Antiepileptic drugs and brain development

doi:10.1016/j.eplepsyres.2009.09.019

Epilepsy Research

Volume 88, Issue 1, January 2010, Pages 11-22

https://doi.org/10.1016/j.eplepsyres.2009.09.019 Get rights and content

Summary

Epilepsy, the most common neurological disorder in young humans, has its highest incidence during the first year of life. Antiepileptic drugs (AEDs) which are used to treat seizures in infants, children and pregnant women target ion channels, neurotransmitters and second messenger systems in the brain. The same targets regulate brain processes essential both for propagation of seizures and for brain development, learning, memory and emotional behavior.

Here we review adverse effects of AEDs in the developing mammalian brain. In addition, we discuss mechanisms explaining adverse effects of AEDs in the developing mammalian brain including interference with cell proliferation and migration, neurogenesis, axonal arborization, synaptogenesis, synaptic plasticity and physiological apoptotic cell death.

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

References (112)

G. Bignami et al.
Selective changes in mouse behavioural development after prenatal benzodiazepine exposure: a progress resport
Prog. Neuropsychopharmacol. Biol. Psychiatry
(1992)
N.K. Blank et al.
Phenytoin neurotoxicity in developing mouse cerebellum in tissue culture
J. Neurol. Sci.
(1982)
A. Caceres et al.
Suppression of MAP2 in cultured cerebellar macroneurons inhibits minor neurite formation
Neuron
(1992)
B.H. Cha et al.
Effect of topiramate following recurrent and prolonged seizures during early development
Epilepsy Res.
(2002)
M.R. Cilio et al.
Anticonvulsant action and long-term effects of gabapentin in the immature brain
Neuropharmacology
(2001)
J. Dobbing et al.
Comparative aspects of the brain growth spurt
Early Hum. Dev.
(1979)
C. Glier et al.
Therapeutic doses of topiramate are not toxic to the developing brain
Exp. Neurol.
(2004)
H.H. Hansen et al.
Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain
Neurobiol. Dis.
(2004)
G.E. Hardingham et al.
The Yin and Yang of NMDA receptor signalling
Trends Neurosci.
(2003)
T. Hatta et al.
Neurotoxic effects of phenytoin on postnatal mouse brain development following neonatal administration
Neurotoxicol. Teratol.
(1999)

C.E. Henderson

Programmed cell death in the developing nervous system

Neuron

(1996)

C. Ikonomidou et al.

Neurotransmitters and apoptosis in the developing brain

Biochem. Pharmacol.

(2001)

C. Ikonomidou et al.

Brain morphology alterations following prenatal exposure to antiepileptic drugs

Eur. J. Ped. Neurol.

(2007)

J.L. Ingram et al.

Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism

Neurotoxicol. Teratol.

(2000)

G.D. Jackson et al.

Vigabatrin-induced lesions in the rat brain demonstrated by quantitative magnetic resonance imaging

Epilepsy Res.

(1994)

C.K. Kellogg

Sex differences in long-term consequences of prenatal diazepam exposure: possible underlying mechanisms

Pharmacol. Biochem. Behav.

(1999)

G. Kempermann et al.

Phenytoin inhibits expression of microtubule-associated protein 2 and influences cell-viability and neurite growth of cultured cerebellar granule cells

Brain Res.

(1995)

P. Levitt et al.

New evidence for neurotransmitter influences on brain development

Trends Neurosci.

(1997)

D. Manthey et al.

Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain

Exp. Neurol.

(2005)

M.L. Martin et al.

The anticonvulsant valproate teratogen restricts the glial cell cycle at a defined point in the mid G1 phase

Brain Res.

(1991)

K.L. Meador et al.

Cognitive/behavioral teratogenic effects of antiepileptic drugs

Epilepsy Behav.

(2007)

E.A. Neale et al.

Differential toxicity of chronic exposure to phenytoin, phenobarbital or carbamazepine in cerebral cortical cell cultures

Pediatr. Neurol.

