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Mechanisms of Epileptogenesis in Pediatric Epileptic Syndromes: Rasmussen Encephalitis, Infantile Spasms, and Febrile Infection-related Epilepsy Syndrome (FIRES)

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  • Published:
Neurotherapeutics

Abstract

The mechanisms of epileptogenesis in pediatric epileptic syndromes are diverse, and may involve disturbances of neurodevelopmental trajectories, synaptic homeostasis, and cortical connectivity, which may occur during brain development, early infancy, or childhood. Although genetic or structural/metabolic factors are frequently associated with age-specific epileptic syndromes, such as infantile spasms and West syndrome, other syndromes may be determined by the effect of immunopathogenic mechanisms or energy-dependent processes in response to environmental challenges, such as infections or fever in normally-developed children during early or late childhood. Immune-mediated mechanisms have been suggested in selected pediatric epileptic syndromes in which acute and rapidly progressive encephalopathies preceded by fever and/or infections, such as febrile infection-related epilepsy syndrome, or in chronic progressive encephalopathies, such as Rasmussen encephalitis. A definite involvement of adaptive and innate immune mechanisms driven by cytotoxic CD8+ T lymphocytes and neuroglial responses has been demonstrated in Rasmussen encephalitis, although the triggering factor of these responses remains unknown. Although the beneficial response to steroids and adrenocorticotropic hormone of infantile spasms, or preceding fever or infection in FIRES, may support a potential role of neuroinflammation as pathogenic factor, no definite demonstration of such involvement has been achieved, and genetic or metabolic factors are suspected. A major challenge for the future is discovering pathogenic mechanisms and etiological factors that facilitate the introduction of novel targets for drug intervention aimed at interfering with the disease mechanisms, therefore providing putative disease-modifying treatments in these pediatric epileptic syndromes.

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Acknowledgments

CAP was supported by The Bart McLean Fund for Neuroimmunology Research-Johns Hopkins Project Restore, and the RE Children’s Project. ASG was supported by a grant from the National Institute of Neurological Disorders and Stroke (NS078333), and by CURE, Autism Speaks, the Department of Defense, and the Heffer Family and Siegel Family Foundations. ASG has received royalties from Morgan & Claypool Publishers and John Libbey Eurotext Ltd, and a consultancy honorarium from Viropharma.

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Authors and Affiliations

  1. Department of Neurology, Division of Neuroimmunology and Neuroinfectious Disorders, Center for Pediatric Rasmussen Syndrome, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Carlos A. Pardo

  2. Centre de Reference Epilepsies Rares, Pediatric Neurology Department, Necker Enfants Malades Hospital, APHP, Inserm U663, University Paris Descartes, Paris, France

    Rima Nabbout

  3. Laboratory of Developmental Epilepsy, Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Montefiore/Einstein Epilepsy Management Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Aristea S. Galanopoulou

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  1. Carlos A. Pardo
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Correspondence to Carlos A. Pardo.

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Pardo, C.A., Nabbout, R. & Galanopoulou, A.S. Mechanisms of Epileptogenesis in Pediatric Epileptic Syndromes: Rasmussen Encephalitis, Infantile Spasms, and Febrile Infection-related Epilepsy Syndrome (FIRES). Neurotherapeutics 11, 297–310 (2014). https://doi.org/10.1007/s13311-014-0265-2

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