Summary
Many new antiepileptic drugs (AEDs) have become available over the past 15 years. At the same time, the emphasis on treating patients with epilepsy has grown from stopping seizures to avoiding side effects and maximizing quality of life. This review summarizes currently available AEDs, and presents general treatment principles and guidelines for AED selection. Unfortunately, despite the increased treatment options of today, seizure freedom without side effects remains unattainable for too many patients with epilepsy. Consequently, there remains a significant need for further development of new therapies.
Key Words: Epilepsy, seizure, antiepileptic drug, refractory, side effects
References
- 1.Schachter SC. Quality of life for patients with epilepsy is determined by more than seizure control: the role of psychosocial factors. Expert Rev Neurother. 2006;6:111–118. doi: 10.1586/14737175.6.1.111. [DOI] [PubMed] [Google Scholar]
- 2.Schachter SC. Improving quality of life beyond seizure control. Epileptic Disord. 2005;7(suppl 1):34–38. [PubMed] [Google Scholar]
- 3.Asconape JJ. Some common issues in the use of antiepileptic drugs. Semin Neurol. 2002;22:27–39. doi: 10.1055/s-2002-33046. [DOI] [PubMed] [Google Scholar]
- 4.Brodie MJ, Schachter SC, Kwan P. Epilepsy. 3rd ed. Oxford, England: Health Press; 2005. [Google Scholar]
- 5.Levy RH, Mattson RH, Meldrum BS, Perucca E. Antiepileptic drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. [Google Scholar]
- 6.Wyllie E, Gupta A, Lachhwani DK, editors. The treatment of epilepsy. Philadelphia: Lippincott Williams & Wilkins; 2006. [Google Scholar]
- 7.Deckers CL, Hekster YA, Keyser A, van Lier HJ, Meinardi H, Renier WO. Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study. Epilepsia. 2001;42:1387–1394. doi: 10.1046/j.1528-1157.2001.30800.x. [DOI] [PubMed] [Google Scholar]
- 8.Genton P, Gelisse P, Thomas P, Dravet C. Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy? Neurology. 2000;55:1106–1109. doi: 10.1212/wnl.55.8.1106. [DOI] [PubMed] [Google Scholar]
- 9.Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64:1134–1138. doi: 10.1212/01.WNL.0000156354.20227.F0. [DOI] [PubMed] [Google Scholar]
- 10.Isojarvi JI, Huuskonen UE, Pakarinen AJ, Vuolteenaho O, Myllyla VV. The regulation of serum sodium after replacing carbamazepine with oxcarbazepine. Epilepsia. 2001;42:741–745. doi: 10.1046/j.1528-1157.2001.34699.x. [DOI] [PubMed] [Google Scholar]
- 11.Yerby MS. Management issues for women with epilepsy: neural tube defects and folic acid supplementation. Neurology. 2003;61:S23–S26. doi: 10.1212/wnl.61.6_suppl_2.s23. [DOI] [PubMed] [Google Scholar]
- 12.Kaaja E, Kaaja R, Hiilesmaa V. Major malformations in offspring of women with epilepsy. Neurology. 2003;60:575–579. doi: 10.1212/01.wnl.0000044157.28073.dc. [DOI] [PubMed] [Google Scholar]
- 13.Artama M, Auvinen A, Raudaskoski T, Isojarvi I, Isojarvi J. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology. 2005;64:1874–1878. doi: 10.1212/01.WNL.0000163771.96962.1F. [DOI] [PubMed] [Google Scholar]
- 14.Spina E, Perucca E. Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs. Epilepsia. 2002;43:37–44. doi: 10.1046/j.1528-1157.2002.043s2037.x. [DOI] [PubMed] [Google Scholar]
- 15.Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16:263–272. doi: 10.2165/00023210-200216040-00005. [DOI] [PubMed] [Google Scholar]
- 16.Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia. 1995;36(suppl 2):S2–S12. doi: 10.1111/j.1528-1157.1995.tb05996.x. [DOI] [PubMed] [Google Scholar]
- 17.Sato S, White BG, Penry JK, Dreifuss FE, Sackellares JC, Kupferberg HJ. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology. 1982;32:157–163. doi: 10.1212/wnl.32.2.157. [DOI] [PubMed] [Google Scholar]
