Managing Common Complex Symptomatic Epilepsies - Hope4Harper

Annual Course

Managing Common Complex Symptomatic Epilepsies: Tumors and Trauma

Symposium Chair: Joseph I. Sirven, MD

Professor and Chairman Department of Neurology

Mayo Clinic in Arizona Phoenix, Arizona

Sunday, December 2, 2012 Convention Center – Ballroom 6C, Upper Level

8:45 am – 5:15 pm

OVERVIEW Trauma and tumors are inextricably linked to epilepsy. Among people with newly diagnosed epilepsy of known cause, primary brain tumors or brain metastasis, and Traumatic Brain Injury (TBI) predominate. Chronic seizures are often the most cited problematic complication to either of these conditions. Both trauma and tumors are complicated by their heterogenous epileptogenic injuries and the spectrum of comorbid conditions. Primary care and specialty physicians alike — including oncologists, neurologists, epileptologists, emergency room physicians — all struggle with how to best manage epilepsy as it pertains to both trauma and tumors as numerous therapeutic strategies are available. This year’s Annual Course will delve into tumor-based and posttraumatic epilepsy, two of the most common yet challenging symptomatic epilepsies faced on a daily basis, through a multidisciplinary approach. The course is divided into two sessions with the morning session devoted to tumor-based epilepsy and the afternoon to posttraumatic epilepsy. Each session will be framed by common clinical scenarios including adults and children and will be used to discuss how disparate mechanisms lead to epilepsy, how the conditions are diagnosed, the questionable role for antiepileptogenic management and how to best manage the conditions from both a medical and surgical vantage point. The goal of the course is to highlight clinical management while illuminating basic science and practice gaps. Each session will end with a summary and offer a potential algorithm for clinical management for epilepsy related to each condition. LEARNER OUTCOMES

Utilize algorithms that describe how best to manage patients with epilepsy related to brain tumors including novel intraoperative monitoring techniques

Use an evidence-based algorithm for management of the patient with posttraumatic epilepsy Perform risk analyses in making treatment decisions regarding prophylactic use of AED in

patients with CNS tumors Manage patients with metastatic brain tumors with treatment options based on evidence-based

best practice. TARGET AUDIENCE Basic: Those new to epilepsy treatment or whose background is limited, e.g., students, residents, general physicians, general neurologists and neurosurgeons, other professionals in epilepsy care, administrators. 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) AGENDA 8:55 am Introduction Overview Joseph Sirven, M.D. 1. Tumors 8:55 a.m. Case Presentation: Benign Tumor Based Epilepsy

Lily Wong Kisiel, M.D.

9:00 a.m. Epidemiology and Semiology of Tumor Based Epilepsy Charles J. Vecht, M.D.

9:25 a.m. Panel Flash Session: Tumor Based Factors – Genetic Factors, Tumor Types, Peritumoral Morphological Changes Lara E. Jehi, M.D., Steve S. Chung, M.D., Joon Uhm,

9:40 a.m. Prevention of Epilepsy in Tumors? (Insights from Basic Science, glutamate receptors)

Joon Uhm

10:05 a.m. Break 10:20 a.m. Case Presentation: Refractory Epilepsy Related to Tumor Based Epilepsy

Jeffrey M. Politsky, M.D. 10:25 a.m. Surgical Issues in Managing Tumor Based Epilepsy: Resection Extent Outcomes/ Timing of Surgery

Edward Chang, M.D.

10:50 a.m. Intraoperative Monitoring: Role in Epilepsy Based Tumor Surgery (Novel techniques) Aatif M. Husain, M.D.

11:15 a.m. Case Presentation: Epilepsy Related to a Malignant Based Tumor

William O. Tatum, IV, D.O.

11: 20 a.m. Debate: Valproic Acid: Drug Pro: Ideal Drug in Tumor based Epilepsy Due to Antineoplastic Properties Charles J. Vecht, M.D. Con: Poor Choice of Drug Due to Adverse Effects and Teratogenic Potential Kimford J. Meador, M.D.

11:50 a.m. Morning Summary- Algorithm and Treatment Summary Jorge G. Burneo, M.D.

Noon – 2:00 p.m. Lunch Break 2. Trauma 2:00 p.m. Case Presentation: Epilepsy Presenting from Recent Civilian Trauma

Katherine Noe, M.D., Ph.D.

2:05 p.m. Panel Flash Session: Epidemiology and Risk Factors for Traumatic Epilepsy Dale C. Hesdorffer , M.D., Susan T. Herman, M.D., Samuel Wiebe, M.D.

2:25 p.m. Epileptogenesis and Treatment Jerome Engel, Jr., M.D., Ph.D.

2:40 p.m. Case Presentation: Epilepsy from a Military Experience

Sara Schrader, M.D.

2: 45 p.m. Epilepsy from the Military Perspective Karen L. Parko, M.D.

3:10 p.m. Debate: Does AED Prophylaxis Work in Post Traumatic Epilepsy Marc A. Dichter, M.D., Ph.D. and Patrick Kwan, M.D., Ph.D.

3:40 p.m. Break 3:55 p.m. Case Presentation: Refractory Epilepsy from Trauma

Eric Kossoff, M.D.

4:00 p.m. Imaging and EEG and Posttraumatic Epilepsy Michael R. Sperling, M.D.

4:25 p.m. Nonepileptic Seizures and Trauma Martin Salinsky, M.D.

4:40 p.m. Surgical Management of Epilepsy: Complexities-Adhesions, Multiple Foci, Encephalomalacia Jeffrey P. Blount, M.D.

5:00 p.m. Conclusion: Algorithm and Treatment Summary Joseph I. Sirven, 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 The American Epilepsy Society designates this educational activity for a maximum of 6.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. ACKNOWLEDGEMENT This program is supported in part by an educational grant from UCB, Inc. and Novartis Pharmaceuticals Corporation. NURSING CREDIT 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, Provider number P208-8/08-11. EDUPRO is also an approved provider by the California Board of Registered Nursing, Provider number CEP-14387. Disclaimer: Accreditation refers to educational content only and does not imply endorsement of products by PSNA, ANCC, CBRN, or EDUPRO Resources LLC. Nurses may claim up to 6.0 contact hours for this session. PHARMACY ACCREDITATION INFORMATION

Projects In Knowledge® is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

This knowledge-based activity provides up to 6.0 contact hours. Following attendance, completion of the activity evaluation and verification of attendance, participants will be provided an electronic statement of credit. ACPE Universal Activity Number (UAN) is 0052-9999-12-2322-L04-P and provides 6.0 contact hours. 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 Annual Course 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: Medical Knowledge, System-Based Practice, and Practice-Based Learning and Improvement 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 Joseph Sirven, M.D. (Chair) Dr. Joseph Sirven (Joe) is a Professor of Neurology and Chairman of the Department of Neurology at the Mayo Clinic in Arizona. He is currently Education chair for the Epilepsy Section of the American Academy of Neurology, Chair of the Annual Course Committee for the American Epilepsy Society and Chair of the Professional Advisory Board for the Epilepsy Foundation. In 2011,he served on the Institute of Medicine committee on the Epilepsies. He is editor- in- chief of Epilepsy.com. He has authored numerous publications in several journals and books. He is editor of four textbooks in epilepsy. Dr. Sirven discloses receiving support as Consulting/Advisory Board Activity from Neuropace Eisai UCB; as Research Funding from For Profit Commercial Sources/Principle Investigator from Eisai. Jeffrey Blount, M.D. Dr. Jeffrey Blount is a Pediatric Neurosurgeon at Children's of Alabama/UAB whose primary academic interest is the surgical treatment of epilepsy in children. Dr. Blount graduated from the University of Rochester School of Medicine in 1989 and completed the Neurosurgery Residency at the University of Minnesota Residency in 1996 (with an infolded fellowship in epilepsy surgery with the MINCEP group /Dr. Robert Maxwell). He completed a fellowship in Pediatric Neurosurgery at the Hospital for Sick Children in 2000 where he worked with Drs. James Rutka, Carter Snead and Hiroshi Otsubo. He is currently the Surgical Director of the Pediatric Epilepsy Surgery Program at Children's of Alabama. Dr. Blount has nothing to disclose.

Jorge Burneo, M.D., M.S.P.H. Associate Professor of Neurology, Biostatistics and Epidemiology, Western University, London, Canada, and Co-Director of the Epilepsy Program. A graduate from Universidad Peruana Cayetano Heredia in Lima, Peru, he completed his residency at the Henry Ford Health System, and epilepsy fellowship at the University of Alabama at Birmingham, were he also obtained a Masters of Science in Public Health, with specialty in Epidemiology. He is currently the Director of the EEG Laboratory at the London Health Sciences Center and Co-Leader of the Epilepsy Discovery Project, a research initiative recently funded by the Ontario Brain Institute. Dr. Burneo, M.D., M.S.P.H. discloses receiving support as Speakers Bureau Member (supported by for-profit entities) from UCB Canada; as Consulting/Advisory Board Activity from UCB Canada; as Research Funding from For Profit Commercial Sources/Principle Investigator from UCB Canada. Edward Chang, M.D. Dr. Edward Chang is Associate Professor of Neurological Surgery at UC San Francisco. His clinical expertise is surgical treatment for intractable epilepsy and brain tumors. He specializes in neurophysiologic brain mapping methods, including awake speech and motor mapping, to safely perform neurosurgical procedures in eloquent areas of the brain. He is the recipient of the NIH Director’s New Innovator Award, Klingenstein Fellowship, and Grass Foundation Young Investigator Award. Dr. Chang directs a clinical research program that focuses on outcomes, decision-making, and safety improvement of surgical treatment options for epilepsy. Dr. Chang has nothing to disclose. Steve Chung, M.D. Dr. Chung is a professor of neruology and epileptologist at the Barrow Neurological Institute in Phoenix. He is also director of clinical epilepsy research and epilepsy monitoring unit at the same institution. Dr. Chung burned his medical degree at the Northwestern University school of medicine in Chicago, Illinois. After graduating, he completed his residency in neurology at UCSF. His fellowship in clinical electrophysiology and epilepsy were also conducted at UCSF. He had received many teaching awards and has been principal investigator for clinical epilepsy research. Dr. Chung discloses receiving support as Speakers Bureau Member (supported by for-profit entities) from GSK, Lundbeck, UCB pharma; as Consulting/Advisory Board Activity from Easi, Lundbeck, UCB Pharma, Upsher-Smith; as Research Funding from For Profit Commercial Sources/Principle Investigator from Esai, GSK, Lundbeck, Medtronix, Neuronex, SK life, Supernus, Sunovion, UCB, Upsher-Smith, UCB. Marc Dichter, M.D., Ph.D. Marc Dichter, M.D., Ph.D. is Professor of Neurology and Pharmacology at the University of Pennsylvania, Director of the Mahoney Institute of Neuroscience, and former Director of the Penn Epilepsy Center. Dr. Dichter is active as a clinician, clinical researcher, basic researcher, and educator. His research involves both basic neuroscience and clinical investigations, focusing on mechanisms underlying seizures, actions of AEDs, and epileptogenesis. His research also involves translational and clinical studies in new approaches to treating intractable epilepsy and methods for preventing epilepsy. Dr. Dichter is a past president of the AES. Dr. Dichter has nothing to disclose.

Jerome Engel, M.D., Ph.D. Jerome Engel, Jr., MD, PhD, is Director of the Seizure Disorder Center, and The Jonathan Sinay Distinguished Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences at UCLA. He is past president of the ACNS, the AES, and the ILAE, and is past co-chair of the Global Campaign against Epilepsy. His bibliography lists over 1,000 publications and over 30 books, and he is principal investigator on three research grants from the NINDS. He has received numerous awards and honors, including a Fulbright Scholarship, a Guggenheim Fellowship, and a Javits Award. Dr. Engel has nothing to disclose. Susan Herman, M.D. Dr. Susan Herman is an Assistant Professor of Neurology at Harvard Medical School and an attending neurologist at Beth Israel Deaconess Medical Center. Dr. Herman received her undergraduate degree from Johns Hopkins University and her medical degree from Columbia University College of Physicians and Surgeons. She completed an internship in internal medicine, residency in neurology, and fellowship in epilepsy and clinical neurophysiology at Columbia-Presbyterian Medical Center in New York. Her clinical research focuses on treatment of refractory epilepsy and continuous EEG monitoring and seizures in critically ill patients. Dr. Herman discloses receiving support as Research Funding from For Profit Commercial Sources/Principle Investigator from Lundbeck, local PI. UCB Pharma, local PI. 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, and the American Academy of Neurology SUDEP guidelines workgroup. 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 on the epidemiology of epilepsy covers many risk factors for developing epilepsy. Dr. Hesdorffer discloses receiving support as Consulting/Advisory Board Activity from Mount Sinai Injury Prevention Center, UCB Pharma, UpsherSmith, Esai. Aatif Husain, M.D. Dr. Husain completed Neurology residency at the Medical College of Pennsylvania and fellowships in clinical neurophysiology, sleep medicine, and EMG at Duke University Medical Center. Currently he is Professor of Medicine in the division of Neurology and Director of the Neurodiagnostic Center, Durham, VAMC. Dr. Husain discloses receiving support as Speakers Bureau Member (supported by for-profit entities) from UCB Pharma, Jazz Pharma; as Consulting/Advisory Board Activity from UCB Pharma, Jazz Pharma, USL Pharma; as Intellectual Property Ownership from Demos Medical Publishing. Lara Jehi, M.D. Dr Lara Jehi is an adult epileptologist at the Cleveland Clinic Epilepsy Center where she serves as the head of the Outcomes Research Program, and the Director of Research. She also serves as the Associate Program Director of the Clinical Research Unit at Cleveland Clinic within the auspices of the Clinical and Translational Science Collaborative. She is board certified in Neurology and Psychiatry, and Clinical Neurophysiology. She has authored several peer-reviewed original manuscripts, editorials and book chapters addressing various aspects of epilepsy surgery outcomes research.

Dr. Jehi has nothing to disclose. Eric Kossoff, M.D. Dr. Kossoff is an Associate Professor of Neurology and Pediatrics at Johns Hopkins University School of Medicine in Baltimore, Maryland. He completed his Pediatrics training at Eastern Virginia Medical School followed by Child Neurology and Clinical Neurophysiology at Johns Hopkins. He is an expert on the use of nonpharmacologic treatments for children with epilepsy, specifically dietary treatments such as the ketogenic and modified Atkins diet. Dr. Kossoff also has specific interests in infantile spasms, hemispherectomy, Doose syndrome, and Sturge-Weber syndrome. Dr. Kossoff discloses receiving support as Consulting/Advisory Board Activity from Atkins Nutritionals, Eisai, Nutricia; as Research Funding from For Profit Commercial Sources/Principle Investigator from Nutricia. Patrick Kwan, M.D., Ph.D. Dr Kwan is Professor of Neurology at the University of Melbourne, Royal Melbourne Hospital, Australia, and Associate Consultant at the Prince of Wales Hospital, Hong Kong. He has published widely on the outcomes of epilepsy and pharmacology of antiepileptic drugs. His other research interests include the mechanisms of drug resistance, personalised medicine, and genetics of epilepsy. He serves on the editorial boards of a number of epilepsy journals. He is currently President of the Hong Kong Epilepsy Society, treasurer of the ILAE Commission on Therapeutic Strategies, and chaired the task force for the definition of drug-resistant epilepsy. Dr. Kwan discloses receiving support as Speakers Bureau Member (supported by for-profit entities) from GSK, UCB Pharma; as Consulting/Advisory Board Activity from GSK, Eisai; as Research Funding from For Profit Commercial Sources/Principle Investigator from Eisai, UCB Pharma. Kimford Meador, M.D. Dr. Meador is Professor of Neurology and Pediatrics at Emory University, and Director of epilepsy and Director of Clinical Neuroscience Research. He is a behavioral neurologist and epileptologist.Dr. Meador has authored over 300 peer reviewed publications. His research interests include: pharmacology and physiology of cognition, and epilepsy with focus on behavioral and cognitive co-morbidities and the impact of therapies. He is PI of a multicenter investigation on pregnancy outcomes in women with epilepsy including neurodevelopmental effects of antiepileptic drugs. Dr. Meador discloses receiving support as Consulting/Advisory Board Activity from the Epilepsy Study Consortium that receives money from multiple pharmaceutical companies; Dr. Meador has consulted in this regard for NeuroPace, Norvartis, UCB Pharma, Upsher Smith Laboratories, and Vivus Pharmaceuticals. Note that funds for consulting for the Epilepsy Study Consortium are paid to Emory University; as Research Funding from For Profit Commercial Sources/Principle Investigator from In last 5 years, Dr. Meador has received research funding from Cyberonics, GlaxoSmithKline, Eisai, Marius, Myriad, Neuropace, Pfizer, SAM Technology, Schwartz Biosciences, UCB Pharma. Katherine Noe, M.D., Ph.D. Katherine Noe is an adult epileptologist practicing at the Mayo Clinic in Arizona, where she is an Assistant Professor of Neurology. Dr. Noe completed her neurology training at Baylor College of Medicine. Fellowship training in EEG and epilepsy followed at Mayo Clinic in Rochester, Minnesota. Dr. Noe discloses receiving support as Research Funding from For Profit Commercial Sources/Principle Investigator from NeuroPace, Inc. - institutional research funding. Karen Parko, M.D.

Karen L. Parko, MD, is the National Director of the Veterans Affairs Epilepsy Centers of Excellence and a professor of neurology at the University of California at San Francisco. Dr. Parko retired from the U.S. Public Health Service after serving 24 years of active duty as a commissioned officer. She is a fellow of the American Academy of Neurology and a member of the American Epilepsy Society. She is active in the Epilepsy Foundation of America and serves on the Professional Advisory Board of the National Organization and previously chaired the Professional Advisory Board of the Northern California Chapter. Dr. Parko has nothing to disclose. Jeffrey Politsky, M.D., FRCP(C) Degrees: BSc (Neuroscience, Psychology) & MSc (Pharmacology) – Univ of Toronto; MD: Univ of Western Ontario, London, ON Neurology Residency: Univ of BC, Vancouver, BC 2-Yr Epilepsy Fellowship: Harvard/MGH, Boston, MA Current Positions: Assoc Director & Research Co-Director, Northeast Regional Epilepsy Group; Medical Director, MEG & Functional Brain Mapping Center and Atlantic Neuroscience Inst Epilepsy Program, Overlook Medical Ctr, Summit, NJ. Current Academic Titles: Clinical Assoc Prof (Neurology), Mt Sinai School of Medicine, NY, NY; Primary Interests: Tumor-Related Epilepsy, ICU Monitoring, Functional Brain Mapping. Dr. Politsky has nothing to disclose. Martin Salinsky, M.D. Dr. Salinsky is Professor of Neurology at the Oregon Health & Sciences University, and director of the Portland VA Epilepsy Center of Excellence, in Portland, Oregon. His primary research interests include the cognitive and EEG effects of antiepileptic drug therapy, and clinical and psychological aspects of psychogenic non-epileptic seizures. He is currently involved in ongoing studies of traumatic brain injuries and seizures in US veterans. Dr. Salinsky discloses receiving support as Speakers Bureau Member (supported by for-profit entities) from UCB, Inc. Sara Schrader, M.D. Dr. Sara Schrader, MD, completed her neurology residency and fellowship in Clinical Neurophysiology at Mayo Clinic in Arizona. She went on to serve active duty in the Air Force at Wilford Hall Medical Center and Brooke Army Medical Center in San Antonio, TX from 2009-2012. She is currently practicing with JWM Neurology in Indianapolis, IN. Dr. Schrader has nothing to disclose. Michael Sperling, M.D. Dr. Sperling is Baldwin Keyes Professor of Neurology at Thomas Jefferson University in Philadelphia and Director of the Jefferson Comprehensive Epilepsy Center. He has published extensively in the fields of epilepsy and clinical neurophysiology and lectures throughout the U.S. and internationally. He is well known for his studies of epilepsy surgery outcome, intracranial EEG, and pharmacological therapy of epilepsy. He is past president of the American Clinical Neurophysiology Society, the Philadelphia Neurological Society, and is an active member of the AES. Dr. Sperling discloses receiving support as Consulting/Advisory Board Activity for research study design: Sunovion, Upsher-Smith; as Research Funding from For Profit Commercial Sources/Principle Investigator from Sunovion, Eisai, UCB Pharma, SK Life Sciences, Vertex Pharm., Medtronics, Neuronex.

