Annual Course

Epilepsy Across the Lifespan

Symposium Chair:

Lara Jehi, M.D.

Sunday, December 3, 2017

Convention Center – Ballroom A/B, Level 3

8:45 am – 5:15 p.m.

EDUCATION CREDITS

Accreditation If you have any questions about this CE activity relative

The American Epilepsy Society is to nursing and/or pharmacy CE, please contact AKH, Inc.
accredited by the Accreditation Council at service@akhcme.com.
for Continuing Medical Education
(ACCME) to provide continuing medical Maintenance of Certification
education for physicians. The American Board of Psychiatry and Neurology has
reviewed the 71st Annual Meeting—American Epilepsy
AMA Credit Designation Statement
Society and has approved this program as part of a
The American Epilepsy Society designates this live comprehensive epilepsy program, which is mandated by
activity for a maximum of 26.5 AMA PRA Category 1 the ABMS as a necessary component of maintenance of
Credits™. Physicians should claim only the credit certification.
commensurate with the extent of their participation in
the activity.
Claiming CME Credit and CME Certificates
International Credits: The American Medical Association
Attendees who registered in the following categories
has determined that non-U.S. licensed physicians who
may claim CME or CE for the meeting: physician, health
participate in this CME activity are eligible for a
care provider, trainee, one-day, and two-day. Meeting
maximum of 26.5 AMA PRA Category 1 Credits™.
registration includes credit claiming. There is no
Physician Assistants: AAPA accepts certificates of separate fee to claim CME/CE.
participation for educational activities certified for AMA
Attendees will receive an emailed notification to access
PRA Category 1 Credits™ from organizations accredited
the online evaluation and credit claim system.
by ACCME or a recognized state medical society.
Physician assistants may receive a maximum of 26.5 The evaluation and credit claim system will remain open
hours of Category 1 credit for completing this program. through Tuesday, February 27, 2018. Evaluations and
credit claims must be completed by this date in order to
record and receive your CME/CE certificate.
Continuing Education for Nurses and
Pharmacists
Attendance Certificate/International Attendees
Jointly provided by AKH, Inc.,
Advancing Knowledge in A meeting attendance certificate will be available at the
Healthcare, and the American registration desk for international meeting attendees on
Epilepsy Society. Tuesday, December 5, 2017.
Nurses: Advancing Knowledge in Healthcare is
accredited as a provider of continuing nursing Resolution of Conflicts of Interest
education by the American Nurses Credentialing It is the policy of the American Epilepsy Society to
Center’s Commission on Accreditation. This activity is ensure balance, independence, objectivity, and scientific
awarded 26.5 contact hours. rigor. All persons involved in the selection, development,
Pharmacists: Advancing Knowledge in and presentation of content are required to disclose any
Healthcare is accredited by the real or apparent conflicts of interest. In accordance with
Accreditation Council for Pharmacy the ACCME Standards for Commercial Support of CME,
Education as a provider of continuing AES implemented the mechanism of prospective peer
pharmacy education. review of this CME activity, to identify and resolve any
conflicts. Additionally, the content of this activity is
Select portions of this Annual Meeting are approved for based on the best available evidence.
pharmacy CE credit. Specific hours of credit for
approved presentations and the Universal Activity
Numbers assigned to those presentations are found
elsewhere in the program materials. Criteria for success:
credit is based on documented program attendance
and online completion of a program evaluation/
assessment.

AES ANNUAL MEETING | meeting.aesnet.org 42 DECEMBER 1-5, 2017 | WASHINGTON, D.C.

EDUCATION CREDITS

Unapproved Use Disclosure Disclaimer

AES requires CME authors to disclose to learners when This CME activity is for educational purposes only and
products or procedures being discussed are off-label, does not constitute the opinion or endorsement of, or
unlabeled, experimental and/or investigational (not FDA promotion by, the American Epilepsy Society.
approved); and any limitations on the information that is Reasonable efforts have been taken to present
presented, such as data that are preliminary or that educational subject matter in a balanced, unbiased
represent ongoing research, interim analyses, and/or fashion and in compliance with regulatory requirements.
unsupported opinion. This information is intended solely However, each activity participant must always use his
for continuing medical education and is not intended to or her own personal and professional judgment when
promote off-label use of these medications. If you have considering further application of this information,
questions, contact the medical affairs department of the particularly as it may relate to patient diagnostic or
manufacturer for the most recent prescribing treatment decisions including, without limitation, FDA-
information. Information about pharmaceutical approved uses and any off-label, investigational, and/or
agents/devices that is outside of U.S. Food and Drug experimental uses.
Administration approved labeling may be contained in
this activity.

Self Assessment
in Epilepsy
VOLUMES 1-4
Created by fellow epileptologists and neurologists—
members of AES—these self-assessment activities
Continuing Education
provide continuing medical education, lifelong
learning, and career development. Also use these
in Epilepsy
activities to fulfill Maintenance of Access continuing education and professional
Certification (MOC) requirements. resources from AES all year long, including:

Visit the SAE Zone during the meeting to Webinars

take advantage of meeting discounts for Online courses
self-assessment activities. Details on page 121. Handouts
Self-Assessment

Get details at Learn more at

a e s n e t . o r g /s a e a es ne t.o rg/p ro fe ss iona l_ ed ucati on

AES ANNUAL MEETING | meeting.aesnet.org 43 DECEMBER 1-5, 2017 | WASHINGTON, D.C.

OVERVIEW
The first quarter of the course will tackle diagnostic challenges across the lifespan. Imaging diagnostic
challenges will be addressed by age group. Diagnostic distinctions between epilepsy and normal aging will be
discussed, along with the diagnostic role of amplitudeintegrated EEG in neonates. A debate will discuss
pertinent issues in genetic testing in adults.

The second quarter of the course will tackle medical management of epilepsy and its comorbidities across the
lifespan. The role of ketogenic diet in infancy will be reviewed, as well as the under-recognized sleep disorders
in children. Psychiatric comorbidities will be discussed by age group and unique therapeutic considerations
when using anti-seizure drugs in the elderly will be reviewed.

The third quarter of the course will elaborate on issues pertaining to surgical therapy in different age groups.
Expanding indications in pediatrics and specific considerations in the elderly will be discussed. Tailoring therapy
choices among the multiple available neuromodulatory options will be discussed.

Finally, a debate will highlight specific risk/benefit considerations while considering the extent of resection in
pediatric versus adult populations with epilepsy. The course will conclude with a look into the future, where
topics such as precision medicine and innovative imaging will be front and center. These innovations will be
placed in the context of bringing appropriate epilepsy care to underserved communities by highlighting the
barriers to care in global health. To wrap up, Dr. Mizrahi, President of the American Epilepsy Society, will
provide a futuristic vision of the most needed future innovations in epilepsy.

LEARNING OBJECTIVES
Following participation in this symposium, learners should be able to:
• Delineate the appropriate role of genetic testing and advanced neuroimaging in children, adults, and the
elderly
• Recognize when genetic testing is appropriate in the work-up of epilepsy at all ages
• Recognize when specific advanced neuroimaging tests are indicated in the work-up of epilepsy at all ages
• Delineate the indications for amplitude integrated EEG in neonates
• Distinguish clinical signs that should raise the suspicion of epilepsy in the elderly population
• Delineate the most critical psychiatric co-morbidities to consider across the lifespan
• Be knowledgeable in the various considerations necessary prior to prescribing seizure medications in the
elderly (metabolism, effectiveness profiles, interactions with other medications, among others)
• Recognize the warning signs of specific comorbidities, mainly sleep disorders, in children with Epilepsy
• Recognize and treat psychiatric co-morbidities across the lifespan in patients with epilepsy.
• Appropriately select candidates for epilepsy surgery in infancy
• Recognize indications and risks of epilepsy surgery in the elderly
• Delineate the distinctions among different neuromodulatory treatments (VNS, DBS, RNS)
• Discuss innovative minimally invasive surgical techniques such as laser and thermal ablation
• Conceptualize methods to incorporate innovative technology into daily practice
• Review and discuss the cutting-edge knowledge regarding diagnosis and treatment of people with
epilepsy
• Identify barriers to care implementation and discuss strategies for overcoming said barriers

TARGET AUDIENCE
Neurologists, epileptologists, pediatric neurologists, nurses, psychologists/neuropsychologists, nurse
practitioners/physician assistants, pharmacists
PROGRAM
Introduction
Lara Jehi, M.D.
DIAGNOSTIC CHALLENGES ACROSS THE LIFESPAN:
8:55 AM – 10:20 AM
Case: Neonate with Failure to Thrive and Myoclonic Jerks
Akila Venkataraman, M.B.B.S.

Lecture: Top Four Imaging Diagnoses You Can’t Miss in Each Age Group
Graeme Jackson, M.D.

Lecture: Just How Valuable is Amplitude Integrated EEG in Neonatal Seizure Detection?
Renée Shellhaas, M.D.

Lecture: Epilepsy or Just Getting Old? Diagnostic Challenges in Elderly

Colin Josephson, M.D.

Debate: Value of Genetic Testing in Adults with Epilepsy

Heather Mefford, M.D., Ph.D., and Ingo Helbig, M.D.

MEDICAL MANAGEMENT AND CO-MORBIDITIES ACROSS THE LIFESPAN: 10:35 AM – 12:00 PM

Case: Elderly Patient with Temporal Lobe Epilepsy and Multiple Medical Co-Morbidities
Kim Pargeon, M.D.

Lecture: Unique Therapeutic Considerations When Using Anti-Seizure Drugs in the Elderly
Ilo Leppik, M.D.

Lecture: Sleep Disorders and Epilepsy in Children

Sejal Jain, M.D.
Lecture: Under-Recognized Psychiatric Co-Morbidities
Per Age Group
Tatiana Falcone, M.D.

Lecture: Ketogenic Diet in Infancy? How Low Can We Go?

Stéphane Auvin, M.D.

LUNCH BREAK: 12:00 PM – 2:00 PM

Lunch available in the Exhibit Hall.

SURGICAL TREATMENT OF EPILEPSY ACROSS THE LIFESPAN: 2:00 PM – 3:25 PM

Case: 36-year-old with Presumed Dominant Hemisphere Drug-resistant Epilepsy and Normal MRI Who Had
Surgery
Jeremy Moeller, M.D.

Lecture: Epilepsy Surgery for Infants? Pushing the Boundaries

Ajay Gupta, M.D.

Lecture: VNS, RNS, DBS: Approved for Adults but What’s the Science for How to Choose One Over the Other?
Robert Fisher M.D., Ph.D.
Lecture: Epilepsy Surgery in the Elderly: Seizure Outcomes and Complications.
Jerome Engel, Jr., M.D., Ph.D.

Debate: Surgical Perspectives

PRO: “Minimally invasive” Epilepsy Surgery Options Are the Future: An Adult Epilepsy Surgeon’s Perspective
Guy McKhann, M.D.

CON: The Bigger the Hole, the Better the Outcome: A Pediatric Epilepsy Surgeon’s Perspective
William Bingaman, M.D.

LOOKING TO THE FUTURE: 3:40 PM – 5:00 PM

Case: 10-year-old Boy with Refractory Epilepsy in Rural Africa
Satya Gedela, M.D.

Lecture: Precision Medicine: How Close Are We to Personalized Care?

Daniel Lowenstein, M.D.

Lecture: What Should an Ideal “Epilepsy Protocol MRI” Look Like in the Future for Adults and for Children?
Neda Bernasconi, M.D., Ph.D.

Lecture: Barriers to Advanced Epilepsy Care: Closing the Gap in Global Health
Gretchen Birbeck, M.D., M.P.H.

Lecture: My Top 3 Innovations Needed for Children, Adults, and Elderly with Epilepsy in the Next Decade
Eli M. Mizrahi, M.D.

Course Wrap-up
Lara Jehi, M.D.

EDUCATION CREDIT
6.0 CME credits

Nurses may claim up to 6.0 contact hours for this session.

Pharmacy Credit
AKH Inc., Advancing Knowledge in Healthcare approves this knowledge-based activity for 6.0 contact
hours (0.6 CEUs). UAN 0077-9999-17-046-L01-P. Initial Release Date: 12/3/17.

COMMERCIAL SUPPORT ACKNOWLEDGEMENT

This educational activity is supported in part by educational grants from Eisai Inc., Lundbeck, UCB Inc., and
Sunovion Pharmaceuticals Inc.

FACULTY/PLANNER DISCLOSURES
It is the policy of the AES to make disclosures of financial relationships of faculty, planners and staff involved in
the development of educational content transparent to learners. All faculty participating in continuing medical
education activities are expected to disclose to the program audience (1) any real or apparent conflict(s) of
interest related to the content of their presentation and (2) discussions of unlabeled or unapproved uses of
drugs or medical devices. AES carefully reviews reported conflicts of interest (COI) and resolves those conflicts
by having an independent reviewer from the Council on Education validate the content of all presentations for
fair balance, scientific objectivity, and the absence of commercial bias. The American Epilepsy Society adheres
to the ACCME’s Essential Areas and Elements regarding industry support of continuing medical education;
disclosure by faculty of commercial relationships, if any, and discussions of unlabeled or unapproved uses will
be made.

FACULTY / PLANNER BIO AND DISCLOSURES

Lara Jehi, M.D. (Chair)
Dr Lara Jehi is an adult epileptologist, head of the Outcomes Research Program, and the Director of Research at
the Cleveland Clinic Epilepsy Center. She is the Associate Program Director of the Clinical Research Unit at
Cleveland Clinic within the auspices of the Clinical and Translational Science Collaborative. She has authored
several peer-reviewed original manuscripts, editorials and book chapters. Her work was published in several
high-impact journals including Brain, Neurology, and Lancet Neurology, among others. She serves on the
editorial board of Epilepsia and Epilepsia Open, and is a guest editor for Neurotherapeutics and Continuum, and
is an ad-Hoc reviewer for the Acute Neuronal Injury and Epilepsy Study Section at NIH. . She has been an invited
speaker in many national and international meetings.

Lara Jehi discloses she has no financial relationships to disclose relevant to this activity.

Stéphane Auvin, M.D., Ph.D. (Faculty)

Stéphane Auvin, MD, PhD. Epileptologist and Child Neurologist. Full professor at Paris-Diderot University. I am
conducting the Epilepsy program at Robert Debré University Hospital, APHP, Paris. I am also conducting
research works in the INSERM U1141, Paris.
My clinical and research activities are focused on pediatric epilepsy and its treatments. The Epilepsy program at
Robert Debré Children Hospital, Paris, is involved in antiepileptic drugs clinical trials as well as preclinical works
in the INSERM U1141. My research team is working on inflammation-epilepsy and on the ketogenic diet.
I am the author of more than 150 peer-reviewed articles or book chapters. I am chair of the pediatric
commission of the Internaional League Against Epilepsy and Associate Editor for Epilepsia. I

Stéphane Auvin discloses receiving the following support: Advicenne Pharma: Consulting Fees, Contracted
Research; Eisai: Consulting Fees, Contracted Research; Epilepsia: NONE, Other Financial or Material Support;
GW Pharma: Consulting Fees; Novartis Pharmaceuticals: Consulting Fees; Nutricia/Danone: Consulting Fees;
Shire: Consulting Fees; UCB Pharma: Consulting Fees, Contracted Research; Zogenix: Consulting Fees; zogenix:
Contracted Research

Samuel Berkovic, MD (Faculty)

Samuel Berkovic AC, MD, FAA, FRACP, FAHMS, FRS is Laureate Professor in the Department of Medicine,
University of Melbourne, and Director of the Epilepsy Research Centre at Austin Health. He is a clinical
neurologist and clinical researcher with a special interest in establishing close research links with basic
scientists. His group, together with molecular genetic collaborators in Adelaide and Germany, discovered the
first gene for epilepsy in 1995 and subsequently have been involved the discovery of many of the known
epilepsy genes. This has changed the conceptualisation of the causes of epilepsy and is having a major impact
on epilepsy research, and strategies for diagnosis and development of new treatments. He was elected a Fellow
of the Royal Society in 2007 and a Member of the National Academy of Medicine in 2017.

Samuel Berkovic discloses receiving the following support: Eisai: Consulting Fees; SciGen: Other Financial or
Material Support, Unrestricted research grant; UCB Pharma: Consulting Fees, Other Financial or Material
Support, Unrestricted research grant; Zynerba: Consulting Fees, Contracted Research
Neda Bernasconi, M.D., PhD (Faculty)
Dr Neda Bernasconi, a Swiss-trained scientist, is Professor in the Department of Neurology at the Montreal
Neurological Institute, McGill University. She is the Director of the Neuroimaging of Epilepsy Laboratory at the
McConnell Brain Imaging Centre. Her research is dedicated to drug-resistant epilepsies. One aspect of her work
focuses on the development of computerized MRI methods that, combined with advanced statistics and
machine-learning, allow detecting subtle epileptogenic lesions that escape conventional radiology. Another
research axis is the study of brain connectomics. She has published >90 peer-reviewed papers and trained > 40
graduates in neuroscience and engineering. Many of her trainees have obtained faculty positions at top
Universities and are recognized leaders in their field.

Neda Bernasconi discloses she has no financial relationships to disclose relevant to this activity.

William Bingaman, M.D. (Faculty)

Dr. Bingaman is currently the Vice Chairman of the Neurological Institute, Professor ofNeurological Surgery of
the Cleveland Clinic Case Western Lerner College of Medicine, Director of the Epilepsy Surgery Program, and
holds the Shusterman Family Chair in Epilepsy Surgery. Since 1997, Dr. Bingaman has developed and led the
epilepsy surgery program in Cleveland, leading it to one of the busiest in the world. He has over 176 peer-
reviewed articles and more than 35 chapters on epilepsy and epilepsy surgery. Dr. Bingaman has served on the
Executive Committee of the Congress of Neurological Surgeons and as Chair of the Council of State
Neurosurgical Societies. He also served in the United States Army Reserve as a combat neurosurgeon achieving
the rank of Lieutenant Colonel.

William Bingaman discloses he has no financial relationships to disclose relevant to this activity.

Gretchen Birbeck, M.D., M.P.H. DTMH (Faculty)

Gretchen L. Birbeck, MD MPH DTMH is the Rykenboer Professor of Neurology in the Epilepsy Division of the
University of Rochester Department of Neurology. Much of Professor Birbeck work and clinical care is based in
Africa where she is Director for the Chikankata Epilepsy Care Team in rural Zambia and the Principal for the
University Teaching Hospital';s Neurology REsearch Office in Lusaka, Zambia. Her interests include clinical
epidemiological studies to identify risk factors for epilepsy and interventions aimed at epilepsy prevention and
amelioration of the social, medical and economic consequences of epilepsy.

Gretchen Birbeck discloses she has no financial relationships to disclose relevant to this activity

Jerome Engel, MD, PhD (Faculty)

Jerome Engel, Jr., MD, PhD, is Director of the UCLA Seizure Disorder Center, The Jonathan Sinay Distinguished
Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences, and a member of the Brain
Research Institute. He completed his BA at Cornell, his MD/PhD at Stanford, his residency at Einstein. He was
president of the ACNS, the AES, and the ILAE, and co-chair of the WHO Global Campaign against Epilepsy. He
lists over 1,000 publications and over 30 books, including Epilepsy: A Comprehensive Textbook, Surgical
Treatment of the Epilepsies, and Seizures and Epilepsy. He is principal investigator on two NINDS grants, and
has received numerous awards and honors, including a Fulbright Scholarship, a Guggenheim Fellowship, the
Javits Award from the NINDS, and the ILAE Lifetime Achievement Award.

Jerome Engel discloses he has no financial relationships to disclose relevant to this activity.

Tatiana Falcone, MD (Faculty)

Dr. Falcone graduated medicine from Universidad Pontificia Bolivariana in Medellin Colombia, where she also
trained in General Psychiatry and Epidemiology. She continue her training in general and Child Psychiatry at
Cleveland Clinic. She participated in the 3 month electrophysiology course at Cleveland Clinic. For the last 10
years she is the child psychiatrist for Pediatric Epilepsy at Cleveland Clinic. Her research has focus in improving
the integration of behavioral care for children with epilepsy, also reducing bullying and stigma (Project Stand
Up). Dr. Falcone has been awarded multiple federal grants to improve the care for children with epilepsy,
including Project COPE, tCARE and IMPACTT. Also Dr. Falcone is currentlly the PI on a NIMH grant to identify
biomarkers to prevent suicide in youth.

Tatiana Faclone discloses she has no financial relationships to disclose relevant to this activity.

Robert Fisher, M.D., Ph.D. (Faculty)

Dr. Fisher is Maslah Saul MD Professor and Director of the Stanford Epilepsy Center and EEG lab. He received
awards from the Klingenstein Foundation, Epilepsy Foundation, CURE and NIH. He has published about 205
peer-reviewed articles and 3 books. He was named from 1996 to 2017 in Best Doctors in America. He received
the Ambassador Award from ILAE, the 2005 American Epilepsy Society Service Award and the 2006 Annual
Clinical Research Award. Dr. Fisher is Past-President of the American Epilepsy Society, and has served on the
Board of the ILAE and as Editor-in-Chief of the Journal, Epilepsia. He is past Editor-in-Chief of epilepsy.com. Dr.
Fisher led the project to develop a formal definition of who has epilepsy and an update of seizure type
classification. His recent research is on new devices to detect and treat seizures.

Robert Fisher discloses receiving the following support: Engage Therapeutics: Consulting Fees

Satyanarayana Gedela, M.D., MRCP (Faculty)

Satyanarayana Gedela, MD, MRCP, Director of Epilepsy and Director of Epilepsy Surgery Program, Nationwide
Children';s Hospital, Associate Professor of Pediatrics and Neurology, Ohio State University, Columbus, Ohio.

Satyanarayana Gedela discloses he has no financial relationships to disclose relevant to this activity.

Ajay Gupta, MD (Faculty)

Ajay Gupta is the Head of Pediatric Epilepsy at The Cleveland Clinic. He is Associate Professor at The Cleveland
Clinic Lerner College of Medicine, Case Western Reserve University. Dr. Gupta is also the founder director of
multidisciplinary Tuberous Sclerosis Program at the Cleveland Clinic. Dr. Gupta serves on the editorial board of
Epilepsy Currents, Pediatric Neurology, and previously served on the editorial board of Epileptic Disorders. He
also serves on the CME committees, Peer-review panels, Scientific Program Committees, and Professional
Advisory Boards of National and International academic societies and associations. Dr. Gupta has chaired,
directed and served as faculty in Epilepsy/EEG courses, workshops, and seminars at the national and
international conferences.

Ajay Gupta discloses receiving the following support: Eisai: Consulting Fees; Mallinckrodt: Honoraria; Sunovion:
Consulting Fees

Ingo Helbig, MD (Faculty)

Ingo Helbig, MD is a child neurologist and epilepsy genetics researcher at the Children’s Hospital of Philadelphia.
He received his MD from the University of Heidelberg, Germany, and completed his pediatric and child
neurology residency in Melbourne (Australia), Kiel (Germany), and Philadelphia (USA). He is currently an
Assistant Professor of Neurology and Pediatrics at the Perelman School of Medicine at the University of
Pennsylvania and The Children’s Hospital of Philadelphia. His group has contributed to the major gene
discoveries in human epilepsies over the last decade and is currently expanding its focus to apply data-driven
approaches to understand epilepsy phenotypes.
Ingo Helbig discloses he has no financial relationships to disclose relevant to this activity.

