Sudden Unexpected Death in Epilepsy During Cenobamate Clinical Development

Abstract found on PubMed

Objective: We assessed mortality, sudden unexpected death in epilepsy (SUDEP), and standardized mortality ratio (SMR) among adults treated with cenobamate during the cenobamate clinical development program.

Methods: We retrospectively analyzed deaths among all adults with uncontrolled focal (focal to bilateral tonic-clonic [FBTC], focal impaired awareness, focal aware) or primary generalized tonic-clonic (PGTC) seizures who received ?1 dose of adjunctive cenobamate in completed and ongoing phase 2 and 3 clinical studies. In patients with focal seizures from completed studies, median baseline seizure frequencies ranged from 2.8 to 11 seizures per 28 days and median epilepsy duration ranged from 20 to 24 years. Total person-years included all days a patient received cenobamate during completed studies or up to June 1, 2022 for ongoing studies. All deaths were evaluated by two epileptologists. All-cause mortality and SUDEP rates were expressed per 1000 person-years.

Results: A total of 2132 patients (n=2018 focal epilepsy; n=114 idiopathic generalized epilepsy) were exposed to cenobamate for 5693 person-years. Approximately 60% of patients with focal seizures and all patients in the PGTC study had tonic-clonic seizures. A total of 23 deaths occurred (all in patients with focal epilepsy), for an all-cause mortality rate of 4.0 per 1000 person-years. Five cases of definite or probable SUDEP were identified, for a rate of 0.88 per 1000 person-years. Of the 23 overall deaths, 22 patients (96%) had FBTC seizures, and all 5 of the SUDEP patients had a history of FBTC seizures. The duration of exposure to cenobamate for patients with SUDEP ranged from 130-620 days. The SMR among cenobamate-treated patients in completed studies (5515 person-years of follow-up) was 1.32 (95% CI 0.84-2.0), which was not significantly different from the general population.

Significance: These data suggest that effective long-term medical treatment with cenobamate may reduce excess mortality associated with epilepsy.

A Unified Hypothesis of SUDEP: Seizure-Induced Respiratory Depression Induced by Adenosine May Lead to SUDEP But Can be Prevented by Autoresuscitation and Other Restorative Respiratory Response Mechanisms Mediated by the Action of Serotonin on the Periaqueductal Gray

Featuring the work of former CURE grantee Dr. Carl Faingold

Abstract found on PubMed

Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in people with epilepsy (PWE). Postictal apnea leading to cardiac arrest is the most common sequence of terminal events in witnessed cases of SUDEP, and postconvulsive central apnea has been proposed as a potential biomarker of SUDEP susceptibility. Research in SUDEP animal models has led to the serotonin and adenosine hypotheses of SUDEP. These neurotransmitters influence respiration, seizures, and lethality in animal models of SUDEP, and are implicated in human SUDEP cases. Adenosine released during seizures is proposed to be an important seizure termination mechanism. However, adenosine also depresses respiration, and this effect is mediated, in part, by inhibition of neuronal activity in subcortical structures that modulate respiration, including the periaqueductal gray (PAG). Drugs that enhance the action of adenosine increase postictal death in SUDEP models. Serotonin is also released during seizures, but enhances respiration in response to an elevated carbon dioxide level, which often occurs postictally. This effect of serotonin can potentially compensate, in part, for the adenosine-mediated respiratory depression, acting to facilitate autoresuscitation and other restorative respiratory response mechanisms. A number of drugs that enhance the action of serotonin prevent postictal death in several SUDEP models and reduce postictal respiratory depression in PWE. This effect of serotonergic drugs may be mediated, in part, by actions on brainstem sites that modulate respiration, including the PAG. Enhanced activity in the PAG increases respiration in response to hypoxia and other exigent conditions and can be activated by electrical stimulation. Thus, we propose the unifying hypothesis that seizure-induced adenosine release leads to respiratory depression. This can be reversed by serotonergic action on autoresuscitation and other restorative respiratory responses acting, in part, via the PAG. Therefore, we hypothesize that serotonergic or direct activation of this brainstem site may be a useful approach for SUDEP prevention.

