Are Febrile Seizures Associated With Increased Sudden Death Risk in Young Children?

Children with febrile seizures (FS) have a small yet elevated risk for death. Recent data suggest that FS may contribute to sudden unexplained death in childhood (SUDC) among cases of sudden explained death in childhood (SEDC). This is according to findings published in JAMA Network Open from one of the largest studies of its kind exploring the role of FS and other risk factors in SUDC.

A total of 622 consecutive cases of sudden child death that occurred from 2001 to 2017 were included in the review. Data were collected from voluntary records of family members who were registered with the SUDC Foundation. The final cause of death resulted in cases categorized as either SEDC or SUDC. The main outcome measure included the certified manner of death as accident, natural, or undetermined.

Ketogenic Diet May Reduce Sudden Unexpected Deaths in Epilepsy, Mouse Study Suggests

Sudden Unexpected Death in Epilepsy (SUDEP) occurs more frequently during early evening and is significantly prevented by prolonged use of the ketogenic diet, research in a mouse model of Dravet syndrome (DS) suggests.

The reasons why this happens are unclear, and should be examined in more depth by future studies, but these findings may be useful to understand why most SUDEP episodes happen at night and how certain diets can benefit epileptics, especially those with Dravet syndrome, researchers say.

Their study, “Time of Day and a Ketogenic Diet Influence Susceptibility to SUDEP in Scn1aR1407X/+ Mice,” was published in the journal Frontiers in Neurology.

Using an established mouse model of Dravet syndrome, the researchers investigated if the time of the day influences the chances of sudden death. They also sought to determine if a ketogenic diet — a high-fat, low-carbohydrate (low-sugar) diet which helps to control seizures in some epileptic patients — can change the frequency of seizures and the rate of mortality.

Mice were continuously recorded on video to monitor for spontaneous seizures and sudden deaths. The recordings showed that SUDEP and spontaneous seizures happened more often during the early evening.

CURE Discovery: Safe, Quick Measurement in Epilepsy Monitoring Units (EMUs) Has Potential To Identify SUDEP Risk

When the body detects high carbon dioxide (CO2) levels in the blood, a condition known as hypercapnia, it responds by moving more air through the lungs. This increased ventilation helps remove the excess CO2. Research by CURE grantee Dr. Rup K. Sainju and his team at the University of Iowa shows that this response may be weakened in some people with drug-resistant epilepsy, which puts them at an increased risk for severe breathing abnormalities and Sudden Unexpected Death in Epilepsy (SUDEP) following a generalized convulsive seizure.

For their CURE-funded project, Dr. Sainju’s team conducted a study in adults with drug-resistant epilepsy who were admitted to the epilepsy monitoring unit (EMU) at the University of Iowa. In addition to comprehensive heart and breathing monitoring, the team measured the hypercapnic ventilatory response (HCVR) in each patient.1,2 The HCVR measurement evaluates how the body responds to increased blood CO2levels. A low HCVR indicates a poor or weakened ability to remove CO2 from the body.

Epilepsy Monitoring Unit

The study found that patients who had a low HCVR were more likely to have severe breathing abnormalities and a longer period of high, potentially dangerous CO2 levels in the blood after a generalized convulsive seizure. Long-term follow-up revealed one of the patients in the study with the third lowest HCVR passed away of SUDEP 11 months after the study.2

Importantly, this is the first time HCVR has ever been studied in patients with epilepsy. The team demonstrated that an HCVR measurement can be conducted in the EMU rapidly and safely.2 The team also reported that the HCVR measurement was well tolerated by the patients.2

Building on their work, Dr. Sainju’s team also conducted a CURE-funded pilot study to determine if the drug fluoxetine, more commonly known as Prozac, could increase HCVR and reduce seizure-related breathing abnormalities. Fluoxetine increases the availability of serotonin in the brain and there is evidence that the serotonin system increases ventilation in response to hypercapnia. Drugs similar to fluoxetine have been safely tested in mice and humans and shown to increase HCVR. The team hypothesized that giving fluoxetine to patients who have a low HCVR would improve the body’s ability to sense high CO2 levels and reduce post-seizure breathing abnormalities. The team has finished this study, which shows that patients completed it with good adherence. We are eager to see their final analysis.

