Antiepileptic drugs and the developing brain
Open accessAbstract
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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Anti-epileptic drugs, given at young age or during pregnancy, can have major neurodevelopmental implications.
“Important is also that the anti-epileptic drugs, given at young age or during pregnancy, can have major neurodevelopmental implications as well.”
From Development of prefrontal cortex (2022) · cites this paper as [391]
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Development of prefrontal cortex
Kolk, S. M., & Rakic, P. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01137-9 · Cited by 378 · see citing works
A developmental and genetic classification for midbrain-hindbrain malformations
Barkovich, A. J., Millen, K. J., & Dobyns, W. B. (2009) · Brain · doi:10.1093/brain/awp247 · Cited by 285 · see citing works
“Thus, just as accentuated apopto- sis can cause cerebral hypoplasia, it causes cerebellar hypoplasia, as well (Kaindl et al., 2006; Takano et al., 2006).”
BackgroundBehavioral and Psychiatric Comorbidities in Pediatric Epilepsy: Toward an Integrative Model
AUSTIN, J. K., & Caplan, R. (2007) · Epilepsia · doi:10.1111/j.1528-1167.2007.01154.x · Cited by 222 · see citing works
“In addition, poorly controlled seizures and AED polytherapy might negatively affect brain development (see review in Kaindl et al., 2006), cognition, language, and behavior in young children (Bulteau et al., 2000; Harbord, 2000).”
BackgroundMartin, J., Heymann, A., Bäsell, K., Baron, R., Biniek, R., Bürkle, H., Dall, P., Dictus, C., Eggers, V., Eichler, I., et al. (2010) · PubMed Central · doi:10.3205/000091 · Cited by 184 · see citing works
“• For premature and fullterm neonates, both chloral hydrate (orally or rectally) and phenobarbital should be used only after careful riskbenefit-analysis (particular consideration should be paid to the effects on cerebral development and duration of ventilation) [208] [209].”
BackgroundArndt, D. H., Lerner, J. T., Matsumoto, J. H., Madikians, A., Yudovin, S., Valino, H., McArthur, D. L., Wu, J. Y., Leung, M., Buxey, F., et al. (2013) · Epilepsia · doi:10.1111/epi.12369 · Cited by 168 · see citing works
“However, it has been shown that antiepileptic drugs (AEDs) do not prevent late PTE and are not without their own risk, particularly on the developing brain (Temkin et al., 1990; Bittigau et al., 1999; Olney et al., 2004; Young et al., 2004; Kaindl et al., 2006).”
BackgroundPediatric traumatic brain injury: not just little adults
Giza, C. C., Mink, R. B., & Madikians, A. (2007) · Current Opinion in Critical Care · doi:10.1097/mcc.0b013e32808255dc · Cited by 164 · see citing works
Boshuisen, K., van Schooneveld, M. M. J., Uiterwaal, C. S. P. M., Cross, J. H., Harrison, S., Polster, T., Daehn, M., Djimjadi, S., Yalnızoğlu, D., Turanlı, G., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24427 · Cited by 138 · see citing works
“Early in life, at least some AEDs can interfere with normal brain development, by inducing neuronal apoptosis, and impairing neurogenesis, synaptogenesis, cell proliferation and migration, and synaptic plasticity.(4,5) Furthermore, it is well recognized that many AEDs have cognitive adverse effects,(6) with attention,…”
A model of symptomatic infantile spasms syndrome
Scantlebury, M. H., Galanopoulou, A. S., Chudomelova, L., Raffo, E., Betancourth, D., & Moshé, S. L. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.11.011 · Cited by 136 · see citing works
“The mechanisms underlying seizure generation as well as the effects of drugs may be completely different in the developing brain compared to adults (Kaindl et al., 2006; Veliskova et al., 2004).”
Cognitive outcome after epilepsy surgery in children
van Schooneveld, M. M. J., & Braun, K. P. J. (2013) · Brain and Development · doi:10.1016/j.braindev.2013.01.011 · Cited by 125 · see citing works
“However, given the known cognitive side effects of AEDs [31,32], the negative influence of many AEDs may have on brain development [33,34] and the improvement of cognitive function after discontinuation of AEDs in non-surgical cohorts [35–37] it can be expected that AED withdrawal increases the chances of postoperativ…”
BackgroundLanguage skills of school-aged children prenatally exposed to antiepileptic drugs
Nadebaum, C., Anderson, V., Vajda, F. J. E., Reutens, D. C., Barton, S., & WOOD, A. G. (2011) · Neurology · doi:10.1212/wnl.0b013e31820d62c7 · Cited by 120 · see citing works
Epilepsy priorities in Europe: A report of the ILAE ‐ IBE Epilepsy Advocacy Europe Task Force
Baulac, M., de Boer, H., Elger, C. E., Glynn, M., Kälviäinen, R. K., Little, A. A., Mifsud, J., Perucca, E., Pitkänen, A., & Ryvlin, P. (2015) · Epilepsia · doi:10.1111/epi.13201 · Cited by 103 · see citing works
Jančić, D., de Armentia, M. L., Valor, L. M., Olivares, R., & Barco, Á. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhp004 · Cited by 102 · see citing works
“Lower than normal neuronal activity can, in the long-term, cause the loss of neurons in hippocampal circuits, especially in juvenile animals (Kaindl et al. 2006).”
