Presidential Symposium Epilepsy Care: A Futurist View · 2016. 11. 29. · Presidential Symposium Epilepsy Care: A Futurist View Symposium Chair: Michael Privitera, M.D. Saturday,

Presidential Symposium Epilepsy Care: A Futurist View

Symposium Chair:

Michael Privitera, M.D.

Saturday, December 3, 2016 Convention Center – General Assembly

8:30 – 11:45 a.m.

Accreditation The American Epilepsy Society is accreditedby the Accreditation Council for ContinuingMedical Education (ACCME) to providecontinuing medical education for physicians.

AMA Credit Designation StatementThe American Epilepsy Society designates this live activity for amaximum of 29.50 AMA PRA Category 1 Credits™. Physiciansshould claim only the credit commensurate with the extent oftheir participation in the activity.

International Credits: The American Medical Association hasdetermined that non-U.S. licensed physicians who participate inthis CME activity are eligible for a maximum of 29.50 AMA PRACategory 1 Credits™.

Physician Assistants: AAPA accepts certificates of participationfor educational activities certified for AMA PRA Category 1Credits™ from organizations accredited by ACCME or arecognized state medical society. Physician assistants mayreceive a maximum of 29.50 hours of Category 1 credit forcompleting this program.

Continuing Education for Nurses andPharmacists

Jointly provided by AKH, Inc.,Advancing Knowledge in Healthcare,and the American Epilepsy Society.

Nurses:Advancing Knowledge in Healthcare is accredited as aprovider of continuing nursing education by the AmericanNurses Credentialing Center’s Commission on Accreditation.This activity is awarded 29.50 contact hours.

Pharmacists:Advancing Knowledge inHealthcare is accredited by the AccreditationCouncil for Pharmacy Education as a provider ofcontinuing pharmacy education.

Select portions of this Annual Meeting are approved forpharmacy CE credit. Specific hours of credit for approvedpresentations and the Universal Activity Numbers assigned tothose presentations are found elsewhere in the programmaterials. Criteria for success: credit is based on documentedprogram attendance and online completion of a programevaluation/assessment.

If you have any questions about this CE activity relative tonursing and/or pharmacy CE, please contact AKH Inc [email protected].

The American Board of Psychiatry and Neurology has reviewedthe 70th Annual Meeting — American Epilepsy Society and hasapproved this program as part of a comprehensive epilpesyprogram, which is mandated by the ABMS as a necessarycomponent of maintenance of certification.

Claiming CME Credit and CME CertificatesAttendees who registered in the following categories may claimCME or CE for the meeting: physician, health care provider,trainee, one-day and two-day. Meeting registration includescredit claiming: there is no separate fee to claim CME/CE.

Attendees will receive an emailed notification to access theonline evaluation and credit claim system.

The evaluation and credit claim system will remain openthrough Tuesday, February 28, 2017. Evaluations and creditclaims must be completed by this date in order to record andreceive your CME/CE certificate.

Attendance Certificate/International AttendeesA meeting attendance certificate will be available at theregistration desk for international meeting attendees onTuesday, December 6.

Resolution of Conflicts of InterestIt is the policy of the American Epilepsy Society to ensurebalance, independence, objectivity and scientific rigor. Allpersons involved in the selection, development andpresentation of content are required to disclose any real orapparent conflicts of interest. In accordance with the ACCMEStandards for Commercial Support of CME, AES implementedthe mechanism of prospective peer review of this CME activity,to identify and resolve any conflicts. Additionally, the content ofthis activity is based on the best available evidence.

Unapproved Use DisclosureAES requires CME authors to disclose to learners whenproducts or procedures being discussed are off-label,unlabeled, experimental and/or investigational (not FDAapproved); and any limitations on the information that ispresented, such as data that are preliminary or that representongoing research, interim analyses and/or unsupportedopinion. This information is intended solely for continuingmedical education and is not intended to promote off-label useof these medications. If you have questions, contact themedical affairs department of the manufacturer for the mostrecent prescribing information. Information aboutpharmaceutical agents/devices that is outside of U.S. Food andDrug Administration approved labeling may be contained inthis activity.

DisclaimerThis CME activity is for educational purposes only and does notconstitute the opinion or endorsement of, or promotion by, theAmerican Epilepsy Society. Reasonable efforts have been takento present educational subject matter in a balanced, unbiasedfashion and in compliance with regulatory requirements.However, each activity participant must always use his or herown personal and professional judgment when consideringfurther application of this information, particularly as it mayrelate to patient diagnostic or treatment decisions including,without limitation, FDA-approved uses and any off-label,investigational and/or experimental uses.

EDUCATION CREDITS

American Epilepsy Society | www.AESnet.org | Houston, Texas 70th Annual Meeting | 6th Biennial North American Regional Epilepsy Congress 23

OVERVIEW This session will begin by outlining the current state of epilepsy diagnosis and treatment, then identify existing roadblocks and speculate on future trends. Key topics for the current and future management of epilepsy will include: 1) existing, new and future approaches to epilepsy surgery and devices; 2) development of new antiepileptic and antiepileptogenic medications; 3) how understanding molecular mechanisms in signaling pathways like mTOR, and new and future gene discoveries will influence diagnosis and treatment; 4) how the expanding field of bioinformatics will influence decision making now and in the future; and 5) how current and future brain imaging methods will be applied to epilepsy. LEARNING OBJECTIVES Following participation in this symposium, learners should be able to: • List several molecular pathways that may be altered in people with epilepsy and identify existing

treatment(s) that can be applied. • Describe the process for the development of new antiepileptic drugs. • Delineate the risks and benefits of the currently available surgical approaches to treating people with

epilepsy. • Employ bioinformatic methods to create performance improvement projects with existing clinical data. • Select the appropriate currently available bioimaging technique(s) to optimize diagnosis and treatment for

people with epilepsy. • Describe how current and future brain imaging methods can supplement and enhance neuropsychological

evaluation and outcomes. TARGET AUDIENCE Intermediate: Epilepsy fellows, epileptologists, epilepsy neurosurgeons, and other providers with experience in epilepsy care (e.g., advanced practice nurses, nurses, physician assistants), neuropsychologists, psychiatrists, basic and translational researchers. Advanced: Address highly technical or complex topics (e.g., neurophysiology, advanced imaging techniques or advanced treatment modalities, including surgery.) PROGRAM Chair: Michael Privitera, M.D. Introduction Michael Privitera, M.D. Current and Future Approaches to Surgery and Devices for Epilepsy Dennis Spencer, M.D. (Change in order from Program Book) Harnessing the Power of Bioinformatics in Epilepsy Tracy Glauser, M.D. Brain Imaging in Epilepsy Now and in the Future Jerzy Szaflarski, M.D., Ph.D. Current and Future Trends in Development of Antiepileptic Drugs Henrik Klitgaard, Ph.D. Genes and Signaling Pathways: Future Therapeutic Strategies Peter Crino, M.D., Ph.D., The Fritz R. Dreifuss Lecture

Conclusions Michael Privitera, M.D. Education Credit 2.5 CME Credits Nurses may claim up to 2.5 contact hours for this session.

Pharmacy Credit Pharmacists: AKH Inc., Advancing Knowledge in Healthcare approves this knowledge-based activity for 2.5 contact hours (0.25 CEUs). UAN 0077-9999-16-085-L01-P. Initial Release Date: 12/3/16.

COMMERCIAL SUPPORT ACKNOWLEDGEMENT 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 Michael D. Privitera, MD, Chair Professor, Director Epilepsy Center University of Cincinnati Gardner Neuroscience Institute Dr. Michael Privitera is Professor of Neurology and Director of the Epilepsy Center at the University of Cincinnati Gardner Neuroscience Institute. He established the Epilepsy Center in Cincinnati in 1987. Dr. Privitera is an expert on advanced treatments for epilepsy, with a research focus on new antiepileptic drugs, generic equivalence of AEDs, and stress as a seizure precipitant. He has over 150 scientific publications. He has mentored dozens of residents, fellows, graduate students and post-docs. He has served as a reviewer for NIH and FDA, earned many honors and awards, and served in many leadership positions at the University of Cincinnati and at the American Epilepsy Society. He is currently President of the American Epilepsy Society. Dr. Privitera discloses receiving support for Consulting Fees (e.g., advisory boards): astellas, Upsher-Smith Laboratories; Contracted Research: GW Pharma, SAGE Therapeutics, UCB Pharma Peter Crino, MD, PhD, Faculty Chairman University of Maryland Peter B. Crino M.D., Ph.D. – brief bio Dr. Crino is Professor and Chair in the Department of Neurology at the University of Maryland School of Medicine. He completed his M.D. at Yale University and Ph.D. at Boston University. He completed neurology residency and post-doctoral fellowship training at the University of Pennsylvania. Dr. Crino is a clinician-scientist

