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The role of inflammation in epilepsy

Nature Reviews Neurology volume 7, pages 31–40 (2011)Cite this article

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Abstract

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.

Key Points

  • 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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Figure 1: Pathophysiological cascade of inflammatory events in epilepsy.

References

  1. Duncan, J. S., Sander, J. W., Sisodiya, S. M. & Walker, M. C. Adult epilepsy. Lancet 367, 1087–1100 (2006).

    PubMed  Google Scholar 

  2. Perucca, E., French, J. & Bialer, M. Development of new antiepileptic drugs: challenges, incentives, and recent advances. Lancet Neurol. 6, 793–804 (2007).

    CAS  PubMed  Google Scholar 

  3. Rogawski, M. A. & Loscher, W. The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci. 5, 553–564 (2004).

    CAS  PubMed  Google Scholar 

  4. Pitkanen, A. & Sutula, T. P. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol. 1, 173–181 (2002).

    PubMed  Google Scholar 

  5. Vezzani, A. & Granata, T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46, 1724–1743 (2005).

    CAS  PubMed  Google Scholar 

  6. Vezzani, A. & Baram, T. Z. New roles for interleukin-1 beta in the mechanisms of epilepsy. Epilepsy Curr. 7, 45–50 (2007).

    PubMed  PubMed Central  Google Scholar 

  7. Riazi, K., Galic, M. A. & Pittman, Q. J. Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy Res. 89, 34–42 (2010).

    CAS  PubMed  Google Scholar 

  8. Choi, J. et al. Cellular injury and neuroinflammation in children with chronic intractable epilepsy. J. Neuroinflammation 6, 38 (2009).

    PubMed  PubMed Central  Google Scholar 

  9. Riikonen, R. Infantile spasms: therapy and outcome. J. Child Neurol. 19, 401–404 (2004).

    PubMed  Google Scholar 

  10. Wheless, J. W., Clarke, D. F., Arzimanoglou, A. & Carpenter, D. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic Disord. 9, 353–412 (2007).

    PubMed  Google Scholar 

  11. Wirrell, E., Farrell, K. & Whiting, S. The epileptic encephalopathies of infancy and childhood. Can. J. Neurol. Sci. 32, 409–418 (2005).

    PubMed  Google Scholar 

  12. Dubé, C. M., Brewster, A. L., Richichi, C., Zha, Q. & Baram, T. Z. Fever, febrile seizures and epilepsy. Trends Neurosci. 30, 490–496 (2007).

    PubMed  PubMed Central  Google Scholar 

  13. Dinarello, C. A. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J. Endotoxin Res. 10, 201–222 (2004).

    CAS  PubMed  Google Scholar 

  14. Rasmussen, T., Olsewski, J. & Lloyd-Smith, D. Focal seizures due to chronic localized encephalitis. Neurology 8, 435–445 (1958).

    CAS  PubMed  Google Scholar 

  15. Bien, C. G. et al. Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology 69, 1236–1244 (2007).

    CAS  PubMed  Google Scholar 

  16. Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Vincent, A. & Bien, C. G. Anti-NMDA-receptor encephalitis: a cause of psychiatric, seizure, and movement disorders in young adults. Lancet Neurol. 7, 1074–1075 (2008).

    PubMed  Google Scholar 

  18. Aarli, J. A. Epilepsy and the immune system. Arch. Neurol. 57, 1689–1692 (2000).

    CAS  PubMed  Google Scholar 

  19. Ravizza, T., Balosso, S., Aronica, E. & Vezzani, A. in Epilepsy: Mechanisms, Models, and Translational Perpsectives Ch. 4 (eds Rho, J. M. et al.) 45–59 (CRC Press, Boca Raton, 2010).

    Google Scholar 

  20. Campbell, I. L. et al. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc. Natl Acad. Sci. USA 90, 10061–10065 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Vezzani, A. et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc. Natl Acad. Sci. USA 97, 11534–11539 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Balosso, S. et al. Tumor necrosis factor-α inhibits seizures in mice via p75 receptors. Ann. Neurol. 57, 804–812 (2005).

    CAS  PubMed  Google Scholar 

  23. Ravizza, T. et al. Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47, 1160–1168 (2006).

    CAS  PubMed  Google Scholar 

  24. Samland, H. et al. Profound increase in sensitivity to glutamatergic- but not cholinergic agonist-induced seizures in transgenic mice with astrocyte production of IL-6. J. Neurosci. Res. 73, 176–187 (2003).

    CAS  PubMed  Google Scholar 

  25. Akassoglou, K., Probert, L., Kontogeorgos, G. & Kollias, G. Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice. J. Immunol. 158, 438–445 (1997).

