Scientists are unraveling the cause behind sudden unexpected death in epilepsy

In the United States, nearly three million adults 18 years and older reported having active epilepsy during 2021 and 2022. SUDEP (sudden unexpected death in epilepsy), however, is rare, occurring in one in 1,000 people and resulting in an estimated 3,000 deaths per year. Its rarity has shrouded it in mystery, although some theories point to seizures disrupting the heart and breathing, ultimately leading to death.

Now, scientists at Southern Methodist University are closing in on some answers, illuminating what might happen in the brain when SUDEP strikes.

In a study published in the journal Brain Communications, the researchers identified neurons in the brain’s corticolimbic system—made up of regions that govern everything from emotions to heart rate—that underlie SUDEP.

When these neurons lacked a protein regulating electrical activity, called Kv1.1, mice had seizures and problems with breath and heart function. In the case of one mouse, the researchers observed a full SUDEP event, with breathing issues followed by heart failure, which matched patterns previously seen in humans.

While animal models aren’t perfect proxies for humans, these findings stand out because they get to the root of SUDEP, at least for one type of rare genetic mutation responsible for epilepsy, said Dr. Michael Privitera, director of the Epilepsy Center at the University of Cincinnati Gardner Neuroscience Institute, who was not involved in the new study.

Searching the brain

It’s been known for over a century that epilepsy—a long-term brain disorder marked by abnormal electrical signals triggering seizures—carries a risk of death. In the 20th century, it became clear that many epilepsy-related deaths happen unexpectedly and under benign circumstances. This phenomenon, called sudden unexpected death in epilepsy (or SUDEP for short), was officially defined in 1997.

“People can have SUDEP at any age,” Privitera said, no matter how healthy they are. Risk factors include uncontrolled seizures and poor adherence to medication, or when people aren’t taking their medicine as prescribed, Privitera explained. He added that men are slightly more at risk than women, though there’s not a big difference.

In 2013, the landmark Mortality in Epilepsy Monitoring Unit Study brought fresh insight into SUDEP. The study reported 16 SUDEP cases and nine near cases from 147 epilepsy monitoring units across Europe, Israel, Australia and New Zealand.

It showed there was a series of events that tended to happen with SUDEP: a tonic-clonic seizure—where a person loses consciousness and has stiffening and jerking of the muscles—followed by breathing problems and heart failure, leading to death.

“The study revealed that it looks like breathing stops sometime in the short window after the seizure, and then the heart fails later,” said Edward Glasscock, a professor of biology at Southern Methodist University who led the new study.

“So that kind of pointed everybody to look at breathing versus the heart, because for a long time, it was thought that maybe seizures just cause you to have lethal cardiac arrhythmia.”

But an underlying biological mechanism for the brain-lung-heart connection remained elusive. What scientists have been able to piece together comes from animal studies, particularly from a type of mouse genetically modified to lack a gene called Kcna1. That gene encodes the protein Kv1.1, which helps regulate electrical activity by controlling the flow of potassium in and out of neurons.

Mice missing Kv1.1 show similar traits to humans with epilepsy and those who experienced SUDEP: frequent seizures and breathing problems that happen before heart issues. (Mutations in Kcna1 happen in humans but are rare, Privitera said.)

For their study, Kelsey Paulhus, the study’s first author and a postdoctoral researcher at SMU, and Glasscock explored whether removing Kv1.1 from neurons was enough to cause the breathing, heart and seizure problems linked to SUDEP. If that was the case, exactly which neurons and in which pathways of the brain were the first to be impacted?

Using a mouse missing the Kcna1 gene but deleting it specifically from neurons in the mouse’s brain, Paulhus and Glasscock found that was enough to cause epilepsy, early death and problems with breathing and heart function.

They then created mice lacking Kv1.1 in forebrain regions where this protein is usually abundant. These regions include the neocortex (in humans, it’s responsible for higher brain functions like learning and consciousness), the hippocampus (plays a major role in learning and memory) and amygdala (key to emotional processing).

The brains and hearts of the mice were then implanted with wires to measure and record electrical signals, and the animals were subsequently placed in a plethysmography chamber that monitored their breathing.

As expected, they experienced spontaneous seizures and related heart and lung issues. One mouse died from SUDEP.

“Catching that was really rare because we only do those recordings with respiration for somewhere between six and eight hours at a time,” Paulhus said. “I feel very fortunate that … we were able to catch that because it’s really important information.”

When mapping out the electrical activity in the brain, Paulhus and Glasscock found that excitatory neurons in the corticolimbic system were setting off the SUDEP chain reaction. Excitatory neurons, as their name suggests, excite other neurons whereas inhibitory neurons dampen electrical activity.

Paulhus and Glasscock’s hypothesis is that during SUDEP, the corticolimbic system influences the autonomic nervous system, the network of nerves that handle unconscious bodily tasks like heartbeat and breathing.

“We know through different experiments that if you manipulate the corticolimbic system, that can affect heart and lung function,” Paulhus said. “We also know that it has direct communication with the brain stem, so that was a really important aspect as to why we honed in there.”

Further research still needed

While these findings reveal some of SUDEP’s unseen cogs, further research is needed to see if the mechanism holds true for epilepsy due to other genetic causes or factors like traumatic brain injury, said Robert Hunt, director of the Epilepsy Research Center at the University of California at Irvine, who was not involved in the study.

“The next question would be: Can we stop SUDEP?” Hunt said. “If we can do that, then can we separate a seizure from at least the cardiac and lung events? Then the next question would be, if we can do that, does that prevent SUDEP? Can we build the tools and technology?”

Privitera said that intracranial devices, which deliver electrical impulses to correct the brain’s abnormal electrical activity, are gaining a foothold in epilepsy treatment and, potentially, in preventing SUDEP.

“There is some indirect evidence, for example, that implanting vagus nerve stimulators doesn’t make a lot of people seizure-free, but it does seem that, if you look at the clinical trials, that there was a slightly reduced risk of SUDEP,” Privitera said.

Paulhus and Glasscock acknowledge their discovery is just the tip of the iceberg. But they hope to expand their findings to uncover biomarkers that identify where communication between the brain, heart and lungs goes awry in their epilepsy models. Such biomarkers could one day help those with epilepsy and their families better manage and navigate the medical condition—hopefully without fear of SUDEP.

“One of the things I would love to emphasize is that the most brilliant minds are devoted to trying to figure this out,” Paulhus said. “There are so many people so devoted to this and trying to take huge steps. I think with the speed research goes, we as a field can make some really significant progress.”

2025 The Dallas Morning News. Distributed by Tribune Content Agency, LLC.