PAME 2016

June 23-26, 2016
Washington, D.C.

2014 PAME Summary

PAME Conference
June 19-22 
Hyatt Regency Minneapolis
Minneapolis, MN

Meeting Summary












FRIDAY, JUNE 20, 2014

PLENARY SESSION: Overview of Mortality in Epilepsy including SUDEP

The day opened with family stories from Bill and Janine Atwell discussing their daughter Stephanie who died while student at University of Vienna. Bill presented a poem he wrote, “Shards of Glass.” The remainder of the day offered medical and scientific research into SUDEP.

David Thurman, M.D.
An overview of short and long-term mortality in epilepsy. Standard Mortality Rate (SMR) for people with epilepsy is 2 -3 times higher than general population. Risk impacted by 1) underlying cause of epilepsy; 2) type of seizures; 3) level of seizure control. True incidence of epilepsy-caused mortality is unknown and dependent on estimates and extrapolation from studies on limited populations. Estimated annual SUDEP incidence from best studies = 1.22 SUDEP/1000/yr (Thurman Epilepsia 2014) = ~2750 cases in 2014 in US. But incidence varies: children ~0.4 Refractory 6.2. Highest incidence ages 21 – 50. An important way of looking at impact of epilepsy related mortality is to measure Years of Potential Life Lost (YPLL) If one accounts for Years of Potential Life Lost (YPLL) due to SUDEP, it is 101 YPLL, higher than many neurologic conditions, with stroke being the only neurologic disorder which is significantly higher.

W. Allen Hauser, M.D. 
People with Epilepsy (PWE) have more frequent accidents than general population (27% vs 17%) but only 24% of accidents are seizure related and there is little difference from general population if seizure related accidents are taken into account.  

Roland Thijs, M.D. 
Discussed how the cause of the epilepsy is related to the cause of death (i.e., death is due to illness, etc. which produced epilepsy). The incidence (new cases per year) of epilepsy in the developed world is half of that in resource poor countries but prevalence (number of existing cases) is similar. Standard Mortality Rate significantly higher in early years after diagnosis when suicide, SUDEP and accidents are rare. This suggests that early death is probably attributable to the cause of the epilepsy.

Dale Hesdorffer, Ph.D. 
Presented the traditional definitions of SUDEP and the changes recommended by Nashef et al. (Epilepsia. 2012 ) in definition and classification of SUDEP. This included replacing “Unexplained” with “Unexpected.” She noted also that ICD 11 codes which are used to classify cause of death will not be adopted by the National Center for Healthcare Statistics for many years.


Lisa Bateman, M.D. 
Human Peri-ictal Physiology: Respiratory: There are respiratory complications of seizures including excess bronchial and oral secretions, central and obstructive apnea, laryngospasm, aspiration pneumonia, neurogenic pulmonary edema, suffocation, hypoxemia and hypercapnia. Apnea correlates with contralateral spread of seizure with 2/3 of apneas being central. Clinical characteristics correlated with ictal hypoxemia:

  • Male gender
  • Younger age
  • Symptomatic generalized epilepsy
  • Temporal lobe onset
  • Contralateral seizure spread
  • Longer seizure duration
  • Non-lesional MRI
  • Multiple AEDs.

SUDEP triangle:

  1. CNS control over cardiac rhythm / respiration
  2. Arrhythmia impairs blood flow to brain
  3. Hypoxia /hypercapnia depress brain function = flat EEG

George Richerson, M.D., Ph.D. 
Presented review of animal models and control of breathing to support hypothesis that the primary failure in SUDEP is respiratory failure. His research focuses on mouse models which demonstrate the role of serotonin in SIDS and, potentially, SUDEP.

Daniel Mulkey, Ph.D. 
Provided an overview of the role of KCNQ and Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels in regulation of respiratory driver and regulate excitability and transmitter modulation of chemosensitive RTN neurons and breathing. He identifies KCNQ channels as potential targets for the treatment of respiratory problems resulting from increased chemoreceptor gain.

Detlev Boison, Ph.D. 
Presented studies on the potential role of adenosine in SUDEP. Adenosine dysfunction is present in epilepsy. Seizures result in adenosine surge. Adenosine in brainstem can decrease respirations. Adenosine deficiency can lead to seizures. Compared role of adenosine in SIDS, SUDEP, TBI


Orin Devinsky, M.D. 
Discussed some basic methodologic issues in understanding SUDEP and studying it. He compared SUDEP and autism. To some extent increased awareness of autism has resulted from expanding definition of autism. He advocates for thinking differently about SUDEP.

Lindsey Thomas M.D., medical examiner (ME) 
Elucidated goal of ME, which is to determine causes of sudden, unexpected or unnatural cause of death.  SUDEP or death during seizure is “natural.” Medical Examiners seek other possible causes. Role of ME is to determine cause of death, excluding other potential causes other than seizures.

