A National Study of Epilepsy-Related Deaths in Scotland: Trends, Mechanisms, and Avoidable Deaths

Abstract, full article originally published in Epilepsia

Objective: This study was undertaken to investigate the trends and mechanisms of epilepsy-related deaths in Scotland, highlighting the proportion that were potentially avoidable.

Methods: This was a retrospective observational data-linkage study of administrative data from 2009–2016. We linked nationwide data encompassing mortality records, hospital admissions, outpatient attendance, antiepileptic drug (AED) prescriptions, and regional primary care attendances. Adults (aged ?16 years) suffering epilepsy-related death were identified for study using International Classification of Diseases, 10th Revision coding combined with AED prescriptions. We reported epilepsy-related mortality rate (MR), age-specific mortality ratios, multiple cause-of-death frequencies, and the proportion of potentially avoidable deaths (identified as those with an underlying cause listed as avoidable by the Office for National Statistics).

Results: A total of 1921 epilepsy-related deaths were identified across Scotland; 1185 (62%) decedents were hospitalized for seizures in the years leading up to death, yet only 518 (27%) were seen in a neurology clinic during the same period. MR remained unchanged over time, ranging from 5.9 to 8.7 per 100 000 Scottish population (95% confidence interval [CI] = ?.05 to .66 per 100 000 for annual change in MR). Mortality ratios were significantly increased in young adults aged 16–54 years (2.3, 95% CI = 1.8–2.8), peaking at age 16–24 years (5.3, 95% CI = 1.8–8.8). Sudden unexpected death in epilepsy (SUDEP) constituted 30% of the 553 young adult epilepsy-related deaths, with several other non-SUDEP fatal mechanisms identified including aspiration pneumonia, cardiac arrest, AED or narcotic poisoning, drowning, and alcohol dependence. Seventy-six percent of young adult epilepsy-related deaths were potentially avoidable.

Significance: Epilepsy-related deaths are a major public health problem in Scotland, given that they are not reducing, people are dying young, and many deaths are potentially avoidable. SUDEP is only one of several important mechanisms by which epilepsy-related deaths are occurring in young adults. Services may need to be re-evaluated to improve specialist referral following seizure-related hospital admissions.

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CURE Epilepsy Discovery: Identification of Environmental Contributors to SUDEP

Key Points:

  • CURE Epilepsy awardee Dr. Franck Kalume and colleagues at the Seattle Children’s Research Institute and New York University sought to identify simple environmental factors that may increase the risk of SUDEP. 
  • The team examined the effects of increased temperature and moderate exercise on several basal involuntary bodily functions of an established mouse model of Dravet syndrome (DS), a severe form of epilepsy with an increased incidence of SUDEP. 
  • When compared to normal mice, DS mice showed diminished regulation of core body temperature as well as cardiac and respiratory function.
  • Understanding the mechanisms behind these impairments might help develop effective approaches to reduce the risk of and perhaps even prevent SUDEP.

Deep Dive:

Sudden unexpected death in epilepsy (SUDEP) is devasting event that occurs in approximately 1 in 1,000 people with epilepsy [1,2]. It appears to be related to seizure-induced dysfunction of the autonomic nervous system (ANS) [3] The ANS controls body functions essential for survival and is responsive to environmental changesSome of these functions include maintenance of core body temperature as well as tight regulation of heart and breathing rates. Previous research has revealed that disruptions in ANS function related to a seizure event are marked by diminished control of these three body processes, but the precise nature and mechanisms of these weakened responses are not clear.

Dr. Franck Kalume, a recipient of CURE Epilepsy’s Sleep and Epilepsy Award, generously funded by the BAND Foundation, explored this important area of research by utilizing his mouse model of Dravet syndrome (DS). [4] DS is a treatment-resistant form of epilepsy with a high risk of SUDEP, and an increased prevalence of ANS dysfunction. This particular mouse model was developed by deleting the gene linked to most cases of DS in humans (known as SCN1A), which is also one of the many genes responsible for propagating electrical signals in the brain.

