Determining the effect of circadian phase on seizure induced respiratory arrest and death

University Of Iowa, Iowa City IA

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Abstract

Epilepsy is highly prevalent. A third of epilepsy patients will be refractory to treatment with antiepileptic drugs. The leading cause of death in patients with refractory epilepsy is sudden unexpected death in epilepsy (SUDEP). There is no reliable way to predict or prevent the occurrence of SUDEP. The conditions which differentiate seizures which result in death from those which do not are unknown. It is known that SUDEP typically happens at night and the primary cause of death is respiratory arrest. Sleep may result in an increased vulnerability to seizure induced respiratory arrest; however, circadian phase affects breathing independent of sleep state and may be an independent risk factor for SUDEP. To explore this possibility, a preliminary investigation was conducted in which maximal electroshock and amygdala kindled seizures were induced at different times of day under normal light/dark conditions. Time of day affected survival and respiratory outcomes independent of sleep state. It is not clear whether this time of day difference in seizure outcomes is endogenously circadian, the result of different lighting conditions or due to some other environmental factor. Furthermore, the mechanism by which circadian phase affects normal breathing is unknown, but may be relevant to SUDEP and many other respiratory diseases. It has been speculated that day/night differences in breathing are dependent on the suprachiasmatic nucleus (SCN), the site of the mammalian central circadian oscillator; however, this has never been experimentally investigated. In this investigation, we will test the working hypotheses that (1) circadian phase alters susceptibility to seizure induced respiratory arrest and death and (2) normal circadian changes in breathing and the respiratory response to seizures are dependent on the SCN. To determine if there are endogenously circadian changes in vulnerability to seizure induced respiratory arrest we will induce seizures at different time points using multiple seizure models in animals entrained to a light/dark schedule and animals maintained in constant conditions and compare respiratory outcomes. To determine whether normal circadian changes in breathing are dependent on the SCN we will perform SCN lesions and assess baseline respiratory parameters as well as the respiratory response to seizures in normal lighting conditions and conditions of constant darkness. In humans, sleep happens during the night so circadian phase and homeostatic sleep processes are often considered together, but failure to differentiate between these two potentially independent risk factors may lead to errant conclusions about SUDEP etiology and misguided treatment strategies.