The 2018 Partners Against Mortality in Epilepsy took place in Alexandria, VA, from June 14–16, 2018. From the first PAME meeting in 2012, this innovative conference has brought together epilepsy researchers, clinicians, advocacy organizations, people living with and bereaved by epilepsy, and their families from around the world. This fourth PAME meeting boasted the largest number of attendees of all PAME events. In an effort to continue to grow research and advocacy in the field of epilepsy mortality, two-thirds of invited presenters had not previously presented at a PAME meeting. Collaboration continued to be a significant thrust, with strong partnerships that included the American Epilepsy Society, Epilepsy Foundation, CDC, NINDS, and Citizens United for Research in Epilepsy coming to the table to build the meeting.
Following, the 2018 PAME co-chairs share their reflections of the meeting and how the field of epilepsy mortality is moving ahead.
Tom Stanton, PAME Co-Chair 2018. Executive Director, Danny Did Foundation
As executive director of the Danny Did Foundation, my place as a PAME co-chair was planted with advocate roots. But 10 years ago, I hardly knew anything about epilepsy. I was working as a consultant, with little connection to the realm of seizures and no connection to epilepsy advocacy.
Then, one morning, I received a call from my older brother. He could hardly speak. He mustered out, “Danny died.” My nephew Danny had experienced just four witnessed seizures, all while he was sleeping. As a happy 4-year-old with no other medical complications, he was taking his daily medication and enjoying life as the third of four siblings. His sudden death sent our family into a dark hole.
Almost 10 years later, the larger epilepsy community held the goal to put advocacy at the forefront of PAME 2018. We accomplished that in several ways:
The PAME meeting was preceded by more than 40 visits to Capitol Hill. Patients, families, providers, and members of industry participated to emphasize needs related to epilepsy and sudden unexpected death in epilepsy (SUDEP) research and policy.
The first-ever PAME plenary session focused entirely on advocacy: “Creating Urgency & Change—The Role Advocacy Plays in Understanding and Preventing Mortality.” Speakers included a bereaved mother, a leading epileptologist, and advocates from three countries.
A breakout session on improving doctor–patient communication around the risk of mortality in epilepsy, featuring tactics that providers can use when having difficult conversations.
The creation of an “Advocacy Toolkit,” with action steps on how to remain engaged long past the PAME meeting. Topics in the toolkit spanned public policy, awareness campaigns, provider disclosure about SUDEP, and improving death certification.
In all, there were more than 20 speaker roles for advocates at PAME. After being a witness to the past 10 years in this community, I am hopeful about what advocacy can spark in the next 10. Continued coordination will bring us closer to our shared goal of reducing the burden of mortality in epilepsy.
Elizabeth Donner, Co-chair PAME 2018. Director, Comprehensive Pediatric Epilepsy Program, The Hospital for Sick Children, University of Toronto
In planning PAME 2018, we strove to expand our focus on mortality in epilepsy, beyond SUDEP. Preventable causes of death remain a significant concern. People with epilepsy are at a 2 to 5 times increased risk of death due to injury, 10 to 20 times increased risk due to drowning, and 10 times increased risk of death due to fire. These facts serve as a reminder that people living with epilepsy and their families must be counseled regarding accident and injury risk and ways to reduce that risk.
Mortality related to status epilepticus (SE) is also of concern, recognizing new data demonstrating that in low- and middle-income countries, 13% of deaths in people with epilepsy were due to SE, similar to SUDEP rates. In addition, other work has shown that up to one-third of individuals with prolonged SE die during initial hospitalization. Severe SE syndromes, such as new-onset refractory status epilepticus (NORSE), are strongly associated with later drug-resistant epilepsy, placing individuals at risk of SUDEP and other epilepsy-related deaths as well as the inherent mortality of status epilepticus itself.
The PAME meeting has always been an opportunity to share new clinical research about SUDEP. This year, much discussion centered around the practice guidelines on SUDEP incidence and risk factors recently developed by the American Academy of Neurology and American Epilepsy Society. The guidelines identified the risk of SUDEP to be 1.2 per 1,000 patient years in adults living with epilepsy. Rates in children had been reported as significantly lower; however, new data from Sweden and Canada show that SUDEP rates in children are equal to those in adults.
The PAME 2018 meeting also saw a shift in how the epilepsy community approaches seizure safety and SUDEP. An increasing number of devices are now available to aid with seizure detection, and work is underway to bring more to market. While there is some evidence that nocturnal supervision may reduce SUDEP risk, it should be recognized that seizure identification does not always mean SUDEP prevention, and immediate first aid following a seizure does not always prevent death.