whose research focuses on mechanisms of abnormal brain development associated with the mTOR signaling pathway. Clinically, he is an epileptologist who specializes in tuberous sclerosis complex and related neurodevelopmental disorders associated with epilepsy, autism, and intellectual disability. Dr. Crino discloses receiving support for Consulting Fees (e.g., advisory boards): Evogen Inc.; Royalties: Evogen Inc.; Stockholder/Ownership Interest (excluding diversified mutual funds): Evogen Inc. Tracy A. Glauser, MD, Faculty Director, Comprehensive Epilepsy Program Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. Tracy A. Glauser, MD, is Professor of Pediatrics and Neurology and Director, Comprehensive Epilepsy Center at Cincinnati Children’s Hospital. Dr. Glauser received his medical degree, cum laude, from Jefferson Medical College. He completed his pediatrics residency at Johns Hopkins Hospital, his child neurology fellowship at The Children’s Hospital of Philadelphia, and his epilepsy/electroencephalography fellowship at Washington University School of Medicine. His research focuses on genetic/nonheritable factors that underlie inter-individual variation in AED response. He directed the Childhood Absence Epilepsy trial and received the AES Epilepsy Research Recognition Award for Clinical Science. His fields of expertise are pediatric epilepsy, clinical trials/pharmacology, and pharmacogenetics. Dr. Glauser discloses receiving support for Consulting Fees (e.g., advisory boards): AssureX Health, Supernus; Intellectual Property / Patents: AssureX Health; Royalties: AssureX Health Henrik Klitgaard, PhD, Faculty Vice President, Fellow Neurosciences Therapeutic Area UCB H. Klitgaard, PhD, VP, Fellow in New Medicines UCB, Braine-l’Alleud, BE. PhD in Human Physiology in 1989 at the August Krogh Institute (University of Copenhagen, Denmark). His Post-Doctoral work was partly performed at the Pasteur Institute in France and Harvard University in US. During the last 3O years, he has worked with discovery and development of antiepileptic drugs in the pharmaceutical industry. Member of the Scientific Advisory Committee for CURE (Citizens United for Research in Epilepsy) and the Steering Committee for the Anticonvulsant Screening Program at the National Institutes of Health (NIH). During his career, Dr. Klitgaard has been involved in the discovery and development of several antiepileptic drugs at both Novo Nordisk A/S and at UCB, including tiagabine, levetiracetam and brivaracetam. Dr. Klitgaard discloses receiving support for Salary: UCB Pharma; Stockholder/Ownership Interest (excluding diversified mutual funds): UCB Pharma Dennis D. Spencer, MD, Faculty Physician/Surgeon Yale School of Medicine Dr. Spencer is the Harvey and Kate Cushing Professor 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. His research has brought together basic scientists and clinicians around a program concerning energetics, glutamate metabolism and the neurobiological study of human epileptogenic tissue. Study techniques include 7T MRS, C13 intraoperative glucose turnover studies, and in vivo and in vitro electrophysiology and

microdialysis, immunohistochemistry, confocal and EM microscopy, and molecular biology. In particular, laboratory discoveries are correlated with the epileptogenic substrate in order to help define human epilepsy pathogenesis and potential therapies. Dr. Spencer was recipient of the 1999 American Epilepsy Society’s Research Award in Clinical Investigation, and the 2006 Society of Neurological Surgeons’ Grass Award for Excellence in Research. He is past Chairman of the American Board of Neurological Surgery, past President of the Society of Neurological Surgeons, and he served as interim dean of the Yale School of Medicine 2003-2004. He is past Vice Chairman of the Neurosurgery Residency Review Committee for Neurosurgery, and past President of the American Epilepsy Society. Dr. Spencer discloses receiving support for Consulting Fees (e.g., advisory boards): Monteris, Inc. Jerzy Szaflarski, MD, PhD, Faculty Professor and Director, UAB Epilepsy Center University of Alabama at Birmingham Jerzy P. Szaflarski, MD, PhD is Professor of Neurology and Director of the UAB Epilepsy Center. After finishing medical school, he worked in the laboratory of Dr. Faye Silverstein at the University of Michigan where he examined molecular responses to ischemic and NMDA-mediated brain injury. He later completed epilepsy training at the University of Cincinnati with Dr. Michael Privitera, and trained in fMRI with Dr. Jeff Binder at the MCW. As part of K23 training, he spent time in the laboratory of Dr. Jean Gotman at MNI learning EEG/fMRI. For almost 20 years he has been examining the effects of brain injury on brain plasticity using MRI, fMRI, DTI and EEG/fMRI. One of his long-term goals is to develop fMRI as a diagnostic tool for various neurological conditions including epilepsy and as a biomarker for treatment response. Dr. Szaflarski discloses receiving support for Honoraria: GW Pharmaceuticals, Inc, Upsher-Smith Laboratories CME REVIEWERS Suchitra Joshi, MD, MS, Reviewer University of Virginia Dr. Sucheta Joshi, MD, MS, FAAP, FAES (Clinical Associate Professor, Pediatric Neurology, University of Michigan) is a Pediatric Epileptologist. She is the Director of Pediatric Telemedicine Services and Associate Residency Program Director. Her interests include pediatric epilepsy, EEG monitoring and improving access to epilepsy care. She is PI for a HRSA funded project to increase access and quality care for epilepsy in Michigan using a learning collaborative and telemedicine. She is Medical Director for the Coordinating Center of the AAP for Children and Youth with Epilepsy, site co-investigator for the Pediatric Epilepsy Research Consortium, and was part of the EEG core for the EPGP study. She serves as faculty for the AAP and CNS, and has published several peer-reviewed manuscripts and book chapters. Dr. Joshi discloses he has no financial relationships to disclose relevant to this activity. Kinshuk Sahaya, MD, Reviewer Dr. Kinshuk Sahaya is an assistant professor in the Department of Neurology and epileptologist at the University of Arkansas for Medical Sciences (UAMS). He is also the Neurology Resiency Program director at UAMS. He completed his medical school training followed by post-doc research in neuropharmacology at the University College of Medical Sciences (UCMS), University of Delhi, India. His Neurology residency was at the University of Missouri-Columbia and fellowships in clinical neurophysiology & epilepsy at the University of Michigan- Ann Arbor.

His clinical and research interests include eduation, clinical epilepsy, EEG, translational research in epilepsy and pre-surgical evaluation of epilepsy patients. He is actively involved in both resident and medical student education. Dr. Sahaya discloses he has no 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 Duffy, PharmD: 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. CLAIMING CREDIT: PHYSICIANS Attendees who registered in the following categories may claim CME or CE for the meeting: physician, health care provider, trainee, one-day and two-day. Meeting registration includes credit claiming: there is no separate fee to claim CME/CE. Attendees will receive an emailed notification to access the online evaluation and credit claim system. The evaluation and credit claim system will remain open through Tuesday, February 28, 2017. Evaluations and credit claims must be completed by this date in order to record and receive your CME/CE certificate. Physicians can claim CME credit online at https://cme.experientevent.com/AES151/ This Link is NOT Mobile-friendly! You must access it from a laptop, desktop or tablet. How to Claim CME Credit To claim CME credits online, please follow the on-screen instructions at the above url. Log in using your last name and zip code, OR your last name and country if you’re not from the United States. All CME credits must be claimed by February 28, 2017. Questions? Contact Experient Customer Service at: 800-974-9769 or [email protected] NURSING & PHARMACY PLEASE NOTE: Providing your NABP e-profile # is required. The National Association of Boards of Pharmacy (NABP) requires that all pharmacists and pharmacy technicians seeking CE credit have an ID number issued by NABP. Pharmacy CE providers, such as AKH Inc., Advancing Knowledge in Healthcare, are required to submit participant completion information directly to NABP with your ID number and birth information to include month and date (not year) as a validation to this ID number. If you do not have an ID number (this is not your license #), go to: www.MyCPEmonitor.net

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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.

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Epilepsy Care: A Futurist View

Michael Privitera, MDUniversity of Cincinnati, Gardner Neuroscience

Institute

Disclosure

UCB‐research GW Pharma‐researchSAGE Therapeutics‐research

Astellas‐DSMBUpsher Smith‐DSMB

• Each speaker will briefly review key aspects of the current state of their assigned area, including current “roadblocks”, then speculate about the future.

• It is not the goal to predict what will happen in the future, but rather use expertise and foresight to describe what could happen in the future and, perhaps, what should happen in the future.

• Can categorize as “residual” as in the ones everyone learned some time ago, “dominant” as in the ones the leaders and advanced thinkers are pushing forward with some data, and “emergent” as in the ones that are more “cutting edge” and may or may not become “dominant” in the future.

Instructions to Speakers: Not Easy!

In 1963, they thought we’d be flying around by now…but they did predict Skype

Electronic tiresShape shifting, self driving, maybe hydrogen powe

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Each pod is a separate “car” that can be re‐arranged

Unclear how it’s powered, but looks really cool

Uber predicts flying commuters in 10 years

Specially designed for Neurologists…

Neurologists are always practical…

#AES2016

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Current and Future Approaches to Surgery and Devices for Epilepsy

Dennis Spencer, M.D.

Yale University

School of Medicine

Disclosure

Name of Commercial Interest

Monteris, Inc.

Type of Relationship

Consulting

Disclosures

• NIH

• Monteris Medical advisory board

Surgical therapies for epilepsyPresent and Future

• The quest for surgical control

• The evolution from focus to network nodes

• Evidence from our surgical patients

• Implications for our present state

• The era of devices

• What we need to move forward

John Hughlings JacksonThe Focus

“There was in every case of epileptiform seizures a persisting discharging lesion whether tumor or not”

“There is very often a dreamy state in cases of this group of epileptic fits, the uncinate group”

Spencer and Ferrier’s stimulation studiesLed him to hypothesize that these seizures started in the uncinate region causing smells and epigastric sensations and then spread to the medulla to cause respiratory arrest rather than starting in the medulla , the conventional wisdom.