Graeme Jackson, M.D., FRACP (Faculty)

Professor Graeme Jackson is a Neurologist in Melbourne Australia and Senior Deputy Director of The Florey
Institute of Neuroscience & Mental Health, Professorial Fellow of the University of Melbourne and Practitioner
Fellow of the Australian National Health and Medical Research Council (NHMRC). He has received awards for
highest ranked clinical fellow and with other chief investigators, for highest ranked research program of the
NHMRC and the Javitz award of the NIH (USA). He has been an Associate Editor of Epilepsia (Imaging) and is on
the Diagnostic Methods commission of the ILAE. In recognition of his seminal and sustained research related to
advances in the treatment of Epilepsy, he was awarded the 2016 Epilepsy Research Recognition Award of the
AES for Clinical Science.

Graeme Jackson discloses he has no financial relationships to disclose relevant to this activity.

Sejal Jain, M.D. (Faculty)

Dr. Sejal Jain, MD is an Associate Professor of Neurology and Pediatrics at the University of Arizona. She is a
pediatric epileptologist with fellowship training in Sleep Medicine. Her research interest includes sleep disorders
in epilepsy. Her clinical interests are medical and surgical management of epilepsy and treatment of sleep
disorders.

Sejal Jain discloses she has no financial relationships to disclose relevant to this activity.

Colin Josephson, M.D., M.Sc. (Faculty)

Colin Josephson MD, MSc, FRCPC, CSCN (EEG) is an Assistant Professor of Neurology and clinician-scientist in the
Department of Clinical Neurosciences, O';Brien Institute for Public Health, and the Hotchkiss Brain Institute. He
completed his medical school and neurology residency at Dalhousie University and has completed fellowships in
intracranial vascular malformations at the University of Edinburgh and epilepsy and EEG at the University of
Calgary. His major research interest using electronic health records to advance epilepsy research. He has been
the recipient of the 2010 European Stroke Conference Young Investigator of the Year Award and has received
funding through the 2014 ABA/AAN/AES/EF Susan S. Spencer Clinical Research Training Fellowship in Epilepsy.

Colin Josephson discloses he has no financial relationships to disclose relevant to this activity.

Ilo Leppik, MD (Faculty)

Dr. Ilo E. Leppik is a Professor of Pharmacy and Neurology at the U. of Minnesota. Key offices: President of the
AES, chair of EFA professional advisory board. He maintains an active practice with UMP MINCEP Epilepsy Care.
Honors: The Penfield Prize from MNI, and the 2007 William G. Lennox Award from AES. He was a founding and
managing editor of Epilepsy Research. Present research interests are canine epilepsy, development of new
drugs for epilepsy (including cannabis) and epilepsy in elderly, especially in nursing homes. He has published
over 245 peer-reviewed articles. He wrote Contemporary Diagnosis and Management of the Patient With
Epilepsy (650,000 copies) and Epilepsy: A Guide to Balance Your Life, sponsored by the AAN.

Ilo Leppik discloses he has no financial relationships to disclose relevant to this activity.

Daniel Lowenstein, MD (Faculty)

Daniel H. Lowenstein, M.D. is the Executive Vice Chancellor and Provost, and the Robert B. and Ellinor Aird
Professor and Vice-Chairman of Neurology at the University of California, San Francisco (UCSF). He received his
BA in Mathematics from the University of Colorado and MD from Harvard Medical School, and completed
neurology residency training at UCSF. Dr. Lowenstein is a clinician-scientist who cares for patients and studies
both basic science and clinical aspects of epilepsy. Dr. Lowenstein has been actively involved in advancing the
cause of epilepsy at the national and international level, and has held leadership posts in numerous
organizations, including the American Epilepsy Society, the International League Against Epilepsy, and the
National Institute of Neurological Disorders and Stroke.

Daniel Lowenstein discloses receiving the following support: Eisai: Provides funds to the Epilepsy Study
Consortium, which oversees funding of the Human Epilepsy Project; Lundbeck: Provides funds to the Epilepsy
Study Consortium, which oversees funding of the Human Epilepsy Project; Pfizer: Provides funds to the Epilepsy
Study Consortium, which oversees funding of the Human Epilepsy Project; Sunovion: Provides funds to the
Epilepsy Study Consortium, which oversees funding of the Human Epilepsy Project; UCB Pharma: UCB provides
funds to the Epilepsy Study Consortium, which oversees funding of the Human Epilepsy Project

Guy McKhann, M.D. (Faculty)

Dr. Guy M. McKhann is the Director of Epilepsy Surgery and Brain Mapping at Columbia University Medical
Center/New York Presbyterian Hospital. His areas of particular clinical expertise are epilepsy surgery, including
stereo EEG and stereotactic laser ablation (LITT); minimally invasive brain tumor microneurosurgery; Gamma
Knife radiosurgery; deep brain stimulation; neuroendoscopy; and cerebrospinal fluid shunting. Dr. McKhann
also works as a translational neuroscientist. His research has been funded by the National Institutes of Health,
the American Association of Neurological Surgeons, the Klingenstein Foundation, the Charles A. Dana
Foundation, the New York Academy of Medicine, Parents Against Childhood Epilepsy, the Irving Center for
Clinical Research, and the Tuberous Sclerosis Alliance.

Guy McKhann discloses he has no financial relationships to disclose relevant to this activity.

Eli Mizrahi, M.D. (Faculty)

Dr. Mizrahi is Chair, Department of Neurology and Professor of Neurology and Pediatrics, Baylor College of
Medicine, Houston, TX. He holds the James A. Quigley Endowed Chair in Pediatric Neurology. He is a long-
standing member of the American Epilepsy Society and throughout his career, has been active in epilepsy
clinical care, clinical research, medical education and advocacy for those with epilepsy.
He received his undergraduate degree from Emory University, Atlanta, GA, his medical degree from the
University of Miami, FL and completed residencies in pediatrics at Albert Einstein College of Medicine, Bronx, NY
and in neurology at Stanford University Medical Center, Palo Alto, CA. Following the completion of a fellowship
in clinical neurophysiology at Baylor he joined the faculty as member of the Peter Kellaway Section of
Neurophysiology, Department of Neurology and the Section of Neurology and Developmental Neuroscience,
Department of Pediatrics. There he eventually directed the Baylor Comprehensive Epilepsy Center, the Peter
Kellaway Section of Neurophysiology, and the Fellowship in Clinical Neurophysiology before being named Chair
in 2008. He has served AES in a number of roles on special and standing committees and on the Board of
Directors. He has also served as president, American Clinical Neurophysiology Society; member of the Board of
Directors of the Epilepsy Foundation; Chair, Professional Advisory Board of EF; and member of the Commission
for Pediatrics, International League Against Epilepsy. He was recently named Ambassador for Epilepsy by ILAE
and International Bureau for Epilepsy and recognized by the EF as a World Changer in Health Care. He has
received the AES/Milken Family Medical Foundation Clinical Research Award and the international Michael
Prize. He has reviewed for AES/EF research grant programs, NIH, FDA, and journals related to neurology,
epilepsy and clinical neurophysiology. He is certified by the American Board of Psychiatry and Neurology
including subspecialty qualifications in Clinical Neurophysiology and in Epilepsy.
Eli Mizrahi discloses receiving the following support: Demos Publishing: Royalties; Elsevier Publishing: Royalties;
McGraw Hill Publishing: Royalties; Neuropace Inc: Contracted Research; UpToDate: Royalties; Wolters Kluwer
Publishing: Royalties

Jeremy Moeller, M.D. (Faculty)

Jeremy Moeller, MD, MSc, FRCPC is Assistant Professor and Residency Program Director in the Department of
Neurology at Yale School of Medicine. He received his medical degree and residency training at Dalhousie
University in Halifax, Canada, and his training in Epilepsy and Clinical Neurophysiology at Columbia University
Medical Center. His major area of scholarly interest is in medical education, particularly neurology education.

Jeremy Moeller discloses he has no financial relationships to disclose relevant to this activity.

Kimberly Pargeon, MD (Faculty)

Kimberly Pargeon, MD is an attending physician/assistant professor at Weill Cornell Medical Center/New York
Presbyterian in the Department of Neurology/Division of Epilepsy. After receiving her medical degree from The
Ohio State University in Columbus, OH, she completed her Neurology residency at the University of Maryland
Medical Center in Baltimore, MD. Following residency, she completed a 2-year fellowship in clinical
neurophysiology and epilepsy at Columbia University/New York-Presbyterian in New York. After fellowship, she
joined the faculty at Montefiore Medical Center in the Bronx, NY, and then most recently, she was on faculty at
the Johns Hopkins Hospital in Baltimore, MD, both in the departments of Neurology, prior to her present faculty
position at Weill Cornell Medical Center.

Kimberly Pargeon discloses she has no financial relationships to disclose relevant to this activity.

Renee Shellhaas, M.D., M.S. (Faculty)

Renée Shellhaas, MD, MS, is a Clinical Associate Professor of Pediatrics at the University of Michigan. She
received her MD from the University of Michigan and completed residency in Pediatric Neurology and a
fellowship in Clinical Neurophysiology at the Children’s Hospital of Philadelphia. Following her fellowship, she
returned to the University of Michigan, where she joined the faculty and completed a Master’s degree in Clinical
Research Design and Statistical Analysis at the UM School of Public Health. Dr. Shellhaas’ clinical practice and
research focus on neonatal brain monitoring and early life epilepsy. Her research is funded by NIH, PCORI, the
Pediatric Epilepsy Research Foundation, the American Sleep Medicine Foundation, and the University of
Michigan';s Charles Woodson Pediatric Research Fund.

Renee Shellhaas discloses receiving the following support: UpToDate: Royalties

Akila Venkataraman, M.D. (Faculty)

Akila Venkataraman, MD is a pediatric neurologist/pediatric epileptologist, affiliated with Staten Island
Univeristy Hospital - Northwell Health, NY. She is an Assistant Professor at the Hofstra Northwell School of
Medicine. Dr. Venkataraman earned her medical degree from Kasturba Medical College in Manipal, India and
completed her residency in Child Neurology at the State University of New York at Buffalo. She completed her
fellowship in Epilepsy at Long Island Jewish Medical Center. She has been on the Professional Advisory Board of
the Epilepsy Foundation of Metropolitan New York and has been associated with the activities of the Epilepsy
Foundation for many years. She also serves on several committees for the Child Neurology Society and
American Epilepsy Society.

Akila Venkataraman discloses she has no financial relationships to disclose relevant to this activity.

CME REVIEWERS
Timothy Ambrose discloses he has not financial relationships to disclose relevant to this activity.
Susanta Bandyopadhyay discloses he has not financial relationships to disclose relevant to this activity.
Jocelyn Cheng discloses she has not financial relationships to disclose relevant to this activity.
Lauren Frey discloses receiving the follow support: Glaxo-Smith-Kline: Stockholder/Ownership Interest
(excluding diversified mutual funds); Johnson and Johnson: Stockholder/Ownership Interest (excluding
diversified mutual funds)
John Pollard discloses receiving the following support: Cognizance Biomarkers, LLC: Other Financial or Material
Support, Own 1.5% of company with no current value.
Ignacio Valencia discloses he has not financial relationships to disclose relevant to this activity.
David Wheeler discloses receiving the following support: Novartis Pharmaceuticals () : Contracted Research
Courtney Wusthoff discloses she has not financial relationships to disclose relevant to this activity.

PHARMACY/NURSE PLANNERS
Gigi Smith, PhD, RN, CPNP-PC: No financial relationships to disclose relevant to this activity.
Dorothy Caputo, MA, BSN, RN - Lead Nurse Planner of AKH: No financial relationships to disclose relevant to this
activity.
Dorothy Duffy, PharmD - Pharmacy Reviewer of AKH: No financial relationships to disclose relevant to this
activity.

AKH STAFF / AES STAFF

AKH staff and planners: No financial relationships to disclose relevant to this activity.
AES staff and planners: No financial relationships to disclose relevant to this activity.

CME claim for Physicians and participation – Deadline: February 28, 2018
Visit https://www.aesnet.org/annual_meeting/program/ce_cme or watch your email for the notification and
link.

For assistance, contact Experient Customer Service:

800-974-9769 (US and Canada)
001-847-996-5892 (International)
aes@experient-inc.com
Hours: Monday – Friday, 8:00 a.m. – 5:00 p.m. (CT)
AES needs your feedback. Don’t forget to complete the session evaluations along with your credit claim.

CE claim for Nurses and Pharmacists – Deadline: January 16, 2018

Visit http://www.akhcme.com/akhcme/pages/2017AES or watch your email for the notification and link.
For assistance, contact AKH at jgoldman@akhcme.com.

DISCLAIMER
Opinions expressed with regard to unapproved uses of products are solely those of the faculty and are not
endorsed by the American Epilepsy Society or any manufacturers of pharmaceuticals.
 11/29/2017

Birth history:
Epilepsy Across the Lifespan
• Antenatally, the baby’s mother noticed increased movements after
Case Presentation 1: Neonate with myoclonus
Akila Venkataraman, MD
20 weeks gestation, but otherwise uneventful pregnancy
Division of Pediatric Neurology and Epilepsy • 37 weeks gestation NSVD with a birth weight of 7lbs 2oz and a
Staten Island University Hospital, Northwell Health
Staten Island, NY head circumference of 35 cm (50th%ile)
• There is no significant family history of epilepsy, or other
neurological disorders and no consanguinity.

Disclosure Hospital admission:

Name of Type of • The baby was sent immediately to the Emergency Room, where
Commercial Interest Relationship examination revealed moderate hypotonia, a poor suck and a weak cry
• None • None
• There were no dysmorphic features and the baby was afebrile
• Within a few hours of presenting to the ER, the baby was noted to have
shallow breathing and frequent apneic episodes requiring ventilatory
support. Soon after, he developed very frequent myoclonic jerks and was
given an IV bolus of phenobarbital 20mg/kg

Case Presentation: Admission diagnostics:

• 3.5 week old FT baby boy was brought to the pediatrician’s • His blood did not show any evidence of infection, acidosis,
office with one week history of poor feeding, lethargy, jerky or ketosis and he had normal lactate and ammonia levels.
movements of his limbs and poor cry. • Detailed metabolic investigations demonstrated a high
• The baby’s mother does report that the baby has frequent CSF/plasma glycine level of 0.19, (normal > 0.08) with CSF
and constant hiccupping since birth along with sudden glycine of 123 (normal range: 0–10 µmol/l), and plasma
jerking movements that occur repeatedly in all extremities glycine of 649 (normal range: 200–600 µmol/l)

1
 11/29/2017

Neuroimaging Points to consider

• Epilepsies/epilepsy syndromes in the neonatal period

T2‐weighted axial magnetic resonance • Other neurologic comorbidities in the age group that impact
images show high signal intensity of neonatal epilepsy
the central tegmental and
corticospinal tracts and an enlarged • How does the age of the patient impact the diagnostic work up
posterior CSF space consistent with a and management?
mega cisterna magna
• Amplitude integrated EEG vs polygraphic video EEG in the NICU
Setting the stage for epilepsy across the lifespan…

EEG findings
EEG showed a characteristic
burst‐suppression pattern
including bursts of high voltage
complex waves of 1‐3 sec,
arising periodically from a
hypoactive background. There
was no correlation between
bursts and the clinical myoclonic
jerks.

Hospital course:

• After confirming the diagnosis of non‐ketotic hyperglycinemia, he

was started on oral dextromethorphan, sodium benzoate and a
ketogenic diet with partial improvement in his seizure control.
• He also continued on maintenance phenobarbital at 8mg/kg/day
• Genetic testing including testing for AMT, GLDC and GCSH gene
mutations was initiated

2
 11/29/2017

Disclosure
Top four imaging diagnoses you can’t miss in Name of Type of
each age group Commercial Interest Relationship
Graeme Jackson, BSc(Hons),MB.BS.,MD,FRACP • none • n/a
Florey Institute, Austin Hospital and University of
Melbourne, Australia.

Learning Objectives What information is essential in all patients with epilepsy

• To consider the aspects of MRI that an

epileptologist should be responsible for
(protocol and review). Clinical History Context
• To understand the imaging features of BOSD,
EEG Function
and other imaging findings that may be hard to
detect. Structural MRI with epilepsy protocol Structure
• To use iterative reviewing of the MRI in the
context of other investigations.

The four top imaging diagnoses you can’t miss

as an epileptologist

‘Obvious’ abnormalities ‘Subtle but obvious’ requires review with other information

Hippocampal sclerosis For sensitivity needs a dedicated epilepsy protocol

Malformations of cortical development (MCD) Good quality imaging

Nothing Nothing is a diagnosis NOT a default equal to ’nothing detected’

1
 11/29/2017

Review images in the

Hippocampal sclerosis hippocampal axis

Subtle lesions that can be missed

• focal cortical dysplasia
• mild or bilateral hippocampal sclerosis
• temporal encephalocele
• small hypothalamic hamartoma
• polymicrogyria
• subcortical band & periventricular nodular heterotopia
JACKSON, G.D., BERKOVIC, S.F., TRESS, • mild tuberous sclerosis
B.M., KALNINS, R.M., FABINYI, G.C., • parahippocampal dysplasia
BLADIN, P.F. ‐
Hippocampal sclerosis can be reliably • bilateral perisylvian polymicrogyria
detected by magnetic resonance imaging.
Neurology. 40: pp. 1869‐75 (1990)

Infant Infant
Look for abnormal myelination on early scans
Look for abnormal myelination on early scans

4 weeks 8 months 22 months 3 years 4 years

2
 11/29/2017

Infant Infant – multilobar dysplasia v. genetic

Look for abnormal grey matter before myelination starts

9 month old infant

Frequent focal seizures in newborn period and at
4 months
Normal MRI, metabolic testing and gene panel
Left sided seizures
Slow development, poor feeding and health
Seizures uncontrolled at 9 month admission

DDx eg SCN1A encephalopathy KCNT1

‘Normal’ MRI

Infant – multilobar dysplasia v. genetic Child Small type II dysplasia

Bottom of sulcus Crown of Gyrus (TS‐like) Complex

BOSD – bottom of sulcus

Seizures can present in infancy
preschool, school years or adult

Focal epilepsy with localisation

consistent with abnormality
Reslicing and
Complete seizure freedom curvilinear surfaces
sometimes for years can help

Development normal

Seizure free with resection of

cortical BOSD in 90%

Hoffmann et al AJNR 2011;196:881

3
 11/29/2017

Small BOSD “Rachel is 17 years of age, she had her first seizure in Year 10
at the age of 15. This lasted a few seconds and was associated
with her dropping an ice-cream, having a blank appearance of
her face and pointing her right finger. The seizure pattern
evolved to being nocturnal with severe convulsive seizures at least
once a month.

She is currently taking levetiracetam 250mg and 500mg at

night, Vimpat 100mg morning and night, and recently started
on clobazam 5mg at night because of frequent severe
nocturnal seizures.

She complains of always feeling tired …. seizures are at 3 to 4

o’clock in the morning and the days after seizures she has a
severe headache and is very lethargic and unwell.”

Small BOSD 13x7x6mm

Seizure free 3 years on Carbamazepine 200mg bd

Adult Adult
SP cont.
SP onset of epilepsy age 18
Parahippocamap changes then noted….
Nonsepcific aura, head turn to
right, speaks gibberish, loss of Subsequent implantation with
awareness. Seizures commonly in parahippocampal electrodes confirmed
sleep. Rare daytime tonic clonic this as the site of origin.
seizures. Seizure free off medications 20 years.
EEG right frontotemporal

ICE seizure onset right inferior

frontal lobe ‐ no change in seizure
pattern.

4
 11/29/2017

Parahippocampal epilepsy Pilay et al, Epilepsia 50(12);2611‐2618:2009

Temporal encephalocele
Adolescent to adult onset
Even when unilateral can present as: Complex partial seizures began at age 24 years,
manifesting as impaired consciousness, right hand
TLE, Bilateral TLE, contralateral TLE posturing, and head version. At the time of assessment
Frontal lobe epilepsy with hypermotor the patient was having multiple daily attacks, frequently
seizures. with secondary generalization.

EEG of seizures showed onset F7, T1, T3

PET hypometabolism L temporal. Normal memory

The electro‐ clinical diagnosis was ‘‘lesion negative’’ left

temporal lobe epilepsy (TLE).

Surgery not offered because of risk to verbal memory in

a highly functional individual.

Abou‐Hamden et al Epilepsia 2010;51:2199

Temporal encephalocele Encephalopathy and LGS Archer et al, Frontiers in Neurology 2014;5:225

Onset adolescent to adult

Present as typical lateralised TLE

Excellent outcome (all seizure free)

with minimal resection of the
encephalocele.

Can be multiple at surgery.

Abou‐Hamden et al Epilepsia 2010;51:2199

Dibbens et al, Nature Genetics 2013;45:546

Genetics and structural abnormality DEPDC5 and familial focal epilepsy Aged
Old age is a common time to develop
new epilepsy (>60)

Atrophy (more than half)

Focal lesions – infarcts, hemorrhages,
granuloma, tumor gliosis ~ 60%
Condsider stroke and medications

Usually assumed that the epilepsy is

focal (most studies about two thirds)

BUT cause not identified in at least one‐

third.

Sinha Ann Indian Acad Neurology 2012;15:273

5
 11/29/2017

Impact on Clinical Care and Practice Acknowledgements Melbourne Research team – retreat 2017
Austin Epilepsy Clinical Team
• Imaging is a core competency for epileptologists Sam Berkovic
John Archer
• Need to ensure an epilepsy protocol and good quality study David Vaughan
• Review images in the context of other localizing data Moksh Sethi
Ingrid Scheffer
• Finding a focal abnormality can change outcome Saul Mullen
Greg Fitt
• Consider the findings that have good surgical outcome
Royal Childrens Hospital
• HS, BOSD, Parahippocampal dysplasia, encephalocele, Simon Harvey
hypothalamic hamartoma and others. Rick Leventer
Simone Mandelstam
Funding
National Health and Medical Research Council (NHMRC) Australia
Lots of Collaborators Victoria Government Operational and Infrastructure fund
All the people in my group National Imaging Facility
Victorian Biomedical Imaging capability

References HS
Jackson et al, Neurology 1990;40:1869
Jackson et al, AJNR 1993;14:753
BOSD
Hofman et al, AJNR 2011;196:881
Harvey et al Neurology 2015;84:2021
Jackson et al Neurology 2017;88:
Parahippocampal epilepsy
Pillay et al, Epilepsia 2009;50:2611
Encephalocele
Abou‐Hamden et al Epilepsia 2010;51:2199
Encephalopathy
References mentioned in this talk Archer et al, Frontiers in Neurology 2014;5:225
for further reading. McTague et al The Lancet Neurology 2016;15;304
Elderly
Note this speaker did not intend a Sinha et al, Ann Indian Acad Neurology 2012;15:273
review of the work in the field. Genetics
Dibbens et al, Nature Genetics 2013;45:546

6
 11/29/2017

Disclosures
Just How Valuable is Amplitude‐Integrated • Research funding: PCORI, NIH, Pediatric Epilepsy
EEG in Neonatal Seizure Detection? Research Foundation, American Sleep Medicine
Renée Shellhaas, MD, MS Foundation, University of Michigan
• Royalties: UpToDate
• Other: Consultant for Epilepsy Study Consortium

Learning Objectives The Bottom Line

• Understand the concepts behind amplitude‐integrated EEG.

• List the best uses for aEEG. If using aEEG means people are thinking about babies’ brains,
that is a good thing!
• Explain the pro’s and con’s of aEEG:
• For background description
• For seizure detection

Why are we talking about this? Neonatal seizures are common and consequential.
Diagnosis by clinical observation is challenging:
‐ many abnormal paroxysmal events are NOT seizures.
‐ many seizures have no observable clinical manifestation.

