Risk of Sudden Unexpected Death in Epilepsy (SUDEP) with Lamotrigine (Lamictal ®) and Other Sodium Channel Modulating Antiseizure Medications

Abstract found on Wiley Online Library

Objective: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti-seizure medication (NaM-ASM), could increase risk of sudden death in patients with structural or ischaemic cardiac disease, however its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear.

Methods: This retrospective, nested case-control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM-ASM use were compared between cases and controls at time of admission, and survival analyses from time of admission up to 16?years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors.

Results: Proportions of cases and controls prescribed lamotrigine (p=0.166), one NaM-ASM (p=0.80) or ?2NaM-ASMs (p=0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR]=0.56; p=0.054), one NaM-ASM (aHR=0.8; p=0.588) or ?2 NaM-ASMs (aHR=0.49; p=0.139) at EMU admission were not at increased SUDEP risk up to 16?years following admission. Active tonic-clonic seizures at EMU admission associated with >2-fold SUDEP risk, irrespective of lamotrigine (aHR=2.24; p=0.031) or NaM-ASM use (aHR=2.25; p=0.029). Sensitivity analyses accounting for incomplete ASM data at follow-up suggest undetected changes to ASM use are unlikely to alter our results.

Significance: This study provides additional evidence that lamotrigine and other sodium channel-modulating anti-seizure medications are unlikely to be associated with an increased long-term risk of SUDEP, up to 16?years post epilepsy monitoring unit admission.

Adherence Patterns in Antiseizure Medications (ASM) Influencing Risk of Sudden Unexplained Death in Epilepsy (SUDEP): a Data Linkage Study Using Dispensed Prescriptions

Abstract found on Pubmed

Objective: Medication adherence is considered an important risk factor for Sudden Unexpected Death in Epilepsy (SUDEP) although measurement accuracy is difficult. Using prescription dispensations, this study aims to estimate antiseizure medication (ASM) adherence and identify adherence patterns that influence epilepsy mortality.

Methods: Retrospective cohort study of tertiary epilepsy outpatients seen at St Vincent’s Hospital (Melbourne), Victoria, Australia, from 1/01/2012 until 31/12/2017. Privacy preserving data-linkage with the Australian national prescription, death and coroner’s databases was performed. We fitted a 4-cluster longitudinal group-based trajectory model for ASM adherence from recurring 90-day windows of prescription dispensations during a 3-year ‘landmark period’ 1/1/2012 to 31/12/2014, using the AdhereR package. We estimated the risk of SUDEP and all cause death for each adherence pattern during an ‘observation period,’ 1/1/2015 to 31/12/2017. The Cox-proportional hazards and logistic regression models were adjusted for age, sex, socioeconomic status, epilepsy duration, comorbidity, drug resistance and inadequate seizure control.

Results: 1,187 participants were observed for a median of 3.2 years (IQR 2.4-4.0 years). We observed 66 deaths with 10 SUDEP cases during the observation period. We identified 4 patterns of ASM adherence: good 51%, declining 24%, poor 16%, and very poor 9%. Declining adherence was associated with an increased risk for SUDEP, hazard ratio 8.43 (95%CI 1.10, 64.45) at 1 year, and HR 9.17 (95%CI 1.16,72.21) at 3 years. Compared to no ASM therapeutic change, the addition of a 2nd to 4th ASM offered increased protection against SUDEP in patients with continuing drug resistant epilepsy.

Significance: ASM non-adherence was observed in half of outpatients with epilepsy. A declining pattern of adherence, observed in a quarter of patients, is associated with more than eight times increased risk of SUDEP. Any ongoing medication interventions must include strategies to maintain and improve ASM adherence if we are to reduce the risk of SUDEP.

Researcher Update: January 2023

In this Researcher Update you’ll find information on:


Last Call to Submit Letters of Intent for CURE Epilepsy’s 2023 Taking Flight and CURE Epilepsy Awards

Last reminder to submit your Letter of Intent for our Taking Flight and CURE Epilepsy awards. All Letters of Intent are due by tomorrow, Tuesday, January 10, 2023, at 9 pm ET.

The Taking Flight Award seeks to promote the careers of early career-stage epilepsy investigators to allow them to develop a research focus independent of their mentor(s).

The CURE Epilepsy Award reflects CURE Epilepsy’s continued focus on scientific advances that have the potential to truly transform the lives of those affected by epilepsy, with prevention and disease modification as critical goals.

Key priority areas for both awards include: 1) basic mechanisms of epilepsy, 2) acquired epilepsies, 3) pediatric epilepsies, 4) SUDEP, 5) treatment-resistant epilepsies, and 6) sleep and epilepsy.

We look forward to receiving your submissions!

See Award Guidelines


NeuroFrontiers Podcast on Childhood-Onset Epilepsy Featuring Research Funded by CURE Epilepsy

Research on the impacts of brain aging in childhood-onset epilepsy supported by funding from CURE Epilepsy is featured in a recent NeuroFrontiers podcast. Listen as Drs. Bruce Hermann, Professor Emeritus at the University of Wisconsin, Madison, WI, and Shlomo Shinnar, Professor Emeritus at Albert Einstein College of Medicine, New York, NY, share insights from a longitudinal study on epilepsy that began in Finland over 50 years ago.

Listen


SUDEP Research Funding Opportunity for Early Career Scientists

PAME (Partners Against Mortality in Epilepsy) is partnering with the American Epilepsy Society (AES) to fund ideas that advance SUDEP Summit priorities through the AES Early Career Grants program. Trainees, fellows, and newly independent investigators are encouraged to apply to any of the eight funding opportunities available. Specifically, PAME is interested in funding projects to advance priorities that will impact SUDEP prevention in the next 5 years. Applications are due Thursday, January 12, 2023.