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Defining a focus and surgical treatment in Temporal Lobe Epilepsy

• Penfield and Baldwin: 1952, report ECOG

• Resection anteromedial to vein of Labbe

• Niemeyer: selective resection

• Murray Falconer at Guy’s Maudsley:

Denis Hill, epileptologist, surgery advocate

Ben Dawson, devised en bloc resection

1955 30 patients from the psychiatric unit

with 50% control and better psychologically

Murray Falconer

The Key ‐ En Bloc Pathology

• 1963 ‐ team approach bears fruit

• Meyer, Cavanagh, Corsellis, and Bruton

• 100 patients ‐ 53% control, 30% improved

• MTS defined ‐ in 47%, 24% tumors, MCD

• David Taylor: psychosocial and cortical dysplasia, results more than seizure frequency

• Talairach: 1958 depth electrodes interictally

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

• Authors record the stories of 82 patients through the 1960’s

• Ictal recordings the rule since 1970• Discharges all medial• Correlated with MTS in 65%, describes fields• No neocortical envolvement

St. Hilaire JM, Bouvier G, Lymburner J, Picard R, Mercier M. Synchronized Stereoelectroencephalography with Visual and Sound Recording in the Chronic Exploration of Epilepsy. In: L’Union Medicale du Canada. 1976: 1538‐1541.

Temporal Lobe Cortical Resection

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Surgical approaches to the medial temporal lobe

• Selective amygdalohippocampectomy

– Transsylvian

– Transcortical

– Subtemporal

• Electrocorticography (ECoG) guided resection

• Anteromedial resection

• Radiofrequency ablation

• Gamma knife radiosurgery (GKS)

• Emerging therapies

– Endoscopic approaches

– Laser thermocoagulation

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Anteromedial resection

• Recent meta‐analysis shows anteromedial resection to be superior to selective amygdalohippocampectomy for seizure control (Josephson et al.; Neurology 2013)

• Effectiveness of the surgery has been recently scrutinized in relation to neuropsych outcomes as larger resections tend to have worse outcomes for verbal and spatial memory

• Temporal lobe epilepsy surgery and the quest for optimal extent of resection: A review—Johannes Schramm. His review found no clear evidence to support one methodology for seizure control and neuropsychology data are hard to generalize

Lobectomy vs. Selective Resection:Seizure Outcomes

• Retrospective review comparing long term seizure outcomes in 30 patients undergoing temporal lobe resection vs. 39 patients undergoing amygdalohippocampectomy, all with MTS

– Patients undergoing temporal lobe resections demonstrated more durable Engel Class IA when compared to selective resections however all other comparisons demonstrated equivalence

Time to loss of Engel I or II Time to loss of Engel I Time to loss of Engel IA

Bujarski KA, et al., Journal of Neurosurgery. 2013; 119:116‐23

0%

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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

MTS Neocortical

Extratemporal resectionDisconnections

Neuromodulation• Extratemporal resections• MCD,Normal MRI,Injury• Children: Engel 1‐34%, 2‐15%, 3‐25%, 4‐26%• Adults:• Disconnections: Corpus Callosotomy‐atonic seizures• Hemispherotomy‐Engel 1‐80‐90%• Multiple subpial transections‐E1‐30• Neuromodulation: Vagal nerve stimulation• Responsive direct stimulation• both show 50% decreased frequency• in 50% of patients

Current Surgical Decision tree

Non-invasive workup (including EEG, PET, MRI, fMRI and Neuropsychology)

+/- WADA

Unilobar lesion(tumor or cavernoma) w/ fullconcordance of preop w/u

MTS Cortical dysplasia,diffuse or multifocal lesion,

normal MRI or any discordance of preop w/u

Intracranial EEG

resection/ablation

functional cortex

not involved

functional cortex

involved

HC fxn preserved

HC fxn notpreserved

TemporalLobectomy vs.Laser Ablation

Lesionectomy Functional mapping

Guided resection/ablation vs. RNS

RNS vs. ?Laser Ablation Unifocal Onset Mulitfocal Onset

Fxnl cortex not involved

Fxnl cortex involved

RNS

RNSDBSVNS

• Emerging Concept of Network Epileptogenesis—Clinical Evidence

• Emerging from the 90’s• Rethinking concept of focal epileptogenesis• Epilepsy more of a distributed disorder because:

• 1) Variable ictal onset in the local MTLE circuit

• 2) Seizures sometimes cured by removing one of the local nodes

• 3) 15‐29% of auras persist after AMTL

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The medial temporal lobe network

• Variable contribution from both hippocampus and entorhinal cortex by subdural and depth electrode analysis

• Therefore, focused ablation to include hippocampus exclusively is likely leaving a significant epileptic substrate behind

Spencer SS & Spencer DD, Epilepsia. 1994; 35(4):721‐7






Laser Ablation: Where are we now?

• Emory’s experience with 49 laser ablations, including 6 reoperations:– Trajectory targets pes hippocampus

and extends posteriorly to include hippocampus at tectal plate

• Ablation extends anteriorly into the amygdala along this trajectory

– Seizure outcomes: 67% of MTS patients seizure free at 1 year, 50% of non‐MTS patients seizure free at 1 year

• Accounting for provoked seizures, 30% (2/7) had no seizures at 2 years

– Neuropsych results suggest improved object naming and recognition when compared to standard resection

Gross RE, et al., Neurosurg Clin N Am. 2016 27:37–50; Drane DL, et al., Epilepsia. 2015 56(1):101‐13

Seizure Outcomes & Safety

• Meta‐analysis of 350 studies of temporal lobectomy including 25,144 cases*– Engel Class I: 72%

– Engel Class II: 16%

– Engel Class III: 9%

– Engel Class IV: 7%

• 36% Complication rate including 26% with quadrantanopsia

• 68 cases of hippocampal ablation with 6‐12 month follow‐up– Engel Class I: 61%

– Engel Class II: 5%

– Engel Class III: 30%

– Engel Class IV: 15%

• 19% complication including 11% with quadrantanopsia

Attiah MA, et al. Epilepsy Research. 2015, 115:1‐7

*Duration of follow‐up not specified

Post‐Op MR Imaging (2 weeks)* Amygdalar ablation

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• 4) Bitemporal epilepsy cured by removing the most dysfunctional hippocampus

• 5) Failure of complete control of MTLE after resection over time

• 6) Difficulty defining epileptogenic regions in neocortical epilepsy

• 7) Distributed deficits in cognitive function by neuropsych testing

• 8) Paradoxical MTLE

• 9) Dual pathology

Hirsch and SpencerBitemporal lobe epilepsy







Long term outcomes in Epilepsy Surgery







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Paradoxical Medial Temporal Lobe epilepsy







Dual Pathology Importance of Seizure freedom

• Seizure freedom by far the most important predictor of post‐surgery QoL

• QoL improvement is 5‐fold lower if seizures only improve but do not cease

• Cognitive decline correlates with worsening of QoL only if seizures don’t improve

WHERE WE ARE

• Three decades of looking for a better sword

• Outcomes have plateaued

• Should be looking at the substrate differently

• Network epileptogenesis

• Laser ablation will be a beneficial tool

• Gold standard will still be intracranial studies

• And human tissue correlative pathology0

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This extensive electrode coverage has identified three common functional networks that may be usurped by the epileptogenic process

Occipital‐Temporal‐Frontal

Frontal ‐Temporal

Frontal –Parietal

Thus when a patient presents with an MRI negative or subtle MRI findings of MCD and noninvasive findings suggestive of a particular lobe the functional network of that lobe is studied with combined surface and depth electrodes

There three common study paradigms

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Seizure onset simultaneous in lateral grid‐19,18 and subtemporal/occipital strip. Onset 3mm from previous depth electrode but was not seen then.Somelanguage in grid but most robust in the strip. Recommended RNS

Research evidence for Epilepsy Networks

Spencer Probe‐ version 2 & Microdialysis Apparatus

Microdialysis CMA/20 probe:• 0.67 mm x 70 mm probe• 10 mm, 20 kDa cut-off membrane

Microdialysis probe inserted into the depth electrode

Depth electrode with perforationsb/w contacts 1 &2 (Ad-Tech)

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Basal Glutamate in Cortex and Hippocampus

Romanyshyn, Cavus et al in prep

NAA Depleted Regions & Overlap w/ EEG Arrays

Single patient MRSI NAA/Cr map of deviation from N=20

normal controls

Overlay of patient’s p-map on the 3D aMRI: intracranial electrode

localization (IcEEG) superimposed

IcEEG positions concordant with significant depletion in N=10 patients

Rigid + nonrigid registration performed to fuse aMRI/EEG/MRSI

data

Voxel Selection and Reconstruction Hippocampus

Voxel Selection and Reconstruction Thalamus and Putamen

Anterior#4-#6

Posterior#1-#3

Network Correlations

Thalamus

Hippocampus

Contra Ipsi

0.58<0.003

0.46<0.03

0.57<0.004

0.48<0.02

0.51<0.01

0.53<0.01

0.76<0.00002

Putamen

The Language of Networks Where are we

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EXPANDING OUR WINDOW TO THE BRAIN

•

Increasing utilization of sophisticated “Bioelectric intracranial integrated devices” to study the “Network Epilepsy Syndromes”

Expansion of intracranial therapeutics-electrical and molecular through feedback loops.

