Elsevier

Epilepsy Research

Volume 88, Issue 1, January 2010, Pages 1-10
Epilepsy Research

Review
Neurodevelopmental effects of anti-epileptic drugs

https://doi.org/10.1016/j.eplepsyres.2009.08.015Get rights and content

Summary

Use of medication with a desired effect on the central nervous system (as with anti-epileptic drugs) in children will undoubtedly cause concern about neurodevelopment. Data are emerging to suggest an effect of anticonvulsants on the developing brain of the unborn child when administered to mothers with epilepsy. This obviously requires detailed evaluation, especially when considering the risks of epilepsy itself. In the child with epilepsy, many of the early onset epilepsies are associated with developmental compromise as part of their clinical profile, and therefore determining the relative effects of the underlying cause, seizures and medication can be difficult. Although data are available with regard to some anti-epileptic drugs (AEDs) they remain lacking particularly in the very young with regard to efficacy as well as neurodevelopmental effects of the newer anti-epileptic drugs. Ongoing evaluation is required to ensure the best clinical practice in each individual.

Introduction

The choice of anti-epileptic drug in the management of epilepsy in childhood is based on the predominant seizure type and where possible the epilepsy syndrome. Whilst the underlying aetiology is a major contributor to cognitive outcome, the presumption in early onset epilepsy is that developmental compromise may be associated with ongoing seizure activity, seen or unseen, so called ‘epileptic encephalopathy’. If this is the case, then treatment of the epilepsy should lead to improved developmental outcome. The natural history of many of the seizure disorders is, however, poorly understood; there is some evidence to suggest that children with longstanding epilepsy make little developmental progress and therefore have an intellectual quotient (IQ) that appears to fall over time. The difficulty we have therefore is that the cause of the developmental compromise is likely to be multifactorial in origin. The extent to which the effects of the anti-epileptic medication might contribute is essentially unknown and likely to vary according to the drug used, the requirement for polypharmacy and individual differences in sensitivity. Of course, the effects of anti-epileptic drugs may not only be seen in the developing child, but also in the unborn child of mothers taking these medications through pregnancy.

Section snippets

Anti-epileptic drug use during pregnancy—the effect on the foetal brain

Exposure to anti-epileptic drugs (AEDs) during pregnancy is associated with an increased risk of congenital malformations and may have an adverse effect on foetal growth and psychomotor development. The first report of a malformation thought to be the result of phenytoin exposure was in 1963 (Mullers-Kuppers, 1963). Subsequently a retrospective survey concluded that congenital malformations were twice as common in infants of mothers on AEDs (Speidel and Meadow, 1972) as in a non-exposed

Anti-epileptic drug use during the neonatal period

The neonatal period (<28 days) has the highest incidence of epileptic seizures throughout the life span (1.8–3.5/1000 life births) (Hauser et al., 1993). Despite the increasing number of AEDs now available to us generally, we still remain relatively limited in our choice of medication in this age range. A Cochrane Review concluded that there is little evidence to support the use of any of the anticonvulsants currently used in the neonatal period with regard to efficacy (Booth and Evans, 2004).

Anti-epileptic drug use during infancy

Outside the neonatal period, the incidence of epilepsy also remains high in the first year of life. Most published series document poor long-term outcome with continuing seizures and neurodevelopmental impairment in 40–60% (Battaglia et al., 1999, Cavazzuti et al., 1984, Chevrie and Aicardi, 1978, Chevrie and Aicardi, 1979, Czochanska et al., 1994, Matsumoto et al., 1983). Etiologies encompass a wide spectrum of developmental brain malformations, acquired brain injuries, genetic and metabolic

Use of anti-epileptic drugs in the older child

As outlined certain epilepsy syndromes are associated with developmental compromise with onset under the age of 5 years; but some degree of epileptic encephalopathy, however, may also be seen in certain syndromes presenting in older children. Although the effects of seizures are believed to have the most effect in the younger age group (Muter et al., 1997) susceptibility may be seen up to 5–6 years of age with certain syndromes presenting with developmental regression alongside catastrophic

Other alternatives to conventional AED's are also available.

The ketogenic diet, a high fat diet low in carbohydrate designed to mimic the effects of starvation, has been shown to be effective in the treatment of seizures resistant to anticonvulsants in older children (Neal et al., 2008). There is increasing evidence that it may be more effective in the younger age group, and should be considered earlier in the clinical course of the epilepsy (Kossoff et al., 2002, Kossoff et al., 2008, Nordli et al., 2002). Again however randomised controlled data is

Conclusions

There will always remain particular concern about the effects of medication on a developing child. This is especially pertinent at times of rapid brain development with regard to drugs primarily targeted at epileptic seizures, both in utero and in early childhood. There is evidence that certain AEDs may have an effect at particular times of exposure although the relative effects of the seizures, underlying aetiology and AEDs are unclear. Whenever the exposure, there is some evidence that some

Conflict of interest

Professor JH Cross has received educational grants and honoraria for educational talks from UCB, Janssen Cilag, Eisai and SHS International. She is a Clinical Advisor to the review of the NICE epilepsy guidelines.

