CURE Discovery: Improving Sleep

CURE Discovery: Improving Sleep with Small Environmental Changes May Decrease Seizures

Relatively small changes in environmental factors which improve the ‘internal clock’ (otherwise known as the circadian rhythm) and the quality of sleep lead to decreases in seizures in mice with similarities to Dravet syndrome, a severe form of epilepsy. These promising results are the latest findings from the lab of CURE grantee Dr. Franck Kalume of Seattle Children’s Hospital, whose grant is generously supported through the BAND Foundation.

Individuals with Dravet syndrome have problems with their circadian rhythm and with regulating their sleep.1 Upon observing that mice with similarities to Dravet syndrome have similar sleep disturbances,2 Dr. Kalume and his team set out to determine if improving circadian rhythm and sleep patterns in these mice could reduce the occurrence of seizures.

To improve circadian rhythm in the mice, the team confined either meals or exercise to nighttime, when mice are typically active. The team limited these activities during the day, when mice typically sleep. As a result of these simple changes, the team found that the mice became more active at night and less active during the day, an indication of improved circadian rhythm. The mice also showed improvements in the quality of their sleep.

Significantly, restricting these activities to nighttime led to a decrease in the incidence of irregular brain activity that is characteristic of an epileptic brain, an indication that improvements in sleep practices may improve epilepsy.

Dr. Kalume and his team next plan to confine both exercise and meals to nighttime to see if this leads to an even greater reduction of seizures. They also plan to determine the effect of these changes on the risk of sudden death in these mice, as these mice and humans with Dravet syndrome are more susceptible to Sudden Unexpected Death in Epilepsy (SUDEP).

These important results contribute to our understanding of the relationship between sleep and epilepsy and provide hope for the development of new therapies to improve epilepsy outcomes. Dr. Kalume and his team hope these studies will lead to practical steps not involving medication that individuals with epilepsy can take to improve their circadian rhythm and sleep to reduce seizures and the risk of SUDEP.

1 Licheni SH et al. Sleep problems in Dravet syndrome: a modifiable comorbidity. Dev Med Child Neurol 2018; 60(2):192-198.
2 Kalume F et al. Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome. Neurobiol Dis. 2015; 77: 141-54.

NightWatch

High-Tech Bracelet Detects Night-Time Epilepsy Seizures

A new high-tech bracelet, developed by scientists from the Netherlands, detects 85 percent of all severe night-time epilepsy seizures. That is a much better score than any other technology currently available.

The researchers involved think that this bracelet can reduce the worldwide number of unexpected night-time fatalities in epilepsy patients.

SUDEP, sudden unexpected death in epilepsy, is a major cause of mortality in epilepsy patients. People with an intellectual disability and severe therapy resistant epilepsy, may even have a 20 percent lifetime risk of dying from epilepsy.

For the sake of comparison, the current detection standard, a bed sensor that reacts to vibrations due to rhythmic jerks, was tested at the same time. This signaled only 21 percent of serious attacks. On average, the bed sensor therefore remained unduly silent once every four nights per patient.

The Nightwatch, on the other hand, only missed a serious attack per patient once every 25 nights on average. Furthermore, the patients did not experience much discomfort from the bracelet and the care staff were also positive about the use of the bracelet.

Epilepsy Society, UCL, and Congenica Join Forces in Genomic Study to Identify Causes of Unexpected Deaths in Epilepsy

Congenica announced a key partnership with the UK’s Epilepsy Society to study the genomics of sudden unexpected death in epilepsy (SUDEP). The new collaboration aims to improve the clinical understanding, prediction and treatment of the devastating and unpredictable condition, which affects approximately 1 in 1,000 adult and 1 in 4,500 pediatric patients with epilepsy every year.

SUDEP, which often occurs while epilepsy patients are asleep, is thought to be caused by a complex interaction of genetic factors rather than a single gene. As part of the partnership, an initial joint study will look at a cohort of 100 SUDEP clinical cases to better understand the condition’s underlying genetic causes. The multi-disciplinary research team will include scientists from the Epilepsy Society and members of Prof Sanjay Sisodiya’s clinical research team at UCL (University College London), alongside Congenica’s clinical scientists.

Acid Reflux Induced Laryngospasm as a Potential Mechanism of Sudden Death in Epilepsy

Objective: Recent research suggests that obstructive laryngospasm and consequent respiratory arrest may be a mechanism in sudden unexpected death in epilepsy. We sought to test a new hypothesis that this laryngospasm is caused by seizures driving reflux of stomach acid into the larynx, rather than spontaneous pathological activity in the recurrent laryngeal nerve.

Approach: We used an acute kainic acid model under urethane anesthesia to observe seizure activity in Long?Evans rats. We measured the pH in the esophagus and respiratory activity. In a subset of experiments, we blocked acid movement up the esophagus with a balloon catheter.

Main results: In all cases of sudden death, terminal apnea was preceded by a large pH drop from 7 to 2 in the esophagus. In several animals we observed acidic fluid exiting the mouth, sometimes in large quantities. In animals where acid movement was blocked, sudden deaths did not occur. No acid was detected in controls.

Significance: The results suggest that acid movement up the esophagus is a trigger for sudden death in KA induced seizures. The fact that blocking acid also eliminates sudden death implies causation. These results may provide insight to the mechanism of SUDEP in humans.

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. We 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.

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.

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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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