See Funding Opportunities


NINDS-Sponsored Workshop on Status Epilepticus After Benzodiazepines: Seizures and Improving Long-Term Outcomes

Register now for this NINDS-sponsored workshop taking place from February 28-March 1. The recent approval of intramuscular midazolam (Seizalam®) for acute treatment of status epilepticus (SE) is an important advancement for the treatment of this epilepsy. However, effective treatments that improve neuropathic outcomes after SE becomes refractory to benzodiazepines are a common unmet medical need. This virtual workshop will convene preclinical and clinical researchers, as well as other relevant stakeholders to discuss and define potential therapeutics needed to improve outcomes following SE.

Register


National Workshop on Experimental Models of Post-Traumatic Epilepsy

Register now for this free workshop taking place both in-person at Texas A&M University and via Zoom on Friday, March 10. The Texas A&M Health Institute of Pharmacology and Neurotherapeutics (IPN) is hosting an AES-sponsored National Workshop on Experimental Models of Post-Traumatic Epilepsy (PTE). The IPN team invites you and your colleagues to learn the various facets of PTE research to discover and advance therapeutic agents for this form of epilepsy. The workshop will provide insights into animal models of PTE, laboratory protocols, biomarkers, and therapeutic interventions for traumatic brain injury-induced seizures and post-traumatic epileptogenesis.

Register


Open Position for a Director of The Spinal Cord and Brain Injury Research Center at University of Kentucky College of Medicine

The University of Kentucky (UK) College of Medicine invites applications and nominations for the position of Director to lead the highly ranked Spinal Cord and Brain Injury Research Center (SCoBIRC).

The UK College of Medicine seeks a visionary director with a successful record of research achievement in neurotrauma specifically in spinal cord injury, traumatic brain injury, or appropriately related fields. Exceptional accomplishments as a researcher and academic are a must as the director’s duties will include continuing their own research program as well as supervising and maintaining academic activities.

Learn More and Apply


Survey for Routine Clinical Care Patient-Centered Outcomes for Adults and Children with Epilepsy

ICHOM (The International Consortium for Health Outcomes Measurement), an international nonprofit organization that aims to improve global healthcare, is developing a minimum set of outcomes to be captured in routine clinical care for adults and children with epilepsy.

The Working Group (WG), consisting of healthcare professionals, researchers, and those with lived experience have identified outcomes to be included in the recommendation and is seeking feedback from epilepsy professionals and experts on the relevance of these elements.

The survey should take 15-20 minutes to complete, and the results will be used to guide the WG’s final recommendations. Please share your expertise and provide feedback to help standardize outcome measurements for epilepsy care globally.

Take Survey

CURE Epilepsy Grantee Announcement Fall 2022

CURE Epilepsy is honored to announce our newest CURE Epilepsy grantees. Our research grants are awarded for cutting-edge, novel research projects that seek to accelerate treatments, improve outcomes, and get us to cures so that we can live in a world free of seizures. This year’s grantees’ research will focus on a wide range of epilepsies – sudden unexpected death in epilepsy (SUDEP), sleep and epilepsy, genetic causes of epilepsy, Lafora disease, post-traumatic epilepsy, pediatric epilepsy, and focal epilepsy.

TAKING FLIGHT AWARD GRANTEES – $100,000 for one year 

This award seeks to promote the careers of early-career epilepsy investigators to allow them to develop a research focus independent of their mentor(s).

Jeffrey Calhoun, PhD
Northwestern University – Chicago, Illinois

With this grant, funded by the Joseph Gomoll Foundation, Dr. Calhoun’s research will work to develop a new method to assess the functionality of variants of the SCN1A gene.
Learn More

William Tobin, PhD
The University of Vermont and State Agriculture  – Burlington, Vermont

With a grant co-funded by the KCNT1 Epilepsy Foundation, Dr. Tobin will test strategies to optimize cutting-edge gene therapy methods for the gene KCNT1.
Learn More

Gerben van Hameren, PhD
Dalhousie University– Nova Scotia, Canada

Dr. van Hameren will study a possible way to prevent the development of post-traumatic epilepsy.
Learn More

_________________

CURE EPILEPSY AWARD GRANTEES – $250,000 over two years  

This award reflects CURE Epilepsy’s continued focus on scientific advances that have the potential to truly transform the lives of those affected by epilepsy, with prevention and disease modification as critical goals.

Gordon Buchanan, MD, PhD
University of Iowa Medicine – Iowa City, Iowa

For this grant, generously funded by The Joanna Sophia Foundation, Dr. Buchanan’s group will examine whether a signaling molecule called serotonin drives a time-of-day vulnerability to SUDEP (Sudden Unexpected Death in Epilepsy).
Learn More

Annaelle Devergnas, PhD
Emory University – Atlanta, Georgia

The hypothesis for Dr. Devergnas’ project is that frontal seizures disrupt the normal function of the brain structure called the pedunculopontine nucleus (PPN), leading to changes in sleep, and that manipulating PPN activity might restore normal sleep activity.
Learn More

Juliet Knowles, MD, PhD
Stanford School of Medicine – Palo Alto, California

For this project, Dr. Knowles and her team will study the therapeutic potential for targeting myelin plasticity in Lennox-Gastaut syndrome.
Learn More

_________________

CATALYST AWARD GRANTEES – $250,000 over two years 

The CURE Epilepsy Catalyst Award stimulates and accelerates the development of new, transformative therapies for epilepsy, moving promising preclinical and/or clinical research closer to clinical application.

