Skip to main content
PMC home page
NeuroRx logoLink to NeuroRx
. 2012 Sep 5;3(2):170–180. doi: 10.1016/j.nurx.2006.01.013

New generation anticonvulsants for the treatment of epilepsy in children

Elizabeth J Donner 1,2,✉, O Carter Snead 1
PMCID: PMC3593448  PMID: 16554255

Summary

In the last 12 years, 10 new anticonvulsants have been approved by the U.S. Food and Drug Administration and. as a result, the treatment options for children and adults with epilepsy have been expanded considerably. These new generation antiepileptic drugs offer equal efficacy with improved tolerability, pharmacokinetic properties, and side effect profiles compared with the traditional drugs. With many new medications available, the clinician treating children with epilepsy must be well versed in the application of these drugs to their patient population. This manuscript will review the indications, mechanism of action, pharmacokinetics, adverse effects, and dosing of the new generation of anticonvulsant medications.

Key Words: Antiepileptic drug (AED), anticonvulsant, epilepsy, children

References

  • 1.Chang BS, Lowenstein DH. Epilepsy. N Engl J Med. 2003;349:1257–1266. doi: 10.1056/NEJMra022308. [DOI] [PubMed] [Google Scholar]
  • 2.Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–319. doi: 10.1056/NEJM200002033420503. [DOI] [PubMed] [Google Scholar]
  • 3.White HS. Animal models of epileptogenesis. Neurology. 2002;12(Suppl 5):S7–S14. doi: 10.1212/WNL.59.9_suppl_5.S7. [DOI] [PubMed] [Google Scholar]
  • 4.Shinnar S, Berg AT. Does antiepileptic drug therapy prevent the development of “chronic epilepsy”? Epilepsia. 1996;37:701–708. doi: 10.1111/j.1528-1157.1996.tb00639.x. [DOI] [PubMed] [Google Scholar]
  • 5.Dodson WE. Pharmacokinetic principles of antiepileptic therapy in children. In: Pellock JM, Dodson WE, Bourgeois BFD, editors. Pediatric epilepsy diagnosis and therapy. Ed 2. New York: Demos Medical Publishing; 2001. pp. 317–327. [Google Scholar]
  • 6.Dunn DW. Neuropsychiatric aspects of epilepsy in children. EpilepsyBehav. 2003;4:101–106. doi: 10.1016/s1525-5050(03)00022-2. [DOI] [PubMed] [Google Scholar]
  • 7.Shinnar S, Pellock JM. Update on the epidemiology and prognosis of pediatric epilepsy. J Child Neurol. 2002;17(Suppl 1):S4–S17. doi: 10.1177/08830738020170010201. [DOI] [PubMed] [Google Scholar]
  • 8.Saint-Martin AD, Seegmuller C, Carcangiu R, Kleitz C, Hirsch E, Marescaux C, Metz-Lutz MN. Cognitive consequences of rolandic epilepsy. Epileptic Disord. 2001;2:S159–S165. [PubMed] [Google Scholar]
  • 9.Camfield P, Camfield C. Epileptic syndromes in childhood: clinical features, outcomes, and treatment. Epilepsia. 2002;43(Suppl 3):27–32. doi: 10.1046/j.1528-1157.43.s.3.3.x. [DOI] [PubMed] [Google Scholar]
  • 10.Yung AW, Park YD, Cohen MJ, Garrison TN. Cognitive and behavioral problems in children with centrotemporal spikes. Pediatr Neurol. 2000;23:391–395. doi: 10.1016/S0887-8994(00)00220-4. [DOI] [PubMed] [Google Scholar]
  • 11.Helmstaedter C, Kurthen M, Lux S, Reuber M, Elger CE. Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy. Ann Neurol. 2003;54:425–432. doi: 10.1002/ana.10692. [DOI] [PubMed] [Google Scholar]
  • 12.Miller V, Palermo TM, Grewe SC. Quality of life in pediatric epilepsy: demographic and disease-related predictors and comparison with healthy controls. Epilepsy Behav. 2003;4:36–42. doi: 10.1016/S1525-5050(02)00601-7. [DOI] [PubMed] [Google Scholar]