    CAS  PubMed  Google Scholar 

  26. Kelley, K. A. et al. Potentiation of excitotoxicity in transgenic mice overexpressing neuronal cyclooxygenase-2. Am. J. Pathol. 155, 995–1004 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. De Sarro, G. et al. Seizure susceptibility to various convulsant stimuli of knockout interleukin-6 mice. Pharmacol. Biochem. Behav. 77, 761–766 (2004).

    CAS  PubMed  Google Scholar 

  28. Ransohoff, R. M., Kivisakk, P. & Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 3, 569–581 (2003).

    CAS  PubMed  Google Scholar 

  29. Banks, W. A. & Erickson, M. A. The blood–brain barrier and immune function and dysfunction. Neurobiol. Dis. 37, 26–32 (2010).

    CAS  PubMed  Google Scholar 

  30. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Nguyen, M. D., Julien, J. P. & Rivest, S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat. Rev. Neurosci. 3, 216–227 (2002).

    CAS  PubMed  Google Scholar 

  32. Appel, S. H., Beers, D. R. & Henkel, J. S. T cell–microglial dialog in Parkinson's disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol. 31, 7–17 (2009).

    PubMed  PubMed Central  Google Scholar 

  33. Allan, S. M., Tyrrell, P. J. & Rothwell, N. J. Interleukin-1 and neuronal injury. Nat. Rev. Immunol. 5, 629–640 (2005).

    CAS  PubMed  Google Scholar 

  34. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2, 675–680 (2001).

    CAS  PubMed  Google Scholar 

  35. Bartfai, T. et al. Interleukin-1 system in CNS stress: seizures, fever, and neurotrauma. Ann. N. Y. Acad. Sci. 1113, 173–177 (2007).

    CAS  PubMed  Google Scholar 

  36. Allan, S. M. & Rothwell, N. J. Cytokines and acute neurodegeneration. Nat. Rev. Neurosci. 2, 734–744 (2001).

    CAS  PubMed  Google Scholar 

  37. Bartfai, T. & Schultzberg, M. Cytokines in neuronal cell types. Neurochem. Int. 22, 435–444 (1993).

    CAS  PubMed  Google Scholar 

  38. Wilson, E. H., Weninger, W. & Hunter, C. A. Trafficking of immune cells in the central nervous system. J. Clin. Invest. 120, 1368–1379 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Szekanecz, Z. & Koch, A. E. Chemokines and angiogenesis. Curr. Opin. Rheumatol. 13, 202–208 (2001).

    CAS  PubMed  Google Scholar 

  40. Semple, B. D., Kossmann, T. & Morganti-Kossmann, M. C. Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J. Cereb. Blood Flow Metab. 30, 459–473 (2010).

    CAS  PubMed  Google Scholar 

  41. Dinarello, C. A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).

    CAS  PubMed  Google Scholar 

  42. Mantovani, A., Locati, M., Vecchi, A., Sozzani, S. & Allavena, P. Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines. Trends Immunol. 22, 328–336 (2001).

    CAS  PubMed  Google Scholar 

  43. Baker, B. J., Akhtar, L. N. & Benveniste, E. N. SOCS1 and SOCS3 in the control of CNS immunity. Trends Immunol. 30, 392–400 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Khuu, C. H., Barrozo, R. M., Hai, T. & Weinstein, S. L. Activating transcription factor 3 (ATF3) represses the expression of CCL4 in murine macrophages. Mol. Immunol. 44, 1598–1605 (2007).

    CAS  PubMed  Google Scholar 

  45. Ho, H. H., Antoniv, T. T., Ji, J. D. & Ivashkiv, L. B. Lipopolysaccharide-induced expression of matrix metalloproteinases in human monocytes is suppressed by IFN-γ via superinduction of ATF-3 and suppression of AP-1. J. Immunol. 181, 5089–5097 (2008).

    CAS  PubMed  Google Scholar 

  46. Blobe, G. C., Schiemann, W. P. & Lodish, H. F. Role of transforming growth factor β in human disease. N. Engl. J. Med. 342, 1350–1358 (2000).

    CAS  PubMed  Google Scholar 

  47. Sapolsky, R., Rivier, C., Yamamoto, G., Plotsky, P. & Vale, W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238, 522–524 (1987).

    CAS  PubMed  Google Scholar 

  48. Rothwell, N. J. CRF is involved in the pyrogenic and thermogenic effects of interleukin 1 beta in the rat. Am. J. Physiol. 256, E111–E115 (1989).

    CAS  PubMed  Google Scholar 

  49. Elenkov, I. J., Webster, E. L., Torpy, D. J. & Chrousos, G. P. Stress, corticotropin-releasing hormone, glucocorticoids, and the immune/inflammatory response: acute and chronic effects. Ann. N. Y. Acad. Sci. 876, 1–13 (1999).