(1985)

J. Nicolai et al.

Neurodevelopmental delay in children exposed to antiepileptic drugs in utero: a critical review directed at structural study-bias

J. Neurol. Sci.

(2008)

H. Ohmori et al.

Effects of low-dose phenytoin administered to newborn mice on developing cerebellum

Neurotoxicol. Teratol.

(1997)

J.W. Olney et al.

Do pediatric drugs cause developing neurons to commit suicide?

Trends Pharmacol. Sci.

(2004)

M. Pawlikowski et al.

Effects of diazepam on cell proliferation in cerebral cortex, anterior pituitary and thymus of developing rats

Life Sci.

(1987)

C.G. Pick et al.

Long-term reduction in eight arm maze performance after early exposure to phenobarbital

Int. J. Dev. Neurosci.

(1985)

M. Picker et al.

Effects of phenytoin, phenobarbital, and valproic acid, alone and in selected combinations, on schedule-controlled behavior of rats

Pharmacol. Biochem. Behav.

(1985)

M.A. Schilling et al.

Prenatal phenytoin exposure and spatial navigation in offspring: effects on reference and working memory and on discrimination learning

Neurotoxicol. Teratol.

(1999)

R.S. Sidhu et al.

Low-dose vigabatrin (gamma-vinyl GABA)-induced damage in the immature rat brain

Exp. Neurol.

(1997)

D.F. Smith

Lithium and carbamazepine: effects on learned taste aversion and open field behavior in rats

Pharmacol. Biochem. Behav.

(1983)

B.D. Speidel et al.

Maternal epilepsy and abnormalities of the fetus and newborn

Lancet

(1972)

S.M. Strickler et al.

Genetic predisposition to phenytoin-induced birth defects

Lancet

(1985)

S. Asimiadou et al.

Protection with estradiol in developmental models of apoptotic neurodegeneration

Ann. Neurol.

(2005)

Z.I. Bashir et al.

Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors

Nature

(1993)

S.A. Bayer et al.

Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat

Neurotoxicology

(1993)

G.K. Bergey et al.

Adverse effects of phenobarbital on morphological and biochemical development of fetal mouse spinal cord neurons in culture

Ann. Neurol.

(1981)

A. Bergman et al.

Neuronal losses in mice following both prenatal and neonatal exposure to phenobarbital

Acta Anat.

(1982)

P. Bittigau et al.

Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

Proc. Natl. Acad. Sci. U.S.A.

(2002)

A.R. Bolanos et al.

Comparison of valproate and phenobarbital treatment after status epilepticus in rats

Neurology

(1998)

W.J. Brooks et al.

Effect of chronic administration of NMDA antagonists on synaptic development

Synapse

(1997)

B.A. Buehler et al.

Prenatal prediction of risk of the fetal hydantoin syndrome

N. Engl. J. Med.

(1990)

J.A. Cohen et al.

The potential for vigabatrin-induced intramyelinic edema in humans

Epilepsia

(2000)

M. Cunnington et al.

International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy

Neurology

(2005)

J. Diaz et al.

Phenobarbital: effects of long-term administration on behavior and brain of artificially reared rats

Science

(1978)

J. Dobbing

The later development of the brain and its vulnerability

J. Dobbing et al.

The quantitative growth and development of the human brain

Arch. Dis. Child.

(1993)

Dolk, H., Jentink, J., Loane, M., Morris, J., De Jong-van den Berg, L.T.W., on behalf of the EUROCAT Antiepileptic Drug...

M.B. Emerit et al.

Trophic effects of neurotransmitters during brain maturation

Biol. Neonate

(1992)

A. Faiella et al.

A mouse model for valproate teratogenicity: parental effects, homeotic transformation, and altered HOX expression

Hum. Mol. Genet.

