Sudden Death Among Children with Epilepsy: 4x More Likely than Previously Thought

1.11 out of 1,000 children with epilepsy die suddenly each year, according to a Canadian study by CURE grantee Dr. Elizabeth Donner of the University of Toronto. (1) Dr. Donner’s estimates confirm 2017 results garnered from the Swedish National Death Registry that also found the annual rate of sudden death to be 1.11 per 1,000 children with epilepsy. (2)

Both of these recent studies are in contrast to previous estimates which showed that Sudden Death in Epilepsy (aka SUDEP) affects 1 in 4,500 children with epilepsy each year. (3)

Dr. Donner has spent much of her career identifying and studying cases of SUDEP to determine how often sudden death occurs in children with epilepsy and who is at risk. A recipient of CURE’s 2009 Sudden Unexpected Death in Epilepsy Award, Dr. Donner set out to create a Canadian pediatric SUDEP registry in collaboration with the Canadian Paediatric Surveillance Program, with the goal of obtaining data on every child with a sudden death and epilepsy.

Dr. Donner hopes that this increased understanding of how many children are affected by SUDEP will lead to the identification of risk factors. She aims to save lives by understanding which children with epilepsy are most at-risk, so that therapies can be developed to prevent sudden death.

Although there is currently no known ‘cure’ for SUDEP, the efforts of Dr. Donner and her team have increased understanding about this devastating consequence of epilepsy. Through the work of dedicated researchers like Dr. Donner, we may soon be able to not only identify those that are at risk for SUDEP but also offer ways to prevent SUDEP from occurring at all.

1 – Keller AE et al. Incidence of sudden unexpected death in epilepsy in children is similar to adults. Neurology 2018; 91(2):e107-e111.
2 – Sveinsson O et al. The incidence of SUDEP: A nationwide population-based cohort study. Neurology 2017; 89(2): 170-177.
3 – Harden C et al. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2017; 88(17):1674-1680.

Supervision and Bathing Precautions Could Be Effective Strategies at Preventing Death in People with Epilepsy Found in Dead Water

OBJECTIVE: Both drowning and sudden unexpected death in epilepsy (SUDEP) are diagnoses of exclusion with predominantly nonspecific autopsy findings. We hypothesized that people with epilepsy found dead in water with no clear sign of submersion could be misdiagnosed as SUDEP.

METHODS: All reported seizure-related deaths undergoing medicolegal investigation in three medical examiner’s offices (New York City, Maryland, San Diego County) over different time periods were reviewed to identify epilepsy-related drownings and SUDEPs. Drowning cases that fulfilled inclusion criteria were divided into two groups according to the circumstances of death: definite drowning and possible drowning. The SUDEP group included two sex- and age (±2 years)-matched definite SUDEP/definite SUDEP plus cases for each drowning case.

RESULTS: Of 1346 deaths reviewed, we identified 36 definite (76.6%) and 11 possible drowning deaths (23.4%), most of which occurred in a bathtub (72.3%). There were drowning-related findings, including fluid within the sphenoid sinuses, foam in the airways, clear fluid in the stomach content, and lung hyperinflation in 58.3% (21/36) of the definite drowning group, 45.5% (5/11) of the possible drowning group, and 4.3% of the SUDEP group (4/92). There was no difference in the presence of pulmonary edema/congestion between the definite drowning group, possible drowning group, and SUDEP group. The definite drowning group had a higher mean combined lung weight than the SUDEP group, but there was no difference in mean lung weights between the possible drowning and SUDEP groups or between the possible drowning and definite drowning groups.

SIGNIFICANCE: No distinguishable autopsy finding could be found between SUDEPs and epilepsy-related drownings when there were no drowning-related signs and no clear evidence of submersion. SUDEP could be the cause of death in such possible drowning cases. As most drowning cases occurred in the bathtub, supervision and specific bathing precautions could be effective prevention strategies.

Heart Abnormalities May Trigger Sudden Unexplained Death in Epilepsy

Featuring the work of CURE Grantee Jack Parent and Lori Isom

New stem cell research reveals dangerous cardiac effects of a gene mutation in patients with Dravet syndrome

Imagine putting your child to bed, only to have them pass away inexplicably in their sleep. This is the chilling reality for many victims of sudden unexpected death in epilepsy, or SUDEP — which claims the lives of 1 in every 1,000 people with epilepsy or other seizure disorders.