    CAS  PubMed  Google Scholar 

  50. Tracey, K. J. The inflammatory reflex. Nature 420, 853–859 (2002).

    CAS  PubMed  Google Scholar 

  51. Najjar, S., Bernbaum, M., Lai, G. & Devinsky, O. Immunology and epilepsy. Rev. Neurol. Dis. 5, 109–116 (2008).

    PubMed  Google Scholar 

  52. Rogers, S. W. et al. Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 265, 648–651 (1994).

    CAS  PubMed  Google Scholar 

  53. Mantegazza, R. et al. Antibodies against GluR3 peptides are not specific for Rasmussen's encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J. Neuroimmunol. 131, 179–185 (2002).

    CAS  PubMed  Google Scholar 

  54. Watson, R. et al. Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis. Neurology 63, 43–50 (2004).

    CAS  PubMed  Google Scholar 

  55. Bien, C. G. et al. Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen's encephalitis. Ann. Neurol. 51, 311–318 (2002).

    CAS  PubMed  Google Scholar 

  56. Baranzini, S. E., Laxer, K., Bollen, A. & Oksenberg, J. R. Gene expression analysis reveals altered brain transcription of glutamate receptors and inflammatory genes in a patient with chronic focal (Rasmussen's) encephalitis. J. Neuroimmunol. 128, 9–15 (2002).

    CAS  PubMed  Google Scholar 

  57. Pardo, C. A. et al. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia 45, 516–526 (2004).

    PubMed  Google Scholar 

  58. Wirenfeldt, M. et al. Increased activation of Iba1+ microglia in pediatric epilepsy patients with Rasmussen's encephalitis compared with cortical dysplasia and tuberous sclerosis complex. Neurobiol. Dis. 34, 432–440 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Takahashi, Y., Mine, J., Kubota, Y., Yamazaki, E. & Fujiwara, T. A substantial number of Rasmussen syndrome patients have increased IgG, CD4+ T cells, TNFα, and granzyme B in CSF. Epilepsia 50, 1419–1431 (2009).

    CAS  PubMed  Google Scholar 

  60. Vincent, A., Irani, S. R. & Lang, B. The growing recognition of immunotherapy-responsive seizure disorders with autoantibodies to specific neuronal proteins. Curr. Opin. Neurol. 23, 144–150 (2010).

    CAS  PubMed  Google Scholar 

  61. Crespel, A. et al. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res. 952, 159–169 (2002).

    CAS  PubMed  Google Scholar 

  62. Aronica, E. et al. Complement activation in experimental and human temporal lobe epilepsy. Neurobiol. Dis. 26, 497–511 (2007).

    CAS  PubMed  Google Scholar 

  63. Ravizza, T. et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol. Dis. 29, 142–160 (2008).

    CAS  PubMed  Google Scholar 

  64. van Gassen, K. L. et al. Possible role of the innate immunity in temporal lobe epilepsy. Epilepsia 49, 1055–1065 (2008).

    CAS  PubMed  Google Scholar 

  65. Maldonado, M. et al. Expression of ICAM-1, TNF-α, NFκB, and MAP kinase in tubers of the tuberous sclerosis complex. Neurobiol. Dis. 14, 279–290 (2003).

    CAS  PubMed  Google Scholar 

  66. Boer, K. et al. Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Epilepsy Res. 78, 7–21 (2008).

    CAS  PubMed  Google Scholar 

  67. Boer, K. et al. Gene expression analysis of tuberous sclerosis complex cortical tubers reveals increased expression of adhesion and inflammatory factors. Brain Pathol. 20, 704–719 (2010).

    CAS  PubMed  Google Scholar 

  68. Iyer, A. M. et al. Tissue plasminogen activator and urokinase plasminogen activator in human epileptogenic pathologies. Neuroscience 19, 929–945 (2010).

    Google Scholar 

  69. Iyer, A. et al. Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia 51, 1763–1773 (2010).

    CAS  PubMed  Google Scholar 

  70. Ravizza, T. et al. The IL-1β system in epilepsy-associated malformations of cortical development. Neurobiol. Dis. 24, 128–143 (2006).

    CAS  PubMed  Google Scholar 

  71. Minami, M., Kuraishi, Y. & Satoh, M. Effects of kainic acid on messenger RNA levels of IL-1β, IL-6, TNF-α and LIF in the rat brain. Biochem. Biophys. Res. Commun. 176, 593–598 (1991).

    CAS  PubMed  Google Scholar 

  72. Vezzani, A. et al. Interleukin-1β immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J. Neurosci. 19, 5054–5065 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. De Simoni, M. G. et al. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur. J. Neurosci. 12, 2623–2633 (2000).

