In September, NINDS issued awards for the creation of a new center to research sudden unexpected death in epilepsy (SUDEP), the sudden and premature death of a person with epilepsy without apparent or known cause of death. SUDEP is the most common cause of premature mortality in human epilepsy. Unlike many NIH center programs, the Center for SUDEP Research will not be confined to a single institution. This unique consortium is the second of NINDS’s Epilepsy “Centers without Walls” (CWOW), which is a program designed to bring together the best expertise from across U.S. and international institutions to address a challenging research problem for people with epilepsy. The Center for SUDEP Research includes dozens of scientists who are armed with the basic science, computational, genetic, and clinical tools necessary to better understand and develop interventions to prevent this devastating consequence of living with epilepsy.While the causes of SUDEP are currently unclear, mounting evidence points to seizures that induce structural defects and/or brain circuit malfunction in areas that control cardiovascular and/or respiratory functions. Using a multidisciplinary approach, scientists and clinicians participating in the new center without walls hope to understand what causes SUDEP and how can it be prevented.
One team of researchers will identify genes, predisposition to neurochemical imbalances, and structural irregularities in the brain that may increase the risk of cardiac arrhythmias and respiratory disruptions in epilepsy. In parallel, another team will develop a sophisticated repository for storing and sharing genetic, tissue and clinical data samples collected from 400 study participants with epilepsy per year for three years at each of 10 clinical sites across the country. This team will also analyze the collected samples to identify risk factors for SUDEP.
The origin of the CWOW concept dates to 2010, when NIH leadership recognized the profound need for a revitalized commitment to research on the epilepsies. The epilepsies are a spectrum of brain disorders characterized by spontaneous seizures, which are caused by disruptions in the brain’s electrical activity and affect 30 million people worldwide. NINDS, in conjunction with the epilepsy research community, conceptualized the idea of a center without walls as a team of investigators that would come together, regardless of their geographical locations, to attack specific challenges in epilepsy research that require multidisciplinary approaches.
The SUDEP CWOW is the second epilepsy CWOW funded by NINDS. The Epi4k CWOW—a collaboration of more than 60 U.S., Irish, and Australian researchers searching for epilepsy genes in 4,000 collected blood samples—is now in its third year. This center has so far made remarkable progress. Researchers have identified a series of genes related to childhood epilepsies. These genes will hopefully form the basis of new epilepsy treatments that can be tailored to each individual’s genetic make-up. Sequencing data generated by the Epi4K CWOW is currently available to other researchers through dbGAP and more will be coming. The Epi4K CWOW has also developed collaborations with several other groups to extend their resources even further into the research community.
In August, a request for applications (RFA) was issued for grants towards the creation of a new epilepsy center or centers focused on therapy development to prevent the genesis of epilepsy or modify its progression. The NINDS has received several applications that will be reviewed this spring, and will be considered for funding at our May 2015 Advisory Council meeting.
The CWOW is a central feature of NINDS’s efforts to stimulate research on SUDEP. While awareness of SUDEP was raised at the 2007 Curing Epilepsy meeting as well as in NINDS’s 2007 Benchmarks for Epilepsy Research, NINDS was funding just a single R01 grant focused on SUDEP at the time the CWOW concept was introduced. Considering the grave danger of SUDEP—individuals with refractory epilepsy have a 35 percent lifetime chance of succumbing to SUDEP—all felt that this is an important research area. In part, the low level of research activity was due to the need for multi-disciplinary teams composed of neuropathologists, cardiologists, pulmonologists as well as epilepsy experts to approach the problem. In addition, a mechanism to document cases of SUDEP and compile the potential risk factors was not in place. The recent launch of the Sudden Death in the Young Registry—a collaboration between NINDS, NHLBI, CDC and state public health departments will hopefully fill this gap. Our hope is that the new CWOW will accelerate the rate of progress in understanding and ultimately preventing SUDEP.
