CURE Discovery: Potential Target Area in the Brain for Prevention of Epilepsy-Related Sudden Death

An area of the brain known as the amygdala may be critical in the conscious control of breathing, making it an important target area for research into epilepsy-related sudden death, according to a study recently published by CURE Grantee Dr. William Nobis of Northwestern University Feinberg School of Medicine.1 As part of a team led by Dr. Christina Zelano, also of Northwestern University, Dr. Nobis found that stimulation of the amygdala consistently induced apnea, or disrupted breathing, in a group of individuals with temporal lobe epilepsy. This finding is significant because it points to a possible role of the amygdala in what may be the most severe epilepsy-related complication, Sudden Unexpected Death in Epilepsy (SUDEP).

SUDEP occurs when a seemingly healthy person with epilepsy dies for no obvious reason,2 most often at night or during sleep. While research suggests that several factors including respiratory and cardiac dysfunction contribute to SUDEP,3,4 the precise biological processes remain unknown. By implanting electrodes into the brains of seven patients undergoing surgical evaluation for temporal lobe epilepsy, Dr. Nobis and his team were able to pinpoint specific regions of the amygdala that are important in controlling respiration, identifying areas possibly important in the cessation of respiration that characterizes SUDEP. Furthermore, the team found that by instructing patients to inhale during an apnea-inducing stimulation of the amygdala, they were able to prevent apnea providing an area upon which to focus development of therapeutic strategies to prevent SUDEP.

With funding from CURE, Dr. Nobis is now pushing this research to uncover the mechanisms behind SUDEP even further. He and his team think that the amygdala may be activated during seizures, causing it to lead to cessation of respiration and SUDEP. By using a genetic animal model of epilepsy that has a high rate of SUDEP, the team hopes to identify and examine the specific neurons within the amygdala that project to important respiratory centers in other parts of the brain, allowing the amygdala to influence respiratory function – and the loss of respiratory function that occurs in SUDEP.

Early results from Dr. Nobis’s current CURE project have begun to identify populations of neurons in the amygdala that project to areas of the brain important in respiration. The team next plans on examining how these neurons are activated in response to seizures, and how changes in the excitability of these neurons might correspond with changes in respiratory function that could lead to SUDEP.

In the future, Dr. Nobis hopes to be able to determine whether it is possible to target this subset of neurons within the amygdala to prevent SUDEP from occurring, providing a large step forward for SUDEP research and possible therapies for SUDEP prevention. Thanks to CURE-funded researchers like Dr. Nobis, we are moving closer to being able to eliminate the sudden and devastating death of individuals with epilepsy.

1 Nobis WP et al. Amygdala-stimulation-induced apnea is attention and nasal-breathing dependent. Ann Neurol 2018; 83(3):460-471.
2 Nashef. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997; 38(11 Suppl):S6-8.
3 Surges et al. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms. Nat Rev Neurol 2009; 5(9):492-504.
4 Bagnall et al. Genetic basis of sudden unexpected death in epilepsy. Front Neurol 2017; 8:348.

Study: Resolving Ambiguities in SUDEP Classification

Objective: To examine the consistency of applying the Nashef et al (2012) criteria to classify sudden unexpected death in epilepsy (SUDEP).

Methods: We reviewed cases from the North American SUDEP Registry (n = 250) and Medical Examiner Offices (n = 1301: 698 Maryland, 457 New York City, 146 San Diego). Two epileptologists with expertise in SUDEP and epilepsy?related mortality independently reviewed medical records, scene investigation, autopsy, and toxicology and assigned a SUDEP class.

Results: Major areas of disagreement arose between adjudicators concerned differentiating (1) Definite SUDEP Plus Comorbidity from Possible SUDEP and (2) Resuscitated (Near) SUDEP from SUDEP. In many cases, distinguishing between contributing and competing causes of death when trying to classify Definite SUDEP Plus Comorbidity versus Possible SUDEP is ambiguous and relies on judgement. Similarly, determining if an intervention was lifesaving or not (Resuscitated SUDEP or Not SUDEP), or if resuscitation merely delayed SUDEP (Resuscitated SUDEP or SUDEP) is often a judgement call and can differ between experienced adjudicators. Given these persisting ambiguities, we propose more explicit criteria for distinguishing these categories.

Significance: Accurate and consistent classification of cause of death among individuals with epilepsy remains a dire public health concern. SUDEP is likely underestimated in national health statistics. Greater standardization of criteria among epilepsy researchers, medical examiners, and epidemiologists to determine cause and classify death will lead to more accurate tracking of SUDEP and other epilepsy?related mortalities.

Study: Decreasing the Risk of SUDEP – Structured Communication of Risk Factors for Premature Mortality in People with Epilepsy

Conclusion: Structured discussion results in behavioural change which reduces individual risk factors. This impact seems higher in those who are at higher risk currently. It is important clinicians share risk information with individuals as a matter of public health and health promotion.

