Presidential Symposium: The Changing Landscape of · PDF filePresidential Symposium: The Changing Landscape of ... Upsher Smith, Valeant, Vertex, Vivus ... residency in Neurology at

Presidential Symposium:

The Changing Landscape of Epilepsy Surgery

Symposium Chairs: Jacqueline French, M.D.

Saturday, December 7, 2013 Convention Center – Ballroom B, Level Three

8:30 a.m. – 11:45 a.m.

OVERVIEW Epilepsy surgery is a very effective intervention for patients with treatment resistant epilepsy. The most successful epilepsy surgery is temporal lobectomy, which traditionally has produced seizure freedom in approximately two-thirds of patients. An AAN / AES guideline recommended temporal lobectomy as the treatment of choice for treatment resistant temporal lobe epilepsy. Yet, in a survey of centers with large epilepsy surgery programs, the number of overall surgeries, as well as the number of temporal lobectomies had decreased almost universally from their peaks. Moreover, surgeries for mesial temporal sclerosis have declined by half, whereas non-lesional cases have increased by a third. This symposium will present the data from various sources that suggest a shift in epilepsy surgery type and possibly location (from established to emerging centers) and will provide available evidence for the theories that may account for these changes. Also, future directions related to these changes, including basic science considerations (should the neocortex receive as much attention as the hippocampus?) will be discussed. LEARNING OBJECTIVES

• Recognize epilepsy syndromes other than temporal lobe epilepsy and evaluate such patients for epilepsy surgery

• Evaluate all patients with refractory epilepsy syndromes including extratemporal and non-lesional epilepsy to provide optimal treatment, identify surgical candidates, and perform epilepsy surgery for those with syndromes other than temporal lobe epilepsy when indicated.

TARGET AUDIENCE Intermediate: Epilepsy fellows, epileptologists, epilepsy neurosurgeons, “mid-level” providers with experience in epilepsy care (e.g., advanced practice nurses, nurses, physician assistants), neuropsychologists, psychiatrists, basic and translational researchers. Advanced: Symposium will address highly technical or complex topics (e.g., neurophysiology, advanced imaging techniques, advanced treatment modalities, including surgery). PROGRAM 8:30 – 9:30 am Research Awards Presentation 9:30 – 9:45 am Introduction

Jacqueline A. French, M.D. 9:45 – 10:05 am Who Was I Treating Then? Who am I Treating Now?

Dennis D. Spencer, M.D. 10:05 – 10:30 am The Changing Surgical Landscape in Kids

Howard L. Weiner, M.D. 10:30 – 11:00 am What Is the Evidence that the Landscape is Changing? Theories of Change

Dale C. Hesdorffer, Ph.D. 11:00 – 11:25 am Perspective of Basic Science: Is There Life Outside the Hippocampus?

Jeffrey A. Loeb, M.D., Ph.D. 11:25 – 11:45 am Conclusions

Jacqueline A. French, M.D. ACCREDITATION The American Epilepsy Society is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CREDIT DESIGNATION

Physicians: The American Epilepsy Society designates this live activity for a maximum of 2.5 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physician Assistant: AAPA accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician Assistants may receive a maximum of 2.5 hours of Category 1 credit for completing this program. Nurses: EDUPRO Resources LLC is an approved provider of continuing nursing education by Pennsylvania State Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. EDUPRO is also an approved provider by the California Board of Registered Nursing, provider number CEP-14387. Nurses who participate in selected AES programs can receive up to 30.75 contact hours. To successfully complete the activities, nurses are required to complete the evaluations for each session attended and to access the Medical Education Evaluator to claim Credit Nurses may claim up to 2.5 contact hours for this session. International Credits: The American Medical Association has determined that non-U.S. licensed physicians who participate in this CME activity are eligible for AMA PRA Category 1 CreditTM. ABPN Core Competencies The American Board of Psychiatry and Neurology has reviewed the Presidential Symposium and has approved this program as part of a comprehensive lifelong learning program, which is mandated by the ABMS as a necessary component of maintenance of certification. Core Competencies: Comprehensive Patient Care, System-Based Practice, and Practice-Based Learning 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 Jacqueline French, M.D. (Chair) Dr. Jacqueline French is a professor in the Department of Neurology NYU, in the Comprehensive Epilepsy Center, and Director of the Clinical Trials Consortium, an academic group that has performed a number of early phase clinical trails in epilepsy, and has developed new methodologies for epilepsy trials. Dr. French trained in Neurology at Mount Sinai Hospital in New York, and did her fellowship training in EEG and epilepsy at Mount Sinai hospital and Yale University. Dr. French is the current president of the American Epilepsy Society. She has focused her research efforts on development of new therapeutics for epilepsy, and new methodologies for clinical trials.

Jacqueline French, M.D. discloses receiving support as Consulting/Advisory Board Activity from Consulting (on behalf of the Epilepsy Study Consortium) Acorda Therapeutics,Aprecia, Avanir, Biotie, Catalyst, Concert, Cyberonics, Eisai Medical Research, Electrocore, Eli Lilly, GlaxoSmithKline, Icagen, Inc .Impax, Johnson & Johnson,LGCH Inc, Mapp Pharmaceuticals, Marinus, Neurelis, Neurotherapeutics, Neuropace, NeuroVista Corporation, Novartis, Ono Pharma USA, Inc., Lundbeck, Pfizer, Sepracor, Sunovion, SK Life Science, Supernus Pharmaceuticals, UCB Inc/Schwarz Pharma, Upsher Smith, Valeant, Vertex, Vivus Advisory board: UCB, Biotie,Electrocore, Eli Lilly,Acorda Therapeutics, Sunovion, Upsher-Smith.; as Research Funding from For Profit Commercial Sources/Principle Investigator from Principle investigator on multicenter trials for UCB, Impax, LGCH, Mapp Pharmaceuticals, Upsher Smith Vertex Funding to support the HEP study: UCB, Pfizer; as Federal/State/Not-for Profit Funding from Investigator (co-PI K Meador, P Pennell) NINDS 2U01NS038455-11A1. 8/01/2012-7/31/2017 Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs This is a multicenter study assessing outcomes of pregnancy in women with epilepsy Co-PI-J French Epilepsy Study Consortium 7/1/2012-7/1/2017 Human Epilepsy Project This is a 26-center prospective observational study to determine clinical, blood and EEG biomarkers of resistance to antiepileptic drugs Support provided by UCB, Pfizer, Lundbeck, FACES Co-PI: J French 7/1/2010-7/1/2013 Milken Foundation WEPOD (Women with Epilepsy, Pregnancy, Outcomes and Delivery) This is a 3-center study of fecundity in epilepsy R01 NS053998 (PI Lowenstein) 05/01/07-04/30/2012 NINDS The Epilepsy Phenome Genome Project (EPGP) The EPGP is a large-scale, national, multi-institutional, collaborative research project aimed at advancing our understanding of the genetic basis of the most common forms of idiopathic and cryptogenic epilepsies and a subset of asymptomatic epilepsy. The Epilepsy Study Consortium 09/01/09-8/31/10 As director of the Epilepsy Study consortium, Dr French receives 25% ongoing salary support for various activities performed; as Participation in Foundation or Not-for-Profit Organizations from President, Epilepsy Study Consortium Head of Scientific Advisory Board Epilepsy Therapy Project Board of Directors: Epilepsy Foundation (until 5/2013; as Other Revenue Source - Are there other revenue/benefits that might be perceived as a conflict? from 25% salary support Salary Support from the Epilepsy Study Consortium (a non-profit organization). Dale Hesdorffer, Ph.D. Dale Hesdorffer, Associate Professor in the Sergievsky Center at Columbia University, serves on several editorial boards, the professional advisory board of the Epilepsy Foundation of America, the American Epilepsy Society Task Force on psychiatric aspects of epilepsy, the American Academy of Neurology SUDEP guidelines workgroup, and is an associate editor of Epilepsia. She was a member of the Institute of Medicine Committee on the Public Health Dimensions of the Epilepsies and the IOM Committee on Gulf War and Health: Long-Term Consequences of Traumatic Brain Injury. Her work focuses on the epidemiology of epilepsy. Dale Hesdorffer, Ph.D. discloses receiving support as Consulting/Advisory Board Activity from UCB pharma. Gave a webinar and they paid me $1,000; as Federal/State/Not-for Profit Funding from the University receives the grants. I get salary from them. Jeffrey Loeb, M.D., Ph.D. Dr. Loeb is professor and head of the Department of Neurology and Rehabilitation at the University of Illinois in Chicago. He received his M.D. and Ph.D. from the University of Chicago, completed a residency in Neurology at the Massachusetts General Hospital and fellowship training in epilepsy at Harvard's Beth Israel Hospital. Dr. Loeb conducted postdoctoral work in the Department of Neurobiology at Harvard Medical School with Dr. Gerald Fischbach where he became interested in how understanding brain development can teach us what goes wrong in human disease and suggest new treatments. He directs a multidisciplinary program in human systems biology of epilepsy.