Acknowledgement

UCL Institute of Child Health receives funding as a National Institute for Health & Research Specialist Biomedical Research Centre.

References (85)

  • V. Muter et al.

    A longitudinal study of early intellectual development in hemiplegic children

    Neuropsychologia

    (1997)
  • E.G. Neal et al.

    The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial

    Lancet Neurol.

    (2008)
  • B.D. Speidel et al.

    Maternal epilepsy and abnormalities of the fetus and newborn

    Lancet

    (1972)
  • B. Zhou et al.

    Effects of levetiracetam as an add-on therapy on cognitive function and quality of life in patients with refractory partial seizures

    Epilepsy Behav.

    (2008)
  • N. Adab et al.

    Additional educational needs in children born to mothers with epilepsy

    J. Neurol. Neurosurg. Psychiatry

    (2001)
  • N. Adab et al.

    The longer term outcome of children born to mothers with epilepsy

    J. Neurol. Neurosurg. Psychiatry

    (2004)
  • J. Aicardi et al.

    Vigabatrim as initial therapy for infantile spasms: a European Retrospective Survey. Sabril IS Investigator and Peer Review Groups

    Epilepsia

    (1996)
  • A.P. Aldenkamp et al.

    A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures

    Epilepsia

    (2000)
  • A.P. Aldenkamp et al.

    Newer antiepileptic drugs and cognitive issues

    Epilepsia

    (2003)
  • M. Artama et al.

    Antiepileptic drug use of women with epilepsy

    Neurology

    (2005)
  • Booth, D., Evans, D.J., 2004. Anticonvulsants for neonates with seizures. Cochrane Database of Systematic Reviews,...
  • G.B. Boylan et al.

    Outcome of electroclinical, electrographic, and clinical seizures in the newborn infant

    Dev. Med. Child Neurol.

    (1999)
  • G.B. Boylan et al.

    Phenobarbitone, neonatal seizures, and video-EEG

    Arch. Dis. Child Fetal Neonatal Ed.

    (2002)
  • R. Canger et al.

    Malformations in offspring of women with epilepsy: a prospective study

    Epilepsia

    (1999)
  • G.B. Cavazzuti et al.

    Follow-up study of 482 cases with convulsive disorders in the first year of life

    Dev. Med. Child Neurol.

    (1984)
  • J.J. Chevrie et al.

    Convulsive disorders in the first year of life: neurological and mental outcome and mortality

    Epilepsia

    (1978)
  • J.J. Chevrie et al.

    Convulsive disorders in the first year of life: persistence of epileptic seizures

    Epilepsia

    (1979)
  • J. Czochanska et al.

    Children who develop epilepsy in the first year of life: a prospective study

    Dev. Med. Child Neurol.

    (1994)
  • J.H. Diliberti et al.

    The foetal valproate syndrome

    Am. J. Med. Genet.

    (1984)
  • V.I. Dzhala et al.

    NKCC1 transporter facilitates seizures in the developing brain

    Nat. Med.

    (2005)
  • European Union 2006 Regulation (EC) No. 1901/2006 of the European Parliament and of the Council on medicinal products...
  • J.J. Engel

    a proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on classification and terminology

    Epilepsia

    (2001)
  • J.R. Farwell et al.

    Phenobarbitol for febrile seizures—effects on intelligence and on seizure recurrence

    N. Engl. J. Med.

    (1990)
  • E. Gaily et al.

    Normal intelligence in children with prenatal exposure to carbamazepine

    Neurology

    (2004)
  • C. Giraud et al.

    In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism

    Drug Metab. Dispos.

    (2006)
  • M.L. Granstrom et al.

    Psychomotor development in children of mothers with epilepsy

    Neurology

    (1992)
  • R. Guerrini et al.

    Lamotrigine and seizure aggravation in severe myoclonic epilepsy

    Epilepsia

    (1998)
  • T. Hallbrook et al.

    Effects of ketogenic diet on epileptiform activity in children with therapy resistant epilepsy

    Epilepsy Res.

    (2007)
  • Hancock, E., Osborne, J., 2004. The treatment of infantile spasms (Cochrane Review). The Cochrane Library Issue 2;...
  • L.A. Harkin et al.

    The spectrum of SCN1A-related infantile epileptic encephalopathies

    Brain

    (2007)
  • W.A. Hauser et al.

    Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984

    Epilepsia

    (1993)
  • L.B. Holmes et al.

    The antiepileptic drug pregnancy registry: a 6-year experience

    Arch. Neurol.

    (2004)
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