Background: Good practice guidelines highlight the importance of making people with epilepsy aware of the risk of premature mortality in epilepsy particularly due to Sudden Unexpected Death in Epilepsy (SUDEP). The SUDEP and Seizure Safety Checklist (“Checklist”) is a structured risk communication tool used in UK clinics. It is not known if sharing structured information on risk factors allows individuals to reduce SUDEP and premature mortality risks.

Aim: To ascertain if the introduction of the Checklist in epilepsy clinics lead to individual risk reduction.

Method: The Checklist was administered to 130 consecutive people with epilepsy attending an epilepsy specialised neurology clinic and 129 attending an Intellectual Disability epilepsy clinic within a 4 month period. At baseline, no attendees at the neurology clinic had received formal risk advice while all attending the ID clinic had on multiple occasions for six years. A year later the Checklist was re?administered to each group and scores were compared with baseline and between groups.

Results: Of 12 risk factors considered there was an overall reduction in mean risk score for the general population (p=0.0049) but not for the ID population (p=0.322). Sub analysis of 25% at most risk of both populations showed both sets had a significant reduction in risk scores (p<0.001).

Study: Cardiac Arrhythmia and Neuroexcitability Gene Variants in Resected Brain Tissue from Patients with Sudden Unexpected Death in Epilepsy (SUDEP)

[Researcher’s] data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.

Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown, but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction.

Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including ARRB2, ITPR1, GABRR2, SSTR5, GRIK1, CTNAP2, GRM8, GNAI2 and GRIK5. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including KCNMB1, KCNIP1, DPP6, JUP, F2, and TUBA3D, which were not present in living epilepsy controls.

Study: Cardiac Arrhythmia and Neuroexcitability Gene Variants in Resected Brain Tissue from Patients with Sudden Unexpected Death in Epilepsy (SUDEP)

[Researcher’s] data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.

Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown, but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction.

Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including ARRB2, ITPR1, GABRR2, SSTR5, GRIK1, CTNAP2, GRM8, GNAI2 and GRIK5. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including KCNMB1, KCNIP1, DPP6, JUP, F2, and TUBA3D, which were not present in living epilepsy controls.

Prof. Ley Sander Discusses Preventing SUDEP and How to Build Research Around SUDEP: Video from CURE Frontiers in Research Seminar Series

Video is available from the CURE Frontiers in Research Seminar Series talk given by Professor Ley Sander, discussing SUDEP prevention and research.

Talk summary: Individuals with epilepsy, particularly those with uncontrolled epilepsy, are at a much greater risk of premature death than those without. In fact, the standardized mortality ratio in those with epilepsy is between 2 and 3. In the UK, the most common cause of epilepsy-related death is due to Sudden Unexpected Death in Epilepsy (SUDEP), which accounts for up to one-fifth of deaths in some series. SUDEP is more common in those with frequent convulsive seizures (particularly nocturnal seizures) and in those with drug-resistant epilepsy. While the causes of SUDEP are unknown, the most commonly suggested underlying mechanisms are cardiac arrhythmias, respiratory depression and “cerebral shutdown.” Because no preventative measures currently exist, an understanding of SUDEP risk factors, potential mechanisms and the effectiveness of preventative measures is essential. To this end, there are a multitude of opportunities available in the field of SUDEP research and these opportunities will be interactively discussed during the presentation.

National Association of Medical Examiners position paper: Recommendations for the investigation and certification of deaths in people with epilepsy

Sudden unexpected death of an individual with epilepsy can pose a challenge to death investigators, as most deaths are unwitnessed, and the individual is commonly found dead in bed. Anatomic findings (eg, tongue/lip bite) are commonly absent and of varying specificity, thereby limiting the evidence to implicate epilepsy as a cause of or contributor to death. Thus it is likely that death certificates significantly underrepresent the true number of deaths in which epilepsy was a factor.

To address this, members of the National Association of Medical Examiners, North American SUDEP Registry, Epilepsy Foundation SUDEP Institute, American Epilepsy Society, and the Centers for Disease Control and Prevention constituted an expert panel to generate evidence-based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of autopsy and toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance of epilepsy-related deaths.

The recommendations provided in this paper are intended to assist medical examiners, coroners, and death investigators when a sudden unexpected death in a person with epilepsy is encountered.

Call for Abstracts: 2018 PAME Conference

The fourth Partners Against Mortality in Epilepsy (PAME) conference will take place June 14-16 in Alexandria, VA. The conference brings together healthcare providers, researchers, public health officials, patient advocates, caregivers, families, and patients living with epilepsy. This diverse group of stakeholders will focus on the shared goal of improving our understanding of mortality in epilepsy, including Sudden Unexpected Death in Epilepsy (SUDEP). The call for abstracts is now open.

DEADLINE

  • All abstracts must be submitted by 11:00 PM EST on Monday, March 19, 2018.

ELIGIBILITY 

  • Abstracts will be considered from all investigators doing epidemiological, basic, translational or clinical research on any aspect of mortality in epilepsy.
  • All submitted abstracts will be reviewed and all accepted abstracts will be presented as posters.

