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  • Review Article
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Epileptogenesis in the immature brain: emerging mechanisms

Nature Reviews Neurology volume 5, pages 380–391 (2009)Cite this article

Abstract

Epileptogenesis is defined as the process of developing epilepsy—a disorder characterized by recurrent seizures—following an initial insult. Seizure incidence during the human lifespan is at its highest in infancy and childhood. Animal models of epilepsy and human tissue studies suggest that epileptogenesis involves a cascade of molecular, cellular and neuronal network alterations. Within minutes to days following the initial insult, there are acute early changes in neuronal networks, which include rapid alterations to ion channel kinetics as a result of membrane depolarization, post-translational modifications to existing functional proteins, and activation of immediate early genes. Subacute changes occur over hours to weeks, and include transcriptional events, neuronal death and activation of inflammatory cascades. The chronic changes that follow over weeks to months include anatomical changes, such as neurogenesis, mossy fiber sprouting, network reorganization, and gliosis. These epileptogenic processes are developmentally regulated and might contribute to differences in epileptogenesis between adult and developing brains. Here we review the factors responsible for enhanced seizure susceptibility in the developing brain, and consider age-specific mechanisms of epileptogenesis. An understanding of these factors could yield potential therapeutic targets for the prevention of epileptogenesis and also provide biomarkers for identifying patients at risk of developing epilepsy or for monitoring disease progression.

Key Points

  • Epileptogenesis is defined as the process of developing epilepsy—a disorder characterized by recurrent seizures—following an initial insult, and the process evolves through acute, subacute and chronic phases

  • The currently available therapies for epilepsy are predominantly anticonvulsant and do not modify the epileptogenic process

  • The immature brain exhibits increased excitation and diminished inhibition, and this enhanced excitability increases the propensity for seizures and epileptogenesis in infancy and early childhood compared with later life

  • The epileptogenic process in the immature brain evolves via alterations in molecular, cellular and neuronal network properties; animal models provide valuable insight into this process

  • Targeting the different phases of epileptogenesis with appropriate therapies might help develop disease-modifying antiepileptogenic treatment paradigms

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Figure 1: Schematic depiction of maturational changes in glutamate and GABA receptor function in the developing brain.30
Figure 2: Time course of epileptogenesis.151

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Acknowledgements

This work was supported by funding from the National Institutes of Health (grants RO1 NS31718 and DP1 OD003347 to F. E. Jensen), the Epilepsy Therapy Development Project (F. E. Jensen), and a grant from the Parents Against Childhood Epilepsy (S. N. Rakhade and F. E. Jensen). Additional support was provided from the National Institutes of Health Mental Retardation and Developmental Disabilities Center (P30 HD18655).

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  1. Department of Neurology, Division of Neuroscience, Children's Hospital and Harvard Medical School, Boston, MA, USA

    Sanjay N. Rakhade & Frances E. Jensen

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Rakhade, S., Jensen, F. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol 5, 380–391 (2009). https://doi.org/10.1038/nrneurol.2009.80

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