Limitations of intracranial EEG monitoringInfectionPatient mobilityMass of wiresSignal to noise ratioModalities, sensor size, spatial sampling

Solution Strategy

Modality– Measure macro and local field potentials

– Improve spatial sampling and brain coverage-thin films

– Perform multi-modal brain sensing -modalities of interest include EEG, temperature, oxygen, pH, ionic current, neurotransmitters, drugs and metabolites

– Transmit data wirelessly

Solution StrategyMaterials

– Use thin-films

– Decrease mass and volume of electrode contacts, sheathing, and wires

– Devise materials which conform better to complex cortical geometry

– Develop coatings to decrease the foreign body response of the brain

3.1 NeuroProbe: Multimodal Brain Monitoring in the Neuro‐ICU*

Team: Mark Reed, Dennis Spencer, Hitten Zaveri, Emily Gilmore, Jason Gerrard, Nihal de Lanerolle, James Goodrich, Jung Kim

Aim:

• Replace multiple devices with a single device to measure icP, CBF*, icT*, icO*, icEEG for TBI

• Obtain regulatory approval

• Perform studies in rat and swine prior to human use

*Funded by the Connecticut Bioscience Innovation Fund (CBIF)

3.6 Types of Electrodes

Spencer depth electrode

Subdural grid electrode

Subdural strip electrode

NeuroGrid (Buzaki)

UtahElectrodeArray

New generation of electrodes

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2.1 Wireless Intracranial EEG 2.1 Wireless Intracranial EEG

Development funded through NIH SBIR awards to ITN Energy Systems (Littleton, CO) and Yale University

NIH SBIR Phase 1 Effort:• 4 channel wireless intracranial EEG device1

• Powered by RF• Employs IR for data and control communication• Can electrically stimulate from any channel

NIH SBIR Phase 2 Effort:• 64 channel wireless intracranial EEG device2,3

• Can be powered by battery, RF, or wired power• Employs IR for data and control communication• Multiple 64 channel devices can be used to achieve

larger channel counts

1 US Patent 8165684, 20122 US Patent 8738139, 20143 US Patent pending

Aim: To develop a cooling, stimulating and sensing array (CSSA) for human use. This will be a brain implantable device.

Team:1. Yale University (Neurology, Neurosurgery)2. ITN Energy Systems (Littleton, CO)3. UNC Charlotte (Charlotte, NC)4. RTI International (RTP, NC)

2.3 Cooling, Stimulating and Sensing Array (CSSA) 2.3 Focal Cooling ‐ Rodent Test

Rodent Device Test: Assess rodent brain response to focal cooling• Device with two cooling elements (1x2

mm) in contact with cortex.• Cooling elements are embedded

within a device containing a heat sink exposed to the air.

• Cool a focal cortical area• Measure cortical temperature

2.3 Focal Cooling ‐ Human Test

Human Prototype Device Test: Assess human brain response to focal cooling• Device with single cooling element (5x4

mm), embedded within a silastic sheet (30x30 mm)

• Cool a focal cortical area exposed during epilepsy surgery

• Measure temperature and intracranial EEG from multiple points

ConclusionEra of Device Integration with the

Brain

• Goal is targeted therapy of the “Epilepsy Network Syndromes”

• Billions spent on pharmaceuticals ,primarily revisions of older drugs discovered empirically

• We have no idea what to target• When we understand the electrochemical milieu of the epilepsy patient then we may be able to direct therapy

• Therapy for the whole patient not just the seizures

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Harnessing the Power of Bioinformatics in Epilepsy

Tracy Glauser, M.D.

Director, Comprehensive Epilepsy Center

Cincinnati Children’s Hospital Medical Center

Disclosure

AssureX Health – royalties, consulting

Claritas ‐ consulting

Department of Justice – expert witness

Supernus ‐ consulting

Learning Objectives

• Recognize the residual and dominant bioinformaticinnovations that can enhance epilepsy clinical care by improving data and information availability.

• Recognize the emergent bioinformatic innovations that can enhance epilepsy clinical care by increasing knowledge and eventually wisdom.

Translational Medicine and Bioinformatics Continuum

Sarkar: Biomedical informatics and translational medicine. Journal of Translational Medicine 2010 8:22.

Basic science, applications, and bioinformatics

Payne et al. BMC Medical Informatics and Decision Making 2013, 13:20

Biomedical Informatics – the Journey from Data to Wisdom

Information

UnderstandingRelationships

Knowledge

WisdomConnectedness

Understandingpatterns

Understandingprinciples

DataAckoff, R.L. From Data to Wisdom, Journal of Applied System Analysis, 16:3‐9, 1989

RelationalDatabases

KnowledgeBases

Understanding

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Residual Innovations

Need for Human + Information Technology- Clinical decision support systems- Universal electronic health records- Tools for database linkage, mining, and use

“…to accommodate the reality that although professional judgment will always be vital to shaping care, the amount of information required for any given decision is moving beyond unassisted human capacity.”

Institute of Medicine (IOM). 2007. page 5, The Learning Healthcare System: Workshop Summary

Residual Innovations – Electronic Health Records

Scope - Epic is the EHR for healthcare systems serving

54% of all US patients

2.5% of all patients in the world

Glaze, Jeff "Epic Systems draws on literature greats for its next expansion". Wisconsin State Journal.

Residual Innovations – tools for database mining

Collects medical record data for querying and distributionDiscovery on enterprise wide scaleGoal: Cohort identification

DataRepository

(CRC)

FileRepository

IdentityManagement

OntologyManagement

CorrelationAnalysis

De ‐Identification

Of data

NaturalLanguageProcessing

AnnotatingGenomicData #1

ProjectManagement

WorkflowFramework

PFTProcessing

AnnotatingGenomicData #2

AnnotatingImagingData

I2b2 ‐ Informatics for Integrating Biology and the Bedside

Dominant Innovation ‐ National Patient‐Centered Clinical Research Network (PCORnet)

Vision: Enable large-scale clinical research conducted with enhanced quality and efficiency.Mission: Enable faster, more trustworthy clinical research that helps people make informed health decisions

Strategy/Tactics: Create infrastructure, tools, and policies to support rapid, efficient clinical researchUtilize multiple electronic health records, insurance claims data, data reported directly by people, and other data sourcesEngage people, clinicians, and health system leaders throughout the nation

Dominant Innovation ‐ PCORnet results to date20 Patient-Powered Research Networks (PPRNs)

including the Rare Epilepsy Network13: Clinical Data Research Networks (CDRNs)People with data available in PCORnet to date: ~110 Million

*Based on data from 64 DataMarts as of April 22, 2016Development of a common data model:

Procedures

Demographic

Condition

Prescribing

Encounters

Lab Results

Patient Satisfaction

Claims

Biospecimen& Genomic

Data

Vital Status

Rare Epilepsy Network (https://ren.rti.org/)

Dominant Innovations – enhancing patient involvementWearable tech (including home diagnostics)Digital therapeutics (gamification wellness)Health Learning SystemsAugmented Reality/Virtual reality

http://www.dailymail.co.uk/health/article‐3704918/Epilepsy‐spotted‐suit‐tunes‐brain‐worn‐home‐everyday‐clothes.html;http://www.akiliinteractive.com/; https://www.magicleap.com/#/home; http://www.dezeen.com/2014/03/14/epilepsy‐aid‐uses‐wearable‐technology‐to‐predict‐seizures/

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Emergent – Integration of Biomedical Informatics with Epilepsy

• At CCHMC, collaboration between epileptologists and computer scientists started 2003

• Accomplishments:

– Created machine learning infrastructure: epilepsy feature selection, ontology development, classifier construction across 3 children’s hospitals

– Automated optimization: automated method for feature optimization, annotation, data extraction, similarity measurement, physician notification

– Translation to epilepsy clinical care (4 examples):

• Created epilepsy clinical decision support (CHRISTINE system)

• Methodological advances: NLP, spreading activation, machine learning

– Early identification of epilepsy surgery candidates – MD language

– Determine clinical trial participant eligibility – MD language

– Epilepsy co‐morbidity ‐ “Language of suicide” – patient language

Multi‐Center machine learning infrastructure

Selecting anti‐epileptic drugs: a pediatric epileptologist’s view, a computer’s view. Pestian, Matykiewicz, Holland‐Bouley, Standridge, Spencer, and Glauser. Acta Neurol Scand. 2013 March ; 127(3): 208–215

Feature Selection

Ontology ‐ Integrated the International League Against Epilepsy’s (ILAE’s) 1989 and 2010 terminology and concepts with NINDS’s Common Data Elements (CDE)

MiPeds consortium (R01LM011180) ‐ CCHMC, CHOP, Colorado Children’s

Automated annotation ‐ teach Automated annotation ‐ improve

Automated optimization Automated similarity measurements

Similarities between hospitals demonstrated in two ways: number of filled boxes and color of the filled boxes

Green - probability of similarity is between 50% and 100%Yellow - probability of similarity is between 5% and 50%Red - probability of similarity is below 5%.