- 18.Meador KJ. Cognitive outcomes and predictive factors in epilepsy. Neurology. 2002;58:S21–S26. doi: 10.1212/wnl.58.8_suppl_5.s21. [DOI] [PubMed] [Google Scholar]
- 19.Mattson RH. Parenteral antiepileptic/anticonvulsant drugs. Neurology. 1996;46:S8–S13. doi: 10.1212/wnl.46.6_suppl_1.8s. [DOI] [PubMed] [Google Scholar]
- 20.Theodore WH, Porter RJ, Raubertas RF. Seizures during barbiturate withdrawal: relation to blood level. Ann Neurol. 1987;22:644–647. doi: 10.1002/ana.410220515. [DOI] [PubMed] [Google Scholar]
- 21.Holmes LB, Wyszynski DF, Lieberman E. The AED (antiepileptic drug) pregnancy registry: a 6-year experience. Arch Neurol. 2004;61:673–678. doi: 10.1001/archneur.61.5.673. [DOI] [PubMed] [Google Scholar]
- 22.Willmore LJ. Epilepsy emergencies: the first seizure and status epilepticus. Neurology. 1998;51:S34–S38. doi: 10.1212/wnl.51.5_suppl_4.s34. [DOI] [PubMed] [Google Scholar]
- 23.Browne TR, Kugler AR, Eldon MA. Pharmacology and pharmacokinetics of fosphenytoin. Neurology. 1996;46:S3–S7. doi: 10.1212/wnl.46.6_suppl_1.3s. [DOI] [PubMed] [Google Scholar]
- 24.Kaneko S, Battino D, Andermann E, et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res. 1999;33:145–158. doi: 10.1016/S0920-1211(98)00084-9. [DOI] [PubMed] [Google Scholar]
- 25.Birnbaum A, Hardie NA, Leppik IE, et al. Variability of total phenytoin serum concentrations within elderly nursing home residents. Neurology. 2003;60:555–559. doi: 10.1212/01.wnl.0000052997.43492.e0. [DOI] [PubMed] [Google Scholar]
- 26.Baumel IP, Gallagher BB, Mattson RH. Phenylethylmalonamide (PEMA). An important metabolite of primidone. Arch Neurol. 1972;27:34–41. doi: 10.1001/archneur.1972.00490130036005. [DOI] [PubMed] [Google Scholar]
- 27.Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002;16:695–714. doi: 10.2165/00023210-200216100-00004. [DOI] [PubMed] [Google Scholar]
- 28.Venkataraman V, Wheless JW. Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients. Epilepsy Res. 1999;35:147–153. doi: 10.1016/S0920-1211(99)00005-4. [DOI] [PubMed] [Google Scholar]
- 29.Wheless J, Venkataraman V. Safety of high intravenous valproate loading doses in epilepsy patients. J Epilepsy. 1998;11:319–324. doi: 10.1016/S0896-6974(98)00044-9. [DOI] [PubMed] [Google Scholar]
- 30.Morrell MJ. Reproductive and metabolic disorders in women with epilepsy. Epilepsia. 2003;44:11–20. doi: 10.1046/j.1528-1157.44.s4.2.x. [DOI] [PubMed] [Google Scholar]
- 31.Isojarvi JI, Tauboll E, Tapanainen JS, et al. On the association between valproate and polycystic ovary syndrome: a response and an alternative view. Epilepsia. 2001;42:305–310. doi: 10.1046/j.1528-1157.2001.t01-1-28899.x. [DOI] [PubMed] [Google Scholar]
- 32.Herzog AG, Schachter SC. Valproate and the polycystic ovarian syndrome: final thoughts. Epilepsia. 2001;42:311–315. doi: 10.1046/j.1528-1157.2001.33500.x. [DOI] [PubMed] [Google Scholar]
- 33.Duncan S, Mercho S, Lopes-Cendes I, et al. Repeated neural tube defects and valproate monotherapy suggest a pharmacogenetic abnormality. Epilepsia. 2001;42:750–753. doi: 10.1046/j.1528-1157.2001.44300.x. [DOI] [PubMed] [Google Scholar]
- 34.Rho JM, Donevan SD, Rogawski MA. Mechanism of action of the anticonvulsant felbamate: opposing effects on N-methyl-D-aspartate and gamma-aminobutyric acid A receptors. Ann Neurol. 1994;35:229–234. doi: 10.1002/ana.410350216. [DOI] [PubMed] [Google Scholar]
- 35.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]
- 36.Ketter TA, Malow BA, Flamini R, et al. Felbamate monotherapy has stimulant-like effects in patients with epilepsy. Epilepsy Res. 1996;23:129–137. doi: 10.1016/0920-1211(95)00089-5. [DOI] [PubMed] [Google Scholar]
- 37.Pellock JM, Brodie MJ. Felbamate: 1997 update. Epilepsia. 1997;38:1261–1264. doi: 10.1111/j.1528-1157.1997.tb00061.x. [DOI] [PubMed] [Google Scholar]
