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

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.

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