  • 13.Austin JK, Huster GA, Dunn D, Risinger MW. Adolescents with active or inactive epilepsy or asthma: a comparison of quality of life. Epilepsia. 1996;37:1228–1238. doi: 10.1111/j.1528-1157.1996.tb00558.x. [DOI] [PubMed] [Google Scholar]
  • 14.Sillanpaa M, Jalava M, Kaleva O, et al. Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998;338:1715–1722. doi: 10.1056/NEJM199806113382402. [DOI] [PubMed] [Google Scholar]
  • 15.Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia. 2001;42:796–803. doi: 10.1046/j.1528-1157.2001.10401.x. [DOI] [PubMed] [Google Scholar]
  • 16.Pellock JM. Felbamate. Epilepsia. 1999;40(Suppl 5):S57–S62. doi: 10.1111/j.1528-1157.1999.tb00920.x. [DOI] [PubMed] [Google Scholar]
  • 17.LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. J Am Med Assoc. 2004;291:605–614. doi: 10.1001/jama.291.5.605. [DOI] [PubMed] [Google Scholar]
  • 18.Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII) Epilepsy Res. 2004;61:1–48. doi: 10.1016/j.eplepsyres.2004.07.010. [DOI] [PubMed] [Google Scholar]
  • 19.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. doi: 10.1056/NEJM199301073280105. [DOI] [PubMed] [Google Scholar]
  • 20.Carmant L, Holmes GL, Sawyer S, et al. Efficacy of felbamate in therapy for partial epilepsy in children. J Pediatr. 1994;125:481–486. doi: 10.1016/S0022-3476(05)83302-5. [DOI] [PubMed] [Google Scholar]
  • 21.Leppik IE. Felbamate. Epilepsia. 1995;36(Suppl 2):S66–S72. doi: 10.1111/j.1528-1157.1995.tb06000.x. [DOI] [PubMed] [Google Scholar]
  • 22.Glauser TA, Graves NM. Phenytoin and fosphenytoin. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Ed 3. Philadelphia: Lippincott Williams & Wilkins; 2001. pp. 853–868. [Google Scholar]
  • 23.McLean MJ. Gabapentin. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Ed 3. Philadelphia: Lippincott Williams & Wilkins; 2001. pp. 853–868. [Google Scholar]
  • 24.Appleton R, Fichtner K, LaMoreaux L, et al. Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicenter, double-blind, placebo controlled study. Epilepsia. 1999;40:1147–1154. doi: 10.1111/j.1528-1157.1999.tb00833.x. [DOI] [PubMed] [Google Scholar]
  • 25.Shapiro DY, Nordli D, Glauser TA, Knapp LE, Greiner M, Purcell T, Brigell M, Fichtner K, Kugler AR, Malicsi M, Smith TM, Garofalo EA. Gabapentin as add-on therapy for refractory partial seizures in children 1–36 months of age: a novel short-term, placebo-controlled trial. Epilepsia. 2000;41(Suppl 7):106–106. [Google Scholar]
  • 26.Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progess report on new antiepileptic drugs: a summary of the Sixth Eilat Conference (EILAT VI) Epilepsy Res. 2002;51:31–71. doi: 10.1016/S0920-1211(02)00106-7. [DOI] [PubMed] [Google Scholar]
  • 27.Bergin AM, Connolly M. New antiepileptic drug therapies. Neurol Clin N Am. 2002;20:1163–1182. doi: 10.1016/s0733-8619(02)00017-8. [DOI] [PubMed] [Google Scholar]
  • 28.Gilliam FG, Gidal BE. Lamotrigine. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Ed 3. Philadelphia: Lippincott Williams & Wilkins; 2001. pp. 853–868. [Google Scholar]
  • 29.Duchowny M, Pellock JM, Graf WD, et al. A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Neurology. 1999;53:1724–1731. doi: 10.1212/WNL.53.8.1724. [DOI] [PubMed] [Google Scholar]
  • 30.Eriksson A-S, Nergardh A, Hoppu K. The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: a randomized, double-blind, crossover study. Epilepsia. 1998;39:495–501. doi: 10.1111/j.1528-1157.1998.tb01411.x. [DOI] [PubMed] [Google Scholar]