Jeffrey Loeb, M.D., Ph.D. discloses receiving support as Consulting/Advisory Board Activity from Consulting for Takeda pharmaceuticals and Neuropace; as Intellectual Property Ownership from submitted a patent through wayne state university on non-coding RNAs as a treatment for epilepsy. Dennis Spencer, M.D. Dr. Spencer is the Harvey and Kate Cushing Professor and Chair of the Department of Neurosurgery at Yale University School of Medicine. He is a graduate of Washington University School of Medicine and completed his neurosurgical residency at Yale in 1977. He joined the Yale neurosurgery faculty following his residency, and became Chief of neurosurgery in 1987. He has an international reputation in the surgical treatment of neurological diseases causing epilepsy and developed a widely used neocortical sparing surgical approach for patients with temporal lobe epilepsy. Dennis Spencer, M.D. has nothing to disclose. Howard Weiner, M.D. Howard L. Weiner, MD is a Professor of Neurosurgery and Pediatrics at the NYU Langone Medical Center, is a Diplomate of the American Boards of Neurological Surgery and Pediatric Neurological Surgery, holds an endowed chair, and is the pediatric epilepsy surgeon in the NYU Epilepsy Center. His clinical and research interests have included novel approaches in epilepsy surgery, Tuberous Sclerosis Complex, and pediatric brain tumors. He has published on these topics, has been invited to speak both in the US and abroad, has been consistently named in Castle Connolly, NY Magazine, and the NY Times Top Doctors lists, and was a recipient of the Van Wagenen Fellowship from the AANS. Howard Weiner, M.D. has nothing to disclose. Ajay Gupta, M.D. (CME Reviewer) Ajay Gupta, M.D., is Head or Pediatric Epilepsy at the Cleveland Clinic Foundation. He is a Professional Staff in the Epilepsy Center/Neurological Institute at The Cleveland Clinic Foundation. He is Associate Professor at The Cleveland Clinic Lerner College of Medicine, Case Western Reserve University. He is also the founder director of multidisciplinary Tuberous Sclerosis Program at the Cleveland Clinic. Ajay Gupta, M.D. discloses receiving support as Speakers Bureau Member (supported by for-profit entities) from Lundbeck Inc; as Consulting/Advisory Board Activity from Questcor; as Federal/State/Not-for Profit Funding from Tuberous Sclerosis Alliance; as Participation in Foundation or Not-for-Profit Organizations from Epilepsy Foundation Editorial Board - Pediatric Neurology Editorial Board - Epileptic disorders. Paul Levisohn (Medical Content Specialist, AES) Dr. Levisohn is a member of the faculty of the section of Pediatric Neurology at The University of Colorado School of Medicine and Children's Hospital Colorado Neuroscience Institute, having joined the faculty over 15 years ago following a similar period of time in the private practice of pediatric neurology. His academic career has focused on clinical care for children with epilepsy with particular interest in clinical trials and on the psychosocial impact of epilepsy. Dr. Levisohn is currently a consultant on medical content for CME activities to staff of AES. He is a member of the national Advisory Board of EF and has been chair of the advisory committee for the National Center of Project Access through EF. Paul Levisohn, M.D. discloses receiving support as Consulting/Advisory Board Activity from CME medical content consultant to AES staff.; as Research Funding from For Profit Commercial Sources/Principle Investigator from Eisai (clinical trials); as Federal/State/Not-for Profit Funding from NIH/NINDS: Childhood Absence Epilepsy, PI. NeuroNEXT, PI.; as Participation in Foundation or Not-

for-Profit Organizations from Professional Advisory Board, Epilepsy Foundation; Co-chair, Advisory Committee National Center for Project Access; Consultant to AES. 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. MEDICAL EDUCATION EVALUATOR® AND CERTIFICATES The Medical Education Evaluator® is an online system that allows any attendee to self-manage the process of completing course evaluations, tracking educational credits and printing out the CME or nursing certificate. Log on to the Evaluator via the AES website at www.AESnet.org. Once you are on the Evaluator, you will be asked to enter your MyAES ID # and password. You must then complete the evaluations and claim credit for the sessions you attended. The certificate(s) are saved to your personal account page and you may print the certificate(s) in PDF format at any time. To help support this process, attendees who want CME will be asked to pay the following rates:

Member Fees: $50 through January 17, 2014 $75 January 18 – February 28, 2014

Non-member Fees: $75 through January 17, 2014 $100 January 18 – February 28, 2014

The online Evaluator will be left open through February 28, 2014. You must complete the evaluations and credit tracking by that date. By completing this information online, attendees greatly assist the Council on Education and Annual Meeting Committee with important needs assessment data whereby the AES can further plan and address educational gaps to meet the needs of our learners. A meeting attendance certificate will be available for international meeting attendees at the registration desk. Handouts Handouts for the educational symposia are available to print in the AES virtualToteBag. Paper handouts will not be provided on site.

11/18/2013

1

The Changing Landscape of Epilepsy Surgery

December 7, 2013

Jacqueline A French MDComprehensive Epilepsy Center

NYU School of Medicine

American Epilepsy Society | Annual Meeting

Brewer K, Sperling M J. Neurosci Nurs 1988 20(6):366‐72Cahan LD, Engel J jr Acta Neurol Scand 1986 73(6):551‐60Hudson LP et al, Ann Neurol 1993 33(6):622‐31Devinsky O, Pacia S, Neurol Clin 1993, 11(4):951‐71Porter, RJ, Sato, S in: Epilepsy Surgery, Hans Luders, ed, Raven Press LTD NY 1991,pp 105‐10Spencer DD, Inserni J in:Epilepsy Surgery, Hans Luders, ed, Raven Press LTD NY 1991,pp 533‐46

Surgery Type Number (%) of surgeries performed

Totals

Anterior Temporal lobectomy

4862 (59%)66%

Amygdalohippocamp‐ 568 (7%)

Number of Surgeries performed worldwide between 1986‐1990

Amygdalohippocampectomy

568 (7%)

Lesionectomy 440 (5%) 5%Extratemporal resection 1073 (13%)

18%Hemispherectomy and Large Lobar Resections

448 (5%)

Corpus Callosotomy 843 (10%) 10%Engel J Jr, Shewmon DA. In: Engel J Jr ed, Surgical Treatment of the Epilepsies, 2nd ed, New York, Raven Press, 1993: 23‐4

Are Times Changing?