William Tatum, D.O. Dr. William Tatum is Professor of Neurology in the Mayo College of Medicine. He is the director of the Epilepsy Monitoring Unit at Mayo Clinic in Florida. He is a fellow in the American Academy of Neurology with qualifications in neurophysiology, president-elect of the American Board of Clinical Neurophysiology, fellow, council member, and Annual Course chairman in the American Clinical Neurophysiology Society. He has authored or co-authored over 90 peer-reviewed articles, 20 book chapter, and 2 books on epilepsy and neurophysiology. His research interests include drug-resistant epilepsy, EEG, and clinical neurophysiology. Dr. Tatum has nothing to disclose. Joon Uhm, M.D., FRCPC Joon Uhm is a staff neurologist in the Department of Neurology at Mayo Clinic with a cross appointment to the Department of Medical Oncology. He obtained his medical degree from McGill University in Montreal, Canada, and completed residency in Neurology at the Montreal Neurological Institute and McGill University. Following fellowship training in Neuro-Oncology at MD Anderson Cancer Center in Houston, TX, he joined the Mayo Clinic staff where his primary responsibilities are for the care of brain tumor patients. Dr. Uhm has nothing to disclose. Charles Vecht, M.D., Ph.D. Charles J. Vecht MD PhD (1947) is a neurologist and founder of Neuro-oncology Dept. at the Rotterdam Cancer Center, and former chairman of the Brain Tumour Group of the EORTC in Bruxelles, Belgium. Since 2000 he is at the Dept. Neurology, Medical Centre The Hague, both as chairman and in charge of the Neurology Residency Program. He has authored >160 peer-reviewed papers on Neuro-oncology or Epilepsy and sits on the board of a number of medical journals. From 2012, he continues to work in Paris (Neuro-oncology Dept, CHU Pitié-Salpêtrière) and in Heemstede, The Netherlands (SEIN Foundation of Comprehensive Epilepsy Clinics). Dr. Vecht discloses receiving support as Consulting/Advisory Board Activity from Consultancy fees from UCB Pharma; as Research Funding from For Profit Commercial Sources/Principle Investigator from Research grants from UCB Pharma, Eisai and GlaxoSmithKline. Samuel Wiebe, M.D. Samuel Wiebe is Professor and Head of Neurology, Deputy Chair of the Department of Clinical Neurosciences, and Associate Dean of Clinical Research at the University of Calgary in Canada. He is Director of the Neurosciences Clinical Research Unit in the Hotchkiss Brain Institute in Calgary, Canada. His areas of academic interest include surgical trials in epilepsy, epidemiological studies, outcome assessment, and health services research. Dr Wiebe is past-chair of the North American Regional Commission of the International League Against Epilepsy and is currently Secretary-General of the International League Against Epilepsy. Dr. Wiebe has nothing to disclose. Lily Wong-Kisiel, M.D. Lily Wong-Kisiel is an assistant professor in neurology at the Mayo Clinic Rochester. She completed her child neurology residency, fellowship in clinical neurophysiology, and fellowship in pediatric epilepsy at the Mayo Clinic. She is involved in the pediatric epilepsy surgery program at there. Her primary research interests are in the presurgical evaluations for medically refractory epilepsy. Dr. Wong-Kisiel has nothing to disclose.

Paul Levisohn (Medical Content Specialist) Dr. Levisohn is Associate Professor of Pediatrics and Neurology at the University of Colorado School of Medicine and Children’s Hospital Colorado. He is former medical director of the Epilepsy Monitoring Unit at The Children's Hospital. He has served as chair of the AES Practice Committee, is co-chair of the advisory committee for the National Center for Project Access at the Epilepsy Foundation and is a member of the EF Professional Advisory Board. He currently serves as consultant to AES on medical content of AES continuing medical education activities. Dr. Levisohn has nothing to disclose. Dave Clarke, (Liaison Reviewer) Dr. Dave Clarke received his medical degree at the University of the West Indies. He completed his residency at Overlook Hospital, an affiliate of Columbia University College of Physicians and Surgeons, and received his Pediatric Neurology training at the University of Michigan Medical Center, and Neurophysiology (Epilepsy and Sleep) at the Hospital for Sick Children, University of Toronto, in Toronto, Canada. Dr. Clarke is currently Director of the Comprehensive Epilepsy Program at Dell Children’s Medical Center of Central Texas in Austin, TX. Dr. Clarke discloses receiving support as Speakers Bureau Member (supported by for-profit entities) from ONFI (Sabril) and Cyberonics. Anne Comi, MD (Liaison Reviewer) Dr. Anne Comi is an Associate Professor in Neurology and Pediatrics at the Kennedy Krieger Institute and Johns Hopkins School of Medicine. She directs the Hunter Nelson Sturge-Weber Center there. She leads a clinical consortium of centers, within the NIH funded Brain Vascular Malformation Consortium, with the goals of developing a national de-identified database and novel biomarkers for Sturge-Weber syndrome and determining the cause of SWS. She oversees NIH funded translational laboratory research dealing with ischemia and seizures and the impact of pharmacologic and cellular interventions upon regeneration in the immature brain. Dr. Comi has nothing to disclose. Kevin Haas, MD (Liaison Reviewer) Dr. Haas is an adult neurologist and epilepsy specialist at Vanderbilt University. He has board certification in neurology, clinical neurophysiology, and epilepsy monitoring and am the director of epilepsy surgery at Vanderbilt. His research interests include epilepsy in neurodevelopmental diseases, pharmacogenomics of antiepileptic medications, surgical treatments for epilepsy, and diagnosis and management of status epilepticus. His basic research experience has focused on GABA-A receptor physiology, synaptic roles of ubiquitination, and epilepsy in Angelman syndrome. Dr. Haas discloses receiving support as Research Funding from For Profit Commercial Sources/Principle Investigator from UCB - PI for drug study Neuronex - PI for drug study. Bassel Shnecker, MD (Liaison Reviewer) Dr. Shnecker is an epileptolgist at Ohio State University. He is an Associate Professor and Vice Chair in the Department of Neurology. Dr. Shneker discloses receiving support as Research Funding from For Profit Commercial Sources/Principle Investigator from Clinical trials: UCB, GSK, Eisai, Upsher-smith, Vertex; as Research Funding from For Profit Commercial Sources/Principle Investigator from UCB, Eisai, Sanovian (CLinical trials).

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 allows any attendee to self-manage the process of completing course evaluations, tracking credits and printing out the appropriate certificate for either AMA PRA Category 1 CreditsTM, CE or ACPE pharmacy statement of credits. 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. The certificate(s) are saved to your personal account page which is cumulative. You may print the certificate(s) in PDF format at any time. To help support this process, AES members who want CME will be asked to pay $35 before January 18 and $50 between January 19 and February 28. Non-AES attendees who want CME will be asked to pay $50 before January 18 and $75 between January 19 and February 28. The online Evaluator will be left open through February 28, 2013. 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. SYLLABUS Syllabi for the educational symposia are available to print in the AES Virtual Tote Bag. Paper handouts will not be provided on site.

!!"!#"$%!$

!

!""#$% &'#()*+ ,$"$-."- &'//'"&'/0%*1 23/04'/$4.5 60.%*0).*)+

7#/'() $"8 7($#/$&'(')*'+ $, $%!$

-./'01 23 45+6'7, 8&9+.:'//.+ ;7< =1;5+);79+.:'//.+ ;7< =1;5+);7&'0;+>)'7> .: ?'@+.A.BC

8;C. =A575( D+5E.7;91.'75F, D+5E.7; G4D

D)'+5(;7 H05A'0/C 4.(5'>C I !""#$% ,**4."-

9.)5%')#(*

H5/;5, 8D9, J'+>'F,G0/1'+ 4)5>1, K@7<*'(L,G=M, ?'@+.0;(', ?2N

O'/';+(1 P+;7>/

D)'+5(;7 H05A'0/C 4.(5'>C I !""#$% ,**4."- :;<:

D77@;A =.@+/' Q6'+65'R

• S+;@); ;7< S@).+/ ;+' A57L'< >. '05A'0/C3• M.>1 SM2 ;7< *+;57 >@).+/ ;+'.6'++'0+'/'7>'< 57 7'RAC <5;B7./'< 0;>5'7>/1 5 5 1 5 <• =1+.75( /'5E@+'/ ;+' >1' )./> (5>'<

0+.*A');>5( (.)0A5(;>5.7 >. '5>1'+ .: >1'/'(.7<5>5.7/

• 8.<'A/ :.+ A';+757B ;7< 0+'6'7>57B'05A'0>.B'7'/5/

!""#$% &'#()*+ =*$("."->?@*54.A*)

• G>5A5E' DAB.+5>1)/ >1;> <'/(+5*' 1.R >. *'/> );7;B'0;>5'7>/ R5>1 '05A'0/C +'A;>'< >. *+;57 >@).+/ 57(A@<57B7.6'A 57>+;.0'+;>56' ).75>.+57B >'(175T@'/•G/' ;7 '65<'7(' *;/'< ;AB.+5>1) :.+ );7;B')'7> .: >1'G/' ;7 '65<'7(' *;/'< ;AB.+5>1) :.+ );7;B')'7> .: >1'0;>5'7> R5>1 0./>>+;@);>5( '05A'0/C•O5/L D7;AC/'/ R5AA *' 0'+:.+)'< 57 );L57B >+';>)'7><'(5/5.7/ +'B;+<57B 0+.01CA;(>5( @/' .: DH&/ 57 0;>5'7>/R5>1 =?4 >@).+/•8;7;B' 9;>5'7>/ R5>1 )'>;/>;>5( *+;57 >@).+/ R5>1>+';>)'7> .0>5.7/ *;/'< .7 '65<'7(' *;/'< *'/> 0+;(>5('/

D)'+5(;7 H05A'0/C 4.(5'>C I !""#$% ,**4."- :;<:

D77@;A =.@+/' Q6'+65'R

• SR. /'//5.7/U S@).+ ;7< S+;@);• H;(1 /'//5.7 :+;)'< *C (A575(;A (;/'/ 576.A657B*.>1 ;<@A>/ ;7< (15A<+'71 1 A < * < A 5• S1+.@B1, A'(>@+'/, <'*;>'/ ;7< 0;7'A /'//5.7/,(A575(;A );7;B')'7> R5AA *' 15B1A5B1>'< R15A'5AA@)57;>57B *;/5( /(5'7(' ;7< 0+;(>5(' B;0/3

• H;(1 /'//5.7 R5AA (.7(A@<' R5>1 ; /@));+C;7< ;7 ;AB.+5>1) :.+ );7;B')'7>3

11/14/2012

1

!"#$%# &'()* +,-" .*"-"#/,/$)#!"#"$%"& '( )*+)

,-./ 0123 4-5-".( 6!755-58928 :&1;"551& -2 <"=&1.13/755-58928 :&1;"551& -2 <"=&1.13/

>?-.@ 92@ 7@1."5#"28 <"=&1.13/( :"@-98&-# AB-."B5/69/1 >.-2-#

C1#?"58"&( 6<

7$"&-#92 AB-."B5/ D1#-"8/ E 0##',1 2""/$#%

3$-41)-'*"

<12"

7$"&-#92 AB-."B5/ D1#-"8/ E 0##',1 2""/$#% 5675

+F G"9& 1.@ C-3?8 H92@"@ I"$9."

• <1 5"-J=&" &-5K ;9#81&

• D-23." 5"-J=&" 5"$-1.13/ 5-2#" 93" ++ /"9&5– L2#&"95"@ ?"9&8 &98" 1& 5"2598-12 1; -28"25" 92M-"8/

D8 8 - . - . %. K N ?-8– D8"&"18/B-# #1$B."M O-5=9. %.9#K N P?-8"?9..=#-298-125

• ,-88." B"1B." @92#-23 9&1=2@ 9 3-928• H"&5".; 5-88-23 12 9 &1#K

– :&"5"&O"@ 5B""#?

– Q* 5"#12@5

73" ++ /"9&5

• 6CL %&9-2 5?1P"@ &-3?8 R$"5-9. 8"$B1&9. 5#."&15-5S

• D?1&8 8"&$ AAT &"B"98"@./ 21&$9.

• :&1.123"@ O-@"1 AAT

D-23." "O"28 1; U;=22/ ;"".-23 NB92-# 5"2598-12V– D-23." "O"28 1; ;=22/ ;"".-23 NB92-# 5"2598-12

– WP1 81 Q HJ @".89 9#8-O-8/ 98 W' ;1& 8"2 5"#12@5

• 69293"$"28

– >9&%9$9J"B-2" 92@ 81B-&9$98"

– D"-J=&" ;&"" ;1& ) /"9&5

D"-J=&" C"#=&&"2#"

• 73" +Q G"9&5– X;; $"@-#98-12 ;1& ' $128?5 %";1&" &"#=&&"2#"

– D9$" 5"$-1.13/

– 6CL %&9-2 5?1P"@ R&-3?8 8"$B1&9. #1&8-#9. @/5B.95-9S

• 73"5 +' +F /"9&5– 0""K./ 5"-J=&"5 @"5B-8" 9@@-8-129. $"@-#98-12 8&-9.5

– <"=&1B5/#?1$"8&-# 8"58-23

• Y"&%9. $"$1&/ -289#8

• Y"&%9. N 212O"&%9. 5K-..5 21&$9.

73" +Q /"9&5

73" ++ /"9&5W+ P-8? [email protected]=$ I,7LC

73" +Q /"9&5W+ P-8? [email protected]=$ I,7LC

I9-28 [email protected]=$ "2?92#"$"28 -2 8?" 928"&1$"@-9. &-3?8 8"$B1&9. .1%"

11/14/2012

2

+F G"9& 1.@ C-3?8 H92@"@ I"$9." L28"&O"28-12

• C-3?8 8"$B1&9. .1%"#81$/ 92@9$/@9.1?-BB1#9$B"#81$/

• :98?1.13/Z• 723-1#"28&-# 3.-1$9 0HX T&9@" L• 723-1#"28&-# 3.-1$9 0HX T&9@" L

• T&155 8189. &"5"#8-12 12 ;1..1P =B 6CL

• 6"@-#98-12 P-8?@&9P9. 98 Q $128?

• D"-J=&" ;&"" 1;; $"@-#98-12 98 +[ $128?5

1

Epidemiology and Semiology of Tumor-based Epilepsy

Ch l J V htCharles J. Vecht

Medical Center The Hague SEIN Epilepsy Foundation, The Netherlands

CHU Pitié-Salpêtrière, Paris, France

Disclosure of Conflicts of Interest

Charles Vecht MD PhD has received Consultancy fees from UCB Pharma;has received Consultancy fees from UCB Pharma;

Research Grants from UCB Pharma, Eisai and GlaxoSmithKline; Travel Funding from UCB Pharma.

Panorama Mesdag

H.W. Mesdag & G.H. Breitner, 1886H.W. Mesdag & G.H. Breitner, 1886Beach of ScheveningenBeach of Scheveningen

Published Papers on Epilepsy & Brain Tumors

> 1992 - ‘12 > 2002 -‘12

Epilepsy 80.967+ 20,1 %

49.822+ 38,4 %

Cancer 1.682.914+ 20,7 %

1.066.927+ 36,6 %

Brain Tumors 93.450+ 20,9 %

57.032+ 39,0 %

Epilepsy & Br.Tumors

3.048+ 17,2 %

1.888+ 38,0 %

Epilepsy & AEDs 21.427 + 21.1 %

13.025 + 39.2 %

Epilepsy in Brain TumoursEpidemiology & Semiology

• Type of Seizures • Type of Tumor • Localization of Tumor• Hereditary Tumors • Systemic Cancer • Diagnostic Issues• Prognostic Factors

Epilepsy in Brain TumoursMechanisms

• Underlying Mechanisms• Genetic Factors• Molecular BiologyMolecular Biology• Peri-Tumoral Changes• Treatment-Resistance

2

Epilepsy in Brain TumoursTreatment

• Medical Management– Prophylaxis of Seizures & Peri-operative Period– Seizure Control with AEDs– Drug-Drug Interactions

• Anti-Tumor Therapypy– Surgery– Radiation Therapy & Systemic Chemotherapy – Interaction of AEDs with Tumor Control

• Toxicity Issues– Side-Effects– Quality of Life / Cognitive Changes

In General Population with New Onset EpilepsyIn General Population with New Onset Epilepsy

• Overall Frequency of Brain Tumors is 4 %• Over 25 years of age 15 %• Surgery for Intractable Epilepsy 12 - 25 %

In Brain Tumors:• Frequency of Epilepsy is > 40 % • In Low-grade Brain Tumors

Frequency of Epilepsy > 75 %

Van Breemen 2007Van Breemen 2007

Epilepsy in Systemic CancerEpilepsy in Systemic Cancer

• In > 4 %

• Metabolic Encephalopathies- Organ Dysfunction

• Toxic Encephalopathies- Iatrogenic Antibiotics, Interferons

S t i Ch thSystemic Chemotherapy (and Intrathecal & I.A.)Antidepressant & Neuroleptic Agents

• Often of Cumulative Nature (Co-Morbidities) • Opportunistic CNS Infections• Radionecrosis

20

40

60

80

100

0DNET GG LGA MG GBM MT PL LM

METASTASISVan Breemen 2007

Underlying MechanismsUnderlying Mechanisms•• Imbalance Adjacent Cortical Inhib. / Excit. MechanismsImbalance Adjacent Cortical Inhib. / Excit. Mechanisms

• Tumour Type: Developmental Tumors assoc. with Cortical Dysplasia and Well-diff. Cells, Time-course

• Aberrant Neuronal Migration, Synaptic Vesicles Glutamate, Glutamate-Decarboxylase, Gaba-Receptor y , p

• Changes in Micro-environment: Angiogenesis, Perfusion, Hypoxia, pH

• Hypoxia: Lower Stability of DNA-Repair, Mutations

• Secondary Epileptogenesis: Temporal Location & Time Course

Disturbed Small Networks

Patient 10. Magnetic resonance imaging (MRI) showing a left temporal tumor (astrocytoma III). (B) Synchronization likelihood (SL) graph at a threshold of 0.15 (0.5–60Hz) obtained from the means of SL values in the whole control subjects population. (C) SL graph (same parameters) from Patient BER. (D) Regions (dashed areas) showing an increase in MCPs in comparison with control subjects (Z-score 1.96). Bartolomei & Stam, 2006Bartolomei & Stam, 2006

3

Disturbed Small-World Network

Patterns of connectivity loss in the gamma band in three patients (14, 10, and 2). Synchronization likelihood (SL) graphs were built at a threshold of 0.05 in the gamma band (30–60Hz). In the last column, the regions (dashed areas) showing a increase in missing connective points in comparison with control subjects (Z-score 1.96) are indicated.