Vicky Whittemore, Ph.D. 
Provided an update on the SUDEP Registry – North American SUDEP Registry (NASR) and Sudden Death in the Young Registry. Need to have registry to have sufficient numbers to study SUDEP. Goal is to create a repository for clinical, imaging, tissue and genetic data. Contact: 1-855-432-8555 or Sudden Death in the Young Registry is the result of collaboration with NHLBI, NINDS, CDC, and state public health and ME offices focusing on sudden death in young, especially cardiac as well as SUDEP.

Cynthia Harden, M.D. 
SUDEP Guidelines: discussed the ongoing development of clinical practice guidelines related to SUDEP, in process at American Academy of Neurology; release is pending soon.

Cyndi Wright 
Provided a summary of SUDEP Surveillance Policy Statement. Approaches: education and awareness; state ME (medical examiner) reporting/surveillance; state legislative approach.


Hal Blumenfeld M.D., Ph.D. 
Human Periictal Physiology: Central Shutdown and Arousal Systems: There is decreased consciousness in seizures and similarly there is decreased brainstem arousal and associated breathing following seizures with evidence of medullary mechanisms. Serotoninergic neurons are involved.

Brian Dhlouhy 
Stimulation of amygdala in patients with implanted electrodes for surgical evaluation results in apnea; patients were not aware of the apnea and resumed normal breathing following cessation of stimulation.

Gordon Buchanan, M.D., Ph.D. 
Serotonin is important in regulation of arousal and breathing, especially in postictal period and dysfunction may contribute to SUDEP. Lmx1bf/f/p mice (who do not have serotonin) are more susceptible to induced seizures as well as increased mortality from seizures.

Carl Faingold, Ph.D. 
Adensonine in DBA/1 mice increases seizure-related respiratory arrest. He hypothesizes that adenosine agonists such as caffeine, which increases respiration, may have impact on SUDEP.

James Tao, Ph.D. (abstract award) 
Prone position is more frequently associated with SUDEP as with SIDS.



Dale Hesdorffer, Ph.D. 
Highest risk of mortality following acute seizures and status epileptics is in symptomatic epilepsy. Case fatality is 24% overall following status epilepticus. Mortality after unprovoked seizure is much lower than that for mortality following symptomatic seizures which suggests that acute symptomatic seizures are a different entity than unprovoked seizures.

Nathalie Jette, M.D., FRCPC 
There are significant methodologic challenges to understand the risk factors for suicide associated with epilepsy. Jones et al. reported increased risk over general population about 10. (Epilepsy and Behavior 2003). Bell et al (Epilepsia 2009) found overall SMR for suicide in patients with epilepsy was 3.3 (95% CI 2.8–3.7). Highest in those with affective disorder, longer duration of epilepsy and older age. Ferrer P. Antiepileptic Drugs and Suicide: A Systematic Review of Adverse Effects: data do not answer question of increased risk of suicide from AEDs.

Daniel Friedman, M.D. 
Non-Adherence to Antiepileptic drugs and the Risk for Death in Epilepsy. Only half of patients maintain > 80% adherence over time. Non-adherence increases risk of hospitalization, injury and death. Several case series of SUDEP report decreased blood levels of AED.

Scott Mintzer, M.D. 
SMR and Standardized Morbidity Ratio show increased risk of vascular disease associated with epilepsy. Medications may be related to this, especially medications which are CYP450 inducers. Likewise there is association with carotid intima-media thickness (a cardiovascular risk factor) and duration of AED therapy. There is an increased use of statins in patients with epilepsy.


Jeffrey Britton, M.D. 
Based on historical recognition of autonomic impact of seizures as well as current data, he concludes that intractable epilepsy is associated with “unbridled sympathetic activation” and “likely contributes” to SUDEP.

Lori Isom Ph.D. 
Neural-cardiac mechanisms of SCN1A-linked Dravet Syndrome and SUDEP. In Dravet mutant mice SCN1A is expressed in brain, heart and autonomic nerves. Cardiac myocytes have increased Na+ current and appear to be hyperexcitable.

Franck Kalume, Ph.D. 
Insights from a mouse model of Dravet. Rate of SUDEP is >30 times than in other pediatric epilepsies, probably due to cardiac dysfuntion. Forebrain epileptic activity transmits to midbrain and produces bradycardia and ventricular dysfunction leading to death.

Rainer Surges, M.D. 
Focused on principle mechanisms that underlie cardiac dysfunction in epilepsy. Peri- or interictal cardiac dysfunction can affect heart rate/rhythm, AV conduction, cardiac excitation, contractility and ejection function.