A significant challenge for SUDEP research has been to identify those at highest risk. While generalized tonic–clonic (GTC) seizures are the most robust risk factor for SUDEP, we know that most people with GTC seizures will not die—so what is it that identifies those at highest risk? Studies are underway to identify genetic, neuroimaging, neurophysiological, or biochemical biomarkers that could help define a high-risk population. Identification of a robust biomarker for SUDEP would allow for better risk stratification, counseling, and application of prevention strategies to those at the most risk. Furthermore, as the research community identifies interventions that reduce SUDEP risk, a biomarker could be used to identify a cohort for interventional studies. By bringing together clinical, translational, and basic science researchers with advocates and people affected by epilepsy, PAME meetings provide the perfect opportunity for collaborations needed to take these ideas to the next level.
George Richerson, Co-chair PAME 2018. Chairman, Department of Neurology, University of Iowa
Having had the good fortune to attend all four PAME meetings, it has been very gratifying to see the tremendous progress made in the field over the last six years. There has been rapid growth in the number of grants submitted and funded on SUDEP, with NIH R and U grants increasing from 7 in 2012 to 24 in 2018. There has also been a large increase in the number of papers over that period, with many new investigators entering the field.
As a basic/translational scientist, I have seen a maturation of hypotheses about the mechanisms of SUDEP since the first PAME meeting, with new insights into pathophysiology from new experimental methods, and potential avenues for treatment that would not have been possible without the new knowledge that has resulted.
New Methods and Models
A key to advancement in any scientific field is development of new experimental methods to study a problem. A large number of mouse models were described at this year's meeting that are being used to study SUDEP, many of which are new or are being used in new ways. These include the DBA/1 mouse in which all 5-HT neurons are genetically deleted, and mice with knockouts or mutations of the 5-HT2c receptor, Scn1a, Scn8a, Kcna1, and the Ryr2 receptor. There was also a rich array of new methods to study animal and human SUDEP, including manganese-enhanced magnetic resonance imaging (MEMRI) for use in rodents, and MRI tractography and high-resolution ex vivo MRI for use in humans. Studies of Scn1a mutations using stem cells (iPSCs) continue to reveal new cellular mechanisms of cardiac and neuronal dysfunction relevant to SUDEP.
New Insights Into Pathophysiology
Studies of SUDEP have long focused on the effect of seizures on myocardial, autonomic, and respiratory functions. However, at PAME 2012, most investigators focused on cardiovascular dysfunction as the primary cause of death. Since then, there has been greater appreciation that respiratory arrest can be the initiating event in many cases of SUDEP. This change in perception has important clinical consequences, as it would be a mistake to implant a cardiac pacemaker to prevent SUDEP without evidence that cardiac mechanisms are the dominant pathway to death in that individual patient.
By definition, all deaths are due to cardiac and respiratory arrest, but the important question in SUDEP is: What are the CNS mechanisms that lead to cardiorespiratory arrest after a seizure? A lot of new data addressing this question has been generated since PAME 2012, with much of it new since PAME 2016. There are a number of possibilities that are not mutually exclusive. They include projections from the amygdala to the respiratory network that cause apnea, brainstem spreading depolarization leading to autonomic and respiratory dysfunction, postictal generalized EEG suppression (PGES), activation of the periaqueductal gray, induction of “brainstem seizures,” and a massive surge in parasympathetic output. How these mechanisms are related is not yet clear.
New Genetic Mechanisms
The role of genetic mutations in SUDEP has simultaneously advanced and become more complicated. “Cardiac genes” linked to SUDEP are also expressed in the brain, where mutations may contribute to epilepsy or cause brainstem dysfunction. Thus, these cardiac “mutations” could cause death due to cardiac arrhythmias, respiratory instability, or increased severity of seizures. It is also more difficult to predict how mutations of individual genes (e.g., Scn1a or Kcna1) will alter SUDEP risk because modifier genes (e.g., Cacna1a, Tau, Scn2a) can decrease the risk of SUDEP, as shown in mice.
New Directions
Finally, two new areas of research were discussed that are likely to become even more important in upcoming years. One of these is the interaction between sleep, seizures and breathing, and how a deficiency in sleep/rest influences the risk of seizures and SUDEP. The second is the relationship between SUDEP and sudden infant death syndrome (SIDS). These two types of sudden death may be related, possibly via shared mechanisms related to sleep. In fact, new data suggest that some cases of SIDS may actually be SUDEP in infants that have undiagnosed epilepsy.
One of the most remarkable things about PAME 2018 was to see how many new discoveries have been made since the first PAME meeting and how many were reported for the first time after PAME 2016. We saw an influx of new ideas and the critical appraisal of established thinking. At the current rate of discovery, we are excited to see what will be presented at the next PAME meeting.