Bartolomei & Stam, 2006Bartolomei & Stam, 2006

Initializing of Abnormal Circuits Inducing Seizures in Brain Tumors

• Disruption of Neuronal Connections with Inhibition of Local Network Regulation

• Impaired Glial Cell Activity

• Increased Vascular Permeability and Abnormal Blood-Brain-Barrier

• Deregulation of Ajacent Brain Areas with Peritumoral Edema and Inflammation, Necrosis, Hemosiderin Deposition

H.W. Mesdag, 1890H.W. Mesdag, 1890Beach of ScheveningenBeach of Scheveningen

Proportion of Drug-Resistant Epilepsies

Gilioli 2012

Miller 2009

Immunohistochemistry: a MRP1expression in an astrocytoma sample (WHO grade II): TCs-, ECs? and b in a GBM sample (WHO grade IV): TC?, EC-. c MRP3 expression in an astrocytoma sample (WHO grade II): TC-, EC? and d in an anaplastic astrocytoma sample (WHO grade III): TC-, EC? Calatozollo 2012Calatozollo 2012

4

Association between MDR Protein Expression and Treatment-Response

Calatozollo 2012Calatozollo 2012

Seizure History in Low-Grade Glioma

Van Veelen 1998; Smits 2011Van Veelen 1998; Smits 2011

Sz. as Presenting Symptomis Favorable Prognostic Factor for Survival

Drug InteractionsDrug Interactionsbetween Antibetween Anti--Epileptic Drugs (AEDs) Epileptic Drugs (AEDs) and Chemotherapeutic Drugs (CTDsand Chemotherapeutic Drugs (CTDs))and Chemotherapeutic Drugs (CTDsand Chemotherapeutic Drugs (CTDs))

Carbamazepine >95% hepatic Inducer

Phenobarbital 75% hepatic, 25% renal Inducer

First-Generation Antiepileptic Drugs

Phenytoin >90% hepatic Inducer

Valproate >95% hepatic Inhibitor

PatsalosPatsalos & & PeruccaPerucca 20032003

CYP 2C

Major CYP-450 Enzymes CYP 3A4 50%CYP 2D6 25%CYP 2C9 15%CYP 2C19 5%

CYP 1A2 CYP 2E1

CYP 3A

CYP 2D6

CYP 2C

Effect of Enzyme-Inducing AEDs on Pharmacokinetics of Chemotherapeutic Drugs

Brodie et al, 2012

5

Survival of Children with B-lineage Leukaemia

Relling 2000Van den Bent 2009

P450 Drug-Drug Interactions Websites:

• http://medicine.iupui.edu/clinpharm/ddis/

• http://en.wikipedia.org/wki/cytochrome_p450

Prophylactic AEDs Trials in Brain TumorsProphylactic AEDs Trials in Brain Tumors

Forsyth Metast PHTAED11/46

Placebo15/54

OR (CI)0.33- 2.01

Glantz MetastGlioma

VPA 13/37 9/37 0.61- 4.63

Franceschetti

MetastGlioma

PHTPHB

3/41 4/22 0.07 - 1.76

North MetastGlioma

PHT 9/42 5/39 0.56 - 6.12

Prophylaxis with LEV vs. PHT in 1st Post-Operative Week

• Seizures in 1st week

• Adverse Drug

• 1/ 105 vs. 9 / 210 (NS)

• 1/ 105 vs. 38 / 210 ( 001)

LEV vs. PHT

Reactions

• Sz. after 1 yr Follow-up

• Retent. Rate after 1 yr

(p.001)

• 26 % vs. 36 % (NS)

• 64 % vs. 26 % (p.<03)

Milligan, 2008; Lim 2009

Type of LowType of Low--Grade TumorsGrade Tumors

• 144 (70 %) Classic Epilepsy-Associated Tumours82 Ganglioglioma29 Dysembryoblastic Neuroepithelial Tumour 33 Pilocytic Astrocytoma5 Pleomorphic Xantho-astrocytoma

• 59 (27 %) Other Tumours• 59 (27 %) Other Tumours38 Astrocytomas gr II17 Oligodendrogliomas gr II

• 4 (2 %) Grade III tumours 3 Astrocytoma gr III1 Ganglioglioma gr III

Luyken 2003Luyken 2003

6

Seizure Semiology in Low-Grade Glioma

• Secondary Generalized Sz. 67.1 % • Simple Partial 23.7 % • Complex Partial 6.6 %• Partial & Sec. Generalized 2.6 %

• Single Pre-operative Sz. 34.3 %

You 2012

Seizure Characteristics in Low-Grade Glioma (n = 508)

• Mean Age 38.1 yrs

• 45 % Astrocytomas, 9 % Oligodendrogliomas, 46 % Oligo-Astrocytomas (LGG)

• Cortical Location 31 % Subcortical 69 %• Cortical Location 31 %, Subcortical 69 %

• Frontal 71 %, Temporal 37 %, Insular 21 %, Parietal 9%

• Pre-op Seizures 68.9 %

• Med. Duration of Sz. Onset and Surgery 10 Mos

You 2012You 2012

• As Presenting Sign• Seizures

• Secondary Generalized

• 123 ( 42.1 % )• 181 ( 62 % )

• 74 ( 40.8 % )

Seizure Semiology in Gliobastoma Multiforme

• Simple Partial• Combined Partial & Sec.

Generalized• Complex Partial

• 59 ( 32.6 % )• 26 ( 14.4 % )

• 9 ( 5 % )

De Wit De Wit -- Kerkhof, 2012Kerkhof, 2012H.W. Mesdag, 1890H.W. Mesdag, 1890

Standard Treatment in Glioblastoma Multiforme (GBM)

Chemoradiation with Temozolomide particularly effective with methylated MGMT

Stupp, 2005Stupp, 2005

Methylation Status of MGMT

Effect of Radiation Therapy and of Systemic Chemotherapy

EORTC Study on Radiotherapy in LGGSeizure-Freedom with Early RT: 75 %( n = 314) Late RT: 59 %

• Temozolomide in Low grade Gliomas• Temozolomide in Low-grade GliomasTMZ Cohort n =39; Control group n= 30

• Median length of F-U: 39 vs. 37 Months• > 50 % Decrease in Sz frequency

With TMZ : 59 %; Control group: 13 % (p <. 001)

Van den Bent 2005; Sherman, 2011Van den Bent 2005; Sherman, 2011

7

RecommendationsRefractory Epilepsy

• Consider Surgery

(rather than Wait & See)

• Consider Radiotherapy & Chemotherapy

Luyken, 2003, Soffietti 2005, Englot 2012Luyken, 2003, Soffietti 2005, Englot 2012

11/14/2012

1

!"#$% &'()" #%* +,$-.,/01 +22.34 )2&'()" &0,.

!"#"$%"& '( ')*'

+,&, -"./( 0!

12"3"2,45 12/4/#

6$"&/#,4 78/2"89: ;<#/"=: > 5%%'#- 6..4$%7

8$/3-)/'".

?<4"

6$"&/#,4 78/2"89: ;<#/"=: > 5%%'#- 6..4$%7 9:;9

<.#"%$%7 =>?.34$@./

• ;@$$,&/A" $<9= "99"4=/,2 B,#=9 &"2,=/4C =@$<&=:8" =< =." #2/4/#,2 $,4/B"9=,=/<49 5%%'#- 6..4$%7 9:;9

<.#"%$%7 =>?.34$@./

• ;@$$,&/A" $<9= "99"4=/,2 B,#=9 &"2,=/4C =@$<&=:8" =< =." #2/4/#,2 $,4/B"9=,=/<49 5%%'#- 6..4$%7 9:;9

A#34 ;1E@$<& =:8" /9 <4" 5%%'#- 6..4$%7 9:;9

A#34 91

E/$/4C 5%%'#- 6..4$%7 9:;9

40% Focal 50% GTC 75% Focal 20% GTC

11/14/2012

2

A#34 B1

E@$<& =:8" /9 <4" 5%%'#- 6..4$%7 9:;9


25%-70% Malformation of

cortical development (Frater, 2000; Morris, 1996;

Jehi, 2008)

Hippocampal sclerosis (Prayson, 2008)

CD#4 $/ >.D$%* 4D. E2#34/FG

6$"&/#,4 78/2"89: ;<#/"=: > 5%%'#- 6..4$%7 9:;9

&'()" 40,.1 H<0)%/I 9::JK

• ?"#&<9/9• 745<=."2/,2 8&<2/B"&,=/<4• 0/=<9/9

• E/99@" /4B/2=&,=/<4

6$"&/#,4 78/2"89: ;<#/"=: > 5%%'#- 6..4$%7 9:;9

Low grade High grade

&'()" 40,.1 H<0)%/I 9::JK

• ?"#&<9/9• 745<=."2/,28&<2/B"&,=/<4

• 0/=<9/9

E/ / B/2 /

• #"22 5",=.• ."$<9/5"&/4 5"8<9/=/<4

• 5/9&@8=/<4 5%%'#- 6..4$%7 9:;9

6.3D#%$/(/)2 +,$-.,/0L

!"="&$/4,4=9 5%%'#- 6..4$%7 9:;9

11/14/2012

3

Fact 1:Tumor type is one of the main determinants

of the risk of epilepsy (Jehi, 2010)


A#34 91

E/$/4C 5%%'#- 6..4$%7 9:;9


Fact 2:Timing of seizures in relation to diagnosis- rather than

tumor type- determines seizure characteristics (Hildebrand, 2005)



A#34 B1

E@$<& =:8" /9 <4" 5%%'#- 6..4$%7 9:;9


25%-70% Malformation of

cortical development (Frater, 2000; Morris, 1996;

Jehi, 2008)

Hippocampal sclerosis (Prayson, 2008)

Association with hippocampal sclerosis

Consideration particularly with long standing epilepsy

Association with MCD (Jehi, 2010, from Wyllie’s textbook of the Treatment of the epilepsies)

Ictal onset 1

Ictal onset 2

11/14/2012

4

A#34 M1

•In general, risk of developing intractability is at least 50% when tumor is the etiology.

•Twice as high as the risk of intractability with

6$"&/#,4 78/2"89: ;<#/"=: > 5%%'#- 6..4$%7 9:;9

other causes of epilepsy.

N(,#34 )% O-$%$3#- O#". #%* P"#34$3.

• M"#<C4/A" ./C. &/9F <B 9"/A@&"9 /4 ,22 8,=/"4=9K/=. %&,/4 =@$<&9D

• M"#<C4/A" =.,= ,5"N@,=" "8/2"89: #<4=&<2&"N@/&"9 ,5"N@,=" =&",=$"4= 5%%'#- 6..4$%7 9:;9

11/14/2012

1

!"#$%&'(#)* +,)-."/ )-012$*"2%(."-"/$/

3"4"'5"# 67 8986

:%";" +,&-.7 <3

!#(="//(# (= >"&#(*(.?

@)##(A >"&#(*(.$4)* B-/%$%&%"

C'"#$4)- 12$*"2/? :(4$"%? D !""#$% &''()"*

8

+),-%.,#/'

Received research grants: Barrow foundation, Esai, GSK, Lundbeck, Medtronics, Neuronex, SK Life Science, Supernus, Sunovion, UCB Pharma, Upsher-Smith, Valeant

Member of speaker’s bureau: GSK, Lundbeck, UCB Pharma

C'"#$4)- 12$*"2/? :(4$"%? D !""#$% &''()"* 0120

Consulting/Advisory Board: Esai, Lundbeck, UCB Pharma, Upsher-Smith

6

3'$/")"* 456'-()7',

• E,)% 4)&/"/ /"$F&#"/ $- 5#)$- %&'(# 2)%$"-%/G

• H-0"#/%)-0 %," ;)#$(&/ 2"#$%&'(#)* 4,)-."/ %,)%4(-%#$5&%" %( /"$F&#"/

C'"#$4)- 12$*"2/? :(4$"%? D !""#$% &''()"* 0120I

3("/ /$F"7 .#)0"7 (# *(4)%$(- ')%%"#G

J K$., .#)0" .*$(')/ )#" *"// (=%"- )//(4$)%"0 A$%,/"$F&#"/ LI9 M9NO7 )-0 /')**"# %&'(#/ )#" '(#" *$P"*?2#"/"-% A$%, /"$F&#"/8

J Q(A .#)0" .*$(-"&#(-)* %&'(#/ L$R"R .)-.*$(.*$(')/ )-03>1S/O )#" '(#" (=%"- )//($)%"0 A$%, /"$F&#"/ LT93>1S/O )#" '(#" (=%"- )//($)%"0 A$%, /"$F&#"/ LT9899NO6

J :"$F&#"/ )#" '(#" *$P"*? %( (44&# $= %&'(#/ )#" $- '"/$)*%"'2(#)* )-0 $-/&*)# /%#&4%&#"/

C#" %&'(# #"*)%"0 /"$F&#"/ 0&" %( 2"#$%&'(#)* 4,)-."/#)%,"# %,)- %," %&'(# $%/"*=G

8 Q"" UER C#4, >"&#(*R 6989V WXLIO6 !#)?/(- YC R C' U :&#. !)%,(* 6989V IM

M

C#" /"$F&#"/ 4)&/"0 5? %," %&'(#(# 2"#$%&'(#)* %$//&"G

• B-%#$-/$4 "2$*"2%(."-$4$%? (= 5#)$- %&'(#/ $/ /&22(#%"0 5? %,"2#"/"-4" (= ,?2"#"Z4$%)5*" -"&#(-)* 4('2(-"-%/ A$%,$- %,"%&'(#8

• $R"R 3?/2*)/%$4 -"&#(-/ )-0 .$)-% 4"**/ (= 4(#%$4)* %&5"#/LC*%"#)%$(- (= .*&%)')%" )-0 [C@C #"4"2%(# "Z2#"//$(-/O6

• C*/(7 %," 0?/2*)/%$4 )-0 0$/(#.)-$F"0 2"#$%&'(#)* #".$(- ')?4)&/" "2$*"2%(."-/$/ ;$) 3$/%(#/$(- )-0 B-=$*%#)%$(-R

\

8]"##$"# !" #$% 12$*"2/$)R 699W6E,$%" !" #$% C--R >"&#(*R 6998

+,)-."/ $- 2"#$%&'(#)* %$//&"&' ()*( *+#,! "-./+0

• Y)2$0 .#(A%, 4)&/"/ %$//&" 0)')." L3$/%(#%$(-O8

• >"4#(/$/• K"'(/$0"#$- 0"2(/$%$(-• !"#$%&'(#)* "0"')

• K$., .#)0" %&'(#/ 2#"/"-% *"// =#"^&"-%*? A$%,/"$F&#"/• $R"R $- [@<7 I9 \9N6

8Y$;) !" #$% >"&#(* :4$R 699\6<((%/ !" #$% C#4, >"&#(*R 8__\

11/14/2012

2

+,)-."/ $- 2"#$%&'(#)* %$//&"12)")#$ "(/-*("0

• !"-=$"*0 $- 8_M9` :"$F&#"/ )#" 0&" %( $'2)$#"0;)/4&*)#$F)%$(- )-0 2"#$%&'(#)* $/4,"'$4 4,)-."/8

• 14,*$- $- 8_\_ 2#(2(/"0 2)#%$)* $/(*)%$(- (# 0"-"#;)%$(-,?2"#/"-/$%$;%? %,"(#?6,?2"#/"-/$%$;%? %,"(#?

8!"-=$"*0 R 3+4( 5!-+/$ 60'4( 8_M9614,*$-R 7$)2 5!-+/8('0)/$ 8_\_876@")&'(-%R 34"# 5!-+/4()+ 6999

X

+,)-."/ $- 2"#$%&'(#)* %$//&"3$"!+!, $)9)2* !29)+/2.!2"

• !"#$%&'(#)* #".$(-/ =)4" )*%"#"0 5$(4,"'$4)*)-0 ,(#'(-)* 2#(=$*"7 ;)/4&*)# (#.)-$F)%$(-7)Z(-)* 4(**)%"#)*/ )-0 -"(/?-)2%(."-/$/R

• <)? "Z2*)$- A,? *(A .#)0" %&'(#/ 4)&/"/"$F&#"/ '(#" =#"^&"-%*?

8Q"" UER C#4, >"&#(*R 6989V WXLIO6 !#)?/(- YC R C' U :&#. !)%,(* 6989V IM

T

+,)-."/ $- 2"#$%&'(#)* %$//&"3$"!+!, $)9)2* !29)+/2.!2" :;<

• B(- 4,-)."/ ')? 4)&/" ,?2"#"Z4$%)5$*$%?8

• 3"4#")/"0 "Z%#)4"**&*)# <.6a

• B-4#")/"0 "Z%#)4"**&*)# ]"Ia

• 2K 4,)-."/ ')? 4)&/" ,?2"#"Z4$%)5$*$%?67 I

• !"#$%&'(#)* 4(#%"Z $/ /$.-$=$4)-%*? )*P)*$-"• C*%"#"0 4)#5(-$4 )4$0 *";"*/• C*P)*$-$%? 5*(4P/ '"'5#)-" ba 4(-0&4%)-4"• 2K $-4#")/" 4)&/"/ #"0&4"0 [C@C *";"*/ )-0 )4%$;)%"/

><3C #"4"2%(#/

8:$-., YR =8)$!80)# 8__96cP)0) dR > 5!-+/0-+* 8__6IS)-. +R 6+/4 5#"$ 34#, ?4) 8__9

_

+,)-."/ $- 2"#$%&'(#)* %$//&"3$"!+!, $)9)2* !29)+/2.!2" :@<

• +,)-."/ $- )'$-( )4$0 4(-4"-%#)%$(-• B-,$5$%$(- (= .*&%)')%" %#)-/2(#%"#/ L[QC:S7 [QS87

1CC+8O "Z%#) 4"**&*)# .*&%)')%" *";"* $-4#")/"8

• C*%"#"0 [C@C *";"* )-0 [C@C-"#.$4 %#)-/'$//$(-6

• B-4#")/"0 *";"* (= 2(*?)'$-"/ L:2"#'$-"7 /2"#'$0$-"72&%#"/4$-"O I

• 1-F?')%$4 4,)-."/ L$R" [*&%)'$-" /?-%,"%)/" O

• S,"/" 4,)-."/ ')? 5" ) 4)&/" (# ) 4(-/"^&"-4" (=/"$F&#"/

8Y(%,/%"$- UR 5!-+/2 8__W6K).*&-0 >R > 5!-+/0-+* 8__6I :"//) CR 7#24!+ A!"" 8__M

89

+,)-."/ $- 2"#$%&'(#)* %$//&"3$"!+!, $)9)2* !29)+/2.!2" :B<C BQ 8

• B''&-" '"0$)%"0 4,)-."/ (44&# $- 2"#$%&'(#)*#".$(-8

• 1*";)%"0 BQ 8 *";"* $- 5#)$- %&'(#6

• 1*";)%"0 BQ 8 $- )4&%"e4,#(-$4 /"$F&#" '(0"*/• !#(4(-;&*/$;" "=="4%/ (= BQ 8 I

• C&.'"-%/ -$%#$4 (Z$0" =(#')%$(-• 3$#"4%*? $-,$5$%/ [C@CC

• B-4#")/"/ ><3C #"4"2%(# =&-4%$(-• B-,$5$%/ ba "==*&Z

8:(*$;"- @R > 5!-+/4(!. 8__66>(A)P <R =8)$!80)# 699_IQ$ [R ?!)D-+! 6988

88

+,)-."/ $- 2"#$%&'(#)* %$//&"3$"!+!, $)9)2* !29)+/2.!2" :E<C S>] 7 @@@

• H2 #".&*)%$(- (= S>] 'Y>C )=%"# /"$F&#"/)-0 $- /&f"4%/ A$%, +>: %&'(#/ L$- )-$')*O8

• S>] ')? 2*)? ) 0$4,(%('(&/ #(*"6? 2 ?

