Neurodevelopmental Effects

Eija Gaily

Kimford J. Meador

Introduction

The increased risk of major malformations after prenatal exposure to antiepileptic drugs (AEDs) has been established by research extending over three decades (see Chapter 110). The neurodevelopmental effects of in utero exposure to AEDs have not been as extensively investigated as AED-induced somatic abnormalities. This may be because the assessment of functional outcomes is more complicated and time consuming than major malformations that are usually detected at birth and are less affected by confounding factors.

Teratogens interact with genotype to produce both anatomic and behavioral defects. Whether a defect occurs depends on a susceptible genotype and may involve the interaction of multiple-liability genes.³⁰ The mechanism of anatomic and behavioral teratogenesis may well differ since it appears that the highest risk of anatomic defects is from first-trimester AED exposure, while the highest risk of behavioral defects appears to be from exposure during the third trimester, when neuronal migration and synaptic organization occur.⁷⁶

Animal studies have clearly demonstrated that prenatal AED exposure can produce behavioral as well as anatomic defects. In contrast to somatic malformations in animals, which usually require AED dosages several times above human therapeutic dosages, behavioral impairments can occur at lower dosages and at blood levels similar to human therapeutic levels.³¹^,⁴²

The first report of mental deficiency after prenatal AED exposure in children with typical minor anomalies but no major malformation was published in 1975.¹⁸ After that, a number of studies have investigated the relationship between typical minor anomalies and cognitive impairment in AED-exposed children, and several antiepileptic drug syndromes have been proposed. More recent studies have also addressed the question of whether prenatal antiepileptic drug exposure increases the risk of cognitive impairment even in the absence of detectable anatomic teratogenesis.

Animal Data

Behavioral Data for Individual Antiepileptic Drugs

Benzodiazepines

Neonatal benzodiazepine exposure produces widespread apoptotic neuronal cell death in rats (see Mechanism section). Gestational or neonatal exposure to benzodiazepines can affect brain chemistry and behavior.¹⁸ For example, diazepam can affect behavior differentially depending on the stage of development at which the exposure occurs. Midgestation exposure causes transient hyperactivity but no learning or retention deficits on a choice discrimination task. Late prenatal exposure caused no hyperactivity but resulted in poor learning and retention. Early postnatal exposure resulted in lasting hyperactivity as well as learning and retention deficits.³⁴

Carbamazepine

Despite the common use of carbamazepine in humans, very few neurobehavioral studies in animals have been published. In utero carbamazepine exposure did not produce hyperexcitability in primates, unlike phenytoin.⁷⁰ A preliminary report found that neonatal rats dosed with carbamazepine slightly above the ED50 for anticonvulsant action produced widespread neuronal apoptosis similar to several other AEDs⁴⁹ (see Mechanism section).

Phenobarbital

Perinatal phenobarbital exposure in rats reduces brain weight.²¹ Phenobarbital causes apoptotic neuronal cell death in neonatal rats (see Mechanism section). Mice exposed prenatally to phenobarbital have neuronal deficits, reduced brain weight, impaired development of reflexes, open-field activity, schedule-controlled behavior, spatial learning, and catecholamine brain levels.³²^,⁵⁷^,⁶¹^,⁶²^,¹⁰³^,¹⁰⁴ Rats that had seizures induced by kainic acid as neonates exhibited deficits in water maze (a measure of visuospatial memory) and open-field activity when tested subsequently. Rats receiving kainic acid followed by phenobarbital exhibited even greater disturbances in memory, learning, and activity levels.⁶³ In contrast, this effect was not seen with topiramate, as described below.

