Postictal Hypoxia as a Mechanism of Sudden Unexpected Death in Epilepsy

Abstract

Epilepsy can be a fatal disease. People with epilepsy face significantly increased incidence of premature death. Sudden unexpected death in epilepsy (SUDEP) is the leading epilepsy-related cause of mortality in people with refractory epilepsy. The incidence of SUDEP is 27 times higher than sudden death in the general population. The mechanism underlying SUDEP is largely unknown but breathing failure after a seizure led to terminal apnea which preceded death in the largest retrospective review of SUDEP cases. Following a seizure, vasoconstriction-induced hypoperfusion and hypoxia occurs in local brain regions involved in a seizure. I propose that forebrain seizures propagate to the brainstem and cause hypoxia in breathing centres. In this thesis I tested the novel neurovascular-based hypothesis of SUDEP in awake, non-anesthetized mice by using two animal models of seizure-induced death: acute intrahippocampal kainic acid model of temporal lobe epilepsy and chronic Kcna1-/- mice. I pharmacologically prevented seizure-induced vasoconstriction with cyclooxygenase-2 (COX-2) or an L-type calcium channel (LTCC) blocker. The COX-2 inhibitor, ibuprofen, and the LTCC blocker, nicardipine, ameliorated postictal hypoxia through fundamentally different mechanisms and extended life in both models. I also examined the potential role of spreading depolarization in the acute model of seizure-induced premature mortality. The data within this thesis provide a proof-of-principle for the neurovascular hypothesis of SUDEP rather than spreading depolarization and the use of currently available treatments to prevent it. Having validated both models of seizure-induced death, I then sought to examine the relationship between adenosine signaling and SUDEP. Here we investigated the effects of caffeine and 2 adenosine receptors. I found that the administration of the non-selective A1/A2A antagonist caffeine or selective A1 agonist N6 reveals a facilitation of postictal hypoxia providing support for caffeine modulating cerebral vasculature leading to brainstem hypoxia and cessation of breathing. Conversely, we found a protective effect of the A2A agonist CGS-21680. The findings contained in this thesis can hopefully serve as a benchmark for future clinical trials in the prevention or reduction of SUDEP risk.