• S>] )4%$;)%"/ 2\\` 2#(4(-;&*/)-% "=="4%

)4%$;)%"/ 2X\` )-%$(-;&*/)-% "=="4%

8[(0*";/P? QR 6/$ > 6(#+.#4/$ 69966Q$ [R ?!)D-+! 6988I<)#4,$ >R =8)$!80)# 699X

• +?%(P$-"/ 4)&/" "-,)-4"0 @@@ 2"#'")5$*$%?I

86

11/14/2012

3

:&'')#?` !"#$%&'(#)* %$//&" )-012$*"2%(."-"/$/

• C5"##)-% -"&#(-)*e.*$)* -"(/?-)2/"/

• 3$/%&#5"0 5)*)-4" (= "Z4$%)%(#?e$-,$5$%(#?$-2&%/

• <"'5#)-" $-/%)5$*$%? )-0 )*%"#"0<"'5#)-" $-/%)5$*$%? )-0 )*%"#"0-"&#(%#)-/'$%%"# 4(-4"-%#)%$(-/

• +?%(P$-"eS>] '"0$)%"0 '"'5#)-" "Z4%$%)5$*$%?

• 3$/#&2%$(- (= %," 5*((0 5#)$- 5)##$"#

8I

Panel Flash Session: Tumor-based Factors: Genetic Factors, Tumor

Types, Peritumoral

Joon Uhm, MD

Slides not available

Prevention of Epilepsy in Tumors: Insights from Basic Science,

Glutamate Receptors

Joon Uhm, MD

Slides not available

!!"!#"$%!$

!

J ff M P lit k MD MS FRCP(C)

Tumor-Related Epilepsy:Case Presentation

Sunday, December 2, 2012

Jeffrey M. Politsky, MD, MSc, FRCP(C)NORTHEAST REGIONAL EPILEPSY GROUP

Medical Director, MEG & Comprehensive Epilepsy CenterAtlantic Neuroscience Institute, Summit, NJ

Clin Assoc Professor of Neurology, Mt Sinai School of Medicine, NY

American Epilepsy Society | Annual Meeting

Name of Commercial Interest

Disclosure

Type of Financial Relationship

• Nothing to Disclose

American Epilepsy Society | Annual Meeting 2012

• Nothing to Disclose

• Mechanism of tumor-induced epilepsy

• Influence of epileptic network on tumor growth

Learning Objectives

• Impact of treatment on epileptogenesis and tumorigenesis

• Standardizing treatment approach• Pharmacologic & Alternative Therapies• Surgical therapy


Case 1Case 1

65 65 yoyo female with a 1female with a 1-- yr yr hxhx of recurrent episodes c/b of recurrent episodes c/b sudden onset of a feeling of dread, associated with sudden onset of a feeling of dread, associated with blurred vision and feeling faint, lasting 1blurred vision and feeling faint, lasting 1--2 2 minsminsFreq: Crescendo characteristic Freq: Crescendo characteristic -- dailydailyERF: negativeERF: negativeERF: negativeERF: negativeCleared by endocrinology, cardiology, rheumatology, Cleared by endocrinology, cardiology, rheumatology, psychiatrypsychiatryPM/S PM/S HxHx: MCTD, cardiac : MCTD, cardiac dysrhythmiadysrhythmia, LASIK, LASIKSoc Soc HxHx: comp programmer, divorced, one child, no : comp programmer, divorced, one child, no tobtob//etohetoh/IDU/IDUNeuroNeuro Exam: elemental exam intactExam: elemental exam intact

44

55 66

!!"!#"$%!$

$

77

Case 1Case 1

88

99 1010

1111 1212

!!"!#"$%!$

&

1313

Case 1Case 1Diagnosis:Diagnosis:–– 1.2 Brain, right craniotomy for tumor resection1.2 Brain, right craniotomy for tumor resection–– MeningiomaMeningioma, grade I (WHO 2007)., grade I (WHO 2007).

nearly onenearly one--year postyear post--opopnearly onenearly one year postyear post opopNo No szszOn AED On AED monotherapymonotherapyFocal slowing on EEGFocal slowing on EEGPrognosis: goodPrognosis: good–– QOL considerations: Duration of therapy? Tumor QOL considerations: Duration of therapy? Tumor

recurrence.recurrence.

1414

Case 2Case 2

43 year old male43 year old malePresented in May 2011 with a 30 sec episode of R facial Presented in May 2011 with a 30 sec episode of R facial twitching and speech arresttwitching and speech arrestSeveral brief (5 s) episodes in prior months discounted Several brief (5 s) episodes in prior months discounted b ti tb ti tby patientby patientEpilepsy Risk Factors: noneEpilepsy Risk Factors: nonePM/S PM/S HxHx: sinusitis, benign vocal cord polyp: sinusitis, benign vocal cord polypSoc Soc HxHx: Wall St Broker, 15 : Wall St Broker, 15 pkpk yr yr hxhx cig; intermittent cig; intermittent binge drinker; binge drinker; intint THC useTHC useNeuroNeuro Exam: R facial droopExam: R facial droop

1515 1616

1717 1818

!!"!#"$%!$

#

1919 2020

2121 2222

2323 2424

!!"!#"$%!$

'

2525

Case 2Case 2

Diagnosis:Diagnosis:–– Brain, left temporal lobe craniotomy for biopsy of mass:Brain, left temporal lobe craniotomy for biopsy of mass:

GlioblastomaGlioblastoma multiformemultiforme, grade IV, (WHO 2007), grade IV, (WHO 2007)

–– Comments: Comments: Proliferation of smallProliferation of small astroctyicastroctyic cells appearing as “naked” nuclei in acells appearing as “naked” nuclei in aProliferation of small Proliferation of small astroctyicastroctyic cells, appearing as “naked” nuclei in a cells, appearing as “naked” nuclei in a fibrillaryfibrillary background;background;HyperchromaticHyperchromatic nuclei nuclei -- round to spindled, coarse chromatin and rare round to spindled, coarse chromatin and rare nucleoli; nucleoli; Vascular proliferation with endothelial hyperplasia and mitotic figures;Vascular proliferation with endothelial hyperplasia and mitotic figures;Cellular proliferation strongly positive for GFAPCellular proliferation strongly positive for GFAP

–– scattered nuclear reactivity for p53 and an 80% labeling index for p67;scattered nuclear reactivity for p53 and an 80% labeling index for p67;

Extensive Extensive tumoraltumoral calcifications in some areas;calcifications in some areas;–– usually associated with usually associated with oligodendroglialoligodendroglial tumors, but in this case overall tumors, but in this case overall

cytomorphologiccytomorphologic and and histologichistologic features are more compatible with GBM.features are more compatible with GBM.

2626

Case 2Case 2

One year postOne year post--opopOn AED On AED polypharmacypolypharmacy (3 AEDs) to maintain (3 AEDs) to maintain reasonable controlreasonable controlAdjuvant Therapy:Adjuvant Therapy: bevacizumabbevacizumab,, temozolomidetemozolomideAdjuvant Therapy: Adjuvant Therapy: bevacizumabbevacizumab, , temozolomidetemozolomideRtRt hemiparesishemiparesis, expressive > receptive aphasia, expressive > receptive aphasia–– rehab programrehab program

Prognosis: poorPrognosis: poor–– QOL considerations: Optimizing QOL considerations: Optimizing TxTx, AE, DDI, tumor , AE, DDI, tumor

recurrence, further recurrence, further TxTx options, progressive disability, options, progressive disability, end of life end of life

2727

TumorTumor--Related EpilepsyRelated EpilepsyMechanism of tumorMechanism of tumor--induced epilepsyinduced epilepsy–– IntraIntra--axial tumors (axial tumors (gliomasgliomas, metastatic lesions), metastatic lesions)–– ExtraExtra--axial tumors (atypical axial tumors (atypical meningiomameningioma))

Influence of epileptic network on tumor growthInfluence of epileptic network on tumor growthue ce o ep ept c et o o tu o g o tue ce o ep ept c et o o tu o g o t

Impact of Impact of TxTx on on epileptogenesisepileptogenesis//tumorigenesistumorigenesis

Standardizing treatmentStandardizing treatment–– Pharmacologic & Alternative TherapiesPharmacologic & Alternative Therapies

KetogenicKetogenic/Low /Low GycemicGycemic Index/Modified Atkins DietsIndex/Modified Atkins Diets–– Surgical therapySurgical therapy

2828

2929

!!"!#"$%!$

!

!"#$%&'( )**"+* %, -','$%,$ ."/0#1'*+2 34%(+4*56 378+,8 9+*+&8%0,

:"8&0/+*; ',2 .%/%,$&'(')*'+ $,$%!$-./0+. 12034, 5&

6378'+97:; <= 10>7=<+370, ?03 @+03(79(<

A)'+7(03 -B7>'B9; ?<(7':; C <,,"'( -++8%,$

!

=%*&(0*"#+

3<3'

A)'+7(03 -B7>'B9; ?<(7':; C <,,"'( -++8%,$ >?@>$

A+'#,%,$ :BC+&8%D+*

• D< E3.'+9:03. :2' B+'.7(:<+9 <= 9'7FE+' =+''.<)73 B0:7'3:9 /7:2 *+073 :E)<+9• D< E3.'+9:03. =0(:<+9 /27(2 0=='(: GE0>7:; <= >7='03. (<437:7<3 73 B0:7'3:9 /7:2 :E)<+ +'>0:'.'B7>'B9;

A)'+7(03 -B7>'B9; ?<(7':; C <,,"'( -++8%,$ >?@>H

3"#04+', E0"#,'( 0F G',&+# @HHI

#

“The increase in epilepsy burden that was associated with significant reductions in all cognitive domains except for attentional and memory functioning could primarily be attributed to the use of AEDs, whereas the decline in HRQOL could be ascribed to the lack of complete seizure control.”

I J

!!"!#"$%!$

$

OR 95% CIGross Total Resection

16 2.2-124

Predictors of Seizure Freedom (Engel Class 1)

Simple partial seizures

0.36 0.18-0.72

Seizures >1 year duration

0.28 0.1-0.56

K

N 773 20 bli h d t di

2011

N=773, 20 published studies

L

M

Take-home for LGG-epilepsy

Tumor control:• GTR 10 year survival = 100%• STR 10 year survival < 50%• STR 10 year survival < 50%Seizure control:• GTR seizure freedom = 85%• STR seizure freedom < 35%

!%

!!

Long-term seizure control outcomes after surgery for gangliogliomas

Southwell D, Chang EF Neurosurgery 2012

!$

!!"!#"$%!$

H

N=15

All ti t iAll patients seizure-free with additional hippocampalresection

Also, all returned to work

!H

Conclusions:

Decision-making for tumor-related epilepsy is more straightforward than non-lesional epilepsy surgery

Subtotal vs Gross-total resection is critical for seizure-freedom and long-term survival

E il h i i t thEpilepsy surgery approach is more appropriate than tumor approach

- Familiarity with intraop electrocorticography- Familiarity with mesial temporal structures/anatomy- Anatomic approach is better - Consideration of risks: memory/eloquence

Does pathology matter? Not really. - Outcomes nearly same for LGG/DNET/GG !#

Controversies:

Timing-

If suspicion of glioma, then operate. Do not wait.- up to 50% of non-enhancing tumors are

anaplastic astrocytomas (worse prognosis, require chemo/radiation)

- GG and DNET can be difficult to distinguish from LGG/AA

!I

Controversies:

Resection- how much to take?

Temporal lobe: lesionectomy vs lobectomy?

Lateral temporal or insular: resect or spare hippocampus?

Extratemporal: lesionectomy vs extended lesionectomy(with intraoperative electrocorticography)?

Is there a role for chronic intracranial monitoring?

!J

Controversies:

Resection- how much to take?

Medial temporal lobe: lesionectomy vs lobectomy?- If refractory epilepsy lobectomy

Lateral temporal or insular: resect or spare hippocampus?If epilepsy resect hippocampus

BOLD= our practice

- If epilepsy resect hippocampus

Extratemporal: lesionectomy vs extended lesionectomy(with intraoperative electrocorticography)?- Extended lesionectomy

Is there a role for chronic intracranial monitoring? - NO, seizure localization rarely difficult; outcomes are excellent without it

!K

)/4'&8 0, G(%,%&'( G'#+ ',2 J#'&8%&+

• D'N:• D'N:• D'N:

!L

!!"!#"$%!$

!

&'()*+,-)*(./- 0+'.(+).'123+4- .' 5,.4-,67 8*6-9 :;<+) =;)1-)7

>-?-<@-) $A $%!$

B*(.C 0D E;6*.'A 0D>D>;F- G'./-)6.(7 *'9 H-(-)*'6 BCC*.)6

0-9.?*4 I-'(-)6A >;)J*<A KI

B<-).?*' 5,.4-,67 =+?.-(7 L !""#$% &''()"*

>.6?4+6;)-6

K*<- +C I+<<-)?.*4&'(-)-6(

:7,- +C M.'*'?.*43-4*(.+'6J.,

GI8 NJ*)<* 3-6-*)?JA ?+'6;4(*(.+'A 6,-*F-)@;)-*;

G,6J-) =<.(J O*@+)*(+).-6 3-6-*)?JA ?+'6;4(*(.+'

P*QQ NJ*)<* I+'6;4(*(.+'A 6,-*F-) @;)-*;

>-<+6 0-9.?*4 N;@4.6J.'1 3+7*4(.-6

B<-).?*' 5,.4-,67 =+?.-(7 L !""#$% &''()"* +,-+

O-*)'.'1 R@S-?(./-6

• G'9-)6(*'9 (-?J'.T;- *'9 ;(.4.(7 +C 4*'1;*1-<*,,.'1

• G'9-)6(*'9 (-?J'.T;-6 ;6-9 C+) <+(+) ?+)(-U4+?*4.Q*(.+'4+?*4.Q*(.+'

• I+<,*)- /*).+;6 (-?J'.T;-6 ;6-9 C+) <+(+)<*,,.'1 *'9 <+'.(+).'1

B<-).?*' 5,.4-,67 =+?.-(7 L !""#$% &''()"* +,-+

R/-)/.-V

• O*'1;*1- <*,,.'1 *'9 <+'.(+).'1• I-'()*4 6;4?;6"<+(+) ?+)(-U 4+?*4.Q*(.+'• 0+(+) ,*(JV*7 <+'.(+).'1

• &'()*+,-)*(./- 5I+W

O*'1;*1- 0*,,.'1

• 3*(.+'*4-– O+?*4.Q*(.+' +C 4*'1;*1- *)-*6 /-)7 /*).*@4-– 3-6-?(.+' .' X-4+T;-'(Y *)-* <*7 @- ,+66.@4-&9-'(.C.-6 ?4.'.?*4 C;'?(.+' +C '-;)*4 (.66;-– &9-'(.C.-6 ?4.'.?*4 C;'?(.+' +C '-;)*4 (.66;-

• I*;(.+'6– 0*,,.'1 <*7 )-6;4( .' 6-.Q;)-6– BC(-) 9.6?J*)1-6 <;6( @- <+'.(+)-9– BV*F- ,*(.-'(

O*'1;*1- 0*,,.'1 Z :-?J'.T;-

• I+)(.?*4 *)-*6 6(.<;4*(-9 V.(J @.,+4*) ?+'6(*'(?;))-'( 6(.<;4*(+) [N-'C.-49 (-?J'.T;-\– ]% EQ ()*.'6 +C @.,J*6.? ,;46-6– 5*?J ,;46- ! <6D [$ !% (J)-6J+49

• K*<.'1 (*6F ,-)C+)<-9

!!"!#"$%!$

$

N*(.-'( !2 $# 7-*) +49A ).1J( J*'9-9 V+<*' 6(*)(-9 J*/.'1 IN= ]<+'(J6 ,).+) (+ )-C-))*4 (+ -,.4-,67 ?-'(-)D =-.Q;)- J*/-?+'(.';-9 9-6,.(- ()-*(<-'( V.(J O5H *'9 OI0D

N*(.-'( !2 BC(-) >.6?J*)1-

N*(.-'( !2 $# 7-*) +49A ).1J( J*'9-9 V+<*' 6(*)(-9 J*/.'1 IN= ]<+'(J6 ,).+) (+ )-C-))*4 (+ -,.4-,67 ?-'(-)D =-.Q;)- J*/- ?+'(.';-99-6,.(- ()-*(<-'( V.(J O5H *'9 OI0D

8)+?* 6̀ *)-* [:*1 !%\

:+'1;- <+(+) [:*1 !\

:+'1;- 6-'6+)7 [:*1 $\

B;9.(+)7 '*<.'1 [:*1 ^%\

=;,-).+)

7 1 [ 1 \

:;<+) [:*1 $!\

!A !% a N)-I-' W7);6$ a N+6(I-' W7);6$%A $$A $#A $] a =:W$!A $Â $_ a 0:W^% a B'( =;,)*<*)1.'*4!?< );4-) *( @+((+< ).1J(

=4.9- ?+;)(-67 =*'9)* =-)*C.'.A NJD>D

N+6(-).+)

N*(.-'( !2 $# 7-*) +49A ).1J( J*'9-9 V+<*' 6(*)(-9 J*/.'1 IN= ]<+'(J6 ,).+) (+ )-C-))*4 (+ -,.4-,67 ?-'(-)D =-.Q;)- J*/- ?+'(.';-99-6,.(- ()-*(<-'( V.(J O5H *'9 OI0D

8)+?* 6̀ *)-* [:*1 !%\

:+'1;- <+(+) [:*1 !\

:+'1;- 6-'6+)7 [:*1 $\

B;9.(+)7 '*<.'1 [:*1 ^%\

=;,-).+)

7 1 [ 1 \

:;<+) [:*1 $!\

!A !% a N)-I-' W7);6$ a N+6(I-' W7);6$%A $$A $#A $] a =:W$!A $Â $_ a 0:W^% a B'( =;,)*<*)1.'*4!?< );4-) *( @+((+< ).1J(

=4.9- ?+;)(-67 =*'9)* =-)*C.'.A NJD>D

N+6(-).+)

B3= b;-6(.+'

=J+;49 4*'1;*1- <*,,.'1 @- ,-)C+)<-9 .' *44?*6-6 +C 9+<.'*'( J-<.6,J-)- C)+'(+ (-<,+)*4,*).-(*4 (;<+)"-,.4-,67 6;)1-)7c

BD d-68D K+ID K+ +,.'.+'

100

002

233

10107

713

N=29 #raw sites=2042V, 10VA, 17VAS

#SpArr=29

11

Visual

Auditory

Sentence Completion

Speech Arrest

222

100

16830

126

8415

412

744

177151

17

!!"!#"$%!$

^

O*'1;*1- 0+'.(+).'1• 3-6-?(.+' );4-2 )-6-?( e ! ?<D C)+<

-66-'(.*4 6.(- (+ */+.9 C;'?(.+'*49-C.?.(– H.6;*4 '*<.'1 (*6F

• 0+'.(+) 4*'1;*1- C;'?(.+' 9;).'1)-6-?(.+'

:-6(.'1 9;).'1 )-6-?(.+'

• f ,*(.-'(6 V.(J OWW .' 8)+?* 6̀ *)-*Z )-6-?(.+' V.(J 4*'1;*1- <*,,.'1*'9 <+'.(+).'1

• =(.<;4*(.+' 9;).'1 )-6-?(.+'?*;6-9 4*'1;*1- 9-C.?.(6– gJ.(- <*((-) @-(V--' *'(-).+)

.'6;4* *'9 ,*)6 +)@.(*4.6 [*'(-).+)– :-6(.'1 9;).'1 )-6-?(.+'– :-6(.'1 V.(J -4-?().?*4 6(.<;4*(.+'