ABSTRACT SELECTION CRITERIA AND PROCESS

  • Abstracts may include basic, translational or applied (clinical) research, patient-oriented research, and health services, epidemiological, behavioral, or social sciences research.
  • Novel and innovative posters are encouraged, though submissions must be based on sound principles of rigorous research.
  • All abstracts should address an appropriate and relevant topic of scientific discussion. Presentations should not include commercial messages or inappropriate references to specific products, services, or commercial concerns.
  • Abstracts will be judged by an Abstract Selection Committee based on the appropriateness and rigor of research methodology, use of reliable quantitative or qualitative data, analytical strength and depth; and the overall quality of the science and scientific impact (e.g., significance, translational potential, and/or innovation).

SUBMISSION GUIDELINES AND GENERAL INFORMATION

  • All abstracts must be submitted through the PAME site.
  • The presenting author should be the first author of the abstract. The presenting author can submit one poster on which they are first author and can be a co-author on other poster submissions.
  • All abstract submissions are final; no changes or modifications will be permitted.
  • Posters will be displayed at the PAME Conference, which will be held June 14-16, Details about your dedicated author time will be included in your confirmation letter.
  • Those selected for poster presentations will be provided with a standard (4-foot by 8-foot) poster board to display their poster.

MicroRNAs as Biomarkers Clinical Trial: Circulating microRNAs as Biomarkers of RESPIratory Dysfunction in Patients With Refractory epilePSY (MIRESPILEPSY)

Sudden and unexpected death in epilepsy (SUDEP) has become a major issue for patients with epilepsy and their physicians. SUDEP is a nontraumatic and non-drowning death in patients with epilepsy, unrelated to a documented status epilepticus, in which postmortem examination does not reveal a toxicologic or anatomic cause of death. It primarily affects young adults with drug-resistant epilepsy, with an incidence of about 0.5%/year. A recent study reported that up to 20% of patients with childhood onset drug resistant epilepsy will die of a SUDEP by the age of 45. Apart from optimizing antiepileptic drugs, no preventive treatment is available to prevent SUDEP. As underscored by the World Health Organization (WHO), there is an urgent need to develop specific therapeutic approaches to tackle this issue.

The primary objective of the proposal is to evaluate the diagnostic value of a set of circulating microRNAs pre-selected because of their implication in the regulation of molecular pathways involved in the respiratory regulation to identify patients with seizure-related respiratory dysfunction, as defined by occurrence ictal/peri-ictal pulse oxymetry < 90%.

A total of 50 patients will be included over a period of one year. Patients undergoing long-term video-EEG/SEEG monitoring will be recruited in the epilepsy monitoring unit of the Department of Functional Neurology and Epileptology, Hospices Civils de Lyon, Lyon, France.

It will be a case-control study in a cohort of patients with drug-resistant focal epilepsy undergoing long-term video-EEG monitoring, in which patients who demonstrate ictal/post-ictal hypoxemia (cases) will be compared with those without seizure-related respiratory dysfunction (controls).

Elibibility Criteria

Inclusion Criteria

For the patients:

  • Adult patient (? 18 years) suffering from drug-resistant focal epilepsy or from drug-resistant generalized epilepsy according to ILAE classification
  • Patient undergoing long-term video-EEG monitoring in Epilepsy unit of Lyon to record and characterize her/his seizure
  • Patient who gave her/his written informed consent to participate to the study
  • Patient affiliated to the French health care system

 

For the healthy volunteers:

  • Adult (? 18 years)
  • Without history of neurological disorders and/or psychiatric disorders, and/or general medical disorders
  • Subject who gave her/his written informed consent to participate to the study
  • Subject affiliated to the French health care system

 

Exclusion Criteria

For the patients:

  • Ongoing major depressive episode as defined by a score ? 15 at the French version of the NDDI-E scale*
  • Current panic disorder as defined by a score ? 7 at the French version of the GAD-7 scale*
  • Ongoing treatment with selective serotonin reuptake inhibitor
  • Patient who benefit from a protective measure

 

For the healthy volunteers:

  • Presence of the symptoms of anxiety and/or depression as defined by a score ? 11 at the French version of the Hospital Anxiety and Depression Scale (HADS)
  • Ongoing treatment with selective serotonin reuptake inhibitor
  • Subjects with these psychiatric comorbidities and/or treatment will be excluded in order to limit risk that the relation previously reported between miR-135a, miR-16, miR-1202 and depression and/or panic disorder and/or response to selective serotonin

Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy

A total of 40,443 patients with vagus nerve stimulation (VNS) therapy were followed up to 10 years post-implantation, accumulating 277,661 person-years of follow-up. There were 3,689 deaths, including 632 SUDEP, with 84% classified as possible and 16% as probable or definite. Age-adjusted SUDEP rates decreased significantly over time (by over 30%) from years 1-to-2 to years 3-to-10.

Several mechanisms could account for these findings including attrition and natural evolution, aging, changes in medications or medical practice over time, or VNS Therapy; the respective impacts cannot be disentangled due to study limitations.