ReviewNeurodevelopmental effects of anti-epileptic drugs
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.
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2015, SeizureCitation Excerpt :The development of children with symptomatic epilepsy starting in the neonatal period or during infancy often tends to take a detrimental course. In part this is due to the underlying brain pathology, but the effects of AED treatment and ongoing seizure activity are also considered to have an influence [23,24]. The relative impacts of these factors vary depending on the condition and even though there is not yet any decisive data on the long-term effects of AED treatment on the developing brain, freedom from both seizures and medication is desirable.
Antiepileptic drugs
2012, Side Effects of Drugs AnnualCitation Excerpt :However, one cannot exclude the possibility that in some patients with epilepsy with a genetic predisposition to cardiac dysrhythmias, the effects of seizures (mainly tonic–clonic seizures) on the repolarization cycle of the heart, and the concomitant effects of some antiepileptic drugs, might cause life-threatening dysrhythmias and possibly SUDEP. Nervous system The neurocognitive effects of antiepileptic drugs, in the developing brains of unborn children when they are given to mothers with epilepsy and in children with epilepsy, have been reviewed [48R,49R]. Antiepileptic drug-induced encephalopathies have been reviewed [50R].