The first set of experiments involved assessing the ability of DS mice to regulate 1) core body temperature, 2) heart rate, and 3) breathing rate in response to an increase in surrounding temperature, i.e., to 86-90°F. Responses from the DS mice and control mice were subsequently compared [5].  

Before elevating the external temperature, the internal body temperatures of both DS and control mice were similar. In the first 15 min after heat exposure, the core body temperature in both groups increased, although the absolute temperature and rate of this increase was much smaller in DS versus control mice. As exposure to heat was reduced, the core body temperature returned to baseline in control animals, but in DS mice, body temperature remained elevated. These observations suggest that DS mice have deficits in thermoregulation (an ability to control core body temperature).  

Dr. Kalume and his team developed another set of DS mice in which the SCN1A gene had been deleted only in neurons responsible for transmitting inhibitory electrical signals in the brain [5]. The same responses were observed in this second group of DS mice, indicating that thermoregulation is most likely mediated by these inhibitory neurons. 

Along with deficits in controlling core body temperature, the DS mice also had problems regulating cardiac and respiratory function in response to elevated temperature. Specifically, although the heart rate of DS mice increased to only half that of control mice, the rate of recovery was much slower after the heat source had been removed. Likewise, even though the breathing rates decreased in both DS and control mice in response to higher temperatures, it recovered partially in control mice but not at all in DS mice.  

The effect of moderate exercise (running on a treadmill) on heart rate as well as heart rate variability was also assessed [5]. During this exercise challenge, the highest heart rate level reached was much lower in DS than in control mice, and it took much longer for DS mice to reach their peak values. Similar responses were observed for heart rate variability, all of which suggest impaired cardiac function in DS. 

Together, these findings imply that there are clear abnormalities within the ANS of DS mice and, by extension, in people with DS and possibly other intractable epilepsies. Understanding the biological bases of these irregularities and how environmental changes may adversely affect them will likely assist in the development of novel methods to reduce seizure-related health consequences as well as the high risk of SUDEP.   

This work was conducted in collaboration with Dr. Orrin Devinsky of New York University. 

Read more about Dr. Kalume’s research in sleep and epilepsy here



Literature Cited

  1. Devinsky, O. et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016; 15(10): 1075-1088. 
  2. Devinsky, O. & Sisodiya, S.M. SUDEP: Advances and challenges. Epilepsy Curr. 2020; 20(6 Suppl): 29S-31S. 
  3. Kalume, F. Sudden unexpected death in Dravet syndrome: respiratory & other physiological dysfunctions. Respir. Physiol. Neurobiol. 2013; 189: 324-328. 
  4. Kalume, F. et al. Sudden unexpected death in a mouse model of Dravet syndrome. J. Clin. Invest. 2013; 123: 1798-1808. 
  5. Sahai, N. et al. Disordered autonomic function during exposure to moderate heat or exercise in a mouse model of Dravet syndrome. Neurobiol. Dis. 2021; 147: 105154. 

Personalized Models Superior to Population-Based Estimates for Predicting SUDEP

Article, published in Healio

Models provided more accurate predictions of risk for sudden unexpected death in epilepsy than population-based estimates, according to results of a study that utilized a Bayesian logistic regression model.

The models remained more accurate even when they were “generalized to unseen data,” researchers noted in Neurology.

“Epilepsy is one of the leading causes of lost life-years worldwide,” Ashwani Jha, PhD, of the National Institute for Health Research University College London Hospitals Biomedical Research Center and the University College London Queen Square Institute of Neurology, told Healio Neurology. “Individuals with epilepsy often completely recover from seizures, but it is unclear why some tragically and unexpectedly die. Although we know of some factors that increase the risk for sudden unexpected death in epilepsy (SUDEP) on average, we cannot determine an individual’s risk. In this study, we developed and validated the first predictive model for individualized SUDEP risk, based on routine clinical information only.”

