Pauline Anderson

December 08, 2014

SEATTLE, Washington — Emerging research is shedding new and important light on the possible involvement of cardiac factors in sudden unexpected death in epilepsy (SUDEP).

The new findings may better explain these sudden deaths and perhaps eventually further inspire successful preventive approaches, researchers say.

Several groups reported new developments at a media briefing here the American Epilepsy Society (AES) 68th Annual Meeting.

Every year, SUDEP affects about 1 in 1000 patients with epilepsy, often among those aged 20 to 40 years. It's more common among certain subpopulations of epileptic patients, including those with Dravet syndrome (DS), a severe and intractable form of pediatric epileptic encephalopathy. SUDEP claims an estimated 15% of patients with DS.

A growing body of evidence suggests that cardiac arrhythmia precedes SUDEP in these patients. To test whether cardiac excitability is altered in patients with DS, researchers compared the beating rate, beat period (time between beats), and sodium current (INa) density in cardiac cells from 2 patients with DS who had distinct mutations in SCN1A and from 1 control.

The research team found that the cardiac cells from the patients with DS beat twice as fast as those from the control, and the sodium current was doubled.

This, said Chad Frasier, PhD, a cardiac physiologist and postdoctoral researcher, University of Michigan Medical School, Ann Arbor, suggests that alterations in cardiac excitability may contribute to the mechanism of SUDEP in patients with DS. This research is important, he said, because if a biomarker in the form of a sodium channel mutation is identified, it may be possible to eventually step in to prevent sudden death.

Dr Frasier noted that experts have discussed trying implantable devices, such as a vagal nerve stimulator, in patients with DS, or some sort of alarm system that goes off should the patient get into cardiac difficulty.

Cardiac Repolarization

In a separate study, researchers at the University of Florida College of Medicine, Gainesville, used video electroencephalography to monitor cardiac abnormalities during the post-ictal state in a 12-year-old and a 17-year old male with drug-resistant epilepsy.

Their data suggest that abnormalities in cardiac repolarization may slow the heart rate and induce asystole during the postseizure state, thereby raising the risk for SUDEP.

Cardiac asystole may be the terminal point of a cascade of autonomic changes occurring in children with poorly controlled seizures, the authors concluded.

Finally, a team at Oxford University in the United Kingdom is making headway in understanding the cardiac as well as the respiratory consequences of seizures using an animal model.

"The big question" in SUDEP "is, does the heart stop first or do you stop breathing first?" said John Jefferys, PhD, professor, neuroscience, University of Oxford. The answer, he said, depends on the individual.

Dr John Jefferys

Although the death is caused by a lack of respiration or lack of cardiac activity, the problem originates in the brain, according to his research colleague, Pedro Irazoqui, PhD, associate head of biomedical engineering and director of the Center for Implantable Devices, Purdue University, West Lafayette, Indiana. "My guess is that you're not going to find the flaw in the heart or the lungs or the diaphragm; you're going to find the flaw in the autonomic descending control from the brain."

Dr Jefferys' research team injected a toxin into the brain of normal rats to mimic temporal lobe epilepsy. They recorded electroencephalograms and electrocardiograms continuously over several weeks while the animals experienced seizures, each lasting 1 to 2 minutes.

Their key finding, according to Dr Jefferys, was that the rats experienced a decrease in heart rate during seizures with arrhythmias and sometimes asystole lasting for several seconds, and then later episodes of tachycardia lasting 30 minutes or more.

He and his colleagues have developed and implanted miniature recording devices that should shed further light on how cardiorespiratory, cerebral, vagal, or other factors contribute to the risk for SUDEP. Although these devices are "pretty good," more work needs to be done to improve the reliability of their wireless power, Dr. Jefferys reported.

"In January, we will implant the next generation of devices, which need less power, are smaller, and will have other modifications to ensure continuity of powering," he said.

Once they understand more about the underlying mechanisms. Dr Jefferys' team plans to use the device's stimulation capability in an attempt to prevent SUDEP.

"I hope we will start that part of the project towards the end of next year. If that works, then we will explore translation to the clinic."

And in the long run, that translation could mean the development of devices or drugs or other preventive measures in patients with epilepsy, said Dr Jefferys.

Dr Jefferys' research is supported by Epilepsy Research UK.

American Epilepsy Society (AES) 68th Annual Meeting. Platform Session C.02, Presented December 8; Poster 2.261, Presented December 7; Poster 3.036, Presented December 8, 2014.


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