(2000)

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Prolonged neonatal seizures are often due to severe acute brain injuries and are known to be harmful to the brain. No predictors have yet been identified to distinguish at an early time-point between brief and long seizures. We investigated the duration of seizures in neonates to determine the relationship between the duration of a seizure and that of subsequent seizures.
We retrospectively reviewed video-electroencephalogram confirmed seizures of 30 preterm and 36 full-term neonates selected from patients admitted to the neonatal intensive care unit of Parma University Hospital. The duration and relationship between successive seizures were investigated. Statistical models were performed to evaluate the risk of long-lasting ictal events among neonates with seizures.
A positive monotonic relationship between the duration of successive seizures was identified. Most seizures were brief. No significant differences in seizure duration were found between preterm and full-term neonates, although a borderline significance emerged.
Neonatal seizures are usually brief, and as the seizure duration increases, the duration of the subsequent seizures tends to increase. We also suggest that full-term neonates could be at higher risk of experiencing long seizures compared to preterm neonates. In summary, estimating the seizure duration is critical to evaluating the optimal timing of therapeutic interventions and can help to predict how seizures evolve.
Neonatal Seizure Management: Is the Timing of Treatment Critical?
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To assess the impact of the time to treatment of the first electrographic seizure on subsequent seizure burden and describe overall seizure management in a large neonatal cohort.
Newborns (36-44 weeks of gestation) requiring electroencephalographic (EEG) monitoring recruited to 2 multicenter European studies were included. Infants who received antiseizure medication exclusively after electrographic seizure onset were grouped based on the time to treatment of the first seizure: antiseizure medication within 1 hour, between 1 and 2 hours, and after 2 hours. Outcomes measured were seizure burden, maximum seizure burden, status epilepticus, number of seizures, and antiseizure medication dose over the first 24 hours after seizure onset.
Out of 472 newborns recruited, 154 (32.6%) had confirmed electrographic seizures. Sixty-nine infants received antiseizure medication exclusively after the onset of electrographic seizure, including 21 infants within 1 hour of seizure onset, 15 between 1 and 2 hours after seizure onset, and 33 at >2 hours after seizure onset. Significantly lower seizure burden and fewer seizures were noted in the infants treated with antiseizure medication within 1 hour of seizure onset (P = .029 and .035, respectively). Overall, 258 of 472 infants (54.7%) received antiseizure medication during the study period, of whom 40 without electrographic seizures received treatment exclusively during EEG monitoring and 11 with electrographic seizures received no treatment.
Treatment of neonatal seizures may be time-critical, but more research is needed to confirm this. Improvements in neonatal seizure diagnosis and treatment are also needed.
Antiepileptic drugs lamotrigine and valproate differentially affect neuronal maturation in the developing chick embryo, yet with PAX6 as a potential common mediator
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Exposing the immature nervous system to specific antiepileptic drugs (AEDs) during pregnancy is linked to neurodevelopmental disorders such as autism spectrum disorder (ASD). Newer AEDs like lamotrigine (LTG) are hailed as safer, but recent epidemiological data suggest that even LTG carries a risk, although much lower than that associated with valproic acid (VPA), an older AED, which is also known to cause morphological alterations in the developing brain. Increasing evidence highlights cerebellar abnormalities as important in ASD pathophysiology. Transcription factor PAX6 is a key activity-dependent mediator and regulates crucial processes during cerebellar development. The chicken cerebellum recapitulates important characteristics of human cerebellar development, and may thus be suitable for the assessment of interventions aiming to modify maturation and cerebellar development.
In the present study, exposure of chicken on embryonic day 16 (E16) to LTG or VPA resulted in decreased cerebellar mass and level of proliferating nuclear cell antigen (PCNA) for clinically relevant concentrations of VPA. However, both AEDs reduced cerebellar protein levels of PAX6 and MMP-9 at E17. Furthermore, PAX6 immunohistochemical staining of coronal sections of chicken cerebellum showed a significant reduction in PAX6-positive cell density and changes in cerebellar cortex thickness, mostly caused by the change in IGL-layer thickness. In conclusion, prenatal exposure to LTG or VPA provoked differential maturational changes in the developing cerebellum that may reflect some of the underlying molecular mechanisms for the observed human ASD pathology after AEDs exposure during pregnancy.
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For each ASM, we selected qualifying cases from children born to PB, CBZ, or PHT monotherapy-exposed and unexposed women. Following the application of inclusion, exclusion, and matching criteria, our sample included 34 PB-exposed, 40 PHT-exposed, and 41 CBZ-exposed children along with matched unexposed children for each drug group. Criteria were applied through examination of maternal medical and educational histories, parental socioeconomic characteristics, and child’s age and gender. Each child’s physical and neuropsychological characteristics were examined, using standardized protocols. We report on the cognitive performance of the children as assessed by the Wechsler Intelligence Scale for Children – III (WISC-III), the leading measure of mental ability in the U.S.
An overall mixed model ANOVA of the adjusted performance of the children across all groups controlling for maternal IQ revealed significant effects on verbal IQ, but not full-scale IQ or performance IQ. In the individual drug and unexposed group comparisons, only reduced verbal and full-scale IQ scores in PB-exposed versus matched unexposed children were found. Comparisons between drug groups revealed a significant reduction in verbal IQ and full-scale IQ in PB-exposed versus PHT-exposed children, but not in other drug–drug comparisons.
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ReviewAntiepileptic drugs and brain development