    CAS  PubMed  Google Scholar 

  74. Turrin, N. P. & Rivest, S. Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol. Dis. 16, 321–334 (2004).

    CAS  PubMed  Google Scholar 

  75. Eriksson, C., Tehranian, R., Iverfeldt, K., Winblad, B. & Schultzberg, M. Increased expression of mRNA encoding interleukin-1β and caspase-1, and the secreted isoform of interleukin-1 receptor antagonist in the rat brain following systemic kainic acid administration. J. Neurosci. Res. 60, 266–279 (2000).

    CAS  PubMed  Google Scholar 

  76. Voutsinos-Porche, B. et al. Temporal patterns of the cerebral inflammatory response in the rat lithium-pilocarpine model of temporal lobe epilepsy. Neurobiol. Dis. 17, 385–402 (2004).

    CAS  PubMed  Google Scholar 

  77. Jung, K. H. et al. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol. Dis. 23, 237–246 (2006).

    CAS  PubMed  Google Scholar 

  78. Lee, B., Dziema, H., Lee, K. H., Choi, Y. S. & Obrietan, K. CRE-mediated transcription and COX-2 expression in the pilocarpine model of status epilepticus. Neurobiol. Dis. 25, 80–91 (2007).

    CAS  PubMed  Google Scholar 

  79. Gorter, J. A. et al. Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy. J. Neurosci. 26, 11083–11110 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Polascheck, N., Bankstahl, M. & Loscher, W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp. Neurol. 224, 219–233 (2010).

    CAS  PubMed  Google Scholar 

  81. Holtman, L. et al. Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res. 84, 56–66 (2009).

    CAS  PubMed  Google Scholar 

  82. Dhote, F. et al. Prolonged inflammatory gene response following soman-induced seizures in mice. Toxicology 238, 166–176 (2007).

    CAS  PubMed  Google Scholar 

  83. Yoshikawa, K., Kita, Y., Kishimoto, K. & Shimizu, T. Profiling of eicosanoid production in the rat hippocampus during kainic acid-induced seizure: dual phase regulation and differential involvement of COX-1 and COX-2. J. Biol. Chem. 281, 14663–14669 (2006).

    CAS  PubMed  Google Scholar 

  84. Rozovsky, I. et al. Selective expression of clusterin (SGP-2) and complement C1qB and C4 during responses to neurotoxins in vivo and in vitro. Neuroscience 62, 741–758 (1994).

    CAS  PubMed  Google Scholar 

  85. Kulkarni, S. K. & Dhir, A. Cyclooxygenase in epilepsy: from perception to application. Drugs Today (Barc.) 45, 135–154 (2009).

    CAS  Google Scholar 

  86. Vezzani, A., Balosso, S. & Ravizza, T. The role of cytokines in the pathophysiology of epilepsy. Brain Behav. Immun. 22, 797–803 (2008).

    CAS  PubMed  Google Scholar 

  87. Fabene, P. F., Bramanti, P. & Constantin, G. The emerging role for chemokines in epilepsy. J. Neuroimmunol. 224, 22–27 (2010).

    CAS  PubMed  Google Scholar 

  88. Xu, J. H. et al. CCR3, CCR2A and macrophage inflammatory protein (MIP)-1a, monocyte chemotactic protein-1 (MCP-1) in the mouse hippocampus during and after pilocarpine-induced status epilepticus (PISE). Neuropathol. Appl. Neurobiol. 35, 496–514 (2009).

    CAS  PubMed  Google Scholar 

  89. Foresti, M. L. et al. Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus. J. Neuroinflammation 6, 40 (2009).

    PubMed  PubMed Central  Google Scholar 

  90. Manley, N. C., Bertrand, A. A., Kinney, K. S., Hing, T. C. & Sapolsky, R. M. Characterization of monocyte chemoattractant protein-1 expression following a kainate model of status epilepticus. Brain Res. 1182, 138–143 (2007).

    CAS  PubMed  Google Scholar 

  91. Wu, Y. et al. Expression of monocyte chemoattractant protein-1 in brain tissue of patients with intractable epilepsy. Clin. Neuropathol. 27, 55–63 (2008).

    CAS  PubMed  Google Scholar 

  92. Fabene, P. F. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat. Med. 14, 1377–1383 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Librizzi, L. et al. Expression of adhesion factors induced by epileptiform activity in the endothelium of the isolated guinea pig brain in vitro. Epilepsia 48, 743–751 (2007).

    CAS  PubMed  Google Scholar 

  94. Librizzi, L., Ravizza, T., Vezzani, A. & de Curtis, M. Expression of IL-1β induced by epileptiform activity in the isolated guinea pig brain in vitro. Presented at the 9th European Congress on Epileptology (Rhodes, 2010).