.'6;4* *'9 ,*)6 +)@.(*4.6 [*'(-).+)<*)1.'\

– M.@-)6 C)+< /-'()*4 ,)-<+(+)?+)(-U [,+6(-).+) <*)1.'\

– B'(-).+) ,*)( +C *)?;*(- C*6?.?;4;6[9-,(J\

– E-*9 +C ?*;9*(- ';?4-;6• N+6(+,-)*(./-47 ()*'6.-'( 4*'1;*1-

V+)6-'.'1 @;( '+ ,-)<*'-'(9-C.?.(6

E*14;'9 00 -( *4D K-;)+6;)1A !hh#i^#2_]f _f]D 8-'Q*1<+;( 0 -( *4D K-;)+6;)1A $%%fi]!2f#! f_^D

No errors in 6 stim trials

Pre-resection

N*(.-'( $2 !_ 7-*) +49 <*4- V.(J 1*'14.+14.+<* *'9 -,.4-,67)-C)*?(+)7 (+ <-9.?*(.+'6i ;'9-)1+.'1 (;<+) )-6-?(./- 6;)1-)7D

Hesitations w/ resection

Post-resection

=4.9- ?+;)(-67 =*'9)* =-)*C.'.A NJD>D

I-'()*4 =;4?;6"0+(+) I+)(-UO+?*4.Q*(.+'

• 3*(.+'*4-– O+?*(.+' +C ?-'()*4 6;4?;6 '+( /.6;*447 +@/.+;6A-6,-?.*447 .' ?*6-6 +C (;<+)6

– 3-6-?(.+' .' X-4+T;-'(Y *)-* <*7 @- ,+66.@4-– &9-'(.C.-6 ?4.'.?*4 C;'?(.+' +C '-;)*4 (.66;-

• I*;(.+'6– 0*,,.'1 <*7 )-6;4( .' 6-.Q;)-6– &'S;)7 (+ VJ.(- <*((-) C.@-) ()*?(6 ?*' ?*;6-?+<,4.?*(.+'6

0-9.*' =5N :-?J'.T;-

• =(.<;4*(.+' +C <-9.*' '-)/-• 3-?+)9.'1 C)+< -U,+6-9 ?+)(-U V.(J 6().,"1).9-4-?()+9-

• X3-C-)-'(.*4 )-?+)9.'1Y V.(J 9.6(*'( )-C-)-'?-3-C-)-'(.*4 )-?+)9.'1 V.(J 9.6(*'( )-C-)-'?-• O*)1-6( *<,4.(;9- K$% +/-) 6+<*(+6-'6+)7 ?+)(-U• B'(-).+) ,+6(-).+) ,J*6- )-/-)6*4 <*)F6 ?-'()*46;4?;6

• 54-?()+9- ,+6.(.+' <;6( @- <+/-9 (+ ?J-?F C+)/*).*(.+'6A -6,-?.*447 VJ-' 4-6.+'6 ,)-6-'(

N*(.-'( $2 _ 7-*) +49 <*4- V.(J (;@-)+;6 6?4-)+6.6 *'9 <;4(.,4-?+)(.?*4 (;@-)6 V.(J <-9.?*447 )-C)*?(+)7 -,.4-,67 Z ;'9-)1+.'16;)1-)7 (+ )-6-?( 4-C( ,*).-(*4 4-6.+'D

N*(.-'( $2 _ 7-*) +49 <*4- V.(J (;@-)+;6 6?4-)+6.6 *'9 <;4(.,4-?+)(.?*4 (;@-)6 V.(J <-9.?*447 )-C)*?(+)7 -,.4-,67 Z ;'9-)1+.'16;)1-)7 (+ )-6-?( 4-C( ,*).-(*4 4-6.+'D

=;,-).+)

N+6(-).+)

$

#

^

:;@-)

_

]

!!"!#"$%!$

#

N*(.-'( $2I-'()*4 =;4?;6 O+?*4.Q*(.+' Z :.@.*4 KD 54-?().?*4 =(.<;4*(.+' :-?J'.T;-

• I+)(.?*4 *)-*6 6(.<;4*(-9 V.(J @.,+4*) ?+'6(*'(?;))-'( 6(.<;4*(+) [N-'C.-49 (-?J'.T;-\

• 5I+W +@(*.'-9 V.(J 6()., -4-?()+9-[6\• R@6-)/*(.+' +C C*?-"4.<@6R@6-)/*(.+' +C C*?-"4.<@6• 50W <+'.(+).'1 +C C*?-"4.<@6• BC(-) 9.6?J*)1-6 <+'.(+)-9• I4.'.?*4 6-.Q;)-6 ?+<<+'

B3= b;-6(.+'

& ;6- -4-?().?*4 6(.<;4*(.+' [N-'C.-49 <-(J+9\ C+)<+(+) ?+)(-U 4+?*4.Q*(.+' 9;).'1 (;<+) 6;)1-)7C+) -,.4-,67D

BD :);-8D M*46-ID G'?-)(*.'

50W 3-?+)9.'1

• 50W )-?+)9.'1 C)+< C*?-A4.<@6 .'?)-*6-9 6-'6.(./.(7+C <+(+) <*,,.'1

• $#j +C ,*(.-'(6 J*94. . 4 @ 4. . 4?4.'.?*4 +) 6;@?4.'.?*46-.Q;)-6 9;).'1 <*,,.'1

d.'14.'1 I> -( *4D P K-;)+6;)1D !hhhih!2h$$ h$fD

• 0*,,.'1 <-(J+9 4-664.F-47 (+ ,)+9;?- 6-.Q;)-6'--9-9

>.)-?( I+)(.?*4 =(.<;4*(.+' :-?J'.T;-

• =(.<;4*(.+' [*'+9-\ V.(J 6()., -4-?()+9- ,4*?-9+' ?+)(-Ui 6*<- -4-?()+9- ;6-9 C+) <-9.*' =5N

• I*(J+9- ,4*?-9 9.6(*447• 0+'+,+4*) 6(.<;4*(+) ?*' @- ;6-9,• =(*'9*)9 6(.<;4*(+) V.(J %D_ <6 ,;46- V.9(J• _ ,;46- ()*.'A $D! # <6 &=&• =(.<;4*(.+' .'(-'6.(7 ;, (+ $% <B"]% H

– =+<- )-,+)( .'(-'6.(.-6 ;, (+ $_ <B"!!% Hk• 50W )-?+)9.'1 -4-?()+9-6 .' C*?-A 4.<@6

kI-9Q.?J I -( *4D K-;)+6;)1A !hh]i^l2h]$ hf%D

>.)-?( I+)(.?*4 =(.<;4*(.+'&$..)"*

• K+')-?;))-'( ,;46- ()*.'6 ;6-9• =;@9;)*4 6()., ,4*?-9

,-),-'9.?;4*) (+ ?-'()*4 6;4?;6• H*).+;6 ?+'(*?(6 +' 6;@9;)*4 6().,

&/")(/0)"*• =()., -4-?()+9- )+(*(-9 (+ 4.-

,*)*44-4 (+ ?-'()*4 6;4?;6• O+V-6( 6(.<;4;6 .'(-'6.(7 (J*(

-/+F-605N ;6-905N 9 9 C ( . ( 96-T;-'(.*447 6(.<;4*(-9

• E*'9 J-49 @.,+4*) +) <+'+,+4*)6(.<;4*(+) ?*' @- ;6-9

• =.(- +C 4+V-6( .'(-'6.(7 6(.<;4;6-/+F.'1 05N )-6,+'6- .6 +/-)<+(+) ?+)(-U

• 05N )-?+)9-9 C)+< )-6().?(-91)+;, +C <;6?4-6

• 0;4(.,4-6 6.(-6 <*7 '--9 (+ @-6(.<;4*(-9 (+ -/+F- J*'9"4-1)-6,+'6-6

• E*'9 *'9 C++( 6.(-6 6(.<;4*(-9 V.(J<+'+,+4*) +) @.,+4*) 9-)./*(.+'

• 3-,-*(-9 (J)+;1J+;( 6;)1-)7

I-9Q.?J I -( *4D K-;)+6;)1A !hh]i^l2h]$ hf%D d.'14.'1 I>D G= K-;)+4+17A $%!!if2]# ]fD

!!"!#"$%!$

_

N*(.-'( $2 _ 7-*) +49 <*4- V.(J (;@-)+;6 6?4-)+6.6 *'9 <;4(.,4- ?+)(.?*4(;@-)6 V.(J <-9.?*447 )-C)*?(+)7 -,.4-,67 Z ;'9-)1+.'1 6;)1-)7 (+)-6-?( 4-C( ,*).-(*4 4-6.+'D

R HAND R ARM R Delt-R Delt' RMG R ANT TIB R FOOT=;,-).+)

N+6(-).+)

l H

!% H

54-?().?*4 /6D >.)-?( I+)(.?*4=(.<;4*(.+'

1%'2(0)2$% 3()4#%$()/"• &'?.9-'?- +C 6-.Q;)-62 hD_j• 0+/-<-'( V.(J 6(.<;4*(.+'• B?(./*(-6 ?+)(.?*4 '-;)+'6

5)0'2( 6/0()2$% 3()4#%$()/"• &'?.9-'?- +C 6-.Q;)-62 !D$j• K+ <+/-<-'( V.(J

6(.<;4*(.+'

• I*''+( @- 9+'- ?+'(.';+;6479;).'1 6;)1-)7

• K+"4.1J( *'-6(J-6.*• E.1J-) (+(*4 ?J*)1- 9-4./-)7• M>B *,,)+/-9

• B?(./*(-6 ?+)(.?*4 '-;)+'6• :+ @- ;6-9 ?+'(.';+;647

9;).'1 6;)1-)7• W-'-)*4 *'-6(J-6.*• 0;?J 4+V-) ?J*)1- 9-'6.(7• K+( M>B *,,)+/-9 [7-(\

=Q-4-'7. B -( *4D P I4.' K-;)+,J76.+4A $%%fi$#2^h #^

=;@?+)(.?*4 0*,,.'1 V.(J&'()*+,-)*(./- &<*1.'1

• #$ ,*(.-'(6 V.(J ?+)(.?+6,.'*4 ()*?( ()*?(+1)*,J7 ?+)-1.6(-)-9 (+ 6;)1.?*4 '*/.1*(.+' 9-)./-9 .<*1-6

• >.)-?( 6;@?+)(.?*4 6(.<;4*(.+' V.(J <+'+,+4*)6(.<;4*(+)A %D! $_ <B .'(-'6.(7i )-?+)9.'1 C)+<<;6?4-6

• &'()*+,-)*(./- ;4()*6+;'9 9;).'1 6(.<;4*(.+'i?+<,*)-9 (+ ()*?(+1)*,J7 @*6-9 '-;)+'*/.1*(.+'

• =(.<;4*(.+' (J)-6J+496 ?+<,*)-9 (+ 9.6(*'?- (+?+)(.?+6,.'*4 ()*?(6K+66-F 5 -( *4D P K-;)+6;)1A $%!!i!!#2f^l f#]D

=;@?+)(.?*4 0*,,.'1 :)*?(+1)*,J7

• =(.<;4*(.+' (J)-6J+49 .'?)-*6-6 *,,)+U.<*(-47 ! <B"<< +C9.6(*'?- C)+< I=:

• =;@?+)(.?*4 05N (J)-6J+49 +C ^ <B .6 ?;(+CC C+) '-V I=: 9-C.?.(6K+66-F 5 -( *4D P K-;)+6;)1A $%!!i!!#2f^l f#]D

B3= b;-6(.+'

0+(+) ?+)(-U <*,,.'1 *'9 <+'.(+).'1 )-9;?-6<+)@.9.(7D

BD :);-8D M*46-ID G'?-)(*.'

3-/.-V +C 0+(+) 0*,,.'1"0+'.(+).'1

0*,,.'1• f% ,*(.-'(6 V.(J @)*.' (;<+)6

;'9-)V-'( <+(+) <*,,.'1 V.(J =5N*'9 <+(+) ?+)(-U 6(.<;4*(.+'

• O+?*4.Q*(.+' +C ?-'()*4 6;4?;6 V.(J =5N.' !%%j

0+'.(+).'1

Ka$_ K+ '-V9-C.?.( [j\

:-<,+)*)7'-V 9-C.?.(

[j\

N-)<*'-'('-V 9-C.?.(

[j\

K+ ?J*'1-6['a!%\ h [h%\ ! [!%\

j• >I= -4.?.(-9 05N .' h_Dfj• >I= 6(.<;4*(.+' .'(-'6.(7 ]D! !!D_ <B

.' ,)-?-'()*4 17);6A ]D$ $_ <B .'+(J-) *)-*6

• K+ ?+<,4.?*(.+'6 +@6-)/-9

:-<,+)*)705N 4+66['ah\

! [!$\ # [##\ # [##\

N-)<*'-'(05N 4+66['a_m!\

% % _ [!%%\

• 05N *<,4.(;9-6 /*)7 V.9-47• O*?F +C ?+<,*)*@4- 6-).-6 Z ;'?-)(*.'

.C <+'.(+).'1 )-9;?-6 <+)@.9.(7

n+<@+6 :J -( *4D B?(* K-;)+?J.)A $%%%i!#$2$]^ $]lD I-9Q.?J I -( *4D K-;)+6;)1A !hh]i^l2h]$ hf%D

!!"!#"$%!$

]

I+'?4;6.+'6

• >.6().@;(.+' +C 4*'1;*1- 6.(-6 /*).*@4- Z <*,,.'1.<,+)(*'( (+ */+.9 9*<*1-

• 0+(+) ?+)(-U 4+?*4.Q*(.+'"<*,,.'1 9+'- V.(J <*'79.CC-)-'( (-?J'.T;-6

• K-V<*,,.'1 (-?J'.T;-6 J*/- *9/*'(*1-6 +/-)+49-) <-(J+96

• 0+(+) <+'.(+).'1 9;).'1 (;<+) 9.66-?(.+' <*7,)-/-'( .'S;)7 (+ I=:

• G(.4.(7 +C <+(+) <*,,.'1 .' )-9;?.'1 <+)@.9.(7;'?-)(*.'

!!"!#"$%!$

!

!"#$%"&' (%$)*%+ *, ) -)$#./)/*0)&%+ 123,4

&'(')*'+ $, $%!$5#$$#)3 67 1)*23 89: ;6: <==>: <=?>

-+'./0'12 '3'(2 4)'+/(51 675+0 78 93/1/(53:';+7<=>./737?>:';+7<=>./737?>

-+78'..7+ 78 :';+737?>@5>7 9733'?' 78 @'0/(/1'

A'1/7+ 971.;32512, @5>7 93/1/( 510 B7.</253&/+'(27+, C</3'<.> @71/27+/1? D1/2

E5(F.71G/33', H37+/05 DA4

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/.

;#&@$,&24%

:5)' 78 97))'+(/53J12'+'.2

:71'

K><' 78 H/151(/53L'352/71.=/<

:71'

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/. ABCA !

D%)4/#/. 6EF%@*#G%&

• K7 <+'.'12 5 +'<+'.'1252/G' (5.' 78 '</3'<.>0;' 27 5 )53/?1512 *+5/1 2;)7+M

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/. ABCA $

?)&% H4%&%/*)*#,/

• LN /. 5 OP >'5+ 730 LBN@ Q5. +'8'++'0 *> 1';+771(737?> #"$%!% 87+ ;1(712+733'0 .'/R;+'.M

•-5.2 =/.27+> /1(3;0'0 =><'+2'1./71, 94& A"- @J A"-.2'12/1? S T, =><'+3/</0')/5, U '+'(2/3' 0>.8;1(2/71M.2'12/1? S T, =><'+3/</0')/5, U '+'(2/3' 0>.8;1(2/71M•:';+737?/(53 'S5)/152/71 17+)53 O"$%!%M

•J1 V"$%%V 582'+ /12'+)/22'12 (='.2 <5/1, 52 $ 5) ='Q5. 87;10 07Q1"(718;.'0 Q/2= 5 271?;' */2'M•J1 2=' C&W 9-X Q5. '3'G52'0 Y0/5?17.'0 Q/2= @JZ510 9K *+5/1 +'G'53'0 5 3'82 8+71253 [.2+7F'\M

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/. ABCA T

-)$#./)/* 04)#/ 123,4

• 6+5/1 @LJ 352'+ .;??'.2'0 3'82 8+71253 2;)7+M• -HBSW ;1+')5+F5*3' 87+ *+5/1 2;)7+. *;2)7) 0/0 =5G' 3';F')/5 510 0/'0 52 V$ >'5+.M

03 / */ "$%% Y / / Z• :''03' 6+5/1 */7<.> !!"$%%V YD1/G'+./2>Z]– !O )/1;2' ?'1'+53/R'0 .'/R;+' <7.2 7<'+52/G'3>M– B/.2737?>]

• ^3/?75.2+7(>27)5 YNB^ ?+50' $Z• HJAB 2'.2/1? <7./2/G' 87+ !-T_ 510 !à!T 0'3'2/71Y85G7+5*3'ZM

#

I7J @3K

L M @3L7M @3K

N7L @3

O

!!"!#"$%!$

$

O#&*,")*P,$,.'6$#.,+%/+4,.$#,3)6$#.,+%/+4,.$#,3)(%*#@2$)4 G)&@2$)4 ")**%4/(%*#@2$)4 G)&@2$)4 ")**%4/

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/. ABCA

-#@4,@'&*& Q#*P 3'R,#+-#@4,@'&*& Q#*P 3'R,#+ $#S% 3)*%4#)$$#S% 3)*%4#)$ T%3#&*,@'*#@ )&*4,@'*%&T%3#&*,@'*#@ )&*4,@'*%&

97;+2'.> &'11/. &/(F.71 @&

_

<,@)$ U%#V24%&

•A')/737?>W•[H5(/53 .'/R;+'.\ Y'G'+> 72='+ 05>ZW

•4;+5W A;*b'(2/G' .'1.' 2=52 '>'. 5+' 0'G/52/1? 27 2=' +/?=2 <+/7+ 2751 /10'.(+/*5*3' 8''3/1? S !O T% .'(710.M•H7(53 .'/R;+' Q/2= 0>.(7?1/2/G' 8'52;+'. 510 +/?=2 85('"b5Q (371/(•H7(53 .'/R;+' Q/2= 0>.(7?1/2/G' 8'52;+'. 510 +/?=2 85('"b5Q (371/(b'+F/1? c $ T )/1;2'. 87337Q'0 *> 'S<+'../G' 0/88/(;32/'. !O $O )/1M

•[H;33 *37Q1 .'/R;+'.\ Y$ 713> 52 71.'2 510 582'+ .;+?'+>ZW•! Q/21'..'0 /1 =7.</253W A<''(= 5++'.2, 37.. 78 (71.(/7;.1'..,*/352'+53 .>))'2+/(53 b'+F/1? S !O )/1;2'. Q/2= ?+50;53 +'(7G'+>M

•H+'d;'1(>W 'G'+> 72='+ 05>• 97;+.'W &+;? +'./.2512] <+7?+'../G'

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/. ABCA V

U%#V24% U%3#,$,.'

