Abstracts

Rationale: Febrile seizures are the most prevalent form of early-life seizures, and febrile status epilepticus (SE) accounts for over 70% of SE in the first two years of life. Among seizures that affect children, febrile seizures intrinsically involve an inflammatory process. Infants and young children develop febrile seizures most often related to ear infection or systemic HHV6 infection. Therefore, we sought to develop a clinically relevant febrile seizure model that combines hyperthermia-induced seizures with stimulation of the peripheral innate immune system with lipopolysaccharide (LPS) to mimic a peripheral infection. Methods: P14 C57Bl/6 mice were injected with saline or LPS (100 ug/kg, i.p.) 2 h prior to induction of febrile convulsions (FCs). Specifically, hyperthermia was induced using a heat lamp over a Plexiglas chamber for 30 min to maintain core body temperature between 38-42 C. Latency to seizure onset, threshold temperature, and total number of seizures were quantified. Controls included hyperthermia alone (HT), LPS alone and normothermic littermates. Blood and hippocampal tissue were collected for cytokine assay 0,2, 4 or 24 h after HT or FCs. To test the long-term effects of early-life FCs on seizure susceptibility in adulthood, animals were allowed to survive until P28 and P49 and seizures were induced by kainic acid (KA) injection (20-25 mg/kg, i.p.)Results: There was significant increase in seizure susceptibility in mice subjected to FCs (LPS+HT) compared to hyperthermia alone (HT). LPS priming decreased HT latency and threshold temperature (p< 0.002) and caused more severe seizures (p< 0.003,). Concomitant with increased seizure susceptibility, FCs in mouse pups activates significant and more sustained proinflammatory cytokine production in the blood and hippocampus while hyperthermia seizures alone had only modest and transient effects. Mice that experienced prolonged FCs in early life exhibited an increased susceptibility to a subsequent KA-induced seizure at 4 weeks and 7 weeks of age compared to their littermate controls ( p<0.01). Conclusions: We show that a systemic injection of LPS primes the brain to more rapidly respond to hyperthermia and exacerbate seizure severity. Peripheral inflammation played a synergistic role in triggering seizures and led to acute production of proinflammatatory cytokines and to long-term increase in seizure susceptibility. Our results support the hypothesis that immunologic responses to early-life FCs cause heightened susceptibility to subsequent seizures. These data are the first to show a clinically relevant mouse model of prolonged febrile convulsions that simulates fever, a regulated increase in body temperature from an immune challenge, as opposed to hyperthermia, an excessive heat load that mobilizes heat dissipation mechanisms. Development of a new murine model of FCs will allow us to utilize mice that possess deficiencies in innate and adaptive immune responses to directly determine the contribution of each arm of the immune system for priming long-term epileptogenic effects of prolonged early life seizures.