Patients with a rare disease called Dravet syndrome are at heightened risk for SUDEP. In the disease, seemingly healthy infants develop frequent and prolonged seizures, catastrophically affecting their development and quality of life.

Michigan Medicine scientists have been on a quest to better understand the connection and potential ways to prevent SUDEP in this population.

Eighty percent of patients with Dravet syndrome have variants in a gene, SCN1A, which codes for Nav1.1 sodium channels in the heart and the brain. Sodium channels are like a gate that allows sodium ions across a cell membrane, producing an electrical charge.

SCN1A mutations in people with Dravet syndrome result in electrical disturbances inside cells. Although seizures are the result of abnormal electrical signals in the brain, researchers suspected that problems may arise in the heart as well.

“We had a hypothesis that since these kids have the same mutation in their sodium channels in the heart and brain, they might have cardiac arrhythmias,” says Lori Isom, Ph.D., chair of the Department of Pharmacology at Michigan Medicine. “We were able to gather evidence that they do.”

The work is published in the journal Stem Cell Reports.

Isom and her clinical colleague, Jack M. Parent, M.D., professor of neurology and co-director of the Comprehensive Epilepsy Center at U-M, first looked to mouse models and then at cells collected from children with Dravet syndrome.

Their discovery: Mutations associated with Dravet syndrome in mice led to irregularities in the heart muscle’s sodium channels.

Cardiac Pathology in SUDEP Compared With Sudden Arrhythmic or Traumatic Deaths

There does not appear to be a higher prevalence of cardiac fibrosis among patients with sudden unexpected death in epilepsy (SUDEP) compared with patients with autopsy-defined sudden arrhythmic death (SAD) or traumatic death, according to a study published in Neurology.

Using data from the Postmortem Systematic Investigation of Sudden Cardiac Death (POST SCD) study, researchers identified 541 sudden cardiac deaths among adult patients (mean age 62.8 years, 69% men). Each heart was weighed, and ventricular and atrial orthogonal dimensions were obtained. In order to compare the prevalence of cardiac fibrosis in SUDEP vs other syndromes, investigators performed quantitative cardiac fibrosis analyses on SUDEP (n=12), SAD (n=90), and trauma (n=57) cases.

In the adjusted analysis of the autopsy-defined SAD (n=285) comparison group, the researchers found that the SUDEP cases demonstrated significantly less gross and histologic evidence of cardiac pathology for coronary artery disease (P <.0024), cardiac mass (P <.0011),  interstitial cardiac fibrosis (P =.013), and total cardiac fibrosis (P =.022). The severity of interstitial cardiac fibrosis and total cardiac fibrosis was similar between SUDEP patients and trauma patients.

The overall small sample size as well as the variance in subgroup sample sizes represent substantial limitations of this analysis.

The researchers suggest that higher cardiac abnormality frequency seen in cases of SUDEP “may relate to the direct or indirect effects of seizures or antiseizure drugs on cardiac tissue, the mechanisms that cause SUDEP, or they may be unrelated to seizures, medications, or SUDEP.”

Epilepsy Research Findings: July 2018

This month’s promising epilepsy news includes the FDA approval of the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with Dravet Syndrome and Lennox-Gastaut Syndrome, two forms of epilepsy that are challenging to treat. This decision brings hope to families facing these difficult diagnoses. In addition, a report discusses epilepsy genetics and the utility of next-generation sequencing in the diagnosis of early-life epilepsies.

In more sobering news, a study shows that the incidence of Sudden Unexpected Death in Epilepsy (SUDEP), once thought to be greater in adults than in children, may be the same in both populations. However, we have included a report discussing the recent discovery of a potential biomarker for SUDEP, which could lead to preventative measures for this devastating occurrence.

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 Prescription Formulation of Cannabidiol (CBD) Approved for Lennox-Gastaut Syndrome 

The US Food and Drug Administration (FDA) approved EPIDIOLEX® (cannabidiol/CBD) for the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients two years of age or older. EPIDIOLEX® is the first prescription pharmaceutical formulation of highly purified CBD and the first in its class of antiepileptic drugs.

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New Technique Fine-Tunes Treatment for Severe Epilepsy Cases 

An advance by researchers will enable surgeons to more precisely target areas of the brain which cause debilitating symptoms in a subset of epilepsy patients. The technology, called magnetoencephalography or MEG, measures small amounts of magnetic-electrical activity on the surface of epileptic brain areas, and researchers have developed a novel way to employ it.