Therefore, EEG is required for accurate diagnosis of neonatal seizures.

1
 11/29/2017

What is amplitude‐integrated EEG? What is amplitude‐integrated EEG (aEEG)?

F P 1 -T 3

T 3 -O 1

7 5 uV
2 se c
F P 2 -T 4

T 4 -O 2

Standard neonatal EEG

F P 1 -C 3

C 3 -O 1

F P 2 -C 4

C 4 -O 2

T 3 -C 3

C 3 -C Z

C Z -C 4

C 4 -T 4

C 3 -C 4

Single channel raw EEG

Filter <2Hz and >15Hz, rectify, smooth, amplitude‐integrate

Amplitude Integrated EEG

(aEEG)

Normal or Continuous Normal Voltage (CNV) Normal or Continuous Normal Voltage (CNV)

10 seconds of raw EEG

Normal or Continuous Normal Voltage (CNV) Normal or Continuous Normal Voltage (CNV)

Semi
Log
Scale

3 hours of aEEG

2
 11/29/2017

Normal or Continuous Normal Voltage (CNV) Normal or Continuous Normal Voltage (CNV)

Which aEEG background classification to use?

• 144 neonatal EEGs

Advanced classification
Simple classification

– Conventional EEG background categorized

– Single channel aEEG assessed by neonatologists
Simple Advanced
Multirater к Multirater к
0.66 0.44

No difference based on aEEG reader experience or presence of seizures.

Thoresen. Pediatrics.
2010; 126:e131–e139 Shellhaas. J Pediatr. 2008;153:369‐74.

Preterm versus term neonates aEEG background is often used as a predictor of outcome.

Any aEEG background abnormality = predictor of poor outcome

Large amplitude changes are normal Amplitude changes may be less dramatic For outcome of DQ <70, CP, or death:
Frequencies are slower Frequencies are a bit faster sensitivity = 0.83 (0.69‐0.92), specificity 0.83 (0/77‐0.87)
Seizures more likely frontal/occipital Seizures more likely central/temporal

Pediatrics. 2017;139(2):e20161951.

3
 11/29/2017

aEEG background is often used as a predictor of outcome. What about seizures?

Best to use aEEG background at 72 hours for outcome prediction

in the era of therapeutic hypothermia.
[vs 36 hours for normothermia]

PLoS One. 2016;11:e0165744.

aEEG is often used to screen for seizures Seizure easily seen in C3C4 channel.
F p 1 -T 3

T 3 -O 1

F p 2 -T 4

T 4 -O 2

F p 1 -C 3

C 3 -O 1

F p 2 -C 4

C 4 -O 2

T 3 -C 3

C 3 -C z

C z -C 4

C 4 -T 4

C 3 -C 4

100 uV
2 sec

Seizure not seen in C3C4 channel. Most neonatal seizures are brief.
F p 1 -T 3
250
T 3 -O 1

F p 2 -T 4 200

T 4 -O 2

150 N=851 seizures

F p 1 -C 3

C 3 -O 1

100

F p 2 -C 4

C 4 -O 2
50

T 3 -C 3

0
C 3 -C z
10 to 30 31 to 60 61 to 90 91 to 121 to 151 to 181 to 211 to 241 to 271 to 301 to 601 to >900
C z -C 4 120 150 180 210 240 270 300 600 900
100 uV
2 sec
60% of neonatal seizures last < 90 seconds  90 sec = 1.3mm on aEEG
C 4 -T 4

C 3 -C 4

Shellhaas. Pediatrics. 2007;120:770‐777.

4
 11/29/2017

aEEG is specific, but not sensitive, for seizure detection. Seizures on aEEG
• 125 routine EEGs with seizures (+19 without), • Factors related to seizure detection by aEEG
recorded from 140 term newborns. (multivariate analysis*):
• Created single‐channel aEEG traces. • Neonatologists’ level of experience with aEEG
– Interpreted by 6 neonatologists with varying expertise. • Visibility in C3C4 raw EEG channel
% of 125 aEEG records with % of 851 individual seizures • Seizure duration
seizures detected detected • Peak‐to‐peak amplitude *P=<0.001 for all variables
Mean = 40.3% ± 16.8% Mean = 25.5% ± 10.6% • Seizure count per hour
(range: 22-57%) (range: 12-38%) Inherent features of neonatal seizures (short duration & low amplitude)
make detection by aEEG very difficult.
* No false positive records; very few false positive individual seizures.
Shellhaas. Pediatrics. 2007;120:770‐777. Shellhaas. Pediatrics. 2007;120:770‐777.

Adding “raw” single‐ or dual‐channel EEG helps.

aEEG alone aEEG + “raw” EEG

Sensitivity 39% (25‐80%) 76% (71‐85%)
Specificity 95% (50‐100%) 85% (39‐96%)

Note: accuracy of aEEG for individual seizure detection is highly variable across studies.

Rakshasbhuvankar. Seizure. 2015: 90‐98. Glass. J Child Neurol. 2013;28:1342‐50

Glass. J Child Neurol. 2013;28:1342‐50 Glass. J Child Neurol. 2013;28:1342‐50

5
 11/29/2017

Use conventional EEG to confirm aEEG findings. The most appropriate roles of conventional EEG and aEEG
depend on the setting:
• Brief, infrequent, low amplitude seizures are hardest
to detect on aEEG.
• If you see a seizure, you’re probably right.
• For research involving detailed diagnosis and quantification
• If you don’t see seizures… doesn’t mean they aren’t there.
of neonatal seizures, conventional EEG is superior.
• Don’t declare victory based on aEEG.
• For clinical care of neonates, aEEG can often be
appropriately used, supplemented by conventional EEG.
• Suspect seizures on aEEG  conventional EEG.
– Confirm diagnosis
– Direct treatment
Shellhaas, et al. ACNS GUIDELINE. J Clin Neurophysiol. 2011;28:611‐7.

Does aEEG monitoring influence NICU care? Summary of aEEG features in clinical practice

YES! Pro’s Con’s

Readily available at the bedside EEGer might not be involved
Use of EEG or aEEG monitoring is associated with: “Simple” to implement and Important learning curve
1) increased diagnostic precision interpret
2) lower seizure burden Background patterns have Artifact can cause trouble
3) And – maybe – LESS anti‐seizure medication administration! predictive value
Can detect some seizures Specific but not sensitive for
seizure detection
Jan. Dev Neurosci. 2017; 39:82‐88
Shellhaas & Barks. Pediatr Neurol. 2012; 46:32‐35
Wietstock. J Child Neurol. 2015;30:1135‐1141
Van Rooji. Pediatrics. 2010; 125:e358‐366

Why do people use aEEG? Do people really use aEEG?

1. They care about babies’ brains. Yes!

2. They want to understand the EEG patterns.
2015 Survey of Neonatologists:
3. They are worried about seizures.
• 55% of 654 survey respondents reported using aEEG.
4. Conventional EEG is not always available. • 87% aEEG interpreted independently by neonatologists.
• ~50% self taught or taught via hospital‐based training.

Shah. Am J Perinatol. 2015;32:755‐760

6
 11/29/2017

Impact on Clinical Care and Practice aEEG=opportunity for collaboration

• aEEG
• Is often used in NICUs
• Offers opportunity for brain‐oriented care!

• aEEG is specific, but not sensitive for seizure detection.

• Confirmation of aEEG findings with conventional EEG is
ideal.

aEEG = cEEG =

The Bottom Line

If using aEEG means people are thinking about babies’ brains,

that is a good thing!

7
 17-10-25

Disclosure
Epilepsy or just ge5ng old? Diagnos;c Name of Type of
challenges in elderly Commercial Interest Rela;onship
Colin Josephson MD, MSc, FRCPC, CSCN (EEG) • Nil • Nil
Assistant Professor of Neurology and Community Health Sciences
University of Calgary

Learning Objec;ves Seizures in the elderly

• Focal seizures may be common (up to 38%) and can be
• Objec&ve 1: to be familiar with the differen&al diagnosis ‘atypical’ in the elderly (i.e. extra-temporal)
of epilepsy in the elderly
• Objec;ve 2: to be familiar with common ae;ologies of
• History is the key:
epilepsy in the elderly
– Preictal (premonitory) symptoms including pallor, cyanosis
• Objec;ve 3: to be familiar with the ‘risks’ of inves;ga;ng – Ictal semiology (abnormal movements, tongue bi;ng, urinary incon;nence,
the elderly with ‘spells’ impaired awareness)
– Pos;ctal symptoms including self-limited confusion, speech disturbance,
headache, Todd’s paresis
Rowan et al., Neurology, 2005; Stephen and Brodie, Lancet, 2000

Imita;on is the sincerest form of flacery More mimics...

Differen&al Symptoms Inves&ga&ons Differen&al Symptoms Inves&ga&ons
Cardiac arrhythmia • Abrupt loss of consciousness • ECG
• Presyncope • Holter monitor TIA/Stroke • ‘Nega;ve’ symptoms • CT/MRI
• Chest pain • Echocardiogram • ‘Limb-shaking TIA’ • Angiography
• Palpita;ons • Loop recorder
• Dyspnoea
• Tinnitus or visual changes Transient global amnesia • Prominent anterograde amnesia • Imaging; yet diagnosis of
• Typically lasts between 1-10 hours exclusion
Hypo/Hyperglycaemia • Tremor • Blood glucose level during
• Anxiety, palpita;ons, diaphoresis the event
• Paresthesias Delirium • Impaired acen;on/concentra;on • Bloodwork
• Behavioural changes • Sun-downing • CT/MRI
• Stroke-like episodes • Sensory hallucina;ons and illusions • Consider LP
• Coma • Language disturbance
• Hypoac;ve delirium
Syncope • Nausea and vomi;ng • Orthosta;c vitals
• Clammy • ECG Sleep disorder • Periodic leg movements of sleep • Polysomnography
• Visual auras or blurry vision • Holter monitor • REM sleep behaviour disorders
• Palpita;ons or shortness of breath • Echocardiogram PNEA • Rare • Video-EEG telemetry
• Chest pain • Tilt tes;ng
Brodie and Kwan, BMJ, 2005 Brodie and Kwan, BMJ, 2005

1
 17-10-25

Polypharmacy Learning Objec;ves

• Among those older than 65: • Objec;ve 1: to be familiar with the differen;al diagnosis of
– 40% take 5-9 medica;ons epilepsy in the elderly
– 18% take 10+ medica;ons • Objec&ve 2: to be familiar with common ae&ologies of
epilepsy in the elderly
• Account for ~1.5% (1 of 67) • Objec;ve 3: to be familiar with the ‘risks’ of inves;ga;ng
hospitalisa;ons in the elderly the elderly with ‘spells’

Budnitz et al., NEJM, 2011

Opera;onal defini;on of epilepsy 2017 classifica;on of the epilepsies

• Once a seizure is confirmed in an elderly pa;ent, it must be
considered focal lesional epilepsy un;l proven otherwise

Fisher et al., Epilesia, 2014 Scheffer et al., Epilepsia, 2017

Features of epilepsy in the elderly Common ae;ologies in the elderly

Ae&ology Frequency

Cerebrovascular disease • 30-50% of cases

Neurodegenera;ve condi;ons • 10-20%

Other (tumour, trauma) • 5-15%

Unknown • 30-50%

Josephson et al., Epilepsia, 2016 Brodie et al., Lancet Neurology, 2009

2
 17-10-25

Ischaemic stroke Ischaemic stroke and the ‘exposome’

• Incidence of epilepsy ranges from 2.5

to 15% aoer 1 year

• Incidence of epilepsy ranges from

7-10% aoer 5 years

Pitkänen et al., Lancet Neurology, 2016 Pitkänen et al., Lancet Neurology, 2016

Haemorrhagic stroke
• Factors associated with
post-stroke epilepsy
• Incidence of
epilepsy ranges
from ~10-20%
Haemorrhage

Early seizures

Pitkänen et al., Lancet Neurology, 2016; Zhang et al., Epilepsy Res, 2014 Ferlazzo et al., Epilepsia, 2016
Cor;cal involvement

Demen;a Tumours

Subota et al., Epilepsia, 2017 van Breemen et al., Lancet Neurol, 2007; Brodie et al., Lancet Neurol, 2009

3
 17-10-25

Autoimmune Autoan;bodies
• Pa;ents with no metabolic or structural
abnormali;es (apart from idiopathic
MTS)

• Median age (range) of posi;ve cases 46

(19-76)
Excluding TPO and
low-;tre GAD65
• Score of 4+ = Sn 82%; Sp 83%; AUC = 0.79

Dubey, JAMA Neurology, 2017 Dubey, JAMA Neurology, 2017

Learning Objec;ves Inves;ga;ons

• Objec;ve 1: to be familiar with the differen;al diagnosis of E&ology Benefits and caveats
epilepsy in the elderly CT/MRI • Abnormal in up to 82%
• Objec;ve 2: to be familiar with common ae;ologies of
Rou;ne scalp EEG • Non-specific abnormali;es in up to 30%
epilepsy in the elderly
• Objec&ve 3: to be familiar with the ‘risks’ of inves&ga&ng
Video-EEG telemetry • Effec;ve with results in up to 80% of pa;ents
the elderly with ‘spells’
Laboratory inves;ga;ons • Should include CVD risk factors and an;cipate
poten;al effects of AEDs

Widdess-Walsh et al., J Clin Neurophysiol, 2005; McBride et al., Epilepsia, 2002; Ramsay et al., Neurology, 2004

Seek and ye shall find... EEG in those greater than 65

• Prevalence of • Non-specific findings

incidental findings on
MRI Finding Frequency

Generalised Slowing • 31%

Focal slowing • 9%

Epilep;form • 5%

Morris et al., BMJ, 2009 Widdess-Walsh et al., J Clin Neurophysiol, 2005

4
 17-10-25

Video-telemetry Diagnosis n (%) Impact on Clinical Care and Prac;ce

Epilepsy 42 (42%)
1. The incidence of epilepsy
• 94 pa;ents (99 PNEA 9 (10%) is increasing in the elderly Await events or:
admissions) aged 60 PNEA and epilepsy 4 (4%) 1) Geriatrics
2) Cardiology
and greater Cataplexy 1 (1%) 2. The diagnosis is more 3) Internal Medicine
Hypotensive episodes 1 (1%) challenging in the elderly 4) Sleep Medicine
Nocturnal confusion 1 (1%) 5) Pharmacists
3. Inves;ga;ons in the 6) Nurse prac;;oners
Episodic vomi;ng 1 (1%) elderly are not without 7) Neuropsychologist
Myoclonic jerks 2 (2%) their ‘risks’ 8) Clinical
psychologist
TIA 2 (2%)
9) Social worker
Behavioral spell NYD 6 (6%) 4. A mul;disciplinary
No events 30 (30%) approach may be ideal
McBride et al., Epilepsia, 2002
Brodie and Kwan, BMJ, 2005

5
 11/29/2017

Disclosure
Value of Genetic Testing in Adults with Epilepsy
Name of Type of
Commercial Interest Relationship
Samuel F Berkovic MD • Eisai • Advisory board, other support
University of Melbourne • SciGen • Advisory board, other support
• UCB Pharma • Advisory board, other support
• Zynerba • Advisory board, contracted research

Learning Objectives Workup of Adult with Epilepsy?

“Genetic testing currently has many clearly defined indications

• History and Physical Examination
in the diagnostic work‐up of adults with epilepsy and should
be routine”
• EEG
• To understand the value of clinical genetic evaluation in
• MRI (most cases)
adult epilepsies
• Gene Panel
• To understand the current place of molecular genetic testing
in adults

Workup of Adult with Epilepsy? An afternoon at the Clinic….Case 1

• Snarling 19 year old youth dragged to clinic ?
first Saturday morning seizure…….
• History and Physical Examination • Clinically ? generalized epilepsy
 What use genetics?
• Clinical Genetic Evaluation  History from mother re wider family
 Diagnosis
? Juvenile Myoclonic Epilepsy
 Why did it occur?
• EEG Juvenile Absence Epilepsy
 Counseling
? Tonic clonic seizure
• MRI (most cases)  Molecular Testing in Genetic Generalized Epilepsy
 Usually not indicated as yet: exceptions
 Early onset absence or Paroxysmal Dystonia – GLUT1 deficiency
• Gene Panel Molecular Genetic Testing in some circumstances  Comorbid ID, ASD, schizophrenia – Copy number variation
 Many affected – GLUT1; GABA receptors;

1
 11/29/2017

An afternoon at the Clinic….. Case 2 An afternoon at the Clinic….Case 3

• Intellectually disabled male brought by his carer with an unusual gait
• Poorly controlled nocturnal seizures • 24 year old woman, first convulsion
• No useful history…….Multiple forms to fill in…… • ? Focal impaired awareness seizures for 6 months
• Right temporal epileptiform discharges
 What use genetics? • No known antecedents, Normal MRI
 History from mother
• Planning pregnancy in next 2 years
 Normal infant
 Multiple febrile seizures, some long
 Never the same after 6 m vaccination…  What use genetics?
 Refractory seizures, regression  Han Chinese background
 Diagnosis?? Dravet Syndrome; SCN1A positive  Decision on use of carbamazepine
 Why bother?  HLA‐B*1502 testing
Closure, end of diagnostic odyssey for family
Better seizure control, cognition, QOL (Catarino et al, Brain 2011)

An afternoon at the Clinic….Case 4 Impact on Clinical Care and Practice

• 26 year old man, refractory focal seizures, probably frontal
• Five drugs in appropriate doses have failed, ? Presurgical evaluation
• Clinical genetic evaluation essential
• Normal MRI • Often overlooked in adult practice
• Maternal aunt and possibly maternal grandfather had seizures • Helps answer “What caused it doctor”
• Aids in counselling assessment
 Molecular Testing in Focal Epilepsy
 Currently, low diagnostic rate in sporadic cases
 Well recognized dominant focal epilepsies (CHRNA4; LGI1; GATOR1 mutations)
• Routine panel screening likely to cause more problems than it solves
 With family history; significant hit rate 5/40 (Perucca P et al. Epileptic Disorders 2017)
• Genetic literacy essential for clinicians
 Does a positive genetic diagnosis preclude surgery? • Specific indications in common adult generalized and focal epilepsies
No single answer • Adults with epileptic encephalopathies poorly studied
Tuberous sclerosis can have very successful surgery
Caution in lesion‐negative cases, even with SEEG localization (Ferri et al, Seizure 2017)
GATOR1 mutations – careful search for subtle focal cortical dysplasia

2
 11/29/2017

Disclosure
Con: Genetic testing in adults is largely Nothing to disclose
research‐oriented and has limited value in
routine clinical practice
Ingo Helbig, M.D.
The Children’s Hospital of Philadelphia

Learning Objectives
• To understand the limitations of genetic testing in adults with epilepsy
STX1B
SLC6A1
Next GABRA1
Generation GABRB3
SIK1
Sequencing Era KCNA2
ALG13
GRIN2B

• Yield of testing not established PURA

KCNB1
KCNC1

• There are few genes for adults with epilepsy DNM1

HCN1
CHD2

• Ongoing research studies (Epi25 project)

SCN8A
SCN2A
GRIN2A
Transitional Era DEPDC5
KCNT1
Channelopathy Era PRRT2
TBC1D24

• Limited clinical utility in adults with epilepsy

STXBP1
PCDH19
LGI1 CACNA1H
GABRG2

• Factors in pediatric patients do not apply GABRA1

SCN1A
SLC2A1
ARX
CDKL5

KCNQ3
KCNQ2 DEPDC5 Gene for familial epilepsy
CHRNA4 SCN1B DNM1 Gene for epileptic encephalopathy

• Clinical implications in adults unclear 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015

• Lack of guidelines
Helbig and Abou Tayoun, 2016
• Field does not implement existing knowledge

1 ‐ Yield of genetic testing in adults is not established

• Yield of 20‐30% for genetic tests

• Applies to the pediatric population only
• Patients with early‐onset, severe epileptic encephalopathy
• In the last 5 years, no gene for sporadic adult epilepsy was discovered

• Ongoing research studies

• Focus in adult epilepsy on gene identification
• Not implementation of existing knowledge
• Identifying genes is a research question
• Ongoing large‐scale research projects (such as Epi25)

1
 11/29/2017

2 – There is limited clinical utility in adults with epilepsy 3 – Clinical implications of epilepsy genetic testing in adults are unclear

• Clinical utility in genetic testing • Lack of guidelines

• “Likelihood that genetic information testing will lead to an • Testing should occur according to established guidelines
improved health outcome” • As of 2017, no comprehensive guidelines have been issued
• Major professional organizations (AAN, AES) not involved in guidelines
• Well‐established examples in pediatric epilepsy
• Medication choices (ketogenic diet in GLUT1 deficiency) • Absence of guidelines
• Concern that commercial interest will dictate testing practice
• Recurrence risk, psychosocial benefits
• Field does not implement existing knowledge
• Situations in adults is different • Example: HLA testing prior to carbamazepine to prevent SJS
• Often less urgency to identify etiology • Need to improve genetic literacy (ILAE Genetics Commission)
• Benefit of medication choices not established • Need to better understand results/consequences of testing
• Lamotrigine in adult patients with Dravet Syndrome? • Need for pre‐test counselling will increase in future

Impact on Clinical Care and Practice

• Con: Genetic testing in adults with epilepsy

• Yield of testing not established
• Limited clinical utility in adults with epilepsy
• Clinical implications in adults unclear

2
 11/29/2017

Disclosure
Case: Elderly Patient with Temporal Lobe
None
Epilepsy and Multiple Medical Co‐morbidities
Kimberly L. Pargeon, MD
Weill Cornell Medical Center
New York, NY

Learning Objectives Case ‐ HPI

• Illustrate complexities of addressing multiple medical • Mr. L is a 74 year‐old man with a history of multiple medical
problems in an elderly patient who is presenting with what problems, including distant history of thyroid cancer s/p
appears to be new onset TLE of unclear etiology partial thyroidectomy on levothyroxine, recent diagnosis of
bladder cancer with treatment TBD, anxiety on standing
alprazolam and buspirone, and anemia of unknown
etiology, presenting for evaluation of new onset events of
altered mental status

Case – HPI, cont. Case – HPI, cont.

• He reports a total of 3 events: • He reports a total of 3 events:

• First event ‐ in 10/2014, night before, missed usual • Next 2 convulsive events in 7/15 & 9/15 seemed to be
dosage of alprazolam and had a few drinks. Following triggered by stress
day, having lunch with son, when noted sudden onset of • Reported a significant increase in stressors, including birth of
sound distortion, then had LOC followed by convulsion his first grandchild, which made him repeatedly think about a
lasting unclear period of time with post‐event confusion baby he and his wife lost to SIDS
• At one of our hospitals, had labs, CTH, but no EEG • Reported that there were certain “trigger words” that would
• Told this was benzo withdrawal. significantly increase his anxiety and one of these led to the
third event, which also started with sound distortion

1
 11/29/2017

Case – HPI, cont. Case – HPI, cont.

