Dr. Jeffrey Noebels, professor of neurology and molecular and human genetics, is leading a new research center of international scientists who seek to answer questions that arise from the mystery of sudden unexpected death in epilepsy (SUDEP).

Called a “Center without Walls,” it was established by the National Institute of Neurological Disorders and Stroke to address the challenges and gaps in epilepsy research.

“The need is simple – thousands of children and adults with epilepsy die suddenly without any warning. Even starting the conversation with patients about sudden unexpected death in epilepsy can be difficult because at present we have no way of determining exactly which patient with epilepsy is at specific risk,” said Noebels, who also holds the Cullen Trust in Health Professions Endowed Chair at Baylor. Experts estimate that as many as 1 in 1,000 people with epilepsy die each year as a result of SUDEP. Many of those deaths affect people ages 20 to 40.

The Center and the nine groups of scientists involved in it have received a five-year, $27.3 million funding award to support the Center for SUDEP Research, a collaborative group working on increasing the understanding of this deadly complication of epilepsy.

Noebels to lead scientific pipeline

Noebels, also the director of the Blue Bird Circle Development Neurogenetics Laboratory at Baylor, has long sought to address this problem and is charged with leading the group.

“The Center for SUDEP Research is made up of nine projects established at different institutions across the U.S. with the common goal of quickly taking SUDEP lab results to the clinic,” Noebels said. “This project is one of life and death, bridging patients past and present, and connecting basic and clinical researchers.”

At Baylor, one of the core sites, researchers will work to develop a risk calculator for physicians to understand personal risk of SUDEP for a patient with epilepsy, identifying the mechanisms behind that risk and working to create way to intervene with a remedy to save lives.

Starts with the patient

It all starts with the patient, said Noebels.

“Most people who have seizures have few complications, but about 5 percent do not. Their heart rates become irregular, and they are slower to recover. Those are the people we seek to monitor, to see what else is going wrong during a seizure.”

Certain clinical sites will act as monitoring units directed by Dr. Sam Lhatoo with Case Western University. Those who suffer seizures complicated by abnormal breathing or heart rate will undergo additional monitoring methods. Researchers also will collect samples of their DNA and skin fibroblasts (a skin biopsy containing stem cells) to share with other cores, including Baylor, where the DNA will be analyzed.

At Baylor, teams lead by Dr. Alica M. Goldman, assistant professor of neurology – neurophysiology, and Dr. John Belmont, professor of molecular and human genetics, pathology & immunology and pediatrics and an expert in cardiac genes, and Dr. Chad Shaw, associate professor of molecular and human genetics, will work to identify patterns of abnormal gene variations that are characteristics of these different vulnerabilities that the patients have.

Goldman also will lead a team made up of researchers and clinicians from Baylor, the University of California San Francisco and Harvard who will examine brain tissue from SUDEP cases, looking for neuropathological and neuroimaging indicators. They will trace the neural pathways to the brainstem, where the autonomic nervous system is regulated.

Noebels added that stem cells from patients will be transformed in the lab (University of Michigan) into several types of brain and heart cells to examine for abnormalities. Genetically engineered mouse models will be created to focus on these defects to examine the underlying physiology and to learn how single gene defects can produce this complication of epilepsy. 

Continues Noebels’ research

This work is a continuation of Noebels’ research. In 2009, he and his colleagues, including Dr. Goldman, were the first group to identify a gene for SUDEP. The gene showed that there is a heart-brain connection, linking epilepsy and sudden death. Those findings have opened the door to further pinpoint what he calls “risk genes” that will one day help clinicians ascertain who is at greater risk.

“These models can help us be certain the gene defect we find in an individual is actually the one that causes the problem, allowing us to develop strategies to prevent SUDEP,” Noebels said. “Once we determine which variations in these genes are dangerous, and which actually might be protective, we will be able to assemble a risk profile to identify those in the greatest need, and find the right treatments, bringing our lab work back to the patient.”

Center for SUDEP Research Cores:

Center for SUDEP Research: Morphometric Core

• Principal Investigator: Dr. Alica M. Goldman, Baylor College of Medicine
• Goldman’s group will focus on changes in the size and structure of the brain and brainstem in individuals who have died due to SUDEP.

Center for SUDEP Research: Molecular Diagnostics Core

• Principal Investigators: Dr. John William Belmont and Dr. Alica Goldman.
• Belmont’s team will conduct DNA genetic analyses on samples obtained from individuals who have died or are at high risk of developing SUDEP. The tissue will be collected from institutions that are part of the Center for SUDEP Research. The goals of this project are to identify the genes that cause SUDEP and allow researchers to develop tools to predict who is at risk for it.

Center for SUDEP Research: Cardiac Gene and Circuit Mechanisms

• Principal Investigator: Dr. Jeffrey Noebels
• Noebels and his colleagues will investigate how changes in genes can increase the risk of SUDEP by causing abnormalities in heart rate and breathing patterns. They will identify genes that contribute to SUDEP and test candidate drugs that may reduce the risk of unexpected death.

Center for SUDEP Research: Administrative Core

• Principal Investigators: Dr. Samden Lhatoo, Case Western Reserve University; Dr. Jeffrey Noebels
• The Administrative Core will serve as a virtual hub for the SUDEP projects. Lhatoo and Noebels will oversee, facilitate and prioritize the research that results from the Center for SUDEP Research projects.

Center for SUDEP Research: Autonomic and Imaging Biomarkers of SUDEP

• Principal Investigator: Dr. Samden Lhatoo
• Lhatoo’s team will examine ways in which changes in brain structure are linked to abnormal physiological responses and altered breathing patterns that occur during seizures. Using various imaging technologies, they will identify risk factors for SUDEP that may eventually be therapeutic targets.

Center for SUDEP Research: The Neuropathology of SUDEP

• Principal Investigators: Dr. Maria Thom, University College London; and Dr. Orrin Devinsky
• Combining the world’s largest collection of brains from individuals who have died from SUDEP with tissue collected from individuals undergoing epilepsy surgery, Thom and her colleagues will use a variety of techniques to examine the role of two chemicals, adenosine and serotonin, in unexpected death associated with epilepsy.

Center for SUDEP Research: Respiratory and Arousal Mechanisms

• Principal Investigator: Dr. George B. Richerson, University of Iowa, Iowa City
• Research from Richerson’s lab suggests that dysfunction in brainstem pathways involved in controlling breathing may be involved in SUDEP. With the help of individuals with epilepsy as well as mouse models, Richerson and his colleagues will investigate these pathways and look for biomarkers that may be used to screen individuals most at risk of developing SUDEP.

Center for SUDEP Research: Induced Pluripotent Stem Cells and Mouse Neurocardiac Models

• Principal Investigators: Dr. Jack M. Parent and Dr. Lori Isom, University of Michigan
• Parent and Isom will examine changes in neuronal function and heart rhythm that may contribute to SUDEP in individuals with Dravet syndrome, a severe form of pediatric epilepsy with higher risk of sudden death. Using stem cells derived from individuals with Dravet syndrome, data obtained from these individuals before, during and after seizures, and mouse models, they will look for biomarkers to identify risk.

Center for SUDEP Research: Informatics & Data Analysis Core

• Principal Investigator: Dr. Guo-Qiang Zhang, Western Reserve University
• The main goal of the Informatics and Data Analysis Core (IDAC) is to make it easier for researchers to share data and resources across all of the institutions in this Center Without Walls. IDAC will also provide support for the SUDEP projects by assisting with data collection, analysis and study design.

For more information about epilepsy, please visit:

http://www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm