News Topics: SUDEP

Why Rates of Sudden Death Due to Epilepsy Are Much Higher for Poorer Patients

Summary, published on Neurology Today

Epilepsy patients in the poorest communities are more than twice as likely to suffer sudden unexplained death due to epilepsy (SUDEP) than their counterparts at the highest end of the socioeconomic ladder, although the reasons for this are difficult to ascertain, according to a review of medico-legal claims and medical examiners’ office records in three geographically diverse areas across the United States.

A team of researchers led by Daniel Friedman, MD, an associate clinical professor of neurology at NYU Langone School of Medicine’s Epilepsy Center, studied all medico-legal investigations for SUDEP at medical examiner (ME) offices in New York City, Maryland, San Diego County, in 2009 and 2010, and again between 2014 and 2015.

The investigators found 159 SUDEP cases in neighborhoods with the lowest socioeconomic status compared with 43 cases in the highest income brackets. The ratio between the lowest and highest socioeconomic status quartiles was 2.6 in 2009 and 2010, and 3.3 in 2014 and 2015. And although overall cases fell by 36 percent between the two study periods, the disparity between groups remained similar over the full five-year study period, the researchers reported in the April 23 online edition of Neurology.

Epilepsy Status by Zip Codes

The researchers identified all decedents for whom epilepsy/seizure was listed on death certificates as a cause/contributor to death, or as a comorbid condition, as well as coding reports and data pertaining to overall socioeconomic status (SES) in each area by ZIP code. The team also utilized data from the Centers for Disease Control and Prevention and the U.S. Census Bureau.

“We found that community socioeconomic status has a significant impact on SUDEP rates,” Dr. Friedman told Neurology Today. “Further studies are needed to understand the causes of disparities in poorer communities in order to identify potential targets for intervention.”

Several possible factors can influence seizure control, he said, including the inability to afford or obtain seizure control drugs, poorer adherence to drug regimens, and limited access to specialty care for treatment-resistant seizures. Mental illness and substance abuse can also interfere with the ability of individuals to self-manage their epilepsy.

Yet, even when the data was adjusted for these factors, the researchers did not find age, adherence to anti-seizure medications, substance abuse history, or comorbidity between the lowest and highest income areas that might explain the SUDEP disparities, especially to the degree that the calculations indicated.

Unfortunately, the team was unable to determine disability status, seizure frequency, or seizure severity for a majority of the cases, Dr. Friedman said. ME reports and death certificates likely underestimate the true number of SUDEP cases, he added.

“Because SUDEP rates were calculated on the basis of ME investigation and coding of death certificates, we very likely did not ascertain all SUDEPs. Moreover, the observed overall SUDEP rate of 0.33 to 0.66 per 1,000 patient-years was lower than the rate by patient-years reported in earlier population-based studies that have examined medical and vital records,” Dr. Friedman noted.

Research Shows that Epilepsy-Related Deaths are Common in Young Adults and Are Not Decreasing

Press release from The European Academy of Neurology

A new study conducted in Scotland and presented at the European Academy of Neurology (EAN) Virtual Congress showed that the burden of potentially avoidable epilepsy-related deaths in young adults remains large, with those aged between 16 and 24 having a six-fold increased risk of epilepsy-related death. In addition, mortality rates for epilepsy-related deaths did not decrease between 2009 (6.8 per 100,000) and 2015 (9.1 per 100,000) despite advances in treatment during this time. Young adult patients in their early 20s and 30s were found to be at the highest risk, with 78% of epilepsy-related deaths under the age of 55 years classified as potentially avoidable. The aim of the study was to identify the burden of epilepsy-related deaths, what proportion of these are potentially avoidable, and determine the factors that may put patients at an increased risk.

The researchers collected anonymous data from healthcare settings for patients who died between 2009 and 2016, identifying 2,149 epilepsy-related deaths. 60% of these patients (1,276) had one or more seizure-related or epilepsy-related hospital admission in the years prior to death, yet less than a quarter (516) were seen in a neurology clinic. The most common causes of death within the study were sudden unexpected death in epilepsy (SUDEP), aspiration pneumonia, cardiac arrest, congenital malformation, and alcohol-related deaths. The data will be compared with data from living patients with epilepsy of the same age and gender. These comparisons will focus on the patients’ epilepsy type, socio-economic class, standards of care received, and the presence of additional disorders such as depression.

Dr Gashirai Mbizvo, completing this Scottish Epilepsy Deaths Study (SEDS) at The University of Edinburgh, comments that “Epilepsy patients are at a higher risk of early death than the general population, but reasons for this are unclear. We hope that we can use these data to learn lessons and reduce the burden of epilepsy-related deaths in the future, many of which we believe are likely to be avoidable. Highlighting such risk factors, and identifying those that could be prevented, might lead to changes in epilepsy care and, ultimately, fewer epilepsy-related deaths in the future.”