Although Jha said that the model should currently be restricted to clinical research use pending further validation in a future cohort, he expressed hope that the models will have two main benefits, with the first being clinical discussions regarding SUDEP potentially becoming more targeted and useful. This may reassure those at lower risk and motivate change, such as optimization of anti-seizure medications, among those at higher risk, according to Jha.

Epilepsy Discovery Reveals Why Some Seizures Prove Deadly

Summary from newswise.com, featuring the research of CURE Epilepsy Grantee Dr. Ian Wenker

New research from the University of Virginia School of Medicine has shed light on the No. 1 cause of epilepsy deaths, suggesting a long-sought answer for why some patients die unexpectedly following an epileptic seizure.

The researchers found that a certain type of seizure is associated with sudden death in a mouse model of epilepsy and that death occurred only when the seizure induced failure of the respiratory system.

The new understanding will help scientists in their efforts to develop ways to prevent sudden unexpected death in epilepsy (SUDEP). Based on their research, the UVA team has already identified potential approaches to stimulate breathing in the mice and prevent death after a seizure. The team believe that this new approach could one day help save lives.

“SUDEP is a major concern for patients with epilepsy and their loved ones,” said Manoj Patel, PhD, of UVA’s Department of Anesthesiology. “Our study has identified a sequence of events that takes place during a seizure which can progress and lead to death. Furthermore, we show that intervention during a seizure can rescue death in mice with epilepsy. This project is a long time in the making, and we are excited to share it with the scientific community.”

a red pencil draws the outline of a human head over a graphic of neurons

CURE Epilepsy’s Impact: Investing in Early-Stage Research Leads to Critical Advancements

Key Points:

  • Nearly 20 years ago, Peter Carlen, MD received a one-year grant from CURE Epilepsy that served as a catalyst for his research into seizure detection and electrical neurostimulation. One of the companies Dr. Carlen established continues the work in seizure detection and is currently building on his lab’s recent identification of a biomarker for sudden unexpected death in epilepsy (SUDEP).
  • For more than 20 years, through investing in paradigm-shifting ideas, CURE Epilepsy has enabled scientists to discover insights essential for advancing the understanding of epilepsy and moving us closer to a cure.

Deep Dive:

Dr. Carlen began his career as a general neurologist at the University of Toronto. He founded the Epilepsy Program at the Toronto Western Hospital 25 years ago and is now one of its staff epileptologists. With his 2002 funding from CURE Epilepsy, he collaborated with mathematician and engineer Dr. Berj Bardakjian and a student with a background in physics, Dr. Houman Khosravani, to investigate the promise of computation and engineering techniques to understand epileptic networks and to ultimately develop the ability to disrupt them.

The work facilitated by his CURE Epilepsy-funded grant has contributed substantially to prediction and treatment of epilepsy. The researchers first published a paper documenting arrest of seizure activity with brief, low frequency electrical pulses delivered to brain tissue [1] and later published two additional papers on electrical neurostimulation [2,3]. Since these initial studies, Carlen’s lab has progressed to more advanced testing paradigms with modified parameters to make the pulses more akin to what actually happens in the brain. Significantly, this newer protocol appears to result in better seizure control than the more traditional pattern of repetitive square pulses.

Perhaps some of the most frightening and challenging aspects of epilepsy are seizure unpredictability and the potential for SUDEP; thus, seizure and SUDEP forecasting remain priorities in epilepsy research. Dr. Carlen’s current research also focuses on the brainstem, a small area at the base of the brain located just above the spinal cord, that regulates functions such as breathing and heart rate. Hypothesizing that SUDEP reflects disturbances in the brainstem, Carlen’s lab measured the electrical activity from this brain region in rats and discovered that seizures originating here led to cardiorespiratory arrest and death [4,5], important findings that continue to influence the field.

