau of Eisai and Questcor. He serves as an expert consultant for the US Department of Justice. He is a consultant for and receives royalties from a patent license from AssureRx Health.


  1. 1.
    Banerjee PN, Hauser WA. Incidence and prevalence In: Engel Jr. J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Wolters Kluwer; 2008. p. 45–57.Google Scholar
  2. 2.
    Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1989;30(4):389–99.Google Scholar
  3. 3.
    Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2006;47(7):1094–120.PubMedCrossRefGoogle Scholar
  4. 4.
    Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013. [Epub ahead of print]Google Scholar
  5. 5.
    French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al. Efficacy and tolerability of the new antiepileptic drugs, II: treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2004;45(5):410–23.PubMedCrossRefGoogle Scholar
  6. 6.
    Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, 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(4):676–85.PubMedCrossRefGoogle Scholar
  7. 7.
    Wheless JW, Neto W, Wang S. Topiramate, carbamazepine, and valproate monotherapy: double-blind comparison in children with newly diagnosed epilepsy. J Child Neurol. 2004;19(2):135–41.PubMedGoogle Scholar
  8. 8.
    Koch MW, Polman SK. Oxcarbazepine versus carbamazepine monotherapy for partial onset seizures. Cochrane Database Syst Rev. 2009(4):CD006453.Google Scholar
  9. 9.
    Bittencourt PR, Antoniuk SA, Bigarella MM, da Costa JC, Doro MP, Ferreira AS, et al. Carbamazepine and phenytoin in epilepsies refractory to barbiturates: efficacy, toxicity and mental function. Epilepsy Res. 1993;16(2):147–55.PubMedCrossRefGoogle Scholar
  10. 10.
    Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy. Canadian Study Group for Childhood Epilepsy. Epilepsia. 1998;39(9):952–9.Google Scholar
  11. 11.
    Bourgeois B, Brown LW, Pellock JM, Buroker M, Greiner M, Garofalo EA, et al. Gabapentin (Neurontin) monotherapy in children with Benign Childhood Epilepsy with centrotemporal spikes (BECTS): a 36-week, double-blind, placebo-controlled study. Epilepsia. 1998;39(s6):163.Google Scholar
  12. 12.
    Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, et al. Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study. Gabapentin Paediatric Study Group. Epilepsia. 1999;40(8):1147–54.PubMedCrossRefGoogle Scholar
  13. 13.
    Nieto-Barrera M, Brozmanova M, Capovilla G, Christe W, Pedersen B, Kane K, et al. A comparison of monotherapy with lamotrigine or carbamazepine in patients with newly diagnosed partial epilepsy. Epilepsy Res. 2001;46(2):145–55.PubMedCrossRefGoogle Scholar
  14. 14.
    Gamble CL, Williamson PR, Marson AG. Lamotrigine versus carbamazepine monotherapy for epilepsy. Cochrane Database Syst Rev. 2006(1):CD001031.Google Scholar
  15. 15.
    Gamble C, Williamson PR, Chadwick DW, Marson AG. A meta-analysis of individual patient responses to lamotrigine or carbamazepine monotherapy. Neurology. 2006;66(9):1310–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Duchowny M, Pellock JM, Graf WD, Billard C, Gilman J, Casale E, 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(8):1724–31.PubMedCrossRefGoogle Scholar
  17. 17.
    Pina-Garza JE, Levisohn P, Gucuyener K, Mikati MA, Warnock CR, Conklin HS, et al. Adjunctive lamotrigine for partial seizures in patients aged 1 to 24 months. Neurology. 2008;70(22 Pt 2):2099–108.PubMedCrossRefGoogle Scholar
  18. 18.
    Pina-Garza JE, Elterman RD, Ayala R, Corral M, Mikati MA, Pina-Garza MJ, et al. Long-term tolerability and efficacy of lamotrigine in infants 1 to 24 months old. J Child Neurol. 2008;23(8):853–61.PubMedCrossRefGoogle Scholar
  19. 19.
    Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology. 2006;66(11):1654–60.PubMedCrossRefGoogle Scholar
  20. 20.
