ReviewAntiepileptic drugs and brain development
Introduction
Epilepsy affects 1–2% of humans worldwide and has a peak incidence in the first year of life (Hauser, 1994). Antiepileptic drugs (AEDs) are used to prevent epileptic seizures. They interact with ion channels, metabolic enzymes, neurotransmitter receptors and transporters in the brain, modify bursting properties of neurons, inhibit spread of epileptic activity and reduce synchronization (Rogawski and Löscher, 2004).
AEDs are among the most common causes of fetal malformations. These include neural tube defects, congenital heart defects, orofacial clefts, digital anomalies, growth retardation, developmental delay and microcephaly (Buehler et al., 1990, Holmes et al., 2001, Jones et al., 1989, Meador et al., 2006, Speidel and Meador, 1972, Strickler et al., 1985, Zahn, 1998). Teratogenic effects have been associated with the use of phenytoin, carbamazepine, valproate and phenobarbital. Increasing maternal blood levels and combinations of AEDs impose an increased risk for human infants (Zahn, 1998). More recent reports also show an increased risk of cleft palate and other malformations with lamotrigine (Holmes et al., 2006, Shor et al., 2007) and carbamazepine (Hernandez-Diaz et al., 2007), but these results could not be confirmed by other investigators (Dolk et al., 2008). Increased risk across malformations for higher doses of lamotrigine was reported by Morrow et al. (2006), however, this dose effect could not be confirmed in two other studies (Cunnington and Tennis, 2005, Holmes et al., 2006).
Cognitive function in children exposed in utero to AEDs has also been investigated. Several studies are reporting that in utero exposure to AEDs increases the risk of cognitive dysfunction later in life (Marsh et al., 2006, Meador et al., 2007, Nicolai et al., 2008, Titze et al., 2008, Vinten et al., 2005).
Section snippets
Susceptibility of the developing brain to environmental agents
Although brain growth varies among mammals, comparisons of brain development between species are possible (Bayer et al., 1993, Passingham, 1985). The developmental ages of human and rat embryos or fetuses are comparable when anatomical features and histological landmarks are similar in appearance in the two species, even though their exact chronological ages are different (Bayer et al., 1993, Rice and Barone, 2000). Table 1, Table 2, Table 3 illustrate timelines of developmental events in the
Adverse effects of AEDs in animal studies
Phenobarbital is the oldest antiepileptic drug available. Adverse effects of phenobarbital on brain growth and behavior have been studied extensively (Bergman et al., 1982, Fishman et al., 1983, Roger-Fuchs et al., 1992). Perinatal exposure to phenobarbital (15–60 mg/kg) can reduce brain weight (Diaz and Schain, 1978), causes a reduction of Purkinje and granule cells in the cerebellum (Yanai et al., 1989) and pyramidal and granule cells in the hippocampus (Pick and Yanai, 1985). Phenobarbital
AEDs cause neuronal apoptosis in the developing brain
Physiological cell death, a process by which redundant or unsuccessful neurons are deleted by apoptosis (cell suicide) from the developing central nervous system, has been recognized as a regular phenomenon in the developing brain. Is has been shown that compounds which are used as sedatives, anesthetics or anticonvulsants in medicine, trigger widespread apoptotic neurodegeneration throughout the developing brain when administered to immature rodents (Bittigau et al., 2002, Ikonomidou et al.,
Influence of antiepileptic drugs on other developmental processes
In addition to their proapoptotic effects in the developing brain, AEDs may also impair cell proliferation and differentiation, synaptogenesis, synaptic plasticity, cell migration and axonal arborization. A disruption of these developmental processes may potentially account for neurological deficits seen in humans exposed to AEDs pre- or postnatally. Unfortunately, the effects of AEDs on these processes in the developing brain have not been systematically analyzed.
Brain morphology following prenatal exposure to antiepileptic drugs
In a recent study, morphological changes in the brains of subjects exposed in utero to AEDs were analysed. For this purpose, a group of healthy young adults with prenatal exposure to AEDs and a group of age-matched unexposed healthy controls were subjected to magnetic resonance imaging (MRI) of the brain and structural differences between the two groups were studied by means of voxel based morphometry (Ikonomidou et al., 2007).
Regional decreases of grey matter volumes were found in subjects
Conclusions and relevance for the clinic
The experimental data presented in this review demonstrate that AEDs may alter normal brain development by influencing cell proliferation, neurogenesis, migration, programmed cell death, synaptogenesis, synaptic plasticity and possibly myelination in the developing brain. Due to the fact that AEDs can influence so many different processes in the context of brain morphogenesis and network formation, various adverse effects can be elicited when exposure occurs during a broad age range which
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