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Treating Refractory Epilepsy with Transcutaneous Vagal Nerve Stimulation 

This study found that transcutaneous vagal nerve stimulation (t-VNS) had no or minimal side effects and significantly reduced seizures in about one third of the enrolled patients.

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Sunovion Announces Health Canada Approval of Aptiom (eslicarbazepine acetate) as Monotherapy to Treat Partial-Onset Seizures in Adults with Epilepsy

Health Canada approved the use of Aptiom (eslicarbazepine acetate) as monotherapy for partial-onset seizures in adults with epilepsy.

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Diagnostic Advances

Next-Generation Sequencing May Improve Pediatric Epilepsy Treatment

Next-generation sequencing can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy, according to a study published in CNS Neuroscience & Therapeutics.

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Prediction Method for Epileptic Seizures Developed 

Scientists have proposed a generalized, patient-specific seizure-prediction method that can alert epilepsy sufferers of the likelihood of a seizure within 30 minutes, according to a paper published in Neural Networks.

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Research Discoveries

Incidence of Sudden Unexpected Death in Epilepsy in Children is Similar to Adults

SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

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Heart Rate Variability in Epilepsy: A Potential Biomarker of Sudden Unexpected Death in Epilepsy Risk

These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of heart rate variability to SUDEP merits further study; heart rate variability may eventually have potential as a biomarker of SUDEP risk. This would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

Learn More

Also Notable

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

This study reports that levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

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Variability in Gene-Sequencing Panels Could Mean Missed Early-Life Epilepsy Diagnoses

Variability among next-generation sequencing (NGS) panels for early-life epilepsies could cause some confirmed epilepsy genes to be missed, researchers report. NGS panels have demonstrated utility for diagnosing genetic variants linked to early-life epilepsies, but little is known about the variability in genes tested among clinically available NGS panels.

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Generic Antiepileptic Drugs — Safe or Harmful in Patients with Epilepsy?

Sufficient evidence indicates that most generic antiepileptic drugs (AEDs) are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. This report recommends administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.

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Health Care Expenditures Among Elderly Patients with Epilepsy in the United States

Epilepsy is common among elderly individuals, and health care expenditures among this growing group are two times higher than in those without epilepsy.

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SUDEP and Seizure Safety Communication: Assessing if People Hear and Act

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death among people with chronic epilepsy. People with intellectual disability (ID) are overrepresented in this population. The SUDEP and Seizure Safety Checklist (“Checklist”) is a tool to discuss risk factors influencing seizures and the risk of SUDEP. It includes questions about the availability of nocturnal monitoring. In Cornwall UK, people with epilepsy and ID and their relatives and carers are routinely advised to consider nocturnal surveillance to reduce harm from potential nocturnal seizures. Researchers assessed the retention of advice provided on nocturnal monitoring and if there were differences between those in residential care and those living with their families.

METHODS: A postal questionnaire was sent to carers of all people with epilepsy and ID in Cornwall followed by the adult specialist ID epilepsy service. All those who were contacted had received the same advice on SUDEP and nocturnal monitoring at least once in the past year. Each person was categorized into living in a residential setting or with their family group. Intergroup differences were compared using Fisher’s exact test.

RESULTS: Carers for 170 people were contacted and 121 responded (71%). The family group had statistically more nocturnal seizures than the residential group. While there was no difference in the awareness of SUDEP, the groups differed in their recollection of the person-centered discussion of risk with carers in residential setting being less aware. Where nocturnal monitoring advice was given, it was followed, and previously unknown seizures were identified in 75%.

CONCLUSIONS: Carers in residential settings are less likely to recall specific person-centered discussion of risks to the individual they support as compared with those living with families although general awareness of SUDEP and implementing advice such as nocturnal monitoring is present equally in both groups. In improving detection of nocturnal seizures, audio monitoring may be a useful strategy to reduce risk of harm for people with intellectual disability.

Incidence of Sudden Unexpected Death in Epilepsy in Children is Similar to Adults

Objective: To determine the incidence of sudden unexpected death in epilepsy (SUDEP) in children in Ontario, Canada.

Methods: Cases of suspected pediatric SUDEP occurring between January 1, 2014, and December 31, 2015, in Ontario, Canada, were eligible for inclusion. Potential cases were identified through 3 sources: a national pediatrician surveillance program, child neurologist report, and screening of provincial forensic autopsies. Cases were classified as definite, definite plus, probable, possible, and near/near plus according to criteria described by Nashef et al. (Epilepsia 2012).

