Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the ≈30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators—released by brain cells and peripheral immune cells—in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis.
Epilepsies of various etiologies not classically linked to immunological dysfunction can be associated with inflammation resulting from increased levels of inflammatory mediators in the brain
Inflammatory mediators can be produced by glia, neurons, endothelial cells of the blood–brain barrier, and peripheral immune cells
Brain inflammation might contribute to the onset and perpetuation of seizures in a variety of epilepsies
Experimental and clinical research is required to generate novel therapeutic anti-inflammatory approaches that ameliorate seizures and modify the underlying pathophysiology of epilepsy
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This work was supported by contributions to A. Vezzani from Fondazione Cariplo, Fondazione Monzino and Parents Against Childhood Epilepsy (P.A.C.E.), the NIH R37 NS35439 and American Epilepsy Society Research Initiative award given to T. Z. Baram, and a Shaw Family Initiative On Inflammation award given to J. French. We apologize to the many authors whose work was not cited because of space limitations.
A. Vezzani is a holder of intellectual property at Vertex Pharmaceuticals, and J. French has received research support from Vertex Pharmaceuticals. T. Z. Baram has received honoraria from Pfizer and Questcor Pharmaceuticals, and has also acted as a consultant for Questcor Pharmaceuticals. T. Bartfai declares no competing interests.
Supplementary Table 1
Inflammatory mediators in human epilepsy (DOC 68 kb)
Supplementary Table 2
Inflammatory mediators in brain tissue from experimental models of seizures and epilepsy (DOC 63 kb)
Supplementary Table 3
Inflammation, seizures and epileptogenesis: representative data from immature and adult animal models (DOCX 29 kb)
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Vezzani, A., French, J., Bartfai, T. et al. The role of inflammation in epilepsy. Nat Rev Neurol 7, 31–40 (2011). https://doi.org/10.1038/nrneurol.2010.178
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