  95. Dubé, C. M. et al. Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers. J. Neurosci. 30, 7484–7494 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. van Vliet, E. A. et al. Blood–brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130, 521–534 (2007).

    CAS  PubMed  Google Scholar 

  97. Marchi, N. et al. Seizure-promoting effect of blood–brain barrier disruption. Epilepsia 48, 732–742 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Oby, E. & Janigro, D. The blood–brain barrier and epilepsy. Epilepsia 47, 1761–1774 (2006).

    CAS  PubMed  Google Scholar 

  99. Marcon, J. et al. Age-dependent vascular changes induced by status epilepticus in rat forebrain: implications for epileptogenesis Neurobiol. Dis. 34, 121–132 (2009).

    CAS  PubMed  Google Scholar 

  100. Majores, M., Eils, J., Wiestler, O. D. & Becker, A. J. Molecular profiling of temporal lobe epilepsy: comparison of data from human tissue samples and animal models. Epilepsy Res. 60, 173–178 (2004).

    CAS  PubMed  Google Scholar 

  101. Lukasiuk, K., Dabrowski, M., Adach, A. & Pitkanen, A. Epileptogenesis-related genes revisited. Prog. Brain Res. 158, 223–241 (2006).

    CAS  PubMed  Google Scholar 

  102. Xiong, Z. Q., Qian, W., Suzuki, K. & McNamara, J. O. Formation of complement membrane attack complex in mammalian cerebral cortex evokes seizures and neurodegeneration. J. Neurosci. 23, 955–960 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Berg, A. T., Darefsky, A. S., Holford, T. R. & Shinnar, S. Seizures with fever after unprovoked seizures: an analysis in children followed from the time of a first febrile seizure. Epilepsia 39, 77–80 (1998).

    CAS  PubMed  Google Scholar 

  104. Zetterstrom, M., Sundgren-Andersson, A. K., Ostlund, P. & Bartfai, T. Delineation of the proinflammatory cytokine cascade in fever induction. Ann. N. Y. Acad. Sci. 856, 48–52 (1998).

    CAS  PubMed  Google Scholar 

  105. Gatti, S., Vezzani, A. & Bartfai, T. in Febrile Seizures Ch. 12 (eds Baram, T. Z. & Shinnar, S.) 169–184 (Academic Press, San Diego, 2002).

    Google Scholar 

  106. Cartmell, T., Luheshi, G. N. & Rothwell, N. J. Brain sites of action of endogenous interleukin-1 in the febrile response to localized inflammation in the rat. J. Physiol. 518, 585–594 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Dubé, C., Vezzani, A., Behrens, M., Bartfai, T. & Baram, T. Z. Interleukin-1β contributes to the generation of experimental febrile seizures. Ann. Neurol. 57, 152–155 (2005).

    PubMed  PubMed Central  Google Scholar 

  108. Virta, M., Hurme, M. & Helminen, M. Increased plasma levels of pro- and anti-inflammatory cytokines in patients with febrile seizures. Epilepsia 43, 920–923 (2002).

    CAS  PubMed  Google Scholar 

  109. Haspolat, S. et al. Interleukin-1β, tumor necrosis factor-α, and nitrite levels in febrile seizures. J. Child Neurol. 17, 749–751 (2002).

    PubMed  Google Scholar 

  110. Ichiyama, T., Nishikawa, M., Yoshitomi, T., Hayashi, T. & Furukawa, S. Tumor necrosis factor-α, interleukin-1β, and interleukin-6 in cerebrospinal fluid from children with prolonged febrile seizures. Comparison with acute encephalitis/encephalopathy. Neurology 50, 407–411 (1998).

    CAS  PubMed  Google Scholar 

  111. Lahat, E., Livne, M., Barr, J. & Katz, Y. Interleukin-1β levels in serum and cerebrospinal fluid of children with febrile seizures. Pediatr. Neurol. 17, 34–36 (1997).

    CAS  PubMed  Google Scholar 

  112. Heida, J. G. & Pittman, Q. J. Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia 46, 1906–1913 (2005).

    CAS  PubMed  Google Scholar 

  113. French, J. A. et al. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann. Neurol. 34, 774–780 (1993).

    CAS  PubMed  Google Scholar 

  114. Scantlebury, M. H. & Heida, J. G. Febrile seizures and temporal lobe epileptogenesis. Epilepsy Res. 89, 27–33 (2010).

    PubMed  Google Scholar 

  115. Dubé, C. et al. Temporal lobe epilepsy after experimental prolonged febrile seizures: prospective analysis. Brain 129, 911–922 (2006).