• IS Temporal lobe epilepsy still the most common type of epilepsy?

• IS Temporal Lobectomy still the most common surgery?surgery?

• IS epilepsy surgery overall rising or falling in utilization?

• If the landscape is changing, how would we know?

Are Times Changing?

To determine whether physicians felt that MTLE was still the most common type of surgical candidate, we used the new “Q‐PULSE”

mechanismmechanism

Intro to Q‐Pulse

• New AES effort• 2 epileptologists invited from every NAEC epilepsy center make up q‐pulse panel– Each filled out a survey providing demographics (age, pediatric vs adult years in practice primary interestpediatric vs adult, years in practice, primary interest, geographic location)

• Q‐Pulse questions pushed to panel via Survey Monkey

• All responses anonymized, but demographics can be linked with responses

• We received 97 replies to the survey

11/18/2013

2

At your center, how many of the treatment resistant epilepsy patients have mesial temporal lobe epilepsy?

10-50% (the minority)

<1% (very few)

The majority Don't know

11%

o ty)

<10 % a small

minority)

*No‐one endorsed “all patients” or “no patients”

51%35%

Compared to 10 years ago, your epilepsy center sees____pts with mesial temporal lobe epilepsy

Not practicing then but

more

Don’t know

16%8 %

Less

Not practicing then but

less

more 64%2%10%

8 %

If the landscape is changing, how can we know for sure?

• Epilepsy centers may behave in different ways:– They may elect to perform only temporal lobe surgeries

• In this case, the absolute number of surgeries at the centerIn this case, the absolute number of surgeries at the center might fall, but the percent of the total made up of TLE would not change

– They may attempt to perform increasing number of neocortical surgeries

• In this case the absolute number of surgeries at a center may stay the same,rise or fall, but the percent of temporal lobectomies would fall

Absolute number of surgeries in Bonn Epilepsy program

Presurgical evaluations

Bien et al Trends in presurgical evaluation and surgical treatment of epilepsy at one centrefrom 1988–2009 J Neurol Neurosurg Psychiatry 2013 vol. 84 no. 1 54‐61

Surgeries performed

Four most common surgeries in Bonn

Bien et al Trends in presurgical evaluation and surgical treatment of epilepsy at one centrefrom 1988–2009 J Neurol Neurosurg Psychiatry 2013 vol. 84 no. 1 54‐61

Absolute numbers of surgeries (Each type)

This Symposium

• A Surgeon’s view of the changing landscape (Spencer)

• What about Children? (Weiner)

• If things are changing, why is it happening? (Hesdorffer)

• What is the implication for Basic Science? (Loeb)

• Where do we go from here? (French)

11/20/2013

1

Who Was I Treating Then? Who Am I Treating Now?December 7, 2013

Dennis Spencer, M.D.Yale University School of Medicine


Disclosure

Nothing to disclose.

American Epilepsy Society | 2013 Annual Meeting

Yale epilepsy surgery 1983‐2009Single Program‐Adults, pediatrics, inclusive of all surgery types

Single Surgeon

Data Base designed in 1982 and implemented in 1983

1022 total cases648 temporal resections65 callosotomies41 hemispherectomies329 neocortical resections7 pure MST’s

What does one program tell us about the changing landscape of epilepsy surgery over time, in particular the medial temporal lobe thought to be the most common source of surgically remediable epilepsy

MTS

MTS Linear (MTS)

Brazier MAB, Crandall PH, Brown WJ: Long‐term follow up of EEG changes following therapeutic surgery in epilepsy. EEG and Clinical Neurophysiology

38: 495‐506, 1975

• The authors record the stories of 82 patients through the 60’s

• Discharges all medialC l d i h S i 6 % d ib fi ld• Correlated with MTS in 65%,describes fields

• No neocortical involvement• Using Falconer’s approach but talking about neocortical sparing

11/20/2013

2

ANTEROMEDIAL TEMPORAL RESECTION

November 20, 2013 9

Total Surgeries Total Temporal Total phase 3's MTS

1983 1984 1985 1986 1987 1988 1989 1990 1991

Surgery Type Number (%) of surgeries performed

Totals

Anterior Temporal lobectomy

4862 (59%)66%

Amygdalohippocamp‐ 568 (7%)

Number of Surgeries performed worldwide between 1986‐1990

Amygdalohippocampectomy

568 (7%)

Lesionectomy 440 (5%) 5%Extratemporal resection 1073 (13%)

18%Hemispherectomy and Large Lobar Resections

448 (5%)

Corpus Callosotomy 843 (10%) 10%Engel J Jr, Shewmon DA. In: Engel J Jr ed, Surgical Treatment of the Epilepsies, 2nd ed, New York, Raven Press, 1993: 23‐4

Total Temporal MTS Total Surgeries

1983 1984 1985 1986 1987 1988 1989

11/20/2013

3


1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

Total Surgeries Total Temporal Total phase 3's MTS

1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Total Temporal MTS Total Surgeries Decline in medial temporal resections for MTS

• Proportionate to decline in all surgeries

• Reflection of increased demand for intracranial studies for neocortical epilepsy

15

20

25

MTS Neocortical Total phase 3's

0

5

10

1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Decline in medial temporal resections for MTS



• Is there more decline in MTS than other temporal substrates?

11/20/2013

4

Total Temporal MTS Tumor Vascular Developmental

1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

40%

50%

60%

70%

80%

90%

MTS Tumor Vascular

0%

10%

20%

30%

40%

1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

50%

60%

70%

80%

90%

MTS Lateral

0%

10%

20%

30%

40%

1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

40%

50%

60%

70%

80%

90%

MTS PTLE Lateral

0%

10%

20%

30%

40%

198319841985198619871988198919901991199219931994199519961997199819992000200120022003200420052006200720082009

40%

50%

60%

70%

80%

90% MTS Developmental Linear (MTS) Linear (Developmental)

‐10%

0%

10%

20%

30%

198319841985198619871988198919901991199219931994199519961997199819992000200120022003200420052006200720082009

Decline in medial temporal resections for MTS



• Is there more decline in MTS than other temporal substrates?

• Are more patients studied but not going to resection?

11/20/2013

5

Total Surgeries non surgical phase3's Total phase 3's

198319841985198619871988198919901991199219931994199519961997199819992000200120022003200420052006200720082009

30%

40%

50%

60%

MTS Neocortical

0%

10%

20%

1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Decline in medial temporal resections for MTS• Proportionate to decline in all surgeries


I h d li i MTS h h l b ?• Is there more decline in MTS than other temporal substrates?

• Are more patients studied but not going to resection?

• Is there a change in referral base?