• After event #3, taken by EMS to one of our hospitals and • Exam: normal and non‐focal, although he is VERY anxious and
admitted overnight is crying throughout the visit
• Started on phenytoin ER 300 mg daily prior to discharge, • Has no known risk factors for seizures/epilepsy
which he is taking when he sees you today • Labs from the last hospital admission (similar to 2014):
• Reports feeling tired, so admits missing some dosages • WBC 14.3
• Also taking alprazolam, fluticasone prn, levothyroxine, • H/H 12.1/37.1 (Reports this is chronic)
tamsulosin, and zolpidem prn • BUN 21.0 (mildly elevated but Cr is wnl)
• Other labs wnl

Case – Results

• Last CTH at hospital showed “no acute abnormalities”

• You order a brain MRI and routine EEG…
• Brain MRI is done on 3T magnet with epilepsy protocol + gad:
• Shows only minimal chronic microvascular ischemic white
matter disease, but the hippocampi are within normal
limits. There is no evidence of infarct or mass.
• EEG shows…

Conclusions Impact on Clinical Care and Practice

• Had no known risk factors with “negative” good quality imaging
• But, EEG demonstrated left temporal slowing, left anterior temporal • Be mindful of co‐morbid medical conditions in elderly
maximal IEDs • Consider how AEDs may affect those conditions or medications
used to treat those conditions
• Did not tolerate phenytoin ER, which also could have interactions
with some of his other medications • Be mindful of how AEDs may uniquely affect the elderly
• Given other co‐morbidities, particularly his significant anxiety, • Elderly pts may require much lower dosages
another medication was tried to treat both seizures and mood • Consider how AEDs may uniquely exacerbate other conditions in
• Currently, well controlled on carbamazepine ER 800 mg BID the elderly, such as bone health
• Monitoring this with his levothyroxine (with help his of his • Check DXA scans, 25‐OH‐Vitamin D levels
endocrinologist) and his bone health

2
11/29/2017

3
 11/29/2017

Disclosure
Unique Therapeutic Considerations of
Name of Type of
AntiSeizure Drugs in Elderly Commercial Interest Relationship
Ilo E. Leppik, MD,FAAN
Professor of Neurology and Pharmacy
University of Minnesota
• NONE • NONE
Department of Neurology
College of Pharmacy

Learning Objectives Case report= the woman who inspired me

Elderly are heterogeneous 76 year old woman referred to me in 1992 because of new onset of seizures,
Elderly health condition is unstable plus “dementia and cerebellar degeneration”
Arrived in wheelchair. Scheduled for NH placement
Routes of ASD elimination Phenytoin total 19, valproate total 86.
Drug interactions Unbound of both very toxic
Left hospital walking on own.
Pharmacokinetic Loved to dance with husband
Pharmacodynamic Last clinic visit summer 2006, in nursing home
Did not want to partake in activities with “old” women.
Now deceased, wrote book when 89 years old

Age‐Specific Incidence of Epilepsy by Gender in

Rochester, Minnesota
200
1935‐1984
Males
Incidence per 100,000

150
Females
Total
100

50

0
0 5 10 15 20 30 40 50 60 70 80
Age (years)
Annegers JF, et al. Epilepsia. 1995;36:327-33.
Hauser WA, et al. Epilepsia. 1993;34:453-68.

1
 11/29/2017

Considerations in
Geriatric Epilepsy Management
Aging Process

Underlying Seizure
Pathology Frequency

Management

Comorbidities Pharmaco‐kinetics

Medication Side
Effects

Evidence‐based guideline: Management of an Evidence‐based guideline: Management of an

unprovoked first seizure in adults unprovoked first seizure in adults
Adults with an unprovoked first seizure: recurrence risk is greatest early • Over a longer term (>3 years), immediate ASD treatment is unlikely to
within the first 2 years (21%–45%) (Level A), improve prognosis as measured by sustained seizure remission (Level B).
Clinical variables associated with increased risk may include: • Risk of AED adverse events (AEs) may range from 7% to 31% (Level B) and
a prior brain insult (Level A), that these AEs are likely predominantly mild and reversible.
an EEG with epileptiform abnormalities (Level A),
• Clinicians' recommendations whether to initiate immediate AED treatment
a significant brain‐imaging abnormality (Level B),
and a nocturnal seizure (Level B).
after a first seizure should be based on:
– individualized assessments that weigh the risk of recurrence against the AEs of AED therapy,
Immediate antiseizure (ASD) therapy, as compared with delay of treatment – consider educated patient preferences,
pending a second is likely to reduce recurrence risk within the first 2 years – advise that immediate treatment will not improve the long‐term prognosis for seizure remission but will
(Level B) but may not improve quality of life (Level C). reduce seizure risk over the subsequent 2 years.

Krumholz et.al. Evidence‐based guideline: Management of an unprovoked first seizure in adults Krumholz et.al. Evidence‐based guideline: Management of an unprovoked first seizure in adults
Neurology 2015;84:1705‐1713 Neurology 2015;84:1705‐1713

Comorbidities and Polypharmacy VA Coop Study #428

Ramsay RE, et al. Neurology. 2004;62(5 suppl 2):S24-9 .

Concurrent Condition
Dyslipidemia 80.0 %
Hypertension 65.8 %
Stroke 50.7 %
Cardiac disease 48.1 %
Diabetes 28.3 %
Cancer 23.8 %
Psychiatric disease 21.6 %
Renal disease 12.3 %
Liver disease 2.7 %
Parkinson’s disease 2.7 %
Number of Prescribed Co-medications
Range 0-15 (mean 6.7)

2
 11/29/2017

Multicenter, double‐blind, randomized comparison between

lamotrigine and carbamazepine in elderly patients with
General Principles for choosing an ASD* newly diagnosed epilepsy

• Consider side effect profile.

• Consider ASDs with minimal drug interactions.

• Treat an older person like you would a woman of

childbearing potential.
• *Time is much too short for review of all AEDs.
• Leppik IE, Birnbaum AK. Epilepsy in the Elderly. Ann NY Acad Sci 2010; 1184:208‐224. Martin J. Brodie a,*, Peter W. Overstall b, Luigi Giorgi c, The UK Lamotrigine
• Elderly Study Group. Epilepsy Research 37 (1999) 81‐87

New onset geriatric epilepsy: a randomized study of

gabapentin, lamotrigine, and carbamazepine. Hyponatremia
Carbamazepine vs Oxcarbazepine
35.0%
• 18-center, randomized, double-blind, double dummy, parallel study of 593 elderly subjects with newly diagnosed 29.9%
seizures. 30.0%
• Patients were randomly assigned to one of three treatment groups: GBP 1,500 mg/day, LTG 150 mg/day, CBZ 600 p<0.0001
mg/day. The primary outcome measure was retention in trial for 12 months. 25.0%
• :
• Mean age was 72 years. 20.0%
13.5% CBZ
• The most common etiology was cerebral infarction 12.4%
15.0% OXC
• Mean plasma levels at 6 weeks were as follows:
• . 10.0%
• Early terminations: LTG 44.2%, GBP 51%, CBZ 64.5% (p = 0.0002).
2.8%
5.0% p<0.001
• CONCLUSIONS:
• The main limiting factor in patient retention was adverse drug reactions. 0.0%
• Patients taking lamotrigine (LTG) or gabapentin (GBP) did better than those taking carbamazepine. Seizure control was Hyponatremia Severe Hyponatremia
similar among groups. 62% of patients on OXC ≥40 yrs of age developed hyponatremia
(Na <135 mEq/L) vs:
– 20% of patients on CBZ, >40 yrs of age
Rowan AJ1, Ramsay RE, Collins JF, Pryor F, Boardman KD, Uthman BM, Spitz M, Frederick T, Towne A, Carter GS, – 10% of patients on OXC, <40 yrs of age
Marks W, Felicetta J, Tomyanovich ML; VA Cooperative Study 428 Group. Neurology. 2005 Jun 14;64(11):1868-73.
Dong X ,Leppik IE et al. Neurology. 2005;65:1976-8.

Effect of CBZ on Serum Simvastastin and

Simvastatin Acid Concentrations
a
Simvastatin (g/mL)

Placebo
CBZ

0 1 2 3 4 6 9 12 24
Simvastatin acid (g/mL)

Time (Hours) b
Placebo
CBZ

0 1 2 3 4 6 9 12 24

Time (Hours)
Ucar M, et al. Eur J Clin Pharmacol. 2004;51:879-82.

3
 11/29/2017

Antiepileptic drugs‐‐best practice guidelines for therapeutic drug monitoring: a position

paper by the subcommission on therapeutic drug monitoring, ILAE Commission on
Therapeutic Strategies

• When therapeutic response has been reached

• When new drug added or other drug removed if there is
potential for drug interaction
– Hepatic
– Absorption
– Renal elimination
• Toxicity
•Patsalos
Breakthrough
PN, Berry DJ, Bourgeoisseizure
BFD, Cloyd JC, Glauser TA,
Johannessen SI, Leppik IE, Tomson T, Perucca E Epilepsia 2008 Jul;49(7):1239‐1276.

4
 11/29/2017

Individual Total Phenytoin Serum Concentrations in Elderly Impact on Clinical Care and Practice
Nursing Home Residents
35
• Elderly are heterogeneous
Total Phenytoin Concentrations (ug/ml)

Aged 65-74 Aged 75-84 Aged 85+

30
(n=18) (n=21) (n=17) • comorbidities
25
• Like woman of childbearing potential
20

15
• Drug interactions
10
• CYP 450
• Pharmacodynamic interactions
5

0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
Individual Elderly Residents Categorized by Age Group at Enrollment

Leppik 2003 Birnbaum, Connway. Leppik et aL, Neurology, 60:555-559 (2003)

Goal ‐ Best Quality of Life

Our latest view of the {beta}-amyloid (A{beta}) cascade hypothesis and resultant hippocampal remodelling My wife’s grandmother:
age 76 in Banff, Canada, 1957

Palop, J. J. et al. Arch Neurol 2009;0:2009.15-6.

Leppik 2007

5
 11/6/2017

Disclosure
Sleep Disorders and Epilepsy in Children Name of Type of
Commercial Interest Relationship
Sejal Jain, MD • None • None
Associate Professor,
Department of Neurology and Pediatrics
University of Arizona

Learning Objectives Overview

• Sleep disorders in epilepsy
• Describe the prevalence of sleep disorders in children with – Overview
epilepsy – OSA
• Understand the evaluation steps for common sleep – Insomnia
disorders in children with epilepsy – RLS/PLMD
– Sleepiness
– CSA
– Parasomnia
• How to evaluate sleep disorders

Polysomnography Polysomnography
• NREM Sleep
– N1
– N2
– N3
• REM

1
 11/6/2017

Spectrum of sleep disorders in patients

Other sleep disorders
with epilepsy
• Retrospective review of patients with epilepsy • 40 children with epilepsy ages 6‐14
referred to CCHMC sleep lab from 2005‐2010 • Referred for sleep related complaints
• PSG
5%
5% Obstructive Sleep Apnea
6%
8%
6% Primary snoring
42% 19%
10%
Insomnia
10% OSA
No sleep disorder identified Hypoventilation
UARS
11% Hypoventilation 13% Primary snoring
PLMD
15% Central Sleep Apnea
Normal
Periodic Limb Movement Disorder 8%
42%
Other

Kaleyias, j et al pediatric neurology 2008

Jain et al Pediatric Neurology 2013

Overview OSA and Epilepsy

• Sleep disorders in epilepsy • 19 months old male with refractory epilepsy, Downs
syndrome
– OSA (obstructive sleep apnea)
• Referred for snoring
– Insomnia • Loud snoring, pauses in breathing
– RLS/PLMD • Frequent arousals
– Sleepiness • Typical Downs Facies‐ with small jaw, large tongue
– CSA • Mallampati IV, Tonsils 2+
– Parasomnia • Hypotonia

• How to evaluate sleep disorders • Polysomnography

OSA and Epilepsy OSA and Epilepsy

• PSG: OI 7.9 • Prospective study in children with epilepsy
• ENT referral and T&A • 30 children who screened positive for sleep apnea (Pediatric sleep
questionnaire) and had other sleep complaints

• Polysomnography (OSA= AHI of 1.5 or more/hour)

• 80% had OSA
• High seizure frequency was associated with the increased length of
apnea
• Increased REM latency
Becker et al Epilepsy and Behavior 2004

2
 11/6/2017

OSA and Epilepsy OSA and Epilepsy

Retrospective
• Prospective studies on risk of OSA Children with epilepsy and snoring were evaluated with
• Screening with PSQ ( score of 0.33 or more suggestive of increased polysomnography
risk of OSA) Diagnosed with obstructive sleep apnea or primary snoring

• Jain et al Subjects with uncontrolled epilepsy

Increase in number of AEDs
– Children with more refractory epilepsy had higher prevalence of risk (44% led to more severe OI
Vs 31%) 47%

– Polytherapy had increased prevalence (46% Vs 31%) 80%

• Maganti et al PS OSA

– 26 Children with epilepsy and controls

– 65% of parents complained of symptoms sleep disordered breathing Subjects with uncontrolled
epilepsy in PS and OSA groups
compared to 4% of controls

Jain et al Pediatric Neurology 2012

OSA and Epilepsy OSA and Epilepsy

• 40 children with epilepsy ages 6‐14, who were referred
to sleep lab
• Control group: 11 patients with mild OSA (AHI of 5‐
10/hr) without epilepsy

• PSG parameters compared to controls (epilepsy group

with AHI 2.9‐4.3)
– Longer SL, higher AI
– More severe O2 desat
– Higher BMI

Kaleyias, j et al pediatric neurology 2008

Gogou et al Sleep and Breathing 2015

Impact of Treatment of OSA

Impact of Treatment of OSA
• Prospective study in patients with refractory epilepsy • Retrospective study, 27 children with uncontrolled epilepsy
• Screening with questionnaires and PSG and OSA who had T&A
• 6/13 adults and 3/5 children had OSA • Three months after surgery
Median seizure frequency
• Treatment with CPAP before was 8.5, after was 3
seizure‐free
• 2 adults and 2 children were intolerant of CPAP
• One adult was treated with an oral appliance with a 22%
>50% seizure‐ 53% median seizure reduction
37% reduction
reduction in nocturnal seizures only 7%
amelioration of
• 3 adult and 1 child were complaint with treatment‐ 45% seizure frequency Multivariate analysis
22% 11%
Trend toward seizure freedom
reduction in seizure frequency in each unchanged seizure‐
with each percentile increase in
frequency

worsening of seizure
body mass index and early age of
frequency surgery

Malow et al Sleep Medicine 2003

Segal et al, pediatric neurology 2012

3
 11/6/2017

OSA and Epilepsy VNS and Sleep Apnea

• Antiepileptic medications
• Benzodiazepam, phenobarbital may cause worsening due to effect on tone
• Depakote may cause worsening due to weight gain, however, not seen in
some studies

VNS and Sleep Apnea VNS and Sleep Apnea

• Khurana, et al, 26 children‐
• The prevalence of OSA 43.1 % (95 % CI16.7–69.5 %) in patients with VNS
– Screening questionnaire before and after VNS
placement
• Higher than the prevalence of OSA in epilepsy overall (43.1 vs 33.4 %) – 4 preexistent OSA, 4 developed OSA on VNS (15%)
– New OSA‐all on rapid cycling, non‐obese
– T&A or A‐
• Sz free 1
• >50% sz reduction in 3

Lin et al Sleep Breath 2016

VNS and Sleep Apnea VNS and Sleep Apnea

• Hseih et al, retrospective study, 9 children
• Case reports of VNS related sleep apnea is sub‐optimally treated with CPAP
– 6 with OSA (66.7%)

• Changing stimulation frequency, amplitude or‐on‐off time of VNS

• Nagarajan, et al, 8 children
suggested by the company manual
– Decrease in TV
– Increased RR (6/8)
– Decrease O2 sat, however did not meet criteria for
CSA

Upadhyay et al Ann Thor Med 2016, Assaad BM et al SLEEP 2016 abstracts

4
 11/6/2017

Overview Insomnia and Epilepsy

• Sleep disorders in epilepsy • 9 years old male with intractable epilepsy‐ tonic seizures,
– OSA severe developmental delay
– Insomnia • Referred for difficulty maintaining sleep
• Bedtime 9 pm , no difficulty falling asleep
– RLS/PLMD
• Multiple awakenings with difficulty falling asleep again
– Sleepiness • History of mild snoring, restlessness
– CSA • Wake up time 530‐6 am
– Parasomnia • Good sleep hygiene
• How to evaluate sleep disorders • Polysomnography

Insomnia and Epilepsy Insomnia/Sleep Disturbance and Epilepsy

• AHI less than 1, no PLMs, poor sleep efficiency, • Prevalence of insomnia/sleep disturbance
increased WASO
– Based on questionnaires‐13.1‐31.5% using the Sleep Disturbance Scale
• Insomnia
for Children (multiple studies)
• SR Melatonin (ultimately eszopiclone)

– Clinical practice‐11%

Menezes Macêdo et al Epilepsy Research 2017, Jain et al journal of Child Neurology, 2013

New onset seizure and Sleep disturbance Epilepsy and Sleep Disturbance
• 349 children with new onset seizures (6‐14 years) • 121 children with epilepsy
• 226 sibling controls
• Age and gender matched controls
• Sleep Behavior Questionnaire, neuropsychological testing, CBCL
• Questionaires
• 45% of patients had sleep disturbances – Sleep habits inventory for 2‐6 years old subjects
• Increased neuropsychological difficulties – Sleep behavior questionnaire for 7‐14 years old

• 14% snored “often”/ “always”

• Bedtime difficulties, daytime drowsiness, parasomnia
• Partial sz with secondary gen. had increased sleep fragmentation

Batista et al epilepsy and behavior 2007

Byars AW, et al: Epilepsy and behavior 2008

5
 11/6/2017

Epilepsy and Sleep Disturbance Epilepsy and Sleep Disturbance

Higher Engel scale score were

associated with higher scores on
sleep questionnaire

Nocturnal seizures increased Focal with sec generalized sz

the scores increased the scores

Batista et al epilepsy and behavior 2007 Batista et al epilepsy and behavior 2007

Insomnia/Sleep Disturbance and Epilepsy Insomnia/Sleep Disturbance and Epilepsy

Menezes Macêdo et al Epilepsy Research 2017 Menezes Macêdo et al Epilepsy Research 2017

Insomnia and epilepsy‐Treatment Study Design

Outcome measures‐ PSG, EEG, PVT, Actigraphy, Questionnaires, diaries, SML
• Treatments Sleep hygiene guideline Eligibility Screen Diaries, Qs, PVT, Actigraphy Consent

– Melatonin 2 wks
Melatonin Placebo

– Pregabalin (adult data) V1-Diaries, Qs,

PVT, Actigraphy 4 wks
V2-Seizure Diary,
Qs, PVT,
Phone 1-
Wash-out 4 wks
V3- Seizure Diary,
Qs, PVT,
PSG, EEG, SML Actigraphy, 1 wk Actigraphy,
Rnd, Blind PSG, EEG, SML PSG, EEG, SML
Placebo Melatonin

10 Pre‐pubertal children with epilepsy and normal

Diaries‐ Sleep diary, Seizure diary
development without sleep disorders other than •• Qs‐ BASC‐PRS and SBQ and QOLCE
insomnia were enrolled • PVT‐ psychomotor vigilance task
SR melatonin 9 mg • EEG‐ electroencephalogram
• PSG‐ polysomnography
Blinding and randomization was done by pharmacy• SML: salivary melatonin level
Outcome measures‐ PSG, EEG, PVT, Actigraphy, • Rnd‐ randomization, Blind‐ blinding
Questionnaires, diaries, SML
Jain et al Sleep Medicine 2015

6
 11/6/2017

Insomnia and epilepsy‐ Insomnia and epilepsy‐

Treatment Treatment
• Conclusions
Placebo Melatonin Difference p-
• SR melatonin improves sleep by reducing SL and WASO in patients with
value
epilepsy
Measure Mean SD Mean SD Mean SD
• Melatonin dose not cause worsening of seizure control or EEG spikes in
SL 19.0 20.1 7.8 5.9 11.4 9.4 0.02
intellectually normal patients with epilepsy.
WASO 57.3 31.6 42.3 30.3 22.2 16.7 0.04
• The study was not powered to detect differences in behavior or quality of
Spike Density
71.9 129.0 31.7 53.5 49.8 59.5 0.13 life outcomes
Seizure
Frequency 2.4 6.6 1.4 3.8 1.2 1.4 0.53

Jain et al Sleep Medicine 2015 Jain et al Sleep Medicine 2015

Insomnia and epilepsy‐Treatment Insomnia and Epilepsy

• Gupta et al 2009 (9 mg for wt > 30 kg, 6 mg for wt <30 kg)
– Randomized double blind placebo controlled study • AEDs which increase N3 and aid sleep consolidation
– Significant difference was seen in median percent reduction in total – gabapentin
sleep score and parasomnia between both groups – Tiagabine
– Significant improvement in QOL subscales pre and post treatment – pregabalin
with melatonin (attention, memory and language)
• Improve total sleep time and efficiency
• Elkhayat HA et al 2010 (1.5 mg) – Carbamazepine
– 23 children with intractable epilepsy – tiagabine
– Improved subjective sleep, excessive daytime sleepiness, nocturnal – pregabalin
enuresis, and Epworth sleepiness scores
– Significant reduction in seizure severity or frequency in 87%

Jain SV, Glauser TA. Epilepsia 2014

Overview PLMD, RLS and epilepsy

• Sleep disorders in epilepsy • 13 y.o. male with idiopathic focal epilepsy, controlled
– OSA • Referred to sleep for evaluation of restless sleep, daytime
drowsiness, decreased grades
– Insomnia • Sleep prone with his legs flexed and torso over his legs
– RLS/PLMD • Difficulty falling asleep and staying asleep
• No snoring, no pauses in breathing
– Sleepiness • A lot of movements in sleep
– CSA • History of nocturnal leg pains, but can not elaborate further
– Parasomnia
• Physical exam normal
• How to evaluate sleep disorders • Polysomnography

7
 11/6/2017

PLMD, RLS and epilepsy RLS & PLMD in epilepsy

• AHI less than 1
• In adult patients with epilepsy, RLS was identified in 18‐35%
• PLMI: 27.5, Ferritin: 25
• Iron supplementation • In studies in adults with epilepsy, 15% had PLMD and 17% had PLMs in sleep.
• Recent study, prevalence of RLS was 5.8% in Turkey. (exclusions were any conditions
know to be associated with RLS)

• PLMD was found in 5‐10% of the children with epilepsy referred to the sleep lab

Malow et al Sleep 1997; Malow et al Neurology 1997, Khatami el al Seizure 2006, Kaleyias et al Pediatric
neurology 2008, Jain et al Pediatric neurology 2013, Öztürk et al Epilepsy and Behavior 2016

RLS & PLMD‐Treatment Overview

• Sleep disorders in epilepsy
• Iron supplementation if low ferritin
• Target ferritin above 50 – OSA
– Insomnia
• AEDs – RLS/PLMD
– (Pregabalin)
– Gabapentin enacarbil (moderate o severe RLS) – Sleepiness
– (gabapentin) – CSA
• DOPA agonists
– Parasomnia
– Ropinirole (moderate to severe RLS) • How to evaluate sleep disorders
– Pramipexole (RLS)

Sleepiness and epilepsy Sleepiness and Epilepsy

• 14 years old male with refractory epilepsy, mitochondrial disorder • Overnight PSG‐ AHI less than 1, no PLMS, Sleep
• Referred for difficulty staying asleep, daytime sleepiness efficiency of 80%, WASO 35 min
• No difficulty falling asleep • MSLT: SL 6 min
• Mild snoring, no pauses in breathing • SOREM in 3 naps
• Mild restlessness • Modafinil
• Sleeping 14‐15 hours a day
• ESS 20
• Referred for PSG with MSLT

8
 11/6/2017

Sleepiness and epilepsy Sleepiness and Epilepsy

• 46% of children with epilepsy have excessive daytime sleepiness • 26 children and matched controls
• These patients are not typically referred for sleep evaluation • Pediatric sleep questionnaire, Pediatric daytime sleepiness scale
• 46.2% of children with epilepsy had EDS compared with only 19.2% of
• In a questionnaire based study, 70% of the physician attributed sleepiness to controls
antiepileptic drugs • EDS associated with
– SDB
– Parasomnia
• No correlation with
– Epilepsy syndrome
– anticonvulsants used
– presence or absence of seizure freedom

Maganti et al Epilepsy and Behavior, 2006 Jain et al Pediatric Neurology 2013 Maganti et al Epilepsy & Behavior 8 (2006)

Sleepiness and Epilepsy‐Treatment Sleepiness and Epilepsy‐Treatment

• If titrating AEDs, wait for few weeks and reevaluate • Several studies evaluating effect methylphenidate for treatment of
• Rule out sleep disorder ADHD in patients with epilepsy
• Overall, studies suggest methylphenidate does not exacerbate seizures
• Modafinil • Atomoxetine was not associated with an increased risk of seizures in
• Stimulants ADHD patients

Wernicke et al Dev Med Child Neurol. 2007; Kaufmann et al J child Neur 2009

Sleepiness and Epilepsy Overview

• Sleep disorders in epilepsy
• Antiepileptic drugs and sleepiness – OSA
• Based on class III evidence in patients with epilepsy, daytime sleepiness was – Insomnia
not changed by topiramate, lamotrigine, zonisamide and vigabatrin – RLS/PLMD
– Sleepiness
– CSA
• Increased by phenobarbital – Parasomnia
• Antiepileptic treatments and sleep
• Daytime sleepiness was unchanged at 1000 mg daily dose for levetiracetam; • Some important issues
however, wakefulness was reduced at 2000 mg daily dose • How to evaluate sleep disorders

Jain SV, Glauser TA. Epilepsia 2014

9
 11/6/2017

CSA and Epilepsy CSA and Epilepsy

• PSG‐ RDI: 231, OI: 11
• 8 y.o. female with intractable generalized epilepsy, • Repeat study with ASV titration, resolution of CSA and
Lennox‐Gaustaut syndrome OSA
• Referred for snoring and pauses in breathing
• Frequent pauses in breathing
• Loud snoring occurring frequently
• No trouble falling asleep
• frequent arousals
• Mild restlessness

• Polysomnography

CSA & epilepsy Overview

• Sleep disorders in epilepsy
• Ictal apnea are associated with pediatric seizures – OSA
• Retrospective analysis of patients with epilepsy who had PSG – Insomnia
• Out of 416 patients tested – RLS/PLMD
– 16 (3.7 %) had CSA – Sleepiness
– 33 (7.9 %) had Complex sleep apnea
– CSA
• CSA was more common males – Parasomnia
• Focal seizures were more prevalent in patients with CSA • How to evaluate sleep disorders

Vendrame et al Sleep Breathing 2013

Parasomnia and Epilepsy Overview

• Sleep disorders in epilepsy
• Parasomnia very common in childhood
– OSA
• May coexist with epilepsy
– Insomnia
• Sometimes confusing with nocturnal seizures
– RLS/PLMD
• VEEG and polysomnography helpful
– Sleepiness
– CSA
– Parasomnia
• How to evaluate sleep disorders

10
 11/6/2017

Evaluation Questions for Screening

• Difficulty falling • Pauses in breathing
asleep • Restless sleep
• Difficulty staying
asleep • Night time events
• Daytime drowsiness • Leg pains in evenings
• Snoring

Jain SV: Epilepsy and Sleep in Pellock et al.