Summary

Introduction

Section snippets

Susceptibility of the developing brain to environmental agents

Adverse effects of AEDs in animal studies

AEDs cause neuronal apoptosis in the developing brain

Influence of antiepileptic drugs on other developmental processes

Brain morphology following prenatal exposure to antiepileptic drugs

Conclusions and relevance for the clinic

Prog. Neuropsychopharmacol. Biol. Psychiatry

J. Neurol. Sci.

Neuron

Epilepsy Res.

Neuropharmacology

Early Hum. Dev.

Exp. Neurol.

Neurobiol. Dis.

Trends Neurosci.

Neurotoxicol. Teratol.

Neuron

Biochem. Pharmacol.

Eur. J. Ped. Neurol.

Neurotoxicol. Teratol.

Epilepsy Res.

Pharmacol. Biochem. Behav.

Brain Res.

Trends Neurosci.

Exp. Neurol.

Brain Res.

Epilepsy Behav.

Pediatr. Neurol.

J. Neurol. Sci.

Neurotoxicol. Teratol.

Trends Pharmacol. Sci.

Life Sci.

Int. J. Dev. Neurosci.

Pharmacol. Biochem. Behav.

Neurotoxicol. Teratol.

Exp. Neurol.

Pharmacol. Biochem. Behav.

Lancet

Lancet

Protection with estradiol in developmental models of apoptotic neurodegeneration

Ann. Neurol.

Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors

Nature

Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat

Neurotoxicology

Adverse effects of phenobarbital on morphological and biochemical development of fetal mouse spinal cord neurons in culture

Ann. Neurol.

Neuronal losses in mice following both prenatal and neonatal exposure to phenobarbital

Acta Anat.

Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

Proc. Natl. Acad. Sci. U.S.A.

Comparison of valproate and phenobarbital treatment after status epilepticus in rats

Neurology

Effect of chronic administration of NMDA antagonists on synaptic development

Synapse

Prenatal prediction of risk of the fetal hydantoin syndrome

N. Engl. J. Med.

The potential for vigabatrin-induced intramyelinic edema in humans

Epilepsia

International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy

Neurology

Phenobarbital: effects of long-term administration on behavior and brain of artificially reared rats

Science

The later development of the brain and its vulnerability

The quantitative growth and development of the human brain

Arch. Dis. Child.

Trophic effects of neurotransmitters during brain maturation

Biol. Neonate

A mouse model for valproate teratogenicity: parental effects, homeotic transformation, and altered HOX expression

Hum. Mol. Genet.

Review
Antiepileptic drugs and brain development