0

5

10

15

20

25

30Ax

is Title

Axis Title

Chart TitleMTS Tumor Developmental neocortical resections

Research in this decade included several NIH grants studying human temporal lobe epilepsy clinically and the hippocampus anatomically,

immunohistochemically and electrophysiologically.


1983 1984 1985 1986 1987 1988 1989

At the end of this decade our human research required combining temporal and extratemporal studies still emphasizing temporal lobe but less stress on medial structures for example with microdialysis

comparing neocortical and temporal lobe substrates


1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

11/20/2013

6

In the past decade human research is balanced with animal models and involves all etiologies with much less emphasis on the hippocampus and much more on developmental issues and neocortical network localization using intracranial studies.


2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

250

300

350

ctro

de C

onta

cts

Yale Experience: 1991‐2006Average Number of Contacts per Patient

0

50

100

150

200

1 21 41 61 81 101 121 141 161 181 201 221 241 261 281 301

Intracranial Study

Num

ber o

f Int

racr

ania

l Ele

c

Present Research Focus

Pub Med review:

Temporal Lobe Epilepsy‐‐‐‐14,998 articlesTemporal Lobe Surgery‐‐‐‐8,493 articlesHippocampal Research and Epilepsy‐‐‐‐9,361Hippocampal Research and Epilepsy 9,361

Neocortical Epilepsy Surgery‐‐‐‐434 articlesNeocortical Epilepsy Research‐‐‐‐772 articles

Yale Experience Summary

• Single Center thirty year experience• Taking into account:• despersment of cases

• change in referral base• new medications• better treatment of complex febrile seizures• Appears to be a decline and flattening in the incidence of MTS • Our clinical and basic research efforts need to recognize this and refocus

11/18/2013

1

The Changing Surgical Landscape in Kids

December 7, 2013

Howard L Weiner MDHoward L. Weiner, MDNYU Langone Medical Center


Disclosure

none


Learning Objectives

• To appreciate two fundamental changes that have led to the expanding surgical landscape in children with epilepsy


The Changing Surgical Landscape in KidsHypothesis

• The landscape is expanding

• This is based on two fundamental changes:

– a change in our understanding of the risk‐benefit profile of pediatric epilepsy surgery

– a change in our overall approach to the evaluation and treatment of children with epilepsy

Hypothesis

• In contrast to adult epilepsy surgery, thechange in surgical landscape in kids does notappear to be epidemiological but, rather, likelyreflects a change in us and how we look at thereflects a change in us and how we look at theproblem

The Established Landscape in Kids

• cortical dysplasia (5)• epilepsy‐associated tumor (3, 6)• cavernoma (4)• hemispheric pathology (8)• MTS (7)MTS (7)• temporal/frontal resections (1)• 20‐35% intracranial electrodes (1)• unifocal, older age (1)

Harvey S et al, Epilepsia 2008 (1); Cossu M et al Epilepsia 2008 (2); Southwell DG et al, Neurosurgery 2012 (3); Baumann CR et al Epilepsia 2007 (4); Palmini A et al Ann Neurol 1995 (5); Thorn M et al, Brain Pathology 2012 (6); Smyth MD et al J Neurosurg 2007 (7), Moosa AN et al Neurology 80:253‐60, 2013 (8)

11/18/2013

2

Pediatric Epilepsy SurgeryNovel Concept

PMG TSC MR negative

The Changing Surgical Landscape in Kids‐‐the default presumption is one of reluctance‐ as

it should be

• Dangerous‐especially in young children

T i i• Too invasive

• Not better than medical therapy

• Costs too much

“pediatric epilepsy surgery”PubMed search

• pre‐1993 (first in 1949) n=97

• 1993‐2003 n=387993 003 38

• 2003‐2013 n=901

My practice the last 12 months

• 78 craniotomies for children with epilepsy

• Cortical dysplasia (38%), Tuberous Sclerosis (30%) L G (6%) I i(30%), Lennox Gastaut (6%), MRI negative (6%), Sturge Weber (6%), brain tumor (5%), cavernoma (3%), porencephalic cyst (3%), encephalitis (3%)

• no mesial temporal sclerosis only

A change in our understanding of the risk‐benefit profile of pediatric epilepsy surgery

In general, weighing the risk of the current course vs. the risk of surgery

• uncontrolled epilepsy is bad for the developing brain, quality of life life expectancyquality of life, life expectancy

• effective epilepsy surgery in kids can improve development, quality of life

• surgery in kids is safe ‐ comparable to other aspects of pediatric neurosurgery

• effective epilepsy surgery can be cost effective in kids

Uncontrolled epilepsy is bad for the developing brain, quality of life, life expectancy

• “Uncontrolled seizures impair cognitive function with effects being most severe in infancy and lessening with increasing age at onset. These findings further emphasize the need for early aggressive treatment and seizure control in infants and

hild ”young children.” Berg AT et al Neurology 79:1384‐91, 2012

• “Relative to the population…sudden and seizure related deaths alone double overall mortality…mortality is significantly higher compared with the general population in children with complicated epilepsy…the SUDEP rate was similar to or higher than sudden infant death syndrome rates.”

Berg AT et al Pediatrics 132:124‐31, 2013

11/18/2013

3

Effective epilepsy surgery in kids can improve development, quality of life

• “After surgery, seizure frequency and developmental quotient improved.”

• “Developmental status before surgery predicted p g y pdevelopmental function after surgery.”

• “Patients who were operated on at younger age and with epileptic spasms showed the largest increase in developmental quotient after surgery.”

Loddenkemper T et al Pediatrics 119:930‐5, 2007

Surgery in kids is safe ‐ comparable to other aspects of pediatric neurosurgery

• “…carefully selected pediatric patients with intractable epilepsy can benefit from subdural invasive monitoring procedures that entail definite but acceptable risks” Onal C et al J Neurosurg 98:1017‐26, 2003

• “There were no surgical complications related to intracranial EEG monitoring…The supplemental depth electrodes conferred an extra dimension of depth to the analysis, which allowed for successful outcome…” Kim H et al J Neurosurg Pediatr 8:49‐56, 2011

• “Placement of subdural grid and strip electrodes…is generally well tolerated in the pediatric population…not associated with higher rates of…complications” Johnston JM Jr et al J Neurosurg 105:343‐7, 2006

Safety• Roth J, Carlson C, Devinsky O, Harter DH, MacAllister WS, Weiner HL

• Safety of Staged Epilepsy Surgery in Children• Neurosurgery (in press)• 161 children (Mean age 7 yo, 8 mos‐16 yo), 200 admissions 496 surgeriesadmissions, 496 surgeries

• No mortality• Neuro deficit 2%, infection 1.5%, bleed 0.5%

• Learning curve: complications down in second half of study (1st v. 2nd 6 yrs, 100 admissions)

Safetythe importance of pediatric “team”, system, and no

egos• Nursing• Neurosurgery• Neurology• Anesthesia• Radiology• Pediatrics/PICU• Psychology/Neuropsychology/Psychiatry• Social work• Child Life• Conference

Effective epilepsy surgery can be cost effective in kids

• “Surgical treatment resulted in greater reduction in seizure frequency compared to medical therapy and was a cost‐effective treatment option in children with intractable epilepsy.” Widjaja E et al Epilepsy Research 94:61‐68, 2011

• Cleveland Clinic, Neurologic Institute, 2011 Outcomes

A change in our overall approach to the evaluation and treatment of children with

epilepsy

In general, kids who previously would not have been candidates for surgery are being considered

• Improved diagnostic evaluations pre‐operatively (MRI PET MEG SPECT fMRI)(MRI, PET, MEG, SPECT, fMRI)

• More comfort with invasive EEG monitoring in kids in challenging cases

• More willingness to consider aggressive surgical resections even in the face of anticipated neurologic deficits

11/18/2013

4

• “Epilepsy surgery may be successful for selected children… with a congenital or early‐acquired brain lesion despite abundant generalized or bilaterallesion, despite abundant generalized or bilateral epileptiform discharges on EEG. The diffuse EEG expression may be due to an interaction between the early lesion and the developing brain”

Wyllie E et al Neurology 69:389‐97, 2007

• “This approach can help to identify both primary and secondary epileptogenic zones in young TSC patients with multiple tubers. Multiple or bilateral seizure foci are not necessarily a contraindication to surgery.”

