ANTI-EPILEPTIC DRUGS AND BRAIN AND BEHAVIOURAL DEVELOPMENT IN ANIMAL MODELS AND HUMANS

Abstract

Women with epilepsy constitute about 0.6% of pregnancies. The potential for major structural malformations following gestational exposure to anti-epileptic drugs (AEDs) is well known and causes concern as how best to manage epilepsy during pregnancy. In this review we focus on the structural and functional effects on the developing brain to complement other recent reviews. We do not cover neural tube defects which have been reviewed elsewhere. Suffice to say that carbamazepine, lamotrigine and, in particular, valproate exposure are associated with them. We discuss studies based on animal models as well as those that have followed-up children exposed to AEDs in-utero. Careful longitudinal human research can document the cognitive and behavioural effects, but the long time scales required and inability to rule out confounding variables, both genetic and environmental, are serious limitations. Animal studies are based on the assumption that many developmental processes are conserved between the animals used in the models (most often rodents) and humans. However, the hugely expanded cortex and cognitive and behavioural repertoire of humans implies that there are aspects that can not be well modelled. In addition, due to differences in how susceptible different species are to various teratogens, studies always need to be done in man as well. Nevertheless, an understanding of the molecular mechanisms of neuro-teratogenesis derived from animal models will help us predict which anti-epileptic drugs are likely to cause fewer neuro-developmental problems in humans.