Until now, there was no clear reason why sudden unexpected death in epilepsy (SUDEP) occurs. In a paper published today in the journal Brain, researchers have identified key aspects of fatal and non-fatal seizures.
SUDEP is unusual, occurring without warning in up to 12 per cent of people with epilepsy and up to 40 per cent of people with uncontrolled seizures, such as those not managed with medication or surgery (refractory epilepsy). SUDEP leaves no anatomical clues behind, making it difficult to understand how a seizure becomes life-threatening.
Building on CURE Epilepsy- and BC Epilepsy Society-funded research that Dr. Stuart Cain and Prof. Terrance Snutch began in 2014, the team has now identified regions of the brain that become inactive after seizures in mouse models. Depolarization of neurons is part of the process by which signals in the brain are normally transmitted between nerve cells. However, following seizures or traumatic brain injury, a severe and long lasting “spreading depolarization” occurs which instead silences activity as it moves through specific brain regions. This new research confirms that if spreading depolarization engages the brainstem, the result is fatal.
Seizures and migraine can engage similar processes in the brain, and so the team took a model with a genetic mutation found in humans causing chronic migraines and severe seizures, then monitored brain cell swelling that occurs simultaneously with spreading depolarization in real time via diffusion-weighted magnetic resonance imaging (MRI). What they found was that during fatal seizure events, depolarization spread to the brainstem, first arresting breathing; cardiac arrest followed, leading to death within a minute of the seizure. The brainstem plays an important role in regulating cardiovascular and respiratory function. In non-fatal seizures, depolarization did not spread to the brainstem.
“Spreading depolarization is the result of an intense excitement of the neurons, such as a seizure, followed by a long-lasting period of inactivity that travels outward to neighbouring neurons from the excitement point,” explains Dr. Cain. “It moves outward like a wave across the brain; the downstream silencing effect of the seizure depends on what region of the brain is affected by the wave.”
Dr. Cain and Prof. Snutch are hopeful that by identifying regions affected by cellular inactivity after seizure their team will be able to find a therapeutic target to prevent sudden death post-seizure. The next phase of this project aims to investigate potential drugs that may prevent the spread of depolarization into the brainstem. Dr. Cain is now involved in the next phase of drug development for neurological disorders at the Centre for Drug Research and Development (CDRD), where they are driving discoveries from the lab into new therapies in the clinic.
“At this stage we’re encouraged that our SUDEP model seems to be effective; these findings add to the fundamental understanding of the processes underlying SUDEP risk, and our model shows promise towards helping us identify predictive biomarkers in people with epilepsy at risk of SUDEP in the future,” says Dr. Cain.
- Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice (Brain, February 1, 2019)
- Commentary: Brainstem spreading depolarization: rapid descent into the shadow of SUDEP (Dr. Jeffrey Noebels, Brain. February 1, 2019)
- New funding to help find cause of sudden unexpected death in epilepsy