Pediatrics 117:1494‐502, 2006

Improved diagnostic evaluations pre‐operatively (MRI, PET, MEG, SPECT, fMRI)

More comfort with invasive EEG monitoring in kids in challenging cases

1) Non-concordant or non-localizing non-invasive studies (implies that complicated cases may still have resectable seizure focus)

2) Normal MRI in setting of refractory partial epilepsy (define resection)

3) Presumed seizure focus overlaps eloquent cortex (define resection)

4) Multiple potential (multifocal) seizure foci with non-localizing non-invasive studies (which one ?)

5) Structural lesion on MRI (define relationship of seizure focus to MRI lesion)

More willingness to consider aggressive surgical resections even in the face of

anticipated neurologic deficits• Would you agree with resecting a seizure focus in eloquent

cortex (motor, visual) if you were confident it could render child seizure free ?

• Painful decision with parents• QOL intervention‐‐Trade off of potential physical deficit for seizure

freedom and developmental improvement• Unique to pediatric medicine

11/18/2013

5

Speculation about future

• Will numbers go down ?• Are local community neurologists more willing to refer young patients for presurgical evaluations earlier ?evaluations earlier ?

• Will long term benefits outweigh natural history ?

• Minimally invasive approaches (diagnostic and therapeutic)

Conclusion

• In contrast to adult epilepsy surgery, thechange in surgical landscape in kids does notappear to be epidemiological but, rather, likelyreflects a change in us and how we look at thereflects a change in us and how we look at theproblem

Impact on Clinical Care and Practice

• a change in our understanding of the risk‐benefit profile of pediatric epilepsy surgery

•a change in our overall approach to the evaluation and treatment of children with epilepsy

11/18/2013

1

What Is the Evidence that the Landscape is Changing? Theories of

ChangeDecember 7, 2013Dale C Hesdorffer, PhDGH Sergievsky CenterColumbia University


Disclosure

Upsher Smith

Esai

Consultant

Consultant


Learning Objectives

• To understand changes in epilepsy surgery for MTS over time•To understand the possible reasons for these changes


Anterior temporal lobectomyAnterior temporal lobectomy

• 1980’s epilepsy surgery became popular– Shown to render 60%‐90% of patients seizure‐free

• 2001 RCT showed efficacy for seizure freedom2001 RCT showed efficacy for seizure freedom for patients with seizures impairing awareness

• 2003 AAN, AES, AANS practice parameter published on temporal lobe and localized neocortical resections

Wiebe et al, NEJM 2001; Engel et al, Neurology 20034

What has happened since 1980?What has happened since 1980?

5

UKUK‐‐wide trends in epilepsy surgery to wide trends in epilepsy surgery to control epilepsycontrol epilepsy

40

60

80

100 Adult 2000 Adult 2011 Pediatric 2010‐2011Percentage

0

20

Neligan et al. Epilepsia 2013;54:e62‐e65

Temporal Extratemporal Neuromodulatory6

11/18/2013

2

Number of epilepsy surgeries in SwedenNumber of epilepsy surgeries in Sweden

50

60

70

80

90 Number

0

10

20

30

40

50

1991 2007

Kumlien & Mattson Seizure 20107

Proportion of total temporal lobectomies Proportion of total temporal lobectomies 19931993‐‐2009, Olmsted County2009, Olmsted County

Van Gompe et al Arch Neurol, 20128

Incidence of temporal lobectomies in Incidence of temporal lobectomies in Olmstead County 1993Olmstead County 1993‐‐20092009


New drugs Guidelines

In a nationwide inpatient sample

Neurology, 2012

10

New drugs Guidelines

Neurology, 2012

11

Have the etiologies of MTS changed Have the etiologies of MTS changed over time?over time?

12

11/18/2013

3

Etiology of MTS:Etiology of MTS:Patients with intracranial electrodes, Patients with intracranial electrodes,

surgery, and seizure freedomsurgery, and seizure freedom

• 67% Febrile seizures Febrile seizures – 73% were SE, repeated or with Todd’s

• (75% among children in Falconer)

• 14 9% Head TraumaHead Trauma• 14.9% Head Trauma Head Trauma – With LOC (70%)

• 9% Birth trauma Birth trauma – 33% with significant birth trauma

• 6% Other • 7% No risk factors

French et al. Ann Neurol 1993; Falconer The Lancet 197413

Trends in incidence of hospitalized TBI Trends in incidence of hospitalized TBI in the USin the US

200

250

300

350198019942003

p<0.01 for all comparisons of 1980 to 1994

Incidence/100,000

0

50

100

150

200

Thurman et al JAMA 1999 for 1980 and 1994; MMWR March 2, 2007 for 200314

Trends in incidence of birth asphyxia Trends in incidence of birth asphyxia in Californiain California

Wu et al. Pediatrics;114:1584‐1590 15

Proportion with febrile seizures in focal epilepsy Proportion with febrile seizures in focal epilepsy of unknown of unknown etiology, Olmstead County etiology, Olmstead County


Proportion of first febrile seizures stopped Proportion of first febrile seizures stopped by a drug in Rochester, MNby a drug in Rochester, MN

60708090

100Percentage

0102030405060

< 5 minutes

5‐9 minutes

10‐14 minutes

15‐19 minutes

20‐29 minutes

30‐59 minutes

60+ minutes

17

How many patients with MTS could be How many patients with MTS could be expected each year in the US?expected each year in the US?

• Assuming 61 million children <15 years in 2010– 1,220,000 (2%) with febrile seizure annually

• Febrile SE is 2% 4% of all febrile seizures in Rochester• Febrile SE is 2%‐4% of all febrile seizures in Rochester– 24,400 – 48,800 with FSE annually

• FEBSTAT shows that 10% with have increased T2 on MRI and at 1 year 86% have hippocampal atrophy– 2,440 – 4,880 with increased T2

• 2,098 – 4,197 with hippocampal atrophy

18

11/18/2013

4

The prevalence The prevalence ‐‐ incidence effectincidence effect

19

21 22

23 24

11/18/2013

5

25 26

27

What is the role of the new AEDs on What is the role of the new AEDs on decreases in epilepsy surgery?decreases in epilepsy surgery?decreases in epilepsy surgery?decreases in epilepsy surgery?

