Plenary 7 Updates and Discussion on Select Programs in ... · Citizens United for Research in Epilepsy (CURE) JUNE 2016 2016 PAMECONFERENCEJUNE23 ‐26|ALEXANDRIA,VA PARTNERS AGAINSTMORTALITYINEPILEPSY

Plenary 7 Updates and Discussion on Select Programs in Mortality Research

June 26, 2106 9:15 a.m. - 10:15 a.m.

Moderator: Maggie Moore, MPH, Centers for Disease Control Panelists:

• Samden Lhatoo, M.D., Case Western University • Brandy Fureman, Ph.D., Epilepsy Foundation • Tracy Dixon-Salazar, Ph.D., CURE • Samuel Wiebe, M.Sc., M.D., FRCPC, International League Against Epilepsy

2015 AES Annual Meeting www.AESnet.org

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2016 PAME CONFERENCE JUNE 23 ‐ 26 | ALEXANDRIA, VA PARTNERS AGAINST MORTALITY IN EPILEPSY

Plenary 7:Major Resources and Programs for Research in Epilepsy Mortality

Moderator: Maggie Moore, MPH

Centers for Disease Control and Prevention

JUNE 2016


Disclosure

None


Learning Objectives

Following participation in this activity, learners should be able to:• Identify at least 5 organizations working in epilepsy mortality

research.• Describe select resources and programs related to epilepsy

mortality research.• Identify gaps in resources and programs related to epilepsy

mortality research.


Panelists and Agenda

PanelistsSamden Lhatoo, MD, Case Western UniversityBrandy Fureman, PhD, Epilepsy FoundationTracy Dixon‐Salazar, PhD, CURESamuel Wiebe, MSc, MD, FRCPC, International League Against Epilepsy

Agenda• Brief panelists’ presentations• Audience questions• Discussion


2016 PAME CONFERENCE JUNE 23 ‐ 26 | ALEXANDRIA, VA

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Updates and Discussion on Select Programs in Mortality Research

Sam Lhatoo, MD FRCP(Lon)Case Western Reserve University& Center for SUDEP Research

JUNE 2016


Disclosure

Sunovion Speakers’ BureauUpsher Smith Advisory Panel


Learning Objectives

Following participation in this activity, learners should be able to:

• Gain knowledge of the organization, infrastructure and scientific projects in the NINDS Center for SUDEP Research

www.sudepresearch.org


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Autonomic and Imaging Biomarkers of SUDEP

Goals

• To create a SUDEP risk index as a tool for all epilepsy patients so as to accurately determine individualized risk

• To further determine SUDEP mechanisms in order to pave the way for prevention

• To create a large SUDEP research database that contains phenotypic, genotypic, physiological (EEG, EKG, breathing, autonomic, biochemical) and imaging data.

• To mentor a new generation of researchers in SUDEP

Center for SUDEP Research

Zhang GQ, Cui L, Lhatoo S, Schuele S, Sahoo S. MEDCIS: Multi-Modality Epilepsy Data Capture and Integration System. AMIA Annual Symp Proc 2014

UCLA

Northwestern

NYUUCL

CWRU

Baylor College of Medicine

IOWA

Columbia

UK

Thomas Jeff.

Wandschneider and Diehl 2014


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Molecular Diagnostics Core

PI and Core Director: Alica M Goldman, MD, PhDAssistant ProfessorNeurologyBaylor College of MedicineHouston, Texas

http://codifiedgenomics.com/

CORE GOALS

• Molecular diagnostics of SUDEP cases and at risk patients with epilepsy

• SUDEP gene/variant research database

• Identify novel SUDEP genes and molecular biomarkers

• SUDEP Genetics Clinic

Morphometric Core

MORPHOMETRIC CORE (MMC)GOALS

SUDEP centered morphometric analytical network aimed to facilitate SUDEP brain collection and to correlate brain morphometric studies with clinical, electrophysiological, and autonomic investigations.