Pediatric Epilepsy and Therapy, 4th edition

Questionnaires Algorithm for Evaluation of Sleep Problems

• Children’s Sleep Habits Questionnaire (CSHQ)
• Sleep Disturbance Scale for Children (SDSC)
• Sleep Behavior Questionnaire (SBQ)
• Sleep disorders inventory for students (SDIS)
• Pediatric Daytime Sleepiness Scale (PDSS)

Jain SV: Epilepsy and Sleep in Pellock et al.

Pediatric Epilepsy and Therapy, 4th edition

Sleep Hygiene Guidelines Stimulus Control Guidelines

• Go to bed and wake up at same time • Restrict activities in bed to sleeping only (no television, reading, playing
• No more than one hour difference between sleep schedule on weekdays and games, texting on phone etc)
weekends • Avoid exposure to bright lights before and during sleep
• Napping should be age and development depended (none after 5‐6 years of • Vigorous activity should be avoided 1‐2 hours before bedtime
age) • Avoid caffeinated beverages and foods (coffee, soda, chocolates, tea, and
• Children and adolescents should sleep in their own beds by themselves certain medications) [and cigarettes] for least 6‐8 hours before going to bed

11
 11/6/2017

Algorithm for Evaluation of Sleep Problems Conclusions

• Sleep disorders are common in patients with epilepsy

• Treatment of sleep disorders may improve epilepsy

• Screen your patients for sleep disorder!

Jain SV: Epilepsy and Sleep in Pellock et al.

Pediatric Epilepsy and Therapy, 4th edition

12
 11/29/2017

Disclosure
Grant Agency topic Relationship to this
Suicide Prevention in patients with epilepsy Project IMPACTT HRSA Improving integration of
presentation
YES
care for children with
epilepsy
Tatiana Falcone MD, FAPA, FAACAP
Project PASS OSPF‐ SAMHSA RCT in children after No
Child and Adolescent Psychiatrist discharge post SA ‐
comparing ETA‐ Suicide
Director of Project IMPACTT Prevention Hotline‐Wrap
around services
Epilepsy Center Peripheral NIMH Inflammatory biomarkers No
Neuroinflammatory to predict suicide risk in
Neurological Institute Predictors of suicidal risk adolescents
Cleveland Clinic at time of inpatient
discharge in adolescents

Honorarium SAMSHA and DoD Grant reviewer‐ Suicide No

prevention grants
Travel Honorarium HRSA and AES This presentation YES

Suicide in the world

Let’s start with the end in mind

Christensen et al., 2007; Fazel et al., 2013; Hesdorffer et al., 2016; Thurman et al., 2017, WHO 2005
WHO, 2014; CDC WISQARS, 2011; Varnik, 2012

Take home messages‐1 Take home messages‐2

1
 11/29/2017

Take home message ‐3 Mortality from medical causes

Tom Insel MD , NIMH

Suicide statistics Underdetection

Prevalence rates of suicide in epilepsy

32.5% of deaths suicide

Pompili, Girardi, &Tatarelli, (2006b).

22% higher
“I’m right there in the room and no
one even acknowledges me”

2
 11/29/2017

Why do patients with epilepsy are at

Suicidal ideation and Suicide attempts
higher risk for suicide?

2.6
4.5

Factors associated with Hopelessness in

patients with epilepsy
Suicide attempts and self harm

Pompili M et al Worl J Psychiatr 2014 Dec 22 4 (4) 141‐149

Profile of the epilepsy patient who

Self Harm in people with epilepsy commits suicide

Meyer Et al Epilepsia, 55(9): 1355‐1365, 2014 Fazel et al., 2013; Gandy et al., 2013; Meyer et al., 2014

3
 11/29/2017

Early onset of epilepsy and suicide Seizure severity and suicidal risk

Suicidal behavior in CYE Youth Suicide in the US

CDC , WISCARS 2016

Negative Perceptions about epilepsy The suicide risk

• Austin et al stated 22% of adolescents reported uncertainty about
epilepsy being contagious Epilepsy Behav. 2002 Aug 3(4): 368‐375.

• Westbrook remarked how up to 50% of the families studied decided to

kept the condition secret from others . J Pediatr Psychol. 1992 Oct; 17(5):633‐49.

• Falcone et al identified that 50% of families decided not to disclose the

epilepsy diagnosis to the school . Epilepsy Currents. 2011;12(1):2.283

• Bauman reported that one out of four of the families surveyed believe
that having a child with epilepsy in the classroom deteriorates the
learning environment. Epilepsia. 1995;36: 1003‐1008.

4
 11/29/2017

Psychopathology associated with

False Myths suicide in patients with epilepsy

AEDs and suicidality Suicide after Temporal lobectomy?

• No
• Analysis of the studies (8) reveal that the data are not supportive for a class
effect on suicide‐related behavior
20% due to suicide
• AEDs are necessary
• Patients with epilepsy are at higher risk because of the high incidence of
untreated depression temporal lobe surgery 13.9
6.37

Treatment that works

Executive dysfunction and Suicide

5
 11/29/2017

Safety plan
Progression of Suicidality*

Suicidal Ideation to plan 34%

Suicidal Ideation to attempt 26% (90% in 1 yr)
Plan to attempt 72% (60% in 1 yr)

*Kessler et al., 1999

How to prevent suicide in

Protective Factors in Adults
• Supportive family patients with epilepsy
• Live with other people (spouse, child)
• Children at home
• Sense of connection and support
• In older people, “pride in aging”
• Sense of purpose

Role of the Neurologist in the management of

Basic concepts depression in epileptic patients

6
 11/29/2017

Education Preventing suicide

• Educate parents and families about depression as a
chronic and recurrent illness
• Educate families about comorbidity between
depression and anxiety and epilepsy
• Depression is nobody’s fault
• Help set reasonable expectations regarding chores,
school, work
• Often family members are worried and want
information and reassurance from a withdrawn and
secretive patient
• Goal to teach family and patient how to monitor for
treatment response, side effects, and long‐term course

When to refer to psychiatry How can you make a difference?

• Learn and share the facts about mental health and about
comorbidities, especially if you hear or read something that isn’t
true
• Listen to your patient and family member concerns, if they are
having symptoms of mental illness
• Treat people with mental illnesses with respect and dignity
• Respect the rights of people with mental illnesses and don’t
discriminate against them

References
Thank you

7
 11/21/17

Disclosure
Ketogenic diet*in*infancy?**
Eisai, GW Pharma, Novartis, • Board3 meeting,3 scientific3 advice
How*low*can*we*go? Nutricia, Shire, Servier, U CB,
Stéphane AUVIN,3 MD,3PhD Ultragenyx, Zogenyx
CHU3 Robert=Debré &3INSERM3 U1141 Advicenn e Pharm a, Biocodex, • Lectures
Université Paris=Diderot,3 Paris,3France Eisai, GW Pharma, Nov artis,
Nutricia, Shire, UCB

Advicenn e Pharm a, Eisai, UCB • Investigators3in3

pharma, Ultragenyx, Zogenyx preclinical/clinical3 trials

Learning3Objectives
Ketogenic diet* in* infancy
• Can3 the3ketogenic diet3be3 used3 in3Infants? • Historical3concerns
• Available3 data
• What3are3the3indications3 of3 ketogenic diet3in3Infants?
• Guidelines3for3the3 use3in3infants
• Implementation3 and3 follow=up?3 – Use3 of3KD3 in3infants
– Follow=up3 of3 KD3in3 infants
• How3low3 can3we3 go?

Ketogenic diet &*Epilepsy

Ketogenic diet* in* infancy
• Randomized3 trials3 2=16Y3(13KD3– 13MAD)
• Historical* concerns
• Numerous3 open3 studies3 in3children
• Available3 data
• International3 consensus320093(>2Y)
• Guidelines3for3the3 use3in3infants
– Use3 of3KD3 in3infants
– Follow=up3 of3 KD3in3 infants
• How3low3 can3we3 go?

1
 11/21/17

KD*in*infants* – A*challenge*? P EDIATR IC S* Vo l.* 1 0 8 * No .* 1 * Ju yl * 2 0 01

Initially3not3recommended3 for3 use3 in3infancy3 (under3the3age3of323years)

Total Sz OFree Improvement No*Improvement p*Value
(n=31)

– Crucial3 period3 of3 development3 Seiz ure*type

G eneraliz ed 103(32%) 2 2 63(60%)
– Risk3to3unmet3 nutritional3requirement Partial
Multifocal
13(3%)
53(16%)
0
0
1
2
0
33(60%)
NS

– Immaturity3 of3 lipase3activity3and3liver3function G al +3Focal

Sz Type
153(50%) 4 6 53(33%)

1 83(26%) 2 3 33(38%)
– Immaturity3 of3 lipid3metabolism 2 113(35%) 1 3 73(63%) NS
>3 123(39%) 3 5 43(33%)
– Difficulty3 to3achieve3 and3maintain3 ketosis Spas ms
Yes 173(55%) 63(35%) 6 53(30%) P<0.05
No 143(45%) 0 5 93(64%)

West%Syndrome
Ketogenic diet* in* infancy 63months3 (4=9)
Seizure3type:3Epileptic3Spams
One%syndrome
Multiple%etiologies
‘Historical’3 triade:3spasms,3 regression,3
• Historical3concerns hypsarrhythmia
• Available* data Beyond3the3historical3 triade
• Guidelines3for3the3 use3in3infants
– Use3 of3KD3 in3infants
Prognosis
– Follow=up3 of3 KD3in3 infants Related3to3 underlying3etiologies
Impact3or3treatment3delay
• How3low3 can3we3 go?
Severe3intellectual3disability3 80%
50=60%3seizure3 persistance

Studies* in* infantile* spasms Report*of*the*use*of*KD*in*infants

n Outcome # AED initiation* (Mo) Criteria Res ults !Publication, bias!
Kos s off 2002 23 33Mo 3.3 5=24Mo >90%3Sz 38%
>50%3Sz 67% • Epileptic3 encephalopathies with3Suppression=Burst
Eun 2006 43 33Mo ??? 18.6±8.2 Sz Free 23/ 43
>90%3Sz 27/ 43 – n=5$Takusa 1995,$Seo 2010,$Ishii$2011,$Sivaraju 2015
Kos s off 2008 133vs 320 13Mo 0 K D:3 53 (2 –1 0 )3 Sz Free3KD 8/ 13
AC TH: 63(1 –1 2 ) Sz Free3ACTH 18/ 20 • Epilepsy3of3 infancy3 with3migrating3seizures
H ong*2010 104 3=6Mo 3.6±0.2 14.4±1.2 Sz Free33Mo 18%
SZ3Free36Mo 28% – 2/33in3Caraballo$2015,313in3Mori$2016,31/23in3Apparu 2016
Numis 2011 26 1—33Mo 4.6±0.5 19.5±2.23 >90%3Sz 12/ 263(46%)
– Ineffective3 n=6
Pires *2013 17 1=3 Mo 2 9.4±1.1 Sz Free31Mo 6/ 173(35%)

• Epilepsy3with3focal3 Sz
Sz Free3 3 3 M o 1 1 /1 7 3 (6 5 %)

Kayyali 2014 20 33Mo 3.23(2 =5 ) 14.4±9.4 >90%3Sz 20%

>50%3Sz 70%
H us s ain*2016 22 33Mo 73(5=7) 33Mo Sz Free 3/ 22 • GLUT1=DS,3 PDHC3 deficiency,3 Mitochondrial3 disorders
6 Mo (2 3 =4 6 ) >50%3Sz 7/ 22

2
 11/21/17

Infantile* guidelines
Ketogenic diet* in* infancy Initial* working* group:*3* DN*and*2*MD
Expanded*to* 7*DN*and*3* MD
• Historical3concerns
• Available3 data
• Guidelines*for*the*use*in*infants
– Use3 of3KD3 in3infants
– Follow=up3 of3 KD3in3 infants
• How3low3 can3we3 go?

Side%effects%at%initiation Side* effects*of* KD

Neal*et*al*2008 Nordli et*al*2001 H ong*et*al*2010 Coppola* et* al*2010 Numis et*al**2011
n=6/32 n=34/104 n=25/38 n=6/26
HYPOGLYCEMIA? HYPERKETOSIS?
Drows ines s / lack3of3 13 19 1
energy
Jittery Rapid% breathing,% Irritability 2 1

Poor% body% tone,% lethargy,% pallor increased% heart% rate Vomiting 13 1 3

Poor% feeding Facial% flushing Diarrhoea 7 13(U C) 3

Low% body% temperature,% cold% and% Irritability Cons tipation 18 7 7

clammy Vomiting Renal3s tones / haematuria 1 1 6 1

Cyanosis Lethargy
Hypoglycaemia 1 1
Poor feeding
G OR 13(G I3bleed) 6 4
Reduced3 12 1
appetite/ hunger
Mostly3 manageable3by3diet3adaptation
Acidos is 3
Hair3 thinning 2
Emergency3intervention3based3on3clinical3symptoms3 Hypercalcemia 2

Kidney*stones
Ketogenic diet* in* infancy
Stone*cases Non*stone* * ** p
(n=18) (n=106)*** • Historical3concerns
____________________________________________________
Mean*age*(months) 34.5 60.3**** *** * <0.05 • Available3 data
Female 33% 49%** *** *** * NS
Severe*motor*delay 28%** ** 32%* NS • Guidelines3for3the3 use3in3infants
Hypercalciuria * 89% 43%** *** *** <0.05 – Use3 of3KD3 in3infants
Urine* pH<5.5 33% 30%** *** NS
History* of*medication* 28% 25%** NS – Follow=up3 of3 KD3in3 infants
increasing* stone* risk
Family*history 17% 27%** *** ** NS • How*low*can*we*go?
*
Fa s ting%urine %Ca :Cr ra tio>0 .2 m g/m g>1 2 m ,%>0 .8 m g/m g%<6 m Furth%et%al.%%2000

3
 11/21/17

Use*of*the*ketogenic diet*in*the*neonatal* intensive*care* unit Use*of*the*ketogenic diet*in*the*neonatal* intensive*care* unit

Safety* and*tolerability Thom pson% et% al.% Epilepsia 2017 Safety* and*tolerability Thom pson% et% al.% Epilepsia 2017
AED *at
Medical* his tory Age* at*KD *(W) KD *duration Outcomes to*date
initiation

PB PB Daily3s eiz ures

LEV TPM Severe3DD
#1 SCN 2A EE 10 2.53years
TPM CLB Cortical3 vis ual3impairment
CLB 4:13KD Dys tonia
LEV
VG B Seiz ure=free3 × 23years
#2 Ohtahara Sd 9 TPM 2.253years
2.75:13 KD Severe3DD
PB
PB PB
LEV3 LEV3 Daily3s eiz ures
#3 KCN T1 early EE 9 103months
CLB CLB Severe DD
PHE 3.25:13 KD
PB PB
LEV LEV Daily3s eiz ures
#4 KCN Q2 EE 6 2.253years
TPM 3.75:13 KD Severe DD
CLB VN S

Any*concern*for*early*brain*development? Impact*on*Clinical* Care*and*Practice

• Ketone bodies intake higher during brain development than in adults • Ketogenic diet*can* be* safely*used* in*infants
De%Vivo%et%al.%1983 • Large3 amount3of3data:3West3syndrome
• Preclinical use o f 4:1 KD during pregnanc y: alteration of organ growth • Other3epilepsy3syndrome
in CD=1 mouse embryos • Metabolic3disorders:3GLUT1=DS,3PDHC3deficiency,3Mitochondrial3
Disorders
Sussman et%al.%2013
• Report of KD during pregnanc y: n=2 epilepsy – Norm al fetal grow th, • Guidelines* available*for*indication,* implementation,* followOup
normal development at M8 and M12, minimal ear abnormalities in 1
van%der%Louw et%al.%2017 • SideOeffects:* hypoglycemia* during* initiation* easily*manageable

4
 11/29/2017

Disclosure
36‐year‐old woman with dominant None
hemisphere epilepsy and normal MRI
Jeremy Moeller, MD, MSc, FRCPC
Department of Neurology, Yale School of Medicine

Learning Objectives Case Summary

• To review one surgical option in a case of a patient with • 36 year old woman who had an episode of viral meningo‐encephalitis at age 25.
dominant hemisphere temporal lobe epilepsy and normal
• Seizures started at age 29, and persisted despite trials of 5 antiepileptic drugs at
MRI. appropriate doses.

• Seizure semiology:
– No warning ‐> behavioral arrest, subtle chewing automatisms, duration 1‐2 minutes.
– Language dysfunction for 5 minutes afterward.
– Occasional progression to generalized tonic‐clonic seizures, but none since starting
lamotrigine.
– Seizure frequency 3‐4 per month on average.
– Longest seizure‐free interval 2 weeks.

MRI Brain (3T Epilepsy Protocol) – Normal Scalp EEG – Left ant.‐inf. temporal onset sz
L inf temp

L temp

L parasag

Midline
R parasag

R temp

R inf temp
FLAIR T2

1
 11/29/2017

PET – Equivocal left mesial temporal

fMRI – Left hemisphere dominant for lang.
hypometabolism

Additional Testing Intracranial EEG

• Blood and CSF autoimmune epilepsy panel negative

• Neuropsychological testing • Broad left hemisphere

coverage with subdural
– Left hemisphere dysfunction grids and strips
– Poor dominant AND non‐dominant memory function • Depth electrodes in
amygdala and
hippocampus
• Wada (Completed twice, with similar results)
– Left hemisphere language dominant
– Left hemisphere memory WORSE than right (poor bilaterally)

Intracranial EEG Surgical Plan and Follow‐Up

• Surgical Plan:
– Laser ablation of amygdala
• Unlikely to affect verbal memory or naming
– If seizures persist, could consider responsive neurostimulation covering
the left hippocampus +/‐ basal temporal structures

• Follow‐up
– Cluster of non‐convulsive seizures 2‐3 days after surgery
– Seizure‐free at 6‐week follow‐up
– No change in subjective memory function, repeat neuropsychological
testing pending
Seizures: Very focal onset in left amygdala, with rapid spread to
hippocampus and basal temporal regions.