Phenytoin

Gestational and neonatal exposure to phenytoin reduces brain weight.⁴³^,⁸³ Phenytoin alters neuronal membranes in the hippocampus.⁹⁴ It also alters critical genes and delays neurodevelopment.⁸ Dose-dependent apoptotic neuronal cell death occurs in neonatal rats (see Mechanism section). Prenatal phenytoin at subteratogenic dosages (100 to 200 mg/kg) in rats produces impaired spatial learning and motor coordination.²⁶^,⁶⁴^,⁷⁷^,⁸⁹^,⁹⁰^,⁹¹^,⁹³^,⁹⁷ A dose-effect relationship was noted at maternal levels (10 to 25 μg/mL) overlapping the human therapeutic range. The adverse behavioral effects do not resolve as the rats grow older.⁹³^,⁹⁴ Prenatal exposure to phe-nytoin in rats results in hyperactivity.⁹¹^,⁹⁷ Similarly, primates who have in utero exposure to phenytoin are hyperactive and hyperexcitable, but those exposed to carbamazepine or stiripentol are not.⁷⁰

Primidone

Gestational primidone can produce behavioral deficits in rats.⁷¹ When tested as adults, the rats that had been exposed in utero to primidone were impaired in their performance of an eight-arm radial maze task and had reduced open-field activity.

Topiramate

Topiramate has been shown to produce adverse cognitive effects in adults. In contrast, the effects of topiramate in neonatal animal models appear to be protective. Topiramate protects against hypoxic-ischemic white matter injury and decreases the subsequent neuromotor deficits when administered posthypoxic insult in neonatal rats.³³ Rats that are treated with to-piramate after a series of 25 neonatal seizures performed significantly better in the water maze than rats treated with saline.¹⁰⁶ These findings are in contrast to the adverse effects of phenobarbital in the same animal model.

Valproate

An in vitro study using rat hippocampus cultures found that valproate interferes with formation of the pyramidal cell layer.²⁹ In utero valproate can alter neuronal membranes in the hippocampus and cortex of rats.⁹⁵ Early postnatal exposure to valproate decreased brain weight in mice.⁸⁵ Exposure of neonatal rats to valproate resulted in widespread neuronal apoptosis (see Mechanism section). Adverse neurobehavioral effects in rats have been seen following in utero exposure at doses of 150 to 200 mg/kg,⁸⁷^,⁹² although these effects were not as marked as phenytoin in the same animal model.

Antiepileptic Drug Effects on Neurodevelopment: Potential Mechanisms

Folate-related Mechanisms

Folate demands are increased during pregnancy, and women with epilepsy who have lower folate levels are more likely to have abnormal pregnancy outcomes.²⁰ Several AEDs are known to affect folate metabolism. Phenobarbital, phenytoin, and primidone, but not carbamazepine, deplete folate.¹²^,¹³^,¹⁵^,¹⁶ Valproate alters folate metabolism.¹²

Ischemia/Hypoxia

Phenytoin can affect cardiac function in fetal rats, and animals exposed in utero to ischemia develop defects that resemble phenytoin-induced defects.¹⁹

Neuronal Suppression

AEDs suppress neuronal irritability and could reduce neuronal excitation, altering in utero synaptic growth and connectivity and producing long-term behavioral deficits.

Reactive Intermediates

The teratogenesis of AEDs may be mediated by toxic intermediary metabolites rather than the parent compound.⁹⁸^,⁹⁹ Oxide intermediates (epoxides) are generated during the metabolism of some AEDs and are highly reactive and can bind nucleic acids. However, the theory of the epoxide mechanism has been questioned because the cytochrome P450 enzymes required for conversion of an AED to an epoxide are not expressed in embryonic tissues.⁵³ An alternative theory posits that AEDs may be metabolized to free-radical reactive intermediates by prostaglandin H synthetase or lipoxygenases, which are active in the fetus.⁹⁸^,⁹⁹ Then, these reactive oxygen species could bind to DNA, protein, or lipids, resulting in teratogenesis.