SA 1: Precision brainstem ANTEMORTEM morphometric analysis (Dr. Susanne Mueller)

Principle: Gray matter voxel‐based morphometry and evaluation of brainstem/diencephalic abnormalities using a high dimensional deformation‐based warping algorithm (Mueller et al. Neuroimage: Clinical 5(2014)208‐216).

Troy 1983-2014


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Left‐Insular Damage, Autonomic Instability and SUDEPNuria Lacuey1,2 , Bilal Zonjy1, Wanchat Theerannaew3, Kenneth A. Loparo3, Curtis Tatsuoka3, Jayakumar Sahadevan4 and Samden D. Lhatoo1,5.

Neuropathology of SUDEPBiomarkers & Physiology, Cortex & Brainstems

Maura Boldrini, MD, PhDColumbia University School of Medicine

Orrin Devinsky, MDNYU Langone School of Medicine

Maria Thom, MDUniversity College London

Biomarkers & Mechanism:The Neuropathology of SUDEP

• Link: biomarkers & mechanisms with surgical tissue, surgical tissue with postmortem tissue: correlate physiology to brainstem

• Potential Biomarkers of SUDEP Risk– Living – PGES, MRI, EKG, genetic, etc– Decedents – neuropathological (serotonergic & adenosine activity), cardiac pathology, genetic

• Understanding mechanisms of SUDEP– Pathophysiological autopsy

The Spreading Wave of Death

Cardiac Gene and Circuit Mechanisms (NS090340)

Cardiac Gene and Circuit Mechanisms


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Project: Center for SUDEP Research: Respiratory and Arousal Mechanisms

Project leader

George Richerson, MD, PhD

University of Iowa

Other personnel

Brian Gehlbach, MD

Mark Granner, MD

Gordon Buchanan, MD, PhD

Doug Nordli, MD (Lurie Children’s Hospital)End-tidal Pco2 (mm Hg)

40 45 50 55 600

20

40

60

80

100

Project Goal: To define the neurobiological basis by which seizures cause respiratory

arrest and post‐ictal coma.

Scope: Adults (Iowa) and children (Lurie Children’s) with epilepsy; synergistic with animal experiments & Human Physiology Network

SA #1: Characterize interictal and ictal respiratory control and arousal in patients with Dravet Syndrome and other forms of epilepsy

SA #2: Determine the relationship between post‐ictal respiratory depression and baseline central chemosensitivity as assessed by the inter‐ictal hypercapnic ventilatory response (HCVR)

SA #3: Investigate the relationship between peri‐ictal respiratory depression, the HCVR, and other clinical phenomena

iPSC and Mouse Neurocardiac Models

0

20

40

60

80

100

120

140

Number of Publications

PUBMED search terms: Epilepsy, Sudden Death, SUDEP (1,319 hits)

0

50

100

150

200

250

300

Total CSR

Number of Publications

Total vs CSR PI‐Co‐I publications for 2014‐2015

45

237


6

Project Title: Role of 5‐HT in seizure‐induced cardiorespiratory inhibition in two mouse models of SUDEP PI: William P. Schilling, Ph.D. Co‐PI: Diana L. Kunze, Ph.D. MetroHealth Hospitals and CWRU

Project Title: Peri‐ictal respiratory dysfunction: A multimodality analysis of sleep and breathing in adults with pharmacoresistant epilepsyPI: Nancy Foldvary‐Schaefer MDCleveland Clinic Foundation

Project Title: Electrical Disturbances in the Brain and Heart in LQTS: A Dangerous SynergyPI: David Auerbach MD PhDUniversity of Rochester

Project Title: Combating SUDEP with Htr2c agonistsPI: Chen Liu PhDUT Southwestern Medical Center

Project Title: High resolution heart and lung structural MR imaging of intractable epilepsy patientsPI: Chris Flask PhDCase Western Reserve University



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Mortality Research Programs: Perspective from the Epilepsy

Foundation

Brandy Fureman, PhD

Epilepsy Foundation

JUNE 2016


Disclosure

None


Learning Objectives


• Describe outcomes from the EF Targeted Program in Morbidity and Mortality, and other related programs