Recognizing that it would be difficult to quickly develop the best teams to address the challenge of SUDEP, the first step in the creation of the SUDEP CWOW was to issue a competition for three-year planning grants. NINDS awarded two planning grants, one to a team led by Samden Lhatoo of Case Western University and the other to the team led by Jeffrey Noebels of Baylor College of Medicine. Dr. Lhatoo used his grant to develop a prototype clinical SUDEP database and Dr. Noebels used his grant to hold a series of think tank-style workshops to discuss possible respiratory and cardiovascular causes of SUDEP. NINDS then issued a call for applications for the full-scale SUDEP CWOW, and in July of this year reviewed a series of linked U01 grant applications from teams of investigators led by these researchers. NINDS program staff worked with Lhatoo and Noebels to combine the best pieces of both projects, which now comprise the Center for SUDEP Research.
The resulting collaboration brings together approximately 40 researchers, including 12 principle investigators, from 11 institutions across the U.S and the U.K. The SUDEP center will receive $3 million per year in funding from NINDS for up to five years. The projects supported by the center will focus on several approaches for researching SUDEP (see below for descriptions of each project).
I hope that the strong multidisciplinary approach envisioned for the Center for SUDEP Research will propel epilepsy research forward in new, groundbreaking ways.
Center for SUDEP Research projects
- Autonomic and Imaging Biomarkers Project
- The goal of this project is to provide insight into mechanisms of failure in SUDEP and suggest potential interventions. Researchers will examine in individuals with epilepsy the relationship between local changes in injured brain structures (measured with diffusion tensor imaging) and breathing patterns/autonomic nervous system diagnostics (EEG, blood pressure, heart rate variability, cardiac arrhythmia) around the time of seizures.
- Performance sites: Ann & Robert H. Lurie Children’s Hospital of Chicago, Case Western Reserve University, Columbia University, Jefferson University, NYU, Northwestern University, University College London, UCLA, University of Iowa
- Neuropathology Project
- Researchers will leverage the world’s largest collection of brains from individuals who succumb to SUDEP to look for specific histopathological and biomolecular abnormalities in the brain, focusing on critical brainstem regions and changes in pathways and neurotransmitters.
- Performance sites: Columbia University, NYU, University College London
- Respiratory Project
- Researchers will identify an anatomical pathway by which cortical seizures can invade the midbrain and brainstem and cause depressed cardiorespiratory function and arousal.
- Performance site: Ann & Robert H. Lurie Children’s Hospital of Chicago, University of Iowa
- iPSC Project
- Researchers will study induced pluripotent stem cells (iPSC) derived from children with Dravet syndrome—a severe form of childhood epilepsy with a high risk of SUDEP—to determine how Dravet-linked genetic mutations influence the autonomic nervous system’s control of over heart function.
- Performance site: Ann & Robert H. Lurie Children’s Hospital of Chicago, University of Michigan
- Cardiac Project
- Researchers will search for genes expressed in the brain and heart that may increase the risk for cardiac arrhythmias. Further investigation of these genes in mouse models will examine the molecular excitability changes in brain circuits that regulate the heart rate and patterns of breathing and explore pharmacological methods for reversing structural and functional defects to reduce SUDEP risk.
- Performance sites: Baylor College of Medicine, Texas Children’s Hospital in Houston
- Informatics and Data Analysis Core
- This core will set up a web-based database for integrated clinical and translational epilepsy data. It will also provide data analytics and statistical support for in-depth analyses of imaging, clinical and physiological data.
- Performance site: Case Western Reserve University in collaboration with all sites
- Molecular Diagnostics Core
- This core will provide DNA sequencing and analysis of samples from individuals with epilepsy who have died prematurely, or those who have a high clinical risk of SUDEP.
- Performance sites: Baylor College of Medicine and USDA/ARS Children’s Nutrition Research Center in Houston in collaboration with all sites
- Morphometric Analysis Core
- This core will perform structural analyses of the brains of a large population of pediatric and adult epilepsy patients at high risk for as well as for brain specimens obtained at autopsy from individuals who died from SUDEP.
- Performance sites: Baylor College of Medicine, Harvard University, UCSF in collaboration with all sites