James Pauly, PhD, Greg Gerhardt, PhD, and Matthew Gentry, PhD
University of Kentucky – Lexington, Kentucky

In collaboration with Enable Therapeutics, Drs. PaulyGerhardt, and Gentry developed a potential drug called VAL-1221 that can penetrate brain cells and degrade the aberrant sugar aggregates therein that cause LaFora disease. Having obtained promising initial results, this project will test the safety and brain distribution of this novel therapy.
Learn More

John Gledhill, PhD
Cognizance Biomarkers, LLC  – Philadelphia, Pennsylvania

Dr. Gledhill and the team at Cognizance will build upon their preliminary research showing that people with treatment-resistant epilepsy have differences in inflammation-associated proteins in the blood compared with those who do respond to treatment. For this project, the team proposes to extend their observations by assessing additional blood samples from treatment-resistant and treatment-responsive people with epilepsy and developing an algorithm to predict response to initial anti-seizure medications.
Learn More

Researcher Update: November 30, 2022

In this Researcher Update you’ll find information on:


Final Reminder to RSVP for CURE Epilepsy’s Reception on December 4th at the AES Meeting in Nashville

RSVP now to join CURE Epilepsy leadership and fellow dedicated researchers in honoring our newest grantees during our reception on December 4th at the 2022 American Epilepsy Society Annual Meeting. Light refreshments will be served.
The reception will be held:

  • Sunday, December 4, 2022 @ 6:00 pm – 7:30 pm CT
  • Location: Omni Nashville Hotel, 250 Rep. John Lewis Way South, Nashville
  • Room: Legends A/B (Level 2)

We look forward to seeing you all!

Please note, this is not an official event of the 2022 AES Annual Meeting, nor is it sponsored or endorsed by AES

RSVP Here


Letter of Intent Submissions Open Today for CURE Epilepsy’s 2023 Taking Flight and CURE Epilepsy Awards

Submit your Letter of Intent for our Taking Flight and CURE Epilepsy awards starting today. All Letters of Intent are due by Tuesday, January 10, 2023, at 9 pm ET.

The Taking Flight Award seeks to promote the careers of young epilepsy investigators to allow them to develop a research focus independent of their mentor(s).

The CURE Epilepsy Award reflects CURE Epilepsy’s continued focus on scientific advances that have the potential to truly transform the lives of those affected by epilepsy, with prevention and disease modification as critical goals.

Key priority areas for both awards include: 1) basic mechanisms of epilepsy, 2) acquired epilepsies, 3) pediatric epilepsies, 4) SUDEP, 5) treatment-resistant epilepsies, and 6) sleep and epilepsy.

We look forward to seeing your submissions!

See Award Guidelines


The Pershing Square Foundation Launches the MIND (“Maximizing Innovation in Neuroscience Discovery”) Prize

With the launch of the MIND Prize, The Pershing Square Foundation strives to change the paradigm of neuroscience research by creating a community of next-frontier thinkers who can uncover a deeper understanding of the brain and cognition. Breakthroughs in basic scientific and translational research will yield critical tools for and knowledge of neurodegenerative diseases, including Alzheimer’s disease and dementia. The MIND Prize will bring together the most talented early-to-mid-career investigators across scientific fields with creative and experimental ideas to solve problems that will transform the current understanding of the brain and its impact on human health. The deadline to submit Letters of Intent is Monday, December 12, 2022.

Learn More


SUDEP Research Funding Opportunity for Early Career Scientists

PAME (Partners Against Mortality in Epilepsy) is partnering with the American Epilepsy Society (AES) to fund ideas that advance SUDEP Summit priorities through the AES Early Career Grants program. Trainees, fellows, and newly independent investigators are encouraged to apply to any of the eight funding opportunities available. Specifically, PAME is interested in funding projects to advance priorities that will impact SUDEP prevention in the next 5 years. Applications are due Thursday, January 12, 2023.

See Funding Opportunities


Apply Now for a Postdoctoral Diversity Enrichment Program (PDEP)

The Sergievsky Award for Epilepsy Health Equity and Diversity provides support for early career physicians and scientists who identify as members of underrepresented racial and ethnic groups, and/or who are researching issues that affect medically underserved individuals with epilepsy or seizures or related aspects of health equity. Proposals are due Thursday, January 12, 2023.

Learn More


Funding Opportunity with Burroughs Wellcome Fund (BWF) Innovation in Regulatory Science Awards (IRSA)

BWF’s Innovation in Regulatory Science Awards provides up to $500,000 over five years to academic investigators developing new methodologies or innovative approaches in regulatory science that will ultimately inform the regulatory decisions made by agencies such as the Food and Drug Administration. The deadline to apply is Friday, February 10, 2023.

Learn More


Register for the NIH and NINDS Workshop “Status Epilepticus after Benzodiazepines: Seizures and Improving Long-Term Outcomes”

This virtual workshop, taking place February 28 – March 1, 2023, will convene preclinical and clinical researchers as well as stakeholders to discuss and define indications of potential therapeutics needed to improve outcomes following status epilepticus. Outcomes of the workshop will include a clearer understanding of the unmet therapeutic needs and identification of key gaps in the research, increasing the potential for new therapeutics development.

Learn More

CURE Epilepsy Discovery: A Look Into the Journeys of CURE Epilepsy Taking Flight Grantees

Key Points:

  • CURE Epilepsy is the leading non-profit organization focused on funding research to find cures for epilepsy.
  • To achieve our mission, CURE Epilepsy created grant mechanisms to support research to understand the basic biological mechanisms or foundations of what causes seizures that become epilepsy as well as awards for pre-clinical research and more.
  • The Taking Flight Award was created to support epilepsy investigators early in their careers to develop a research focus separate from their mentor’s.
  • This Discovery highlights three Taking Flight awardees who received grants for diverse projects, ranging from work on sudden unexpected death in epilepsy (SUDEP) to mapping epileptic brain networks, to an exploration of circadian function as a potential mechanism and a therapeutic target for epilepsy.
  • The three awardees are Dr. William Nobis from Vanderbilt University Medical Center, Dr. Flavia Vitale from The University of Pennsylvania, and Dr. Cristina Reschke at the Royal College of Surgeons in Ireland. These awardees share their motivations for pursuing epilepsy research as a career, the importance of the CURE Epilepsy Taking Flight in their careers, and the impact they hope to have in the epilepsy community.

