Key Points

• A biomarker is something that can be objectively measured, such as protein in blood or electrical activity in the brain and is used as an indicator of abnormal biological activity. In epilepsy, a biomarker could be used to predict individuals with epilepsy who are at a high risk of sudden death.
• Previous studies have shown the usefulness of cardiac measures such as heart rate and heart rate variability (HRV, or the amount of time between heartbeats) as potential biomarkers for seizures. Dr. David Auerbach at the Upstate Medical University is extending this knowledge to understand if cardiac measures can distinguish between epileptic seizures and functional or dissociative seizures (FDS), also known as psychogenic non-epileptic seizures (PNES). While FDS are not categorized as epileptic seizures, understanding FDS could have an impact on treating and curing the epilepsies.
• Dr. Auerbach was recently awarded The CURE Epilepsy Cameron Boyce SUDEP Research Award to explore the role of cardiac biomarkers for Sudden Unexpected Death in Epilepsy (SUDEP). His cross-disciplinary work applies techniques from the field of cardiology to epilepsy.

Deep Dive

Epileptic seizures (ES) are caused by disturbances in electrical activity in the brain. However, in 20-40% of individuals whose seizures are not controlled by antiseizure medications, seizure activity does not correlate with changes in an electroencephalogram (EEG).[1] These seizures are classified as psychogenic non-epileptic seizures (PNES), also known as functional or dissociative seizures (FDS).[2] Many people with FDS have experienced abuse, trauma, or neglect. FDS can co-occur with depressive disorders, personality disorders, and post-traumatic stress disorders. FDS are often debilitating and are associated with a decreased quality of life, substantial emotional burden, and financial and psychosocial loss.[3,4] There is value to the epilepsy field in understanding and studying FDS for several reasons: first, ES and FDS can co-exist,[5] and second, both ES and FDS can impact the cardiac system, leading to changes in heart rate, arrhythmias, and other abnormalities seen on an electrocardiogram (ECG).[6,7] Disturbances in the autonomic nervous system have been seen in individuals with ES and FDS, and this is especially true in drug-resistant epilepsy and cases of Sudden Unexpected Death in Epilepsy (SUDEP).[8,9]

It is important to be able to differentiate between ES and FDS because the characteristics and treatment options for each differ. Similar to ES, there is a high risk of sudden death in individuals with FDS. Alarmingly, those with FDS have 2.5 times the rate of sudden death compared to the general population.[10] People with suspected FDS may undergo testing in an epilepsy monitoring unit using video EEG, but tests done there can lead to inconclusive results. Not being able to properly diagnose FDS can have many detrimental impacts such as delays in getting proper treatment, and inappropriate or even inadvertently dangerous medical treatment.[11,12] Hence, there is an urgent need to develop ways to diagnose FDS and differentiate ES from FDS.

In a recently published paper funded by the University of Rochester Provost Research Award, Dr. Auerbach’s team applied their knowledge of cardiac biomarkers in the study of the autonomic nervous system and FDS.[1] An important function of the autonomic nervous system is to regulate cardiac activity.[13] One measure of autonomic system function is the heart beat-to-beat variability (also known as heart rate variability, or HRV). HRV is the time between each heartbeat. There is generally some variation in the time between heartbeats; this is considered adaptive because it means that the heart can respond to changes in situations, being ready for either increasing or decreasing the heart rate as needed. The team performed ECG to measure the heart’s electrical activity and track the evolution of HR and HRV, to understand if they could be used to distinguish between ES and FDS.[1] In this study, the authors evaluated the evolution of autonomic function for five hours surrounding seizures; they also developed HR and HRV algorithms to differentiate between ES and FDS.16 The authors found that HR and HRV measures such as the HR after the seizure (“post-ictal HR”), and change in HR before and after seizures (“pre-to-post ictal change”) did indeed distinguish between ES and FDS, and that this effect was specific to convulsive events (i.e., those with a significant physical component), and not non-convulsive, seizures (i.e., those without a significant physical component).[1] By taking inputs and knowledge from the field of cardiology, Dr. Auerbach’s team was able to develop biomarkers for FDS, signaling once again that a holistic, interdisciplinary approach to understanding epilepsy is critical.