9#+%,

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/. ABCA

9#+%,

P

14%)*3%/*•A'/R;+' K+'52)'12

•-5.2 4C&.W -BK Y852/?;'Z, e-4 Y[./(F\, 15;.'5, 0/RR>,.3''<>, 2+')7+Z, -L@ Y.3''<>Z, fCe Y/1'88'(2/G'Z, ^c9Y/1'88'(2/G'Z, f9A Y/1'88'(2/G'ZM9 0/ / $ % /0 ^c9 _%%•9;++'12 @'0/(/1'.W -L@ $O% )? <7 2/0, ^c9 _%% )? <72/0] &g- $MO )? <7 d/0 hK7<+73 CL O% )? <7 d0] 4A4 P!)? <7 d0] f/</27+ #% )? <7 d0iM

•6+5/1 K;)7+ K+'52)'12•K')7R737)/0' S $% )712=. Y_"$%%`Z•B/?= 07.' cLK 27 _% j>

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/. ABCA `

?$#/#@)$ ?,24&%•@53/?1512 6+5/1 K;)7+ Y;1+'.<71./G' 272='+5<>ZM•9712/1;'0 87(53 .'/R;+'. 0'.</2' 4C&.M•H7337Q'0 37(533> 87+ 71?7/1? (5+'M

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/. ABCA !%

?)&% ?,/@$2&#,/

•&+;? +'./.2512 87(53 .'/R;+'.M•-533/52/G' +'.'(2/G' .;+?'+> Q5. 0/.(;..'0M•:';+7.2/);352/71 Q5. +'(7))'10'0 *;2•:';+7.2/);352/71 Q5. +'(7))'10'0 *;20'(3/1'0M•K;)7+ Q/2=7;2 +'.<71.' 27 2+'52)'12M

4)'+/(51 C</3'<.> A7(/'2> I =//2)$ -%%*#/. ABCA !!

!!"!#"$%!$

T

83")@* ,/ ?$#/#@)$ ?)4% )/+ H4)@*#@%

•6+5/1 2;)7+ <52/'12. Q/2= '</3'<.>5+' )7.2 (71('+1'0 Q/2= a7fM•A'/R;+'. 588'(2 51 /10/G/0;53k.A'/R;+'. 588'(2 51 /10/G/0;53 .2=+'.=730 87+ +'352/G' 0/.5*/3/2>M•A/0' '88'(2. )5> *' )7+' 0/.5*3/1?2=51 .'/R;+'.M

!$©2011 MFMER | slide-14

[email protected]

!!"!#"$%!$

!

&'()*+,-./-,01.203'(.4*56.,7.859+*:;'<30.=),(3)<>.053.?+./7?,73+)('<?,-.

@*+)3*?,3<

AB'*(3<.CD.&3-B?

E30,-'(.A37?3*.8B3.F'653.G=2H.=),(3)<>.I+570'?,+7J.8B3.H3?B3*('70<

AFK.@,?,L:G'()M?*,N*3J.@'*,<J.I*'7-3

4,<-(+<5*3.+O.A+7O(,-?<.+O.27?3*3<?

AB'*(3<.&[email protected]'<.*3-3,P30.-+7<5(?'7->.O33< O*+9 KAQ @B'*9'R S3<3'*-B 6*'7?< O*+9O33<.O*+9.KAQ.@B'*9'R.S3<3'*-B.6*'7?<.O*+9.KAQ.@B'*9'J.=,<',J.'70.T('U+G9,?BV(,73R.'70.

O570,76.O+*.?*'P3(.O*+9.KAQ.@B'*9'D

TDFD.Q*3,?73*J.!WXYTDFD.Q*3,?73*J.!WXYDam SquareDam Square

ZB,-B./=4<.?+.5<3.,7.?B3.A(,7,-'(.@*'-?,-3.

+O.H35*+:+7-+(+6>.[

AB+,-3.+O./=4<.O+*.@'*?,'(.=),(3)<>.,7./05(?<

\ 4,OO3*37?.O+*.Q*',7.859+5*<.[\ =U)3*?.]),7,+7.;>.V'*-3<^,.3?.'(.$%%_.1

\ `/E]8S2T2H=.. ab"b+.-+:9+*;,0,?>c\ A/SQ/E/d=@2H=.. a?B+56B.7+?.,7.;*',7.?59+5*<c\ `=&=82S/A=8/E. ab,?B.-+:9+*;,0,?>c.

E'*<+7.$%%%R.@*,P3?3*'.$%%eR.T'9;(3.$%%f.E'*<+7.$%%%R.@*,P3?3*'.$%%eR.T'9;(3.$%%f.A('<<.!.=P,037-3A('<<.!.=P,037-3

S3-+99370'?,+7<.,7.Q*',7.859+*<

\ 8+./P+,0.=7g>93:2705-,76./=4<.,D3D.@B37>?+,7J.A'*;'9'g3),73J.@B37+;'*;,?'(

\ 27.73b(>.0,'67+<30.Q*',7.859+*<J.H+.@*+)B>('U,<.b,?B./=4<

\ 27.73b(>.0,'67+<30.Q*',7.859+*<.b,?B+5?.GgJ.8')3*"4,<-+7?,753./=4<.'O?3*.!<?..@+<?:+)3*'?,P3.Z33^

//H//H1.T('7?g.$%%%J.Q*+0,3.$%!$.T('7?g.$%%%J.Q*+0,3.$%!$.

!!"!#"$%!$

$

E'*<+7J.$%%$E'*<+7J.$%%$

V')('7hE3,3*.-5*P3<.O+*.?,93.?+.!<?.G3,g5*3.O+*.`=&.P<.<?'70'*0./=4<R.`=&.P<.&@/:=S.'70.`=&.P<.AQd:AS

8*,7^'.=.3?.'(D.$%!!8*,7^'.=.3?.'(D.$%!!

i.G3,g5*3<4,<-+7?j0

!X"$Y..aY%D#.icY"$Y..a$f....ic

!W"e_.a_!.ic!$"e_.ae#..ic

!_"e#..a##.icY"e#..a$%.ic

A'*;'9'g3),73 @B37>?+,7 &'()*+'?3

K<3.+O./=4G.,7.T(,+9'.@'?,37?<

F,(03;*'70.$%%_J.Z,-^.$%%_J.k+5.$%!$F,(03;*'70.$%%_J.Z,-^.$%%_J.k+5.$%!$

G5*P,P'(.b"+.=7g>93:2705-,76.,7.TQE.'70./0l5P'7?.AAHK

/....am.WWcH+.G3,g5*3<

Q.am.#ecG3,g5*3<

A.am.eYcG3,g5*3<

/0l5P'7?.AAHK.

=2:/=4< H+7.=2:/=4<

a`+95<?,73cAQd..aW!.ic

&@/a.W_.ic

G5*P,P'(a,7.9+7?B<c

!!Df !%DW !eDXn)..%D%!f

];3*70+*O3*J.$%%_];3*70+*O3*J.$%%_

A+9)*+9,<30./-?,P,?>.+O.A84.A+9)*+9,<30./-?,P,?>.+O.A84.;>.A+;>.A+::/09,7,<?*'?,+7.+O./=4</09,7,<?*'?,+7.+O./=4<A>-(+)B+<)B'9,03 @Q2O+<O'9,03 @Q8B,+?3)' @QQ5<5(O'7 @F8H,?*+<+5*3'< @QE3?B+?*3U'?3 @F8J.AQdJ.@Q

T*+<<9'7.!XXW.T*+<<9'7.!XXW.S3((,76.$%%%S3((,76.$%%%&3-B?.$%%_&3-B?.$%%_

&,7-*,<?,73 @F8J.AQdJ.@Q@'-(,?'U3( @F8J.AQdJ.@Q8+)+?3-'7 @F82*,7+?3-'7 @F8/9,7+-'9)?B+?3-,7 @F8J.AQdJ.@Q837,)+<,03 @F8J.AQdJ.@Q4+U+*5;,-,7 @Q@*+-'*;'g,73 @Q8'9+U,O37 @Q

!!"!#"$%!$

e

&'()*+,-./-,0.o.F,<?+73.43'-3?>('<3.27B,;,?+*.aF4/Ac

G-B39'?,-.,((5<?*'?,+7.+O.F4/A2.93-B'7,<9.+O.'-?,+7D.GB+b7.,<.'<-B39'?,-.,((5<?*'?,+7.+O.93-B'7,<9<.;>.bB,-B.B,<?+73.03'-3?>('<3,7B,;,?+*<.aF4/A2cJ.B,<?+73.03'-3?>('<3<.aF4/Ac.'70.B,<?+73.'-3?>(?*'7<O3*'<3<aF/8c.9+05('?3.6373.3U)*3<<,+7D.F/8<.-'?'(>g3.?B3.'00,?,+7.+O'-3?>(.6*+5)<.?+.(><,73.*3<,053<.+O.B,<?+73.?',(<J.-+7?*,;5?,76.?+.'7.+)37'70.'--3<<,;(3.-B*+9'?,7.<?*5-?5*3D.F4/A<.*39+P3.?B3<3.6*+5)<J.*3<5(?,76,7.'.-(+<30.<?*5-?5*3J.'70.F4/A2<.*3P3*<3.?B,<.3OO3-?

&'()*+'?3

I*33.I'??>./-,0

Q*+'0.G)3-?*59./7?,-+7P5(<'7?F,<?+73:03'-?>('<3.27B,;,?+*

V')('7:E3,3*.A5*P3.+O.TQE.@'?,37?<..a7.o.$X!cb,?B.AB39+*'0,'?,+7.;>.8Ed.b,?B.'70.b,?B+5?.&@/.

43.Z,?.43.Z,?.:: V3*^B+OJ..$%!$V3*^B+OJ..$%!$

E30,'7.G5*P,P'(.fX.b^<.pX_i.A21f!DYRfYDeq.P<Df!.b^<.pX_i.A2._$D_RfXD_qR.).D%!fDaFS.%Dfe.pX_i.%D#e:%DX$q

27,?,'(.&@/.......!%%.".!#_27,?,'(.`=&.........eY."..!%%&@/.'70.`=&.!!f

#!.".!%%..a.#!D%.i.c!f."...eY..a.#eDe.i.cWX.".!!f..a.YfDY.i.c

Initial Therapy Seizure-Freedom

G3,g5*3.A+7?*+(.,7.@'?,37?<.b,?B.TQE.a7.o.$X!c

Final Treatment Seizure-Freedom

&@/.E+7+?B3*')>`=&.E+7+?B3*')>&@/.'70.`=&.@+(>?B3*D.

$W.".ef......a.YYDW.i.c$_.".ef......a.fXD_.iceW.".fe......a.f%De.i.c

43.Z,?.43.Z,?.:: V3*^B+OJ..$%!$V3*^B+OJ..$%!$

!!"!#"$%!$

#

&/`@S]2A./A24&/`@S]2A./A24

\ Q*+'0.G)3-?*59./=4\ `+763*.G5*P,P'(.b,?B.&@/.P<D.AQd\ F,<?+73:43'-3?>('<3.27B,;,?+*

/0P'7?'63<

4,<'0P'7?'63<

\ =7g>93:27B,;,?+*\ 8B*+9;+)37,'

];3*70+*O3*.%_R.=>'(.];3*70+*O3*.%_R.=>'(.%fR%fR A('<<.e.=P,037-3A('<<.e.=P,037-3

Q+73:9'**+b.8+U,-,?>.+O......AB39+?B3*')>.b,?B.&'()*+,-.'-,0

\ G3*,3<.+O.Y%.@'?,37?<.b,?B.F,6B:T*'03.T(,+9'

\ I+?+95<?,73 a0e1....!%%.96"9$c

\ A,<)('?,7 a0!:e1 ee 96"9$cA,<)('?,7 a0! e1...ee.96"9$c

\ =?+)+<,03. a0!:e1...Y_.96"9$c

27.@'?,37?<.+7.&'()*+,-./-,01.e.U.9+*3.O*3r537?1.T*'03.e:#.8B*+9;+)37,'.s.H35?*+)37,'

Bourg, Lebrun, FrenayBourg, Lebrun, Frenay 20012001

F'39+<?'?,-.S,<^<.b,?B.&'()*+,-./-,0

H.o.WY.

@*3+)D.8B*+9;+->?3<.abJ.b"+.&@/c........$e_.vsD.$YY" `

NoNo 4,OO3*37-3<.O+*........... @+<?+)D.Q(++0.`+<<SQA &+(593SQA.&+(593m.@+<?+)D.8*'7<O5<,+7<

H.o.!!!.b,?B.&@/J.$%$.b"+.&@/8B*+9;+->?3<...$W#.vsD.$YX" `

NoNo 4,OO3*37-3<.O+*........... @+<?+)D.Q(++0.`+<<@+<?+)D.Z+570.4,<-B'*63

/703*<+7.!XXYJ..Z'*0.$%%#/703*<+7.!XXYJ..Z'*0.$%%# TDFD.Q*3,?73*J.!WX%TDFD.Q*3,?73*J.!WX%Rokin in Amsterdam

H+.F3)'?,-.E3?';+(,<9.'70.H+.27?3*'-?,+7<

\ T';')37?,7

\ `3P3?,*'-3?'9

\ &,6';'?*,7

\ @*36';'(,73

\ `'-+<'9,03

`3P3?,*'-3?'9.E+7+?B3*')>.,7.Q*',7.859+*<

\ t._%.i.G3,g5*3.*3<)+7<31. X$.: X_.i

\ G3,g5*3:I*330+91. fe.: Xe.i

Z'673*J.$%%eR.@'*?').$%%WJ.E'<-B,+.$%!%J.K<3*>.$%!%Z'673*J.$%%eR.@'*?').$%%WJ.E'<-B,+.$%!%J.K<3*>.$%!%

!!"!#"$%!$

_

AB+,-3.+O./=4<.O+*.@'*?,'(.=),(3)<>.b"b+.G3-D.T373*'(,<'?,+7.,7.Q*',7.859+*<

\ &/`@S]2A./A24n

\ `/E]8S2T2H=

8]@2S/E/8=\ 8]@2S/E/8=

\ `=&=82S/A=8/En a7+?.*36,<?3*30.'<..9+7+?B3*')>.;>.I4/.,7.KGc

E'*<+7.$%%%R.@*,P3?3*'.$%%eR.T'9;(3.$%%fE'*<+7.$%%%R.@*,P3?3*'.$%%eR.T'9;(3.$%%fR.Q*+0,3.$%%YR.Q*+0,3.$%%YA('<<.!J.$..=P,037-3A('<<.!J.$..=P,037-3

S3-+99370'?,+7<1.E30,-'(.8B3*')>

\ /P+,0.=7g>93:,705-,76./=4<

\ &'()*+,-./-,0nn.\ `3P3?,*'-3?'9n

\ &'()*+,-./-,0.b,?B.`3P3?,*'-3?'9n

\ `'9+?*,6,73..\ 8+),*'9'?3.

nn Survival Advantage May Justify Side-effects

Z'673*.$%%eR.V'*-3<^,.$%%_J.Z3((3*.$%!!J.Z'673*.$%%eR.V'*-3<^,.$%%_J.Z3((3*.$%!!J.43.Z,?.43.Z,?.:: V3*^B+OJ..$%!$V3*^B+OJ..$%!$

A('<<.$.@S=I=S=HA=A('<<.$.@S=I=S=HA=

\ &'()*+,-./-,0...... a!%%%.: e%%%.96c

\ `3P3?,*'-3?'9 a!%%% #%%% 96c\ `3P3?,*'-3?'9..... a!%%%.: #%%%.96c

\ A+9;,7'?,+7..h&'()*+,-./-,0.... a!%%%..: !_%%.96ch`3P3?,*'-3?'9...a!%%%..: $%%%.96c

Bois de Boulogne, Paris 22<''-.2<*'3(<J.!X%f

A+7-(5<,+7<\ Q3??3*.?+./P+,0.=7g>9,76:2705-,76./=4<.

\ F4/A2./-?,P,?>.+O.&'()*+,-./-,0.b+*^<.<>73*6,<?,-'((>.b,?B.AB39+?B3*')35?,-./637?<

\ 270,-'?,+7<.?B'?.&'()*+,-./-,0.b,?B.839+g+(+9,03.)*+(+76< <5*P,P'( 27 T(,+;('<?+9')*+(+76<..<5*P,P'(.27..T(,+;('<?+9'.

\ I,*<?:(,73./=4<.,7.Q*',7.859+*<1.&'()*+,-./-,0..+*..`3P3?,*'-3?'9

2O.G3,g5*3<.-+7?,7531.&@/.'70.`=&.,7.-+9;,7'?,+7

V'*,7.Q+5?*5<.F'773^3.db,7^3(<.E3(,<<'.03.Z,?:V3*^B+O.C'773^3.4,3(39'7<.E3('7,3.P'7.Q*33937`+5,< Z'673*`+5,<.Z'673*`>77.S,l<9'7E'*?,7.8')B++*7.=*,^.Z,(9<AB'*(3<.&3-B?

!!"!#"$%!$

!

!"#$%&"'( )&*+,&&% )-&./( &0 1%23 45( 62( '&

768(%5( 900(/'5 :;(%"'&3(*./ ,&'(*'."#&'(')*'+ $, $%!$,

Kimford Meador, MDProfessor of Neurology & PediatricsEmory UniversityAtlanta, Georgia

-)'+.(/0 12.3'245 67(.'85 9 7**2"# <(('.*3

1.5/#&52%(5=%"*'5+ :6;, 1.4/., </+.0=4, <5+./>, ?'=+72/(', @A.B'+, 6-< C'(D, 6(DE/+8B

F.74(., G HIFJ>?@A>?>1B CDEF >BGHIJJK <("6&% L,?MK >(2%&6(8(#&$N(*'"# 900(/'5 &0

7*'.($.#($'./ 1%235O>?@A>?>1B F4PF >BPQQGRR PFK<("6&% L,?MK 9N&%S >9T; B.'(O

?KL !MI!<&%%#NOPJ CD7)2470 Q@KRJ @+'S'08.0T >'2+'44.70 .0 2'723' E.8D'2.3'245J

12.3'245 U7=0>/8.70 7A -)'+.(/J V7+.0T Q@KRJ <'8/*73.( /0> &C- /*07+)/3.8.'4.0 CV1 E.8D /0> E.8D7=8 (7 )7+*.> >'2+'44.70.0 CV1 E.8D /0> E.8D7=8 (7 )7+*.> >'2+'44.70J

)&*52#'"*' Q?78' 07 2'+470/3 .0(7)'R+ -**788, I5*'+70.(4, 1.4/., :6;,<'>8+70.(4, W+8D7 <(?'.3, 62D'+.(4, HIF, G

9$.#($5S )&*5&%'.2N L02*65 "%( $".6 '& 9N&%S 4MO A7+ ?'=+7@/(',?7S/+8.4, HIF @D/+)/, H24D'+ 6).8D G X.S=4J

;%"8(#+ B"*&0. 78(*'.5O

E'-(%+ )#.*./"# .*/&N(+ 99= $%&/(62%(5 "*6 $"'.(*' /"%(O

O?'(N5 U.'- "5'(%.5V .*8&#8( .*/&N( W XFPYPPP 0&% '-( #"5' S("%K7## .*625'%S %(#"'(6 .*/&N( 3&(5 '& '-( 2*.8(%5.'S &% /-"%.'.(5K

-)'+.(/0 12.3'245 67(.'85 9 7**2"# <(('.*3 CPFC

Z("%*.*3 E[\(/'.8(5

• C7 =0>'+48/0> 7=+ (=++'08 Y07E3'>T' 7A 8D'+'3/8.S' +.4Y4 7A S/32+7/8' A7+ (70T'0.8/3)/3A7+)/8.704 /0> 277+ 0'=+7>'S'372)'08/37=8(7)'4 >=' 87 A'8/3 'Z274=+'47=8(7)'4 >=' 87 A'8/3 'Z274=+'4J

• C7 +'S.'E 78D'+ 278'08./3 />S'+4' 'AA'(84 /48D'5 +'3/8' 87 78D'+ >+=T (D7.('4J

-)'+.(/0 12.3'245 67(.'85 9 7**2"# <(('.*3 CPFC

<('" "*"#S5.5+ ,%(3*"*/SE2'/&N(5 .* ]&N(* U.'- 9$.#($5S

;%("'N(*' <"#0&%N"'.&*5[ \]N[ IK^

_7)'0 E.8D7=8 '2.3'245 GKCQ \!JP`, NJ!`^

791 <&*&'-(%"$SI/+*/)/B'2.0' #JO$ \PJ#a, NJÒ^V/)78+.T.0' $J]! \$J%%, PJa$^@D'07*/+*.8/3 #J]! \PJ$$, OJN]^@D'0587.0 `JPO \PJO%, !!J!!^!"#$%&"'( FPKQG ^HKFRY FGKC_`

Meador KJ, et al. Epilepsy Research 2008;81(1):1-13.