Deep dive

Epilepsy is one of the most common neurological disorders and affects 65 million people worldwide [1] and 3.4 million Americans [2]. Epilepsy can impact a person at any point in their lifetime, regardless of age, demographics, race, or socioeconomics. Those who live with epilepsy can face a lifetime of challenges. CURE Epilepsy’s mission is to find a cure for epilepsy, by promoting and funding patient-focused research, CURE Epilepsy has developed a variety of granting mechanisms [3], including the Taking Flight Award.[4] This one-year, $100,000 grant is meant to fund studies that will provide new insights into epilepsy, its prevention, and cures. An additional goal of the Taking Flight Award is to foster scientific independence of early career investigators and provide them with the means to collect the necessary data to apply for subsequent funding, thus further advancing their career in epilepsy research.[4]

Through 2021, CURE Epilepsy has funded 48 early career scientists through the Taking Flight Award, supporting them on their path to research independence. Recently, we spoke with three Taking Flight awardees about their research, the impact that receiving the Taking Flight Award had on their research and their vision for the future of their research. The three awardees and their projects were: Dr. William Nobis at Vanderbilt University Medical Center who studied a part of the brain called the amygdala and its role in sudden unexpected death in epilepsy (SUDEP); Dr. Flavia Vitale at The University of Pennsylvania who explored a technique to accurately map epileptic brain networks; and Dr. Cristina Reschke at the Royal College of Surgeons in Ireland, who examined the role of the circadian function in epilepsy.

The awardees noted varying inspirations to pursue the field of epilepsy research. For example, Dr. Nobis mentioned, “I have always been interested in neuroscience research, my initial motivation for training to be a physician-scientist was my experience with my grandmother and Alzheimer’s disease. During my residency training in neurology, I had exposure to epilepsy patients and experience with epileptologists, and I liked the impact you could have on patients’ lives by controlling seizures.” Dr. Nobis continues to be inspired by the patients he aims to serve. He says, “I want to do research that has the opportunity to make an impact on my patients’ lives – this is something that is within reach for epilepsy researchers. We have come far with controlling epilepsy but there are still so many people impacted by seizures.

Controlling epilepsy and preventing SUDEP are both interesting problems that will involve cutting edge circuit-based science and are also of immense importance and impact for the lives of our patients.” Previous research on SUDEP had shown that difficulties in breathing (respiratory depression) could lead to deficits in heart function, ultimately leading to death.[3] To understand this process better, Dr. Nobis’ team analyzed intracranial electroencephalograph (EEG), i.e., electrical signals from deep within the brain, and combined this with the measurement of breathing.[4] They found a specific role of the amygdala and the brainstem in respiratory depression during seizures. The discovery that this circuit may play a role in SUDEP means that in the future, we may be able to target it with interventions to prevent SUDEP.

According to Dr. Nobis, the Taking Flight Award gave him the capability to commit full-time to the SUDEP research, which had been a side project that he was working on in his mentor’s lab. He was able to publish his studies and take the next step in his career by accepting a position at Vanderbilt University Medical Center.[5] Subsequent mentored career-development awards helped him launch his research program centered on the physiological mechanisms of SUDEP. Looking into the future, Dr. Nobis commended the epilepsy research community with these words, “I love the epilepsy research community; I have not been around a group of more earnest and supportive group of scientists that are dedicated to improving the treatment of epilepsy patients. To do something that will improve the lives of epilepsy patients and work towards the goal of no SUDEP, no seizures, and no side effects.”

The basis for Dr. Vitale’s research is the premise that epilepsy arises from disrupted brain networks. To properly treat seizure-related conditions, it is important to map these networks as precisely as possible, but current methods of mapping epileptic neuronal networks do not provide the fine level of detail that is necessary. As part of Dr. Vitale’s Taking Flight research project, she developed miniature, flexible electrodes that could be controlled independently after they were implanted in the brain.[10] This technology has already shown success in detecting seizures in mice [6,7], and it is envisioned that this work of detecting seizure activity in experimental animals could ultimately lead to technologies to map epileptic networks in patients in a highly precise manner.

Speaking to her motivation, Dr. Vitale, was interested in joining a multidisciplinary team that “brings together engineers, clinicians, and neuroscientists to develop novel technological and therapeutic approaches to understand, diagnose, and treat neurological disorders, and in particular epilepsy.” Dr. Vitale found that working closely with clinicians and surgeons whose mission is to fight epilepsy, made her realize how engineers developing new devices, algorithms, modeling, and analysis tools can play a key role in supporting clinicians in their decision-making and provide them with more accurate and effective tools to diagnose and treat their patients. She also mentioned that the personal stories from patients and families reinforced her decision to start a career in neuro-engineering for epilepsy research.

Dr. Vitale describes the Taking Flight Award as an “inflection point” in her career, as the award enabled her to start her lab at the University of Pennsylvania.[8] In her words, “this award jumpstarted my research program in epilepsy research and helped me to gather key preliminary data that later supported successful grant applications and publications. Finally, the award provided recognition among the epilepsy research community and helped me establish new fruitful collaborations.” She summarizes her views on epilepsy research as, “Our mission is to ultimately translate our findings and technological innovations to patients. With more precise and safer electrodes, it will be easier to find and remove the areas of the brain where seizures originate, which has been shown to improve seizure-free rates. We are also developing easier-to-use, portable, and low-cost non-invasive brain monitoring systems to improve access and quality epilepsy care in low-resource settings and for at-home monitoring. Such technologies will offer more accurate data for diagnosis and therapy and reduce the burden of travel to patients in remote areas.”