2
 11/29/2017

MRI Brain – 2 weeks post‐op laser

3
 11/13/2017

Epilepsy Surgery for Infants:

Disclosures
Pushing the Boundaries!
• Consultant: Mallinckrodt, Eisai,
Sunovion
Ajay Gupta, M.D. • Tuberous Sclerosis Alliance – Research
Pediatric Epilepsy Grant
Cleveland Clinic • Editorial board: Pediatric Neurology,
Epilepsy Currents

Why? - Rapidly Progressive

Objectives Course
• Infantile onset epilepsies are often
• Pushing boundaries in infants – why? explosive in onset
• High burden of daily seizures
• Observations using scalp VEEG and • May show ‘EEG progression’ and
brain MRI +/- brain PET - How? ‘clinical regression’ often labeled as
– Catastrophic epilepsies
• Next Boundaries? – Epileptic Encephalopathy

Example: Emergence of Epileptic Age: 3 months; Hypomotor seizures

Awake
Encephalopathy LT
Sleep spindles
Focal Cortical Dysplasia on brain MRI
LC

RC

Lateralized: Hemihyps- or Modified Hypsarrhythmia RT

Hypsarrhythmia

Electro-clinical progression in an T6-O2 SW Hypomotor ictus: T6-O2

infant from 3 to 5 months age

R posterior epilepsy (hypomotor
seizures) -> R Hemi-hypsarrhythmia (+
Spasms) -> Hypsarrhythmia (Spasms)

1
 11/13/2017

Age 4 months; Hemi- hypsarrhythmia Age: 5 months with infantile spasms

Awake: Hemi-hyps Sleep: Hyps- Awake Sleep: Synchrony
LT LT

LC RT

RC LC

RT RC

Spasm -> Hypomotor: T6-O2 Sleep: Independent Spasms

Spasm clusters

Pre-op Brain MR
Medical Refractoriness is
Rapid
• Medical refractoriness is predictable
• Medical treatment fails within weeks
• Toxic polypharmacy = encephalopathy
Post-op MR EEG • Developmental regression sets in
• Risk of SUDEP is high
• Overall long term outlook dismal

Development Quotient is Low

With:
Increasing
percentage
of life with
epilepsy

Early age of
epilepsy
onset

Vendrame M Epilepsy Behav. 2009;16: 431-5

Morse AM et al., Pediatr Neurol 2016; 57: 7-16

2
 11/13/2017

Surgical Risks Pale in Probability of seizure freedom after

Comparison to Futile Medical hemispherectomy (N= 170)
Treatment  78% at 6 months
(95% CI= 75%-
81%)
• Low peri-opertive Risk in modern day
 76% at 1 year
• Deficits – difficult to confirm pre-op in (95% CI= 73%-
79%)
infants but some may be acceptable Likelihood of such outcome
with medical treatment is  71% at 2 years
• Good plasticity may help low (95% CI= 68%-
74%)
• Effectiveness of surgery – in relative
terms appear favorable  63% at 5 years
Time since surgery (yrs) 1 3 5 7
and beyond (95%
CI= 59%-67%)
N patients at risk 124 86 54 37
N patients with follow-up 160 121 84 51

Moosa ANV et al., Neurology 2013; 80: 253-60

Cognitive and Function Improvement Early Surgery in Frontal Epilepsy:

After Hemispherectomy (N=115) Better Chance of Seizure Freedon
Lesional
Most likely
 83% walk unaided
Function
 76% no post op visual disability attained
 73% no behavior/psychiatry issues
 69% verbally communicate at or just
below age (routine life)
 42% read at or just below age level Advantage of MRI lesion vanished Non-lesional
Less likely when epilepsy duration was
Likelihood of such outcome with continuing considered – poor prognosis with
medical treatment is low > 5 years of epilepsy regardless
of lesional or non-lesional MRI
Moosa ANV et al., Epilepsia 2013; 54:1771–1779
Simaasthien et al., Annals of Neurol 2013; 73: 646-54

3 mth, Hypomotor sz.; EEG: R P-O Onset

T1W T2- GM: Hypo FLAIR

Understanding Changing
Appearance of Dysplastic
Lesions in a Developing Brain on
MRI Helped further Facilitate 10 mth, Spasms; EEG: Hypsarrhythmia
T1-GM: Hypo T2– GM = / mild > WM FLAIR: Iso-intense GWM
Pushing the Boundaries for
surgery

3
 11/13/2017

Review of First Brain MRI Critical Clinical-EEG-MRI Correlation

Age Clinical-EEG Brain MRI

< 6 months Focal seizures Lesion (Atypical)

6-18 months Spasms- MRI lesion -ve

Hypsarrhythmia ?FDG-PET +/-

• 9 month old, male

> 2 years Epileptic Lesion +ve
• 4 month old • Infantile spasms Encephalopathy (Tip of Iceberg)
• Left temporal
• EEG: Left temporal
seizures +
Hypsarrhythmia
sz + Hypsarrhythmia
• ACTH, VGB Understanding these dynamics - opportunity to
• Before VGB, ACTH
intervene for early epilepsy surgery

In a larger retrospective series (n

=50) , this observation held true
Seizure outcome after resection of the MR lesion was
similar with or without focal clinical features during
seizures, with or without SSWC, and whether a
substantial proportion, majority, or all of the ictal or
interictal epileptiform discharges (or both) were
generalized or contralateral.

First studies were case series in

desperate children and families who were
at the end of their medical treatment

Gupta A et al., Pediatric Neurology 2007:37; 8-15

Wyllie E et al., Neurology 2007:69; 389-397

Conclusions
Kwon HE et al., Neurology 2016:87; 945-51
• Some Children with partial epilepsy develop
 N = 75 FCD
Epileptic Encephalopathy
- Challenge to the concept of focal and
 Focal epilepsy =
51 (68%) static “epileptogenic zone”
 Epileptic • Understanding dynamic EEG patterns and
encephalopathy brain MRI maturation is imperative and
= 24 (32%)
 16 Lennox fundamental to the practice of Pediatric
Gestaut epilepsy surgery
syndrome
 8 West • Each pediatric case should be critically
syndrome
evaluated based on all data and past studies

4
 11/13/2017

Future Directions THANK YOU

• Basic mechanisms that aid development of
of epileptic encephalopathies?
• Mrs. and Mr. Z:
- FCD are somatic mutations in mTOR
pathways – “Here is your child’s
epileptogenic zone.”

• Reverse engineer pivotal brain network

nodes/regions in patients of epileptic
encephalopathies who are non-lesional?

• Would there be epileptic encephalopathies

amenable to other surgical approaches:
ablation, neuromodulation?

5
 11/29/2017

Disclosure
VNS, RNS, DBS: approved for adults but what’s the science for
how to choose one over the other? Name of Type of
Commercial Interest Relationship
Robert S. Fisher, M.D., Ph.D. • Avails Medical (testing) • Stock option
Professor of Neurology & Neurological Sciences • Zeto, Inc (dry EEG) • Stock option
Stanford University School of Medicine • Cerebral Therapeutics (ICV Rx) • Stock option
• Smart Monitor (shake‐detector watch) • Stock option
• Engage Therapeutics (inhaled AEDs) • Consulting

None relevant to this talk

Learning Objectives Refractory Focal, MRI, PET, SPECT Negative

• Review mechanisms of VNS, RNS, DBS modulation

• Consider factors in choosing one or the other

Impact on Clinical Care and Practice What to do?

o VNS
• Clarify approach to neuromodulation for epilepsy • Nothing / meds fiddle o RNS
Anterior nucleus of thalamus (ANT) DBS
• Invasive studies o
• VNS Centromedian (CM) DBS
• Estimate best surgical side o
• RNS • Ketogenic diet o Hippocampal / Other DBS
• DBS • Neuromodulation o Neuropace in cortex / thalamus
Transcranial magnetic stimulation
• Understand mechanisms of neuromodulation o
o Transcranial electrical stimulation

Electrical Stimulation for Epilepsy The Ideal Circumstance for Choosing

Brainstem Network Thalamocortical Network Neocortical Network

CM Anterior thalamus DBS = deep brain stimulation
Motor Cortex
Caudate
Hypothalamus
solitarius
Subthalamus Direct Focus RNS = responsive neurostimulation

Hippocampus
Callosum
Cerebellum C
Vagus VNS = vagus neve stimulation vagus nerve stimulation deep brain stimulation responsive neurostimulation
Brainstem
Alas . . . The involved networks usually are undefined
No clinical evidence this approach would work
Randomized trials Does the underlying science of VNS, RNS, DBS help?

1
 11/29/2017

What are the mechanisms of VNS? VNS and the Blood Flow Theory of Epilepsy

Corning, J.L., 1883. Considerations on the pathology and therapeutics of epilepsy. J.

1882 Nerv. Ment. Dis. 10, 243–248.

When was the first human VNS for epilepsy?

a. 1882 In the 1880’s, a theory was that seizures resulted from
b. 1952 too much blood flow, since the face was flushed
during seizures and the carotid pulse was bounding.
c. 1961
d. 1972 Carotid compression was attempted to stop seizures.
e. 1986
In 1882, Corning, an American Neurologist, used
transcutaneous electrical stimulation of the vagus nerve
to attempt to reduce the pulse and cerebral blood flow.

Vagus Nerve Afferents to Brain

What happens in vagus doesn’t stay in vagus !
Rutecki P. Anatomical, physiological, and theoretical basis for the antiepileptic
effect of vagus nerve stimulation. Epilepsia. 1990;31 Suppl 2:S1‐6.

80% of vagal fibers (especially on

the left) are somatic and visceral
afferents to brain

The vagus sends ipsilateral afferents

to the dorsal motor nucleus of the
vagus, nucleus ambiguus, area
postrema, medullary reticular
formation, and the spinal trigeminal
nucleus and the nucleus of the
solitary tract.

Therefore . . .

VNS affects the Reticular Activating System, indirectly activation

Zanchetti Moruzzi
Moruzzi, G., Magoun, H.W., 1949. Brain stem reticular formation and activation of
the EEG. Electroencephalogr. Clin. Neurophysiol. 1, 455–473. The effect of vagal afferent stimulation on the EEG pattern of the cat. 1952; 4:357–361.

Cortical strychnine spikes

Reticular stimulation

• Cerveau isole cats

• Chlorolose anesthesia
• Left reticular stimulation 1.5 V, 300 Hz at the bar
• Suppression of ongoing activity

2
 11/29/2017

Salinsky MC, Burchiel KJ: Vagus nerve stimulation has no effect on awake EEG rhythms in humans.
Epilepsia 1993; 34: 299–304. Efficacy of VNS in a Rat Seizure Model

Woodbury, D.M., Woodbury, J.W., 1990. Effects of vagal stimulation on experimentally induced
seizures in rats. Epilepsia 31, S7–S19.

PTZ‐induced seizures

Clinical effect for VNS first suggested by Jacob Zabara First Clinical Use of VNS for Epilepsy

Zabara, J., 1985. Peripheral control of hypersynchronous discharge in Penry JK, Dean JC. Prevention of
epilepsy. Electroencephalogr. Clin. Neurophysiol. 61, S162.
intractable partial seizures by
Zabara, J., 1985. Time course of seizure control to brief, repetitive intermittent vagal stimulation in
stimuli. Epilepsia 26, 518.
humans: preliminary results.
Zabara, J., 1992. Inhibition of experimental seizures in canines by Epilepsia. 1990;31 Suppl 2:S40‐3.
repetitive vagal stimulation. Epilepsia 33, 1005–1012.

Between November 1988 and

September 1989, the stimulator
was successfully implanted in 11
patients at three centers:
Bowman Gray; University of
Miami University of Florida

Zabara co‐founded Cyberonics, now LivaNova

Does VNS work by changing autonomics?

Could VNS have a Direct Electrical Effect?

Garamendi I, Acera M, Agundez M, Galbarriatu L, Marinas A, Pomposo I, Valle E, Palma JA, Gomez‐Esteban Larsen LE, Wadman WJ, Marinazzo D, van Mierlo P, Delbeke J, Daelemans S, Sprengers M, Thyrion L, Van
JC. Cardiovascular autonomic and hemodynamic responses to vagus nerve stimulation in drug‐resistant Lysebettens W, Carrette E, Boon P, Vonck K, Raedt R. Vagus nerve stimulation aApplied with a rapid cycle
epilepsy. Seizure. 2016 Dec 2;45:56‐60. has more profound influence on hippocampal electrophysiology than a standard cycle.
Neurotherapeutics. 2016 13:592‐602.
Answer: Probably not.
Most autonomic measures
are not affected by chronic VNS in freely moving rats, using 2
VNS duty cycles: a rapid cycle (7 s on,
VNS
VNS shifts peak of 18 s off) and standard cycle (30 s on,
dentate EP 300 s off) and various output
currents. Rapid‐cycle VNS had a
greater effect than standard‐cycle
VNS on all outcome measures.

3
 11/29/2017

Could VNS mechanism be via neurotransmitters? VNS Increases Norepinephrine in Cortex and Hippocampus
Krahl SE, Clark KB, Smith DC, Browning RA: Locus coeruleus lesions suppress the seizure‐attenuating Roosevelt RW, Smith DC, Clough RW, Jensen RA, Browning RA. Increased extracellular concentrations of
effects of vagus nerve stimulation. Epilepsia 1998; 39:709–714. norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat. Brain Res.
2006;1119:124–32.
Duration of hind‐limb extension (sec)

20‐Hz train of 800‐pA, 0.5‐ms

pulses to a left vagus nerve Effect of various intensities of
cuff electrode VNS on extracellular NE in the
hippocampus of freely moving
Lesioning the locus coeruleus
with 6‐hydroxyl‐dopamine rats . . .
eliminated the anti‐seizure
effect of VNS against acute But in human epilepsy, GABA
maximal electroshock and glutamate are key.

Not Much Amino Acid Change in Human CSF with VNS VNS and anti‐inflammatory effects

Ben-Menachem E, Hamberger A, Hedner T, Hammond EJ, Uthman BM, Slater J, et al. Effects of Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW,
vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial Tracey KJ: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.
seizures. Epilepsy Res. 1995;20:221–7. Nature 2000; 405: 458–462
Patients with > 40% seizure reduction by 9 months
p‐value
No change in Tumor necrosis factor (TNF) response
• GABA to endotoxin is reduced by vagotomy
• GLU (VGX) and by vagus STIM

Reduced
• Phenylalanine
• Alanine

VNS for Seizures: What is the Mechanism ? What are Possible Mechanisms of DBS?

• EEG desynchronization
• Increase inhibition over excitation
• Effect on blood flow
• Neurotransmitters
• Autonomic mechanisms • Retrograde propagation
• EEG desynchronization • Synaptogenesis
• Increase inhibition over excitation • Effects on glia
• Anti‐inflammatory
• Neurotransmitters
• Disrupt synchrony
• Anti‐inflammatory
• Affect brain circuits
• Disrupt synchrony
Image from Medscape
• Affect brain circuits McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain
stimulation work? Present understanding and future questions. J Clin
Neurophysiol. 2004 Jan-Feb;21(1):40-50.

Lozano AM, Eltahawy H. How does DBS work? Suppl Clin Neurophysiol. 2004;57:733-6.

4
 11/29/2017

Network Effects of Vagus Nerve Stimulation

Henry TR, Bakay RAE, Pennell PB, Epstein CE, Votaw JR. Brain blood‐flow alterations induced by therapeutic vagus nerve
Physiology of Electrical Stimulation stimulation in partial epilepsy: II. Prolonged effects at high and low levels of stimulation. Epilepsia 2004; 45:1064–1070.

15
At the level of a neuronal network, the effects are O PET
not predictable
• Excitation of inhibitory neurons
• Spread across multiple neurons and networks
• Depolarization block close; excitation more distant
• Dependence on stimulus parameters
• Complex functions cannot be replicated by stimulation

Excitatory surround

Inhibitory center

Thalamic Stimulation in Cats Increases Synapses What are the mechanisms of RNS?

 Electrodes in awake cat VPL

 20 uA pulses, 0.5 s each sec at

50 Hz x 4 days
 Stimulation led to more
synapses in cortex

Fisher, rat, unpublished Lesser et al, human, Neurology 1999;53:2073‐81.

Keller A, Arissian K, Asanuma H. Synaptic proliferation in the motor cortex of adult
cats after long-term thalamic stimulation. J Neurophysiol. 1992;68:295-308. But also probably has a neuromodulatory effect

Direct Cortical Stimulation Disrupts Synchrony Stimulation of Rat Anterior Thalamus

Anterior Nucleus Thalamic Stimulation Interrupts EEG Spikes after PTZ

Mirski and Fisher

Sohal, V.S., Sun, F.T., 2011. Responsive neurostimulation suppresses synchronized cortical
rhythms in patients with epilepsy. Neurosurg. Clin. N. Am. 22, 481–488.

5
 11/29/2017

ANT Stimulation in Sheep Thalamic DBS increases cortical GABAergic inhibition

Stimulate AN, record TMS paired pulse, record motor response

spontaneous hippocampal Higher means more short‐interval cortical (GABA‐A) inhibition
field
Recovery time after cycle
stimulation off
continuous

normal

Molnar, G.F., Sailer, A., Gunraj, C.A., Cunic, D.I., Wennberg, R.A., Lozano, A.M., Chen, R., 2006. Changes
in motor cortex excitability with stimulation of anterior thalamus in epilepsy. Neurology 66, 566–571.
Stypulkowski PH, Giftakis JE, Billstrom TM. Development of a large animal model for investigation
of deep brain stimulation for epilepsy. Stereotact Funct Neurosurg. 2011;89:111-22.

Comparison
Neurostimulation Benefits for Epilepsy Over Time
FEATURE VNS Responsive Thalamic DBS
Neurostimulation
VNS RNS
Invasive Yes (minimally) Yes Yes

Reversible Yes (except for lead) Yes Yes

Class I evidence in favor Yes Yes Yes

Responds to a seizure Yes (Model 106) Yes No

DBS Need to know focus location(s) No Yes No

Seizure must get started No Unclear No

Efficacy (blinded phase) 31% vs. 11% (month 3) 40% vs. 9 % (month 5) 41% vs. 15% (month 4)

Efficacy (long-term) About 50% reduction About 66% reduction About 69% reduction

Side Effects Throat symptoms As expected for As expected + ? depression

implants
Approval Worldwide In US (FDA) In over 30 countries, not yet
US

Choice Algorithm (personal opinion)

single focus yes safe to resect and yes resect the

identified patient wants to focus
no no

2 foci identified yes comorbid

depression
yes
VNS or RNS
The End
e.g., bitemporal

no no
RNS or DBS
multifocal yes
DBS or VNS
or unclear

Favors VNS Favors RNS Favors DBS

Wants less invasive surgery Bitemporal foci Focus multifocal or unlocalized
Accepts possibly less efficacy Good efficacy over time Good efficacy over time
Accepts chest implant Likes cosmetics of skull device Accepts chest implant
Accepts throat/voice symptoms Likes responsive therapy Easy: “set and forget”
Concurrent depression Accepts high work load

6
11/29/2017

7
 Epilepsy surgery in the elderly: Support
seizure outcome and complications NIH P01 NS02808
R01 NS33310
U01 NS42372
Jerome Engel, Jr.
P20 NS80181
David Geffen School of Medicine at UCLA
CURE
Los Angeles, CA
Epilepsy Foundation
Epilepsy Therapy Project
Resnick Family Foundation

State of the Art

Conflicts of interest
Much research effort is being expended to improve the
diagnosis and treatment of pharmacoresistant
epilepsy, but the greatest impact on reducing disability,
I am the director of an epilepsy center. today, would derive from:
• Early recognition of pharmacoresistant epilepsy by
neurologists
• Early referral to full-service epilepsy centers

Consequences of pharmacoresistance
Major Misconceptions
• Epileptic encephalopathies
• All epilepsy centers offer is surgery. • Developmental delay
• My patient is not a surgical candidate/does not want • Interference with acquisition of interpersonal and
surgery. vocational skills
• There’s no reason to refer my patient to an epilepsy • Interictal behavioral problems – depression
center. • Neurologic impairment? – memory loss
• Increased morbidity
• Mortality rate 5-10x the general population

1
Consequences of pharmacoresistance Advances in pharmacotherapy
• Epileptic encephalopathies • Over 20 new anti-seizure drugs in the last 3
• Developmental delay decades
• Interference with acquisition of interpersonal and • No change in the percentage of pharmaco-
vocational skills
resistant patients
• Interictal behavioral problems – depression
• New medications treat the same patient
• Neurologic impairment? – memory loss
population as the old medications, with
• Increased morbidity different side effects
• Mortality rate 5-10x the general population

Definition of Drug Resistant Epilepsy

Intractable epilepsy
It is proposed as a testable hypothesis that
drug resistant epilepsy is defined as a failure
• Given the large number of antiseizure drugs
of adequate drug trials of two tolerated
available today, it would take a lifetime to carry out
appropriately chosen and used antiepileptic
an appropriate trial of each one in high dose drugs (whether as monotherapy or in
monotherapy, and in all conceivable combinations, combination) to achieve sustained seizure
in any given patient. Consequently, it is no longer freedom
practical to prove that a patient has medically
Kwan et al., Epilepsia 2010;51:1069-77.
intractable epilepsy.

Pseudopharmacoresistance Triage of epilepsies

• Epileptic seizures that can actually be treated. • Benign epilepsy: easily treated
• Seizures that are not epileptic. • Severe epilepsies:
• Remediable – require specialized diagnostic and
therapeutic approaches (pseudoresistance)
• Nonremediable – require supportive care
• Distinction between remediable and non-remediable
severe epileptic disorders must be made quickly to
avoid irreversible adverse consequences

2
Treatment Objectives Early interventon offers the best
chance to prevent:
No seizures • Irreversible psychosocial problems

No side effects • A lifetime of disability

• Premature death
As soon as possible

Early Effective Interventions

Referral to an Epilepsy Center Surgical Referrals in the US

• If first choice AEDs fail and seizures are 3,000,000 - people with epilepsy
interfering with school, work, or interpersonal 1,000,000 - have pharmacoresistant epilepsy
relationships, or there is developmental delay 100-500,000 - potential surgical candidates
in infants or young children – refer to an 4,000 - estimated referrals to epilepsy centers
epilepsy center per year (Less than 1%)
2,000 - surgical procedures per year (1-2%)
• Patient may not have refractory seizures or
may have a surgically remediable syndrome

Delay to referral US hospital referrals for refractory

epilepsy 1999-2008
• 333 patients who had surgery at 7 different centers
1996-2001 • Increase in hospital admissions for epilepsy
• Decrease in surgical procedures
• It took an average of 22 years before referral for
surgery • Increased referrals to low volume hospitals
• Decreased referrals to epilepsy centers
Berg et al., Neurology 60:186-190, 2003 • White patients more likely to receive surgery than racial
minorities

Englot et al. Neurology 78:1200-1206, 2012.

3
 Delay to referral for surgery at UCLA*
Practice Parameter: Temporal lobe and
localized neocortical resections for 1995-1998 17.1 years

epilepsy 2005-2008 18.6 years

Report of the Quality Standards Subcommittee of the *From diagnosis to referral

American Academy of Neurology, in Association with the

American Epilepsy Society and the American Haneef et al., Neurology 75:699-704, 2010.
Association of Neurological Surgeons

Evidence Based Review 1997-2001

Engel et al., Neurology, 2003.

Causes of Pharmacotherapy
Epilepsy Center
Failure
Pseudo pharmacoresistance • Identify specific syndromes.
• Noncompliance • Recognize nonepileptic seizures.
• Seizures not epileptic • Diagnose underlying treatable cause.
• Misdiagnosed epilepsy condition • Use specialized pharmacologic approaches.
• Wrong drug or dosage • Consider alternative treatments.
• Lifestyle issues • Address psychosocial problems.
Pharmacoresistance
• Ineffective standard treatments

Reasons physicians and patients give for why

epilepsy surgery is considered as a last resort, Common Misconceptions about Epilepsy Surgery
or not at all Misconception Fact
• Fear of surgery Seizure freedom is unlikely after two
All drugs need to be tried.
(Morbidity and mortality from recurrent seizures is greater than drugs have failed.
that from epilepsy surgery)
Bilateral EEG spikes are a Patients with unilateral onset seizures
• Lack of information about improvements in safety and efficacy contraindication to surgery. usually have bilateral spikes.
(In spite of hundreds of papers and over 20 books in the past
15 years) Normal MRI is a contraindication to Other techniques often detect a single
surgery. epileptogenic zone in patients with
• Epilepsy surgery is expensive normal MRIs.
(If performed early, the cost of surgery is considerably Multiple or diffuse lesions on MRI are a The epileptogenic zone may involve
less than the cost of a lifetime of disability) contra-indication to surgery. only a part of the lesion.
• There has never been a randomized controlled trial (RCTs of
Surgery is not possible if primary cortex Essential functions can be localized
MTLE were published in the NEJM in 2001 and JAMA in 2012)
is involved. and protected.
Engel, Seizures and Epilepsy, Oxford Press, 2013.

4
Common Misconceptions about Epilepsy Surgery Common Misconceptions about Epilepsy Surgery
Misconception Fact Misconception Fact

Surgery will make memory worse if Poor memory usually will not get My patient is too old. Older patients do as well as
there is an existing memory deficit. worse and could get better. younger ones.

Chronic psychosis is a contraindication Patients will still benefit if seizures

to surgery. are eliminated.

I.Q. less than 70 is a contraindication to Outcome depends on the type of

surgery. epilepsy and the type of surgery.