28

From: J French29

Ezogabine(PotigaTM)

Eslicarbazepine (ZebinixTM)

10

15

20

Vigabatrin (Sabril TM)

Perampanel (FycompaTM)

Pregabalin (LyricaTM)

Clobazam (OnfiTM)

Rufinamide (BanzelTM)

of A

EDs

Timeline: ASD approvals by FDA since 1990

Brivaracetam (RikeltaTM)

Lacosamide (VimpatTM)

1990 1995 2000 2005 2010 2015 20200

5

10

Felbamate

Zonisamide (ZonegranTM)

Lamotrigine (Lamictal TM)Gabapentin (NeurontinTM)

Topiramate (TopamaxTM)

Oxcarbazepine (TrileptalTM)

Tiagabine (GabitrilTM)

Pregabalin (LyricaTM)

Year

Num

ber

Levetiracetam (KeppraTM)

http://www.accessdata.fda.gov

Not approved

(FelbatolTM)

30

11/18/2013

6

RCTs of adjunctive therapy for focal epilepsy resistant RCTs of adjunctive therapy for focal epilepsy resistant to standard AEDsto standard AEDs

Percentage achieving >50% reduction in seizures minus placebo

From: French Epilepsia, 2007 Based on studies by: Cramer et al Epilepsia, 1999; Barcs et al, Epilepsia 2000; Cereghino et al Neurology 2000; Faught et al, Neurology 2001

31

The proportion with treatment resistant focal The proportion with treatment resistant focal epilepsy has not changedepilepsy has not changed

• 3% to 37% of treatment resistant focal epilepsy in RCT have a >50% reduction in p p yseizures

HOWEVER• Few stop having seizures

32

The role of new AEDsThe role of new AEDs

• If seizure frequency in treatment resistant focal epilepsy has decreased due to the new AEDs

• Then the proportion of patients who wish to have surgery may have decreased over time

33

Effect of treatment changes in 139 patients with drug‐resistant epilepsy

336

300

350

400Number of AED changes over 6 years

48% of patients had a 50%‐100% sz reduction

7437

0

50

100

150

200

250

<50% reduction (N=72) 50%‐99% reduction (N=41) 1+ yrs sz free (N=26)

Neligan et al. J Neurol Neurosurg Psychiatry 201234

Has the profile of surgical referrals Has the profile of surgical referrals changed over time?changed over time?

35

AED duration before and after the surgery RCT for AED duration before and after the surgery RCT for referred TLE patientsreferred TLE patients

n.s.

Haneef et al, Neurology 201036

11/18/2013

7

What is the influence of patient refusal What is the influence of patient refusal of surgery after preof surgery after pre‐‐surgical surgical

l ti ?l ti ?evaluation?evaluation?

37

Outcomes of Outcomes of presurgicalpresurgical evaluations evaluations for epilepsy surgeryfor epilepsy surgery

Bien et al. J Neurol Neurosurg Psychiatry 2013

1995 1994

1991 1990

Opinions about surgery Opinions about surgery in adult epilepsy patientsin adult epilepsy patients

Erba et al. Epilepsy Behav 201239

Risk factors for positive and negative opinions Risk factors for positive and negative opinions about surgery about surgery in in adult epilepsy patientsadult epilepsy patients

Erba et al. Epilepsy Behav 201240

Comparison of naïve and nonComparison of naïve and non‐‐naïve adult patients naïve adult patients and parents of children regarding epilepsy surgeryand parents of children regarding epilepsy surgery

Erba et al Epilepsy Behav 201341

Patient educationPatient education

• Education about epilepsy surgery is needed– Most particularly in patients with

• below a high school education• disabilitydisability• a lack of trust in their doctor

– Erba et al. Epilepsy Behav 2012

• Racial minorities and those with medicaid, medicareand no insurance

– Englot et al Neurology 2012

• Otherwise……

42

11/18/2013

8

Effect of treatment changes in 139 Effect of treatment changes in 139 patients with drugpatients with drug‐‐resistant epilepsyresistant epilepsy

336

300

350

400Number of AED changes over 6 years

48% of patients had a 50%‐100% seizure reduction

7437

0

50

100

150

200

250

<50% reduction (N=72) 50%‐99% reduction (N=41) 1+ yrs sz free (N=26)

Neligan et al. J Neurol Neurosurg Psychiatry 201243

What do neurologists think about What do neurologists think about epilepsy surgery?epilepsy surgery?

44

Swedish study of neurologist who treat Swedish study of neurologist who treat epilepsy regularlyepilepsy regularly

• Response rate 66%– 81% from hospitals– 57% from private practices

R f l t

Factor examined Percent

Effectiveness on seizure frequency

38.8% no experience

QOL 45.5% no experience

Neurological complications 43 9% no experience• Referral to surgery– 36% 2‐5 patients– 32% >=6 patients– 32% Never referred

Neurological complications 43.9% no experience

Cost effectiveness 88.2% high/v high

Number of AEDs to try before surgery

4+ AEDs 24.2%

3 AEDs 57.9%

2 AEDs 17.9%

1 AEDs 0%Kumlien & Mattsson Seizure 2010

45

Michigan study of neurologists’ views of Michigan study of neurologists’ views of epilepsy surgery in 2006epilepsy surgery in 2006

• Response rate 20% (N=84)• 11% never discussed epilepsy surgery with their patients

• Among those with patients who had surgery, 70% g p g y,were seizure free– 31% of those with surgery had serious complications

• ~50% did not get appropriate feedback from the epilepsy center– For 76%, this was an important factor for further referrals– 38% said their patient never returned to the practice

• 48% said this was very important when considering referrals

Hakimi et al Epilepsy & Behav 200846

Italian study of barriers towards epilepsy surgery Italian study of barriers towards epilepsy surgery among adult and child neurologists caring for epilepsyamong adult and child neurologists caring for epilepsy

The 23 academic& clinical leaders

More negative More positive

183 neurologists

61% of neurologists’ scores were outside red lines

Erba et al. Epilepsia 201247

What are the barriers?What are the barriers?

• Lack of experience in patient referral for

• Lack of feedback from the surgical center

Communication betweenCommunication betweenNeurologists need Neurologists need epilepsy epilepsy centers and centers and ssurgery education urgery education neurologistsneurologists

psurgery

• Variability in understanding epilepsy surgery

• Lack of alignment with experts about epilepsy surgery

the surgical center• Failure of neurologists’ patients to return to them

48

11/18/2013

9

Why is surgery for MTS decreasing?Why is surgery for MTS decreasing?

• Prevalence – incidence effect

• Decrease in the occurrence of risk factors for MTSAnd the possibility that patients with febrile seizures who– And the possibility that patients with febrile seizures who receive drugs to stop seizures, have shorter duration seizures than they would have had without drugs

• Increasing patient refusal rates

49

What factors can be addressed?What factors can be addressed?

• Lack of patient education

• Lack of outreach to poorer communities

• Lack of neurologist education

• Lack of communication between epilepsy centers and neurologists

50


To benefit patients with treatment resistant epilepsy:•It is important to educate patients with treatment resistant epilepsy about surgery• Neurologists treating epilepsy patients also need education about surgery• Surgical centers need to develop protocols for communication with neurologists about surgery and return of their patients to the referring practice

11/18/2013

1

Perspective of Basic Science: Is There Life Outside the Hippocampus?

