Nav: Home

Leaky calcium triggers brainstem blackout that results in sudden cardiac death

August 01, 2016

Epilepsy is an extremely common disorder affecting people of all ages, from infants through teenagers to older adults. One of the most mysterious things about this disorder is that about 6 percent of the people with epilepsy have an unusually high incidence of sudden unexpected death. In a paper published today on the Proceedings of the National Academy of Sciences researchers from Baylor College of Medicine report how a mutation in a gene involved in the regulation of calcium inside brain cells can help trigger blackouts of the brainstem, the center that controls heartbeat and breathing, and increase the risk of sudden unexpected death.

"Sudden unexpected death in epilepsy - SUDEP - turns out to be the most common cause of premature death in people with epilepsy. It's not accidents or suicide, it's just this unexplained mortality," said senior author Dr. Jeffrey L. Noebels, professor of neurology, neuroscience, and molecular & human genetics, and director of the Blue Bird Circle Developmental Neurogenetics Laboratory at Baylor. "Most people with epilepsy live long lives and do not seem to have an increased risk of SUDEP. But there is a subset of people at additional risk. We have been looking for genes that cause epilepsy to see if any of them might give us a clue as to who might be at risk. Specifically, we have been looking at genes that might explain what appears to be a collapse of the cardiac and respiratory system after a seizure."

In their years-long quest to understand the cellular and genetic mechanisms that may trigger SUDEP, Noebels and his colleagues have studied the genes that are involved in the heart beat. Some of these genes are already well known to be related to sudden unexpected cardiac death.

"We wondered whether some of those same genes could also cause seizures if they were expressed in the brain, and, if so, whether those genes would also place people with epilepsy at risk, not only for having epilepsy, but an abnormal heart beat and risk of death," said Noebels. "In our first experiments we found several genes that actually filled that description: they are expressed in the brain and the heart, and mutations of those genes cause an abnormal heart beat and epilepsy in mouse models." The researchers then found that these same genes carry an additional risk for a phenomenon called spreading depolarization, a slowly-progressing, temporary electrical blackout of a region in the brain. During a blackout, the brain cells in that area cease their activity until it is restored.

"Spreading depolarization is well known in people with migraine headaches," said Noebels. "Many people with migraines have an aura or a sensation before they feel pain. If the blackout occurs in the visual cortex, the region of the brain that helps us see, then the person can develop a blind spot that slowly expands and then disappears. If it occurs in the motor region of the brain, they become weak on one side of the body. And then they develop a terrible head pain. It's called migraine aura. After 20 to 30 minutes, they recover their vision or their ability to move. Not all the migraines have an aura."

In 2015, Noebels and Dr. Isamu Aiba, a research fellow in neurology at Baylor, published a paper in Science Translational Medicine in which they described in a mouse model what would happen if spreading depolarization, the blackout of brain activity, occurred deep in the brainstem - which controls the heart beat and breathing.

"We worked with mice carrying genes that predisposed them to epilepsy and premature death. We found that, indeed, it's much easier to trigger these blackouts experimentally in the brainstem of those mice, while in normal mice we could not trigger them at all," said Noebels. "Mice could have seizures and nothing would happen, but, then, one seizure would finally trigger a blackout event in the brainstem and the mice would die."

In the 2016 paper discussed here, Noebels and colleagues studied another gene - RyR2 - which is also expressed in the heart and known to cause heart problems. They showed that RyR2, which is also expressed in the brain, also causes epilepsy in mice and sets up an electrical surge that makes a fatal blackout likely.

"What is especially interesting about RyR2 is that it works inside the cell as a regulator of intracellular calcium. Ions such as calcium are important because they affect the release of neurotransmitters, the molecules that mediate communication between brain cells," said Noebels. "RyR2 is a mutation - we call it 'leaky' RyR2 - that increases the normal amount of calcium inside the cell which, in turn, triggers the release of an increased amount of neurotransmitters. And that increased release of neurotransmitters somehow makes it much easier to trigger a blackout."

Noebels is director of the Center for SUDEP Research located in Baylor College of Medicine. Researchers at eight other institutions are members of the Center and are dedicated, like Noebels' group, to increase our understanding of epilepsy and deadly complications such as SUDEP. The Center and the groups of scientists are supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

For Noebels and colleagues, the discovery of how the 'leaky' RyR2 increases the chances of SUDEP is a step forward toward a future in which neurologists could sit with a patient and their family and have a conversation about the possibility of offering an accurate prediction of the risks of SUDEP and effective interventions.
Isamu Aiba and Xander H.T. Wehrens were authors of this paper.

Support for this work was provided by the National Institutes of Health Center for SUDEP Research Grants NS090340 and

NS29709; NIH HL089598, HL091947, HL117641, and HL129570; American Heart Association Grants 13EIA14560061 and 14POST20130031 and the Blue Bird Circle Foundation.

Baylor College of Medicine

Related Epilepsy Articles:

Good news for kids with epilepsy
There's good news for kids with epilepsy. While several new drugs have come out in the last several years for adults with epilepsy, making those drugs available for children and teenagers has been delayed due to the challenges of testing new drugs on children.
People with epilepsy: Tell us about rare risk of death
People with epilepsy want their health care providers to tell them about a rare risk of death associated with the disorder, according to a preliminary study released today that will be presented at the American Academy of Neurology's 69th Annual Meeting in Boston, April 22 to 28, 2017.
New epilepsy gene network identified by scientists
Scientists have discovered a gene network in the brain associated with epilepsy.
Epilepsy -- why do seizures sometimes continue after surgery?
New research from the University of Liverpool, published in the journal Brain, has highlighted the potential reasons why many patients with severe epilepsy still continue to experience seizures even after surgery.
Redox biomarker could predict progression of epilepsy
Approximately 2.9 million people in the United States suffer from epilepsy, according to the CDC.
Many Malaysian children with epilepsy are vitamin D deficient
Long-term use of antiepileptic drugs is a significant risk factor for vitamin D deficiency in children with epilepsy.
Changes in heart activity may signal epilepsy
Researchers at Case Western Reserve University have found that the parasympathetic nervous system modulates breathing and slows the heart rate of sleeping children with epilepsy substantially more than in healthy children.
Few answers in understanding death from epilepsy
To increase understanding of mortality in epilepsy, including SUDEP, Partners Against Mortality in Epilepsy (PAME) unites physicians, scientists, health care professionals, people with epilepsy, caregivers and bereaved family members for a unique conference that facilitates collaboration and spurs action.
New insights into epilepsy drug Retigabine
A study published ahead of print in the Journal of General Physiology has revealed new insights into Retigabine, a known pharmacological treatment for epilepsy.
Are women with epilepsy using effective contraception?
In the largest study of contraceptive practices of women with epilepsy, 30 percent did not use highly effective contraception despite being at higher risk of having children with fetal malformations due to the anti-epilepsy medications they take.

Related Epilepsy Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#530 Why Aren't We Dead Yet?
We only notice our immune systems when they aren't working properly, or when they're under attack. How does our immune system understand what bits of us are us, and what bits are invading germs and viruses? How different are human immune systems from the immune systems of other creatures? And is the immune system so often the target of sketchy medical advice? Those questions and more, this week in our conversation with author Idan Ben-Barak about his book "Why Aren't We Dead Yet?: The Survivor’s Guide to the Immune System".