Antiepileptic Drug–induced Neuronal Apoptosis

The observation that third-trimester gestational ethanol exposure can produce widespread neuronal apoptosis and neurobehavioral deficits led to the hypothesis that the adverse behavioral effects of AED exposure might be due to a similar mechanism.⁴⁸ The effect of ethanol is mediated by combined N-methyl-D-aspartate (NMDA) glutamate receptor blockade and γ-aminobutyric acid (GABA)_A receptor activation,⁴⁸ which are receptor mechanisms affected by some AEDs. Recently, several AEDs have been tested for similar apoptotic effects in a neonatal rat model. Widespread neuronal apoptosis occurs as a result of neonatal exposure to clonazepam, diazepam, phenobarbital, phenytoin, vigabatrin, or valproate.⁹^,¹⁰ The effect appears to be due to reduced expression of neurotrophins and levels of protein kinases, which are important for neuronal growth and survival. Of note, the adverse effects were ameliorated by β estradiol, which has neurotrophic effects.⁶^,¹⁰^,³⁹ Similar apoptotic effects were not seen at therapeutic dosages for levetiracetam or topiramate.³⁹^,⁵⁶^,⁶⁰ Additional studies are needed to examine the effects of other AEDs in this animal model, extend the studies to gestational animal models, and determine if a similar mechanism occurs in humans.

Human Data from Offspring of Mothers with Epilepsy

Syndromes and Minor Anomalies

The fetal hydantoin syndrome (FHS) was first described by Hanson and Smith⁴² in five unrelated children whose mothers had epilepsy. Four mothers had taken 100 to 400 mg of phe-nytoin (one monotherapy) and one had been treated with 300 mg of mephenytoin during pregnancy. Four children had also been exposed to barbiturates and one to additional phensuximide. All displayed a characteristic pattern of craniofacial abnormalities (including short nose with low nasal bridge, and hypertelorism) (Fig. 1 ⁶⁵), hypoplasia of nails and distal phalanges, and postnatal growth deficiency, and four had motor or mental deficiency. In a later cohort study, Hanson et al.⁴¹ estimated that 11% of phenytoin-exposed children showed enough unusual features to be clearly classified as having FHS. Patterns of minor anomalies similar to phenytoin combined with developmental delay have been described in association with prenatal carbamazepine⁵² and primidone⁶⁶ exposure, but these have never been established as separate syndromes. A different pattern of abnormalities has been described for valproate, as discussed below.

Of the typical FHS features, distal digital hypoplasia (Fig. 2) has been most consistently associated with prenatal phenyt-oin exposure in prospective studies blinded to exposure.⁴^,⁵⁵^,³⁷ Two studies have used anthropometric methodology. Kelly⁵⁴ made a radiologic diagnosis of distal phalangeal hypoplasia based on measurements from hand radiographs in 15 of 47 phenytoin-exposed and one of ten control children. In a controlled population-based study, prenatal phenytoin exposure was observed to have a significant dose-related negative correlation with distal phalangeal length measured from hand radiographs.³⁶ A radiologic diagnosis of distal phalangeal hypoplasia was made in 8 of 75 (11%) phenytoin-exposed children compared with 1 of 130 children not exposed to phenytoin (p = 0.003).³⁶ In most of these children, distal digital hypoplasia was not obvious on a clinical examination. Growth and intelligence were within the normal range in all.

Controlled prospective and retrospective studies blinded to prenatal AED exposure have consistently shown that the craniofacial minor anomalies considered typical of FHS are increased in children of mothers with epilepsy compared with control children of mothers without epilepsy.³⁷^,⁴⁶^,⁶⁷^,¹⁰¹^,¹⁰⁵ Most studies observed no increased minor anomalies in
nonexposed children of mothers with epilepsy,⁴⁶^,¹⁰¹^,⁴⁷ while one study found that some of the facial features such as epicanthus were increased not only in the nonexposed children, but also in the mothers with epilepsy.³⁷ Although the results on whether these typical anomalies are associated with impaired cognitive development are controversial,³⁵^,⁴⁵ multiple minor anomalies in general are known to be associated with delayed development⁸¹^,⁸⁶ and should alert the clinician to do a systematic developmental evaluation and follow-up.

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