    Pina-Garza JE, Nordli DR Jr, Rating D, Yang H, Schiemann-Delgado J, Duncan B. Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures. Epilepsia. 2009;50(5):1141–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Guerreiro MM, Vigonius U, Pohlmann H, de Manreza ML, Fejerman N, Antoniuk SA, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res. 1997;27(3):205–13.PubMedCrossRefGoogle Scholar
  22. 22.
    Novartis-Pharmaceutical. Trileptal prescribing information. East Hanover, NJ, 2004.Google Scholar
  23. 23.
    Muller M, Marson AG, Williamson PR. Oxcarbazepine versus phenytoin monotherapy for epilepsy. Cochrane Database Syst Rev. 2006(2):CD003615.Google Scholar
  24. 24.
    Glauser TA, Nigro M, Sachdeo R, Pasteris LA, Weinstein S, Abou-Khalil B, et al. Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group. Neurology. 2000;54(12):2237–44.PubMedCrossRefGoogle Scholar
  25. 25.
    Pina-Garza JE, Espinoza R, Nordli D, Bennett DA, Spirito S, Stites TE, et al. Oxcarbazepine adjunctive therapy in infants and young children with partial seizures. Neurology. 2005;65(9):1370–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Sommerfeld-Ziskin E. The effect of phenobarbital on the mentality of epileptic patients. Arch Neurol Psychiatry. 1940;43:70–9.CrossRefGoogle Scholar
  27. 27.
    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(9095):19–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Mitchell WG, Chavez JM. Carbamazepine versus phenobarbital for partial onset seizures in children. Epilepsia. 1987;28(1):56–60.PubMedCrossRefGoogle Scholar
  29. 29.
    Chiron C, Tonnelier S, Rey E, Brunet ML, Tran A, d’Athis P, et al. Stiripentol in childhood partial epilepsy: randomized placebo-controlled trial with enrichment and withdrawal design. J Child Neurol. 2006;21(6):496–502.PubMedGoogle Scholar
  30. 30.
    Gilliam FG, Veloso F, Bomhof MA, Gazda SK, Biton V, Ter Bruggen JP, et al. A dose-comparison trial of topiramate as monotherapy in recently diagnosed partial epilepsy. Neurology. 2003;60(2):196–202.PubMedCrossRefGoogle Scholar
  31. 31.
    Glauser TA, Dlugos DJ, Dodson WE, Grinspan A, Wang S, Wu SC. Topiramate monotherapy in newly diagnosed epilepsy in children and adolescents. J Child Neurol. 2007;22(6):693–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Elterman RD, Glauser TA, Wyllie E, Reife R, Wu SC, Pledger G. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group. Neurology. 1999;52(7):1338–44.PubMedCrossRefGoogle Scholar
  33. 33.
    Novotny E, Renfroe B, Yardi N, Nordli D, Ness S, Wang S, et al. Randomized trial of adjunctive topiramate therapy in infants with refractory partial seizures. Neurology. 2010;74(9):714–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Loiseau P, Cohadon S, Jogeix M, Legroux M, Dartigues JF. Efficacy of sodium valproate in partial epilepsy. Crossed study of valproate and carbamazepine. Rev Neurol (Paris). 1984;140(6–7):434–7.Google Scholar
  35. 35.
    Verity CM, Hosking G, Easter DJ. A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group. Dev Med Child Neurol. 1995;37(2):97–108.PubMedCrossRefGoogle Scholar
  36. 36.
    Shakir RA, Johnson RH, Lambie DG, Melville ID, Nanda RN. Comparison of sodium valproate and phenytoin as single drug treatment in epilepsy. Epilepsia. 1981;22(1):27–33.PubMedCrossRefGoogle Scholar
  37. 37.
    Rastogi P, Mehrotra TN, Agarwala RK, Singh VS. Comparison of sodium valproate and phenytoin as single drug treatment in generalised and partial epilepsy. J Assoc Phys India. 1991;39(8):606–8.Google Scholar
  38. 38.
    Callaghan N, Kenny RA, O’Neill B, Crowley M, Goggin T. A prospective study between carbamazepine, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy. J Neurol Neurosurg Psychiatry. 1985;48(7):639–44.PubMedCrossRefGoogle Scholar
  39. 39.
    de Silva M, MacArdle B, McGowan M, Hughes E, Stewart J, Neville BG, et al. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet. 1996;347(9003):709–13.PubMedCrossRefGoogle Scholar
  40. 40.
