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Insights into epileptogenesis from post-traumatic epilepsy

Nature Reviews Neurology (2024)Cite this article

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Abstract

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies. The incidence of PTE after traumatic brain injury (TBI) depends on the severity of injury, approaching one in three in groups with the most severe injuries. The repeated seizures that characterize PTE impair neurological recovery and increase the risk of poor outcomes after TBI. Given this high risk of recurrent seizures and the relatively short latency period for their development after injury, PTE serves as a model disease to understand human epileptogenesis and trial novel anti-epileptogenic therapies. Epileptogenesis is the process whereby previously normal brain tissue becomes prone to recurrent abnormal electrical activity, ultimately resulting in seizures. In this Review, we describe the clinical course of PTE and highlight promising research into epileptogenesis and treatment using animal models of PTE. Clinical, imaging, EEG and fluid biomarkers are being developed to aid the identification of patients at high risk of PTE who might benefit from anti-epileptogenic therapies. Studies in preclinical models of PTE have identified tractable pathways and novel therapeutic strategies that can potentially prevent epilepsy, which remain to be validated in humans. In addition to improving outcomes after TBI, advances in PTE research are likely to provide therapeutic insights that are relevant to all epilepsies.

Key points

  • Post-traumatic epilepsy (PTE) is highly prevalent after traumatic brain injury, impairing neurological recovery and leading to worse functional outcomes.

  • Current epilepsy therapeutics symptomatically treat seizures but do not modify epileptogenesis, the process by which brain tissue becomes prone to seizures.

  • The unique nature of PTE, occurring after a well-defined epileptogenic insult, makes it a promising model system for understanding epileptogenesis.

  • Future research in individuals with PTE populations might not only reveal novel mechanisms of epileptogenesis but also enable anti-epileptogenic therapies to be tested.

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Fig. 1: Prevalence of post-traumatic epilepsy after moderate or severe traumatic brain injury.
Fig. 2: Mechanisms of epileptogenesis after traumatic brain injury.

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Acknowledgements

The authors thank Christopher Brown (Indiana University) for his contributions to the design of the figures for this manuscript.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Indiana University, Bloomington, IN, USA

    Matthew Pease

  2. Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA

    Kunal Gupta

  3. The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA

    Solomon L. Moshé, Daniel J. Correa & Aristea S. Galanopoulou

  4. Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA

    Solomon L. Moshé & Aristea S. Galanopoulou

  5. Department of Paediatrics, Albert Einstein College of Medicine, New York, NY, USA

    Solomon L. Moshé

  6. Department of Neurosurgery, University of Pittsburgh, Pittsburgh, PA, USA

    David O. Okonkwo, Jorge Gonzalez-Martinez & Lori Shutter

  7. Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Lori Shutter

  8. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

    Lori Shutter & James F. Castellano

  9. Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

    Ramon Diaz-Arrastia

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Contributions

M.P., K.G., S.M., A.G., D.O.O., J.G.-M., L.S. and J.F.C. researched data for the article. All authors contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Matthew Pease.

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Competing interests

S.M. is the Charles Frost Chair in Neurosurgery and Neurology and partially funded by grants from NIH U54 NS100064 (EpiBioS4Rx), R01-NS43209 and R01-NS127524, the US Department of Defense (W81XWH-22-1-0510, W81XWH-22-1-0210), a pilot grant from the National Institute of Child Health and Human Development (NICHD) centre grant (P50 HD105352) for the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK-IDDRC), the Heffer Family and the Segal Family Foundations, the Isabelle Rapin and Harold Oaklander Child Neurology Research Fund in the Isabelle Rapin Child Neurology Division and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. He is on the editorial boards of Brain and Development, Paediatric Neurology, Annals of Neurology, MedLink and Physiological Research. He receives compensation from MedLink for his work as Associate Editor; and royalties from books he co-edited. A.G. acknowledges research grant support from NINDS R01-NS127524, US Department of Defense (W81XWH-22-1-0210, W81XWH-22-1-0510, EP220067), a pilot grant from the NICHD centre grant (P50 HD105352) for the RFK-IDDRC, R01-DA019473, R01-AI164864, the Heffer Family and the Segal Family Foundations, the Isabelle Rapin and Harold Oaklander Child Neurology Research Fund in the Isabelle Rapin Child Neurology Division and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. She is the Editor-in-Chief of Epilepsia Open and associate editor of Neurobiology of Disease and receives royalties from Elsevier, Walters Kluwer and MedLink for publications. J.G.-M. receives consulting fees for Zimmer Biomet. D.C. receives compensation as lead editor for the Brain and Life podcast for the American Academy of Neurology and is co-editor of a new textbook on health equity among neurological disorders including chapters on traumatic brain injury and epilepsy. J.F.C. and K.G. accept fees from NeuroOne Medical Technologies Corporation for consulting. The other authors declare no competing interests.

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Nature Reviews Neurology thanks S. Shultz and D. Duncan for their contribution to the peer review of this work.

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Glossary

Anti-epileptogenic medications

(AEMs). Therapies that ameliorate epileptogenesis, with lasting effects beyond the period of drug exposure.

Anti-seizure medications

(ASMs). Medications that treat seizures but do not modify the process of epileptogenesis or alter the disease course of epilepsy.

Cerebrospinal fluid shunting

A common neurosurgical procedure to drain cerebrospinal fluid, usually from the ventricular system, thereby decreasing intracranial pressure.

Encephalomalacia

A radiological finding denoting an area of brain tissue that has undergone liquefactive necrosis.

Engel Epilepsy Surgery Outcome Scale

A classification scheme of seizure outcomes after epilepsy surgery using four classes: 1, free of disabling seizures; 2, rare disabling seizures; 3, worthwhile improvement; and 4, no worthwhile improvement.

Extended GOS

(GOSE). An extension of the Glasgow Outcome Scale that subdivides the categories of severe disability, moderate disability and good recovery into lower and upper categories.

Glasgow Coma Scale

(GCS). A broadly utilized clinical scale describing the level of consciousness after traumatic injury.

Glasgow Outcome Scale

(GOS). A global scale for functional outcome after brain injury that rates patient status using five categories: dead, vegetative state, severe disability, moderate disability and good recovery.

Mild TBI

Traumatic brain injury with post-impact (may not need resuscitation) Glasgow Coma Scale score 13–15.

Moderate TBI

Traumatic brain injury with post-resuscitation Glasgow Coma Scale score 9–12.

Pathological posturing responses

Stereotypical movements of the trunk and extremities in response to stimuli, typically indicative of significant CNS injury.

Severe TBI

Traumatic brain injury with post-resuscitation Glasgow Coma Scale score ≤ 8.

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Pease, M., Gupta, K., Moshé, S.L. et al. Insights into epileptogenesis from post-traumatic epilepsy. Nat Rev Neurol (2024). https://doi.org/10.1038/s41582-024-00954-y

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