• Apply for the SUDEP Institute Biomarker Challenge

Morbidity and Mortality in Epilepsy

• Targeted Grant Program:

– 2015 Buchanan "NE and 5‐HT in seizure‐induced respiratory arrest and death"

– 2014 Mueller "Brainstem atrophy: A SUDEP Biomarker"

• Fellowships/Career Development awards

• New devices supported in New Therapy Commercialization Grants, Shark Tank awards

• Research Roundtable in Epilepsy meeting May 19‐20: “Reducing placebo exposure in epilepsy clinical trials”

SUDEP Institute Challenge Initiative: Predictive biomarkers of epilepsy

seizures

• Level One Goal: identify human biomarker(s) that can predict and allow development of interventions for people at high risk of SUDEP (up to 10 prizes worth a total of $150,000)


The Third Challenge: Predictive Biomarkers of Epilepsy SeizuresLevel Two Goal: validate that the Biomarker can predict the risk for SUDEP and be used for intervention (prizes total, $1M)

“…The biomarker(s) must serve as an endpoint or surrogate endpoint that will drive human SUDEP interventions. For example, the biomarker(s) may identify a high risk patient group that could be used to test existing candidate interventions such as seizure detection devices in a clinical trial.”

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Impact on Clinical Care and Practice

• Identify those at high risk• Act on modifiable factors: seizure control, safe sleep,

wellness practices• Find targets for prevention

• Identify those at low risk• Reduce burden of fear for individuals and families


Director, SUDEP Institute and Targeted Programs

• Read the Position Description and Apply –

• http://www.epilepsy.com/director‐sudep‐institutetargeted‐projects

• Are you passionate about ending SUDEP? • Can you drive a project forward? • Can you rally diverse stakeholders to the cause?

We are looking for YOU!



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CURE’s SUDEP Research Program

Tracy Dixon‐Salazar, PhD

Citizens United for Research in Epilepsy (CURE)

JUNE 2016


Disclosure

None


Learning Objectives


• Understand CURE’s SUDEP Research Efforts


1 in 26 Americans Will Develop Epilepsy in their Lifetime.

2016 PAME CONFERENCE JUNE 23 ‐ 26 | ALEXANDRIA, VA PARTNERS AGAINST MORTALITY IN EPILEPSY 2016 PAME CONFERENCE JUNE 23 ‐ 26 | ALEXANDRIA, VA PARTNERS AGAINST MORTALITY IN EPILEPSY

1993 FDA & Burroughs

Wellcome Committee to define SUDEP

2002In memory of her son, Christopher, Jeanne Donalty teams up with CURE for SUDEP

Research

2003CURE & Jeanne Donalty speak about SUDEP at AES for the first

time

2004CURE launches SUDEP research program and

funds first grant

2005CURE and AES co‐

host 1st AES SUDEP Workshop

1995Epilepsy Bereaved established in England, later called SUDEP

Action

Late 1990’s Epilepsy Australia efforts in SUDEP

begin

1993 1995 2000 2002 2003 2004 2005


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Sudep Aware in Canada forms

2008NINDS & CURE co‐host 1st ever SUDEP meeting

2011NINDS, with CURE input,

identifies SUDEP as topic for 2nd

CWOW

2012CURE Board Chair Gardiner Lapham

co‐chairs 1st

PAME meeting

2013SUDEP Institute Forms, Gardiner Lapham, Board Chair on the SI

Board

2014Gardiner co‐

chairs 2nd PAME meeting

2015 NINDS funds SUDEP CSR

2008 In memory of her

son, Henry, Gardiner Lapham joins forces with

CURE

CURE SUDEP funding reaches

$3M

2008 2010 2011 2012 2013 2014 2015

NASR forms, Gardiner on

Executive Cmte

AES SUDEP taskforce formed

w/ CURE

2010NINDS and CURE develop CWW concept to

advance epilepsy research



CURE Funded Breakthroughs• Respiratory arrest established as a leading cause of SUDEP and studies

suggest that this may be helped with caretaker intervention or use of serotonin reuptake inhibitors (SSRI).

• Revealed link between SUDEP and genes found in both the brain and heart.