Dr. Sainju’s study suggests that HCVR is a key measurement which may be useful in predicting the risk of breathing abnormalities and SUDEP. It can be easily and rapidly performed in the EMU with minimal discomfort to people with epilepsy. Future studies will build on this work, analyzing the usefulness of HCVR as a biomarker for SUDEP. Having demonstrated the feasibility of a randomized trial of fluoxetine versus placebo to improve HCVR, the team plans to continue studying fluoxetine and other therapeutic targets.

1 Gehlbach BK et. al. Tolerability of a comprehensive cardiorespiratory monitoring protocol in an epilepsy monitoring unit. Epilepsy Behav. 2018 Aug;85:173-176.
2 Sainju R.K. et. al. Ventilatory response to CO2 in patients with epilepsy. Epilepsia. 2019 Mar;60(3):508-517.
3 Hodges MR, Richerson GB. Medullary serotonin neurons and their roles in central respiratory chemoreception. Respir Physiol Neurobiol. 2010 Oct 31;173(3):256-63.

Epilepsy Research Findings: April 2019

This month’s news features technological advances that may make seizure detection more reliable and surgery for intractable epilepsy more accurate, while also deepening our understanding of how epilepsy arises in a healthy brain.

In other news, important research on Sudden Unexpected Death in Epilepsy (SUDEP) highlighted the association between SUDEP and change in tissue volume in areas of the brain important in cardiorespiratory function, as well as the lack of understanding about SUDEP among people with epilepsy and their relations.

In addition, we spotlight a recent statement by the FDA reporting that some people, mainly youth and young adults, who use e-cigarettes are experiencing seizures, as well as a recent TEDx Talk about how artificial intelligence may be used to help prevent SUDEP.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

First Clinical Trial of Reformulated Antiepileptic Drug to Treat Medically Refractory Epilepsy
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An approved antiepileptic drug used to treat seizures has been modified and is currently being used in an Australian clinical trial for medically refractory epilepsy. The trial tests a proprietary, reformulated, specialty pharmaceutical, which bypasses the blood-brain barrier using a chronic implantable infusion system.

Multicenter Clinical Study of Long-Term Brivaracetam Use Finds It Effective and Well-Tolerated in Patients with Drug-Resistant Epilepsy
Learn More

Researchers assessed long-term effectiveness and tolerability of brivaracetam in patients with focal epilepsy. According to this multicenter, retrospective study, brivaracetam was effective and well-tolerated in a large population of patients with predominantly drug-resistant epilepsy. There were no unexpected adverse side effects over 1 year. The most frequently reported adverse side effects were somnolence, irritability, and dizziness.

Diagnostic Advances

Motion Recognition Technology Assists Epilepsy Diagnosis
Learn More

Motion recognition technology is being used to help neurologists study patients’ behavior during seizures. They hope to get clues on the sub-type of epilepsy the patient has and identify unusual seizure movements requiring further investigation.

Model Developed to Help Identify Patients Who Will Not Experience Remission Again After Breakthrough Seizures
Learn More

A model has been created to help identify people with epilepsy who are unlikely to regain seizure remission within 2 years after experiencing a breakthrough seizure following an initial 12-month remission. Researchers note that their model is a useful first step in developing a tool for identifying patients who develop drug resistance after an initial remission.

Research Discoveries

Potential Biomarkers of Cardiac Stress After Generalized Convulsive Seizures Identified
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The measurement of certain substances in the blood, such as the protein high-sensitive troponin T and the peptide copeptin, may be helpful as biomarkers to identify cardiac stress after generalized convulsive seizures in patients with refractory epilepsy, according to study results published in Epilepsia.

SUDEP Associated with Tissue Volume Change in Brain Areas Important in Cardiorespiratory Recovery
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In a retrospective imaging study of SUDEP cases, researchers found that people who passed away due to SUDEP show significant tissue loss in areas of the brain essential for cardiorespiratory recovery. They also found enhanced volumes in areas that trigger hypotension or impede respiratory patterning. According to the study, these changes in brain tissue may shed light on the mechanisms of SUDEP and help detect patterns to identify those at risk for SUDEP.

Literature Review Shows That There is a Lack of Understanding of SUDEP for People with Epilepsy and Their Relations
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A comprehensive electronic search of peer-reviewed qualitative studies showed an overall lack of understanding about unexpected epilepsy-related death among people with epilepsy and their relations. The authors conclude that it would be appropriate and necessary to discuss SUDEP with patients and their family members upon diagnosis.