Since the initial research supported by their 2002 CURE Epilepsy grant, Carlen and Bardakjian have continued to collaborate, recently making a breakthrough that could reduce overall morbidity and mortality in epilepsy: they have developed a seizure alarm and identified SUDEP biomarkers in the unique electrical patterns of the electroencephalogram (EEG) [6]. They have since founded a company called Neurometrics Technologies to develop this technology further, with the goal of combining a wireless headset with complex computer algorithms capable of analyzing a patient’s EEG patterns to predict seizures and detect SUDEP biomarkers.

Carlen finds serving as the bridge between his patients in the clinic and the basic research in his lab especially rewarding. As an epileptologist, he witnesses firsthand the intense suffering endured by people with epilepsy and, as a scientist, he is in a unique position to develop more effective treatments with little to no side effects, a true cure.

CURE Epilepsy is proud to have played a role in advancing research by Dr. Peter Carlen and his colleagues, building hope for prevention and cures, and ultimately, a world without epilepsy.

Literature Cited
[1] Khosravani, H., Carlen, P.L., & Velazquez, J.L.P. The control of seizure-like activity in the rat hippocampal slice. Biophys. J. 2003; 84: 687-695.
[2] Chiu, A.W.L., Jahromi, S.S., Khosravani, H., Carlen, P.L. & Bardakjian, B.L. The effects of high-frequency oscillations in hippocampal electrical activities on the classification of epileptiform events using artificial neural networks. J. Neural Eng. 2005; 3(1): 9-20.
[3] Khosravani, H., Pinnegar, C.R., Mitchell, J.R., Bardakjian, B.L., Federico, P., & Carlen, P.L. Increased high-frequency oscillations precede in vitro low-Mg2+ seizures. Epilepsia 2005; 46(8): 1188-1197.
[4] Salam, M.T., Montandon, G., Genov, R, Devinsky, O., Del Campo, M., & Carlen, P.L. Mortality with brainstem seizures from focal 4-aminopyridine-induced hippocampal seizures. Epilepsia 2017; 58(9): 1637-1644.
[5] Lertwittayanon, W., Devinsky, O., & Carlen, P.L. Cardiorespiratory depression from brainstem seizure activity in freely moving rats. Neurobiol. Dis. 2020; 134: 104628.
[6] Grigorovsky, V. et al. Delta-gamma phase-amplitude coupling as a biomarker of postictal generalized EEG suppression. Brain Commun. 2020; 2(2): fcaa182.

The SANTÉ Study at 10 Years of Follow-Up: Effectiveness, Safety, and Sudden Unexpected Death in Epilepsy

Summary, originally published in Epilepsia

Objective: We evaluated the efficacy and safety of deep brain anterior thalamus stimulation after 7 and 10 years, and report the incidence of sudden unexpected death in epilepsy (SUDEP) and overall mortality in adults in the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTÉ) study.

Methods: After the 3?month blinded and 9?month unblinded phases, subjects continued to be assessed during long?term follow?up (LTFU) and later a continued therapy access phase (CAP), to further characterize adverse events and the incidence of SUDEP. Stimulus parameter and medication changes were allowed.

Results: One hundred ten implanted subjects accumulated a total of 938 device-years of experience (69 subjects during the LTFU phase and 61 subjects in the CAP phase). Prior to study closure, 57 active subjects continued therapy at 14 study centers, with follow-up of at least 10 (maximum 14) years. At 7 years, median seizure frequency percent reduction from baseline was 75% (p < .001), with no outcome differences related to prior vagus nerve stimulation or resective surgery. The most severe seizure type, focal to bilateral tonic-clonic, was reduced by 71%. Adding new antiseizure medications did not impact the pattern of seizure reduction over time. There were no unanticipated serious adverse events in the study. The definite-plus-probable SUDEP rate, based on SANTÉ study experience (two deaths in 938 years) and previous pilot studies (0 deaths in 76 years), indicated a rate of 2.0 deaths for 1000 person-years. Overall mortality was 6.9 deaths per 1000 person-years.

