SUDEP, although rare, remains the most important epilepsy-related cause of death among people with seizures. Even in 2020, we do not yet have satisfying answers regarding the exact cause of SUDEP. However, dysfunction in the autonomic nervous system is potentially responsible, particularly in patients with repetitive, uncontrolled convulsive seizures (the greatest risk factor for SUDEP). In particular, having 3 or more generalized tonic-clonic seizures per year is associated with dramatically increased risk, although a heavy convulsive seizure burden is not the only risk factor. 

Because no single satisfactory explanation for the cause of SUDEP is available, there is growing interest in seeking predictive biomarkers. The 2013 MORTEMUS study, a retrospective analysis of patients who had succumbed to SUDEP in epilepsy monitoring units, revealed the presence of respiratory decline prior to the terminal event in the vast majority of patients. While it may not be the only factor in SUDEP, respiratory decline is believed to constitute part of the cascade of events that results in many cases of SUDEP. Severe alteration of cardiac function has also been observed during epilepsy monitoring unit admissions in patients who ultimately went on to die suddenly and unexpectedly.

With respect to genetics, children with conditions such as Dravet syndrome, who have an SCN1A mutation, are known to be at extremely high risk of SUDEP. In patients with epilepsy who do not have that specific mutation, there is interest in examining the entirety of their genome for genes or combinations of genes that can put patients at risk. Genetic autopsies are being performed on individuals who die of SUDEP to identify genes that increase the risk of or predisposition to SUDEP. Further, a potential overlap has been identified between the genetics of SUDEP and sudden cardiac death–related and arrhythmia‐related genes. Other work is being done to explore defects in serotonin-related signaling that may be involved in SUDEP. 

Such lines of evidence could lead to clinical trials aimed at finding specific interventions to reduce SUDEP risk. These studies are difficult to perform because of the fortunate rarity of SUDEP and the number of patients needed to participate in such studies. In the meantime, the only truly effective interventions available to reduce the risk of SUDEP consist of obtaining the best possible seizure control through medications, resective surgery, devices, or diets. Research indicates that SUDEP risk drops significantly among patients who undergo successful resective epilepsy surgery, especially those who are free of generalized tonic-clonic seizures afterwards.