  • 31.Motte J, Trevathan E, Arvidsson JFV, et al. The Lamictal Lennox-Gastaut Study Group. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med. 1997;337:1807–1812. doi: 10.1056/NEJM199712183372504. [DOI] [PubMed] [Google Scholar]
  • 32.Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia. 1999;40:985–991. doi: 10.1111/j.1528-1157.1999.tb00807.x. [DOI] [PubMed] [Google Scholar]
  • 33.Yuen AWC, Land G, Weatherley BC, et al. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol. 1992;33:511–513. doi: 10.1111/j.1365-2125.1992.tb04079.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Wong IC, Lahtoo SD. Adverse reactions to new anticonvulsant drugs. Drug Saf. 2000;23:35–56. doi: 10.2165/00002018-200023010-00003. [DOI] [PubMed] [Google Scholar]
  • 35.Beydoun A, Sachdeo RC, Kutluay E, et al. Sustained efficacy and long term safety of oxcarbazepine: one-year open-label extension of a study in refractory partial seizures. Epilepsia. 2003;44:1160–1165. doi: 10.1046/j.1528-1157.2003.54102.x. [DOI] [PubMed] [Google Scholar]
  • 36.Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res. 1997;27:205–213. doi: 10.1016/S0920-1211(97)00025-9. [DOI] [PubMed] [Google Scholar]
  • 37.Sillanpaa ML. Carbamazepine and Oxcarbazepine. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Ed 3. Philadelphia: Lippincott Williams & Wilkins; 2001. pp. 853–868. [Google Scholar]
  • 38.Van Amelsvoort T, Bakshi R, Devaux CB, et al. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia. 1994;35:181–188. doi: 10.1111/j.1528-1157.1994.tb02930.x. [DOI] [PubMed] [Google Scholar]
  • 39.Smith PEM. Clinical recommendations for oxcarbazepine. Scizure. 2001;10:87–91. doi: 10.1053/seiz.2001.0536. [DOI] [PubMed] [Google Scholar]
  • 40.Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45(Suppl 6):13–18. doi: 10.1111/j.0013-9580.2004.455003.x. [DOI] [PubMed] [Google Scholar]
  • 41.Brodie MJ. Pregabalin as adjunctive therapy for partial seizures. Epilepsia. 2004;45(Suppl 6):19–27. doi: 10.1111/j.0013-9580.2004.455004.x. [DOI] [PubMed] [Google Scholar]
  • 42.Stratton SC, Large CH, Cox B, Davies G, Hagan RM. Effects of lamotrigine and levetiracetam on seizure-development in a rat amygdala kindling model. Epilepsy Res. 2003;53:95–106. doi: 10.1016/S0920-1211(02)00254-1. [DOI] [PubMed] [Google Scholar]
  • 43.Lynch B, Lambeng N, Nocka K, Kensel-Hammes P, Bajjellieh SM, Matagne A, Fuks B. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA. 2004;10:9861–9866. doi: 10.1073/pnas.0308208101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Bourgeois BFD, Holder DL, Valencia I, et al. Open label assessment of levetiracetam efficacy and adverse effects in a pediatric population. Epilepsia. 2001;42(Suppl 7):253–254. [Google Scholar]
  • 45.Glauser T, Bebin M, Ritter F, et al. Open-label efficacy and safety of levetiracetam in pediatric patients with partial-onset seizures (abstract) Epilepsia. 1999;40:161–161. doi: 10.1111/j.1528-1157.1999.tb00780.x. [DOI] [Google Scholar]
  • 46.Lagae L, Buyse G, Deconinck A, Ceulemans B. Effect of levetiracetam in refractory childhood epilepsy syndromes. Eur J Pediatr Neurol. 2003;7:123–128. doi: 10.1016/S1090-3798(03)00041-2. [DOI] [PubMed] [Google Scholar]
  • 47.Kossoff EH, Bergey GK, Freeman JM, et al. Levetiracetam psychosis in children with epilepsy. Epilepsia. 2001;42:1161–1163. doi: 10.1046/j.1528-1157.2001.32101.x. [DOI] [PubMed] [Google Scholar]