Overall crude pediatric SUDEP incidence and the incidence of definite or probable pediatric SUDEP were calculated using estimates of the prevalence of pediatric epilepsy in Canada drawn from government survey data and the number of children living in Ontario. Capture-recapture analysis was used to estimate the number of missing cases and determine an adjusted definite/probable SUDEP incidence.

Results: Seventeen cases of pediatric SUDEP resulted in an overall incidence of 1.17 (95% confidence interval 0.68–1.88) per 1,000 pediatric epilepsy person-years. The definite/probable incidence, including definite (n = 11), definite plus (n = 2), or probable (n = 3) SUDEP cases, was 1.11 (0.63–1.79). Capture-recapture analysis indicated an estimated 21 (16–39) definite/probable SUDEP cases occurred during the study period, giving an adjusted incidence of definite/probable SUDEP of 1.45 (0.90–2.22) per 1,000 pediatric epilepsy person-years.

Conclusion: SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

Heart Rate Variability in Epilepsy: A Potential Biomarker of Sudden Unexpected Death in Epilepsy Risk [Study Featuring the Work of CURE Grantee, Kenneth Myers]

Significance: These findings suggest that autonomic dysfunction is associated with Sudden Unexpected Death in Epilepsy (SUDEP) risk in patients with epilepsy due to sodium channel mutations. The relationship of heart rate variability to SUDEP merits further study; heart rate variability may eventually have potential as a biomarker of SUDEP risk, which would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

Objective: SUDEP is a tragic and devastating event for which the underlying pathophysiology remains poorly understood; this study investigated whether abnormalities in heart rate variability (HRV) are linked to SUDEP in patients with epilepsy due to mutations in sodium channel (SCN) genes.

Methods: We retrospectively evaluated HRV in epilepsy patients using electroencephalographic studies to study the potential contribution of autonomic dysregulation to SUDEP risk. We extracted HRV data, in wakefulness and sleep from 80 patients with drug?resistant epilepsy, including 40 patients with mutations in SCN genes and 40 control patients with non?SCN drug?resistant epilepsy. From the SCN group, 10 patients had died of SUDEP. We compared HRV between SUDEP and non?SUDEP groups, specifically studying awake HRV and sleep:awake HRV ratios.

Results: The SUDEP patients had the most severe autonomic dysregulation, showing lower awake HRV and either extremely high or extremely low ratios of sleep?to?awake HRV in a subgroup analysis. A secondary analysis comparing the SCN and non?SCN groups indicated that autonomic dysfunction was slightly worse in the SCN epilepsy group.

Wearable Devices for Sudden Unexpected Death in Epilepsy Prevention

Sudden unexpected death in epilepsy (SUDEP) is most often associated with the occurrence of generalized tonic-clonic seizures (GTCS), a seizure type that can now be detected with high sensitivity and specificity by wearable or bed devices. The recent development in such devices and their performance offer multiple opportunities to tackle SUDEP and its prevention. Reliable GTCS detection might help physicians optimize antiepileptic treatment, which could in turn reduce the risk of SUDEP. GTCS?triggered alarms can lead to immediate intervention by caregivers that are also likely to decrease the odd of SUDEP.

The biosignals used to detect GTCS might provide novel SUDEP biomarkers, in particular, by informing on several important characteristics of the ictal and postictal periods (type of GTCS duration of tonic phase, rotation in the prone position, presence and duration of postictal immobility and bradycardia, rise in electrodermal activity). Other biosensors not yet used for detecting GTCS might provide complementary information, such as the presence and intensity of ictal/postictal hypoxemia.

The above biomarkers, if strongly predictive, could help identify patients at very high risk of SUDEP, enabling better assessment of individual risk, as well as selection of appropriate patients for clinical studies aiming at preventing SUDEP. The same biosignals could also be used as ancillary biomarkers to test the impact of various interventions before moving to highly challenging randomized controlled trials with SUDEP as a primary outcome.

Findings on Bradycardia Detailed by Investigators at Veterans Affairs Medical Center (Severe Peri-Ictal Respiratory Dysfunction is Common in Dravet Syndrome)

Bradycardia are discussed in a new report. According to news reporting out of Iowa City, Iowa, by NewsRx editors, research stated, “Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms.”

A quote from the research from Veterans Affairs Medical Center: “Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1a(R1407x/+) loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death.”

According to the news editors, the research concluded: “SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia, presumably via a direct effect of hypoxemia on cardiac muscle.”