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Bioinformatics and epilepsy clinical care –Epilepsy decision support (CHRISTINE system)

Bioinformatics and epilepsy clinical care –Epilepsy Surgery Candidate Identification

e e eee ee

ee

ee

Year 1

Year 10Year 6Year 4

Patient Encounter With Neurologist (e)

Bioinformatics and epilepsy clinical care –Epilepsy Surgery Candidate Identification

• Put in production June 2016

• Every Sunday SAM looks for new

candidates

• To date, four new epilepsy surgery

patients identified

• Sends a message to Epilepsy

Surgery Program and the patient’s

attending neurologist

• One R21 (AHRQ - HS024977)

examining optimal method to notify

clinicians about potential epilepsy

surgery candidatesBiomed Inform Insights. 2016 May 22;8:11-8

Bioinformatics and epilepsy clinical care –Clinical Trial Participant Eligibility

Structured Unstructured Structured & Unstructured Precision Sensitivity Specificity Precision Sensitivity Specificity Precision Sensitivity Specificity

Proof of concept study 1 Carbonic anhy-drase inhibitors

0.73 0.48 0.87 0.68 0.65 0.77 0.88 0.30 0.97

Carboxamides 0.77 0.56 0.92 0.56 0.78 0.69 0.89 0.44 0.97

Valproic Acid 0.8 0.27 0.91 0.87 0.9 0.82 ≈1 0.23 ≈1

Succinimides 0.91 0.91 0.98 0.89 0.73 0.98 ≈1 0.64 ≈1

Generalized Epilepsy

0.81 0.61 0.85 0.89 0.86 0.89 0.94 0.57 0.96

Localization related epilepsy

0.64 0.58 0.75 0.83 0.79 0.875 0.86 0.5 0.94

Undetermined Epilepsy Type

0.41 0.63 0.54 0.64 0.37 0.89 0.67 0.21 0.95

Proof of concept study 2 Clinical Trial Simulation

0.67 0.5 0.89 0.69 0.69 0.86 0.88 0.31 0.97

Study 1: 60 patients with epilepsy (average visits = 7). An epileptologist validated the classifiers’ results.Study 2: Review of 60 patients with epilepsy for possible enrollment in a typical epilepsy investigational AED trial. Inclusion criteria: children with localization related epilepsy currently receiving either valproic acid or a carboxamide(carbamazepine or oxcarbazepine). Exclusion criteria: diagnosis of generalized epilepsy or undetermined epilepsy type or absence of valproic acid or carboxamide use.

Suicide – a national issue

• In 2010, 38,364 people in the United States died by suicide.

• About every 13.7 minutes someone in this country intentionally ends his/her life.

• Age

– 10 to 24 Third leading cause of death

– 25 to 34 Second leading cause of death

– 18 to 65 Fourth leading cause of death

www.cdc.gov, MMWR March 2015

Anxiety, Depression, Suicidality How do you make the diagnosis?

• Linguistics, Acoustics, Facial/body expressions are markers of a person’s thoughts

– thought markers Tm• Measuring thought markers is challenging

• Not the same as other biological markers (DNA)

What do people say?

How do they say it?

What is their body language?

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Spreading Activation ‐Mathematical Embodiment

Processing text with domain‐specific spreading activation methods issued 2015 CCHMC US Patent No. 8,930,178

Repeated Suicide Attempts

• Multi‐center study to validate algorithm– Video, audio, linguistic features – Genetic features– In the ED and 30 days later (prediction phase)

• Unique in size and type– N=375– Princeton Community Hospital, Cincinnati Children’s Hospital, University of Cincinnati

• Goal: separate suicidal versus other mental health issues versus controls

Impact on Clinical Care and Practice

• Residual (EHR, database mining tools) and dominant (wearable tech, gamification, health learning systems and augmented and virtual reality) innovations can enhance epilepsy clinical care by improving data and information availability.

• However emergent innovations can transform epilepsy clinical care by increasing knowledge and eventually improving wisdom.

#AES2016

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Page 1

Brain Imaging in EpilepsyNew and into the Future

Jerzy P. Szaflarski, MD, PhDUniversity of Alabama at Birmingham and

UAB Epilepsy Center, Birmingham AL

Page 2

Disclosure

Funding: NIH, Department of Defense, FDA, AES, EFA, NSF, UCB Biosciences, Epilepsy Study Consortium, Shor Foundation for Epilepsy Research, Neuroscan Compumedics Inc., SAGE Therapeutics Inc., GW Pharmaceuticals, and Eisai, Inc.

Consulting/Advisory Boards: Serina Therapeutics, SAGE Therapeutics Inc., Biomedical Systems Inc., GW Pharmaceuticals Inc., NeuroPace, Inc., Upsher-Smith Laboratories, Inc., AL State Medical Board, and Elite Medical Experts LLC.

Editorial board membership: Epilepsy & Behavior, Journal of Epileptology, Restorative Neurology and Neuroscience, Journal of Medical Science, Epilepsy Currents, and Folia Medica Copernicana.

Page 3

Learning Objectives

• Briefly discuss the history of neuroimaging

• Review current state of knowledge regarding MRI in epilepsy

• Discuss future directions and where the future may take us

Page 4

http://my.dmci.net/~casey/experiments.htmMemory and Brain, by Larry R. Squire ISBN-0-19-504208-5Picture circa 1962

Page 5

25 years ago…

Churchland and Sejnowski, 1988, Science

Levels of organization

- CNS- Systems- Maps- Networks- Neurons- Synapses- Molecules

Page 6

Today: Neuroimaging In Epilepsy EEG and MEG

Interictal and Ictal SPECT

TMS

MRI

Structural MRI

Functional MRI

EEG and fMRI (EEG/fMRI)

PET and MRI (PET/MRI)

Multimodality Image Fusion

Now:

Levels of organization

- CNS- Systems- Maps- Networks- Neurons- Synapses- Molecules

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Page 7

Initial structural MRI

Three main circumstances requiring MRI:

Any patient with new onset seizures

Any patient who has long-standing seizures and who has not been properly evaluated

Presurgical evaluation

From Kuzniecky and Jackson “Imaging in Epilepsies” - AT2 weighted image from a 0.5T scanner at MNI showing hippocampal sclerosis - 1986

Page 8

MRI in new onset epilepsy

177/764 had potentially epileptogenic lesion (23%)

28% in patients with an epileptic seizure

53% of patients with focal onset seizures

8% in patients who had non-epileptic event

Lesion types (standard or TLE protocols):

Gliosis or encephalomalacia – 49%

Tumor – 15%

Cavernoma – 9%

MTS 9%

165/764 had non-epileptogenic lesion (22%)

Hakami et al., 2013, Neurology

Page 9

MRI and seizure outcomes

Semah et al., 1998, Neurology

• 2200 adults with epilepsies with 1-7 years follow-up

Page 10

New onset seizure guideline (AAN 2015)

Seizure related to brain lesion – 2-fold higher risk of seizure recurrence when compared to patients with seizures of “unknown cause” (MRI(-))

Krumholz et al., 2015, Neurology

Page 11

AEDs: Diminishing returns

Kwan and Brodie NEJM 2000

TRE = Time to consider epilepsy surgery evaluation

Page 12

MRI findings: Normal vs. Abnormal TLE – 50-80% seizure-free outcome

Presence of HS typically predicts favorable outcome in univariate analyses

May not be an independent predictor in multivariate analyses

E-TLE - seizure-free rates are typically lower in extratemporal neocortical epilepsies

FLE – 13-80%

Presence of extra-frontal abnormality or HS predicted poor outcome

OLE – 46%

TLE w/lesion – 2.5 times higher chance of seizure freedom

E-TLE w/lesion – 2.7 times higher chance of seizure freedom

Jeha et al., 2007 Brain, Salanova et al., 1992 Brain, Tellez-Zenteno et al., 2010 Epilepsy Research

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Page 13

Negative MRI – what next?

What when MRI is “negative”?

Special MRI techniques

High-field / high-resolution

MRS

Special MRI processing techniques

MAP

Page 14

High-field / High-resolution 3T HR-MICRA scan 7T SPACE

Images courtesy of Larry Ver Hoef, MD; UAB

Page 15

HR-MICRA R TLE

Images courtesy of Larry Ver Hoef, MD; UAB Page 16

3T vs. 7T anatomical imaging

Images courtesy of Dr. Jullie Pan, MD, PhD

Page 17

7T MR Spectroscopy

Images courtesy of Dr. Jullie Pan, MD, PhD

Page 18

Morphometric Analysis Program (MAP)

MAP implemented and used in 2005

150 MRI negative patients identified retrospectively (all received surgery prior to MAP)

43% detection rate (sensitivity 0.9 / specificity 0.67)

Resection of entire MAP-identified brain region resulted in significantly improved outcome (p < 0.001)

Huppertz et al., 2005 Epilepsy Research Wang et al., 2015, Annals of Neurology

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Page 19

3T 3D-FLAIR3T T1w

7T T1w 7T T2*GRE

The MAP difference

Images courtesy of Irene Wang, MD; CCF Page 20

Structural MRI Summary - What is missing?

Structural MRI is widely available and a must in patients with epilepsy but

Many patients with TRE are “MRI(-)”

New MRI techniques

Higher resolution / higher SNR

New data processing strategies

Typically small, retrospective analyses are available

Needed are prospective studies evaluating emerging techniques and analysis methods

Page 21

Functional MRI

FMRI is gradually becoming the study of choice for function mapping in the presurgical evaluation

Main areas of use include Imaging of language lateralization and localization

Mapping of memory

Mapping of motor cortex

Localization of interictal epileptiform discharges (EEG/fMRI)

fMRI vs. IAP

Page 22

IAP and fMRI –Not as simple as replacing old with new

Page 23

IAP vs. fMRI – A paradigm shift

Page 24

IAP vs. fMRI

IAP (“gold standard”)

Standard procedure

Invasive

5% risk of complications

Lateralization no localization

Potential for false lateralization

fMRI

New(er) procedure

Non-invasive

0% risk of complications

Lateralization andlocalization

Potential for false lateralization

Data analysis issues i.e. “now you see it, now you don’t”

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Page 25

Semantic Decision/Tone Decision (SD/TD)

Active Condition

hear “horse“ Respond “YES” (button push) if animal is found in the U.S. and is used by people.

Control Condition

hear Respond “YES” (button push) if tone train contains 2 "high" tones.