  • 48.Shinnar S, Sommerville KW. Tiagabine. In: Pellock JM, Dodson WE, Bourgeois BFD, editors. Pediatric epilepsy diagnosis and therapy. Ed 2. New York: Demos Medical Publishing; 2001. pp. 489–498. [Google Scholar]
  • 49.Eckardt KM, Steinhoff BJ. Nonconvulsive status epilepticus in two patients receiving tiagabine treatment. Epilepsia. 1998;39:671–674. doi: 10.1111/j.1528-1157.1998.tb01438.x. [DOI] [PubMed] [Google Scholar]
  • 50.Ettinger AB, Bernai OG, Andriola MR, Bagchi S, et al. Two cases of nonconvulsive status epilepticus in association with tiagabine therapy. Epilepsia. 1999;40:1159–1162. doi: 10.1111/j.1528-1157.1999.tb00835.x. [DOI] [PubMed] [Google Scholar]
  • 51.Snead OC, Depaulis A, Vergnes M, Marescaux C. Absence epilepsy: advances in experimental animal models. Adv Neurol. 1999;79:253–278. [PubMed] [Google Scholar]
  • 52.Shinnar S, Berg AT, Treiman DM, Hauser WA, Hesdorffer DC, Scakellares JC, Leppik I, Sillanpaa M, Sommerville KW. Status epilepticus and tiagabine therapy: review of safety data and epidemiologic comparisons. Epilepsia. 2001;42:372–379. doi: 10.1046/j.1528-1157.2001.01600.x. [DOI] [PubMed] [Google Scholar]
  • 53.Krauss GL, Johnson MA, Sheth S, Miller NR. A controlled study comparing visual function in patients treated with vigabatrin and tiagabine. J Neurol Neurosurg Psychiatry. 2003;74:339–343. doi: 10.1136/jnnp.74.3.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Kalviainen R, Hache JC, Renault-Dijouadi JA.A study of visual fields in patients receiving tiagabine as monotherapy versus carbamazepine or lamotrigine monotherapy Epilepsia 200142Suppl 7256–256.11240599 [Google Scholar]
  • 55.Schachter SC. Tiagabine. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Ed 3. Philadelphia: Lippincott Williams & Wilkins; 2001. pp. 853–868. [Google Scholar]
  • 56.DeLorenzo RJ, Sombati S, Coulter DA, et al. Effects of topiramate on sustained repetitive firing and spontaneous recurrent seizure discharges in cultured hippocampal neurons. Epilepsia. 2000;41(Suppl 1):S40–S44. doi: 10.1111/j.1528-1157.2000.tb06048.x. [DOI] [PubMed] [Google Scholar]
  • 57.Gibbs JW, Sombati S, Delorenzo RJ, et al. Cellular actions of topiramate: blockade of kainite-evoked inward currents in cultured hippocampal neurons. Epilepsia. 2000;41:510–516. doi: 10.1111/j.1528-1157.2000.tb02164.x. [DOI] [PubMed] [Google Scholar]
  • 58.White HS, Brown SD, Woodhead JH, et al. Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res. 1997;28:167–179. doi: 10.1016/S0920-1211(97)00045-4. [DOI] [PubMed] [Google Scholar]
  • 59.Qian J, Noebels JL. Topiramate alters excitatory synaptic transmission in mouse hippocampus. Epilepsy Res. 2003;55:225–233. doi: 10.1016/S0920-1211(03)00120-7. [DOI] [PubMed] [Google Scholar]
  • 60.Russo E, Constanti A. Topiramate hyperpolarizes and modulates the slow poststimulus AAHP of rat olfactory cortical neurons in vitro. Br J Pharmacol. 2004;1441:285–301. doi: 10.1038/sj.bjp.0705617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Gryder DS, Rogawski MA. Selective antagonism of gluR5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons. J Neurosci. 2003;23:7069–7074. doi: 10.1523/JNEUROSCI.23-18-07069.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Angehagen M, Ben-Menachem E, Shank R, Ronback L, Hanson E. Topiramate modulation of kainite-induced calcium currents is inversely related to channel phosphorylation level. J Neurochem. 2004;88:320–356. doi: 10.1046/j.1471-4159.2003.02186.x. [DOI] [PubMed] [Google Scholar]