Yi-Chen Lai, M.D. 
Using pilocarpine induced SE in rat model, showed EKG changes which occurred with appearance of recurrent spontaneous seizures following SE.

  • Objectives of this session were identified as:
    • Review stages of grief.
    • Understand differences between complicated and uncomplicated grief.
    • Understand predisposing factors for complicated risk.
    • Identify when grief counseling is needed.
    • Grief support resources.

Andres Kanner, M.D. 
Grief begins with the occurrence of the 1st seizure.  Linda Coughlin Brooks, RN, BSN, CT 
Discussed awareness of complicated grief. Paul Scribner identified resources for grief support. He also stressed need for sensitivity to cultural, religious and crisis support needs.


Alicia Goldman M.D., Ph.D. 
Used genetics of child with SUDEP and  both SCN1A mutation and KCN1A mutation with combination of de novo single nucleotide polymorphisms (SNPs) and CNVs back to understanding genetics and SUDEP, e.g., copy number variant, multiple gene mutations and to interpreting genetic changes: de novo; pathogenic; innocuous or modulating/contributing.

Jeffrey Noebels, M.D., Ph.D. 
Need to identify “candidate genes” and the need to be focused on initial evidence that gene is potentially pathogenic. Use of “reverse genetics” can efficiently identify pathogenic genes and mechanisms. Exome sequencing of sporadic cases uncovers multiple candidates. Is the variant deleterious? Is penetrance high? What is mechanism? Are there multiple genes that share the same pathway? He cites examples such as kvLQT1 mutations; genotyped LQT Syndrome; a new SUDEP gene with same functional pathway found in mouse model; Tau deletion which rescues seizures / SUDEP in Kv1.1 mice.

Miriam Meisler,  Ph.D.
Sodium channel mutations and SUDEP: “a tale of two channels and a new mouse model of SUDEP.” SCN1A and SCN8A are closely related, both localized at axon initial segment. SCN1A produces loss-of-function (50%). SCN8A produces gain-of-function and both appear pathogenic.

SUNDAY, JUNE 22, 2014


This last day of the conference began with a family presentation by Dennis and Kari Knapp, who read a description of the impact of seizures on his life by their son, Jake, a moving bookend to the initial poem, Shards of Glass.

Elizabeth Donner, M.D. 
Surgical and Pharmaceutical Treatment to Prevent SUDEP. Surgery may decrease risk of SUDEP by decreasing number of seizures, limiting number of generalized tonic clonic seizures, reducing comorbidities and stabilizing autonomic dysfunction. Successful surgery likely decreases SUDEP risk although good study demonstrating that is lacking. AEDs do not increase SUDEP risk and in controlled trials, active treatment may decrease SUDEP risk (Relative Risk active drug = 6, placebo = 9).

Lisa Bateman, M.D. 
Nocturnal Seizures, Stimulation and Supervision: MORTEMUS study (Ryvlin Lancet Neurology 2013) In monitored patients, nocturnal seizures are prominent although not necessarily in sleep. Circadian rhythms may play role. Nocturnal seizes are unsupervised, and studies from Great Britain suggest supervision is protective.  MORTEMUS study indicates that intervention within 3 minutes is protective.

Daniel Freidman, M.D. 
Reviewed principles of seizure detection including EEG features, motor activity, other physiological parameters (heart rate, pulse oximetry, galvanic skin response), multimodal detectors. He reviewed commercially available devices and the evidence that they detect seizures. Caveat: no FDA approved and controlled trials for SUDEP specifically may not be possible.

Tom Stanton, Executive Director, Danny Did Foundation. 
Explored how monitoring devices fit into management? He emphasized need to set right expectations and to ask provider and device manufacturer.

Martha Sajatovic, M.D. 
The role of self-management in managing epilepsy and reducing complications: “Broadly speaking, epilepsy self-management is the sum total of steps taken and processes used by a person to control seizures and manage the effects of a seizure disorder,” Dilorio 1997.  Sajatovic focused on the role of depression and other mental illness. “Education is not enough.” Focusing on the Managing Epilepsy Well (MEWS) program, she reviewed 3 approaches: PEARLS; UPLIFT; WebEase plus others. She described a program for mental disorders and diabetes as self-management prototype.

Tanya Spruill, Ph.D. 
SUDEP prevention: From a Public Health Perspective: changing behavior. Focus on medication adherence. Discussed strategies for intervention based on reasons for non-adherence. Bellevue Hospital program to improve adherence shows impact of depression in nonadherence but others include SES, race/ethnicity, physician, system (access, cost).

Senay Imam (abstract awardee) Advance Warning of Epileptic Measures of Cerebral Blood Flow. There are no mathematical model that can predict onset based on CBF. His study applied complexity measures to seizure prediction.