Skip to main content

Advertisement

SpringerLink
Log in

Neurodevelopmental Effects of Antiepileptic Drugs

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical periods of development may induce transient or long-lasting neurodevelopmental deficits across cognitive, motor and behavioral domains. The developing nervous system may endure prolonged chronic exposure to AEDs during pregnancy (in utero) or during childhood, which can lead to neurodevelopmental defects such as congenital neural tube defects, lower IQ, language deficits, autism and ADHD. To date, valproate is the most widely recognized AED to significantly negatively affect neurodevelopment, and demonstrates greater adverse effects than any other AEDs that have been assessed. Although some AEDs appear to have low risk (i.e., lamotrigine, levetiracetam), other AEDs have been implicated in a variety of studies detailed below, and many AEDs have not been adequately assessed. The purpose of this review article is to summarize our current understanding of the neurodevelopmental effects of AEDs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Levy R, Mattson R, Meldrum B, Perucca E (2002) Antiepileptic drugs. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  2. Meador KJ, Loring DW (2016) Developmental effects of antiepileptic drugs and the need for improved regulations. Neurology 86:297–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lagae L (2016) The importance of assessing behaviour and cognition in antiepileptic drug trials in children and adolescents. Acta Neurol Belg. doi:10.1007/s13760-016-0734-y

    PubMed  Google Scholar 

  4. Bath KG, Scharfman HE (2013) Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research. Epilepsy Behav 26:427–439

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bittigau P et al (2002) Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci 99:15089–15094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Forcelli PA, Kim J, Kondratyev A, Gale K (2011) Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain. Epilepsia 52:e207–e211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yanai J et al (1989) Neural and behavioral alterations after early exposure to phenobarbital. Neurotoxicology 10:543–554

    CAS  PubMed  Google Scholar 

  8. Morte MI et al (2013) Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons. Toxicol In Vitro 27:2193–2202

    Article  CAS  PubMed  Google Scholar 

  9. Ikonomidou C et al (2000) Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287:1056–1060

    Article  CAS  PubMed  Google Scholar 

  10. Velez-Ruiz NJ, Meador KJ (2015) Neurodevelopmental effects of fetal antiepileptic drug exposure. Drug Saf 38:271–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Forcelli PA, Kozlowski R, Snyder C, Kondratyev A, Gale K (2012) Effects of neonatal antiepileptic drug exposure on cognitive, emotional, and motor function in adult rats. J Pharmacol Exp Ther 340:558–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Verrotti A, Scaparrotta A, Cofini M, Chiarelli F, Tiboni GM (2014) Developmental neurotoxicity and anticonvulsant drugs: a possible link. Reprod Toxicol 48:72–80

    Article  CAS  PubMed  Google Scholar 

  13. Halbsgut LR, Fahim E, Kapoor K, Hong H, Friedman LK (2013) Certain secondary antiepileptic drugs can rescue hippocampal injury following a critical growth period despite poor anticonvulsant activity and cognitive deficits. Epilepsy Behav 29:466–477

    Article  PubMed  Google Scholar 

  14. AED Pregnancy Registry (2016) http://www.aedpregnancyregistry.org/. Accessed 29 Dec 2016

  15. Meador KJ et al (2006) In utero antiepileptic drug exposure: fetal death and malformations. Neurology 67:407–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Meador KJ et al (2013) Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 12:244–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Meadow SR (1968) Anticonvulsant drugs and congenital abnormalities. Lancet Lond Engl 2:1296

    Article  CAS  Google Scholar 

  18. Weston J et al (2016) Cochrane database of systematic reviews. Wiley, Hoboken

    Google Scholar 

  19. Harden CL et al (2009) Management issues for women with epilepsy: focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes. Epilepsia 50:1237–1246

    Article  PubMed  Google Scholar 

  20. Bromley R et al (2014) Cochrane database of systematic reviews. Wiley, Hoboken

    Google Scholar 

  21. Baker GA et al (2015) IQ at 6 years after in utero exposure to antiepileptic drugs a controlled cohort study. Neurology 84:382–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bromley RL et al (2010) Early cognitive development in children born to women with epilepsy: a prospective report. Epilepsia 51:2058–2065

    Article  PubMed  Google Scholar 

  23. Rihtman T, Parush S, Ornoy A (2013) Developmental outcomes at preschool age after fetal exposure to valproic acid and lamotrigine: cognitive, motor, sensory and behavioral function. Reprod Toxicol 41:115–125

    Article  CAS  PubMed  Google Scholar 

  24. Nadebaum C et al (2011) Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology 76:719–726

    Article  CAS  PubMed  Google Scholar 

  25. Donegan S, Dixon P, Hemming K, Tudur-Smith C, Marson A (2015) A systematic review of placebo-controlled trials of topiramate: how useful is a multiple-indications review for evaluating the adverse events of an antiepileptic drug? Epilepsia 56:1910–1920

    Article  CAS  PubMed  Google Scholar 

  26. Videman M et al. (2016) Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs. Epilepsy Behav 64:62–68

    Article  PubMed  Google Scholar 

  27. Meador KJ et al (2011) Relationship of child IQ to parental IQ and education in children with fetal antiepileptic drug exposure. Epilepsy Behav 21:147–152

    Article  PubMed  PubMed Central  Google Scholar 

  28. Inoyama K, Meador KJ (2015) Cognitive outcomes of prenatal antiepileptic drug exposure. Epilepsy Res 114:89–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Adab N et al (2004) The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 75:1575–1583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bromley RL et al (2013) The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry 84:637–643

    Article  PubMed  PubMed Central  Google Scholar 

  31. Christensen J et al (2013) Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309:1696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wood AG et al (2015) Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia 56:1047–1055

    Article  CAS  PubMed  Google Scholar 

  33. Cohen MJ et al (2013) Fetal antiepileptic drug exposure: adaptive and emotional/behavioral functioning at age 6years. Epilepsy Behav 29:308–315

    Article  PubMed  PubMed Central  Google Scholar 

  34. Glauser TA et al (2010) Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 362:790–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Veiby G, Bjørk M, Engelsen BA, Gilhus NE (2015) Epilepsy and recommendations for breastfeeding. Seizure 28:57–65

    Article  PubMed  Google Scholar 

  36. Veiby G et al (2013) Exposure to antiepileptic drugs in utero and child development: a prospective population-based study. Epilepsia 54:1462–1472

    Article  PubMed  PubMed Central  Google Scholar 

  37. Meador KJ et al (2014) Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years. JAMA Pediatr 168:729–736

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Mail Code 120, Portland, OR, 97239-3098, USA

    Marissa Kellogg

  2. Department of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA

    Kimford J. Meador

Authors
  1. Marissa Kellogg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimford J. Meador
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marissa Kellogg.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kellogg, M., Meador, K.J. Neurodevelopmental Effects of Antiepileptic Drugs. Neurochem Res 42, 2065–2070 (2017). https://doi.org/10.1007/s11064-017-2262-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-017-2262-4

Keywords

Search

Navigation