  • 63.Elterman RD, Glauser TA, Wyllie E, Topiramate YP Study Group et al. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Neurology. 1999;52:1338–1344. doi: 10.1212/WNL.52.7.1338. [DOI] [PubMed] [Google Scholar]
  • 64.Glauser TA, Clark PO, Strawsburg R. A pilot study of topiramate in the treatment of infantile spasms. Epilepsia. 1998;39:1324–1328. doi: 10.1111/j.1528-1157.1998.tb01331.x. [DOI] [PubMed] [Google Scholar]
  • 65.Glauser TA. Topiramate in the catastrophic epilepsies of childhood. J Child Neurol. 2000;15(Suppl 1):S14–S21. doi: 10.1177/088307380001500104. [DOI] [PubMed] [Google Scholar]
  • 66.Sachdeo RC, Glauser TA, Ritter F, Topiramate YL Study Group et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Neurology. 1999;52:1882–1887. doi: 10.1212/WNL.52.9.1882. [DOI] [PubMed] [Google Scholar]
  • 67.Grosso S, Galimberti D, Fametani MA, Cioni M, Mostardini R, Vivarelli R, Di Bartolo RM, Bemardoni E, Berardi R, Morgese G, Balestri P. Efficacy and safety of topiramate in infants according to epilepsy syndromes. Scizure. 2005;14:183–189. doi: 10.1016/j.seizure.2005.01.006. [DOI] [PubMed] [Google Scholar]
  • 68.Battino D, Croci D, Rossini A, et al. Topiramate pharmacokinetics in children and adults with epilepsy: a case-matched comparison based on therapeutic drug monitoring data. Clin Pharmacokinet. 2005;44:407–416. doi: 10.2165/00003088-200544040-00005. [DOI] [PubMed] [Google Scholar]
  • 69.Hammoudi DS, Lee SSF, Madison A, et al. Reduced visual function associated with infantile spasms in children on vigabatrin therapy. Invest Ophthamol Visual Sci. 2005;46:514–520. doi: 10.1167/iovs.04-0559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Mackay MT, Weiss SK, Actams-Webber T, et al. Practice parameter: medical treatment of infantile spasms. Neurology. 2004;62:1668–1681. doi: 10.1212/01.WNL.0000127773.72699.C8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Curatolo P, Verdecchia M, Bombardieri R. Vigabatrin for tuberous sclerosis complex. Brain Dev. 2001;23:649–653. doi: 10.1016/S0387-7604(01)00290-X. [DOI] [PubMed] [Google Scholar]
  • 72.Westall CA, Logan WJ, Smith K, Buncic JR, Panton CM, Abdolell M, The Hospital for Sick Children, Toronto. Longitudinal ERG study of children on vigabatrin.Doc Ophthalmol 104:133-149, sofaction. [DOI] [PMC free article] [PubMed]
  • 73.Macdonald RL, Duche B. Zonisamide: mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, editors. Antiepileptic drugs. Ed 5. Philadelphia: Lippincott, Williams & Wilkins; 2002. pp. 867–872. [Google Scholar]
  • 74.Brodie MJ, Duncan R, Vespignani H, et al. Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebocontrolled study in patients with refractory partial seizures. Epilepsia. 2005;46:31–41. doi: 10.1111/j.0013-9580.2005.14704.x. [DOI] [PubMed] [Google Scholar]
  • 75.Fisher RS, Kerrigan JF, Pellock JM. Zonisamide. In: Pellock JM, Dodson WE, Bourgeois BFD, editors. Pediatric epilepsy diagnosis and therapy. Ed 2. New York: Demos Medical Publishing; 2001. pp. 509–512. [Google Scholar]
  • 76.Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol. 2004;3:618–621. doi: 10.1016/S1474-4422(04)00882-8. [DOI] [PubMed] [Google Scholar]
  • 77.Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5:553–564. doi: 10.1038/nrn1430. [DOI] [PubMed] [Google Scholar]

Articles from NeuroRx are provided here courtesy of Am. Soc. for Experimental NeuroTherapeutics

RESOURCES