Epileptogenesis after febrile status epilepticus: a role of hyperthermia

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DESCRIPTION (provided by applicant): The goal of this project is to develop a model which will tell us if correcting hyperthermia after the first seizure reduces the long-term consequences of febrile status epilepticus (epileptogenesis and brain damage). The long-term goal is to understand the relationship between seizures in early life and the later development of chronic epilepsy. This project studies the role of temperature in the epileptogenic effects of febrile status epilepticus. We have begun to develop a model in which status epilepticus of similar severity can be triggered in 10-day-old rat pups maintained at a body temperature of either 39 or 35 degrees Celsius (35 degrees C being close to the physiological temperature of pups in the nest). Animals subjected to status epilepticus at 39 degrees Celsius develop spontaneous recurrent behavioral and EEG seizures within 4 months, while the 35 degree C group develops no behavioral seizures and few EEG seizures. Brain damage is also more extensive and affects more brain locations in the 39 degree group than in the 35 degree group. We want to fully develop this model to study the role of brain and body temperature in the long-term consequences of status epilepticus. We will follow the physiological and anatomical consequences of status epilepticus in those 2 groups and in several control groups, using telemetry-video monitoring of seizures, and using several anatomical markers of neuronal injury and death. These include immunocytochemistry for active caspase-3, and quantitative unbiased stereology. We will also correct the hyperthermia with alcohol sponges after the first seizure, and expect this to prevent the epileptogenic effects of hyperthermia. We also expect this treatment to reduce brain damage, to prevent caspase-3 activation and to reduce the amount of neuronal necrosis of hippocampal neurons.Epileptogenesis after febrile status epilepticus: role of hyperthermia. PUBLIC HEALTH RELEVANCE There is a strong association between the occurrence of febrile status epilepticus (FSE) in childhood and the later development of intractable epilepsy. Recent evidence suggests that experimental prolonged febrile convulsions are epileptogenic, but we do not know whether the presence of hyperthermia has any effect on epileptogenesis. Our preliminary data suggest that hyperthermia acts as a `second hit which enhances status epilepticus- induced epileptogenesis. This project will determine the role of hyperthermia in FSE- induced epileptogenesis in experimental animals, in a way which will be easily translated into human studies and treatments.