Also Notable

Some E-cigarette Users Are Having Seizures; Most Reports Involving Youth and Young Adults
Learn More

The FDA has become aware that some people who use e-cigarettes have experienced seizures, with most reports involving youth or young adult users. A recent uptick in voluntary reports of adverse events with tobacco products that mentioned seizures occurring with e-cigarette use (e.g., vaping) signal a potential emerging safety issue, according to the FDA.

New TEDx Talk Issues Call to Action for SUDEP
Learn More

Every year worldwide, more than 50,000 otherwise healthy people with epilepsy suddenly die — a condition known as SUDEP. These deaths may be largely preventable, says artificial intelligence researcher Rosalind Picard. Learn how Picard helped develop a cutting-edge smartwatch that can detect epileptic seizures before they occur and alert nearby loved ones in time to help.

Laser Light Examines How Epilepsy Arises in the Healthy Brain
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Scientists have developed a new method to study how seizures arise in healthy brains. Using laser light guided through ultra-thin optic fibers in rodent brains, the researchers “turned on” light-sensitive proteins in selective brain cells and were able to eventually cause seizures through repeated laser stimulation.

Developing a Universal Automated Tool for Reliable Seizure Detection in Rodent Models of Acquired and Genetic Epilepsy
Learn More

The development of an automated tool for reliable seizure detection has the potential to improve the efficiency and rigor of preclinical research and therapy development for rodent models of acquired and genetic epilepsy, according to research published in Epilepsia.

Robotics Makes Intractable Epilepsy Surgery More Accurate
Learn More

Patients with intractable epilepsy who had a minimally invasive surgery evaluation procedure called robotic stereoelectroencephalography (SEEG) experienced fewer complications, according to a study published in JAMA Neurology. Those who went on to have brain surgery were more likely to be seizure-free than patients who had the more invasive evaluation procedure.

New TEDx Talk Issues Call to Action for SUDEP

Every year worldwide, more than 50,000 otherwise healthy people with epilepsy suddenly die — a condition known as SUDEP. These deaths may be largely preventable, says AI researcher Rosalind Picard. Learn how Picard helped develop a cutting-edge smartwatch that can detect epileptic seizures before they occur and alert nearby loved ones in time to help.

This talk was presented to a local audience at TEDxBeaconStreet, an independent event. TED’s editors chose to feature it for you.

CURE Discovery: Using Patient-Specific Cardiac Cells to Predict SUDEP Risk

CURE-funded researchers are using a novel technique to discover ways to predict patients at an increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Lori Isom, her team, and co-investigator Dr. Jack Parent at the University of Michigan are transforming skin cells from patients with developmental and epileptic encephalopathy (DEE) syndromes into induced pluripotent stem cells (iPSCs). The team then generates cardiac cells from the iPSCs which retain the patients’ exact genetic information. These unique, patient-specific cardiac cells are used as models to understand if DEE-associated genes play a role in causing heart abnormalities which may lead to SUDEP. The team also hopes to develop measurable indicators, known as biomarkers, of SUDEP risk.

Severe DEE syndromes, such as Dravet syndrome, are associated with a high incidence of SUDEP. It is estimated that up to 20% of patients with Dravet syndrome die from SUDEP.1 There is still much to be understood about the mechanisms of SUDEP and how to predict who is at risk for it.

Dravet syndrome and other DEEs are often associated with variants in genes, such as SCN1A, SCN1B, and SCN8A. These genes provide instructions to make sodium ion channels, which are very important proteins that help brain cells transmit electrical signals. The same genes are also expressed in the heart; thus, the team hypothesizes that any variants in these genes that disrupt electrical signaling in the brain would affect normal electrical function of the heart as well. In support of this hypothesis, the investigators’ previous work in mouse models of Dravet syndrome and DEEs showed that these mice exhibited irregular heartbeat, which in some cases preceded SUDEP-like events.2-4

In this CURE-funded project, the investigators expanded upon their previous work by testing their hypothesis in heart muscle cells called cardiac myocytes, generated in the laboratory from skin cells of patients with Dravet syndrome or other DEEs using iPSC technology. This Nobel Prize-winning technology involves obtaining skin or blood cells from patients and converting them to iPSCs. These are stem cells that can be converted into almost any specialized cell type in the body, such as heart, muscle, pancreatic, or neuronal cells. The cells are patient-specific, meaning they retain the unique genetic make-up of the patient they originated from, allowing investigators to study cell types which would otherwise be very difficult or impossible to obtain from a living patient.