Epilepsy is a chronic noncommunicable disease of the brain that affects around 50 million people globally, making it one of the most common neurological diseases worldwide. It can cause seizures or periods of confusion in patients, which can either occur randomly or from triggers, such as a lack of sleep, stress or drinking alcohol. In many cases, people with epilepsy suffer from negative stigma and discrimination.

Causes and Effects Contributing to SUDEP and the Rationale for Prevention and Intervention

Abstract, published in Frontiers in Neurology

Sudden unexpected death in epilepsy (SUDEP) claims the lives of one in every thousand epileptic patients each year, but the precise cause(s) had not yet been identified. The researchers propose a single sequence of causes and effects that collectively focus on obstructive apnea that occurs during the seizure itself. Obstructive apnea is a condition in which the muscles supporting the soft tissues in the throat (tongue & soft palate) temporarily relax, thereby narrowing or closing off the airway to cut off breathing.

Based on detailed animal studies that are sometimes impossible in humans, and striking parallels with a growing body of clinical examples, this framework (1) accounts for the autonomic, cardiac, and respiratory data to date by showing the causal relationships between specific elements, and (2) highlights specific kinds of data that can be used to precisely classify various patient outcomes. The framework also justifies a “near miss” designation to be applied to any cases with evidence of obstructive apnea even, and perhaps especially, in individuals that do not require resuscitation. Lastly, the rationale for preventative oxygen therapy is demonstrated.

With better mechanistic understanding of SUDEP, this team suggests changes for detection and classification to increase survival rates and improve risk stratification.

A man checking his smart watch

Post-Ictal Accelerometer Silence as a Marker of Post-Ictal Immobility

Abstract, published in Epilepsia

Objective: Movement-based wearable sensors are used for detection of convulsive seizures. The identification of the absence of motion following a seizure, known as post-ictal immobility (PI), may represent a potential additional application of wearables. PI has been associated with potentially life-threatening complications and with sudden unexpected death in epilepsy (SUDEP). This study aimed to assess whether wearable accelerometers (ACCs) could be used as a digital marker of PI.

Method: Devices with embedded ACCs were worn by patients admitted to an epilepsy monitoring unit. Participants with convulsive seizures were included in the study. PI presence and duration were assessed by experts reviewing video recordings. An algorithm for the automatic detection of post-ictal ACC silence and its duration was also developed and the relationship between the automatically detected duration of post-ictal ACC silence and the duration of the expert-labeled PI was analyzed.

Results: Twenty-two convulsive seizures were recorded from 18 study participants. Twenty were followed by PI and two by agitation. The automated estimation of post-ictal ACC silence identified all the 20 expert-labeled PI. Analysis showed that the duration of the post-ictal ACC silence was correlated with the duration of PI, the age of study participants and the duration of post-ictal generalized electroencephalography suppression (PGES), defined as the immediate post-ictal, generalized absence of EEG activity.

Significance: Researchers highlight a novel application of wearables as a way of recording post-ictal manifestations associated with an increased risk of SUDEP. The occurrence of a fatal seizure is unpredictable and the continuous, non-invasive, long-term identification of risk factors associated with each individual seizure may assume great clinical importance.

Seizure and Sudden Unexpected Death in Epilepsy (SUDEP) Characteristics in an Urban Intellectual Disability Service

Abstract, published in Science Direct

Purpose: This study identifies epilepsy-related characteristics and SUDEP risk factors in people with epilepsy (PWE) attending an urban community intellectual disability (ID) service in the United Kingdom (UK). Managing epilepsy is not part of the provided service, but it is important to understand the care provided to this vulnerable population.

Methods: An electronic database search in a north London community ID service (catchment population approx. 290,000) identified relevant ID/epilepsy characteristics in PWE to compare those with mild ID to moderate-profound ID. The SUDEP and Seizure Safety Checklist was administered to patients and families/care givers. Risk management data was compared to similar data from Cornwall UK, where PWE are supported within the ID service and the Checklist is used annually.

Results: One fifth of people attending the service had epilepsy. Over 75% had moderate-to-profound ID. Neurodevelopmental disorders were coexistent in ~66%, psychiatric conditions in 33%, (25% of which was psychosis). The mean number of anti-seizure drugs was 1.45 ± 0.98, and 25% were taking psychotropic medications. Over 33% did not have an epilepsy care plan. None contacted (n =103) had SUDEP awareness. The median number of Checklist risk factors was seven. Thirty-three percent had experienced seizures lasting >5 mins or status epilepticus. In comparison to the Cornish ID data significant differences were evident in four of seven modifiable risk factors.