Page 26

What is BOLD signal?Active condition

Control condition

L=L

Page 27

Correlation between fMRI and IAP

0%

0%

0%

0%

44%

20%

10%

8%

8%

12%a

17%

17%

11%b

5%

24%c

0%

12%

11%d

29%e

29%f

9%

0 10 20 30 40 50 60 70 80 90 100

Woermann et al. 2003

Benke et al. 2006

Arora et al. 2009

Szaflarski et al. 2008

Gaillard et al. 2004

Binder et al. 1996

Spreer et al. 2002

Sabbah et al. 2003

Adcock et al. 2003

Rutten et al. 2002

Gaillard et al. 2002

Deblaere et al. 2004

Yetkin et al. 1998

Benson et al. 1999

Lehericy et al. 2000

Carpentier et al. 2001

Worthington et al. 1997

Baciu et al. 2001

Bahn et al. 1997

Desmond et al. 1995

Hertz-Pannier et al. 1997

Liegeois et al. 2002

Sample Size

Concordance

Discordance

0%

Janacek et al., 2013 Epilepsia Page 28

Discordance between fMRI and IAP

Discordance in ~15% of patients (32/229)

What predicts discordance?

No variable predict discordance

Except when you are atypical on one test you may be more likely to be atypical on the other

Not clear when discordant which one is correct

Janacek et al., 2013 Epilepsia

Page 29

ATL patients with discordant IAP and fMRI

Janacek et al., 2013 Epilepsy & Behavior Page 30

Memory task – Scene encoding

Bigras et al., 2013 EB, Binder et al., 2010 Epilepsia, Mechanic-Hamilton et al., 2009 EB, Rabin et al., 2004 Brain

Active Condition

See: Memorize picture and decide whether this is an indoor (“YES”button push) or outdoor (“NO” button push) scene

See:

Decide whether figures are same or different

Control Condition

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Page 31

Scene encoding 200 patients with TLE (91 L) included

Typically memory activation lateralized to the contralateral (healthy) side

Weak and variable correlation with IAP results

Strong correlation with NP measures

Poor correlation with long-term outcomes

SD/TD better than scene encoding for verbal memory outcome prediction

Bigras et al., 2013 EB, Binder et al., 2010 Epilepsia, Mechanic-Hamilton et al., 2009 EB, Rabin et al., 2004 Brain Page 32

Predictors of Naming Decline in Left ATL

FMRI LI:

Wada Language LI:

Pre-operative BNT Score:

Age at Seizure Onset:

R p

-.64 <.001

-.50 <.05

-.40 n.s.

-.35 n.s.

FMRI: 100% sensitivity, 73% specificityWada: 92% sensitivity, 45% specificity

Binder et al., 2008 Epilepsia

Page 33

Memory outcomes with fMRI

44 TLE patients (24 LTLE)

Covert verb generation task (letter – word task)

Stronger pre-resection L frontal activation in LTLE -> greater post-resection naming decline naming

Stronger activation in R after resection -> better naming performance

Bonelli et al., 2012 Epilepsia Page 34

Memory outcomes with fMRI

50 TLE patients (23 L); memory encoding task

Covert memorization of presented concrete nouns

Stronger pre-resection L frontal and ATL activation in LTLE -> greater post-resection verbal memory decline

Bilateral posterior hippocampal activation -> less post-resection verbal memory decline

Sidhu et al., 2015 Neurology

Page 35

FMRI Summary – What is missing?

Studies of fMRI’s ability to predict language and memory outcomes in various surgical treatments (ATL vs. amygdalo-hippocampectomy vs. laser ablation)

Comparisons of various fMRI language and memory tasks in regard to their ability to lateralize functions, their level of agreement with IAP, and their ability to predict postsurgical outcomes

Comparisons of various fMRI analysis methods

Multicenter replicability studies

Studies of patients with E-TLE and lesional epilepsy

Studies specifically targeting pediatric epilepsy population

Page 36Binder et al., 2011, NeuroImage

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Page 37

Why simultaneous EEG and fMRI?

Understanding mechanisms and significance of rhythms and spontaneous brain activity

Health (e.g., alpha rhythm, sleep waves)

Evoked potentials (health and disease)

Localization of abnormal activity (SWD)

Presurgical evaluation

Planning of the extent of surgical resection

Page 38

Estimated/standard hemodynamic response curve of BOLD signal

Hawco et al., 2007 NI, de Munck et al., 2007 NI, Szaflarski et al., 2010 EB

Page 39Bai et al., 2010 J Neuroscience Page 40Szaflarski et al., 2013 Epilepsia

Page 41

EEG combined with fMRI (EEG/fMRI)

In Idiopathic Generalized Epilepsies

Cortical BOLD signal changes typically occur before the thalamic changes

There is directionality of signal flow from cortex to thalamus

There is beginning evidence that different thalamic nuclei are involved in different way in GSWD generation and maintenance

GSWDs have affect resting state

fMRI can be used to constrain source localization

Applicable to focal onset seizures

Page 42

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Page 43

EEG/fMRI and surgical outcomes

Non-lesional FLE – in 2/2 operated patients EEG/fMRI correlated with previously not visualized cortical abnormalities

6/7 seizure-free patients BOLD signal was concordant with area of resection (3/4 not-seizure-free BOLD signal outside of resection area)

In 35 patients surgical outcome correlated with the degree of overlap between EEG/fMRI BOLD changes and surgical resection

In 4/8 previously denied surgical treatment EEG/fMRI provided complimentary information that resulted in IC monitoring

Moeller et al., 2009 Neurology, Thornton et al., 2010 JNNP, An et al., 2013 Epilepsia Page 44

EEG/fMRI Summary - What is missing?

Unified data collection and analysis methods

Prospective studies of non-lesional (MRI(-)) patients

Randomized studies assessing the contributions of fMRI to the surgical decision-making

Randomized studies assessing the issue of BOLD signal area resection

Page 45

Today

Churchland et al. 2014, Nature Page 46

One day in the future

Sequence development

Data processing and merging

Hybrid systems

Higher field

Portability

Therapy delivery

Page 47

Sequences

Improved MR sequences will result in spatial resolution closer to histology HR-MICRA

Gadolinium and oxide nanoparticles

Chemical imaging Neuro-inflammation

BBB

GluCEST (glutamate chemical exchange saturation transfer)

Structural imaging as an early predictor of outcome of medical vs. surgical therapies

Davis et al., 2016, Sci Transl Med

Page 48

Data processing and merging

Machine learning algorithms to personalize diagnosis and outcome predictions Merging with genetics and neuropsychology

Subjective interpretation supplemented with or replaced by personalized tools

Connectivity analyses and connectomics Connectomics predicted outcomes in TLE (Bonilha et al., 2015,

Neurology; Keller et al., 2016, Brain)

Understanding of structural and functional network redundancy and connectivity will allow treatment via modifying nodes remote to the ictal onset zone

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Page 49

Hybrid systems

Hybrid MEG/MRI Feasibility?

MEG signal: 10-15T – 12-14 orders of magnitude lower than MRI field

Hybrid PET/MRI Utility?

Improvements in sub-millimeter imaging may result in additional implementation

Hybrid SPECT/MRI Utility?

Mainly animal research

VEP maps withECD projections

Vesanen et al., 2013, MRM Page 50

Higher field

7T Systems

E.g., Siemens 7T Magnetom Terra or Philips 7T Achieva Goal of improving SNR

Better contrast and smaller voxel size

Better metabolic imaging

Higher field for research and clinical applications

8T, 9.4T or higher?

Better metabolic imaging?

Page 51

Portability AM-PET (ambulatory micro-dose PET)

10% od standard dosage of radioisotope

Lightweight and motion-tolerant

In epilepsy

Ictal AM-PET FDG

5-HT1A

GABAA (Flumazenil)

CB1

Opioid

nAChR

Courtesy of Julie Brefczynski-Lewis, PhD

Wearable MRIwww.Nano-Tera.ch

Page 52

Therapy delivery

MRI-guided therapy

Therapeutics (e.g., AEDs) or “cytotoxic agents” conjugated to e.g., iron oxide nanoparticles and targeting ligands

Binding receptors to cells important for seizure initiation

MRI-guided release of agents to modulate or destroy targeted cells (magnetized nanoparticles)

Page 53

THANK YOU

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Current and Future Trends in Development of Antiepileptic Drugs

Henrik Klitgaard, Ph.D.Vice President, Fellow, Neuroscience Research

UCB Pharma

Disclosure

Henrik Klitgaard is an employee of UCB Pharma

This presentation is not accredited for CME credit.