Dr. Isom, Dr. Parent, and their colleagues previously used iPSC technology to generate heart muscle cells from four patients with variants in the SCN1A gene and found increased sodium currents and spontaneous contraction rates in these cells, suggesting cardiac electrical dysfunction.5 Cardiac abnormalities were subsequently found in the patient with the highest increase in sodium current.5 These data suggest that iPSC-cardiac cells may be useful models for identifying and developing biomarkers, such as increased sodium current, as indicators of SUDEP risk.

The investigators used the same technique to study variants in the SCN1B and SCN8A genes. The team observed that iPSC-cardiac myocytes derived from a patient with SCN1B Dravet syndrome had increased sodium currents similar to those seen in iPSC-cardiac myocytes from the patient with SCN1A Dravet syndrome, suggesting that variants in these two different genes could cause heart abnormalities through similar mechanisms. Preliminary data in iPSC-cardiac myocytes from patients with DEE caused by variants in SCN8A, suggest that these cells have altered beating rates but no change in sodium current, which is aligned with their observations in a mouse model with a variant in SCN8A.

Taken together, these results reveal mechanisms by which different epilepsy-related genes can affect heart function and SUDEP. Future research will investigate the impact of variants of a specific non-ion channel gene to see if it causes altered cardiac beating. Patient-specific iPSC cardiac myocytes are a very useful model to study SUDEP mechanisms and could be developed as diagnostic biomarkers to identify SUDEP risk in patients.

1 Cooper MS et al. Mortality in Dravet Syndrome. Epilepsy Res. 2016 Dec; 128:43-47.
2 Auerbach DS et al. Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome. PLoS One. 2013;8(10).
3 Lopez-Santiago LF et al. Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. J Mol Cell Cardiol. 2007;43(5):636-47.
4 Frasier CR et al. Cardiac arrhythmia in a mouse model of SCN8A Epileptic Encephalopathy. Proc Natl Acad Sci U S A. 2016; in press.
5 Frasier CR et al. Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient Derived Cardiac Myocytes. Stem Cell Reports. 2018 Sep 11;11(3):626-634.

Literature Review Shows There is a Lack of Understanding of SUDEP for People with Epilepsy and Their Relations

People with epilepsy (PWE) have a two- to threefold increased chance of premature death due to the condition. Interested in exploring the first-person perspective on this topic, researchers conducted a narrative synthesis to present the qualitative insight of PWE, their family, friends, and healthcare providers (HCPs) in relation to epilepsy-related death.

A comprehensive electronic search of all peer-reviewed qualitative studies was conducted through databases using relevant keywords and Medical Subject Headings (MeSH) terms. Handsearching and exploration of pertinent gray literature was conducted thereafter. After a comprehensive literature search, the decisions of inclusion of literature were discussed and confirmed between the two authors. A total of 20 peer-reviewed papers were included. Within this, 17 were qualitative or mixed methods studies, and three were gray literature and guidelines/recommendations in discussing sudden unexpected death in epilepsy (SUDEP) with PWE and their families. The resultant main categories were the following: a) understanding of SUDEP and b) discussion of SUDEP.

Findings show that there is an overall lack of understanding of unexpected epilepsy-related death for people with epilepsy and their relations. The literature focused on the education of PWE and their family in relation to SUDEP, and therefore, there is a lack of discussion on the general topic of epilepsy-related death. Findings show the conflicting perceptions, feelings, and thought processes that occur in learning about and deciding to discuss SUDEP as a healthcare provider, person with epilepsy, or family/friend of a person with epilepsy. The literature suggests that it would be appropriate and necessary to discuss the topic of SUDEP with patients and their family members upon diagnosis.

Sudden Unexpected Death in Epilepsy Associated with Tissue Loss in Brain Areas Important in Cardiorespiratory Recovery

Objective: The processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk.

Methods: Researchers retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high-risk (n = 25) or low-risk (n = 23), and age- and sex-matched healthy controls (n = 25) with identical high-resolution T1-weighted scans. Regional gray matter volume, determined by voxel-based morphometry, and segmentation-derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex.

Results: Substantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high-risk subjects and absent in low-risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High-risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high-risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging.

Significance: SUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.

CURE Discovery: Potential Genetic Link Between Epilepsy and Sudden Unexpected Death in Children

This grant is generously supported by the Isaiah Stone Foundation.

