Cited by 122Pharmacological Effects and Toxicity StudiesEpilepsy research and treatmentAnesthesia and Neurotoxicity Research

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Antiepileptic drugs and the developing brain

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Kaindl, A. M., Asimiadou, S., Manthey, D., Hagen, M. v.d., Turski, L., Ikonomidou, C.·2006·Cellular and Molecular Life Sciences CMLS

DOI 10.1007/s00018-005-5348-0PMC PMC11136147

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Abstract

Epilepsy is the most common neurological disorder in young humans. Antiepileptic drugs (AEDs) which are used to treat seizures in infants, children and pregnant women can cause cognitive impairment, microcephaly and birth defects. Ion channels, neurotransmitters and second messenger systems constitute molecular targets of AEDs. The same targets regulate brain processes essential both for propagation of seizures and for learning, memory and emotional behavior. Thus, AEDs can influence brain function and brain development in undesired ways. Here we review mechanisms of action of AEDs, examine clinical evidence for their adverse effects in the developing human brain, and present studies on cognitive and behavioral effects in animal models. Furthermore, we discuss mechanisms responsible for adverse effects of AEDs in the developing mammalian brain, including interference with cell proliferation and migration, axonal arborization, synaptogenesis, synaptic plasticity and physiological apoptotic cell death.

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Wang, Y., Xia, L., Li, R., Li, Y., Li, J., Zhou, Q., & Pan, S. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.669703 · Cited by 9
“The continued use of ASM may have some adverse effects, such as drug reactions, impaired brain development (3), and increased psychological and economic burdens (4, 5), and remaining on ASM may not fully protect patients from seizure recurrence (6).”
Background
Risk of seizure recurrence from antiepileptic drug withdrawal among seizure-free patients for more than two years
Li, Y., Chen, S., Qin, J., She, Y., Chen, Y., Liu, X., Yu, H., & Zhou, L. (2020) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2020.107485 · Cited by 9
Traumatic Brain Injury in Children
Lerner, J. T., & Giza, C. C. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-37101-8.00102-8 · Cited by 8
Cumulative effects of antiseizure medication on intelligence in children with focal epilepsy
Stevering, C. H., Lamberink, H. J., Woodfield, J., van Schooneveld, M. M. J., Otte, W. M., Chin, R., Bastin, M. E., Geleijns, K. P. W., & Braun, K. P. J. (2022) · Epileptic Disorders · doi:10.1684/epd.2022.1467 · Cited by 7
Epilepsiechirurgie bei Kindern und Jugendlichen
Ramantani, G., & Zentner, J. (2017) · Aktuelle Neurologie · doi:10.1055/s-0043-103083 · Cited by 7
“In den ersten Lebensjahren können einige Antikonvulsiva durch das Triggern der neuronalen Apoptose und das Verhindern der Neurogenese, Synaptogenese, Zellproliferation und -migration sowie der synaptischen Plastizität die normale Hirnentwicklung negativ beeinflussen [107, 108].”
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Understanding Drug-Induced Movement Disorders: Causes, Symptoms, and TreatmentPreprint
Santos, E. R. (2024) · Preprints.org · doi:10.20944/preprints202402.1258.v1 · Cited by 6
Short-term use of antiepileptic drugs is neurotoxic to the immature brain
Yang, L., Liu, Y., Wang, Y., Li, D., & Huang, S. (2015) · Neural Regeneration Research · doi:10.4103/1673-5374.155434 · Cited by 6
“Additionally, some AEDs are neurotoxic, and administration of AEDs to embryos, neonates and infants can cause cognitive impairment, microcephaly and birth defects (Sulzbacher et al., 1999; Jevtovic-Todorovic et al., 2003; Kaindl et al., 2006; Viinikainen et al., 2006; Verrotti et al., 2014).”
Background
Neurologic birth defects after prenatal exposure to antiepileptic drugs
Uziel, D., & Rozental, R. (2008) · Epilepsia · doi:10.1111/j.1528-1167.2008.01925.x · Cited by 6
“Chronic administration of antiepileptic drugs (AEDs) to suppress or prevent seizures in epileptic women results in a significant decrease in seizure-related morbidity and mortality, but at the same time it places the fetus at risk (Janz, 1975; Kaindl et al., 2006).”
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Mons, F., de Lendeu, P. K., Marret, S., & Laudenbach, V. (2010) · Annales Françaises d Anesthésie et de Réanimation · doi:10.1016/j.annfar.2010.02.031 · Cited by 5
Diphenylhydantoin Promotes Proliferation in The Subventricular Zone and Dentate Gyrus
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“Other mechanisms possibly contributing to the antiepileptic activity of phenytoin include a suppression of sodium action potentials by stimulating the sodium pump, inhibition of calcium influx in neurons, blockage of ionotropic receptors for glutamate and enhancement of GABA neurotransmission (Escueta and Appel, 1971;…”
Evaluation of a Human Neural Stem Cell Culture Method for Prediction of the Neurotoxicity of Anti-epileptics
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“Its embryotoxicity arises in polytherapy, especially when combined with PHB, since the children of epileptic mothers exposed to CBZ and PHB have lower developmental and language scores (45) than those in monotherapy.”
Background
Prescription patterns of antiepileptic drugs in young women: development of a tool to distinguish between epilepsy and psychiatric disorders
Naldi, I., Piccinni, C. P., Mostacci, B., Renzini, J., Accetta, G., Bisulli, F., Tappatà, M., Piazza, A., Pagano, P., Bianchi, S., et al. (2016) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.3984 · Cited by 5
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Stereological examination of curcumin’s effects on hippocampal damage caused by the anti-epileptic drugs phenobarbital and valproic acid in the developing rat brain
Yılmaz, B. D., Eren, B., Sağır, D., Eren, Z., & Gökçe, A. B. (2019) · Acta Histochemica · doi:10.1016/j.acthis.2019.03.007 · Cited by 4
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Soul, J. S. (2015) · Journal of Pediatric Neurology · doi:10.3233/jpn-2009-0271 · Cited by 4
“Data from neonatal animal experiments show increased apoptosis and reduced brain weight resulting from administration of commonly used AEDs such as phenobarbital, benzodiazepines and phenytoin [37,38].”
Background
Synthesis, Crystal Structure and Hydrogen-bonding Patterns in Rac-N-acetyl-2-thiohydantoin-leucine
Delgado, G. E., Sulbaran, M. E., & Mora, A. J. (2013) · International Journal of Materials and Chemistry · Cited by 4
1H‐MRS reveals metabolic alterations in generalized tonic‐clonic seizures before and after treatment
Wan, X., Liu, L., Wang, W., Tan, Q., Su, X., Zhang, S., Yang, X., Yue, Q., & Gong, Q. (2021) · Acta Neurologica Scandinavica · doi:10.1111/ane.13534 · Cited by 4
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“However, the current seizure management guidelines are to treat clinical seizures identified through direct observation, with or without EEG confirmation, and this may increase the neonates to expose the risks of possible harm, either by medication overuse or undertreatment of subclinical seizures [33].”
Background
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The Effects of Levetiracetam on Neural Tube Development of Chick Embryos
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“These results suggest that the use of anti-epileptic drugs for preventing seizures are also likely to induce damages to brain function and development [17] , resulting in learning, memory, and other cognitive functional deficits in patients, in particular the fetus and newborn.”
Background
Anticonvulsant Activities of Various Series of Heterocyclic Compounds Containing Triazole, Thiadiazine, Benzo-triazole, Benzothiazole, Oxadiazole Ring Systems
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Triggers of Cell Death in the Developing Brain
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Self-citation
Posttraumatic Seizures and Epileptogenesis
Giza, C. C. (2010) · Epilepsy · doi:10.1201/9781420085594-c12 · Cited by 3
Lacosamide and Levetiracetam Are Not Toxic to the Developing Mouse Brain
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Self-citation
Epilepsy Surgery in Children and Adolescents
Ramantani, G., & Zentner, J. (2017) · Neurology International Open · doi:10.1055/s-0043-102834 · Cited by 2
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Grígelová, A., Mikulecká, A., & Kubová, H. (2025) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2025.110307 · Cited by 1
“Several experimental studies have suggested that antiseizure medication as well as general anesthetics and sedatives may have adverse effects on brain development [3] or can aggravate seizure-induced neuronal damage [4].”
β-Asaronol, the Neuroactive Component of Acorus tatarinowii: Mitigating Seizures with Minimal Developmental Risk in Dravet Syndrome
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Neonatal seizures and GABAergic drugs: Scylla and Charybdis?
Thompson, K. W., Suchomelová, L., & Wasterlain, C. G. (2026) · Epilepsia Open · doi:10.1002/epi4.70231 · Cited by 1
“52 This includes clinically used ASMs such as phenobarbital (Ph) and benzodiazepines, which enhance ongoing programmed cell death in the early postnatal period.”
Phenobarbital: Too much of a good thing?
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Background
Neurobiology of TBI sustained during development
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Defects of Midbrain/Hindbrain Development: Defects of Anteroposterior and Dorsoventral Patterning
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“Just as pronounced apoptosis can lead to cerebral hypoplasia, 57 – 60 and it can also result in cerebellar hypoplasia.”

