Brain on Fire: How Brain Infection and Neuroinflammation Drive Worldwide Epilepsy Burden

Melissa Barker-Haliski, Ana Beatriz DePaula-Silva, Julika Pitsch, Harald Sontheimer, Lawrence J. Hirsch, Aristea S. Galanopoulou, Jennifer A. Kearney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Roughly 80% of the global burden of epilepsy resides in low- and middle-income countries (LMICs; WHO, 2022). Despite numerous new therapies for the treatment of epilepsy, the number of patients who remain resistant to available medications is unchanged. Additionally, no therapy has yet been clinically proven to prevent or attenuate the development of epilepsy in at-risk individuals. Unfortunately, access to next generation therapies in LMICs is low, the stigma associated with epilepsy remains high, and access to adequate resources is unchanged. Thus, the global epilepsy burden disproportionately falls on LMICs such that strategies to conscientiously integrate global epilepsy risk factors into preclinical research may meaningfully advance 21st century epilepsy therapies. Brain infections are one of the main risk factors for epilepsy in resource-poor settings. Further, both infection- and autoimmune-associated encephalitis contribute to worldwide epilepsy risk and remain relatively understudied. For example, clinical SARS CoV-2 infection can induce rare instances of encephalopathy and acute seizures. Among viruses known to cause acute brain infection, enteroviruses increase risk for encephalitis-induced epilepsy, but are not associated with risk for other neurodevelopmental disorders (eg, autism spectrum or attentional deficit hyperactivity disorders). Naturally occurring models of viral infection-induced epilepsy therefore provide an exquisite opportunity to uncover novel contributors to epileptogenesis. Moreover, the convergent neuroinflammatory pathways that are associated with viral infection-induced encephalitis and autoimmune encephalitis reflect an untapped therapeutic opportunity to meaningfully reduce the global burden of epilepsy. This review summarizes the latest advances in translational research integrating encephalitis-induced seizure and epilepsy models, in tandem with progress in clinical diagnosis of inflammation and virally mediated epilepsy. This improved awareness of the shared biological underpinnings of epileptogenesis following brain infection or autoimmune encephalitis is anticipated to beneficially impact the global burden of epilepsy.

Original languageEnglish (US)
JournalEpilepsy Currents
DOIs
StateAccepted/In press - 2024

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MB-H acknowledges research funding from the University of Washington Plein Center, and the National Institutes of Health R01AG067788 and R61NS126626. ABD-S was supported by the National Institute of Health under Ruth L. Kirschstein National Research Service Award NIH 2T32AI055434 from the National Institute of Allery and Infectious Diseases (NIAID), National Institute of Neurological Disorders and Stroke (NINDS) K22NS123547, and Citizens United for Research in Epilepsy (CURE). HS acknowledges NIH grants R01-7 NS036692, R01-NS082851, and R01-NS052634. ASG 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 center grant (P50 HD105352) for the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK-IDDRC), R01DA019473, R01AI164864, the Heffer Family and the Segal Family Foundations, the Rapin Oaklander family funds, and the Abbe Goldstein/Joshua Lurie, and Laurie Marsh/Dan Levitz families. JAK acknowledges research funding from the National Institutes of Health R01 NS084959, R21 NS134236, R44 AG071062, and U54 NS108874, and investigator-initiated research funding from Neurocrine Biosciences and Praxis Precision Medicines. MB-H acknowledges research funding from the University of Washington Plein Center, and the National Institutes of Health R01AG067788 and R61NS126626. ABD-S was supported by the National Institute of Health under Ruth L. Kirschstein National Research Service Award NIH 2T32AI055434 from the National Institute of Allery and Infectious Diseases (NIAID), National Institute of Neurological Disorders and Stroke (NINDS) K22NS123547, and Citizens United for Research in Epilepsy (CURE). HS acknowledges NIH grants R01-7 NS036692, R01-NS082851, and R01-NS052634. ASG 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 center grant (P50 HD105352) for the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK-IDDRC), R01DA019473, R01AI164864, the Heffer Family and the Segal Family Foundations, the Rapin Oaklander family funds, and the Abbe Goldstein/Joshua Lurie, and Laurie Marsh/Dan Levitz families. JAK acknowledges research funding from the National Institutes of Health R01 NS084959, R21 NS134236, R44 AG071062, and U54 NS108874, and investigator-initiated research funding from Neurocrine Biosciences and Praxis Precision Medicines.

Keywords

  • autoimmune encephalitis
  • cytokines
  • drebin
  • FIRES
  • global health
  • minocycline
  • NORSE
  • perineuronal nets
  • refractory status epilepticus
  • SARS-CoV2
  • Theiler’s virus

ASJC Scopus subject areas

  • Clinical Neurology

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