Dr. Reschke’s work focuses on how circadian rhythms may impact epilepsy.[9,11] Previous studies have hypothesized a link between epilepsy and the 24-hour biological rhythms present in humans that are called “circadian rhythms.”[12] Dr. Reschke’s award, funded by The Cameron Boyce Foundation, aims to explore whether the mechanisms that control circadian rhythms are involved in the process of epileptogenesis (the process by which a non-epileptic circuit is transformed into an epileptic circuit). She will also develop a gene therapy approach in mice to see whether restoring a gene involved in circadian rhythms can halt epileptogenesis.[9,11] 

Dr. Reschke emphasized the excitement of discovery and the patient-centeredness of research as two main reasons she was attracted to working in epilepsy. “If we understand a bit more about the brain, we can develop focused and tailored approaches to epilepsy and accompanying comorbidities.” To her, while the science and research are extremely interesting, the possibility of impacting people with epilepsy, “makes the long hours worthwhile.”

Dr. Reschke also found her independence as a researcher thanks to the Taking Flight Award. The award allowed her to obtain, first, a temporary, and later, a permanent position at the Royal College of Surgeons in Ireland. She was able to secure lab space and personnel to do the work. The Taking Flight Award, in her words, “was extremely important and instrumental in establishing my career in epilepsy in academia.” In addition to the support for research, the award also gave her international recognition and helped her enhance her professional networks. Leveraging her research, recognition, and networks, Dr. Reschke is heavily involved in advocacy and education as well. She feels that “communicating research to patients’ families and caregivers is crucial,” and she feels that it is critical to put her clinical work into practice. She is also passionate about educating the next generation of epilepsy researchers by promoting training and fellowships to give them, “the opportunities that I have; to give them a chance to work on research that is deeply meaningful.”

The Taking Flight Awards have deeply impacted the grantees, and through them, numerous people that are affected by epilepsy every day. Awardees cited the capacity to contribute to scientific excellence while having a positive impact on patients with epilepsy and their caregivers as the most rewarding aspect of the award. The money granted by CURE Epilepsy to the researchers to gain scientific independence, develop new techniques, and discover novel mechanisms of epileptogenesis will help the organization achieve our goal of a world without epilepsy.

 

Literature Cited:

  1. Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Estimation of the burden of active and lifetime epilepsy: a meta-analytic approach Epilepsia. 2010 May;51:883-890.
  2. National and State Estimates of the Numbers of Adults and Children with Active Epilepsy — United States, 2015.
  3. CURE Epilepsy: Grant Opportunities Available at: https://www.cureepilepsy.org/grants-program/. Accessed November 11
  4. CURE Epilepsy Taking Flight award Available at: https://www.cureepilepsy.org/wp-content/uploads/2022/10/2023-Taking-Flight-Award-LOI-Full-Propsal-Guidelines.pdf. Accessed November 11
  5. Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study Lancet Neurol. 2013 Oct;12:966-977.
  6. Nobis WP, González Otárula KA, Templer JW, Gerard EE, VanHaerents S, Lane G, et al. The effect of seizure spread to the amygdala on respiration and onset of ictal central apnea J Neurosurg. 2019 Apr 5;132:1313-1323.
  7. Department of Neurology; William P. Nobis, MD, Ph.D. Available at: https://www.vumc.org/neurology/person/william-p-nobis-md-phd. Accessed November 11
  8. Mulcahey PJ, Chen Y, Driscoll N, Murphy BB, Dickens OO, Johnson ATC, et al. Multimodal, Multiscale Insights into Hippocampal Seizures Enabled by Transparent, Graphene-Based Microelectrode Arrays eNeuro. 2022 May-Jun;9.
  9. Driscoll N, Rosch RE, Murphy BB, Ashourvan A, Vishnubhotla R, Dickens OO, et al. Multimodal in vivo recording using transparent graphene microelectrodes illuminates spatiotemporal seizure dynamics at the microscale Commun Biol. 2021 Jan 29;4:136.
  10. Flavia Vitale, Ph.D.; Penn Medicine Available at: https://www.med.upenn.edu/apps/faculty/index.php/g324/p8887287. Accessed November 11
  11. Restoration of Circadian Function as a Novel Therapy for Epilepsy. Available at: https://www.cureepilepsy.org/grant_type/restoration-of-circadian-function-as-a-novel-therapy-for-epilepsy/. Accessed November 11.
  12. Jin B, Aung T, Geng Y, Wang S. Epilepsy and Its Interaction With Sleep and Circadian Rhythm Front Neurol. 2020;11:327.

CURE Epilepsy Discovery: CURE Epilepsy Grantees Explore Genetic Determinants of Sudden Unexpected Death in Pediatrics (SUDP)

Key Points:

  • Sudden infant death syndrome (SIDS), sudden unexpected infant death (SUID), and sudden unexplained death in childhood (SUDC) are tragic conditions referring to the unexplained death of an infant or child. While previously thought of as separate entities, evidence suggests that there is an overlap between these conditions and that they may be considered under the overarching umbrella of sudden unexpected death in pediatrics (SUDP).
  • A previous study awarded by CURE Epilepsy and made possible by funding from the Isaiah Stone Foundation to Dr. Annapurna Poduri and colleagues suggested that genes associated with epilepsy may be involved in SUDP.[1]
  • A new study*, which was an outgrowth of the earlier CURE Epilepsy funded research, included 352 SUDP cases and employed state-of-the-art genetic techniques, in-depth analysis of family history and circumstances of death, and analysis of parental genetic information as well.[2]
  • The study showed evidence for genetic factors that may play a role in SUDP; while some genes were already potentially associated with sudden death in children, several variants in genes previously not associated with SUDP were identified.
  • In addition to providing genetic information about SUDP, the group’s work is proof of concept that a multidisciplinary lens to study SUDP is not only feasible, but necessary to advance the field.

