Abstracts

Rationale: Febrile Infection-Related Epilepsy Syndrome (FIRES), categorized under New Onset Refractory Status Epilepticus (NORSE), represents a severe epileptic condition triggered by febrile illnesses or infections. Managing FIRES poses significant challenges, often leading to refractory epilepsy and neurobehavioral impairments. Recently, we established a novel FIRES/NORSE model using interleukin-1 receptor antagonist (IL-1RA) deficient mice, which faithfully recapitulates key clinical features observed in FIRES patients including the emergence of spontaneous recurrent seizures after status epilepticus without latent period and cell death accompanied by marked microglia and astrocyte activation in the hippocampus. Addressing the combined neurobehavioral impairments in FIRES/NORSE is crucial but remains an unmet goal, partly due to the lack of a suitable animal model. This study aims to explore the neurobehavioral dimensions of our developed FIRES/NORSE model, with an ultimate goal of utilizing it as a platform for developing treatments targeting FIRES/NORSE.


Methods: IL-1RA deficient (knockout and heterozygous) mice and wildtype (WT) littermates were utilized for the FIRES or the NORSE model procedure. FIRES modeling consists of systemic lipopolysaccharide (LPS) injection along with hyperthermia at 25 days of age (P25) followed by intrahippocampal kainic acid (IHKA) injection at P30 to induce seizures. NORSE modeling consists of a single IHKA injection at P40. Control mice for these models received no treatment. All animals were subjected to neurobehavioral assessments (open field, Y-maze, and Barnes maze) at 1, 3, and 5 weeks after FIRES/NORSE modeling to evaluate potential changes in locomotor activity, anxiety levels, and cognitive performance. Mice behavior was monitored and analyzed in real-time using the ANY-maze system. A subset of mice, after behavioral tests, was implanted with intracranial electrodes for a 24-hour EEG evaluation of seizure burden.


Results: The open field test assessed both anxiety-like behavior and locomotor activity. Total distance traveled and speed moved showed no significant deficits in locomotor function in FIRES/ NORSE mice vs controls. FIRES/NORSE mice demonstrated enhanced level of anxiety-like behavior vs corresponding controls, as early as 1 week after the modeling. The evaluation of cognitive function through Y-maze and Barnes maze showed no cognitive deficits at 1 week after modeling. However, at 5 weeks, Y-maze showed FIRES mice spent less time in novel arm vs controls and Barnes maze showed a longer latency to target in NORSE mice vs controls, indicating impaired cognitive function.


Conclusions: Anxiety-like behavior and cognitive impairments were revealed to develop at different time periods in our mouse model of FIRES/NORSE, which warrant further investigation for utilizing our model as a platform for pharmaceutical evaluation against FIRES/NORSE.


Funding: The Child Health Research Institute Foundation