2

Learning Objectives

• Inform on discovery approach leading to the existing armamentarium of AEDs

• Detail screening approach and key pharmacology for current focus on discovery of new AEDs for treatment of sub‐populations with drug refractory epilepsy

• Describe preclinical models, emerging biology and biomarkers for future identification and translation of antiepileptogenictreatments

• Address perspectives for future innovation in AED development

3

Significant number of AEDs available for epilepsytreatment

RetigabinePerampanel

Brivaracetam

Adapted from Löscher and Schmidt ‐ Epilepsia 2011; 52:657‐78

4

Majority of AEDs discovered by seizure protection in MES and PTZ tests

Phenytoin (1937)

Pentylenetetrazol

Trimethadione (1944)

MES PTZ

Klitgaard et al. ‐ In Animal and Translational Models of Behavioral Disorders. Volume 2. McArthur RA & Borsini F (Eds.), Elsevier, NY, pp 311–35, 2008

5

The availability of the MES test was a revolution



Brivaracetam

AfterMES

Before MES

6

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And improved treatment of epilepsy – residual innovation

• More treatment options

• Improved tolerability and safety profile

• Lower risk of drug‐drug interactions

Löscher et al. ‐ Nature Review Drug Discovery 2013, 12:757‐776

7

But current AEDs focus on reductionistic and neurocentric concept of excitation/inhibition balance

EXCITATION INCREASE

SEIZURE

INHIBITION DECREASE

SEIZURE

Na+ channel antagonistsCa2+ channel antagonistsAMPA receptor antagonists GABAA agonists

Enhance GABA levels

Margineanu and Klitgaard ‐ Expert Opinion Drug Discovery; 2009; 4(1):23‐32

8

Prior incentives for AED development has disappeared

placebo response of add‐on POS trials

Risk/benefit tolerance regulatory requirements and class labelling

Differentiation impact on pricing

Generics competition

Attrition


9

Serious unmet medical need remains


• Drug refractory epilepsy

• Comorbidities

• Absence of treatments that prevent epilepsy or

alter the course of the disease

10

The ASP at NIH was instrumental to maximize the drugdiscovery potential of the MES test


Brivaracetam


11

Pharmacoresistance Epilepsy Workflow for ETSP

Courtesy from Dr. John Kehne, Ph.D., Program Director, Epilepsy Therapy Screening Project (ETSP), NIH

12

Acute Seizure Models • 6 Hz Electrical Stimulation (m,r)• Maximal Electroshock Test (m,r)

Behavioral Toxicity Screens• Rotarod (m)• Neurological Impairment (r)• Locomotor Activity (r)

Chronic Seizure Models• Corneal Kindled Seizure Test (m)• Spontaneous Bursting Slice from

Post‐kainate Status Epilepticus Rat (in vitro)

Mesial Temporal Lobe Epilepsy Model (m)

Lamotrigine‐Resistant Amygdala Kindling (r)

Post‐Kainate Status Epilepticus‐Induced

Spontaneous Recurrent Seizures (r)

Video‐EEG monitoring

IDENTIFICATION DIFFERENTIATION

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3

New pharmacology target pharmacoresistance:mTOR pathway

13

Meng et al. – J. Neurol. Sci. 2013; 332:4‐15

New pharmacology target pharmacoresistance: cannabinoids

14

Adapted from Ibeas Bih et al. – Neurotherapeutics 2015; 12:699‐730

10

10

13

32

Receptor targets

Ion channel targets

Transporter targets

Enzyme targets

New pharmacology target pharmacoresistance: neurosteroids

15

Reddy and Estes – Trends Pharmacol. Sci. 2016; 37(7):543‐561

New pharmacology target pharmacoresistance: pre‐ and post‐synaptic inhibition

16

Recent explosion of genetic discoveries in epileptic encephalopathies may enable precision medicine

0

5

10

15

20

25

30

35

40

45

50

2002 2004 2005 2008 2009 2010 2012 2013 2014

• Exponential growth with recent sequencing technologies

• GRIN2A → Memantine

• KCNT1 → Quinidine

Courtesy of Dr Jonathan Van Eyll, UCB

17

# of genesidentified

New pharmacology and gene discovery now permit to target sub‐populations with refractory epilepsy –dominant innovation


BLOCKBUSTER MODEL

Large clinical trials Tailor-made drugs

SUB‐POPULATIONS

MINI BUSTER MODEL

18

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• Comorbidities



19

Strong platform of animal models for epileptogenesisresearch

Developmental alterations

Kindling acquisition

Latent period

Latent period

Genetic models

TRIGGERING EVENT EPILEPTOGENESIS EPILEPSY

Disease modifying therapy

Antiepileptogenictherapy

Significant reduction

in seizure threshold /

spontaneous seizures

Fully kindled

Spontaneous seizures

Spontaneous seizures

Birth

Initiation of chronic stimulation

Initiate and terminate SE

Traumatic Brain Injury

Kindling models

Status epilepticusmodels

Insult specific models

Simonato et al. ‐ Epilepsia 2012; 53(11):1860‐7

20

New biology reveal promising antiepileptogenicproperties in preclinical models – emergent innovation


21

New biology with antiepileptogenic potential: microRNAs

22

mRNA degradation

Translational repression

• miRNAs bind via imperfect complementary base pairing to 3’UTR of messenger RNAs resulting in

translational repression

• A single miRNA can bind and regulate multiple different mRNAs

• miRNAs cause blockage of networks and pathways rather than single gene inhibition

From Castanotto et al. ‐ Nature 2009; 457(7228):426‐33

Silencing microRNA‐134 produces neuroprotectiveand prolonged seizure‐suppressive effects

23

Jimenez‐Matheos et al. – Nature Medicine 2012; 18(7): 1087‐1094Scr: scrambled sequenceAnt: antagomer

Prevention of epilepsy and anxiety: TrkB kinase

Chemical‐genetic approach

TrkB sensitive to inhibition by 1NMPP1.

1NMPP1

Chen et al. ‐ Neuron 2005; 46(1):13‐21

24

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Prevention of epilepsy and anxiety: TrkB kinase

Liu et al. ‐ Neuron 2013; 79:31‐38

25




• Comorbidities



26

Attrition will be a major challenge for successful translation of emergent innovation

26.1%

19.1%17.1% 16.3% 15.3% 15.1% 14.7%

13.2% 12.8%11.4% 11.1%

9.6%8.4%

6.6% 6.2%5.1%

0%

5%

10%

15%

20%

25%

30%

LOA from phase 1

Likelihood of approval (LOA) from phase 1

Adapted from Bio Industry Analysis Report, Clinical Development Success Rates 2006–2015, June, 2016

27

Failure

Lack of efficacy is primary reason for attrition during clinical development


63.2%

30.7%

58.1%

85.3%

9.6%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Phase 1 tophase 2

Phase 2 tophase 3

Phase 3 toNDA/BLA

NDA/BLA toapproval

Phase 1 toapproval

Probab

ility of success

Probability of success

All diseases

28

Minimal attrition of previous AED development facilitated by predictable animal models



All diseases

63.2%

30.7%

58.1%

85.3%

9.6%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Phase 1 tophase 2

Phase 2 tophase 3

Phase 3 toNDA/BLA

NDA/BLA toapproval

Phase 1 toapproval

Probab

ility of success

EPILEPSY

70%

29

Reduce attrition by optimal design of preclinical studies

Important parameters to control:

• Choice of species, strains and age of animals

• Methodology for in vivo seizure initiation, termination, recording and typing

• Determine PK/PD relationship

• Sample size to reflect purpose of experiment

• YES/NO (limited sample size)

• SUPERIOR/INFERIOR vs placebo/comparator (randomized, blinded and potentially multicenter approach)

Important parameters for conclusions:

• Therapeutic gain – to be assessed by impact on both seizure and behavioral recordings and biological processes of the target

• Determine therapeutic treatment window and duration of treatment effect

• Establish therapeutic index based on tolerability and safety measures

30

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Reduce attrition by biomarkers that permit patient stratification


63%

28%

55%

83%

8.4%

76%

46%

76%

94%

25.9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Phase 1 tophase 2

Phase 2 tophase 3

Phase 3 toNDA/BLA

NDA/BLA toapproval

Phase 1 toapproval

Pro

bab

ility

of

succ

ess

Without biomarkers With selection biomarkers


With or without selection biomarkers

31

Biomarker discovery – progress but still lacking validation and clinical translation

32

• Genome‐wide association studies reveal possible associations between genetic variants and epilepsy

• Dysregulation of miRNA observed in surgical specimens and plasma from epilepsy patients

• MRI studies associate structural changes and damage with epilepsy

• Invasive EEG identify high‐frequency oscillations as an interictal marker of epileptogenic zones

• Imaging techniques visualize neuroinflammation and microvascularinjury, associated with epilepsy

Pitkänen et al. ‐ Lancet Neurol 2016; 15: 843‐856

Reduce attrition by combination therapy with approved drugs targeting different epileptogenic processes?

33

Proposal by Dr. Pavel Klein; Hunt et al. ‐ Front. Cell. Neurosci; 2013; Jun 18;7:89. doi: 10.3389/fncel.2013.00089

Current and Future Trends in Development of AEDs ‐2016

Residual innovation:

• Screening in seizure tests have identified most of the current AEDs

Dominant innovation:

• New pharmacology and gene discovery now permit to target sub-populations with refractory epilepsy – a 4th generation of AEDs is coming!

Emergent innovation:

• Several antiepileptogenic mechanisms identified in preclinical models

• Some of these inhibit development of both seizures and psychiatric comorbidities

• Minimize attrition of translation by optimal design of preclinical studies, biomarkers and combination therapy

34

Future trends in the development of AEDs – two wild cards

35

CRISPR – gene editing

36

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7

Advances in device technologies will result in paradigm shift from chronic to acute AED treatment?

37

Kim et al. ‐ Science Advances 2016; 2:e1600418

Materials and engineering advances create an opportunity to shift from periodic clinical visits to continuous monitoring (e.g. non‐invasive physiologic signal sensors)

Portable, predictive analytics create an opportunity to shift from chronic, systemic medication usage to intermittent, targeted administration “as needed” in periods of high risk.

