Hypothesis: Febrile infection‐related epilepsy syndrome is a microglial NLRP3 inflammasome/IL‐1 axis‐driven autoinflammatory syndrome

FIRES (febrile infection‐related epilepsy syndrome) is a protracted neuroinflammatory condition of obscure cause. It mainly afflicts school‐age children and often leads to permanent neurological sequelae. Most treatments to date have been of limited efficacy, while ketogenic diet and anti‐interleukin‐1 therapy appear beneficial for some patients. Research into this clinical entity is hampered by its rarity and complexity. Nonetheless, accumulating evidence derived from basic investigations and clinical observations converges to implicate the autoinflammatory nature of this syndrome. A closer analysis of current literature suggests that microglia and the NLRP3 inflammasome might be the pivotal cellular and molecular players in FIRES pathogenesis, respectively. Through evidence synthesis, herein we formulate the working hypothesis of overactivation of microglial NLRP3 inflammasome/interleukin‐1 axis as the driving event in FIRES by creating a proinflammatory and proconvulsive milieu. The reverberation between neuroinflammation and seizure forms a vicious cycle. The unique properties of microglia might also contribute to unopposed IL‐1 signalling and incessant sterile neuroinflammation in this context. The potential therapeutic relevance of the proposed conceptual framework is discussed.