CURE Epilepsy has long been leading the charge in funding research on seizure-related biomarkers and is committed to advancing this research as it will have the potential to improve outcomes for people with epilepsy by identifying, for example, who may be at risk for epilepsy after a stroke to who may be at risk for epilepsy following a brain injury to who may not respond to antiseizure medications. By using tools that are new to the field of epilepsy and SUDEP but well-accepted in the field of cardiology, Dr. Auerbach’s team is using funding from The CURE Epilepsy Cameron Boyce SUDEP Research Award to explore potential biomarkers, including cardiac biomarkers that may help predict who is at greater risk for SUDEP. His long-term goal is to develop a risk assessment tool for SUDEP based on various biological markers, including cardiac arrhythmias. Additionally, Dr. Auerbach has recently been awarded a $1M grant by the National Institute of Neurological Disorders and Stroke (NINDS). This grant builds on his previous project looking at a cardiac abnormality known as Long QT Syndrome (LQTS), which showed a link between LQTS and an increased prevalence and risk of seizures.[14] Dr. Auerbach’s scientific work is just one example of CURE Epilepsy’s influence on the field, where supporting a promising scientist early in their career has exponential impact when they go on to gain additional government funding, train new epilepsy researchers, and advance their research which will ultimately impact the millions of people living with epilepsy.

By funding transformational research, CURE Epilepsy continues to be committed to advancing the study of biomarkers within priorities areas including SUDEP and post-traumatic epilepsy (PTE); the organization is poised to make even more progress in the area of biomarkers in 2024.

Literature Cited:

1. Ryan M, Wagner K, Yerram S, Concannon C, Lin J, Rooney P, et al. Heart rate and autonomic biomarkers distinguish convulsive epileptic vs. functional or dissociative seizures Seizure: European Journal of Epilepsy. 2023 Aug; 111: 178-186.
2. Ertan D, Aybek S, LaFrance WC, Jr., Kanemoto K, Tarrada A, Maillard L, et al. Functional (psychogenic non-epileptic/dissociative) seizures: why and how? J Neurol Neurosurg Psychiatry. 2022 Feb;93:144-157.
3. Dworetzky B. The Impact of PNES is About More than Counting Events Epilepsy Curr. 2016 Sep-Oct;16:314-315.
4. Rawlings GH, Reuber M. What patients say about living with psychogenic nonepileptic seizures: A systematic synthesis of qualitative studies Seizure. 2016 Oct;41:100-111.
5. El-Naggar H, Moloney P, Widdess-Walsh P, Kilbride R, Delanty N, Mullins G. Simultaneous occurrence of nonepileptic and epileptic seizures during a single period of in-patient video-electroencephalographic monitoring Epilepsia Open. 2017 Dec;2:467-471.
6. Romigi A, Ricciardo Rizzo G, Izzi F, Guerrisi M, Caccamo M, Testa F, et al. Heart Rate Variability Parameters During Psychogenic Non-epileptic Seizures: Comparison Between Patients With Pure PNES and Comorbid Epilepsy Front Neurol. 2020;11:713.
7. Costagliola G, Orsini A, Coll M, Brugada R, Parisi P, Striano P. The brain-heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention Ann Clin Transl Neurol. 2021 Jul;8:1557-1568.
8. Anzellotti F, Dono F, Evangelista G, Di Pietro M, Carrarini C, Russo M, et al. Psychogenic Non-epileptic Seizures and Pseudo-Refractory Epilepsy, a Management Challenge Front Neurol. 2020;11:461.
9. Müngen B, Berilgen MS, Arikano?lu A. Autonomic nervous system functions in interictal and postictal periods of nonepileptic psychogenic seizures and its comparison with epileptic seizures Seizure. 2010 Jun;19:269-273.
10. Nightscales R, McCartney L, Auvrez C, Tao G, Barnard S, Malpas CB, et al. Mortality in patients with psychogenic nonepileptic seizures Neurology. 2020 Aug 11;95:e643-e652.
11. Devinsky O, Gazzola D, LaFrance WC, Jr. Differentiating between nonepileptic and epileptic seizures Nat Rev Neurol. 2011 Apr;7:210-220.
12. Yeom JS, Bernard H, Koh S. Myths and truths about pediatric psychogenic nonepileptic seizures Clin Exp Pediatr. 2021 Jun;64:251-259.
13. Huikuri HV, Stein PK. Heart rate variability in risk stratification of cardiac patients Prog Cardiovasc Dis. 2013 Sep-Oct;56:153-159.
14. Auerbach DS, McNitt S, Gross RA, Zareba W, Dirksen RT, Moss AJ. Genetic biomarkers for the risk of seizures in long QT syndrome Neurology. 2016 Oct 18;87:1660-1668.

