Grant: Project Grant

People with epilepsy often die suddenly and unexpectedly. In fact they are 27 times more likely to do so compared with the general population. This unfortunate occurrence is called Sudden Unexpected Death in EPilepsy (SUDEP) and it is the leading cause of death in persons with epilepsy. SUDEP most often occurs where an individual with a history of epilepsy is found dead with evidence of a prior seizure. From the few studies on patients in a hospital setting, that would have died if not for medical intervention; we know that SUDEP is ultimately caused by failure to breathe either during a seizure or very soon after a seizure ends followed quickly by heart failure. What we don't know is what causes the failure to breathe. My laboratory has recently discovered a period of severely low oxygen levels (hypoxia) during and following a seizure. The hypoxia is found only in brain regions involved in the seizure and is severe enough to cause behavioural dysfunction. I hypothesize that SUDEP occurs when seizures invade the breathing centers in the brainstem and local tissue oxygen falls below a critical level impairing the function of those areas which leads to breathing failure and death. We will first determine the relationship between seizure activity and local oxygen levels in brain breathing centers on breathing behaviour. To do this we will use an implantable device that continuously measures the absolute levels of oxygen in awake behaving mice. We will next determine more drugs that can prevent seizure-induced hypoxia. We have previously identified two kinds of drugs that prevent the seizure-induced blood vessel constriction and low oxygen levels. We will use these to determine the effect of preventing the seizure-induced hypoxic period on mouse breathing and survival. We believe that SUDEP is preventable and that the knowledge generated by these proposed studies will ultimately save lives.