Could Oxygen Starvation of the Brain Cause SUDEP?

Sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. The rate of SUDEP over a one-year period in persons with some types of poorly controlled epilepsy is as high as 1 in 100 persons. Even in 2013, the exact mechanisms resulting in SUDEP have not been fully determined. However, there is increasing evidence to suggest that seizure-related hypoxemia (low amount of oxygen in the blood) may be partially responsible for the sudden death. Up to 80% of cases of witnessed SUDEP have been marked by respiratory difficulties, suggesting a role for oxygen desaturation in the ensuing death. Autopsies documenting pulmonary edema in a majority of SUDEP cases have also implicated hypoxemia as a potential contributor. It is possible such hypoxemia and resulting acidosis (excessive acidity of the blood) could contribute to heart failure, further increasing the risk of sudden death.

Drops in blood oxygenation are not rare during epileptic seizures. They have been documented using digital pulse oximetry (which measures oxygenation from either a finger or toe) in 25 to 33% of seizures in both adults and children. Such hypoxemia is more common in seizures that generalize (i.e. start as or become generalized tonic clonic seizures) and/or are prolonged. It is felt that hypoxemia is likely a consequence of seizure-related hypoventilation (diminished breathing) and/or transient apnea (brief cessation of breathing). This is supported by concurrent rises in end-tidal CO2 (the level of carbon dioxide released at the end of expiration) documented during seizures that were recorded in the epilepsy monitoring unit. Such hypoventilation/apnea may be secondary to disruption of brainstem respiratory centers by repetitive seizure discharges.

Given that seizure-related hypoxemia is observed much more often than SUDEP, it cannot be the sole mechanism resulting in sudden death. Rather, it has been hypothesized that such hypoxemia may need to directly affect brain structures and be part of a vicious cycle (including generalized suppression of brainwave activity, reduced activity of pulmonary stretch receptors, increased carotid chemoreceptor sensitivity, and/or bradycardia/asystole) to ultimately result in death. Given that most of the previous studies documenting seizure-related hypoxemia have utilized digital pulse oximetry (the results of which can be contaminated by constriction of finger or toe blood vessels during seizures), they may not directly reflect brain oxygenation. Until recently, a noninvasive way to measure brain oxygenation was not available. However, this changed with the advent of noninvasive near-infrared spectroscopy (NIRS) based cerebral oximetry devices. Such devices use near-infrared light to measure cerebral blood supply via two adhesive pads placed on both sides of the forehead. A recent feasibility study performed at the Mayo Clinic in Rochester, MN, showed that such devices safely and effectively recorded data in 6 patients with convulsive seizures while they were in the epilepsy monitoring unit. The cerebral oximeters were worn for more than 3 days on the average, and they yielded more reliable data than digital pulse oximeters. Recorded generalized tonic clonic seizures were marked by significant decreases in brain oxygenation values, providing the first noninvasively obtained proof that drops in brain oxygen do occur with generalized convulsive seizures. Patients with more risk factors for SUDEP also tended to have more significant brain oxygenation dips during or after seizures, suggesting a possible association between the two. Larger studies of people with epilepsy using cerebral oximeters are now needed to confirm the accuracy and reproducibility of these results. If confirmed, it is possible such devices may one day be used to identify patients at greater risk for SUDEP, so that preventative measures can be taken in these patients.

Suggested Readings

1. Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain 2008;131:3239-3245.

2. Moseley BD, Britton JW, Nelson C, Lee RW, So E. Periictal cerebral tissue hypoxemia: a potential marker of SUDEP risk. Epilepsia 2012;53:e208-211.