94DE)7;1=+72'/0 6=+S'.33/0(' 7A I70T'0.8/3 -07)/3.'4

)"5( /&*'%&# 5'26S]a,%`N (/4'4 E.8D )/3A7+)/8.704/)70T PJa ).33.70 *.+8D4 .0 1=+72'

!] +'T.48+.'4 .0 !# (7=08+.'4 A+7) !]]N b $%%N

!"#$%&"'( E665 D"'.& L_Ja )?5MB$.*" [.0.6" FC Q LQ Q CP QMB$.*" [.0.6" FCKQ LQKQ b CPKQM7'%."# 5($'"# 6(0(/' CKJ LFKI b IKIM)#(0' $"#"'( JKC LCKH b _K_M@S$&5$"6.25 IKH LCK_ b HKFM,&#S6"/'S#S CKC LFKP b IKJM)%"*.&5S*&5'&5.5 RKH LFKH b FHKHM

)"%["N"c($.*(B$.*" [.0.6" CKR LFKC b JKGM

Jentnik et al, NEJM 2010;362:2185-93 & BMJ 2010;341:6582

94D7,+ 1&5( 1($(*6(*' 900(/'5 &* <)<57*'.($.#($'./ 1%23 > a B(.c2%( d%(( a<)<5)"%["N"c($.*(c#%% )T"> !#a O#[ GKIa#%% 87 c!%%% )T"> !%#` O`[ JKGa Od!%%% )T"> $%` O$[ HKQa OZ"N&'%.3.*(cP%% )T"> aPO O`[ CKPa

Tomson et al., Lancet Neurol 2011;10: 609-17O <&%( <)<5 '-"* Z;=eGPPN3A6

dP%% )T"> ### Oa[ IKJa O,-(*&["%[.'"#c!N% )T"> !OO `![ JKIa Od!N% )T"> N! O][ FGKQa O!"#$%&"'(c`%% )T"> #P! `![ JKRa O`%% 87 c!N%% )T"> #a% OO[ FPKIa Od!N%% )T"> ]] O![ CIKCa O

!!"!#"$%!$

$

<'/0 Ke4 Q]N[ IK4 >.AA'+'0(' A+7) X@-R />f=48'> A7+)/8'+0/3 Ke /T' -1& >74' T'48/8.70/3 /T' G A73/8'g

>971 B'26S

NEAD Age 3 Results:Valproate Group with Lower IQ

)/8'+0/3 Ke, /T', -1& >74', T'48/8.70/3 /T' G A73/8'g

)fg Z;= ,@; !,7

<("* ?h _H FPF __ _C&.AA'+'0(' IK4 Q%JOg!$J%R QPJ!g!#JOR Q%J$g!#J%R

h ID.3>+'0 `P a# #a NP

<("6&% (' "#K >9i< CPP_jGRP+FJ_Q RPJ

d17 ]"%*.*3 RAGPACPFFd('"# !"#$%&"'( 9k$&52%(

: )&3*.'.8( 1(0./.'5ID.3>+'0 *7+0 87 )78D'+4 ED7 8/Y' 8D'/08. 4'.B=+' )'>.(/8.70 S/32+7/8' i >=+.0T2+'T0/0(5 D/S' /0 .0(+'/4'> +.4Y 7A 37E'+(7T0.8.S' 8'48 4(7+'4 8D/0 (D.3>+'0 'Z274'> 8778D'+ /08. 4'.B=+' )'>.(/8.704JD882g""EEEJA>/JT7S"&+=T4"&+=T6/A'85"=()$O!

N#PJD8)

<'/0 Ke4 Q]N[ &.AA'+'0(' IK4 A+7) X@-R />f=48'> A7+)/8'+0/3 Ke, -1& >74', T'48/8.70/3 /T' G A73/8'g

)fg Z;= ,@; !,7<("* ?h FPJ O FPH O FPH O _Q

NEAD Age 6 Results: Valproate Group with Lower IQ

h

1.00(%(*/( H FF FF

1)?5 LG+FCM LR+FJM LJ+FRM

h ID.3>+'0 ]P !%% NO O$* Significantly better than VPA. P values: CBZ = .0015, LTG = .0003, PHT = .0006

CBZ LTG PHT VPA

IQ -.08 .19 -.11 .56*Verbal Index - 03 12 06 - 40*

1&5( 1($(*6(*' 900(/'5+,"%'."# )&%%(#"'.&*5

>971 B'26S

Verbal Index -.03 .12 .06 -.40Non-verbal Index -.17 .10 -.17 -.42*GMI -.06 .05 -.20 -.30*Nepsy Exec Index -.05 .03 -.10 -.42*BRIEF** -.20 .15 .31 .35*O B.3*.0./"*' /&%%(#"'.&*5j OOZ&U(% fD?9d 5/&%(5 [(''(%

E'-(% 768(%5( )&*/(%*50&% !"#$%&"'(

• _'.TD8 T/.0• L/.+ V744• @735(548.( WS/+./0 V.Y' 650>+7)'• &+=T K08'+/(8.704• I7T0.8.S' 6.>' 1AA'(84• @78'08./3 /=8.4) 7+ 78D'+ *'D/S.7+/32+7*3')4 A+7) A'8/3 'Z274=+'

E$'.&*5 0&% !"#$%&"'(

• :'0'+/3.B'> 12.3'245• -*7=8 !N[ E.33 +'4270> 7035 87 S/32+7/8'

(7)2/+'> 87 3/)78+.T.0' 7+ 872.+/)/8'Jj• ? D > 8 D > A 8D 8.• ?7 D'/> 87 D'/> A7+ 78D'+ 728.704

• <.T+/.0'• <=38.23' 78D'+ 728.704

• F.273/+ &.47+>'+ G W8D'+ @45(D &.47+>'+4• <=38.23' 78D'+ 728.704

O <"%5&* 7=Y (' "#K : B7>71 B'26S 3%&2$K Z"*/('K CPPQjGR_L_JRRM+FPFR CRK

!!"!#"$%!$

P

?N$"/' &* )#.*./"# )"%( "*6 ,%"/'./(

• !"#$%&"'( .5 " $&&% F5' /-&./( 6%23 0&%N&5' U&N(* &0 /-.#6[("%.*3 $&'(*'."#K

• 7$$%&$%."'( .*0&%N(6 /&*5(*' '& U&N(*5-&2#6 .*/#26( "* &2'#.*( &0 %.5V5 $%.&% '&$%(3*"*/SK

• ?0 8"#$%&"'( .5 (N$#&S(6Y 6&5( 5-&2#6 [(V($' "5 #&U "5 $&55.[#(K

!!"!#"$%!$

!

!"#$% %&'()&* +,-'&,./0 1'2$%-)34(4* )%&()#&4) ."##(%/

&'(')*'+ $, $%!$

-.+/' 0 12+3'., 4&, 45678 8 9 : : 9;<<.(=>?' 6+.8'<<.+ .8 @'2+.9./A >3: BC=:')=.9./A

D. &=+'(?.+, BC=9'C<A 6+./+>), E'<?'+3 F3=G'+<=?AH.3:.3, I3?>+=., D;@;&;

;)'+=(>3 BC=9'C<A 5.(='?A J 144"(' 5&&)-42

6-.7'$."%&

0+>3?<K I3?>+=. 1+>=3 L3<?=?2?', E'<?'+3 F3=G'+<=?A,H>M<.3 N'<'>+(O L3<?=?2?', FD1 D>3>:>

5C'>P'+K FD1 D>3>:>B:2(>?=.3>9 >(?=G=?='<K FD1 D>3>:>, BL5;L D>3>:>

D.3<29?>3?K FD1 D>3>:>, 05Q D>3>:>B:=?.+=>9 1.>+:K D>3 - @'2+.9 5(=, BC=9'C 1'O>G, D9=3

@'2+.9 @'2+.<2+/, N'G @'2+.C<=R

;)'+=(>3 BC=9'C<A 5.(='?A J 144"(' 5&&)-42 89:8

;&(%4-42 <=>&7)-?&.

• S. C+.G=:' > <2))>+A >3: >3 >9/.+=?O) 8.+ ?O'?+'>?)'3? .8 ?2).+ +'9>?': 'C=9'C<A

;)'+=(>3 BC=9'C<A 5.(='?A J 144"(' 5&&)-42 89:8

BC=:')=.9./A

• 1+>=3 S2).+<• T+'R2'3(A .8 'C=9'C<A U#%V• H.M /+>:' WXYV• &@BS WW />3/9=./9=.)> WW 9.M /+>:' /9=.)><• 5'=Z2+'< >< C+'<'3?=3/ <A)C?.) 8>G.+>*9'C+./3.<?=( 8>(?.+ 8.+ <2+G=G>9

• &2>9 C>?O.9./AK&@BS

4D&<

4S5[>3 1+'')'3 '? >9, $%%X

\'C=:')=.9./A

• N=(?>*=9=?A Y%V]]]]?M=(' >< O=/O ><.?O'+ (>2<'<

• H.3/'+ ?O' :2+>?=.3 .8 'C=9'C<A M.+<' ?O'.2?(.)'.2?(.)'

5')=.9./AH.M /+>:' G<] 014

H.M/+>:'

^ _`V <'=Z2+'<^T+.3?>9 WW ?')C.+>9 W=3<29>+ W .?O'+=3<29>+ W .?O'+

014^ #$V <'=Z2+'<aC+'<'3?=3/ <A)Cb

^_$V <'=Z2+'<

!!"!#"$%!$

$

S+'>?)'3?K 0'3'+>9 6+=3(=C9'<

L3?'+>((=.3 ;3?=3'.C9><?=(< >3:

BL;B&<

@. 'G=:'3('<2CC.+?=3/

C+.COA9>(?=( Nc

@'M'+ ;B&< *'??'+?.9'+>?':

N>:=>?=.3 >3: (O').aS4db :'(+'><'

<'=Z2+'<KY`V G<] !eV a(.3?+.9b

5c 8.+ +'8+>(?.+A'C=9'C<A a9.M /+>:'b

E>/3'+ $%%ef Q>+('<P= $%%Y, E'99'+ $%!!, &' E=? Q'+PO.8, $%!$

EO>? ;B&<g

[6; HB[ HS0"S64".?O'+

7=/O9A S'+>?./'3=(hhD./3=?=G' B88'(?< =3 .88<C+=3/ 4>+<.3 $%%%f 6+=G'?'+> $%%ef 0>)*9'

$%%_f 1+.:=' $%%X

;9/.+=?O)

5'=Z2+' " 1+>=3 S2).+

@.3 4>9=/3>3? 4>9=/3>3?

S2).+ <2+/'+A >3: ;B&<;B&<

5 8 @ ? 8

D.3?=32' M=?O ;B&< BC=9'C<A 52+/'+A

5Z 8+'' @.? <Z 8+''

[>9C+.>?'K (.3('+3<

g <2+G=G>9 BL;B& 1.3'4>++.M

Jentnik et al, NEJM 2010

52+/=(>9 ?+'>?)'3?

S=)=3/ 5..3h

+'<'(?=.3 ;< )2(O ><

C.<<=*9'a=3(92:=3/ 9A

9'<=.

3g N'<'(?=.3*'A.3:9'<=.3

7.M)2(O+ a=3(92:=3/

O=CC.(>)C>9<?+2(?2+'3/ '? >9, $%!%

11/14/2012

1

! "#$% &' ()*+%)$, -.%$%/0*/1'.&2 "*3*+*#/ 4.#52#!"#"$%"& '( ')*'+,-."&/0" 12"( 34!4( 5.4!4

3,62 78/0/# 9&/:20,

9$"&/#,0 ;</8"<=6 >2#/"-6 ? !//5#+ 6%%0*/1

7*$8+&$5.%

1"@&25,#"( A0#4 A0=-/-@-/20,8 B"=",&#.>@<<2&-

9$"&/#,0 ;</8"<=6 >2#/"-6 ? !//5#+ 6%%0*/1 9:;9

7/C/8/,0 D&,@$, 7,="

• E' 6",& 28F =#/"0-/=- /0 "G#"88"0- .",8-. @0-/8=-&@#H %6 , #,& I./8" J2KK/0K

• L"M- M&20-2-"$<2&,8 ."$,-2$, I/-. =./M-&"N@/&/0K #&,0/2-2$6 "C,#@,-/20 $@8-/<8"&"N@/&/0K #&,0/2-2$6 "C,#@,-/20( $@8-/<8"2&-.2<"F/# /0J@&/"=

• A0 A7O G E I""H=( M2882I"F %6 2@-<,-/"0- &".,%• >"/:@&"= =-,&-/0K <2=- 2< I""H '

D&,@$, 7,=" P#20-4Q

• R12- -." =,$" <"&=20S• A&&/-,%8"( "$2-/20,886 8,%/8"( ,0G/2@=(F"<&"=="F>. 8 /• >.2&- -"&$ $"$2&6 82==( ,02$/,( <22&#20#"0-&,-/20( =82I"F <&2#"==/0K( <22&2&K,0/:,-/20

• O0,%8" -2 &"-@&0 -2 I2&H( F/C2&#"F

D&,@$, 7,=" P#20-4Q

• 5,&-/,8 #2$<8"G ="/:@&"= *TGU$20-.( &,&"="#20F,&6 K"0"&,8/:,-/20( F"=</-" @=" 2M '9;!= ,- ./K. F2="=

• >"$/282K6V #20M@="F "G<&"==/C" ,0F• >"$/282K6V #20M@="F( "G<&"==/C" ,0F&"#"<-/C" ,<.,=/,( ,8"G/,( ,K&,<./, 8,=-/0K * *T$/0@-"=

• B2@-/0" ;;WV 8"M- -"$<2&,8 =.,&< I,C"= ,0F$/8F M2#,8 =82I/0K 8"M- M&20-2-"$<2&,8

3BA3BA

Axial FSE T2 Coronal FLAIR

11/14/2012

2

D&,@$, 7,=" P#20-4Q• B"M"&&"F M2& C/F"2 ;;W $20/-2&/0K ' 6",&=,M-"& -&,@$,-/# %&,/0 /0J@&6

• A0-"&/#-,8V 8"M- M&20-,8( -"$<2&,8( ,0F #"0-&,8=.,&< I,C"=<

• A#-,8V 8"M- <2=-"&/2& -"$<2&,8• >A>7X3V 8,-"&,8/:"F -2 8"M- ."$/=.<"&"( 02082#,8/:"F

• 1"@&2<=6#.282K/#,8 -"=-/0KV $2F"&,-" -2="C"&" &"=-&/#-/20 /0 0,$/0K( $/8F /$<,/&$"0-/0 C"&%,8 $"$2&6

A0-&,#&,0/,8 ;8"#-&2F" A$<8,0-,-/20

• 4%8</*8#++, =*''*85+0*2)+#/0#0*&/ =5% 0&=%/$% #=<%$*&/$>%0?%%/ =5.# >.#*/>%0?%%/ =5.#@ >.#*/@8&.0*8#+ 3%$$%+$

D&,@$, #,=" P#20-4Q

• A/8.%#$%= #)<#$*#/&0%= &/ -B7 C9

• 4#D%/ >#8D 0& BE '&.%3#85#0*&/ &' '+5*=8&++%80*&/

• F5>$%G5%/0+, 0&+%.#0%=2&/*0&.*/1 ?%++

D&,@$, 7,=" P#20-4Q

• Y #8/0/#,8 ,0F Z "8"#-&2K&,<./# ="/:@&"=&"#2&F"F[ $@8-/ M2#,8 20="-= PM&20-,8( ,0-"&/2&\ <2=-"&/2& -"$<2&,8 0"2#2&-/#,8Q

• 12 &"="#-/20• 12 &"="#-/20• ],K@= 0"&C" =-/$@8,-2& <8,#"F• E 6",&= 8,-"& #20-/0@"= -2 .,C" ' Y <,&-/,8#2$<8"G ="/:@&"=U$20-. 20 E 9;!= \ ]1>

• O0,%8" -2 I2&H 2& F&/C"

!!"!#"$%!$

!

!""#$$%&"% '&( )*+, -'"./$+ 0/$!""#$$%&"% '&( )*+, -'"./$+ 0/$11/+./+. .$'#2'.*" 34*5%4+6 *& 7*8*5*'&.$'#2'.*" 34*5%4+6 *& 7*8*5*'&

1/#5'.*/&+1/#5'.*/&+&'(')*'+ $, $%!$

&-.' / 0'123+44'+, 56&

70 8'+9:';1<= /'>?'+, /3.@)*:-

A>:;'+1:?=

B)'+:(-> CD:.'D1= 83(:'?= E 9&&#'5 :%%.*&;

<*+"5/+#$%

F-)' 34 /3))'+(:-. G>?'+'1?

A/H 56-+)-

AD16'+8):?6

C1-:

I=D' 34 J:>->(:-. K'.-?:3>16:D

B2;:13+= *3-+2

B2;:13+= *3-+2

B2;:13+= *3-+2C1-:

B)'+:(-> CD:.'D1= 83(:'?= E 9&&#'5 :%%.*&; =>?=

B2;:13+= *3-+2

@%'$&*&; !AB%".*8%+

• I3 @>2'+1?->2 ?6' D+3D3+?:3> 34 'D:.'D1= 2@' ?3?+-@)-?:( *+-:> :>L@+= MIHGN :> :>(:2'>? ->2 D+';-.'>?

(363+?1O

•I3 @>2'+1?->2 ?6' (@)@.-?:;' +:1< 43+ 'D:.'D1= *= IHG

1';'+:?= :> (:;:.:-> [email protected]?:3>1

•I3 @>2'+1?->2 +:1< 4-(?3+1 43+ D31? ?+-@)-?:( 'D:.'D1=

:> (:;:.:-> [email protected]?:3>1 ->2 +:1< 43+ 1D'(:4:( 1':P@+' ?=D'1

B)'+:(-> CD:.'D1= 83(:'?= E 9&&#'5 :%%.*&; =>?=

Q:>:)-. (+:?'+:- 43+ *+-:> :>L@+=Q:>:)-. (+:?'+:- 43+ *+-:> :>L@+=

• R311 34 (3>1(:3@1>'11 M';'> 1'(3>21N

• &:1?@+*->(' 34 (3>1(:3@1>'11 M-)>'1:-,

(3)D+3):1'2 -S-+'>'11, 2-P'2N

. . : 2 4: :• J3(-. >'@+3.39:( 2'4:(:?

'O9OOO 6'):D-+'1:1, -D6-1:-

• G>L@+= 3> /I 3+ QKG G)-9:>9

M(3>?@1:3>, :>?+-(+->:-. 6')-?3)-N

• K'1:2@-. 3> >'@+3D1=(63.39:(-. ?'1?:>9

I+-@)-?:( *+-:> :>L@+= 1';'+:?=I+-@)-?:( *+-:> :>L@+= 1';'+:?=

7.-193S /3)- 8(-.'

• Q:.2 H+-:> G>L@+= 7/8 !T !U

• Q32'+-?' H+-:> G>L@+= 7/8 V !$

• 8';'+' H+-:> G>L@+= 7/8 T W

8'X@'.-'8'X@'.-' 34 I+-@)-?:( H+-:> G>L@+=34 I+-@)-?:( H+-:> G>L@+=

• 531? (3>(@11:3> 1=>2+3)'

• J3(-. >'@+3.39:(-. 2'4:(:?