December 7, 2013

Jeffrey A. Loeb, M.D, .Ph.D.Department of Neurology & Rehabilitation

University of Illinois at Chicago


NeurologyRehabilitation

1

Disclosure

Funding Support: NINDS/NIH NS049776, R01 NS058802, R01 NS045207, P20 NS080181, Ralph Wilson Foundation,

Epilepsy Foundation, WSU Research Enhancement Program, Charles Gershenson Fellowship

Takeda PharmaceuticalsNeuropace

UCB


ConsultingConsulting

Research collaboration (no financial support)

Program, Charles Gershenson Fellowship

2

Learning Objectives

• The neocortex is not the hippocampus

• Reverse Translational Research and Systems BiologyReverse Translational Research and Systems Biology to understand and develop treatments for human neocortical epilepsy

American Epilepsy Society | 2013 Annual Meeting3

The neocortex is not the hippocampus

4


5


6

11/18/2013

2

Number of Articles in PubMed:

“Epilepsy + Hippocampus” → 12,464 hits


p p y pp p ,

“Epilepsy + Neocortex” → 1,620 hits

7


Neocortex

• Many Lesions Associated with Neocortical Epilepsy

• Epileptogenic Zones are most often normal.GFAP

8

Reverse Translational ResearchReverse Translational Research

9

Interictal spiking is far more frequent than seizures

10

Interictal spiking is far more frequent than seizures

11

•Shah AK, Agarwal R, Carhupoma JR, Loeb JA (2006) Compressed EEG pattern analysis for critically ill neurological-neurosurgical patients. Neurocritical Care 5(2):124-33.

•Yadav R, Shah AK, Loeb JA, Swamy MNS, Agarwal R (2011) A Novel Unsupervised Spike Sorting Algorithm for Intracranial EEG. Conf Proc IEEE Eng Med Biol Soc. 2011:7545-8.

•Barkmeier DT, Agarwal R, Atkinson M, Flanagan D, Shah AK, Jafari-Khouzani K, and Loeb JA, (2012) High inter-reviewer variability of spike detection on intracranial EEG addressed by an automated multi-channel algorithm, Clin Neurophysiol, 123(6):1088-95.

•Yadav R, Shah AK, Loeb JA, Swamy MNS, Agarwal R (2012) Morphology-based Automatic Seizure Detector for Intracerebral EEG Recordings. IEEE Trans Biomed Eng, 59(7):1871-

12

11/18/2013

3

Systems Biology - “The ability to obtain, integrate and analyze complex data from multiple experimental sources using interdisciplinary tools.”

13 14

15 16

What is different about brain regions that produce seizures?

Internal Control: Epileptic vs. “Less-Epileptic”

E il tiE il tiControlControl EpilepticEpileptic

Rakhade SN, Yao B, Ahmed S, Asano E, Beaumont TL, Shah AK, Draghici S, Krauss R, Chugani HT, Sood S, Loeb JA (2005) A Common Pattern of Persistent Gene Activation in Human Neocortical Epileptic Foci, Ann. Neurol. 58:736-747.

Beaumont TL, Yao B, Shah A, Kapatos G, Loeb JA. (2012) Layer-Specific CREB target gene induction in human neocortical epilepsy, J Neurosci, 32(41):14389-14401.

17

Genomics: Genome-wide transcriptome analysis

Microarray: Each spot measures mRNA levels of a single gene from a sample of tissue.

Covers 43,000 genes across the entire Human Genome!

18

11/18/2013

4

Area of OverlapSuggests CommonPathophysiology

19

Seizure Onset vs. Interictal Spiking


20


Lipovich L, Dachet F, Bagla S, Balan K, Cai J, Jia H, Loeb JA, (2012) Activity-dependent human brain coding / non-coding gene regulatory networks, Genetics, 192(3):1133-1148

21

Validation:Validation:

1.1. Where in the human genomeWhere in the human genome??

2.2. What Pathways are involved?What Pathways are involved?

3.3. Where in the neocortex?Where in the neocortex?•• LayersLayers•• CellsCells

22





23


Lipovich L, Dachet F, Bagla S, Balan K, Cai J, Jia H, Loeb JA, (2012) Activity-dependent human brain coding / non-coding gene regulatory networks, Genetics, 192(3):1133-1148

24

11/18/2013

5

Common Pathway ActivationCommon Pathway Activationin Human Seizure Onset Neocortexin Human Seizure Onset Neocortex

Ontology Ontology ModelModel

MAPK

Epileptic Activity

25

MAPK

Pathway Analysis ModelPathway Analysis ModelEpileptic Activity

Common Pathway ActivationCommon Pathway Activationin Human Seizure Onset Neocortexin Human Seizure Onset Neocortex

CREBactivation

ImmediateEarly Genes

Synapse strengthening and plasticity

26





27

Layer 2/3

MAPK CREBEpilepticActivity

ImmediateEarly Genes

Synapse Strengtheningand Plasticity


28

Why Layer 2/3 Neurons?Why Layer 2/3 Neurons?Hypothesis: Layer 2/3 neurons have cortical

connections that lead to hypersynchrony

29





30

11/18/2013

6


31

Cell BCell A

32

Profile of gene 2Profile of gene 1

0.50

0.60

0.70

0.80

0.90

1.00

0.90‐1.00

0.80‐0.90

0.70‐0.80

0.60‐0.70

0.50‐0.60core

33

ACTG2ADAMTS9AOC3ATP2A3CD55COL14A1COL3A1CPA3CTSGFLT1GPR183IL8LIFLUMMMRN1OR51E2RBPMSSVILTHBDVCAM1

0.00

0.10

0.20

0.30

0.40

0 50 0 60

0.40‐0.50

0.30‐0.40

0.20‐0.30

0.10‐0.20

0.00‐0.10

Sc

Cell Types

Layer-specific activation of MAPK-CREB in neocortical epilepsy linked to epileptic spiking and microlesions.

How to prove MAPK-CREB is necessary and translate (forward) this into therapeutics?

34

Tetanus Toxin Somatosensory CortexInterictal Spiking Model

Setup

Record

35 36

11/18/2013

7

Focal interictal spiking

Chronic and progressive

37 CREB is phosphorylated on spiking side in layers 2/338

Identification of drug candidates to test in this model:

SL327SL327SL327

DRUG TARGETS MAPK

39Barkmeier DT,, Senador D, Leclercq K, Pai D, Hua J, Boutros NN, Kaminski RM, Loeb JA. (2012) Electrical, Molecular and Behavioral Consequences of the Interictal Epileptic State in the Rat, Neurobiol Disease, 47(1):92-101.

40

Barkmeier DT,, Senador D, Leclercq K, Pai D, Hua J, Boutros NN, Kaminski RM, Loeb JA. (2012) Electrical, Molecular and Behavioral Consequences of the Interictal Epileptic State in the Rat, Neurobiol Disease, 47(1):92-101.

41

MAPK Inhibitor Blocks the Development of Epileptic Spiking (Interictal)

Barkmeier DT,, Senador D, Leclercq K, Pai D, Hua J, Boutros NN, Kaminski RM, Loeb JA. (2012) Electrical, Molecular and Behavioral Consequences of the Interictal Epileptic State in the Rat, Neurobiol Disease, 47(1):92-101.

