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 studyNeurology. 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.

Clinical Risk Factors in SUDEP: A Nationwide Population-Based Case-Control Study

In this nationwide case-control study performed in Sweden, researchers tested the hypothesis that specific clinical characteristics are correlated with a heightened risk of sudden unexpected death in epilepsy (SUDEP).

Using medical records and the National Patient Register, they obtained data from 255 SUDEP cases (definite and probable) and 1,148 matched controls. A 27-fold increased risk was observed in correlation to experiencing generalized tonic-clonic seizures (GTCS) during the preceding year, whereas there was no excess risk in those with exclusively non-GTCS seizures.

A 15-fold risk was observed in correlation with the presence of nocturnal GTCS during the last year of observation. A 5-fold increased risk of SUDEP was observed in correlation with living alone and as per interaction analysis, the combination of not sharing a bedroom and having GTCS conferred an OR (odds ratio) of 67.10, with AP (attributable proportion due to interaction) estimated at 0.69. Excess risk of SUDEP was observed in correlation with a previous diagnosis of substance abuse or alcohol dependence among comorbid diseases. Results suggest that among patients who have GTCS and live alone, 69% of SUDEP cases could be averted if the patients were not unattended at night or were free from GTCS.

News from American Epilepsy Society Meeting 2019

Sepsis Linked to Elevated Risk for New-Onset Epilepsy in Young Individuals

Patients with sepsis, particularly younger patients and those with chronic kidney disease, may be at an elevated risk for new-onset epilepsy, according to research presented at the 2019 American Epilepsy Society Annual Meeting, held December 6-10, 2019, in Baltimore, Maryland.

Researchers conducted a population-based, retrospective, matched-cohort study to estimate the risk for new-onset epilepsy among patients hospitalized in the intensive care unit (ICU) for sepsis treatment. Researchers collected data from the patients in the Discharge Abstract Database between 2010 and 2015.

“These findings indicate that sepsis may be an unrecognized epilepsy risk factor,” the researchers concluded. “Possible mechanisms include damage to the blood-brain barrier as a result of renal dysfunction, persisting inflammation after the acute episode, and increased risk of cardiovascular events following sepsis.”

Learn more

Variable Long-Term Cognitive Changes in Pediatric Epilepsy

Children with pediatric epilepsy who undergo surgery may experience changes in verbal and nonverbal IQ, particularly when associated with abnormal electroencephalogram (EEG), according to research presented at the 2019 American Epilepsy Society Annual Meeting.

Researchers sought to assess the long-term, postsurgery cognitive outcomes of patients with pediatric epilepsy. Investigators assessed 24 participants, all of whom had pharmacoresistant epilepsy. Participants underwent a neuropsychological evaluation that included intellectual functioning assessments (overall IQ, verbal IQ, and nonverbal IQ), as well as an evaluation of postsurgical seizure status.

Learn more

Teenagers With Epilepsy Frequently Post Online Messages Related to Suicide

Using artificial tools to collect and analyze conversations and comments about epilepsy posted online, researchers revealed that 7.8% of all posts by teenagers with epilepsy were related to suicide, compared with 3.2% of adult posts, according to study results presented at the American Epilepsy Society 2019 Annual Meeting.

Previous studies have reported that roughly 30%-50% of patients with epilepsy may suffer from depression and the incidence of suicide in this population was found to be approximately 12%, which is 22% higher than the general population.2 The goal of the current study was to assess the major motivations for suicide thoughts among teenagers and adults with epilepsy, using artificial tools to analyze online conversations.

Learn more

Apnea and Arrhythmia Associated With Increased Mortality Among Patients With Epilepsy

Cardiac arrhythmias with or without apnea among patients with epilepsy are associated with increased mortality risk.  This risk may play an important role in cases of sudden unexpected death in epilepsy (SUDEP), according to study results presents at the American Epilepsy Society 2019 Annual Meeting.

Previous studies have reported that cardiac arrhythmias and apnea may play a significant part in cases of SUDEP, the second most common cause potential life-years lost in patients with epilepsy. The incidence rate of SUDEP is 1.16 cases per 1000 patients, but may be higher in those with intractable epilepsy.

Learn more

CURE Discovery: Novel Strategies to Understand SUDEP Risk and Ways to Prevent It

Key Takeaways

  • This CURE-funded study aims to develop biomarkers to assess the risk of Sudden Unexpected Death in Epilepsy (SUDEP) and therapies to prevent it.
  • By studying breathing and heart abnormalities in a mouse model of SUDEP, the researchers are trying to understand if there are specific patterns which can be detected early and used as a marker to predict risk of SUDEP.
  • Studies show that administering a drug to block a protein in the brain called orexin improved breathing and heart rate in the mouse models and potentially increased their longevity.

Deep Dive

This grant was supported generously by the Cameron Benninghoven Award.

Dr. Kristina SimeoneThe ability to predict and prevent SUDEP is a vital need for the epilepsy community, and a recent discovery by CURE Grantee Dr. Kristina Simeone and co-investigators Dr. Peter Abel and Dr. Timothy Simeone at Creighton University could lead to strategies that can help do so. The team is studying specific changes in cardiac and respiratory function health that can lead to SUDEP in hopes of developing biomarkers to predict SUDEP risk and treatments to prevent it.

The researchers are conducting experiments in a mouse model called Kv1.1 KO, which lacks part of the potassium channel, an important component of electrical signaling in the brain. These mice develop spontaneous seizures which progressively become more severe until the mice reach a specific age and are impacted by SUDEP.1

A 2013 study of SUDEP in humans noted a pattern of rapid breathing followed by apnea and bradycardia (slow heart rate) which eventually led to SUDEP.2 In their studies with the Kv1.1 KO mice, Dr. Simeone and her team similarly found that these mice had chronic periods of hypoxia (low oxygen), experienced apnea caused by periods of rapid breathing, and had periods of bradycardia. They found that these breathing and heart problems were more likely to occur as the mice approached SUDEP age. The researchers are interested in understanding whether this abnormal pattern of breathing and bradycardia can be detected early and used as a novel marker to predict SUDEP risk.

Cameron BenninghovenThe researchers also gathered evidence suggesting that a protein in the brain called orexin, which is known to regulate breathing and heart rate, may be a central player in causing SUDEP. They previously found that blocking orexin’s actions can improve sleep and reduce seizures in the Kv1.1 KO mice model.3 The team treated mice with a drug which blocks orexin’s actions and found that it beneficially increased heart rate in mice with bradycardia, and improved abnormal breathing patterns. The team also found that treating mice at high risk for SUDEP daily with the drug may increase their lifespan.

Dr. Simeone and her co-investigators are interested in using these important new discoveries to develop monitoring strategies for estimating SUDEP risk and eventually developing therapies to prevent SUDEP.

1 Simeone KA, Matthews SA, Rho JM, et al. Ketogenic Diet increases longevity in a model of Sudden Unexpected Death in Epilepsy, the Kv1.1KO mice. Epilepsia. 2016;57:178–82
2 Ryvlin P, Nashef L et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013 Oct;12(10):966-77
3 Roundtree HM, Simeone TA et al. Orexin Receptor Antagonism Improves Sleep and Reduces Seizures in Kcna1-null Mice. Sleep. 2016 Feb 1;39(2):357-68