 

Deep dive

The sudden death of a child is a tragic occurrence. Of all the child and infant deaths in the United States, more than 10% occur without any apparent cause, compounding the grief of families who have lost their children.[3] These sudden, unexpected deaths typically impact seemingly healthy children and are classified as sudden infant death syndrome (SIDS), sudden unexpected infant death (SUID), or sudden unexplained death in childhood (SUDC). Together, these three entities are thought of as sudden unexpected death in pediatrics (SUDP).[4] Through the generous support of the Isaiah Stone Foundation, CURE Epilepsy funded Dr. Annapurna Poduri and colleagues Rick Goldstein, Hannah Kinney, and Ingrid Holm in Robert’s Program** at Boston Children’s Hospital to explore the genetic basis of SUDP; the hypothesis for this work is that there are common, underlying, genetic mechanisms behind the three entities of sudden childhood death, epilepsy and sudden unexpected death in epilepsy (SUDEP).

Earlier work from these researchers had highlighted a link between SIDS and variants in a gene called SCN1A, which is associated with epilepsy and SUDEP.[1, 5, 6] What was notable is that while this gene is traditionally thought to be related to epilepsy, the children who died suddenly and unexpectedly had no history of seizures or epilepsy. This and other studies have suggested that SUDP is an overarching disorder consisting of rare and yet-undiagnosed diseases with potentially overlapping genetic mechanisms.[1, 7, 8]

To build on the previous work supported by CURE Epilepsy, Dr. Poduri and colleagues conducted a larger, more extensive study* to explore genetic risk factors for SUDP.[2] The ultimate goal was to find more accurate ways of diagnosing children at risk of sudden death and eventually prevent such incidences. The current study led by Dr. Poduri and her colleagues Drs. Hyunyong Koh and Alireza Haghighi included 352 SUDP cases.[2] This study looked at “trio-based” cohorts; meaning they studied the child and the child’s parents. This is a stronger approach to studying genetic contributions to a disease process, especially for SUDP, where a genetic link is suspected.[9, 10] Additionally, since the mechanisms underlying SUDP are complex and not yet fully known, the team took a “multidisciplinary undiagnosed diseases approach”[11] that combined genetic analysis, autopsy data, and in-depth study of the child’s phenotype (or observable characteristics). Parents agreed to all analyses performed. 

The genetic analysis included a candidate-gene approach where scientists have some information to suggest that a certain gene may be associated with a certain disease. In this case, 294 genes plausibly related to SUDP, called SUDP genes were studied, many of which were associated with neurologic disorders, cardiac disorders, or systemic/syndromic conditions. [12, 13] Systemic conditions and associated genes affect the entire body, and syndromic conditions include genes for metabolism and those responsible for the functioning of multiple body systems. The team performed a genetic technique called exome sequencing, where the parts of genes that eventually become functional proteins were analyzed for variants that may have caused or contributed to sudden death.[2]

The multidisciplinary team at Robert’s Program on SUDP, directed by Dr. Rick Goldstein, characterized fully the conditions surrounding the death of the child, performed an in-depth analysis of the child’s medical and family history, and conducted exome sequencing. The study showed that SUDP was associated with specific genetic factors, some of which were previously known, but many of which were novel. Detailed analysis showed that the majority of the children were between two and six months old, and 57% were male. Out of the 352 cases, death was associated with sleep in an overwhelming majority (346 children).[2] Genetic analysis revealed variants in genes related to cardiac disease, neurologic diseases, and systemic/syndromic diseases. Most variants were de novo, or new, while some were inherited. Burden analysis, in which the trios were compared to controls, showed that there were more SUDP trio cases with rare, damaging de novo variants as compared to controls. There were also clues as to the presence of febrile seizures, a family history of SIDS or SUDC, and a family history of epilepsy and cardiac disease in several cases. When the genes implicated in SUDP were classified by the age of death of the child, a pattern emerged. Specifically, variants in neurological and syndromic genes appeared in the age ranges associated with SIDS (the child being less than one year old) and SUDC (the child is greater than one year old), and variants in cardiac genes were preferentially seen only in the earlier age range, i.e., associated with SIDS.[2]

Overall, the study found that there was a genetic contribution to SUDP in 11% of the cases and suggests that these genetic variants may increase susceptibility to sudden death. Many genes that were previously not linked with SUDP were able to be reclassified as being associated with SUDP. The power of this study is that the genes for SUDP that were investigated were not the ones previously examined. A few specific genes found to be implicated in SUDP are SCN1A and DEPDC5, which have also been shown to be relevant in SUDEP. Other genes were associated with cardiac issues such as arrhythmia and cardiomyopathy (a condition that makes it harder for the heart to pump blood).[2]

The study also shows the importance of looking at trio data, as in this case, it led to the reclassification of several genetic variants. SUDP is a particularly difficult condition to study because unfortunately, a genetic condition may never have been diagnosed or suspected. Hence, the trio approach was instrumental in the success of the current study. The study also adds to evidence [7, 8] that conditions such as stillbirth, SIDS, and SUDC are not separate entities, but represent a continuum of events associated with unexplained death from fetal life to childhood.[14] It is possible and even likely that there are overlapping genetic variants (SCN1A being one) common to these conditions. Notably, another study from a different group also performed genetic analysis from trios and found de novo mutations associated with sudden unexplained death in childhood.[15]

Future studies will look at more trio data and an even more detailed genetic analysis. While many genetic risk factors were found in the current study, it does not mean that they were necessarily the cause of death; more work will be needed to look at specific neurologic mechanisms. In addition to the scientific findings, the study also sets the scene for a model where a multidisciplinary team engages with parents who have lost their children to unexplained death. In addition to providing scientific answers, a multidisciplinary team also can help provide counseling for family members at a much-needed time.