Conclusions: This real-world study highlights the complexity and risks among people with epilepsy and intellectual disability. The lack of a collaborative approach can undermine the safety of this vulnerable population. Person-centered risk communication and care plans are easily achievable and essential. Kindly check editorial remark and do the needful.

Heart Abnormalities Unlikely behind Sudden Unexpected Deaths in Dravet

Heart abnormalities are unlikely to be the reason behind the high rate of Sudden Unexpected Death in Epilepsy (SUDEP) in people with Dravet syndrome, a new study suggests, though further research is needed. The underlying cause of SUDEP in people with Dravet is unclear, but multiple interconnecting factors are likely at play. Better understanding these factors could aid in the development of strategies to help prevent SUDEP.

Studies in mice have suggested that SUDEP might be related to heart rhythm abnormalities, but it is unclear whether these findings might also translate to human disease.

The new study reports findings from a clinical trial (NCT02415686) in which people with Dravet wore electrocardiogram (ECG or EKG) devices to monitor their heartbeats. The devices were worn daily and continuously recorded data. For each Dravet patient, researchers identified two people who were similar in age and sex to serve as controls.

Researchers looked for seizure-associated heart abnormalities that were more common among the Dravet patients than the controls. Such abnormalities could explain the comparatively high rate of SUDEP in Dravet.

Although some of the findings may warrant further study, the researchers found that none of the seizure-associated heart abnormalities could account for the comparatively high SUDEP rate in Dravet Syndrome.

Epilepsy Research Findings: April 2020

Research findings reported over the past month include advances in our understanding of an area of the brain that may contribute to Sudden Unexpected Death in Epilepsy (SUDEP) in children, as well as intriguing discoveries about autoantibody-induced epilepsy. In addition, scientists are turning to plants to identify novel anti-seizure drugs (ASDs) for novel anti-seizure medications. Finally, we spotlight a development for a model of the NeuroPace responsive neurostimulator (RNS®), which will broaden its availability as a treatment option, and strike a precautionary note about the effectiveness of multiple epilepsy surgeries.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • SUDEP in Children: A specific area of the brain called the amygdala may play a role in causing children to stop breathing during a seizure. The findings could have important implications for predicting, treating, and/or preventing SUDEP in children. Learn More
  • Immune System and Epilepsy: In some people with epilepsy, an autoantibody (an antibody that attacks a person’s own body instead of a disease-causing agent) appears to “sneak” into neurons in an area of the brain called the hippocampus, leading to inflammation and then seizures. This study also suggests that it may be possible to prevent these types of seizures with immunosuppressant drugs. Learn More
  • Novel Anti-Seizure Drugs (ASDs): Extracts made from magnolia bark, a plant used in traditional Chinese medicine as an anti-seizure remedy, reduced seizures in both zebrafish and mouse models of epilepsy, according to a recent study. The researchers state the isolated compound, magnolol, may serve as a starting point for the development of improved treatments for drug-resistant epilepsy. Learn More
  • RNS Device: The NeuroPace RNS system, model RNS-320, received FDA approval for use with magnetic resonance imaging (MRI) machines. This approval means that epilepsy patients who require MRI monitoring can now be offered this model of the RNS as a treatment option as appropriate. Learn More
  • Neurosurgery: For patients with drug-resistant epilepsy who undergo multiple neurosurgeries, the likelihood of long-term seizure control decreases with each attempt, according to this study. Learn More

Scientists Pinpoint a Brain Region that Stops Breathing in Pediatric Epilepsy

University of Iowa neuroscientists have identified a specific area of the brain involved in the loss of breathing that occurs during a seizure. The findings, published in JCI Insight on March 12, could have important implications for predicting, or even treating and preventing sudden unexpected death due to epilepsy (SUDEP).

Although it has been known for more than a century that seizures can cause people to stop breathing, for much of that time this transient effect has not been taken very seriously. More recently, evidence has been building, though studies done at the UI and elsewhere, suggesting that seizure-induced loss of breathing plays a critical role in SUDEP, which is the leading cause of death in people who have uncontrolled epilepsy.

In the new study, the UI team led by neurosurgeon Brian Dlouhy, MD, studied eight pediatric patients with epilepsy, ranging in age from 3 to 17, who were undergoing seizure mapping with implanted, intracranial electrodes. Previous studies in adults from UI and elsewhere have shown that the amygdala is important for seizure-induced loss of breathing (apnea), but no one has looked at the role of the amygdala and loss of breathing in children with epilepsy.

Using brain recordings from the implanted electrodes and continuous monitoring of breathing, the researchers showed that a specific (medial) subregion of the amygdala was the critical site in the children’s brains. In two patients they observed loss of breathing when the seizure reached the amygdala; and electrically stimulating the amygdala, but not other parts of the brain, produced apnea in all eight patients. These effects did not depend on the age of the child or type of epilepsy affecting the children.