- 38.Carrazana EJ, Wheeler SD. Exacerbation of juvenile myoclonic epilepsy with lamotrigine. Neurology. 2001;56:1424–1425. doi: 10.1212/wnl.56.10.1424-a. [DOI] [PubMed] [Google Scholar]
- 39.Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia. 1998;39:508–512. doi: 10.1111/j.1528-1157.1998.tb01413.x. [DOI] [PubMed] [Google Scholar]
- 40.Kanner AM, Frey M. Adding valproate to lamotrigine: a study of their pharmacokinetic interaction. Neurology. 2000;55:588–591. doi: 10.1212/wnl.55.4.588. [DOI] [PubMed] [Google Scholar]
- 41.Faught E, Morris G, Jacobson M, et al. Adding lamotrigine to valproate: incidence of rash and other adverse effects. Postmarketing Antiepileptic Drug Survey (PADS) Group. Epilepsia. 1999;40:1135–1140. doi: 10.1111/j.1528-1157.1999.tb00831.x. [DOI] [PubMed] [Google Scholar]
- 42.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]
- 43.Tran TA, Leppik IE, Blesi K, Sathanandan ST, Remmel R. Lamotrigine clearance during pregnancy. Neurology. 2002;59:251–255. doi: 10.1212/wnl.59.2.251. [DOI] [PubMed] [Google Scholar]
- 44.Maison AG, Hutton JL, Leach JP, et al. Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res. 2001;46:259–270. doi: 10.1016/S0920-1211(01)00287-X. [DOI] [PubMed] [Google Scholar]
- 45.Harden C. Safety profile of levetiracetam. Epilepsia. 2001;42:36–39. [PubMed] [Google Scholar]
- 46.Ragueneau-Majlessi I, Levy RH, Janik F. Levetiracetam does not alter the pharmacokinetics of an oral contraceptive in healthy women. Epilepsia. 2002;43:697–702. doi: 10.1046/j.1528-1157.2002.57701.x. [DOI] [PubMed] [Google Scholar]
- 47.Radtke RA. Pharmacokinetics of levetiracetam. Epilepsia. 2001;42:24–27. doi: 10.1046/j.1528-1157.2001.0420s4024.x. [DOI] [PubMed] [Google Scholar]
- 48.Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther. 2000;85:77–85. doi: 10.1016/S0163-7258(99)00052-2. [DOI] [PubMed] [Google Scholar]
- 49.Shorvon S. Oxcarbazepine: a review. Seizure. 2000;9:75–79. doi: 10.1053/seiz.2000.0391. [DOI] [PubMed] [Google Scholar]
- 50.Schmidt D, Sachdeo R. Oxcarbazepine for treatment of partial epilepsy: a review and recommendations for clinical use. Epilepsy Behav. 2000;l:396–405. doi: 10.1006/ebeh.2000.0126. [DOI] [PubMed] [Google Scholar]
- 51.Lauria-Homer BA, Pohl RB. Pregabalin: a new anxiolytic. Expert Opin Investig Drugs. 2003;12:663–672. doi: 10.1517/13543784.12.4.663. [DOI] [PubMed] [Google Scholar]
- 52.French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA. Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology. 2003;60:1631–1637. doi: 10.1212/01.wnl.0000068024.20285.65. [DOI] [PubMed] [Google Scholar]
- 53.Schachter SC. A review of the antiepileptic drug tiagabine. Clin Neuropharmacol. 1999;22:312–317. [PubMed] [Google Scholar]
- 54.Kellinghaus C, Dziewas R, Ludemann P. Tiagabine-related non-convulsive status epilepticus in partial epilepsy: three case reports and a review of the literature. Seizure. 2002;11:243–249. doi: 10.1053/seiz.2001.0594. [DOI] [PubMed] [Google Scholar]
- 55.Schachter SC. Pharmacology and clinical experience with tiagabine. Expert Opin Pharmacother. 2001;2:179–187. doi: 10.1517/14656566.2.1.179. [DOI] [PubMed] [Google Scholar]
- 56.Leppik IE, Gram L, Deaton R, Sommerville KW. Safety of tiagabine: summary of 53 trials. Epilepsy Res. 1999;33:235–246. doi: 10.1016/S0920-1211(98)00094-1. [DOI] [PubMed] [Google Scholar]
- 57.Lau AH, Gustavson LE, Sperelakis R, et al. Pharmacokinetics and safety of tiagabine in subjects with various degrees of hepatic function. Epilepsia. 1997;38:445–451. doi: 10.1111/j.1528-1157.1997.tb01734.x. [DOI] [PubMed] [Google Scholar]
