J Clin Neurol.  2008 Sep;4(3):99-106. 10.3988/jcn.2008.4.3.99.

Cognitive Effects of Antiepileptic Drugs

• Park SP
• Kwon SH

• KMID: 2287672
• DOI: http://doi.org/10.3988/jcn.2008.4.3.99

Abstract

Antiepileptic drugs (AEDs) can adversely affect cognitive function by suppressing neuronal excitability or enhancing inhibitory neurotransmission. The main cognitive effects of AEDs are impaired attention, vigilance, and psychomotor speed, but secondary effects can manifest on other cognitive functions. Although the long-term use of AEDs can obviously elicit cognitive dysfunction in epilepsy patients, their cognitive effects over short periods of up to a year are inconclusive due to methodological problems. In general, the effects on cognition are worse for older AEDs (e.g., phenobarbital) than for placebo, nondrug condition, and newer AEDs. However, topiramate is the newer AED that has the greatest risk cognitive impairment irrespective of the comparator group. Since the cognitive impact of AEDs can be serious, clinicians should be alert to adverse events by evaluating cognitive function using screening tests. Adverse cognitive events of AEDs can be avoided by slow titration to the lowest effective dosage and by avoiding polytherapy.

Keyword

Cognition; Antiepileptic drug; Adverse event

MeSH Terms

Anticonvulsants
Cognition
Epilepsy
Fructose
Humans
Mass Screening
Neurons
Synaptic Transmission
Anticonvulsants
Fructose

Reference

1. Motamedi G, Meador K. Epilepsy and cognition. Epilepsy Behav. 2003. 4:Suppl 2. S25–S38.

2. Aldenkamp AP, De Krom M, Reijs R. Newer antiepileptic drugs and cognitive issues. Epilepsia. 2003. 44:Suppl 4. S21–S29.

3. Ortinski P, Meador KJ. Cognitive side effects of antiepileptic drugs. Epilepsy Behav. 2004. 5:Suppl 1. S60–S65.

4. Meador KJ. Cognitive outcomes and predictive factors in epilepsy. Neurology. 2002. 58:S21–S26.

5. Bourgeois BF. Determining the effects of antiepileptic drugs on cognitive function in pediatric patients with epilepsy. J Child Neurol. 2004. 19:Suppl 1. S15–S24.

6. Loring DW, Marino S, Meador KJ. Neuropsychological and behavioral effects of antiepilepsy drugs. Neuropsychol Rev. 2007. 17:413–425.

7. Carpay JA, Aldenkamp AP, van Donselaar CA. Complaints associated with the use of antiepileptic drugs: results from a community-based study. Seizure. 2005. 14:198–206.

8. Loring DW, Meador KJ. Cognitive side effects of antiepileptic drugs in children. Neurology. 2004. 62:872–877.

9. Holmes GL. Epilepsy in the developing brain: lessons from the laboratory and clinic. Epilepsia. 1997. 38:12–30.

10. Garrard J, Harms S, Hardie N, Eberly LE, Nitz N, Bland P, et al. Antiepileptic drug use in nursing home admissions. Ann Neurol. 2003. 54:75–85.

11. Smith DB, Mattson RH, Cramer JA, Collins JF, Novelly RA, Craft B. Results of a nation-wide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone. Epilepsia. 1987. 28:Suppl 3. S50–S58.

12. Prevey ML, Delaney RC, Cramer JA, Cattanach L, Collins JF, Mattson RH. The Department of Veterans Affairs Epilepsy Cooperative Study 264 Group. Effect of valproate on cognitive functioning. Comparison with carbamazepine. Arch Neurol. 1996. 53:1008–1016.

13. Pulliainen V, Jokelainen M. Effects of phenytoin and carbamazepine on cognitive functions in newly diagnosed epileptic patients. Acta Neurol Scand. 1994. 89:81–86.

14. Meador KJ, Loring DW, Allen ME, Zamrini EY, Moore EE, Abney OL, et al. Comparative cognitive effects of carbamazepine and phenytoin in healthy adults. Neurology. 1991. 41:1537–1540.

15. Meador KJ, Loring DW, Moore EE, Thompson WO, Nichols ME, Oberzan RE, et al. Comparative cognitive effects of phenobarbital, phenytoin, and valproate in adults subjects. Neurology. 1995. 45:1494–1499.

16. Tonekaboni SH, Beyraghi N, Tahbaz HS, Bahreynian SA, Aghamohammadpoor M. Neurocognitive effects of phenobarbital discontinuation in epileptic children. Epilepsy Behav. 2006. 8:145–148.

17. Chadwick DW, Anhut H, Greiner MJ, Alexander J, Murray GH, Garofalo EA, et al. International Gabapentin Monotherapy Study Group 945-77. A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. Neurology. 1998. 51:1282–1288.