Remarkably, none of the children were aware that they had stopped breathing during the stimulation trials, and none of them had any of the normal feelings of stress or discomfort that usually happen if a person stops breathing.

Doctor wearing a white coat typing at a computer

CURE Discovery: Two Major SUDEP Risk Factors Identified in Nationwide Swedish Study

This grant was generously supported by the Leisher Family Award.

Key Takeaways:

  • Dr. Torbjörn Tomson’s study confirms previous research suggesting that generalized tonic-clonic seizures (GTCS) are a significant risk factor for Sudden Unexpected Death in Epilepsy (SUDEP)
  • The study found that for people with GTCS, living and sleeping alone are also significant SUDEP risk factors
  • The research suggests that treatments to reduce the occurrence of GTCS or to convert GTCS to non-GTCS would be useful in reducing SUDEP risk

Deep Dive:

Dr. TomsonDr. Torbjörn Tomson at the Karolinska Institute in Sweden, whose 2010 CURE-funded study was supported generously by the Leisher Family Award, recently published his findings from a large, nationwide study on factors associated with increased risk of SUDEP.1

For this study, Dr. Tomson and his team analyzed medical records for 255 people who passed away due to SUDEP between July 1, 2006 and December 31, 2011. These SUDEP cases were classified as either “definite SUDEP” or “probable SUDEP”2 based on available information. To build a strong understanding of SUDEP risk factors, the investigators compared each case of SUDEP to the medical records for 5 people with epilepsy of the same sex who were alive at the case’s time of death. These individuals served as controls against which to compare factors that might contribute to SUDEP risk. For SUDEP cases and controls, the team used medical records to collect information on age, sex, epilepsy type, and occurrence of seizures, as well as lifestyle information on whether the individuals lived alone or with someone and if they shared a bedroom. The team performed analyses to understand how each of these factors contributed to SUDEP risk.

The analyses of these data found that the presence and frequency of GTCS was the most important risk factor for SUDEP. A history of GTCS was associated with a ten-fold greater risk of SUDEP. Of those with this increased risk, patients who had 4-10 GTCS in the year preceding SUDEP had a 32-fold increase in SUDEP risk. Dr. Tomson’s team also found that the presence of nocturnal GTCS in the year preceding SUDEP was associated with a 15-fold increased risk of SUDEP. Further, this study found that there was no increased risk of SUDEP in people with only non-GTCS, suggesting that treatments to convert GTCS to non-GTCS could reduce SUDEP risk.

Importantly, the team observed a substantial increase in SUDEP risk for individuals with GTCS who lived alone and those who live with other people but don’t share a bedroom. The combination of sleeping alone and having at least one GTCS in the preceding year resulted in a 67-fold increased risk for SUDEP compared to not having GTCS and sharing a bedroom. This data confirms previous research suggesting that unattended GTCS are the most significant risk factor in SUDEP.3

This important study identifies GTCS and sleeping alone as significant risk factors for SUDEP. In addition, Dr. Tomson’s work makes the case for improved seizure monitoring devices to alert caregivers of night-time seizures and for people with GTCS to share a room with someone when sleeping whenever possible. The research further suggests that treatments to reduce occurrence of GTCS would be useful in reducing SUDEP risk.

1 Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T, Clinical risk factors in SUDEP: A nationwide population-based case-control study, Neurology. 2020 Jan 28;94(4):e419-e429
2 SUDEP was defined as “definite” or “probable” based on previously developed criteria. When these criteria were met with a sufficient description of the circumstances of death and a postmortem report was available, SUDEP was classified as “definite”. When criteria were met but a postmortem report was not available, SUDEP was classified as “probable”. A third category of “possible” SUDEP included cases where SUDEP could not be ruled out but did not have sufficient evidence or a postmortem report. Possible SUDEP was not included in this study.
3 Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention, Lancet Neurol. 2016 Sep;15(10):1075-88

Progressive Cardiorespiratory Dysfunction in Kv1.1 Knockout Mice May Provide Temporal Biomarkers of Pending Sudden Unexpected Death in Epilepsy (SUDEP): The Contribution of Orexin

Featuring the work of CURE Grantee Kristina Simeone, which was supported by the generosity of the Benninghoven Family in honor of Cameron Benninghoven

Abstract

Objective: Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic-clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, the research team determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2) in low-risk and high-risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high-risk KO mice.

Methods: Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry.

Results: Intermittent bradycardia was more prevalent in high-risk KO mice, an effect that may be the result of increased parasympathetic drive. High-risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild-type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea-apnea. Blocking orexin receptors prevented the methacholine (MCh)-induced increase in breathing frequency in KO mice and reduced MCh-induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high-risk KO mice increased longevity.

Significance: High-risk knockout mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.