    Zamponi N, Cardinali C. Open comparative long-term study of vigabatrin vs carbamazepine in newly diagnosed partial seizures in children. Arch Neurol. 1999;56(5):605–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Sobaniec W, Kulak W, Strzelecka J, Smigielska-Kuzia J, Bockowski L. A comparative study of vigabatrin vs. carbamazepine in monotherapy of newly diagnosed partial seizures in children. Pharmacol Rep. 2005;57(5):646–53.PubMedGoogle Scholar
  42. 42.
    Chadwick D. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Vigabatrin European Monotherapy Study Group. Lancet. 1999;354(9172):13–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Eun SH, Kim HD, Eun BL, Lee IK, Chung HJ, Kim JS, et al. Comparative trial of low- and high-dose zonisamide as monotherapy for childhood epilepsy. Seizure. 2011;20(7):558–63.PubMedCrossRefGoogle Scholar
  44. 44.
    Arroyo S, Boothman BR, Brodie MJ, Duncan JS, Duncan R, Nieto M, et al. A randomised open-label study of tiagabine given two or three times daily in refractory epilepsy. Seizure. 2005;14(2):81–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Jedrzejczak J. Tiagabine as add-on therapy may be more effective with valproic acid–open label, multicentre study of patients with focal epilepsy. Eur J Neurol. 2005;12(3):176–80.PubMedCrossRefGoogle Scholar
  46. 46.
    Uthman BM, Rowan AJ, Ahmann PA, Leppik IE, Schachter SC, Sommerville KW, et al. Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial. Arch Neurol. 1998;55(1):56–62.PubMedCrossRefGoogle Scholar
  47. 47.
    Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med. 1985;313(3):145–51.PubMedCrossRefGoogle Scholar
  48. 48.
    Faught E, Sachdeo RC, Remler MP, Chayasirisobhon S, Iragui-Madoz VJ, Ramsay RE, et al. Felbamate monotherapy for partial-onset seizures: an active-control trial. Neurology. 1993;43(4):688–92.PubMedCrossRefGoogle Scholar
  49. 49.
    Bourgeois B, Leppik IE, Sackellares JC, Laxer K, Lesser R, Messenheimer JA, et al. Felbamate: a double-blind controlled trial in patients undergoing presurgical evaluation of partial seizures. Neurology. 1993;43(4):693–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Sachdeo R, Kramer LD, Rosenberg A, Sachdeo S. Felbamate monotherapy: controlled trial in patients with partial onset seizures. Ann Neurol. 1992;32(3):386–92.PubMedCrossRefGoogle Scholar
  51. 51.
    Canger R, Vignoli A, Bonardi R, Guidolin L. Felbamate in refractory partial epilepsy. Epilepsy Res. 1999;34(1):43–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Avanzini G, Canger R, Dalla Bernardina B, Vigevano F. Felbamate in therapy-resistant epilepsy: an Italian experience. Felbamate Italian Study Group. Epilepsy Res. 1996;25(3):249–55.PubMedCrossRefGoogle Scholar
  53. 53.
    Faught E. Antiepileptic drug trials: the view from the clinic. Epileptic Disord. 2012;14(2):114–23.PubMedGoogle Scholar
  54. 54.
    Beghi E, Gatti G, Tonini C, Ben-Menachem E, Chadwick DW, Nikanorova M, et al. Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial. Epilepsy Res. 2003;57(1):1–13.PubMedCrossRefGoogle Scholar
  55. 55.
    Nordli DR Jr, Bazil CW, Scheuer ML, Pedley TA. Recognition and classification of seizures in infants. Epilepsia. 1997;38(5):553–60.PubMedCrossRefGoogle Scholar
  56. 56.
    Nordli DR Jr, Kuroda MM, Hirsch LJ. The ontogeny of partial seizures in infants and young children. Epilepsia. 2001;42(8):986–90.PubMedCrossRefGoogle Scholar
  57. 57.
    Garofalo E. Obtaining pediatric indications for new anti-epileptic drugs: how and when. Epilepsy Res. 2006;68(1):38–42.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Comprehensive Epilepsy Center, Division of Neurology, MLC# 2015, Cincinnati Children’s Hospital Medical CenterCincinnatiUSA

Personalised recommendations