BackgroundBehavioral changes in dogs associated with the development of idiopathic epilepsy
Shihab, N. K., Bowen, J., & Volk, H. A. (2011) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2011.03.018 · Cited by 97 · see citing works
“In human medicine it is considered possible that both cortical development and mental functions are negatively influenced by seizures and that the use of antiepileptic drugs may also have adverse effects on the developing brain by interfering with neuronal migration, differentiation, and plasticity [51].”
BackgroundCognitive/behavioral teratogenetic effects of antiepileptic drugs
Meador, K. J., Baker, G. A., Cohen, M. J., Gaily, E. K., & Westerveld, M. (2007) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2007.08.009 · Cited by 94 · see citing works
“The immature brain is susceptible towidespread neuronal apoptosis secondary to a variety of insults including trauma, seizures, excessive oxygen, and certain drugs [36–43].”
BackgroundHamed, S. A. (2009) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2008.00062.x · Cited by 94 · see citing works
Neonatal Seizure Management: Is the Timing of Treatment Critical?
Pavel, A. M., Rennie, J. M., de Vries, L. S., Blennow, M., Foran, A. M., Shah, D. K., Pressler, R., Kapellou, O., Dempsey, E. M., Mathieson, S., et al. (2021) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2021.09.058 · Cited by 77 · see citing works
“Number of seizures, median (IQR) 21 (9-52) 23 (5-33) 28 (12-52) 32 (12-60) 10 (2-32)”
GABAA Receptors, Anesthetics and Anticonvulsants in Brain Development
Henschel, O., Gipson, K. E., & Bordey, A. (2008) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152708784083812 · Cited by 70 · see citing works
Kim, J., Cho, J., Kim, S. H., Kang, H., Kim, D.-S., Kim, V. N., & Lee, J. H. (2019) · Journal of Clinical Investigation · doi:10.1172/jci127032 · Cited by 65 · see citing works
Kaindl, A. M., Koppelstaetter, A., Nebrich, G., Stuwe, J., Sifringer, M., Zabel, C., Klose, J., & Ikonomidou, C. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800030-mcp200 · Cited by 65 · see citing works
“Neurological abnormalities associated with developmental exposure to such drugs and to environmental toxins such as ethanol, phencyclidine, lead, and methylmercury (1, 2) have been reported and point out that disturbances in neurotransmitter signaling during critical periods can influence developmental events in their…”
BackgroundSelf-citationClinical Features and Neurologic Progression of Hyperargininemia
Carvalho, D. R., Brum, J. M., Speck‐Martins, C. E., Ventura, F. D., Navarro, M. M., Coelho, K. E. F. A., Portugal, D., & Pratesi, R. (2012) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2012.03.016 · Cited by 61 · see citing works
“Some patients with a small head circumference were taking antiepileptic drugs while their brains were still growing, which may have contributed to the development of microcephaly [16].”
BackgroundTreatment of neonatal seizures
Rennie, J. M., & Boylan, G. B. (2007) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/adc.2004.068551 · Cited by 61 · see citing works
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“The broad spectrum of available antiepileptic drugs has expanded the choice of treatment, as well as the variety of possible adverse reactions.(4) Antiepileptic drugs adverse reactions, including hepatotoxicity, are rare but potentially fatal, especially among children.”
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“However anti-epileptic drugs may themselves contribute to the development of cognitive impairments (Kaindl et al., 2004).”
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“(ASD) [1,2].”
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“There exists, however, only a small body of literature that describes the effects of AED exposure during infancy and early childhood, and animal models have not been extensively developed (Kaindl et al., 2006; Motamedi and Meador, 2006).”
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“The earlier publications on the matter, which yielded some inconsistent conclusions, were reviewed by Bartlett and Richens [44] and Kaindl [87] .”
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“Both topiramate and levetiracetam demonstrate no enhancement of neuronal apoptosis at therapeutic doses in the immature rat.(77) Current recommendations, then, do not support the use of antiseizure medication for long-term prevention of posttraumatic epilepsy after traumatic brain injury in either adults or children.”
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“antagonists of NMDA receptors (ketamine, nitrous oxide), agonists of GABA subtype A receptors (barbiturates, benzodiazepines, propofol) and sodium channel blockers (phenytoin, valproic acid) (Kaindl et al., 2006; Bittigau et al., 2002; Ikonomidou et al., 1999, 2000; Jevtovic-Todorovic et al., 2003).”
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KCNQ2- and KCNQ3-Associated Epilepsy
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“In the early postnatal brain, phenytoin increases the volume of the DG (Kaindl et al., 2006).”
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Effects of Levetiracetam on neural tube development and closure of the chick embryos in ovo
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“5,6 However, the seizure recurrence rate increases when ASMs are discontinued even for short periods, because there is a direct correlation between a greater risk of seizure recurrence and the withdrawal effects of certain ASMs.”
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“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).”
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“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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“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).”
BackgroundNeurologic birth defects after prenatal exposure to antiepileptic drugs
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“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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“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.”
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“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].”
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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.”
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“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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“[19] present evidence that phenytoin, diazepam, clonazepam, vigabatrin, and valproate, as well as phenobarbital, when administered to young rats results in neurodegeneration.”
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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.
- Venue
- Cellular and Molecular Life Sciences CMLS
- Published
- 2006-01-02
- Volume
- 63
- Issue
- 4
- Pages
- 399-413
- ISSN
- 1420-682X (ISSN-L)
- 1420-9071
- 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
- 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 › Psychiatry and Mental health › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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