Febrile seizures and nervous system inflammation

Abstract

  The pathogenesis of febrile seizures (FS) remains unknown. It is also unclear whether prolonged FS in childhood facilitate mesial temporal lobe epilepsy (MTLE) in adulthood. Previous studies found that various inflammatory mediators play an important role in childhood convulsive disorders. The present review demonstrates the role inflammatory cytokines and high-mobility group box 1 (HMGB1), an important nucleokine, in FS and acquired epilepsy-associated prolonged FS. Experimental hyperthermia-induced seizures (HS) and prolonged HS have been used in animal models to clarify the mechanisms involved in FS and prolonged FS. In the HS rodent model, interleukin (IL)-1β enhanced HS, conversely, IL-1 receptor antagonist, IL-6 and IL-10 suppressed HS. A case-control study of Japanese patients with FS demonstrated that the −511C/T polymorphism of the IL1B gene was associated with development of simple FS. In contrast, the frequencies of the IL10−592C allele and −1082A/−819C/−592C haplotype were significantly decreased in patients with FS. In the prolonged HS model, IL-1β enhanced acquired epilepsy-associated prolonged HS. HMGB1 also enhanced HS and acquired epilepsy-associated prolonged HS with enhancing astrocytosis in the hippocampus and corpus callosum. The activation of IL-1β and HMGB1 signaling activates the N-methyl-D-aspartate (NMDA) receptor pathways in neurons. A long-term decrease in seizure threshold has also been observed, possibly mediated by acquired epilepsy-related prolonged HS. These findings suggest that IL-1β and HMGB1 might contribute to FS pathogenesis, and infantile prolonged FS combined with IL-1β or HMGB1 overproduction could enhance adulthood epileptogenesis, potentially contributing to the development of MTLE.