Key Points

• Sudden Unexpected Death in Epilepsy (SUDEP) is a tragic outcome defined by premature death in people with epilepsy that is not caused by drowning, injury, or other known causes of mortality.
• CURE Epilepsy has been a leader in driving awareness and research on SUDEP since 2004, when it started the first private research program to investigate SUDEP and its prevention.
• CURE Epilepsy has advanced the understanding of risk factors associated with SUDEP which   healthcare providers can use to talk to patients about epilepsy and SUDEP.
• CURE Epilepsy also commemorates individuals who have passed away due to SUDEP. For example, CURE Epilepsy actively participates in an annual SUDEP Action Day in October, when families and organizations across the epilepsy community come together to raise awareness about SUDEP.  

Deep Dive

Sudden Unexpected Death in Epilepsy (SUDEP) refers to deaths in people with epilepsy not caused by drowning, injury, or other known causes of mortality. There is often evidence of an associated seizure, and the death is usually unwitnessed. Unfortunately, SUDEP is underrecognized and underestimated, as coroners and medical examiners may be unaware of the diagnostic criteria that define SUDEP.[1, 2] CURE Epilepsy has been the leading force driving research and raising awareness about SUDEP and since 2004 has funded over 40 projects totaling nearly $6 million to understand the basic biological mechanisms underlying this tragic outcome.   

Former CURE Epilepsy Board Director, Research Committee member, and SUDEP pioneer Jeanne Donalty has been a prominent voice in raising awareness of SUDEP and has worked tirelessly on grassroots approaches for awareness and prevention. Her work was motivated by the loss of her son Christopher when he was 21 years old, the recognition that healthcare providers rarely talked about SUDEP as a potential outcome of epilepsy, and the minimal research at the time in understanding SUDEP. Together with CURE Epilepsy, Jeanne worked with the National Institute of Neurological Disorders and Stroke (NINDS) to help create a “Center Without Walls” called the Center for SUDEP Research (CSR). The CSR employed a range of strategies to explore the causes of SUDEP and identify risk factors that may help prevent it. Former CURE Epilepsy Board Chair and volunteer Gardiner Lapham, who lost her son Henry to SUDEP, was instrumental in the formation of an organization called Partners Against Morality in Epilepsy (PAME). PAME continues to be a driving force in reducing epilepsy mortality by convening an annual conference of diverse stakeholders to discuss epilepsy mortality causes, share research discoveries, and identify means of prevention. CURE Epilepsy is a founding member of PAME and continues to be deeply involved by sitting on the Governance Committee, partnering on annual webinars, and financially sponsoring the annual meeting. 

In addition to advocacy and education, CURE Epilepsy funds innovative research in this field of study. Specifically, CURE Epilepsy researchers have developed SUDEP registries to get a more accurate understanding of the number of people affected, investigated risk factors for SUDEP, and studied the underlying biological mechanisms of SUDEP.   

Impact of SUDEP registries  

A registry is a database of people who have been diagnosed with a certain condition; it can be used to track the outcomes of participants and inform the care of other individuals with the same condition. Dr Elizabeth Donner at the University of Toronto was a recipient of CURE Epilepsy’s 2009 Sudden Unexpected Death in Epilepsy Award. With this funding, she developed a pediatric SUDEP registry in Canada to obtain data on every child with epilepsy who died suddenly and unexpectedly. While previous studies estimated that SUDEP affects 1 in 4,500 children with epilepsy each year,[3] Dr. Donner’s work estimated a much higher number: 1.11 cases of SUDEP per 1,000 children with epilepsy.[4] Her estimate is also in line with another study that made use of the Swedish National Death Registry.[5] Additionally, Dr. Donner and colleagues used the North American SUDEP Registry (NASR) and found that even those with well-controlled epilepsy may be at risk for sudden death.[6] Previous studies had suggested that SUDEP risk was highest in those with treatment-resistant epilepsy; however, the NASR study showed that sudden death can happen to anyone with epilepsy and that it should be discussed with everyone with epilepsy and their caregivers. Specifically, the study revealed that the risk of sudden death appeared to be higher in individuals who had not taken their most recent dose of anti–seizure medication, those who were sleep-deprived, and those with psychiatric disorders.[6]  

Understanding the risk factors for SUDEP  

Dr. Torbjörn Tomson at the Karolinska Institute in Sweden was awarded a CURE Epilepsy grant in 2010, which was supported by the Leisher Family Award. His research involved a large, nationwide study on factors associated with increased risk of SUDEP; his findings confirm previous findings that generalized tonic-clonic seizures (GTCS) are a significant risk factor for SUDEP.[7] He found that individuals with GTCS living and sleeping alone are at significant risk for SUDEP. His work supports the use of seizure-monitoring devices to alert caregivers and the recommendation that people with GTCS should share a room with someone when sleeping whenever possible. Also, any treatments to reduce the occurrence of GTCS or to convert GTCS to non-GTCS could be useful in reducing SUDEP risk.[7] 

