Developmental Neurotoxicity of Antiepileptic Drugs

Hansen, Deborah K.; Holson, R.Robert

doi:10.1016/b978-012648860-9/50046-7

Cited by 5 publications

(1 citation statement)

References 150 publications

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“…[46][47][48] Antiepileptic and anaesthetic drugs can induce apoptosis in the developing brain. [46][47][48] Antiepileptic and anaesthetic drugs can induce apoptosis in the developing brain.…”

Section: Anti-epileptic Drugs and Brain Morphologymentioning

confidence: 99%

Anti-Epileptic Drugs and Brain and Behavioural Development in Animal Models and Humans

O’Donoghue

2010

Fet. Matern. Med. Rev.

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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.

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Section: Anti-epileptic Drugs and Brain Morphologymentioning

confidence: 99%

Anti-Epileptic Drugs and Brain and Behavioural Development in Animal Models and Humans

O’Donoghue

2010

Fet. Matern. Med. Rev.

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Managing Epilepsy and Anti‐Epileptic Drugs During Pregnanc

O’Donoghue¹,

Hayes²

2007

Prescribing in Pregnancy

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Neurotoxic Damage of Granule Cells in the Dentate Gyrus and the Cerebellum and Cognitive Deficit Following Neonatal Administration of Phenytoin in Mice

Ogura

Yasuda

Nakamura

et al. 2002

J Neuropathol Exp Neurol

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The use of antiepileptic drugs during human gestation probably increases the risk of causing CNS disorders in later life. In brain, granule cells in the dentate gyrus (DG) and cerebellum are still developing in the last trimester of human gestation and a similar development is taking place during the mouse perinatal period. We treated newborn C57BL/6 mice orally with 35 mg/kg phenytoin (PHT) daily during postnatal days (PD) 5 to 14. Histopathological investigation revealed that the layer of mature granule cells in the DG that was immunoreactive to anti-calbindin D28k was thinner in PHT-treated mice. Purkinje cells in the treated group also had poor, immature arbors with an irregular arrangement. A number of TUNEL-positive cells were observed in the DG and cerebellum during the treatment. PHT-treated mice were impaired in the acquisition of a hidden platform task in the water maze and committed significantly more errors during the learning process in theradial arm maze. These findings demonstrate that neonatal administration of PHT interferes with the development of granule cells in the hippocampus and the cerebellum and causes spatial leaning deficits in later life. Cautious clinical use of this drug for pregnant patients is warranted, especially in the last trimester.

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Developmental Neurotoxicity of Antiepileptic Drugs

Cited by 5 publications

References 150 publications

Anti-Epileptic Drugs and Brain and Behavioural Development in Animal Models and Humans

Anti-Epileptic Drugs and Brain and Behavioural Development in Animal Models and Humans

Managing Epilepsy and Anti‐Epileptic Drugs During Pregnanc

Neurotoxic Damage of Granule Cells in the Dentate Gyrus and the Cerebellum and Cognitive Deficit Following Neonatal Administration of Phenytoin in Mice

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