A potential link between epilepsy- and SUDEP-associated SCN1A gene variants and Sudden Infant Death Syndrome (SIDS) has been discovered by CURE Grantee Dr. Annapurna Poduri of Boston Children’s Hospital.1 Her work, generously supported by the Isaiah Stone Foundation, may provide insight into SIDS and support genetic evaluation focused on epilepsy genes in SIDS. In Dr. Poduri’s analysis of 10 infants who died of SIDS, two children were found to have disease-associated variants in the SCN1A gene. Despite finding variants in an epilepsy-related gene and hippocampal lesions that are commonly associated with temporal lobe epilepsy, these children had no history of seizures or epilepsy.

SIDS occurs when a seemingly healthy baby dies suddenly. The sudden death of a child is a tragic occurrence and even more distressing when there is no known cause. There are several categories of this type of death: SIDS if the child is less than one year old; Sudden Unexplained Death in Childhood (SUDC) if the child is greater than one year old; and Sudden Unexpected Death in Epilepsy (SUDEP) if the child has epilepsy.

These types of childhood death are traditionally thought of as separate entities and the causes behind them are largely unknown. However, by finding a link between SIDS and SCN1A mutations,2,3 Dr. Poduri and her colleagues have deepened our understanding of the potential genetic factors behind sudden death in children. This research also suggests epilepsy genes may be more widely important in cases of sudden death in children than originally thought.

In fact, as an integral part of her CURE-funded work, Dr. Poduri and her colleagues in Robert’s Program on Sudden Death in Childhood set out to understand the genetic basis of these sudden childhood deaths, with the hypothesis that there may be a common mechanism between some cases of SIDS, SUDC, SUDEP, and epilepsy. This hypothesis is based on neuropathological abnormalities seen in the hippocampal region of approximately 40% of cases with SIDS and SUDC.4

Although typically considered rare, more children die each year from Sudden Unexplained Death in Pediatrics (SUDP), a category that includes SIDS and SUDC, than from childhood cancer or heart disease.5 Understanding the reasons behind these types of death is important in understanding how to prevent them.

Besides finding variants in the SCN1A gene in two children who died of SIDS, Dr. Poduri and her colleagues also found variants in the epilepsy-related SCN1B gene in two siblings who died suddenly and unexpectedly.6 These important findings identify additional epilepsy-related genes which may underlie some cases of sudden death in children, supporting the team’s idea that there are shared mechanisms between SIDS, SUDC, and epilepsy.

In the future, Dr. Poduri and her colleagues plan to continue their analysis of potential epilepsy-associated genetic variants, which may contribute to sudden childhood death, to better understand causes of these devastating occurrences. They are hopeful their findings will apply to children with and without epilepsy who may be at risk for sudden death. Their overall goal is to identify not only genetic risk factors for SIDS and SUDC, but also other means of identifying children at risk for sudden death. This work could lay the foundation for strategies which can be systematically implemented to prevent these deaths from occurring.

1 Brownstein CA et al. SCN1A variants associated with sudden infant death syndrome. Epilepsia 2018; 59(4):e56-e62.
2 Escayg A and Golding AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 2010; 51(9):1650-1658.
3 Goldman AM. Mechanisms of sudden unexpected death in epilepsy. Curr Opin Neurol 2015; 28(2):166-174.
4 Kinney HC, Poduri A et al. Hippocampal formation maldevelopment and sudden unexpected death across the pediatric age spectrum. J Neuropathol Exp Neurol 2016. 75(10):981-997.
6 Poduri, unpublished.

Low Interictal Hypercapnic Ventilatory Response May Increase the Risk of Severe Respiratory Depression and SUDEP After Generalized Convulsive Seizures

Featuring work by CURE Grantee Dr. Rup K. Sainju

Objective: Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO2 (hypercapnic ventilatory response [HCVR] or central respiratory CO2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs).

Methods: Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (VE), tidal volume, respiratory rate, end tidal (ET) CO2 and O2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope for each subject was determined by linear regression. During the video–electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO2, and capillary oxygen saturation (SPO2).

Results: Sixty-eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from 0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO2. Both the duration and magnitude of postictal tcCO2 rise following GCSs were inversely correlated with HCVR slope.

Significance: Measurement of the hypercapnic ventilatory response is well tolerated and can be performed rapidly and safely at the bedside in the epilepsy monitoring unit. A subset of individuals has a very low sensitivity to CO2, and this group is more likely to have a prolonged increase in postictal CO2 after generalized convulsive seizures. Low interictal hypercapnic ventilatory response may increase the risk of severe respiratory depression and SUDEP after generalized convulsive seizures and warrants further study.