Patients with focal epilepsy and a focal Focal lesions can be incidental
lesion can have the lesion removed findings unrelated to the epilepsy;
without detailed presurgical evaluation. epileptogenicity of a lesion always
needs to be confirmed.

Engel, Seizures and Epilepsy, Oxford Press, 2013.

Percent seizure free after different

Epilepsy Surgery for Older Patients
surgical procedures
Class (%)
No. Pts. Age F/U TLE I II
Complications
Hemispher- Boling 2001 Canada 18 >50 >2 yrs. All 61 22
6% transient
Limbic Cortical Lesion ectomy Multilobar Murphy 2010 Australia 21 >50 >1 yr. All 81 14
14% transient
* Srikijrilaikul 2011 Thailand 16 >50 >1 All 56 19
25% transient
Palm Desert I before 1985 55% 43% 77%
Pieriorgio d’Oro 2017 Italy 50 >50 >2 28% 78 14
10% half
transient
Palm Desert II 1986-1990 68% 45% 66% 67% 45% ______________________________________________________________________________________
Acosta 2008 U.S. 7 >60 86% 57 29
* * Patra 2014 U.S. 11 >60 91 9 14% transient
Western Ontario RCT 200 64% Dewar 2016 U.S. 16 >60 >1 yr. 69% 50 42 25% transient
______________________________________________________________________________________
Practice Parameter 1997-200 67% 50% Punia 2017 U.S. 7 >70 >1 yr. All 57 29 3 decreased
memory
Spencer and Huh, 2008 53-84% 36-76% 43-79% Comparison Studies
(1990-2008) * Older group had worse outcome, more complications
* * Older group had better outcome, some complications

Conclusions
• Anterior temporal lobe resections are as effective in
the elderly as in the general population.
– Aspects of HS are no different than in younger
patients.
– Complications are comparable to those in younger
patients and most deficits are transient.
• Extratemporal resections also appear to be effective
and safe in the elderly, but data are incomplete.
• In patients who do not have medical contraindications,
age should not be a deterrent to epilepsy surgery.

5
 11/29/2017

Learning Objectives
“Minimally invasive” epilepsy surgery
PRESENT
options are the future • At the end of this session, participants will be able to
discuss indications and limitations of minimally invasive
Guy M. McKhann II, M.D. treatment options in epilepsy surgery.
Columbia Comprehensive Epilepsy Center
New York Presbyterian Hospital

Disclosures
• None Epilepsy Surgery: Rates of Seizure Freedom
Acknowledgements TLE: Epilepsy Surgery is Effective, but UNDERUTILIZED.
• Many Dr. Catherine A. Schevon
Dr. Lisa M. Bateman Temporal lobectomy (MTS)
Dr. Neil A. Feldstein Dr. Carl W. Bazil
Dr. Sameer A. Sheth Dr. Alison Pack
Dr. Shradda Srinivasan Lesionectomy
Dr. Garrett P. Banks
Dr. Brett E. Youngerman Dr. Hyunmi Choi
Dr. Paul F. Kent Nonlesional resection
Justin Oh, B.S.
Dr. Anil Mendiratta (temporal)
Dr. Jorge Gonzalez Martinez Dr. Deepti Anbarasan Nonlesional resection
Dr. Bill Bingaman D. James Riviello (extratemporal)
Dr. Patrick Chauvel Dr. Cigdem I. Akman
Dr. Imad Najm Dr. Danielle McBrian 0% 10% 20% 30% 40% 50% 60% 70%
Dr. Juan Balacio Dr. Tiffani McDonough
Dr. Irene Wang et al (CCF) Dr. Paul D. Mullin ETLE: Epilepsy Surgery is Invasive, and Not That Effective!
Dr. Robert Gross (Emory) Adapted from Tellez-Zentano et al, 2010

Epilepsy Surgery Goals: Selective Amygdalohippocampectomy (SAH)

Balancing Risk and Benefit

• How do we improve epilepsy surgery?

• TLE: Make it less invasive and safer
• ETLE: Make it less invasive, safer, and more
effective.

1
 11/29/2017

“Superselective” treatment: Gamma Knife “Superselective” Treatment:

Stereotactic Image Guided Laser Ablation

Laser Interstitial Thermal Therapy

• Stereotactically implantable optical fiber for delivery of laser energy
• Real‐time MRI‐thermometry and irreversible damage zone
prediction

ATL/SAH Stereotactic • SLAH works

Ablation (LITT/SLAH)
• SLAH is safe and cost effective.
• ~70‐90% 1 year sz free
• ~50‐60% 1 year sz free
• “Collateral damage” from approach to • For patients unwilling to undergo open surgery.
mesial temporal lobe • Minimize “collateral damage”:
• Transtemporal craniotomy neurocognitive benefit? • First line treatment option, with repeat ablations or open
• Health care utilization • 3mm twist drill hole resection still viable for patients who fail to achieve seizure
– 4‐6 hr surgery freedom.
• Health care utilization
– ICU stay
– LOS 2‐4 days – Shorter procedure time • Works in MRI normal MTLE if seizures localized by SEEG
– Longer recovery – No ICU stay
– Shorter LOS (~1 day) • Prospective trial ongoing (SLATE) to further optimize ablation
– Earlier return to work volume/targets and patient selection.

2
 11/29/2017

Epilepsy Surgery is Changing:

‐ Less Mesial Temporal/MTS
‐ More Extratemporal
‐ More MRI Negative Cases
? Epidemiological shift
? Selection bias Subdural‐guided resections – Outcome

Temporal Subdural Electrodes: Stereo EEG:

• Functional Mapping. • Anatomo-electro-clinical
• 2-D aspect of the EZ. correlation of the seizure.
Extra‐Temporal • 3-D aspect of the EZ.
Bulacio et al., 2012

Workflow for SEEG procedures

A‐E‐C planning of SEEG Robotic CT/MRI Trajectory Planning

Penfield et al, Subdural implant Bancaud et al, SEEG implant

Old Techniques…Why Change Now?

SEEG implantation Robotic trajectory planning summary
Slide modified from Jorge Gonzalez Martinez “Tipping Point” = Robotics + Imaging

Advantages of SEEG MRI normal TLE

• “3‐D” placement from lateral to • 36 yo s/p viral meningoencephalitis.
medial cortical structures
• Can be easily augmented during • Probable left mesial onset seizures (scalp EEG, PET).
same hospitalization if needed • MRI normal, Left lanuage dominant
• Extensive bilateral coverage, if
indicated. • Poor verbal memory bilaterally, worse on left (how
• No large incisions or bone flaps to bad?)
heal or infect
• CSF leakage virtually non‐existent
• Less pain, OR time, morbidity
• Increases the number of potential
surgical candidates

3
 11/29/2017

Surgical Options SEEG implant (Hair Sparing)

• Subdural implant?
• SEEG?
• Laser ablation?
• Anterior temporal lobectomy (ATL)?

LITT of amygdala onsets

LITT: ? HC also. Risk of memory decline?

Combining SEEG + LITT + Surgery SEEG Implant

Deep Frontal Complex FCD Lesion
Pediatric Intermittent Status Epilepticus

4
 11/29/2017

Epilepsy Surgery Stage 1

Epilepsy Surgery Stage 2
• LITT to the deep regions of the lesion
• Seizures only mildly improved.

• ECoG guided surgical resection of

readily accessible medial basal
dysplastic cortex.

Outcome Improving FCD Detection: Voxel Based Morphometry (MAP)

• Pathology: Type IIb focal cortical dysplasia.

• No change in neurological function.
• 18 months seizure free

Slide: Dr Irene Wang, CCF

Summary
• Epilepsy Surgery is rapidly changing.
• Advanced imaging combined with minimally invasive
techniques are decreasing morbidity and mortality.
• Long term benefit of newer approaches needs to be
demonstrated.
• Many challenges remain: e.g. interictal, noninvasive
detection of epileptogenic zone.
• New techniques are coming: focused ultrasound (FUS),
automated MRI detection +/‐ robotic ablation or FUS.

5
 11/29/2017

Disclosure
Should We Go Big?
Name of Type of
William Bingaman, MD
Commercial Interest Relationship
Vice Chair, Neurologic Institute Cleveland Clinic
Head and Program Director Epilepsy Surgery
NONE NONE
Shusterman Family Chair of Epilepsy Surgery
Professor of Neurological Surgery, Cleveland Clinic Lerner College of Medicine of CWRU
Cleveland Clinic Department of Neurological Surgery
Cleveland, Ohio

Learning Objectives Outcomes of Epilepsy Surgery remain

Stagnant Kaplan-Meier estimates of postoperative seizure-
free (SF) survival by early landmark.

• Examine the variables associated with positive

outcome after epilepsy surgery. • Outcomes no better despite
improvements in computers,
• Consider the extent of resection on improving imaging, EEG/MEG, and N. Foldvary et al. Neurology
2000;54:630

outcomes after epilepsy surgery surgical technology.

• Does removing more tissue
lead to better outcomes? Children
• Hemispherectomy data: 80% All Patients

seizure free long term Adults

• Moosa et al, Neurology 2012

Epilepsy Surgery in 1,418 patients (1996‐2009)

Pediatric Perspective The Epileptogenic Zone

• Younger patients, cognitive and neurodevelopmental concerns
• Pathology often different than adult onset with higher percentage of
cortical dysplasia, tumoral +/‐ MCD, and hemispheric pathology
(RE,MCD/HM,PI,SWD)

1
 11/29/2017

The epileptogenic zone Epileptogenic lesion

 Lesion itself is not part of seizure
Actual seizure onset zone onset zone unless it includes neurons
or has intermixed neurons (cortical
dysplasia, infiltrating tumor).
Potential seizure onset zone
 The most abnormal portion of a lesion
even when it contains neurons (for
example portion of cortical dysplasia
with balloon cells) tends to be less
epileptogenic than the adjacent
pathologically less abnormal cortex.
Seizure free
after surgery

Surgical excision
Resection of “blue circle” = seizure free

Extent of Resection Literature

• See SJ, Jehi LE, Vadera S, Bulacio J, Najm I, Bingaman W . Surgical outcomes in patients
with extratemporal epilepsy and subtle or normal magnetic resonance imaging findings.
Neurosurgery 2013;73:68–77.
• Dario J. Englot, MD, PhD Seunggu J. Han, MD Mitchel S. Berger, MDNicholas M. Barbaro,
MD Edward F. Chang, MD Extent of Surgical Resection Predicts Seizure Freedom in Low‐
Grade Temporal Lobe Brain Tumors. Neurosurgery, April 2012
• Allen R. Wyler, M.D. Bruce P. Hermann, Ph.D. Grant Somes, Ph.D. Extent of Medial
Temporal Resection on Outcome from Anterior Temporal Lobectomy: A Randomized
Prospective Study. Neurosurgery, November 1995, Pages 982–989.
• Lara E. Jeha Imad Najm William Bingaman Dudley Dinner Peter Widdess‐Walsh Hans “ “
Lüders. Surgical outcome and prognostic factors of frontal lobe epilepsy surgery. Brain,
February 2007, Pages 574–584
• Kim D., Kim H., Lee S., et al. Extent of neocortical resection and surgical outcome of
epilepsy: Intracranial EEG analysis. Epilepsia, April 2010.
• Rashid Jooma, Hwa‐shain Yeh, Michael D. Privitera, Maureen Gartner. Lesionectomy “ “
versus electrophysiologically guided resection for temporal lobe tumors manifesting with
complex partial seizures. Journal of Neurosurgery, August 1995 Pages 231‐236

Review of 47 studies with at least 30 patients published since 1984 on epilepsy surgery.

Lesionectomy for Cavernoma

• Chang et al, 2011: meta analysis of 1226 patients. 75% seizure free
with lesionectomy. Positive predictors were gross total excision,
surgery within one year of onset, lesion size <1.5cm. Resection of
hemosiderin ring not significantly predictive.
• McKhann et al, 2008: lesionectomy for patients with recent onset
seizures and no GTC. “Epilepsy surgery” for those with chronic
epilepsy, many seizures, +GTC.
• Meyer et al, 2009: 64 surgeries with 37 in mesial TL and 27 in TL
neocortex. Overall seizure freedom of 88% at two years. The use of
ECoG and lobectomy led to a 10% increase in seizure freedom at
one year.
• Knosp et al, 2008: complete removal of lesion plus
hemosiderin/gliosis and early surgery led to better outcome. From: Surgical outcome and prognostic factors of frontal lobe epilepsy surgery
Brain. 2007;130(2):574-584. doi:10.1093/brain/awl364
Brain | © The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For
Permissions, please email: journals.permissions@oxfordjournals.org

2
 11/29/2017

•Intracranial EEG studies in 177 consecutive patients

•Seventy-five patients (42%) were seizure free

Completeness of resection of SD grid ictal onset electrodes (p=0.0025)

But…

• Removing more tissue won’t help with EZ localization issues

Complete resection • Removing more tissue won’t help if EZ is “network‐wide”
• The Brain Connectome as a Personalized Biomarker of Seizure Outcomes
After Temporal Lobectomy. Bonilha L, Jensen JH, Baker N, Breedlove J,
Nesland T, Lin JJ, Drane DL, Saindane AM, Binder JR, Kuzniecky RI.
Neurology2015; Apr 8.
• Thalamotemporal Alteration and Postoperative Seizures in Temporal Lobe
Epilepsy. Keller SS, Richardson MP, Schoene‐Bake JC, O’Muircheartaigh J,
Incomplete resection Elkommos S, Kreilkamp B, Goh YY, Marson A, Elger C, Weber B. Annals of
Neurology 2015;77:760–774.

See et al, Neurosurgery, 2013, Jul:73 (1):68‐76.

Bigger not always better…but smaller likely Earlier is always better!

worse!
• Bigger…
• Increased risks?? Honest discussions with patients.
• Longer hospital stay, more postoperative pain.
• More likely to include EZ as resected tissue volume increases.
Non‐ lesional FLE

• Smaller…
Lesional FLE
• Less invasive ways to monitor and record seizures may lead to smaller and
less invasive resections i.e. SEEG guided laser ablation, GKRS for MTS. Self-fulfilling prophecy
• Leaves more tissue behind that is potentially epileptic.
• Does shorter hospital stay and less postoperative pain justify less successful
outcome?
• Honest discussion with patients. The price of waiting too long…
Simasathien et al., 2013

3
 11/29/2017

So...
FL MCD
• We have difficulty localizing EZ. • Normal perinatal history and development until seizure onset age 14
• We have difficulty understanding network involvement in generation months.
of epilepsy. • 50‐60 per day with head drops.
• We have difficulty visualizing extent of lesional brain intra‐operatively. • Right Frontal resection based on MR at 21 months age. Path: MCD.
• Continued daily seizures with little in way of semiology and EEG to
• Thus, larger resection of cortex (when safe to do so) may maximize localize.
the chances of removing the EZ and may be the most practical • 7 med failure and on three meds. Trial of medical marijuana (moved
approach until the time comes when accurate pinpoint localization of to CO).
the EZ is a reality. • Now non verbal, normal motor exam.

Preop MRI and PET: Age 20 months EEG: Generalized spike and wave
Postop partial anterior FL: immediate seizure
recurrence with same semiology and frequency

Interictal: Abundant generalized SWC

Ictal: Diffuse/ generalized

4
 11/29/2017

Removal more FL and TL. Path: FL gliosis, TL FCD.

Seizure free x 15 months. Post op EEG no clear Summary
epileptiform discharges seen.
• Resecting the EZ leads to seizure freedom and this
requires more precise knowledge from an epilepsy
mechanistic perspective...
• EZ may be big or small but this knowledge is hard to
come by...
• Earlier and larger resections make sense!

5
 11/29/2017

Disclosure
10 year old boy with refractory epilepsy
None
in rural Africa

Satya Gedela, MD, MRCP

Director of Epilepsy
Medical Director of Epilepsy Surgery
Nationwide Children’s Hospital
Columbus, Ohio

Learning Objectives History

10 year old right handed with focal onset seizures of
• Able to identify refractory epilepsy malignant onset
• Able to chose appropriate therapeutic option
Seizure onset: 8 months back

Semiology: Staring, eye deviation to the left,

unresponsiveness. Sometimes will progress to left
face/hemi body twitching. Recently she started to
fall over, then will develop rhythmic shaking on left
side. She will have left sided Todd’s paralysis.

Frequency: 4‐5 seizures per day, getting more

intense with falls.

Investigations in Africa Medications

EEG – not done Current AEDs

Levetiracetam 80 mg/kg/day
MRI – not done
Onfi 1 mg/kg/day
LP – not done
Past AEDs
Oxcarbazepine (exacerbated drop seizures)
VPA, carbamazepine tried in Ghana

1
 11/29/2017

Arrived in America June 2017 – Investigations MRI‐ right sided atrophy

EEG: Multi focal sharp waves from right side. Had multiple seizures
from 3 different right sided regions
Axial Coronal
LP: Normal cell count, protein, glucose, oligo clonal bands and
encephalitis panel.

Serum: Normal cbc, Malaria smear negative, Quant gold negative, CMV +IgG,
IgM negative, Cat scratch negative, and arbovirus negative

MRI – progressive right sided atrophy

PET: diffuse right sided hypometabolism

Neuropsychology: FSIQ =78, VCI = 95, VSI = 81, FRI = 74, WMI = 74, PSI = 77

PET – right sided diffuse Diagnosis and treatment

hypometabolism
Axial Coronal • Longitudinal imaging and clinical course consistent with Rasmussen
encephalitis
• Notable decline per mom over past couple of weeks with increase in
frequency of seizures causing Inez to fall and also new onset weakness.
• No change noted with IVIG
• Mom states she is ready for surgery ‐ Right sided hemispherectomy ‐
scheduled for surgery

Conclusion
• It matters where in the world you are getting treatment for
epilepsy! Some of us are more privileged.

• New onset seizure/epilepsy patient needs basic investigations

like EEG and MRI.

• Rapidly progressive intractable epilepsy with new onset gradual

focal weakness – most probably Rasmussen’s encephalitis.

2
 11/29/2017

Precision Medicine: How Close are We to Disclosure

Personalized Medicine in Epilepsy?
Name of Type of
Commercial Interest Relationship
• UCB, Eisai, Lundbeck, • Funding for the Human
Pfizer, Sunovion Epilepsy Project

Eddie Chang, M.D.

Dan Lowenstein, M.D.
Vikram Rao, M.D., Ph.D.
University of California, San Francisco

Learning Objectives What will precision

• Understand the conceptual basis of the “knowledge network” and
medicine in epilepsy look
its relationship to precision medicine like in the future?
• Recognize the gap in our understanding of the microbiome and
exposome as potential determinants of seizures and epilepsy
Precision at multiple levels of
• Describe the manner in which genetic discoveries are beginning to
directly impact epilepsy therapy complex systems, many of which
• Appreciate the implications of collecting real‐time patient‐derived we are only beginning to
data as a means for tailoring treatment and cures understand

The Knowledge Network Clear evidence of the dawn of precision

medicine in epilepsy – genetic diagnosis
Genome
as a guide to individualized therapy
Transcriptome Data Mining
of Huge
Microbiome
Datasets
Exposome
Artificial
Clinical tests
Intelligence
Other patient
data

Modified from Hawgood et al. Science Translational Medicine 7:300, 2015.

1
 11/29/2017

Approximately 40‐50% of the

epileptic encephalopathies can
now be explained genetically

Inherited and de novo genetic diagnoses

that influence epilepsy treatment in 2017
Gene Treatment considerations
SCN1A avoid sodium channel blockers (generally)
cannabidiol, fenfluramine
SCN2A high‐dose phenytoin helpful
SCN8A high‐dose phenytoin helpful
SLC2A1 ketogenic diet
PRRT2 carbamazepine
PLCB1 inositol

Retrospective multicenter study of AED in 58 female patients with PCDH19 ALDH7A1 pyridoxine
mutations and epilepsy aged 2–27 years (mean age 10.6 years) PNPO pyridoxal‐5‐phosphate
PCDH19 clobazam; avoid phenytoin
KCNQ2 (consider ezogabine), sodium channel blockers?
KCNT1 (consider quinidine)
GRIN2A consider memantine
GRIN2D consider memantine
TSC consider everolimus Ann Poduri
CAD consider uridine Children’s Hospital Boston

Lancet 1997: 350:485‐87

2
 11/29/2017

Chronic ambulatory electrocorticography (ECoG) with Detecting epileptiform activity with the
the NeuroPace RNS® System RNS® System
Remote Wand Telemetry Online Data Review

Detection count = Interictal discharge

Patient uploads neurostimulator Provider views ECoG data

data to secure website on secure website

HOME ENVIRONMENT, NORMAL INTRACRANIAL RECORDINGS FOR

ACTIVITIES, ON MEDS MONTHS—YEARS Long Episode = Electrographic seizure
Baud M, et al Nature Comm (in press)

Rhythms in detection counts are apparent in the raw data Rhythms of interictal epileptiform activity (IEA)

Baud M, et al Nature Comm (in press)

Baud M, et al Nature Comm (in press)
Baud MO et al. (Nature Communications, in press)

One minute Decoding Mood

One day
Multi-timescale
view of seizure
One week
activity

One month

Baud M, et al Nature Comm (in press) Rao V, Chang E, et al (unpublished)

3
 11/29/2017

Impact on Clinical Care and Practice

Electrical stimulation
enhances learning, • Large‐scale collaborations are the key to developing the full‐
scale epilepsy knowledge network
“calms” mood
• Data mining and AI will increasingly become part of regular clinical
practice
• We are not there yet, but the microbiome and exposome worlds
may become part of the care of the patient
• Genetic testing will eventually become standard practice
• We need to encourage the development of real‐time,
continuous cerebral monitoring
Rao V, Chang E, et al (unpublished)

4
 11/29/2017

Disclosure
What should an ideal MRI epilepsy protocol look
Name of Type of
like in the future for adults and for children? Commercial Interest Relationship
• none • none
Neda Bernasconi, MD PhD
Montreal Neurological Institute
McGill University, Canada

THE IDEAL MRI EPILEPSY PROTOCOL Learning objectives

High‐resolution conventional and quantitative contrasts of structure,
• Identify minimal requirements for an optimal clinical MRI epilepsy
function and metabolism obtained in clinically‐plausible time, combined with
protocol
post‐processing for objective assessment

… unlikely to become reality since rapidly evolving technical advances are • Understand the potential of advanced MRI techniques to localize
not systematically translated into clinical practice the epileptogenic focus and predict outcomes
 Variability in economic resources and technical infrastructures
 Difficulty to perform prospective, randomized controlled trials to assess level of
evidence and added value of a given test
 Lack of standardized acquisition protocols and post‐acquisition analyses methods

CONVENTIONAL MRI – A POWERFUL TOOL OUTLINE

 Non‐invasive, cost effective, flexible
1) Realistic epilepsy MRI protocol today
 Revolutionized management of drug‐resistant epilepsy by allowing reliable
detection of epileptogenic lesions
2) Means to optimize focus localization and surgical planning
 Hippocampal sclerosis and malformations of cortical development
 Surgical removal of the lesion is the only effective treatment to control seizures
3) Using MRI to predict outcomes
 Optimal sensitivity for lesion detection achieved when
 Images examined by expert reader (epileptologist and/or neuroradiologist) with 4) Future perspectives
appropriate clinical information (expert 91% vs. non‐expert 39%)
 Using high‐resolution MRI with multiple head coils (ideally 3Tesla)

Jobst & Cascino (2015) JAMA; VonOertzen (2002) JNNP; Winston (2013) Epilepsy Research

1
 11/29/2017

OUTLINE REALISTIC MRI EPILEPSY PROTOCOL

 High‐contrast, 3D sequences with isotropic voxels (i.e., identical dimensions across planes)
1) Realistic epilepsy MRI protocol today
 Complete brain coverage

2) Means to optimize focus localization and surgical planning  No need for operator‐dependent slice angulation
 Images may be reformatted in any plane without loss of resolution
3) Using MRI to predict outcomes  Greatly reduce partial volume effect (i.e., multiple tissue types present within a given voxel)
 Multiple phased‐arrays head coils
4) Future perspectives  Improved SNR/CNR
 Accelerated image acquisition (GRAPPA, ASSET, SENSE)
Cendes (2013) Continuum; Craven (2012) BJR; Daghistani (2013) Bran Dev; Duncan (2010) Nat Rev Neurol; Duncan (2016) Lancet Neurol
Griffiths (2005) Clin Radiol; Jackson (2011) Epil Behavior; Jayakar (2014) Epilepsia; Urbach (2012) Neuroimag Clin North Am
Wellmer (2013) Epilepsia; Woermann (2009) Epil Behav

EPILEPSY PROTOCOL 3D MRI EPILEPSY PROTOCOL 2D MRI

T1‐weighted Coronal T2‐weighted
Sequence type: gradient echo (GRE) Sequence type: turbo spin echo (TSE)
Voxel size: 1mm x 1mm x 1mm Voxel size: 0.4mm x 0.4mm x 2mm; no
Best to evaluate: anatomy and inter‐slice gap
morphology (volume, thickness, sulco‐ Best to evaluate: Hippocampal internal
gyral shape, GM‐WM interface integrity) structure (distinction of CA subfields,
MPRAGE – 1.0 mm isotropic dentate gyrus), amygdala, and
Ant Mid Post
parahippocampal cortices
T2 coronal ‐ 0.4 mm in‐plane resolution / 60 slices

Post
FLAIR
Sequence type: turbo spin echo (TSE) Mid

Voxel size: 1mm x 1mm x 1mm Ant

MRI slices acquired perpendicular to
Best to evaluate: signal intensity the long axis of the hippocampus
CAVEAT ‐ Not sensitive in neonates and children
<24 months of age due to incomplete myelination
FLAIR – 1.0 mm isotropic

MRI EPILEPSY PROTOCOL – SUMMARY HIPPOCAMPAL SCLEROSIS FOCAL CORTICAL DYSPLASIA

MRI positive “MRI‐negative” MRI positive “MRI‐negative”
 Can be obtained on 1.5T and 3T scanners, applicable to adults and children

 Time‐effective
 20 min. (<6min./scan) when using multiple phased‐array coils (e.g., 32‐channels)
 However, do not compromise quality for time! Repeat bad quality scans
 When a tumor, vascular malformation, or infectious process is suspected,
additional contrasts needed
 Gadolinium (enhancement ?)
 Susceptibility weighted/T2* (blood, iron deposits, calcifications ?)