Current and Future Trends in Development of AEDs ‐2031

Residual innovation:

• A new, marketed generation of “mini-buster” AEDs that target specific sub-populations with refractory epilepsy

• Precision medicine an established and beneficial approach

Dominant innovation:

• Advances in genetic and biomarker research and in processing of big data permit clinical development projects to be associated with a diagnostic and target specific etiologies

• Antiepileptogenic and disease modifying drug candidates under clinical development

Emergent innovation:

• Advances in disease understanding of autoimmune diseases permit curative treatment of autoimmune epilepsy

• Impact of device(s) enabling seizure prediction permit acute treatment of chronic epilepsy

38

Future trends: towards 4 and 5 generation AEDs!



Brivaracetam

1st generation

2nd generation

3rd generation

39

Future trends: towards 4 and 5 generation AEDs!

Adapted from Löscher and Schmidt ‐ Epilepsia 2011; 52:657‐78Adapted from Löscher and Schmidt ‐ Epilepsia 2011; 52:657‐78


Brivaracetam

1st generation

2nd generation

3rd generation

2020 2030 2040

4th generation

AEDs that targetspecific sub‐

populations with drugrefractory epilepsy

AEDs that targetspecific sub‐

populations with drugrefractory epilepsy

5th generation

. AEDs with a diagnostic that target specificetiologies. Antiepileptogenic and disease modifying drugs. Acute treatment of chronic epilepsy

. AEDs with a diagnostic that target specificetiologies. Antiepileptogenic and disease modifying drugs. Acute treatment of chronic epilepsy

#AES2016

11/28/2016

1

Epilepsy Genetics and Cell Signaling Pathways:

A Futurists ViewPeter B. Crino M.D., Ph.D.

Professor and ChairDepartment of Neurology

University of Maryland School of Medcine

Disclosure

•R01NS082343-01•R21NS087181-01•EUREKA•STTRSAB and Inventor, Evogen Inc.UPN-X5727C1U.S.A/U.S. Patent Application No. 14/943,101 Provisional patent applications 62/274,551 and 62/274,578 (January 2016)

Learning Objectives

• To define how gene sequencing will aid with epilepsy diagnosis and treatment

• To define how identification of cell signaling pathway alterations will affect treatment options

“Futures cannot be predicted, but futures can be invented.”-Dennis Gabor, 1971 Nobel Prize in Physics, invention of holograms

What SHOULD happen, not necessarily what WILL happen….

mTOR Signaling Nodes 2001

NUCLEUS

CYTOPLASM

TSC1

TSC2

S6

eIF4E

Rapamycin

mTORC1

S6K1

mTOR

raptor

P

P

P

P

4E‐BP1

Akt

PDK1

PI3KIRS

EXTRACELLULAR SPACE

P

P

IGF1EGFHGF

mTOR Function in brain??

AMP/ATP

Lysosome

CYTOPLASM

TSC1

TSC2

S6

eIF4E

AMPK

Rapamycin

mTORC1

S6K1

MO25

STRAD

LKB1

mTOR

raptor

PP

P

P

P

P

P

4E‐BP1

Akt

PDK1PTEN

PI3KIRS

EXTRACELLULAR SPACE

P

P

NPRL2

P

ACC

P

REDD1

DEPTOR

TBC1D7

IGF1EGF

B‐RAF

O2

HGF

STAT3

VEGF

A.A.

DEPDC5

Cell SizeCell Migration

Stem Cell DifferentiationDendrite Outgrowth

Axon OutgrowthDendritic protein syntesisSynaptic plasticity -LTP

GATOR1GATOR1

mTOR Signaling Nodes 2016

11/28/2016

2

Future Genome and Signalome Strategies

DiagnosticsPrognosticsDiscoveryPreventionTargeted Therapeutics

Twenty‐five Years ago….

NO…….High-throughput gene sequencingMassively parallel signature sequencingDNA Arrays/target/panel/platformshRNA/GFP/CRISPRAnd….Numerous epilepsy genes were unknownCould we have predicted this?

Future Genome and Signalome Strategies

Change the Landscape for……‐Diagnostics‐Prognostics‐Discovery‐Prevention‐Targeted Therapeutics

All Human Epilepsy Genes Will Be Known and Full Variant Maps Will Be Available - Germline

“Epilome”“Ictome”“Fitome”“Focal Dyscognitome”

Monogenic causesSyndromic links

AutosomalX-linkedMitochondrial

Ethnic VariantsSex Variants

Causative Variants

ALL patients will have full exome screening

‐Inexpensive

‐Rapid turnaround (hours)

‐Available to ALL individuals‐no fiscal, geographic, regulatory barriers

Blood, saliva or buccal?

Single Cell SequencingGawad et al., 2016

11/28/2016

3

All Causative Variants Will Be MappedAt presentation:-all patient exomes are screened-Pathogenic variants identified-Computational “GO” analysis for protein targets-Computational pharmacopaiea analyzed-Best fit for patient-Clinical implementation and therapy

Use of Variants for Early identification and Prediction: Precision Medicine - SUDEP

At presentation:-all patients screened-variants detected-predictive algorithms-actionable preventions-AICD/pacemaker, drugs

SUDEP eradicated

Causative Variants

New Genomics: Rheostatic Susceptibility for Seizures and Epilepsy

ACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTG

ACTGACTGACTGACTGAGTGACTGACTGACTTACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTTACTGACTGACTGACTGACTGACTGACTG

ACTGAATGACTGACTGGCTGACTGACTGACTTACTGACTGACTGACTGACTGACTGACTGACTGAATGACTGACTGGCTGACTGACTGACTTACTGACTGACTGACTGACTGACTGACTG

LOW

MEDIUM

HIGH

ACTGAATGACTGACTGGCTGACTGACTGACTTACTGACTGACTGACTGACTCACTGACTGACTGAATGACTGACTGGCTGACTGACTGACTTACTGACTGACTGACTGACTCACTGACTG

ACTGACTGACTGACTGAGTGACTGACTGACTGACTCACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTCACTGACTGACTGACTGACTGACTG

Rheostatic Susceptibility for Seizures and Epilepsyand Co‐Variation with Known Epilepsy Genes

ACTGACTGACTGACTGAGTGACTGACTGACTTACTCACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTTACTCACTGACTGACTGACTGACTGACTG

ACTGAATGACTGACTGGCTGACTGACTGACTTACTCACTGACTGACTGACTGACTGACTGACTGAATGACTGACTGGCTGACTGACTGACTTACTCACTGACTGACTGACTGACTGACTG

LOW

MEDIUM

HIGH

PleotropyGenotype‐Phenotype

ACTGAATGACTGACTGGCTGACTGACTGACTTACTCACTGACTGACTGACTCACTGACTGACTGAATGACTGACTGGCTGACTGACTGACTTACTCACTGACTGACTGACTCACTGACTG

Rheostatic Analysis Will Require Massive Parallel Bioinformatics

ACTGACTGCCTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGTCTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACGGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACAGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGAGTGACTGACTGACTGACTGACTGACTGACCGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTCACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAATGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTG ACTTACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTGAGTGACTGACTGACTGACTGACTGACTGACTGACTGACTGACTG

Epistasis and Gene Modifiers Will Be Defined

At presentation:‐all patients screened‐variants detected‐predictive algorithms‐actionable preventions‐AICD/pacemaker, drugs

SUDEP eradicated

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4

All Human Epilepsy Genes Will Be Known and Full Variant Maps Will Be Available ‐ Somatic

“Epilome”“Ictome”“Fitome”“Focal Dyscognitome”

Monogenic causesSyndromic links

Extreme High Depth Sequencing‐detect somatic variants in blood

Ethnic VariantsSex Variants

iPSC Based Advanced Human Stem Cell Modeling of All Epilepsy Gene Mutations in All Types of Neurons

Gene Editing Tools for Mutation Correction in Isogenic Cell Lines – Test Rescue Effect

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas (CRISPR‐associated) system, TALENs (Transcription activator‐like effector nucleases), ZFNs (Zinc finger nucleases)

Ongoing Somatic Mutagenesis in BrainContributes to Epilepsy Susceptibility

Somatic mutations in:‐dentate gyrus progenitor cells‐SVZ progenitor cells‐reactive astrocytes‐pericytes‐microglia‐Confers differential susceptibility or resistance

Highly dynamic mutational landscape

Pharmacogenomics

Predictive Landscape for Drug Responsiveness-beyond HLA typing

Predictive Landscape for Drug Resistance

Predictive Landscape for Drug Adverse Effects-Allergic reactions i.e., angioedema, respiratory failure, TEN-Sedation

Predictive Landscape for Drug Teratogenicity

Mouse Models for Epilepsy Blood sample from patient

High depth whole exome/genome sequencing

Mutation identification

Mouse Model engineered with human mutation-knockdown, knockout, overexpression are obsolete-ES cell bank for all known variants

Identification of variants-modifiers-epistasis-critical, relevant, unknown

11/28/2016

5

Polygenic inheritance of susceptibility and resistance to cancer in mouse models.

Tommaso A. Dragani Cancer Res 2003;63:3011-3018

©2003 by American Association for Cancer Research

Epileptogenesis

Use of Mouse Models – with modifier loci

Mouse engineered with human mutation

Identification of known human variants‐modifiers‐epistasis

Mouse Model engineered with human mutation‐knockdown, knockout, overexpression are obsolete‐ES cell bank for all known variants

Differential Mouse models

It Should Be Very Interesting…….

#AES2016

Documents

Presidential Symposium Epilepsy Care: A Futurist View · 2016. 11. 29. · Presidential Symposium Epilepsy Care: A Futurist View Symposium Chair: Michael Privitera, M.D. Saturday,