Many people with epilepsy die suddenly for no apparent reason. Friends or loved ones find them on the floor or in bed, without pulse or respiration, and pathologists can find no obvious cause of death. This “sudden unexplained death in epilepsy” (SUDEP) syndrome kills nearly one out of every 100 people with severe, surgery-eligible epilepsy per year.  The syndrome has long puzzled neurologists, but new research, including the discovery of epileptic baboons that seem to die from SUDEP, offers hope that its causes will soon be understood and treatment made possible.

SUDEP is more likely to strike epileptics whose seizures are more frequent and more resistant to medicines. It seems to strike more often when people are asleep or otherwise alone. In most—but not all—cases, there is evidence of a recent seizure. Aside from knowing these risk factors, researchers have little ability to predict when SUDEP will strike.

Because SUDEP is associated with epilepsy and kills so suddenly, those who study it think that it results when an epilepsy-related electrical storm in the brain somehow affects the regulation of the two most vital functions, heartbeat and breathing.  But does the regulation of heartbeat become disrupted first, leading to breathing problems, or vice versa?

Heartbeat as key?

Some evidence points to the disruption of normal heartbeat rhythm as the earlier event. “We’ve published papers, as have others, showing that a significant percentage of people during seizures or in the immediate aftermath of seizures have [cardiac] arrhythmias,” says Michael Sperling, a neurologist at the Jefferson Medical College of the Thomas Jefferson University in Philadelphia, Pa., and co-author of a recent review of SUDEP research.

Studies of a rare genetic disease known as long QT syndrome also suggest a linkage between epilepsy and cardiac problems. People with QT syndrome have heart muscle cells with abnormal electrical characteristics that can cause the heart to stop suddenly.

In a presentation at the annual American Epilepsy Society (AES) meeting in San Antonio, Texas, in early December, Alica Goldman and colleagues at the Baylor College of Medicine in Houston reported on  a defective gene in long QT syndrome that controls a channel in cell membranes through which potassium ions flow. Goldman’s team found that the same gene is also expressed in the brain.  In mice engineered to have the defective gene, the researchers observed epilepsy-like abnormal electroencephalograph (EEG) recordings as well as abnormal heart rhythms.

The pulmonary hypothesis

“That was a very interesting finding,” says Charles A. Szabo, a neurologist at the University of Texas Health Sciences Center in San Antonio. But it doesn’t solve the mystery, he notes, because no one has yet linked the same gene defect to human SUDEP cases.

By contrast, at the same meeting, researchers from the University of California, Davis, led by neurologist Lisa M. Bateman, presented findings from two SUDEP cases and four near-SUDEP cases in hospitalized epilepsy patients. The patients were monitored with EEGs and electrocardiographs (EKGs), and in some cases with blood oxygen and carbon dioxide measuring equipment designed to detect respiratory problems.

Based on respiratory signs seen in these cases, Bateman and her colleagues propose a chain of events that may lead to SUDEP. First, a person has a seizure, which briefly exhausts neurons’ ability to fire normally and depresses functions in many regions throughout the brain. This leads to reduced breathing, which in turn causes a drop in blood levels of oxygen and a corresponding buildup of carbon dioxide. These pulmonary changes then disturb heart function, ending with the “failure of recovery of cortical function and eventual cardiac failure.”

Pulmonary signs consistent with this hypothesis are often found in autopsies of SUDEP cases. Indeed, Szabo and colleagues recently have found similar results in a completely different group—epileptic baboons.

A colony of about 2,000 baboons is housed at the Southwest National Primate Center in San Antonio, one of five such U.S. government-supported facilities. Researchers observe the baboons mainly to investigate genetic influences upon major illnesses such as diabetes and arteriosclerosis.

Apparently because of a genetic predisposition among the colony’s founding members, some 20 percent of current colony occupants have seizures—a prevalence about twice as high as that seen among humans. Many of these epileptic animals also die suddenly, for reasons that can’t be determined from the thorough pathological examinations that all deceased animals in the colony are given.

Szabo has been studying the baboons for nearly 10 years. In a paper published in the August 2009 issue of Epilepsia, he and his colleagues reported on an analysis of recent deaths among the baboons. They found that epileptic baboons that had died suddenly of no evident cause showed one distinctive sign: Nearly all had a buildup of lung fluid known as pulmonary edema. Such edema was seen in only a small minority of baboons who had died of known causes. Pulmonary edema can occur as a result of heart problems, but the “SUDEP” baboons did not show any consistent heart abnormalities. Szabo also says that his ongoing monitoring of the epileptic baboons with EKGs has turned up little evidence of abnormal heart rhythms.

“This is a very elegant study that demonstrates, for the first time, a possible natural model of SUDEP,” says Fulvio A. Scorza, chief of experimental neurology at Brazil’s Federal University of São Paulo and a prominent SUDEP researcher.

Szabo and his colleagues don’t know what brain mechanisms would link seizures in such animals to pulmonary edema but, Szabo says, “there is evidence that severe brain injuries can be associated with pulmonary edema, and these cases probably have something to do with a brainstem dysfunction.”

Is the culprit in the brainstem?

A brainstem dysfunction leading to inadequate breathing has been blamed for sudden infant death syndrome (SIDS). In particular, SIDS researchers have focused on brainstem regions that are sensitive to the neurotransmitter serotonin, theorizing that defects in these systems can cause a normal arousal response to high carbon dioxide levels to fail. Thus, for example, a SIDS-prone infant who sleeps face down would fail to turn over normally as the concentration of carbon dioxide in the blood increased.

Szabo considers it plausible that a similar mechanism may be involved in SUDEP cases. He is now working to set up more intensive monitoring of the epileptic baboons in the colony, including long-term studies with implanted EEG electrodes and EKGs, as well as serotonin-related analyses and studies of behavioral differences from non-epileptic baboons.

Rainer Surges, a SUDEP researcher at University College, London, argues that the syndrome ultimately may be found to have more than one cause:  “In some patients, [seizure-caused] respiratory dysfunction, such as massive neurogenic edema or apnea, could be the predominant cause, whereas in others primary cardiac failure due to [abnormal heart rhythms] might lead to sudden death,” he says.

Sperling notes that, however the SUDEP debate is resolved, it will be useful to have a good animal model of SUDEP, which occurs too infrequently in human patients to be easily studied. “You can’t monitor people forever,” he says.  “A primate model would really come in handy, and would probably be a better analogy [to human SUDEP] than a rat model or some other animal model.”