An Explanation for Sudden Death in Epilepsy (SUDEP)

Stewart M. Journal of Physiological Sciences, 2018 Jul;68(4):307-32.

A recent review of the causes of sudden unexpected death in epilepsy (SUDEP) highlights findings from studies in animals. This information helps scientists explore how and why SUDEP may happen in people with epilepsy.

What is SUDEP?

• SUDEP is defined as a sudden death in person with epilepsy who is otherwise healthy.
• SUDEP can be
  • Definite, an instance when other causes of death are ruled out by an autopsy
  • Probable, when autopsy is not possible and other causes of death are benign or not likely
  • Possible, when another cause of death is possible and autopsy data is unavailable
• Each year, about 1 in 1,000 people with epilepsy die from SUDEP.
• This is the leading cause of death in people with uncontrolled seizures.

Animal Models for SUDEP

• To study the progression of seizures, animal models are used to record and study seizure activity.
• A wide range of animals exist for studying heart (cardiac) and breathing (respiratory) problems associated with seizures. Finding the perfect model to study SUDEP in animals is difficult, because there may be different causes of death.
• Audiogenic seizure-prone mice are commonly used. These mice are modified to be susceptible to sound-induced seizures.
• However, the link between the convulsive seizures in audiogenic mice and those seen in people is unclear.
• The author of this paper used a unique animal model of kainic acid-mediated seizures under urethane anesthesia. Kainic acid acts by setting off a specific type of glutamate receptors in the central nervous system and inducing excitatory impulses, in this case seizures.
• Urethane has minimal effects on cardiovascular and respiratory systems and maintenance of spinal reflexes. Inducing seizures in this animal model under urethane anesthesia ensures the animals do not feel any pain during seizure progression.
• The absence of muscle jerks helped scientists see and record movements of the larynx or voice box during seizures. Movements called laryngospasms and blockages of the upper airway are potential explanations for SUDEP.

Do epileptic seizures affect major body functions?

• Seizures affect autonomic systems like cardiac, respiratory, gastrointestinal, and genitourinary (genital and urinary organs) functions before, during, and after they occur.
• Fortunately, some of these changes do not last long if seizures stop on their own.
• Extreme cases of convulsions could, however, lead to cardiac or respiratory failure causing death.

Is SUDEP a result of ventricular fibrillation?

• A variety of unusual cardiac changes caused by seizures can potentially be responsible for SUDEP.
• The vagus nerve of the autonomic nervous system is critically involved in maintaining normal heart function.
• When vagal nerve action is compromised, ventricular fibrillation (VF) occurs. This is a condition where the lower chambers of the heart quiver or shake instead of pumping.
• In this study, the author looked at whether VF could be the main cause of seizure-induced cardiac arrests by studying the effects of ventricular tachycardia (irregular heart rhythms) and moderate hypoxia (decreased oxygen levels in the tissue) in rats given kainic acid.
• They found that repeated seizures in these rats made their hearts’ lower chambers (i.e., ventricles) larger and the walls thinner. Thus, there was a lower risk of VF.
• This implies that while VF is a major cause of heart attacks, it does not appear to be the major cause of seizure-induced cardiac arrests.

Does apnea or respiratory failure cause SUDEP?

• Seizures greatly affect breathing rate and lead to a decrease in blood oxygen levels.
• Animal studies show that in seizure-induced deaths, measured saturated oxygen levels (the amount of oxygen in the blood) are extremely low.
• Seizures also cause laryngospasm (convulsions of the vocal cords). These spasms can lead to obstructive apnea (a condition where breathing stops because the airway is completely closed).
• This prevents airflow, rapidly reduces blood oxygen levels, and leads to cardiac and respiratory arrest and finally death.
• However, study animals that had an airway protecting device inserted into their trachea or wind pipe never died during seizure activity.
• These observations show that obstruction of the larynx or vocal chords during an epileptic seizure could be a potential reason for SUDEP.

What does this mean for people with epilepsy?

• Animal studies on epileptic seizures and their effects on cardiac (heart) and respiratory (breathing) systems unearthed some potential ways to treat seizures and minimize the risk of SUDEP.
• Results from the MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) showed a series of events between seizure and death, including the onset of apnea followed by cardiac arrest.
• Animal models that look at how seizures occur offer critical points where steps like cardiopulmonary resuscitation (CPR) can be done to minimize SUDEP.
• Airway obstruction in animals having seizures and human clinical data confirm a definite link to SUDEP.
• This particular animal model has helped identify potential targets in the seizure progression pathway where preventative and therapeutic measures could be undertaken.