• Funded SUDEP registries in Canada, Sweden and the U.S.

• Six new animal models of SUDEP now exist and are being extensively studied to further our understanding of the mechanisms that underlie SUDEP.

• Generalized tonic‐clonic seizures have been established as a clear risk factor for SUDEP.

• Increase in SUDEP awareness and research funding overall.


0

200

400

600

800

1000

1200

1400

1600

1800

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

# of New

s Articles (Google Tren

ds)

# of SUDEP News Articles 2004‐2015

SUDEP Awareness Metrics


SUDEP Awareness Metrics

0

20

40

60

80

100

120

140

1970 1975 1980 1985 1990 1995 2000 2005 2010 2015

# of Publications (PubMed

)

Sudden Death in Epilepsy Publications1940‐2015


NIH SUDEP Funding History

NIH SUDEP funding over time Source: NIH RePORTER

$0

$1,000,000

$2,000,000

$3,000,000

$4,000,000

$5,000,000

$6,000,000

$7,000,000

$8,000,000

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015


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2016 PAME CONFERENCE JUNE 23 ‐ 26 | ALEXANDRIA, VA PARTNERS AGAINST MORTALITY IN EPILEPSY 2016 PAME CONFERENCE JUNE 23 ‐ 26 | ALEXANDRIA, VA PARTNERS AGAINST MORTALITY IN EPILEPSY

Impact on Clinical Care and Practice

• Patient organizations can significantly help advance the research efforts



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Advocacy and Research PerspectiveInternational League Against Epilepsy

Samuel Wiebe, MD, MScExecutive Board, International League Against Epilepsy

University of Calgary, Canada

JUNE 2016


Disclosure

Served advisory boards:ElectrocoreSunovion

Sponsored lecture and seminar:UCB


Learning Objectives

Following participation in this activity, learners should be able to discuss:• Epilepsy burden of disease and mortality in global context• Research/advocacy in non‐US non‐European countries• Role of international organizations (ILAE) in research/advocacy


LOST YEARS DUE TO EPILEPSY (death + disability)per 100,000 people

>275<50

Source: global burden of disease, WHO 2012


GLOBAL CAUSE OF DEATH 2012 – by income group

53

37

1.7 0.8

32

57

1.6 0.5

10

81

1.4 0.2

6.6

87

6.3

0.1

Communicable NutritionalPerinatal

Non‐communicable Neurological Epilepsy

Percent of all deaths

low low‐mid upper‐mid high

http://www.who.int/healthinfo/global_burden_disease/estimates/en/index1.html

1.7

1.6

1.4

6.3

0.8

0.5

0.2

0.1

Epilepsy Neurological


SUDEP RESEARCH

Rest of the World10‐1920‐30>30 01‐45‐9

(8) MechanismsClinical

(34) GeneticsClinical

(20) Mechanisms

(5) Clinical

(6) Reviews

(1) Review

(5) Clinical

(1) Review(1) Epidemiol(1) Epidemiol

(3) Clinical

(1) Clinical

(57) Clinical MechanismsSocial, therapy

(1) Clinical


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INTERNATIONAL LEAGUE AGAINST EPILEPSYVehicles for Advocacy – Education – Research

Congresses

INTERNATIONAL ‐ REGIONALSessions, courses, workshops

Wikipedia

ALL EPILEPSY MATERIALSUDEP 125 views per day

Collaboration

AWARENESS, EDUCATIONIBE, WHO, WFN, AES, EFN

World View

114 COUNTRIESAll world regions

Task Forces

MORTALITY, EPIDEMIOLOGY, THERAPEUTICS

Analyses, Standards, Definitions

3 Journals

RESEARCH, CARE ,EDUCATIONEpilepsia, Epileptic Disorders,

Epilepsia Open



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Documents

Plenary 7 Updates and Discussion on Select Programs in ... · Citizens United for Research in Epilepsy (CURE) JUNE 2016 2016 PAMECONFERENCEJUNE23 ‐26|ALEXANDRIA,VA PARTNERS AGAINSTMORTALITYINEPILEPSY