Understanding the genetic mechanisms underlying SUDEP    

CURE Epilepsy-funded grantees have investigated a multitude of targets and biological mechanisms in people affected by SUDEP, as well as in experimental animal models. The work of Dr. Annapurna Poduri and colleagues in Robert’s Program[1] at Boston Children’s Hospital explored common, underlying, genetic mechanisms that may be associated with SUDEP and other sudden unexpected pediatric deaths. Her team employed a “trio-based” approach, meaning that the child and their parents were studied to understand genetic changes that may have contribute to sudden unexpected death in these children.[8] Using this approach, many genes that were previously not associated with sudden death were reclassified; for example, genes such as SCN1A and DEPDC5 that are implicated in sudden pediatric death have also been shown to be relevant in SUDEP. Dr. Poduri also examined ten infants who died of sudden infant death syndrome (SIDS) and found that two children had variants of the SCN1A gene, which is also implicated in SUDEP.[9] Genes associated with cardiac issues such as arrhythmia and cardiomyopathy (a condition that makes it harder for the heart to pump blood) were also implicated in SUDEP.[8] In a separate study, CURE Epilepsy Award grantee Dr. Christopher Reid at the Florey Institute of Neuroscience & Mental Health at the University of Melbourne sought to understand the risk between SUDEP and cardiac arrhythmia (abnormal or irregular heartbeat). His team studied a gene called KCNH2, as mutations in this gene are linked to cardiac arrhythmias. His work demonstrated the role of KCNH2 mutations in SUDEP and suggests that genetic screening for KCNH2 could help understand an individual’s risk for SUDEP.[10, 11]

In addition to these and dozens of other scientific studies that CURE Epilepsy has funded and is currently funding on SUDEP, CURE Epilepsy is leading a project to standardize the data collected and reported in preclinical studies to improve transparency and rigor. Epilepsy researchers have an opportunity to comment on the common data elements (CDEs) developed through this project until December 31, 2023, after which CURE Epilepsy will distill and publish these best practices. Over the past 25 years, CURE Epilepsy has funded transformative science and significantly furthered awareness of SUDEP, and the organization will continue to prioritize this important area of research going forward in hopes of eventually preventing this tragic outcome.

Literature Cited:

1. Sudden Unexpected Death in Epilepsy (SUDEP). Available at: https://www.cdc.gov/epilepsy/about/sudep/index.htm. Accessed October 5.
2. Devinsky O. Sudden, unexpected death in epilepsy N Engl J Med. 2011 Nov 10;365:1801-1811.
3. Harden C, Tomson T, Gloss D, Buchhalter J, Cross JH, Donner E, et al. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society Neurology. 2017 Apr 25;88:1674-1680.
4. Keller AE, Whitney R, Li SA, Pollanen MS, Donner EJ. Incidence of sudden unexpected death in epilepsy in children is similar to adults Neurology. 2018 Jul 10;91:e107-e111.
5. Sveinsson O, Andersson T, Carlsson S, Tomson T. The incidence of SUDEP: A nationwide population-based cohort study Neurology. 2017 Jul 11;89:170-177. 
6. Chloe V, Fizza H, Elizabeth D, Brian DM, Jeffrey B, Dale H, et al. SUDEP in the North American SUDEP Registry Neurology. 2019;93:e227.
7. 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 28;94:e419-e429.
8. Koh HY, Haghighi A, Keywan C, Alexandrescu S, Plews-Ogan E, Haas EA, et al. Genetic Determinants of Sudden Unexpected Death in Pediatrics Genet Med. 2022 Apr;24:839-850.
9. Brownstein CA, Goldstein RD, Thompson CH, Haynes RL, Giles E, Sheidley B, et al. SCN1A variants associated with sudden infant death syndrome Epilepsia. 2018 Apr;59:e56-e62.
10. Bleakley LE, Soh MS, Bagnall RD, Sadleir LG, Gooley S, Semsarian C, et al. Are Variants Causing Cardiac Arrhythmia Risk Factors in Sudden Unexpected Death in Epilepsy? Front Neurol. 2020;11:925.
11. Soh MS, Bagnall RD, Bennett MF, Bleakley LE, Mohamed Syazwan ES, Phillips AM, et al. Loss-of-function variants in K(v) 11.1 cardiac channels as a biomarker for SUDEP Ann Clin Transl Neurol. 2021 Jul;8:1422-1432