    PubMed  Google Scholar 

  116. Sayyah, M., Javad-Pour, M. & Ghazi-Khansari, M. The bacterial endotoxin lipopolysaccharide enhances seizure susceptibility in mice: involvement of proinflammatory factors: nitric oxide and prostaglandins. Neuroscience 122, 1073–1080 (2003).

    CAS  PubMed  Google Scholar 

  117. Galic, M. A. et al. Postnatal inflammation increases seizure susceptibility in adult rats. J. Neurosci. 28, 6904–6913 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Auvin, S. et al. Inflammation in rat pups subjected to short hyperthermic seizures enhances brain long-term excitability. Epilepsy Res. 86, 124–130 (2009).

    CAS  PubMed  Google Scholar 

  119. Auvin, S., Mazarati, A. Shin, D. & Sankar, R. Inflammation enhances epileptogenesis in the developing rat brain. Neurobiol. Dis. 40, 303–310 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Kovacs, Z. et al. Facilitation of spike–wave discharge activity by lipopolysaccharides in Wistar Albino Glaxo/Rijswijk rats. Neuroscience 140, 731–742 (2006).

    CAS  PubMed  Google Scholar 

  121. Mouihate, A. et al. Early life activation of toll-like receptor 4 reprograms neural anti-inflammatory pathways. J. Neurosci. 30, 7975–7983 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Harre, E. M., Galic, M. A., Mouihate, A., Noorbakhsh, F. & Pittman, Q. J. Neonatal inflammation produces selective behavioral deficits and alters N-methyl-D-aspartate receptor subunit mRNA in the adult rat brain. Eur. J. Neurosci. 27, 644–653 (2008).

    PubMed  PubMed Central  Google Scholar 

  123. Maroso, M. et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat. Med. 16, 413–419 (2010).

    CAS  PubMed  Google Scholar 

  124. Buckmaster, P. S. & Dudek, F. E. Network properties of the dentate gyrus in epileptic rats with hilar neuron loss and granule cell axon reorganization. J. Neurophysiol. 77, 2685–2696 (1997).

    CAS  PubMed  Google Scholar 

  125. Rizzi, M. et al. Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development. Neurobiol Dis. 14, 494–503 (2003).

    CAS  PubMed  Google Scholar 

  126. Ravizza, T. & Vezzani, A. Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system. Neuroscience 137, 301–308 (2006).

    CAS  PubMed  Google Scholar 

  127. Plata-Salaman, C. R. et al. Kindling modulates the IL-1β system, TNF-α, TGF-β1, and neuropeptide mRNAs in specific brain regions. Brain Res. Mol. Brain Res. 75, 248–258 (2000).

    CAS  PubMed  Google Scholar 

  128. Ravizza, T. et al. Interleukin converting enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1β production. Neurobiol. Dis. 31, 327–333 (2008).

    CAS  PubMed  Google Scholar 

  129. Longhi, L. et al. C1-inhibitor attenuates neurobehavioral deficits and reduces contusion volume after controlled cortical impact brain injury in mice. Crit. Care Med. 37, 659–665 (2009).

    CAS  PubMed  Google Scholar 

  130. Clausen, F. et al. Neutralization of interleukin-1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice. Eur. J. Neurosci. 30, 385–396 (2009).

    PubMed  Google Scholar 

  131. Lloyd, E., Somera-Molina, K., Van Eldik, L. J., Watterson, D. M. & Wainwright, M. S. Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury. J. Neuroinflammation 5, 28 (2008).

    PubMed  PubMed Central  Google Scholar 

  132. Schwartz, M. & Shechter, R. Systemic inflammatory cells fight off neurodegenerative disease. Nat. Rev. Neurol. 6, 405–410 (2010).

    CAS  PubMed  Google Scholar 

  133. Liesz, A. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat. Med. 15, 192–199 (2009).

    CAS  PubMed  Google Scholar 

  134. Kelley, B. J. & Rodriguez, M. Seizures in patients with multiple sclerosis: epidemiology, pathophysiology and management. CNS Drugs 23, 805–815 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Perkins, N. D. Integrating cell-signaling pathways with NF-κB and IKK function. Nat. Rev. Mol. Cell. Biol. 8, 49–62 (2007).

    CAS  PubMed  Google Scholar 

  136. Hoebe, K. & Beutler, B. Forward genetic analysis of TLR-signaling pathways: an evaluation. Adv. Drug Deliv. Rev. 60, 824–829 (2008).

    CAS  PubMed  Google Scholar 

  137. Gilmore, T. D. Introduction to NF-κB: players, pathways, perspectives. Oncogene 25, 6680–6684 (2006).

    CAS  PubMed  Google Scholar 

  138. O'Neill, L. A. & Kaltschmidt, C. NF-κB: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci. 20, 252–258 (1997).

    CAS  PubMed  Google Scholar 

  139. Pitkanen, A. & Lukasiuk, K. Molecular and cellular basis of epileptogenesis in symptomatic epilepsy. Epilepsy Behav. 14 (Suppl. 1), 16–25 (2009).