 

Footnotes:

*Supported by funds from the Robert’s Program on Sudden Unexpected Death in Pediatrics, the Cooper Trewin Memorial SUDC Research Fund, CURE Epilepsy through the Isaiah Stone Foundation Award, Three Butterflies SIDS Foundation, The Florida SIDS Alliance, Borrowed Time 151, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development under grant numbers R21 HD096355 and R01 HD090064.

**Robert’s Program at Boston Children‘s Hospital provides comprehensive clinical care to those that have lost a child suddenly and unexpectedly and performs research to better understand SUDP.

 

Literature Cited:

  1.      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.
  2.      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.
  3.      About Underlying Cause of Death, 1999-2020. Available at: https://wonder.cdc.gov/ucd-icd10.html. Accessed October 4.
  4.     Goldstein RD, Nields HM, Kinney HC. A New Approach to the Investigation of Sudden Unexpected Death Pediatrics. 2017 Aug;140.  
  5.     Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms Epilepsia. 2010 Sep;51:1650-1658.
  6.    Goldman AM. Mechanisms of sudden unexplained death in epilepsy Curr Opin Neurol. 2015 Apr;28:166-174.
  7.    Perrone S, Lembo C, Moretti S, Prezioso G, Buonocore G, Toscani G, et al. Sudden Infant Death Syndrome: Beyond Risk Factors Life (Basel). 2021 Feb 26;11.
  8.    Weese-Mayer DE, Ackerman MJ, Marazita ML, Berry-Kravis EM. Sudden Infant Death Syndrome: review of implicated genetic factors Am J Med Genet A. 2007 Apr 15;143a:771-788.
  9.    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med. 2015 May;17:405-424.
  10.   Rehm HL. A new era in the interpretation of human genomic variation Genet Med. 2017 Oct;19:1092-1095.
  11.   MacNamara EF, D’Souza P, Tifft CJ. The undiagnosed diseases program: Approach to diagnosis Transl Sci Rare Dis. 2020 Apr 13;4:179-188.
  12.   An Online Catalog of Human Genes and Genetic Disorders (OMIM). Available at: https://www.omim.org/. Accessed October 4.
  13.   The Human Gene Mutation Database (HGMD®). Available at: https://www.hgmd.cf.ac.uk/ac/index.php. Accessed October 4.
  14.   Goldstein RD, Kinney HC, Willinger M. Sudden Unexpected Death in Fetal Life Through Early Childhood Pediatrics. 2016 Jun;137.
  15.   Halvorsen M, Gould L, Wang X, Grant G, Moya R, Rabin R, et al. De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca(2+) regulation Proc Natl Acad Sci U S A. 2021 Dec 28;118.

Drug-Resistant Epilepsy and Mortality-Why and When Do Neuromodulation and Epilepsy Surgery Reduce Overall Mortality

Abstract found on Wiley Online Library

Patients with drug-resistant epilepsy suffer from an increased mortality rate, with the majority of deaths being epilepsy-related and 40% due to sudden unexpected death in epilepsy (SUDEP). Impact of epilepsy surgery on mortality has been investigated since the 1970s, with increased interest in this field during the past 15?years.

We systematically reviewed studies investigating mortality rate in patients undergoing epilepsy surgery or neuromodulation therapies. Quality of available evidence proved heterogenous and often limited by significant methodological issues. Peri-operative mortality following epilepsy surgery was found <?1%. Meta-analysis of studies that directly compared patients who underwent surgery to those not operated following presurgical evaluation showed that the former have a two-fold lower risk of death and a three-fold lower risk of SUDEP than the latter (Odds ratio (95% CI): 0.40 (0.29-0.56, p<0.0001) for overall mortality and 0.32 (0.18-0.57, p<0.001) for SUDEP). Limited data are available regarding the risk of death and SUDEP in patients undergoing neuromodulation therapies, though some evidence indicate that vagus nerve stimulation might be associated with lower risk of SUDEP.

Several key questions remain to be addressed in future studies, considering the need to better inform patients about the long-term benefit-risk ratio of epilepsy surgery. Dedicated long-term prospective studies will thus be required to provide more personalized information on the impact of surgery and/or neuromodulation on the risk of death and SUDEP.

Perinatal Risk Factors for SUDEP: A Population-Based Case-Control Study

Abstract found on Wiley Online Library

Sudden unexpected death in epilepsy (SUDEP) is a leading epilepsy related cause of death. Researchers have highlighted the similarities between SUDEP and Sudden infant death syndrome (SIDS) but perinatal risk factors such as those identified for SIDS, have not been assessed previously for SUDEP. We carried out a population-based case-control of 58 SUDEP individuals and 384 living epilepsy controls born after 1982 utilizing the Swedish Medical Birth Register together with other national health registers and individual medical records to examine if pre- and perinatal factors are associated with SUDEP risk. We observed a threefold SUDEP risk increase for infants who were small for gestational age (SGA) (OR 3.13; 95% CI 1.05-9.30) and for those with an Apgar score of 0-6 compared to 9-10 at 10 minutes (OR 3.22; 95% CI 1.05-9.87). After adjusting for a number of known SUDEP risk factors, we observed that Apgar score between 0-6 after 10 minutes had a tenfold increased risk for SUDEP OR 10.37 (95% CI 1.49-72.01) and over a twofold risk for those born after the 40th gestational week OR 2.42 (95% CI 1.03-5.65). Potential mechanisms linking low Apgar score, gestational age and SGA to SUDEP risk remain to be explored.