Significance: The long-term efficacy and safety profiles of the deep brain stimulation (DBS) system for epilepsy are favorable and demonstrate stable outcomes. Improvement in frequency of the most severe seizure type may reduce SUDEP risk. The SUDEP rate with DBS (2.0) is comparable to other neuromodulation treatments (i.e., vagus nerve stimulation, responsive neurostimulation) for drug-resistant focal epilepsy.

Study Finds that Iron Accumulation in the “Epileptic Heart” May Contribute to Sudden Unexpected Death in Epilepsy

Abstract, originally published in Frontiers in Neurology

Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in models such as Pentylenetetrazole kindling (PTZ-K) or pilocarpine-induced Status Epilepticus (SE-P), which share similar alterations in cardiac function, with a high risk of SUDEP. Terminal cardiac arrhythmia in SUDEP can develop as a result of a high rate of hypoxic stress-induced by convulsions with excessive sympathetic overstimulation that triggers a neurocardiogenic injury, recently defined as “Epileptic Heart” and characterized by heart rhythm disturbances, such as bradycardia and lengthening of the QT interval.

Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosis was described at the brain level in both the PTZ-K and SE-P experimental models. However, seizure-related cardiac ferroptosis has not yet been reported. Iron overload cardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with high production of reactive oxygen species (ROS), lipid peroxidation, and accumulation of hemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overload cardiomyopathy is the leading cause of death in patients with iron overload secondary to chronic blood transfusion therapy; it is also described in hereditary hemochromatosis. GTCS, through repeated hypoxic stress, can increase ROS production in the heart and cause cardiomyocyte ferroptosis.

We hypothesized that iron accumulation in the “Epileptic Heart” could be associated with a terminal cardiac arrhythmia described in the iron overload cardiomyopathy and the development of state-potentially in the development of SUDEP. Using the aforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitive GTCS, we observed an increase in the cardiac expression of hypoxic inducible factor 1?, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areas were related to the possible hemosiderin production in the PTZ-K model. Furthermore, we demonstrated for the first time an accumulation of hemosiderin in the heart in the SE-P model.

These results suggest that uncontrolled recurrent seizures, as described in refractory epilepsy, can give rise to high hypoxic stress in the heart, thus inducing hemosiderin accumulation as in IOC, and can act as an underlying hidden mechanism contributing to the development of a terminal cardiac arrhythmia in SUDEP. Because iron accumulation in tissues can be detected by non-invasive imaging methods, cardiac iron overload in refractory epilepsy patients could be treated with chelation therapy to reduce the risk of SUDEP.

Epilepsy Research News: January 2021

This month’s research news includes announcements about CURE Epilepsy’s Frontiers in Research seminar series, and an announcement from the CDC about an incidence and etiology funding opportunity.

We also share that the NINDS Clinical Trials Methodology Course is accepting applications, and that the deadline to apply to the National Science Foundation Enabling Discovery Through Genomics (EDGE) Program is March 16.

These news items are summarized below.

Research Highlights

CURE Epilepsy’s Frontiers in Research Seminar Series has gone virtual!

As part of our on-going commitment to supporting the research community through these difficult times, we are conducting our research seminar series virtually with the topics below. Mark your calendars!

The virtual Frontiers in Research Seminar Series is sponsored by the Nussenbaum-Vogelstein Family.

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CDC Epilepsy Incidence and Etiology Funding Opportunity Announcement
Projects are intended to inform incidence and social determinants of epilepsy including risk factors and protective factors that affect epilepsy incidence. Information about epilepsy incidence will provide invaluable information to help better guide interventions or services for preventing epilepsy, treating and rehabilitating people with epilepsy, and minimizing their health disparities and adverse outcomes.

Click here for details. Search opportunity number by RFA-DP-21-004 and SIP 21-007.

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NINDS Clinical Trials Methodology Course-Application Deadline February 28
The NINDS Clinical Trials Methodology Course (CTMC) is accepting applications for the 2021 cohort. The overarching goal of the CTMC is to help investigators develop scientifically rigorous, yet practical clinical trial protocols. The focus is on investigators who have not previously designed their own prospective, interventional clinical trials.