    PubMed  Google Scholar 

  140. Balosso, S. et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1β. Brain 131, 3256–3265 (2008).

    PubMed  PubMed Central  Google Scholar 

  141. Viviani, B. et al. Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J. Neurosci. 23, 8692–8700 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Davis, C. N., Tabarean, I., Gaidarova, S., Behrens, M. M. & Bartfai, T. IL-1β induces a MyD88-dependent and ceramide-mediated activation of Src in anterior hypothalamic neurons. J. Neurochem. 98, 1379–1389 (2006).

    CAS  PubMed  Google Scholar 

  143. Sanchez-Alavez, M., Tabarean, I. V., Behrens, M. M. & Bartfai, T. Ceramide mediates the rapid phase of febrile response to IL-1β. Proc. Natl Acad. Sci. USA 103, 2904–2908 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Tabarean, I. V., Korn, H. & Bartfai, T. Interleukin-1β induces hyperpolarization and modulates synaptic inhibition in preoptic and anterior hypothalamic neurons. Neuroscience 141, 1685–1695 (2006).

    CAS  PubMed  Google Scholar 

  145. Zhang, R. et al. Acute p38-mediated inhibition of NMDA-induced outward currents in hippocampal CA1 neurons by interleukin-1β. Neurobiol. Dis. 38, 68–77 (2010).

    PubMed  Google Scholar 

  146. Viviani, B., Gardoni, F. & Marinovich, M. Cytokines and neuronal ion channels in health and disease. Int. Rev. Neurobiol. 82, 247–263 (2007).

    CAS  PubMed  Google Scholar 

  147. Bezzi, P. et al. CXCR4-activated astrocyte glutamate release via TNF-α: amplification by microglia triggers neurotoxicity. Nat. Neurosci. 4, 702–710 (2001).

    CAS  PubMed  Google Scholar 

  148. Hu, S., Sheng, W. S., Ehrlich, L. C., Peterson, P. K. & Chao, C. C. Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation 7, 153–159 (2000).

    CAS  PubMed  Google Scholar 

  149. Stellwagen, D., Beattie, E. C., Seo, J. Y. & Malenka, R. C. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-α. J. Neurosci. 25, 3219–3228 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Ferguson, A. R. et al. Cell death after spinal cord injury is exacerbated by rapid TNFα-induced trafficking of GluR2-lacking AMPARs to the plasma membrane. J. Neurosci. 28, 11391–11400 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Chen, C. & Bazan, N. G. Lipid signaling: sleep, synaptic plasticity, and neuroprotection. Prostaglandins Other Lipid Mediat. 77, 65–76 (2005).

    CAS  PubMed  Google Scholar 

  152. Slanina, K. A. & Schweitzer, P. Inhibition of cyclooxygenase-2 elicits a CB1-mediated decrease of excitatory transmission in rat CA1 hippocampus. Neuropharmacology 49, 653–659 (2005).

    CAS  PubMed  Google Scholar 

  153. David, Y. et al. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? J. Neurosci. 29, 10588–10599 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Cacheaux, L. P. et al. Transcriptome profiling reveals TGF-β signaling involvement in epileptogenesis. J. Neurosci. 29, 8927–8935 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Dantzer, R. Cytokine, sickness behavior, and depression. Neurol. Clin. 24, 441–460 (2006).

    PubMed  PubMed Central  Google Scholar 

  156. Cunningham, C. & Sanderson, D. J. Malaise in the water maze: untangling the effects of LPS and IL-1β on learning and memory. Brain Behav. Immun. 22, 1117–1127 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Bien, C. G. & Schramm, J. Treatment of Rasmussen encephalitis half a century after its initial description: promising prospects and a dilemma. Epilepsy Res. 86, 101–112 (2009).

    PubMed  Google Scholar 

  158. Joels, M. & Baram, T. Z. The neuro-symphony of stress. Nat. Rev. Neurosci. 10, 459–466 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Brunson, K. L., Khan, N., Eghbal-Ahmadi, M. & Baram, T. Z. Corticotropin (ACTH) acts directly on amygdala neurons to downregulate corticotropin-releasing hormone gene expression. Ann. Neurol. 49, 304–312 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Baram, T. Z. & Hatalski, C. G. Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain. Trends Neurosci. 21, 471–476 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Pellock, J. M. et al. Infantile spasms: a U. S. consensus report. Epilepsia 51, 2175–2189 (2010).

