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, 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.”

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.

Deciphering Key Regulators Involved in Epilepsy-Induced Cardiac Damage Through Whole Transcriptome and Proteome Analysis in a Rat Model

Abstract, originally published in Epilepsia

Objective: Sudden unexpected death in epilepsy (SUDEP) is a major outcome of cardiac dysfunction in patients with epilepsy. In continuation of our previous work, the present study was envisaged to explore the key regulators responsible for cardiac damage associated with chronic seizures using whole transcriptome and proteome analysis in a rat model of temporal lobe epilepsy.

Methods: A standard lithium-pilocarpine protocol was used to induce recurrent seizures in rats. The isolated rat heart tissue was subjected to transcriptomic and proteomic analysis. An integrated approach of RNA-Seq, proteomics, and system biology analysis was used to identify key regulators involved in seizure-linked cardiac changes. The analyzed differential expression patterns and network interactions were supported by gene and protein expression studies.

Results: Altogether, 1157 differentially expressed genes and 1264 proteins were identified in the cardiac tissue of epileptic animals through RNA-Seq and liquid chromatography with tandem mass spectrometry-based proteomic analysis, respectively. The network analysis revealed seven critical genes—STAT3, Myc, Fos, Erbb2, Erbb3, Notch1, and Mapk8—that could play a role in seizure-mediated cardiac changes. The LC-MS/MS analysis supported the activation of the transforming growth factor β (TGF-β) pathway in the heart of epileptic animals. Furthermore, our gene and protein expression studies established a key role of STAT3, Erbb, and Mapk8 to develop cardiac changes linked with recurrent seizures.

Significance: The present multi-omics study identified STAT3, Mapk8, and Erbb as key regulators involved in seizure-associated cardiac changes. It provided a deeper understanding of molecular, cellular, and network-level operations of the identified regulators that lead to cardiac changes in epilepsy.

Epilepsy Research News: December 2020

This month’s research news includes announcements about the Curing the Epilepsies 2021 Conference, and a reminder about the Cure Epilepsy and Taking Flight grant letters of intent (LOIs).

We also share that the Health Disparities Research Institute will be accepting applications, and that the TESS Research Foundation is hiring.

These news items are summarized below.

Research Highlights

Curing the Epilepsies 2021 Conference–January 4-6, 2021

Please join the epilepsy community from around the world to discuss the progress made in understanding the biological mechanisms underlying the epilepsies, and the inroads being made towards potential cures.

The main outcome and priority of the meeting will be to identify transformative research priorities that will accelerate development of cures and improve outcomes for people with epilepsy. The meeting takes place from January 4-6, 2021. It will be open to the public and freely available via livestream.

Learn more

Understanding & Treating Temporal Lobe Epilepsy
A team of researchers has found that an amino acid produced by the brain could play a crucial role in preventing cell loss and seizures associated with temporal lobe epilepsy. Utilizing an animal model of temporal lobe epilepsy, the research team found that administration of the amino acid D-serine prevented cell loss characteristic of temporal lobe epilepsy and reduced the number and severity of seizures.

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CURE Epilepsy and Taking Flight Grant Timeline–Letter of Intent (LOI) due January 11, 2021 9 PM EST
Reminder, CURE Epilepsy is accepting LOIs for both the CURE Epilepsy and Taking Flight grant awards now through Monday, January 11, 2021 at 9 PM ET. Don’t miss your opportunity to be considered!

  • CURE Epilepsy Award, $250,000 over two years: This award reflects CURE Epilepsy’s continued focus on scientific advances that have potential to truly transform the lives of those affected by epilepsy.
  • Taking Flight Award, $100,000 for one year: This award seeks to promote the careers of young epilepsy investigators, allowing them to develop a research focus independent of their mentors.
  • Research areas: Sudden unexpected death in epilepsy (SUDEP), acquired epilepsy, treatment-resistant epilepsy, pediatric epilepsy, and sleep and epilepsy

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2021 Health Disparities Research Institute–Accepting Applications February 1-March 8, 2021The next Health Disparities Research Institute–featuring lectures on minority health and health disparities research, mock grant review, seminars and more–will be held virtually August 9-13, 2021.

The program’s intent is to support early-career minority health/health disparities research scientists and stimulate research in the disciplines supported by health disparities science. Admission to this program is by application only. The application cycle is open February 1-March 8, 2021.

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Job Opportunity: Research Program Manager Position with TESS Research Foundation
Looking for an opportunity to make a difference in the area of rare epilepsies? The TESS Research Foundation is seeking a Research Program Manager to oversee all scientific research focused on SLC13A5 Epilepsy, including research coordination, grant program oversight, community outreach, and scientific communication and cultivation.

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Epilepsy Research News: December 2020

In this month’s news, we spotlight a publication describing CURE Epilepsy’s Infantile Spasms (IS) Initiativea collaborative research program that brought a team science approach to understanding the causes and potential treatments for IS. Running from 2013-2016, this program led to numerous advances in understanding the pathways in the brain involved in IS. 

Also, this month we feature news from the EPISTOP study showing that preventative treatment with the drug vigabatrin decreased the number of days with seizures as well as the severity of epilepsy in infants with tuberous sclerosis complexWe also highlight recent work from CURE Epilepsy Grantee Dr. Jeffrey Loeb, whose team identified a protein found in healthy brain tissue that may work to prevent the spread of seizures. 

These studies and more are summarized below. 

Research Highlights

Infantile Spasms
This recent publication highlights CURE Epilepsy’s Infantile Spasms (IS) Initiative, established in 2013 to support collaborative, team science-based and milestone-driven effort to advance the understanding of causes of and potential treatments for IS. The combined efforts of the research team led to numerous advances in understanding the causes of IS. It also brought together a diverse group of investigators–who otherwise would not have collaborated–to study therapies for IS.

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Preventing the Spread of Seizures
New research may explain what prevents seizures in certain areas of the brain from spreading to other areas of the brain. In a study funded by the National Institutes of Health/American Epilepsy Society, CURE Epilepsy Grantee Dr. Jeffrey Loeb and his colleagues found that a protein called DUSP4 was increased in healthy brain tissue directly next to epileptic brain tissue. The research suggests that DUSP4 may work to prevent the spread of epilepsy in the brain and that boosting levels of DUSP4 could be a novel way of preventing or treating epilepsy.

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Tuberous Sclerosis Complex Treatment
Preventive treatment with vigabatrin effectively decreased the risk and severity of epilepsy in infants with tuberous sclerosis complex who were enrolled in the EPISTOP multi-center study. Vigabatrin resulted in a significantly longer time to first clinical seizure compared with conventional treatment as well as a lower proportion of days with seizures until age 2, according to the study findings. The EPISTOP study has shown that it may be possible to change the natural history of severe infantile epilepsy through early intervention with antiepileptic therapy,” the researchers wrote.

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Epilepsy and Dementia
Late-onset epilepsy has been linked to a substantially increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy. “We are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other on-going studies are finding similar results,” she added.

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Epilepsy Treatment Expansion Approval
The FDA expanded its approval of lacosamide, marketed as Vimpat, to include add-on therapy for primary generalized tonic-clonic seizures as well as an IV formulation for patients aged 4 years and older.

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