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 priority 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:
- 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.
- 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.
- Dworetzky B. The Impact of PNES is About More than Counting Events Epilepsy Curr. 2016 Sep-Oct;16:314-315.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Devinsky O, Gazzola D, LaFrance WC, Jr. Differentiating between nonepileptic and epileptic seizures Nat Rev Neurol. 2011 Apr;7:210-220.
- Yeom JS, Bernard H, Koh S. Myths and truths about pediatric psychogenic nonepileptic seizures Clin Exp Pediatr. 2021 Jun;64:251-259.
- Huikuri HV, Stein PK. Heart rate variability in risk stratification of cardiac patients Prog Cardiovasc Dis. 2013 Sep-Oct;56:153-159.
- 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.