    PubMed  Google Scholar 

  162. Brunson, K. L., Avishai-Eliner, S. & Baram, T. Z. ACTH treatment of infantile spasms: mechanisms of its effects in modulation of neuronal excitability. Int. Rev. Neurobiol. 49, 185–197 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Sinclair, D. B. Prednisone therapy in pediatric epilepsy. Pediatr. Neurol. 28, 194–198 (2003).

    PubMed  Google Scholar 

  164. Mikati, M. A., Kurdi, R., El-Khoury, Z., Rahi, A. & Raad, W. Intravenous immunoglobulin therapy in intractable childhood epilepsy: open-label study and review of the literature. Epilepsy Behav. 17, 90–94 (2010).

    PubMed  Google Scholar 

  165. Marescaux, C. et al. Landau–Kleffner syndrome: a pharmacologic study of five cases. Epilepsia 31, 768–777 (1990).

    CAS  PubMed  Google Scholar 

  166. Villani, F. & Avanzini, G. The use of immunoglobulins in the treatment of human epilepsy. Neurol. Sci. 23 (Suppl. 1), S33–S37 (2002).

    PubMed  Google Scholar 

  167. You, S. J., Jung, D. E., Kim, H. D., Lee, H. S. & Kang, H. C. Efficacy and prognosis of a short course of prednisolone therapy for pediatric epilepsy. Eur. J. Paediatr. Neurol. 12, 314–320 (2008).

    CAS  PubMed  Google Scholar 

  168. Mikati, M. A., Saab, R., Fayad, M. N. & Choueiri, R. N. Efficacy of intravenous immunoglobulin in Landau–Kleffner syndrome. Pediatr. Neurol. 26, 298–300 (2002).

    PubMed  Google Scholar 

  169. Verhelst, H. et al. Steroids in intractable childhood epilepsy: clinical experience and review of the literature. Seizure 14, 412–421 (2005).

    PubMed  Google Scholar 

  170. Baram, T. Z. et al. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics 97, 375–379 (1996).

    CAS  PubMed  Google Scholar 

  171. Mackay, M. T. et al. Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology 62, 1668–1681 (2004).

    CAS  PubMed  Google Scholar 

  172. Lux, A. L. et al. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicenter randomised trial. Lance Neurol. 4, 712–717 (2005).

    CAS  Google Scholar 

  173. Gayatri, N. A., Ferrie, C. D. & Cross, H. Corticosteroids including ACTH for childhood epilepsy other than epileptic spasms. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD005222. doi:10.1002/14651858.CD005222.pub2 (2007).

  174. Crow, A. R., Song, S., Semple, J. W., Freedman, J. & Lazarus, A. H. A role for IL-1 receptor antagonist or other cytokines in the acute therapeutic effects of IVIg? Blood 109, 155–158 (2007).

    CAS  PubMed  Google Scholar 

  175. Cullingford, T. Peroxisome proliferator-activated receptor alpha and the ketogenic diet. Epilepsia 49 (Suppl. 8), 70–72 (2008).

    PubMed  Google Scholar 

  176. ClinicalTrials.gov Study of VX-765 in subjects with treatment-resistant partial epilepsy [online], (2010).

  177. Tsan, M. F. & Gao, B. Endogenous ligands of Toll-like receptors. J. Leukoc. Biol. 76, 514–519 (2004).

    CAS  PubMed  Google Scholar 

  178. Shlosberg, D., Benifla, M., Kaufer, D. & Friedman, A. Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat. Rev. Neurol. 6, 393–403 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Hawkins, B. T. & Davis, T. P. The blood–brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57, 173–185 (2005).

    CAS  PubMed  Google Scholar 

  180. Utech, M., Mennigen, R. & Bruewer, M. Endocytosis and recycling of tight junction proteins in inflammation. J. Biomed. Biotechnol. 2010, 484987 (2010).

    PubMed  Google Scholar 

  181. Gloor, S. M. et al. Molecular and cellular permeability control at the blood–brain barrier. Brain Res. Brain Res. Rev. 36, 258–264 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Via Giuseppe La Masa 19, Milan, 20156, Italy

    Annamaria Vezzani

  2. NYU Comprehensive Epilepsy Center, 223 East 34th Street, New York, 10016, NY, USA

    Jacqueline French

  3. Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, CA, USA

    Tamas Bartfai

  4. Pediatrics, Anatomy and Neurobiology, and Neurology, UC Irvine, ZOT 4475, Irvine, 4475, CA, USA

    Tallie Z. Baram

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  1. Annamaria Vezzani
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Contributions

A. Vezzani, J. French, T. Bartfai and T. Z. Baram contributed equally to researching data for the article, discussion of content, writing, and reviewing and/or editing of the manuscript before submission.

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Correspondence to Annamaria Vezzani.

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Competing interests

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 information

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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