42

11/18/2013

8

MAP Kinase inhibition blocks the development of interictal spiking

“Morning after pill”Morning after pill

43

Conclusions• The hippocampus is not the neocortex

• Reverse Translation: Systems biology of well‐characterized human cortex generates new hypotheses

•Chromosomal Hotspots of epileptic gene transcription

•Biomarkers of epileptic spiking localized to Layer 2/3

• A new gene clustering method predicts novel ‘Microlesions’ in deeper layers of epileptic spiking

•Animal models (forward translation) turn biomarkers into new Drug Targets

44

Collaborators

Aashit Shah (Neurology)Darren FuerstMaysaa BashaMarie AtkinsonShahram KhalidSandeep Mittal (Neurosurgery)Harry Chugani (Pediatric Neurology) Eishi Asano Sandeep Sood (Peds Neurosurgery)Rodrigo Andrade (Pharmacology)Nash Boutros (Psychiatry)Jeff StanleyMatt GallowayFarhad GhoddoussiWilliam Kupsky (Neuropathology)Leonard Lipovich (CMMG)Juan CaiHui JiaGreg Kapatos

Sharlin Ahmed

Shruti Bagla (PhD student)

Karina Balan

Daniel Barkmeier MD, PhD

Thomas Beaumont MD, PhD

Fabien Dachet PhD

Samantha Dettloff

Jessin John (MD PhD student)

Eric Kim (MD PhD student)

Sanjay Rakhade MD, PhD

Danielle Senador PhD

Ruggero Serafini MD, PhD

Ri k S ith (PhD t d t) Greg KapatosJing Hua (Computer Science)Sorin DraghiciDarshan PaiFarshad FatouhiYong Xu (Electrical Engineering)Jessin JohnJing Li (Karmanos/Pharmacology)

Other Collaborators

Rajeev Agarwal (Leap Medical, Inc)RajeevYadav (Concordia University)Ed Dratz (Montana State University)Gal AviramAmy Bernard (Allen Brain Institute)Joe Craig (Ideacore)Ravinder JilkapallyKourosh Jafari-Khouzani (Henry Ford Hospital)Raul Krauss (Vertex Pharma)Rafal Kaminski (UCB Pharma)Karine Leclercq

Rick Smith (PhD student)

Fei Song MD, PhD

Kiyotaka Suwa MD, PhD

Helen Wu (MD PhD student)

Bin Yao MD, MS

Wendy Yang

45

11/19/2013

1

Where do we go from Here?December 7, 2013

Jacqueline A French MDEpilepsy Center

NYU School of Medicine


DisclosureI have received grant funding from The Milken Foundation, the Epilepsy Therapy Project, and NINDS. I serve as the president of The Epilepsy Study Consortium, a non profit organization. NYU receives a fixed amount from the Epilepsy Study Consortium towards my salary. The money is for work performed by me on behalf of The Epilepsy Study Consortium, for consulting and clinical trial related activities. I receive no personal income for these activities.

Within the past year, The Epilepsy Study Consortium received payments for research services p y p p y y p yfrom:•Acorda, Eisai Medical Research, GlaxoSmithKline, Impax, Johnson & Johnson, Mapp Pharmaceuticals, Marinus, Novartis, Lundbeck, Pfizer, Sepracor, Sunovion, SK Life Science, Supernus Pharmaceuticals, UCB Inc/Schwarz Pharma, Upsher Smith, Vertex•I am an investigator at NYU on studies for Eisai Medical Research, LCGH, Impax, Mapp Pharmaceuticals, Novartis, UCB Inc/Schwarz Pharma, Upsher Smith, Vertex.•The HEP project receives research support from UCB, Pfizer and Lundbeck. The ASERT trial (completed) Received support from UCB, Supernus, Eisai, GSK, Lundbeck, J & J, Upsher‐Smith, and Pfizer.


Learning Objectives

Learn to provide optimal treatment, identify surgical candidates, and perform epilepsy surgery for those with syndromes other than temporal lobe

il h i di depilepsy when indicated.


The changing landscape

• There are clear trends towards– A reduction in surgery for mesial temporal lobectomy at major epilepsy centers

– A reduction in epilepsy surgery overallA reduction in epilepsy surgery overall

• There are no clear trends towards– A reduction in treatment resistant epilepsy patients overall1

1. Brodie et a. Patterns of treatment response in newly diagnosed epilepsyl Neurology. 2012 May 15;78(20):1548‐54

The world as seen in 2000

• Many patients with treatment resistant epilepsy, “The majority” with temporal lobe epilepsy

• Not enough surgical programs• Not enough surgical programs• Conclusion: If we could increase the number of surgeries, we could make a serious dent in the number of treatment resistant patients

The world as seen in 2013

• There are probably still a substantial number of patients who have not been referred for epilepsy surgery who are good candidates, howeverhowever….

• The majority of treatment resistant epilepsy patients at most epilepsy centers– Do not have clear surgically remediable epilepsy– Do not have temporal lobe epilepsy

11/19/2013

2

What does this mean?• We need to:

– Continue efforts to find TLE patients (who most benefit from resective surgery) and promote early referral

– Identify better methods of improving the lives of those who are not currently candidates for surgery• Better strategies for evaluating patients who currently are considered poor surgical candidates

• Enhanced basic research on non‐temporal lobe epilepsy

• Continued search for non‐surgical effective therapies

FINDING TLE PATIENTS: EPILEPSY SURGERY GRADING SCALE

• Hypothesis: A simple instrument based upon seizure semiology, intelligence quotient (as a dichotomous variable), neuroimaging, and electroencephalographic findings will successfully predict patient that are likely to 1) progress to epilepsy surgery and 2) achieve seizure freedom following surgery.

• Could be used by neurologists to identify patients for early referral to surgical centers

RESULTS OF GRADING SCALE

60%

80%

100%

NYU AUSTIN (MELBOURNE)

0%

20%

40%

ESGS 1 ESGS 2 ESGS 3

Seizure Free from Surgery

78%

ESGS 1 ESGS 2 ESGS 3

Buiskool et al, Epilepsy Surgical Grading Scale (ESGS): Utilization in epilepsy surgery cohorts at two Centers in different countries 2013, Poster International Epilepsy Congress Montreal

72%

Better strategies for Extra‐temporal lobe and non‐lesional epilepsy

Téllez Zenteno J et al, Surgical outcomes in lesional and non‐lesional epilepsy: a systematic review and meta‐analysis. Epilepsy Res. 2010 May;89(2‐3):310‐8

Non‐lesional treatment resistant patients are common

MRI results in 93 treatment resistant patients enrolled in multicenter AED trialsFrench et al,2013 unpublished data

What new strategies can we use?

• Ways to make “non‐lesional” epilepsy “lesional”– SISCOM– Ictal SpectMeasurement of cortical thickness– Measurement of cortical thickness

– PET– MR spectroscopy

11/19/2013

3

Conclusion

• The landscape IS changing– Surgery for kids: Expanding– Surgery for adults: Shrinking (for now)

• With better strategies this can turn around• With better strategies, this can turn around

– It is not the strongest of the species that survives, nor the most intelligent that survives. It is the one that is the most adaptable to change. ‐Darwin


•New methods are needed to identify good candidates for surgery

•Patients with lesions and/or temporal lobe epilepsy should be referred earlyepilepsy should be referred early

•Neocortical (extratemporal) and non‐lesional surgery is currently challenging

Documents

Presidential Symposium: The Changing Landscape of · PDF filePresidential Symposium: The Changing Landscape of ... Upsher Smith, Valeant, Vertex, Vivus ... residency in Neurology at