- 58.Mula M, Trimble MR, Thompson P, Sander JW. Topiramate and word-finding difficulties in patients with epilepsy. Neurology. 2003;60:1104–1107. doi: 10.1212/01.wnl.0000056637.37509.c6. [DOI] [PubMed] [Google Scholar]
- 59.Lee S, Sziklas V, Andermann F, et al. The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilepsia. 2003;44:339–347. doi: 10.1046/j.1528-1157.2003.27402.x. [DOI] [PubMed] [Google Scholar]
- 60.Cerminara C, Seri S, Bombardieri R, Pinci M, Curatolo P. Hypohidrosis during topiramate treatment: a rare and reversible side effect. Pediatr Neurol. 2006;34:392–394. doi: 10.1016/j.pediatrneurol.2005.10.004. [DOI] [PubMed] [Google Scholar]
- 61.Johannessen SI. Pharmacokinetics and interaction profile of topiramate: review and comparison with other newer antiepileptic drugs. Epilepsia. 1997;38(suppl 1):S18–S23. doi: 10.1111/j.1528-1157.1997.tb04512.x. [DOI] [PubMed] [Google Scholar]
- 62.Kyllerman M, Ben-Menachem E. Zonisamide for progressive myoclonus epilepsy: long-term observations in seven patients. Epilepsy Res. 1998;29:109–114. doi: 10.1016/S0920-1211(97)00069-7. [DOI] [PubMed] [Google Scholar]
- 63.Kubota M, Nishi-Nagase M, Sakakihara Y, et al. Zonisamide-induced urinary lithiasis in patients with intractable epilepsy. Brain Dev. 2000;22:230–233. doi: 10.1016/S0387-7604(00)00118-2. [DOI] [PubMed] [Google Scholar]
- 64.Knudsen JF, Thambi LR, Kapcala LP, Racoosin JA. Oligohydrosis and fever in pediatric patients treated with zonisamide. Pediatr Neurol. 2003;28:184–189. doi: 10.1016/s0887-8994(02)00511-8. [DOI] [PubMed] [Google Scholar]
- 65.Shinoda M, Akita M, Hasegawa M, Hasegawa T, Nabeshima T. The necessity of adjusting the dosage of zonisamide when coad-ministered with other anti-epileptic drugs. Biol Pharm Bull. 1996;19:1090–1092. doi: 10.1248/bpb.19.1090. [DOI] [PubMed] [Google Scholar]
- 66.French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1261–1273. doi: 10.1212/01.wnl.0000123695.22623.32. [DOI] [PubMed] [Google Scholar]
- 67.French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252–1260. doi: 10.1212/01.wnl.0000123693.82339.fc. [DOI] [PubMed] [Google Scholar]
- 68.Hixson JD, French JA. Guidelines for new antiepileptic drug evaluation. Rev Neurol Dis. 2004;1(suppl 1):S18–S26. [PubMed] [Google Scholar]
- 69.Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav. 2005;7(suppl 1):S1–S64. doi: 10.1016/j.yebeh.2005.06.001. [DOI] [PubMed] [Google Scholar]
- 70.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]
- 71.Lhatoo SD, Wong IC, Polizzi G, Sander JW. Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy. Epilepsia. 2000;41:1592–1596. doi: 10.1111/j.1528-1157.2000.tb00165.x. [DOI] [PubMed] [Google Scholar]
- 72.Eadie MJ. Can anticonvulsant drug therapy ‘cure’ epilepsy? CNS Drugs. 2001;15:679–690. doi: 10.2165/00023210-200115090-00002. [DOI] [PubMed] [Google Scholar]
- 73.Berg AT, Shinnar S. Relapse following discontinuation of antiepileptic drugs: a meta-analysis. Neurology. 1994;44:601–608. doi: 10.1212/wnl.44.4.601. [DOI] [PubMed] [Google Scholar]
- 74.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]
- 75.Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia. 2001;42:515–524. doi: 10.1046/j.1528-1157.2001.28900.x. [DOI] [PubMed] [Google Scholar]
- 76.Rogawski MA. Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res. 2006;69:273–294. doi: 10.1016/j.eplepsyres.2006.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Bialer M. New antiepileptic drugs that are second generation to existing antiepileptic drugs. Exp Opin Investig Drugs. 2006;15:637–647. doi: 10.1517/13543784.15.6.637. [DOI] [PubMed] [Google Scholar]
- 78.Schmidt D, Rogawski MA. New strategies for the identification of drugs to prevent the development or progression of epilepsy. Epilepsy Res. 2002;50:71–78. doi: 10.1016/S0920-1211(02)00070-0. [DOI] [PubMed] [Google Scholar]