SMU Biosciences Professor Receives NIH Grant for Research on Epilepsy

Article published by News Wise

Featuring the work of former CURE Epilepsy grantee Dr. Edward Glasscock

An estimated 50 million people worldwide have epilepsy, making them 16 times more likely to die suddenly compared to the general population. SMU biology researcher Edward Glasscock has received a 5-year, $3 million grant from the National Institutes of Health for a study that he hopes will lead to the identification of biomarkers to help identify people at risk for sudden unexpected death in epilepsy, known as SUDEP.

What causes sudden death in people with epilepsy is largely unknown, making it difficult for clinicians and researchers to predict who is most at risk. However, one popular theory is that seizures initiate faulty electrochemical signals in brain regions that control the heart and breathing, causing miscommunication between the brain, heart, and lungs leading to respiratory failure or heart arrhythmias. If the patterns of this faulty inter-organ crosstalk could be identified in people with epilepsy, then it could serve as an indicator for who is most at risk for sudden death, as well as lead to the development of new treatments to prevent SUDEP.

Glasscock, associate professor of biological sciences at SMU (Southern Methodist University) is working in collaboration with Leonidas Iasemidis, of the Barrow Neurological Institute in Phoenix, to investigate how these faulty electrochemical signals affect the brain-heart-lung pathways. Glasscock and Iasemidis are using a multidisciplinary bioengineering systems approach that would not only identify biomarkers but also provide insight on the biological basis of SUDEP, which can lead to better targeted therapies.

Epilepsy, with new cases often diagnosed in young children, occurs because of abnormal electrical activity in the brain that causes seizures. Because there are many different causes and types of epilepsy, it is described as a spectrum disorder, which makes it difficult to study. However, scientists have made strides in discerning the genetic factors and mechanisms that cause some people to develop epilepsy.

In the body, electrochemical signals are related to chemical ion gradients, like potassium or sodium. Cells allow these ions to pass into and out of the cell membrane through channels. These channels are highly regulated because too few or too many of the ions can cause problems with the brain’s signaling pathways. It is thought that one cause of epilepsy is related to genetic mutations that cause these ion channel regulators to malfunction. This results in abnormal interactions between the brain, heart, and lungs, which in turn may cause sudden death.

Researcher Update: April 2023

In this Researcher Update you’ll find information on:

CURE Epilepsy’s Frontiers in Research Seminar Series

The goal of CURE Epilepsy’s Frontiers in Research Seminar Series program is to expose researchers, clinicians, and students to exciting epilepsy research and provide opportunities for young investigators to interact with leaders in the field. CURE Epilepsy will provide $2,500 to each of the selected institutions to offset the costs associated with hosting a seminar. Apply for CURE Epilepsy’s Frontiers in Research Seminar Series by Wednesday, May 31, 2023.

Learn More

Partners Against Mortality in Epilepsy (PAME) Call for Abstracts

The 7th Partners Against Mortality in Epilepsy (PAME) Conference will be held on Thursday, November 30, 2023, in Orlando, FL. This conference brings together healthcare providers, researchers, public health officials, patient advocates, caregivers, bereaved families, and people living with epilepsy to discuss topics related to mortality in epilepsy. Abstracts will be considered from all investigators doing epidemiological, basic, translational, or clinical research on any aspect of mortality in epilepsy. All accepted abstracts will be presented as posters at the PAME meeting.

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A Free PAME Webinar: Sudden Death in Epilepsy (SUDEP): Common Misconceptions

Misunderstandings about SUDEP impact how providers discuss SUDEP risk, how researchers track and investigate the problem, how we think about prevention, and much more. Dr. Orrin Devinsky, a leader in SUDEP research, will challenge our thinking and help identify misunderstandings so we can more effectively study and prevent SUDEP. This one-hour webinar, to be held on Friday, April 28 at 1PM CT, is geared toward healthcare providers, researchers, people with epilepsy, and other interested parties.