18. Leach JP, Girvan J, Paul A, Brodie MJ. Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy. J Neurol Neurosurg Psychiatry. 1997. 62:372–376.

19. Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Nichols ME, et al. Differential cognitive effects of carbamazepine and gabapentin. Epilepsia. 1999. 40:1279–1285.

20. Salinsky MC, Binder LM, Oken BS, Storzbach D, Aron CR, Dodrill CB. Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers. Epilepsia. 2002. 43:482–490.

21. Mortimore C, Trimble M, Emmers E. Effects of gabapentin on cognition and quality of life in patients with epilepsy. Seizure. 1998. 7:359–364.

22. Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Perrine KR, et al. Differential cognitive and behavioral effects of carbamazepine and lamotrigine. Neurology. 2001. 56:1177–1182.

23. Aldenkamp AP, Arends J, Bootsma HP, Diepman L, Hulsman J, Lambrechts D, et al. Randomized double-blind parallel-group study comparing cognitive effects of a low-dose lamotrigine with valproate and placebo in healthy volunteersa. Epilepsia. 2002. 43:19–26.

24. Cohen AF, Ashby L, Crowley D, Land G, Peck AW, Miller AA. Lamotrigine (BW430C), a potential anticonvulsant: Effects on the central nervous system in comparison with phenytoin and diazepam. Br J Clin Pharmacol. 1985. 20:619–629.

25. Hamilton MJ, Cohen AF, Yuen AW, Harkin N, Land G, Weatherley BC, et al. Carbamazepine and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage. Epilepsia. 1993. 34:166–173.

26. Placidi F, Marciani MG, Diomedi M, Scalise A, Pauri F, Giacomini P, et al. Effects of lamotrigine on nocturnal sleep, daytime somnolence and cognitive functions in focal epilepsy. Acta Neurol Scand. 2000. 102:81–86.

27. Smith D, Baker G, Davies G, Dewey M, Chadwick DW. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia. 1993. 34:312–322.

28. Pressler RM, Binnie CD, Coleshill SG, Chorley GA, Robinson RO. Effect of lamotrigine on cognition in children with epilepsy. Neurology. 2006. 66:1495–1499.

29. Kang KH, Lee JM, Lee HW, Jung DK, Suh CK, Kwon SH, et al. Cognitive profiles of lamotrigine in epilepsy patients: a comparative study with valproate. J Korean Epilepsy Soc. 2006. 10:146–152.

30. Seo JG, Lee DI, Hwang YH, Lee HW, Jung DK, Suh CK, et al. Comparison of cognitive effects of lamotrigine and oxcarbazepine in epilepsy patients. J Clin Neurol. 2007. 3:31–37.

31. Sabers A, Møller A, Dam M, Smed A, Arlien-Søborg P, Buchman J, et al. Cognitive function and anticonvulsant therapy: effect of monotherapy in epilepsy. Acta Neurol Scand. 1995. 92:19–27.

32. Aikiä M, Kälviäinen R, Sivenius J, Halonen T, Riekkinen PJ. Cognitive effects of oxcarbazepine and phenytoin monotherapy in newly diagnosed epilepsy: one year follow-up. Epilepsy Res. 1992. 11:199–203.

33. Park SP, Hwang YH, Kim JI, Kim JY, Kwon SH, Jung BW, et al. Cognitive function in epileptic patients treated with oxcarbazepine: neuropsychologic test and event-related potential. J Korean Neurol Assoc. 2002. 20:27–33.

34. Salinsky MC, Spencer DC, Oken BS, Storzbach D. Effects of oxcarbazepine and phenytoin on the EEG and cognition in healthy volunteers. Epilepsy Behav. 2004. 5:894–902.

35. Donati F, Gobbi G, Campistol J, Rapatz G, Daehler M, Sturm Y, et al. Effects of oxcarbazepine on cognitive function in children and adolescents with partial seizures. Neurology. 2006. 67:679–682.

36. Donati F, Gobbi G, Campistol J, Rapatz G, Daehler M, Sturm Y, et al. The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures. Seizures. 2007. 16:670–679.

37. Mula M, Trimble MR, Thompson P, Sander JW. Topiramate and word-finding difficulties in patients with epilepsy. Neurology. 2003. 60:1104–1107.

38. Lee S, Sziklas V, Andermann F, Farnham S, Risse G, Gustafson M, et al. The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilepsia. 2003. 44:339–347.

39. Kockelmann E, Elger CE, Helmstaedter C. Significant improvement in frontal lobe associated neuropsychological functions after withdrawal of topiramate in epilepsy patients. Epilepsy Res. 2003. 54:171–178.

