When Melanie Whittamore-Mantzios’ teenage son, Nick, was diagnosed with epilepsy, the family was told he would outgrow it. His seizures happened when he was asleep, but were largely controlled by medication. This treatment plan worked well enough for him to graduate from Case Western University with a degree in biomedical engineering.
But rather than going away on its own, epilepsy ultimately claimed his life: Nick died in 2019, at age 28, from Sudden Unexpected Death in Epilepsy (SUDEP).
“We had never heard the term ‘Sudden Unexpected Death in Epilepsy’ until we saw the cause of death spelled out on Nick’s death certificate.[Now] we would like to help in any way we can to prevent SUDEP from occurring. Nick would have been happy to contribute to this with his scientific background.”
Melanie Whittamore-Mantzios
SUDEP refers to death in a seemingly healthy person with epilepsy that is not due to obvious causes like drowning, injury, or poisoning. Adding to the mystery, SUDEP deaths are usually unwitnessed, and often occur at nighttime. Though likely to be underreported, SUDEP is a leading cause of death among those with epilepsy: in the US, approximately 3000 people die each year from it. The risk is particularly high in those with uncontrolled epilepsy, with 1 in 150 dying from SUDEP [1].
The shock of SUDEP leaves many families looking for explanations, but the biological causes remain hazy. Current thinking links SUDEP to seizure-related disruptions in breathing, heart rhythms, or brain function [2], but there is as yet no clear biological signal for SUDEP. To address this, in 2004 CURE Epilepsy established the SUDEP Research Initiative to fund research seeking to understand these tragic deaths. Forty research grants and $5.8 million dollars later, progress has been made toward defining signs of SUDEP in the brain, as well as establishing databases, called registries, that contain information about people who have succumbed to SUDEP. These registries have provided important information about the incidence of SUDEP.
CURE Epilepsy has played a transformational role in fostering, advocating for, promoting and funding epilepsy research in general, and research into SUDEP in particular. Their work is invaluable.
Neurologist, UT Health Houston
Now, CURE Epilepsy is helping to pull together research results from different labs into cohesive answers on SUDEP in two different initiatives. Through its SUDEP Data Standardization project, scientists will better characterize their SUDEP-related findings in a way that is mutually understandable between researchers. In addition, CURE Epilepsy has initiated a SUDEP Risk Assessment and Prevention Project, which seeks to identify risk factors for SUDEP, and compile them into a risk assessment tool, similar to those available for other diseases like cancer.
“To really move the needle on SUDEP research, we need to bridge two key topics: advancing our understanding of SUDEP risk through existing data and leveraging that knowledge to develop tools that help individuals and healthcare providers better understand and communicate risk. We are excited to be leading, with likeminded partners, targeted efforts to push the field forward.”
Dr. Laura Lubbers, Chief Scientific Officer at CURE Epilepsy
Data standardization
To examine the causes of SUDEP, researchers have developed different kinds of animal models. For example, mice engineered to carry epilepsy-related genetic mutations can die from seizures [3]. The seizures can be spontaneous or triggered and may happen under specific laboratory conditions. Given the diversity of animal models, seizure types, and experimental designs that researchers explore, it is challenging to compare findings from one study to another, even though they are all SUDEP studies.
To help labs speak the same data language, in 2022 CURE Epilepsy established a new effort called the SUDEP Data Standardization Project and assembled experts from around the globe to identify the key pieces of information that need to be collected from SUDEP experiments. Funded by the BAND Foundation, this group of experts will soon finalize two new publications: one that outlines the most important characteristics of SUDEP animal models and another that lists supplemental data points that could be useful, depending on the nature of the experiment. Together the papers will provide standardized data tools that will facilitate data sharing and interpretation across different lab, and could even enable the growth of centralized databases that will help collaboration.
Risk Assessment
Data from people with epilepsy are also now being mined to search for SUDEP risk factors. Ongoing studies are following participants throughout their lives and will include some who eventually die from SUDEP. Funding by CURE Epilepsy supported a study that found the greatest risk for SUDEP in people with generalized tonic-clonic seizures that occur at night who also slept alone[4]. This suggests that measures like seizure detection devices or medications that can control these seizures could reduce SUDEP risk.
Ideally, all healthcare providers would have an easy-to-use risk assessment tool that could take into account the characteristics of a person’s epilepsy, and flag those most at risk for SUDEP. To address this need, CURE Epilepsy partnered with the Epilepsy Foundation and the Cameron Boyce Foundation to host the SUDEP Risk Assessment and Prevention workshop in October in New York City. For two days, over 20 SUDEP experts discussed what is needed to develop refined SUDEP risk assessment tools. With actionable information already available in registries, researchers prioritized potential risk factors that warrant additional study, as well as identified missing information and new experimental endpoints that could provide clues about SUDEP risk. They also discussed analysis methods, including artificial intelligence, that may combine different risk factors together to create the most accurate risk assessment tools.
“Our workshop highlighted the need for all voices—including those of families with lived experience with SUDEP—to come together to develop a SUDEP risk assessment tool. We must strive to equip our community with actionable tools that foster understanding, risk assessment and actionable steps people can take to reduce their risk of SUDEP—essential elements for safer, more effective management,” Lubbers says.
Future iterations
Once a refined SUDEP risk assessment tool is completed, it can be further improved as future SUDEP data becomes available. Thus, CURE Epilepsy continues to fund innovative studies by individual researchers to provide even more clues about SUDEP risk. For example, Sanjay Sisodiya at the University College London is looking for genetic markers associated with SUDEP. Because SUDEP commonly occurs at night, Gordon Buchanan of the University of Iowa is exploring whether a brain chemical that changes during the night, called serotonin, might contribute to SUDEP vulnerability. Using established cardiac tools, David Auerbach of SUNY Upstate Medical University is evaluating data from people with epilepsy for irregular heart rhythms that may predispose them to SUDEP. Funding these individual, investigator-initiated projects can provide seed data needed to inform larger collaborations that make even bigger contributions to understanding SUDEP. This happened for Lhatoo, whose funding from CURE Epilepsy helped him detect brainstem abnormalities in SUDEP, which paved the way for a large consortium effort to understand their role.
“CURE Epilepsy’s role in the larger ecosystem [of SUDEP research], in bringing biomarker discovery and preventive strategy development to the forefront, has been foundational, and [it] will have lasting impact,” Lhatoo says.
Literature Cited:
- Hirsch LJ, Donner EJ, So EL, Jacobs M, Nashef L, et al. Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy. Neurology. 2011 May; 76: 1932-1938.
- Faingold CL, Feng HJ. A unified hypothesis of SUDEP: Seizure-induced respiratory depression induced by adenosine may lead to SUDEP but can be prevented by autoresuscitation and other restorative respiratory response mechanisms mediated by the action of serotonin on the periaqueductal gray. Epilepsia. 2023 Apr; 64: 779-796.
- Gu J, Shao W, Liu L, Wang Y, Yang Y, Zhang Z, et al. Challenges and future directions of SUDEP models. Lab Anim (NY). 2024 Sep; 53:226-243.
- Sveinsson O, Andersson t, Mattsson P, Carlsson S, Tomson T. Clinical risk factors in SUDEP: A nationwide population-based case-control study. Neurology. 2020 Jan; 94:e419-e429.