NIH Free, Virtual Conference: Ableism in Medicine and Clinical Research

The National Center for Medical Rehabilitation Research (NCMRR) is holding a free, virtual conference on Ableism in Medicine and Clinical Research on April 27-28. This 2-day, virtual workshop focuses on awareness and research opportunities to mitigate the effect of “ableism”—defined by the American Psychological Association as prejudice and discrimination aimed at people with disabilities—in both clinical care and the biomedical and behavioral research enterprise.

Learn More

SUDEP Counseling: Where do we stand?

Abstract found on PubMed

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in children and adults living with epilepsy. Several recent clinical practice guidelines have recommended that all individuals living with epilepsy and their caregivers be informed about SUDEP as a part of routine epilepsy counseling. Further, several studies over the last two decades have explored the state of SUDEP counseling. Patients with epilepsy and their families want to be informed about the risk of SUDEP at or near the time of diagnosis and preferably in person. Despite guideline recommendations, many pediatric and adult neurologists do not routinely inform individuals with epilepsy and their families about SUDEP. Some neurologists discuss SUDEP with only a subset of patients with epilepsy, such as those with risk factors like frequent generalized or focal to bilateral tonic-clonic seizures, nocturnal seizures, non-compliance, or medically refractory epilepsy. Proponents of routine SUDEP counseling argue that patients with epilepsy and their families have a “right to know” and that counseling may positively impact epilepsy self-management (i.e., behavioral modification and risk reduction). Some neurologists still believe that SUDEP counseling may cause unnecessary stress and anxiety for patients and their families (although this is erroneous) and that they also have a “right not to know.” This narrative review explores the current gaps in SUDEP counseling, patients’ and caregivers’ perspectives of SUDEP counseling, and SUDEP prevention.

Life After SUDEP: Experiences of Traumatic Loss and Growth

Abstract found on PubMed

Purpose: To understand the experiences of bereaved relatives of individuals who passed due to sudden unexpected death in epilepsy (SUDEP) and to explore the impacts of death in their lives.

Methods: The principles of fundamental qualitative description informed all design decisions. Stratified purposeful sampling included 21 bereaved relatives (parent, sibling, or spouse/partner), aged at least 18 years, of persons who passed away because of SUDEP. In-depth one-to-one interviews were conducted. Directed content analysis was used to code, categorize, and synthesize the interview data.

Results: There was some criticism of emergency response and medical professionals involved in providing insensitive or poor care immediately after SUDEP occurred. Personal hardships described by participants following SUDEP included loss of personal identity, feeling depressed, experiencing guilt, having panic attacks, requiring therapy, as well as having difficulty with anniversaries, dates, and cleaning up a child’s room. Bereaved spouses and parents in particular spoke of experiencing challenges in maintaining other relationships following the death. Some participants spoke of experiencing increased financial hardships. Ways of coping included keeping oneself busy, honoring the memory of the loved one, relying on friends and families, and engaging in advocacy/community work, including raising awareness on epilepsy and SUDEP.

Conclusions: Sudden unexpected death in epilepsy affected several aspects of the day-to-day lives of bereaved relatives. Though methods of coping were similar to the usual strategies adopted by all bereaved relatives, advocacy work related to raising awareness about epilepsy and SUDEP was unique to this group. Guidelines on SUDEP should ideally include recommendations for trauma-informed support and assessment for depression and anxiety to the bereaved relatives as well.

Research Identifies Potential Treatment Target for of Infantile and Epileptic Spasms Syndrome

Article published by News Medical Life Science

New research from Tufts University School of Medicine and the Graduate School of Biomedical Sciences suggests that the timing of the death of certain inhibitory neurons in the brain shortly after birth may be at least partly to blame for infantile and epileptic spasms syndrome (IESS), a rare but devastating form of epilepsy that develops most frequently between four and eight months of age but can emerge within weeks of birth until ages 4 or 5.

Their research in mice suggests both a potential new target for treatment and raises the hope that, in the future, early diagnosis and treatment could detect and prevent some of the most significant impairments associated with the syndrome. The research was published Jan. 30 in the Journal of Neuroscience.