Authors: Kaindl, A. M., Asimiadou, S., Manthey, D., Hagen, M. V. D., Turski, L., & Ikonomidou, C.
Affiliations: Stiftung Charité (DE)
Technische Universität Dresden (DE)
Solvay (Netherlands) (NL)
Corresponding author: Ikonomidou, C.
ORCID: Kaindl, A. M.
Hagen, M. v.d.
Ikonomidou, C.
Venue: Cellular and Molecular Life Sciences CMLS
Publisher: Springer Science and Business Media LLC
Published: 2006-01-02
Volume: 63
Issue: 4
Pages: 399-413
ISSN: 1420-682X (ISSN-L)
1420-9071
DOI: 10.1007/s00018-005-5348-0
PMC: PMC11136147
OpenAlex: W1963567657
Cited by: 121
References: 179
Citations by year: 2026: 4 · 2025: 6 · 2024: 5 · 2022: 5 · 2021: 7 · 2020: 2 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 2 · 2015: 12 · 2014: 5 · 2013: 6 · 2012: 7
FWCI: 8.68
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Cellular and Molecular Life Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
Keywords: antiepileptic drugs, adverse drug reactions, developing brain, epilepsy, cognitive impairment, microcephaly, congenital malformations, ion channels, neurotransmitters, second messenger signaling, seizure propagation, learning and memory, behavioral effects, cell proliferation, neuronal migration, axonal arborization, synaptogenesis, synaptic plasticity, apoptosis, prenatal drug exposure
MeSH terms: Animals, Anticonvulsants, Brain, Epilepsy, Humans, Neurons, Apoptosis

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Antiepileptic drugs and the developing brain

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