40. Fritz N, Glogau S, Hoffmann J, Rademacher M, Elger CE, Helmstaedter C. Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy. Epilepsy Behav. 2005. 6:373–381.

41. Meador KJ, Loring DW, Hulihan JF, Kamin M, Karim R. CAPSS-027 Study Group. Differential cognitive and behavioral effects of topiramate and valproate. Neurology. 2003. 60:1483–1488.

42. Meador KJ, Loring DW, Vahle VJ, Ray PG, Werz MA, Fessler AJ, et al. Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers. Neurology. 2005. 64:2108–2114.

43. Salinsky MC, Storzbach D, Spencer DC, Oken BS, Landry T, Dodrill CB. Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers. Neurology. 2005. 64:792–798.

44. Blum D, Meador K, Biton V, Fakhoury T, Shneker B, Chung S, et al. Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy. Neurology. 2006. 67:400–406.

45. Kim SY, Lee HW, Jung DK, Suh CK, Park SP. Cognitive effects of low-dose topiramate compared with oxcarbazepine in epilepsy patients. J Clin Neurol. 2006. 2:126–133.

46. Lee HW, Jung DK, Suh CK, Kwon SH, Park SP. Cognitive effects of low-dose topiramate monotherapy in epilepsy patients: A 1-year follow-up. Epilepsy Behav. 2006. 8:736–741.

47. Park SP, Jung DK. Topiramate related cognitive dysfunction during migraine prevention. J Korean Neurol Assoc. 2005. 23:55–61.

48. Kang HC, Eun BL, Lee C Wu, Moon H Ku, Kim JS, D Wook Kim, et al. The effects on cognitive function and behavioral problems of topiramate compared to carbamazepine as monotherapy for children with benign rolandic epilepsy. Epilepsia. 2007. 48:1716–1723.

49. Dodrill CB, Arnett JL, Sommerville KW, Shu V. Cognitive and quality of life effects of differing dosages of tiagabine in epilepsy. Neurology. 1997. 48:1025–1031.

50. Aikiä M, Jutila L, Salmenperä T, Mervaala E, Kälviäinen R. Comparison of the cognitive effects of tiagabine and carbamazepine as monotherapy in newly diagnosed adult patients with partial epilepsy: pooled analysis of two long-term, randomized, follow-up studies. Epilepsia. 2006. 47:1121–1127.

51. Dodrill CB, Arnett JL, Sommerville KW, Sussman NM. Evaluation of the effects of vigabatrin on cognitive abilities and quality of life in epilepsy. Neurology. 1993. 43:2501–2507.

52. Kälviäinen R, Aikiä M, Saukkonen AM, Mervaala E, Riekkinen PJ Sr. Vigabatrin vs carbamazepine monotherapy in patients with newly diagnosed epilepsy. A randomized, controlled study. Arch Neurol. 1995. 52:989–996.

53. Berent S, Sackellares JC, Giordani B, Wagner JG, Donofrio PD, Abou-Khalil B. Zonisamide (CI-912) and cognition: results from preliminary study. Epilepsia. 1987. 28:61–67.

54. Wilensky AJ, Friel PN, Ojemann LM, Dodrill CB, McCormick KB, Levy RH. Zonisamide in epilepsy: a pilot study. Epilepsia. 1985. 26:212–220.

55. Park SP, Kim SY, Hwang YH, Lee HW, Suh CK, Kwon SH. Long-term efficacy and safety of zonisamide monotherapy in epilepsy patients. J Clin Neurol. 2007. 3:175–180.

56. Park SP, Hwang YH, Lee HW, Suh CK, Kwon SH, Lee BI. Long-term cognitive and mood effects of zonisamide monotherapy in epilepsy patients. Epilepsy Behav. 2008. 12:102–108.

57. Hindmarch I, Trick L, Ridout F. A double-blind, placebo- and positive-internal-controlled (alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers. Psychopharmacology (Berl). 2005. 183:133–143.

58. Ciesielski AS, Samson S, Steinhoff BJ. Neuropsychological and psychiatric impact of add-on titration of pregabalin versus levetiracetam: a comparative short-term study. Epilepsy Behav. 2006. 9:424–431.

59. Meador KJ, Gevins A, Loring DW, McEvoy LK, Ray PG, Smith ME, et al. Neuropsychological and neurophysiologic effects of carbamazepine and levetiracetam. Neurology. 2007. 69:2076–2084.

60. Gomer B, Wagner K, Frings L, Saar J, Carius A, Härle M, et al. The influence of antiepileptic drugs on cognition: a comparison of levetiracetam with topiramate. Epilepsy Behav. 2007. 10:486–494.