CURE Epilepsy Discovery: Identifying Human Brain Regions that Regulate Breathing as Eventual Targets for Direct SUDEP Intervention

Key Points:

  • CURE Epilepsy Award grantee Dr. Nuria Lacuey and her team sought to identify specific parts of the brain essential for regulating breathing, a fundamental function whose failure following a seizure is primarily responsible for Sudden Unexpected Death in Epilepsy (SUDEP).
  • The team recruited patients who were being evaluated for epilepsy surgery and who formally agreed to enroll in a study that had them perform various breathing exercises while having different areas of their brain electrically stimulated with varying intensities.
  • Quantitative analyses of the data revealed that four specific areas of the cortex of the brain affected the patients’ breathing responses, depending on the strength and frequency of the electrical stimulation. Two of these areas resulted in enhanced respiratory activity.
  • Additional data from more patients is needed, but Dr. Lacuey hopes to use these valuable results to develop a device that will stimulate critical areas of the brain following seizures to enhance breathing and avoid its cessation, thereby preventing SUDEP.


Deep Dive:

SUDEP is the most frequent cause of death among people with drug-resistant epilepsy [1,2]. Although different biological processes may contribute to SUDEP, the most prominent appears to be a phenomenon known as central apnea, a condition in which breathing repeatedly stops and starts, usually while sleeping, during or immediately after a severe seizure [3,4]. There is compelling evidence that breathing irregularities are an underlying cause of SUDEP. Research to date has almost exclusively concentrated on the role of an area of the brain called the brainstem [5], which ultimately connects higher cortical regions of the brain to the spinal cord. Although the brainstem plays a crucial role in maintaining respiratory activity, it may not be the only contributing area. Indeed, areas of the cortex have also been implicated [6], but the specific roles different areas of the cortex play in modulating breathing is unclear. Most importantly, there are currently no strategies for directly improving respiratory function during the dangerous period between seizure-induced central apnea and death.

One possible approach would be to electrically stimulate specific areas of the brain to maintain respiratory function during this critical period. As a first step, it is vital to assess the role of specific areas of the brain and what intensity and frequency of the electrical current might have beneficial or detrimental effects on breathing. Developing such an innovative method requires a detailed understanding of the relationship between brain electrical activity and breathing responses, specifically how brain regions are structurally and functionally linked through their neuronal connections, collectively known as the connectome [7,8].

Research on this approach was conducted by Dr. Lacuey and her team in the Department of Neurology at the University of Texas Health Science Center  in Houston, TX. Nineteen patients who suffered from drug-resistant epilepsy and who were being evaluated for epilepsy surgery consented to be enrolled in the study [9]. Pinpointing the exact seizure focus without damaging surrounding healthy tissue necessitated placing electrodes directly on the brains of these patients and then, electrically stimulating various brain regions for clinical mapping.

Electrodes were implanted in seven brain regions common to all 19 participants, and thus, these were the regions selected for comprehensive investigation. The goal was to ascertain whether electrical stimulation of each of these seven regions would affect breathing responses and, if so, whether the resulting respiratory activity would be enhanced or inhibited. Equally important was to determine the stimulation intensity as well as frequency necessary to elicit such responses. Electrical stimulation was carried out at a current of 1-10 milliamps (mA) and a frequency of 50 Hertz for 0.2 milliseconds [9].

Quantitative analyses of the data showed that electrical stimulation affected breathing responses in four of the seven different brain regions tested. Stimulation of two of these regions, specifically within the frontal portions of areas called the temporal lobe and cingulate gyrus, promoted breathing enhancement at a relatively low current (less than 3 mA) but not at the higher electrical current conditions tested [9]. Future experiments will require a larger group of patients, finer mapping of the identified brain regions, and exploration of brain regions other than the seven examined in the current study. Subsequent experiments will also include an evaluation of electric current and frequency as well as how any observed changes in respiratory control interact with the breathing mechanisms of the brainstem.

The fact that electrical stimulation of four cortical regions affected respiration, and that two of these areas enhanced breathing is an exciting finding. Significantly, this CURE Epilepsy funded research supports the idea that an implantable device capable of electrically stimulating pre-identified cortical regions of the brain to enhance breathing at critical times to prevent SUDEP may eventually be possible.

 

Literature Cited:

  1. Jones, L.A. & Thomas, R.H. Sudden unexpected death in epilepsy: insights from the last 25 years. Seizure 2017; 44: 232-236.
  2.   Devinsky, O. et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016; 15(10): 1075-1088.
  3.   Vilella, L. et al. Postconvulsive central apnea as a biomarker for sudden unexpected death in epilepsy (SUDEP). Neurology 2019; 92(3): e171-e182.
  4.   So, E.L., Sam, M.C., & Lagerlund, T.L. Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident. Epilepsia 2000; 41(11): 1494-1497.
  5.   Patodia, S. et al. The ventrolateral medulla and medulla raphe in sudden unexpected death in epilepsy. Brain 2018; 141(6): 1719-1733.
  6.   Herrero, J.L. Breathing above the brain stem: volitional control and attentional modulation in humans. J. Neurophysiol. 2018; 119(1): 145-159.
  7.   Bethlehem, R.A.J. et al. Brain charts for the human lifespan. Nature 2022; 604(7906): 525-533.
  8.   Fan, Q. et al. Mapping the human connectome using diffusion MRI at 300 mT/m gradient strength: Methodological advances and scientific impact. Neuroimage 2022; 254:118958.
  9.   Ganne, C. et al. Limbic and paralimbic respiratory modulation: from inhibition to enhancement. Epilepsia 2022; Epub