In their research, the Tufts scientists focused their studies on the b-catenin signaling pathway in a mouse model, originally developed by neuroscientist and School of Medicine professor Michele Jacob, that develops a condition analogous to IESS. The mice also demonstrate intellectual disabilities and behavioral abnormalities corresponding to human autism spectrum disorder.

The researchers determined that cortical parvalbumin-positive interneuron development and function are altered in the mice. These neurons are the largest class of GABAergic, inhibitory neurons in the central nervous system.

Assessment of an Under-Mattress Sensor as a Seizure Detection Tool in an Adult Epilepsy Monitoring Unit

Abstract found on PubMed

Objective: Because of SUDEP (Sudden and unexpected death in epilepsy) and other direct consequences of generalized tonic-clonic seizures, the use of efficient seizure detection tool may be helpful for patients, relatives, and caregivers. We aimed to evaluate an under-mattress detection tool (EMFIT®) in real-life hospital conditions, in particular its sensitivity and false alarm rate (FAR), as well as its impact on patient care.

Methods: We carried out a retrospective study on a cohort of patients with epilepsy admitted between September 2017 and June 2021 to Amiens University Hospital for a video-EEG of at least 24 h, during which at least one epileptic seizure was recorded. All video-EEGs records were analyzed visually in order to assess the sensitivity of the under-mattress tool (triggering of the alarm) and to classify the seizure type (convulsive/non convulsive). We also considered whether nurses intervened during the seizure, and the time of their intervention if applicable. An additional prospective survey was conducted over 272 days to analyze the FAR of the tool.

Results: A total of 220 seizures were included in the study, from 55 patients, including 23 convulsive seizures from 15 patients and 197 non-convulsive seizures. Sensitivity for convulsive seizure detection was 69.6%. As expected, none of the non-convulsive seizures was detected. The false alarm rate was 0.007/day. Median trigger time was 74 s, decreasing to 5 s for generalized tonic-clonic seizure. The frequency of nurses’ intervention during convulsive seizures was significantly greater in case of the alarm triggering (100% vs 57%, p<0.02).

Significance: These results suggest that EMFIT® sensor is able to detect convulsive seizures with good sensitivity and low false alarm rate, and allows caregivers to intervene more often in the event of a nocturnal seizure. This would be an interesting complementary tool to better secure the patients with epilepsy during hospitalization or at home.

Communication About Sudden Unexpected Death in Epilepsy: Understanding the Caregiver Perspective

Abstract found on Wiley Online Library

Objective: We aimed to characterize (1) the caregiver experience of learning about sudden unexpected death in epilepsy (SUDEP), and (2) caregiver preferences for SUDEP risk disclosure.

Methods: We distributed a 24-question survey to caregivers of children with epilepsy. Free text questions were analyzed using a rapid qualitative analysis approach.

Results: Two hundred and twelve caregivers of people with epilepsy completed the survey, including 12 bereaved caregivers. Caregivers’ children had a high seizure burden, with a median seizure frequency of 24 seizures per year (range: 1 to ?100). Most participants were aware of SUDEP at the time of the survey (193/212; 91%) though only a minority had learned about SUDEP from a healthcare provider (91/193; 47.2%). Caregivers typically learned about SUDEP from a nonprofit or online source (91/161; 56.5%). Almost all caregivers wanted to discuss SUDEP with their child’s healthcare provider (209/212; 98.6%), and preferred disclosure from epileptologists (193/212; 91%), neurologists (191/212; 90.1), and/or primary care providers (98/212; 46.2%). In open-ended responses, caregivers highlighted the value of learning about SUDEP from a healthcare provider, the importance of pairing SUDEP risk disclosure with a discussion of how to mitigate risk, and the need for educational resources and peer support.

Interpretation: Caregivers of people with epilepsy appreciate when healthcare providers disclose information about SUDEP, yet typically hear about SUDEP elsewhere. These findings underscore the importance of interventions to improve and support SUDEP risk disclosure. Future work should evaluate strategies to disclose SUDEP risk and the impact of early SUDEP risk disclosure.

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.