For release: Friday, September 17, 2010
In the brains and hearts of animal models, neuroscientists have uncovered new clues about molecular triggers for sudden unexplained death in epilepsy, or SUDEP. Evidence from two studies linked SUDEP to faulty ion channels, protein gateways essential for transmitting electrical signals. The discoveries could help medical researchers predict or find ways to reduce the risk of death in epilepsy, according to Jeffrey L. Noebels, M.D., Ph.D., the senior investigator on both studies. Dr. Noebels is professor of neurology, neuroscience, and molecular and human genetics at Baylor College of Medicine in Houston, Texas, where the research took place.
Most people with epilepsy have a normal lifespan, but for poorly understood reasons the seizure disorder is associated with a higher incidence of unexplained death, classified as SUDEP. Studies indicate that SUDEP accounts for between 2 to 18 percent of deaths in individuals with idiopathic epilepsy (epilepsy with an unknown cause) and that it appears to occur more frequently in younger patients with treatment-resistant forms of the disorder. Although researchers have long suspected a connection between SUDEP and underlying cardiac or respiratory problems, the recent research is among the first to pinpoint several key biological mechanisms.
In a study published in April 2010, Baylor investigators led by Edward Glasscock, Ph.D., examined mice bred to lack a gene for Kv1.1 ion channels(1). Previous research showed that such mice have severe epilepsy and often die very young.
Dr. Glasscock and colleagues recorded electrical signals in the brains and hearts of the mutant mice. They observed that when the mice had epileptic seizures their heartbeats became erratic. In some cases this led to death by cardiac arrest. The investigators determined that defective ion channels were present in the vagus nerve, which runs from the brainstem to the heart and regulates cardiac rhythms.
“In mice without Kv1.1 channels, we think the vagus nerve loses control and sends extra nerve impulses to the heart, telling it to slow down — and even stop beating — when it shouldn’t,” Dr. Glasscock said.
This was the second gene that scientists in Dr. Noebel’s laboratory have implicated in SUDEP. In a study published in October 2009, investigators led by Baylor’s Alica M. Goldman, M.D., Ph.D., examined a gene mutation associated with Long QT syndrome (LQTS) (2). According to Dr. Goldman, this syndrome is marked by irregular heartbeats (cardiac arrhythmias), frequent fainting spells and a higher risk of sudden death. Some research suggests that the fainting spells are actually epileptic seizures. Mutations in the gene for the KvLQT1 ion channel are the most common cause of LQTS.
Dr. Goldman’s team observed that mice bred with this genetic mutation had both life-threatening heart rhythm irregularities and frequent epileptic seizures. Previously it was thought that the gene affected only heart cells; however, this study showed for the first time that the flawed KvLQT1 ion channels were also present in neurons. According to Dr. Noebels the study demonstrated the long-sought molecular link between heart and brain in epilepsy.
Dr. Goldman said this important evidence suggests that one way to reduce the risk of SUDEP in people with idiopathic epilepsy is to check for heart rhythm irregularities. This can be done through a test called an electrocardiogram (ECG, or EKG). Until very recently, she explained, people with seizure disorders did not routinely receive ECG tests because there was no firm evidence of a relationship between LQTS and epilepsy. Dr. Goldman is now screening epilepsy patients to determine whether they have the same gene mutations associated with seizures and sudden death as those seen in the mice in the study.
Both teams of investigators at Baylor were supported in part by grants from the National Institute of Neurological Disorders and Stroke (NINDS).
“The identification of these genetic and molecular triggers associated with SUDEP represents a major step forward,” said Brandy Fureman, Ph.D., an NINDS neuroscientist and a program director for epilepsy research. “Future studies can build on these insights to broaden our understanding of other genes and risk factors involved, and guide efforts to translate research into therapeutic interventions to safeguard patients who are at risk,” she said.
Image Caption: The pair of traces shows 25 seconds of simultaneous brain and heart activity, as recorded by electroencephalography (EEG)-electrocardiography (ECG), during a seizure in a mouse lacking Kv1.1 ion channels shortly before it suffered sudden death. As the seizure progresses, the regular cardiac rhythm disappears temporarily and the heart beats only intermittently. Credit: Used with permission: Glasscock et al. The Journal of Neuroscience 2010.
-By Gregory Roa, NINDS
1. Glasscock, E, et al. “Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy.” Journal of Neuroscience, April 14, 2010, Vol. 30(15), pp. 5167-5175.
2. Goldman, AM, et al. “Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death.” Science Translational Medicine, October 14, 2009, Vol. 1(2), p. 2ra6.
Last Modified September 19, 2014