2
 11/29/2017

OUTLINE COMPUTER‐AIDED
IMAGE ANALYSIS
T1 T2/FLAIR DIFFUSION fMRI
1) Realistic epilepsy MRI protocol today \

2) Means to optimize focus localization and surgical planning

EXTRACTS RELEVANT INFORMATION
SURFACE‐BASED ANALYSIS
NOT READILY VISIBLE TO THE EYE
3) Using MRI to predict outcomes Optimal integration of multiple modalities
and inter‐subject correspondence

4) Future perspectives MORPHOMETRY INTENSITY MICROSTRUCTURE BOLD SIGNAL

volume, cortical thickness, gradient, texture MD, FA, FD, spontaneous fluctuations, ALFF,
QUANTITATIVE MARKERS OF DISEASE shape, sulco‐gyral complexity NODDI ReHo
cell loss, maldevelopment gliosis, myelin damage axonal damage abnormal neuronal activity

AUTOMATED T2 RELAXOMETRY OF THE HIPPOCAMPUS

AUTOMATED HIPPOCAMPAL SEGMENTATION

CA1 GFAP FF (z‐score)

r = 0.84
Overlap with manual segmentation: 80‐90%
N=180
P<0.001
Seizure focus lateralization
Lateralization performance comparable to manual volumetry

Increased lateralization performance compared to visual evaluation

TLE‐HA: 100%
TLE‐NV: 20‐80%
CA1 T2 (z‐score)

Caldairou (2016) MICCAI; Hosseini (2016) Med Phys; Sone (2016) Neuroimage Clin. Kubota (2015) Epilepsy Behav
Iglesias (2015) Neuroimage; Kim (2014) MICCAI; Winston (2013) Epilepsia; Kim (2012) Neuroimage Kosior (2011) NeuroImage
Kosior (2009) Epilepsy Res
Abbott (2009) NeuroImage
Pell (2008) NeuroImage
GFAP GFAP field fraction
n=10 Bartlett (2007) AJNR
Townsend (2004) NeuroImage
Similarity (Dice index) Goubran (2015) Hum Brain Mapping Brillmann (2004) AJNR
Automatic – Manual Von Oertzen (2002) Neurology
Controls (40) 88% ± 2% Bernasconi (2000) NeuroImage
Kim (2012) Med Image Analysis Final
TLE (140)
Segmentation
TLE ‐ ipsi 86% ± 3% (deformable model)
Winston (2013, 2017) Epilepsia
TLE ‐ contra 88% ± 3%
L R

AUTOMATED LAMINAR ANALYSIS OF HIPPOCAMPAL SUBFIELDS AUTOMATIC DETECTION OF “MRI‐ NEGATIVE” FCD TYPE II
MORPHOLOGY INTENSITY
TLE – GLIOSIS ONLY TLE – HIPPOCAMPAL SCLEROSIS

medial sheet
+
Gill (2017) MICCAI
Laplace field 83% sensitivity in MANUAL SEGMENTATION AUTOMATIC DETECTION
“MRI‐negative” FCD

T1 T2 DWI
3.0 Tesla 1.5 Tesla
CLASS II EVIDENCE
FOR DIAGNOSTIC
Adler (2017) NeuroImage Clinical
ACCURACY
73% sensitivity in children with
MRI‐positive FCD
VOLUME INTENSITY MD FA ipsilateral contralateral
CA4 ‐ DG
Seizure focus lateralization in TLE‐NV Hong (2014) Neurology
CA1 ‐ 3
Besson (2008) MICCAI
sub Volume T2 intensity Volume + T2 intensity Colliot (2006) NeuroImage
Antel (2003) NeuroImage Classification
Global 56% 68% 68% of Evidence I‐IV
Kim (2014) MICCAI; Caldairou (2016) MICCAI; Bernhardt (2016) Ann Neurol 74% sensitivity 100% specificity 100% specificity 71% sensitivity 95% specificity Neurology 2012
Laminar 75% 94% 100%

3
 11/29/2017

LOCALIZING THE EPILEPTOGENIC ZONE – S IMULTANEOUS SCALP EEG‐ FMRI LOCALIZING THE SEIZURE ONSET ZONE – RESTING‐ STATE FMRI
Maps hemodynamic changes associated with inter‐ictal epileptic
discharges ‐ as long as they are seen on scalp EEG

Sensitivity: 60‐80%

Good intra‐subject reproducibility Stufflebeam (2011) J Neurosurg

Useful to plan SEEG: may highlight seizure onset zone and

epileptogenic networks

Centeno (2017) Ann Neurol

Khoo (2017) Ann Neurol
Van Graan (2015) Quant Imaging Med
Surg
Chaudhary (2012) Brain
Pittau (2012) Neurology Weaver (2015) Front Neurol
Grouiller (2011) Brain
Thornton (2011) Ann Neurol
Gholipour (2011) Epilepsia Lee (2014) Neurology
Zijlmans (2007) Brain
Salek‐Haddadi (2006) Brain Res Concordance between metrics of local function (ReHo, IRC)/connectivity (ICC) and SOZ (SEEG): 40% ‐ 70%
Jacobs (2009) NeuroImage
Benar (2002) NeuroImage Need for further validation in larger series with standardized metrics
Khoo (2017) Epilepsia
Zhang (2010) Hum Brain Mapping; Bettus (2010); JNNP; Morgan (2012) Epilepsia; Chiang (2015) JMRI

D IFFUSION TRACTOGRAPHY – O PTIMIZING SURGICAL PLANNING

Optic radiation tractography Limitation of diffusion tensor model ‐ Cannot resolve crossing fibers
avoiding damage to
Meyer’s loop Greater extent of
UF resection leads
to seizure‐freedom
after surgery

Keller (2017) Brain

Solution ‐ High angular diffusion imaging (HARDI) combined with novel

reconstruction techniques (e.g., CHARMED, NODDI, kurtosis, fixel)
 Provide refined markers of microstructure (e.g., axonal radius; fiber
orientation, density, cross‐sectional area; intra/extra‐axonal compartment;
dispersion; kurtosis)

Tuch (2002) Magn Reson Med

Assaf (2005) NeuroImage
Jensen (2005) Magn Reson Med
Alexander (2008) Magn Reson Med
Zhang (2012) NeuroImage
Raffelt (2012, 2017) NeuroImage
Real‐time display
Vaughan (2017) Ann Neurol
for surgical guidance

Duncan (2016) Lancet Neurol

Raffelt (2017) NeuroImage

D IFFUSION TRACTOGRAPHY – P OTENTIAL FOR PREDICTING COGNITIVE OUTCOMES

OUTLINE
Damage of the Inferior longitudinal fasciculus (ILF)
correlates with post‐OR episodic memory deficits
1) Realistic epilepsy MRI protocol today ILF MacDonald (2014) Cortex

2) Means to optimize focus localization and surgical planning

Memory - I

To date, most studies have been

3) Using MRI to predict outcomes group‐based

Need for assessing predictive value at

4) Future perspectives individual‐level
Memory - II

Winston (2013) Epilepsia; Riley (2010) Epilepsia; Diehl (2008) Epilepsia; Yogarajah (2008) NeuroImage

4
 11/29/2017

MACHINE LEARNING OF SURFACE‐BASED MORPHOMETRY – SEIZURE OUTCOME PREDICTION MACHINE LEARNING OF DIFFUSION‐DERIVED CONNECTOME – SEIZURE OUTCOME PREDICTION

Seizure free

114 TLE patients with unilateral EEG focus

ipsilateral

VOLUMETRY SURFACE MAPPING

Not seizure free
ACCURACY

Bonilha (2015) Neurology

Bernhardt (2015) Ann Neurol

MACHINE LEARNING OF MULTIMODAL MRI – FCD HISTOLOGY PREDICTION

FCD
OUTLINE
1) Realistic epilepsy MRI protocol today

2) Means to optimize focus localization and surgical planning

FCD IIA
3) Using MRI to predict outcomes
FCD IIB
IN VIVO MRI‐BASED STAGING MAY…

ASSIST MINIMALLY INVASIVE SURGERY 4) Future perspectives

MR‐guided interstitial thermal therapy

GUIDE SELECTION AND MONITOR NEW DRUGS

e.g., mTOR inhibitors

Hong (2017) Neurology

High field imaging ‐ Quantitative MRI (qMRI) contrasts Ultra‐High resolution 7T‐MRI – Optimal visualization of the laminar structure
Contrary to conventional images in which the
contrast is a mix of multiple parameters, qMRI
contrasts:
1. Provide microstructural features (e.g., cortical
myeloarchitecture, white matter axonal
properties)

2. Are crucial for understanding mechanisms that

drive morphology and signal

3. Are expected to provide specific in vivo

markers of pathology (through biophysical
modeling validated by ex vivo MRI)
32‐channel phased array coil
4. Yield standardized metrics, facilitating 3D TSE ‐ 0.38x0.38x0.38 mm
multicenter studies time: 29 min (for 1 acquisition)

5. Possible at 3T, but optimal at 7T 32‐channel phased array coil

MP2RAGE‐0.35x0.35x0.35 mm
time: 31 min (for 1 acquisition)
Weiskopf (2015) Current Opinion Neurol Federau (2016) PLOS One

5
 11/29/2017

7T MRI OF EPILEPTOGENIC LESIONS – D ETECTION OF “MRI‐ NEGATIVE” FCD TYPE II 7T MRI OF EPILEPTOGENIC LESIONS – I N VIVO STAGING OF HS

Hippocampal sclerosis
type 1
Neuronal loss Reactive astrogliosis

T2‐w, 2D FSE
0.33 x 0.33 x 1.5 mm (25 slices)

De Ciantis (2016) Epilepsia Stefanits (2017) Invest Radiol

Impact of MRI on Clinical Care and Practice

• Unique, versatile, non‐invasive tool for brain‐wide evaluation of epilepsy

• Powerful lesion detection technique

– By revealing lesions unseen by conventional neuroradiology, 3D structural MRI combined with
post‐processing has the ability to transform MRI‐negative into MRI‐positive, offering the life‐
changing benefits of epilepsy surgery to more patients

• Functional mapping may localize the seizure onset zone and epileptogenic networks

• Ongoing developments in quantitative contrasts and machine learning provide

unprecedented opportunities for the design of new biology‐derived biomarkers to
stage and monitor the disease, and to predict outcomes

6
 11/10/2017

No commercial
disclosures

Barriers to Advanced
Epilepsy Care-Closing
the Gap in Global Health

Gretchen L. Birbeck, MD MPH DTMH

Barriers to advanced care Barriers to advanced care

• Aims are to • Epilepsy care availability
1. Review what has to be in place for – Systems of care
advanced epilepsy care to be provided – Provider capacity
• Knowledge
2. Discuss barriers specific to epilepsy care
• Resources for Dx
3. Propose possible solutions to barriers • Resources for Rx
• Patient knowledge and expectation
• Political will
– Data to “persuade”
• (or twist arms or whatever it takes)

Additional challenges Additional challenges

• We have a general consensus that very • Even where the highest quality, most
basic care should be available to all (i.e. sophisticated epilepsy care is theoretically
the epilepsy treatment gap) available, there are extreme disparities in
• BUT there is no explicit agreement as to care.
what level of care should be considered – Regional distribution of care
‘acceptable’ within a particularly setting – Payer status (private insurance vs. other)
– LMIC<UMIC<HIC… – Social determinants of health
– Determined by general sophistication of
healthcare system?
– ILAE Task force challenge?

1
 11/10/2017

Epilepsy Care Availability-

Provider Capacity

Dall et al. Neurology 2013

Global Provider Capacity? Global Provider Capacity?

Global Provider Capacity

Guidelines for providers Challenges
• Overall number of providers
• Distribution of specialists
• How specialists spend their time especially
where there are a limited number of them
– Hands on patient care vs. guidelines
development and training of others

2
 11/10/2017

Overcoming challenges in
Resources for Dx and Rx?
provider capacity
• Train more • In general, resources only flow after
• Task shift providers and advocates are on the ground
– Advanced practice providers, clinical officers • In additional to training as medical
• Programs aimed at trainees likely to work in specialists, epilepsy care provider need
relatively deprived areas additional training as advocates and
communicators
• Reconsider work effort allocation
– Follow the money…

Patient Knowledge and

Role for global advocacy
Expectation
• Public education
– Capacity for care needs to be there, at some
level, before pulling people “out of the
shadows”
• Stigma reduction
– Aimed at people with epilepsy
– Aimed at “power” groups
• HCWs, teachers, clerics, police, employers
– Unclear that campaigns diffusely aimed at all
do much

Challenges arising from

Political Will
growing expectation
• Challenged by macro-level, systemic and
• Profit motivated institutionalized stigma
• Low quality services – More research needed…
– Dangerous at times… • Advocacy and ‘marketing’ struggle with the
• Unregulated duality and heterogeneity of the condition

Vs. all the devastating

conditions in which epilepsy is a
• Whose responsibility to component of larger
problems…place dysmorphic
constrain? and or seriously disabled
person’s photo here….

3
 11/29/2017

Disclosure
Innovations for Children, Adults and Elderly
with Epilepsy Royalties:
Eli M. Mizrahi, MD Demos Medical Publishers, McGraw Hill Medical Publishers,
Chair, Department of Neurology UpToDate, Wolters Kluwer Publishers
Professor of Neurology and Pediatrics
James A. Quigley Endowed Chair in Pediatric Neurology
Baylor College of Medicine Research Support:
Houston, TX
NeuroPace, Inc

Consulting:
Eisai, Inc

Innovation Age‐Dependent Innovations for Epilepsy Care

• Neonates

• Children

• Adults

• Elderly

Age‐Dependent Innovations for Epilepsy Care Innovation for Neonates with Seizures
• Consider innovation Shellhass RA, Wusthoff CJ, Tsuchida TN, Glass HC, Chu CJ, Massely SL,
• Based upon publications in 2017 Soul JS, Wiwattanadittakun N, Abend NS, Cilio MR, for the Neonatal
• Innovative ideas which guide the direction of care Seizure Registry.
• Improve diagnosis Profiles of neonatal epilepsies. Characteristics of a prospective US cohort.
• Enhance efficiency and quality of care Neurology. 2017; 89:893‐899.
• Promote self‐management
• Allow epilepsy diagnosis and treatment to be part of broader brain disorders
and their more effective management Novotny EJ. Early genetic testing for neonatal: When, why and how?
Neurology. 2017; 89: 880‐881.
• Less emphasis on devices or technical advances

1
 11/29/2017

Potential Yield of Rapid Genetic Testing in Rationale for Rapid Genetic Testing in
Neonates with Seizures Neonates with Seizures
• Early identification of etiology
• Enhanced data for prognosis
• Early institution of disease modifying therapy
• Implications for seizure control
• Implications for developmental outcome

Shellhass RA, Wusthoff CJ, Tsuchida TN, Glass HC, Chu CJ, Massely SL, Soul JS, Wiwattanadittakun N, Abend NS, Cilio MR, for the Neonatal Seizure Registry. Profiles of neonatal
epilepsies. Characteristics of a prospective US cohort. Neurology. 2017; 89:893‐899.

Innovation: Neonates
Treatment of KCNQ2 Seizures with
Rapid Screening for Neonatal Genetically‐Determined
Disease‐modifying Therapy Channelopathies Associated with Seizures
• KCNQ2 mutation associated with encephalopathy
• Potassium channelopathy
• KCNQ2 deficiency leading to limited channel opening

• Some drugs promotes KCNQ2 channel opening

• Binds to a subunit site on the ion channel pore (widely expressed in CNS)
• Targeted, disease modifying treatment
• Stabilizes the membrane

• Potential therapeutic impact on encephalopathy and seizure control

• Caution: investigations with off‐label agents

Transition of Care in Epilepsy Transition of Care in Epilepsy

Childhood to Adulthood Childhood to Adulthood
Brown LW, Camfield P, Capers M, Cascino G, Ciccarelli M, Gusmao C, Downs SM, • Patients and families have strong bonds with pediatric care givers
Majnemer A, Miller AB, SanInocencio C, Schultz R, Tilton A, Winokur A, Zupanc M.
The neurologist’s role in supporting transition to adult health care. • Transitions are difficult; factors include
Neurology 2016; 87:1‐6. • Epilepsy
• Some pediatric epilepsies and their treatments may persist into adulthood
Andrade DM, Bassett AS, Bercovici E, Borlot F, Bui E, Camfield P, Clossa GQ, Cohen E, • typically not seen in adult epilepsy practices
Gofine T, Graves L, Greenway J, Guttman B, Guttman‐Salter M, Hassan A, Henze M, • Co‐morbidities
Kaufman M, Lawless B, Lee H, Lindoson L, Lomax LB, McAndrews MP, Menna‐Dack D, • Family dynamics
Minassian BA, Mulligan J, Nabbout R, Neim T, Secco M, Sellers L, Shapiro M, Slegr M,
Smith R, Szafmari P, Tao L, Vogt A, Whiting S, Carter Snead O 3rd. • Acceptance of new role as “CEO”
Epilepsy: Transition from pediatric to adult care. Recommendations of the Ontario epilepsy • Shared task
implementation task force.
Epilepsia 2017. 58(9): 1502‐1517. • Patient, family, pediatric team, adult team

2
 11/29/2017

Epilepsy: Transition from pediatric to adult care. Epilepsy: Transition from pediatric to adult care.
Recommendations of the Ontario epilepsy Recommendations of the Ontario epilepsy
implementation task force implementation task force

Epilepsia
Volume 58, Issue 9, pages 1502‐1517, 6 JUL 2017 DOI: 10.1111/epi.13832
http://onlinelibrary.wiley.com/doi/10.1111/epi.13832/full#epi13832‐fig‐0001 Epilepsia
Volume 58, Issue 9, pages 1502‐1517, 6 JUL 2017 DOI: 10.1111/epi.13832
http://onlinelibrary.wiley.com/doi/10.1111/epi.13832/full#epi13832‐fig‐0002

Innovation: Children to Adults

Transition of Care in Epilepsy
Universal Acceptance of Transition of Care Best
Child Neurology Foundation Practice
• Universal application of common principles of transition of care
• Effective continuity of treatment
• Early self‐management
• Stronger sense of self for the patient

www.childneurologyfoundation.org

Innovation for the Elderly with Seizures

Lam AD, Deck G, Goldman A, Eskandar EE, Noebels J, Cole AJ.
Silent hippocampal seizures and spikes identified by foramen ovale
electrodes in Alzheimer’s disease.
Nature Medicine 12, 678‐680. 2017

Vassil KA, Tartaglia MC, Nygaard HN, Adam ZZ, Miller B.

Epileptic activity in Alzheimer’s disease: causes and clinical relevance.
Lancet Neurology 16:311‐322, 2017
Lam AD, Zepeda R, Cole AJ, Cash SS. Widespread changes
in network activity allow non‐invasive detection of mesial
temporal lobe seizures. Brain. 139: 2679‐2693, 2016

3
 11/29/2017

Epilepsy as a Network Disorder Innovation for the Elderly with Seizures

Kanner AM, Scharfman H, Jette N, Anagnostou E, Bernard C, Camfield C, Camfield P,

Legg K, Dinstein I, Giacobe P, Friedman A, Pohlmann‐Eden B.
Epilepsy as a Network Disorder (1): What can we learn from other network disorders
such as autistic spectrum disorder and mood disorders. Epilepsy & Behavior, 2017
(on‐line)

Scharfman HE, Kanner AM, Friedman A, Blümcke I, Crocker CE, Cendes F, Diaz‐
Arrastia R, Först H, Fenton AA, Zgrace AA, Palop J, Morrison J, Nehlig A, Prasad A,
Wilcox KS, Jette N, Pohlmann‐Eden B.
Epilepsy as a Network Disorder (2): What can we learn from other network disorders
such as dementia and schizophrenia, and what are the implications for translational
research? Epilepsy & Behavior, 2017 (on‐line)
Vassil KA, Tartaglia MC, Nygaard HN, Adam ZZ, Miller B.
Epileptic activity in Alzheimer’s disease: causes and clinical
relevance. Lancet Neurology 16:311‐322, 2017

Innovation for the Elderly with Seizures

Wider Consideration of Epilepsy as a Network Conclusions
Disorder within the Context of Dementia
• The foundations for innovation are within current concepts
• Effective screening for seizure disorder within the context of emerging • Current ideas need to be examined more closely
neurodegenerative disorders • Develop systems for application and translation to clinical practice
• Therapies which minimize cognitive fluctuations and provide a more • The review is not comprehensive: 3 examples in this presentation
clear understanding of the primary disorder
• Principles of acceleration of the application of current concepts can be
wide‐spread and form the basis of innovation in clinical practice

Innovation Innovation