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National Science Foundation Enabling Discovery Through Genomics (EDGE) Program-Application Deadline March 16
The goal of the EDGE program is to provide support for genomic research and associated theory, approaches, tools, and infrastructure development to address the mechanistic basis of complex traits in diverse organisms within the context (environmental, developmental, social, and/or genomic) in which they function.

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Autopsy-Reported Cause of Death in a Population-Based Cohort of Sudden Unexpected Death in Epilepsy

Abstract, originally published in Epilepsia

Objective: Sudden unexpected death in epilepsy (SUDEP) is a diagnosis of exclusion; the definition includes individuals with epilepsy who die suddenly without an identifiable toxicological or anatomical cause of death. Limited data suggest underidentification of SUDEP as the cause of death on death certificates. Here, we evaluate the autopsy-reported cause of death in a population-based cohort of SUDEP cases.

Methods: Case summaries of forensic autopsies conducted in Ontario, Canada between January 2014 and June 2016 were retrospectively screened using a language processing script for decedents with a history of epilepsy or seizures. After manual review for potential SUDEP cases, two neurologists independently examined the autopsy reports and classified deaths by Nashef criteria. Demographic characteristics and consideration by the forensic pathologist of the role of epilepsy, seizure, and SUDEP in death were summarized.

Results: One hundred and eight Definite, 34 Definite Plus, and 22 Possible SUDEP cases were identified. Seventy-five percent of Definite/Definite Plus SUDEP cases identified by the neurologists were attributed to SUDEP, epilepsy, or seizure disorder in the autopsy report. There was a significant association between the proportion of cases listed in the autopsy report as SUDEP, epilepsy, or seizure disorder and neurologists’ SUDEP classification (86% of Definite, 38% of Definite Plus, 0% of Possible). Age was significantly associated with SUDEP classification; Definite cases were younger than Definite Plus, which were younger than Possible SUDEP cases.

Significance: Most SUDEP cases identified by neurologists were classified concordantly by forensic pathologists in Ontario, Canada; however, concordance decreased with increased case complexity. Although the role of epilepsy/seizures was considered in most Definite/Definite Plus cases, this study highlights the need for autopsy report review of potential SUDEP cases in research studies and assessments of the public health burden of SUDEP. The relationship between age and SUDEP classification has important public health implications; SUDEP incidence may be underappreciated in older adults.

Why Child Neurologists Talk About SUDEP: Results From Two Cross-Sectional Surveys

Summary, originally published in Epilepsia Open

Objective: To characterize SUDEP discussion practices of child neurologists approximately 6- and 12 months after publication of the American Academy of Neurology SUDEP Clinical Practice Guideline and explore factors associated with discussion practice.

Methods: Child Neurology Society members (~2450) were electronically surveyed in November 2017 and May 2018 regarding their practice of discussing SUDEP with patients with epilepsy or their caregivers. Multivariable proportional odds ordinal logistic regression evaluated factors associated with discussing SUDEP with a greater proportion of epilepsy patients/caregivers. Reasons for changing practice were described.

Results: Among the 369 child neurologist respondents, 36% reported discussing SUDEP with at least half of their epilepsy patients/caregivers including 12% who discuss with all or almost all (>90%) of their epilepsy patients/families. Those who discussed SUDEP with an increased proportion of their patients were more likely to agree that they knew enough to talk about SUDEP, agree that healthcare providers have an ethical obligation to discuss SUDEP, and disagree that there isn’t enough time to talk about SUDEP. Those who agreed SUDEP could provoke excessive anxiety or worry were less likely to discuss SUDEP with an increased proportion of their patients. Reading the SUDEP Clinical Practice Guideline was a frequently cited reason among respondents who reported a recent change in discussion practice.

Significance: Most child neurologists do not follow the current SUDEP Clinical Practice Guideline regarding SUDEP discussion. Feeling sufficiently knowledgeable and ethically obligated to discuss SUDEP were associated with increased discussion practice, suggesting an educational intervention may be effective at increasing SUDEP discussion rates.