• /39>:?:;' :)D-:+)'>?

• 1/+. .$'#2'.*" %4*5%4+6

!!"!#"$%!$

$

G>(:2'>(' ->2 2:1?+:*@?:3> 34G>(:2'>(' ->2 2:1?+:*@?:3> 34

I+-@)-?:( H+-:> G>L@+=I+-@)-?:( H+-:> G>L@+=

• !W%"!%%,%%% ?3 $W!"!%%,%%%

• G>(:2'>(' D'-<1 :> =3@>9 -2@.?1 ->2 :> ?6'

'.2'+.==

• IHG :1 !OW ?3 $OW 43.2 )3+' (3))3> :> )-.'1

• J-..1 ->2 ?+->1D3+?-?:3> +'.-?'2 -((:2'>?1

D+'23):>-?', -((3@>?:>9 43+ YTZ ?3 [VZ 34

:>L@+:'1O

/33D'+ '? -.O F'@+3'D:2'):3.39= !VWT\$][% WW\ I:+'? '? -.O G> ^ CD:2'):3. !VV%\!V]!TT !#%\

_.-@*'+ '? -.O F'@+31@+9'+= !VW!\V]$TY $#!O

5+3D3+?:3> 34 :>(:2'>? 'D:.'D1= *= '?:3.39=,5+3D3+?:3> 34 :>(:2'>? 'D:.'D1= *= '?:3.39=,

K3(6'1?'+, QF !VTUK3(6'1?'+, QF !VTU W#W#

WZ

CDCD#Z #Z TZ

A><>3S>"9'>'?:(

`-1(@.-+

.

YUZ

!%Z

/3>9'>:?-.

E$'#2'E$'#2'I@)3+

&'9'>'+-?:;'

G>4'(?:3>

0-@1'+ '? -.O CD:.'D1:- !VVT\T#]#UT #UW

5+3D3+?:3> 34 D+';-.'>? 'D:.'D1= *=5+3D3+?:3> 34 D+';-.'>? 'D:.'D1= *=

'?:3.39=, K3(6'1?'+, QF !V#%'?:3.39=, K3(6'1?'+, QF !V#% !VW%!VW%

YZ

FDFDUZ

#Z $Z !Z !Z

A><>3S>"9'>'?:(

`-1(@.-+

E$'#2'E$'#2'

[YZ

&';'D)'>?-.

G>4'(?:3>

I@)3+

&'9'>'+-?:;'

a?6'+

0-@1'+ '? -.O CD:.'D1:- !VV!\T$]#$V ##U

/@)@.-?:;' :>(:2'>(' 34 @>D+3;3<'2/@)@.-?:;' :>(:2'>(' 34 @>D+3;3<'2

1':P@+' *= IHG 1';'+:?=1':P@+' *= IHG 1';'+:?=

B>>'9'+1 '? -.O F C>9. ^ Q'2 !VVW\TTW]$% $#

G>(:2'>(' 34 @>D+3;3<'2 1':P@+'1 *=G>(:2'>(' 34 @>D+3;3<'2 1':P@+'1 *=

IHG 1';'+:?= 3> ?6' 7/8IHG 1';'+:?= 3> ?6' 7/8

I')<:> '? -.O CD:.'D1:- $%%T\##]!W $%

R-?' 8':P@+'1R-?' 8':P@+'1

I')<:> '? -.O CD:.'D1:- $%%T\##]!W $%

!!"!#"$%!$

T

K'.-?:;' K:1< 43+ 'D:.'D1= *= IHG 1';'+:?= :> (6:.2+'>K'.-?:;' K:1< 43+ 'D:.'D1= *= IHG 1';'+:?= :> (6:.2+'>

/6+:1?'>1'> '? -.O R->('? $%%V\T[T]!!%U !!!%

K:1< J-(?3+1 43+ 531??+-@)-?:( 8':P@+'1K:1< J-(?3+1 43+ 531??+-@)-?:( 8':P@+'1

:>:> B2@.?1B2@.?1

G%&&%.. 34*5%4+6 '0.%$ &/&2*++*5% H%'( *&B#$*%+I @/&(/&J K*55*'2 L%*&%2'&& 2%(*"'5 M//,+N ?OPF

K:1< 4-(?3+1 43+ @>D+3;3<'2 1':P@+'1K:1< 4-(?3+1 43+ @>D+3;3<'2 1':P@+'1

-4?'+ (:;:.:-> IHG-4?'+ (:;:.:-> IHG

W

!%

!$

!#

K-?' K-?:3

%

$

#

Y

W

B>>'9'+1 '? -.O F C>9. ^ Q'2 !VVW\TTW]$% $#

IHG ->2 +:1< 43+ 2:44'+'>? 1':P@+' ?=D'1 *'43+'IHG ->2 +:1< 43+ 2:44'+'>? 1':P@+' ?=D'1 *'43+'

-9' TU ='-+1-9' TU ='-+1

!%

!$

!#

!Y

/58

7I/8

b

ba221 +-?:3

%

$

#

Y

W

!%

IHG S:?6 .:>'-+ 1<@.. 4c IHG S"3@? .:>'-+ 1<@.. 4c

Q

b

K3((- '? -.O B>> F'@+3. !VW[\$!]$$ T!\ K3((- '? -.O F'@+3.39= !VW[\T[]!T!U $$O

G)D-(? 3> /.:>:(-. /-+' ->2 5+-(?:('G)D-(? 3> /.:>:(-. /-+' ->2 5+-(?:('

• I6' :>(+'-1'2 +:1< 43+ 'D:.'D1= :1 .:):?'2 ?3 )32'+-?' ->2 1';'+'

(:;:.:-> IHG, S6:(6 (3)D+:1'1 dUZ 34 -.. :>(:2'>? ->2 -.. D+';-.'>?

'D:.'D1=

• G> D'3D.' @>2'+ TU ='-+1 34 -9', IHG :>(+'-1'1 ?6' +:1< 43+ 7I/8 ->2

43+ /58, *@? >3? 43+ -*1'>(' 1':P@+'1

• K:1< 4-(?3+1 43+ 'D:.'D1= -4?'+ IHG :>(.@2' *+-:> (3>?@1:3>, 8&0,

.:>'-+ 3+ 2'D+'11'2 4+-(?@+', Ra/"5IB e$# 63@+1, ->2 -9' eYU ='-+1

• I6' +:1< 43+ 'D:.'D1= -4?'+ (:;:.:-> IHG :1 9+'-?'1? :> ?6' 4:+1? ?S3

='-+1 -4?'+ IHG :> )31? 1?@2:'1 'c('D? K3(6'1?'+ S6'+' ?6' 9+'-?'1?

+:1< 43+ 1';'+' IHG D'+1:1?1 43+ !% ='-+1

11/19/2012

1

!"#$%&#'(')* '+ ,-./0#12 3456'71 48$ 946:74( ;#16'7*

!"#"$%"& '( ')*'+,-./ 01 2"&$./( 3!

4"56 7-&."8 !".#9/"-- 3":;#.8 <"/5"&2.&=.&: 3":;#.8 +#6998


<#15('1:7%

>.$" 9? <9$$"&#;.8 7/5"&"-5@<4 A6.&$.B,/:%"#C( 7/#1

0DE" 9? F;/./#;.8 G"8.5;9/-6;EG"-".&#6 +,EE9&5( B9#.8 A7G"-".&#6 +,EE9&5( B9#.8 A7

6 8H"&5"IF;:"8;5D 4;9-#;"/#"- G"-".&#6

7/;5;.5;="


G"-".&#6 +,EE9&5( B9#.8 A7G"-".&#6 +,EE9&5

=%478#8) >?@%56#A%1

• 7:"/5;?D #9$$9/ &;-C ?.#59&- ?9& E9-5 5&.,$.5;#"E;8"E-D• JIE89&" 56" &"8.5;9/-6;E %"5K""/ ".&8D ./: 8.5"E9-5 5&.,$.5;# -";L,&"-• !"-#&;%" 56" /.5,&.8 6;-59&D 9? E9-5 5&.,$.5;#"E;8"E-D ./: &;-C 9? ;/5&.#5.%8" "E;8"E-D


!"#$%"&'(%)%*#*!"#$%"&'(%)%*#*

Latent period Spontaneous Late Seizures

Age Genetic factors

Initial Precipitating

Injury

Epilepsy

Recurrent in >80%

Acute Symptomatic

Seizures

Epileptogenesis

?

+,-&%./01"&'12&#,./%#3-4%*+,-&%./01"&'12&#,./%#3-4%*Provoked seizuresFirst 1-2 weeks after brain injuryMarker of severity of underlying disorder

Temkin N et al. New Horiz 1995:3:518-22

+,-&%./01"&'12&#,./%#3-4%*+,-&%./01"&'12&#,./%#3-4%*Associated with development of epilepsyLate seizures occur in 47% of patients with clinical ASclinical ASAS are independent predictor (OR 2.84) for development of late seizures

Hesdorffer et al, Ann Neurol. 1998; 44:908-12

11/19/2012

2

/%#3-4%.54%6%)&#').74#2$*.28&%4./%#3-4%.54%6%)&#').74#2$*.28&%4.742-12&#,.942#).:);-40742-12&#,.942#).:);-40

15

20

25

30

s w

ith s

eizu

re

PlaceboPHT

0

5

10

15

% o

f pat

ient

s

Early Late Early Late

PHTVPA 1 moVPA 6 mo

PHT vs. placebo PHT vs. VPATemkin et al., J Neurosurg 1999;91:593-600Temkin et al., N Engl J Med 1990;323:497-502

!$%,&4'(42"<#,./%#3-4%*.#).79:!$%,&4'(42"<#,./%#3-4%*.#).79:Seizures in critically ill patients often subclinicalSeizures in critically ill patients often subclinical

Paralytic or sedative agentsParalytic or sedative agentsConcurrent medical illnessesConcurrent medical illnessesUnderlying neurological deficitUnderlying neurological deficitAdministration of AEDsAdministration of AEDsAdministration of AEDs Administration of AEDs

Prospective study of 91 patients with severe TBIProspective study of 91 patients with severe TBIEEG monitoring for 7EEG monitoring for 7--10 days10 daysAll patients received prophylactic phenytoinAll patients received prophylactic phenytoin22% had seizures22% had seizures

57% only subclinical57% only subclinical6/6 patients with status epilepticus died6/6 patients with status epilepticus died

Vespa et al., J Vespa et al., J NeurosurgNeurosurg, 1999;97:750, 1999;97:750--760760

Fp1-F3F3-C3C3-P3P3-O1Fp2-F4F4-C4C4-P4P4-O2Fp1-F7F7-T3T3-T5T5-O1Fp2-F8F8-T4T4-T6T6-O2Fz-CzCz-PzEKG



!24$0.57/.2)=.!"#$%"*0!24$0.57/.2)=.!"#$%"*0Retrospective analysisRetrospective analysis140 patients with moderate to severe TBI, CEEG140 patients with moderate to severe TBI, CEEG

16 patients volumetric MRI, acute and 6 months 16 patients volumetric MRI, acute and 6 months 6 patients with early seizures, 10 age6 patients with early seizures, 10 age-- and GCSand GCS--matched matched patients with TBI, no seizures patients with TBI, no seizures Patients with seizures showed greater hippocampal atrophy Patients with seizures showed greater hippocampal atrophy (21 +/(21 +/-- 9 9 vsvs 12 +/12 +/-- 6%, p = 0.017), especially 6%, p = 0.017), especially ipsilateralipsilateral to the to the electrographic seizure focuselectrographic seizure focus

Vespa PM et al. Neurology 2010;75:792-798

:)&%4#,&2$:)&%4#,&2$ !"#$%"&#8'41.>#*,<24(%*!"#$%"&#8'41.>#*,<24(%*Animal model of TBIAnimal model of TBI

IEDs and brief electrographic IEDs and brief electrographic SzSz precede clinical precede clinical seizuresseizures

Inadequately studied in humansInadequately studied in humansNonNon--standardized timing and methods for EEGstandardized timing and methods for EEGggMost utilize routine EEGMost utilize routine EEG

IEDs are rare in adults, even those with acquired IEDs are rare in adults, even those with acquired brain injuriesbrain injuries

Presence of IEDs +/or focal slowing at 1 month Presence of IEDs +/or focal slowing at 1 month associated with 3.5associated with 3.5--fold higher risk of developing late fold higher risk of developing late seizures (n=137, 18 with epilepsyseizures (n=137, 18 with epilepsy

Angeleri F et al. Epilepsia. 1999; 40:1222-301D'Ambrosio R et al. Brain 2009;132:2805-2821

11/19/2012

3

5'*&5'*&??&42-12&#,.!"#$%"*0&42-12&#,.!"#$%"*0@#$#&240.!A"%4#%),%.BC'4%2D@#$#&240.!A"%4#%),%.BC'4%2D

Category Characteristics Incidence (%)

I Blow to head w/o LOC 7

II Blow to head w/ LOC <6 hr 10

Caveness, Epilepsia 1976;17:207

III Penetration of dura w/o apparent brain damage 39

IV Dura penetration w/o LOC and no neurologic deficit

20

V Dura penetration with evident neurologic deficit 51

VI Penetration of dura and brain of profound degree

57

@#$#&240.E%2=.:);-40@#$#&240.E%2=.:);-40Iraq and Afghanistan veterans Iraq and Afghanistan veterans

6.76.7--14.9% diagnosed with or self14.9% diagnosed with or self--reported TBI reported TBI Many with recurrent mild TBIMany with recurrent mild TBIWalter Reed Army Medical Center trauma admissionsWalter Reed Army Medical Center trauma admissions

Mechanism % TBI Mild Moderate Severe

Taylor BC et al. Med Care. 2012. Epub.Wilk JE et al. J Head Trauma Rehabil. 2010;25(1):9–14Carlson KF et al. J Head Trauma Rehabil. 2012;27(1):14–25Xydakis MS et al. Ann Neurol 2012, Epub 10/2012.

Mechanism % TBI Mild Moderate SeverePenetrating (n = 15)

100

Blunt trauma (n = 102)

56.6 58.1 32.6 9.3

Blast trauma (n = 365)

54.3 67.5 27.8 4.6

79:.2)=.5*0,<'(%)#,.F')%"#$%"&#,.79:.2)=.5*0,<'(%)#,.F')%"#$%"&#,.!6%)&*!6%)&*

Retrospective study of EMU admissions to VAMCRetrospective study of EMU admissions to VAMCPsychogenic nonepileptic event diagnosisPsychogenic nonepileptic event diagnosis

26 % of 726 civilians26 % of 726 civiliansAverage 12.5 months to diagnosisAverage 12.5 months to diagnosis

25% of 203 veterans 25% of 203 veterans Average 60.5 months to diagnosisAverage 60.5 months to diagnosis4x greater AED exposure4x greater AED exposure58% thought to be related to TBI58% thought to be related to TBI

Salinsky M et al. Neurology. 2011;77(10):945–50

F2&-42$.E#*&'40.'8.57!F2&-42$.E#*&'40.'8.57!86% of patients with 1 late unprovoked post86% of patients with 1 late unprovoked post--traumatic traumatic seizure experience a second seizure within 2 years seizure experience a second seizure within 2 years 11

2525--40% seizure remission rate in non40% seizure remission rate in non--penetrating TBI penetrating TBI 22

39 selected adult patients (25 male) with moderate TBI 39 selected adult patients (25 male) with moderate TBI 33

36% required more than 1 AED trial36% required more than 1 AED trial36% required more than 1 AED trial36% required more than 1 AED trial8% failed multiple AEDs8% failed multiple AEDs

TBI associated with increased risk of refractory epilepsyTBI associated with increased risk of refractory epilepsy44

27% of patients with TBI and PTE died at 8 to 15 years 27% of patients with TBI and PTE died at 8 to 15 years after injury vs. 10% of matched TBIafter injury vs. 10% of matched TBI--only patients only patients 55

1. Haltiner AM et al. Arch Phys Med Rehabil. 1997;78(8):835–402. Schmidt D, Sillanpää M. Curr Opin Neurol. 2012. Epub.3. De Reuck J. Clin Neurol Neurosurg 2011;113:469-4714. Semah F et al. Neurology 1998;51:1256-12625. Harrison-Felix CL. Arch Phys Med Rehabil. 2009;90(9):1506–13

54%=#,&'4*.'8.:)&42,&2G$%.!"#$%"*054%=#,&'4*.'8.:)&42,&2G$%.!"#$%"*0

Hitiris et al. Epilepsy Res 2007;75:192-196

/-11240/-11240Early seizures are associated with higher risk of PTEEarly seizures are associated with higher risk of PTE

Pathogenic significance remains unclearPathogenic significance remains unclearFurther exploration of IEDs as risk factor / biomarker is Further exploration of IEDs as risk factor / biomarker is warrantedwarrantedPTE i i t d ith hi h i k f f t ilPTE i i t d ith hi h i k f f t ilPTE is associated with higher risk of refractory epilepsyPTE is associated with higher risk of refractory epilepsyFurther studies of PTE needed to better understand Further studies of PTE needed to better understand natural historynatural history

11/14/2012

1

!"#$%"&'(%)%*#*!"#$%"&'(%)%*#* +,&%- ./01+,&%- ./01/#'2+-3%-* +)4 5+-#+6#$#&7/#'2+-3%-* +)4 5+-#+6#$#&7

!"#"$%"& '( ')*'

+,$-". /0"%"( 1!2304"&5067 89 :,.;,&7


8#*9$'*:-%

<,$" 89 :8$$"&#0,. =36"&"56<83"

>7?" 89 @03,3#0,. A".,60835B0?None


;%+-)#)( <6=%9&#>%*

• >8 "C?.8&" %08$,&D"&5 98& ?856 6&,-$,60# "?0."?57• E08#B"$0#,.( ;"3"60#( 0$,;03;( #.030#,.

•>8 "C?.8&" 6B" B"6"&8;"3"067 89 &05D 98& ?8566&,-$,60# "?0."?57


<,6-&" <-&6-&" 03 F?0."?57

Berkovic, Trends in Neurosci 2006

<8 F3G8?B"3867?" 98& H>F

• =9 >"$?8&,. .8%" "?0."?57( I)J B,4" 1>+• 1A= ;.0860# 5#,& ,3G #8&60#,. B"$850G"&03• A8-603" FFK 386 B".?9-.• L0G"8 FFK

– +"0M-&"5 ,&" $856 #8$$83.7 98#,. NO)JP• >"$?8&,. IQJ• @&836,. RRJ

– +"."#6083 %0,5

Jennett et al, Epilepsia 1975; Diaz-Arrastia et al, Epilepsia 2009

S,?68;.8%03 ,5 , %08$,&D"& 89 H>F

• <"-6&,.0M"5 ,3G &"$84"5 "C6&,#"..-.,&B"$8;.8%03

• S? 03#&",5"G ,96"& >E=S * * 99 60 6B S ' '• S? * * $8&" "99"#604" 6B,3 S? ' '

• A,608 89 S? ' ' 68 S? * * 03#&",5"G 03;"3"&,.0M"G "?0."?57

• 1,&D"& 98& G"4".8?$"36 89 H>FT

Anderson et al, E&B 2009

11/14/2012

2

+"&-$ S,?68;.8%03 HB"3867?"5#,5" #836&8. 56-G7


UHVF Q

• H&8G-#"G 03 &"5?835" 68 03W-&7• U3608C0G,36( ,360 039.,$$,68&7( ,360"C#06868C0#

.. . . 9 %.• Q ,.."." ."55 9,48-&,%." 8-6#8$"


UHVF ;"3867?" ,5 , $,&D"&#8B8&6 56-G7 3X*)Y

Diaz-Arrastia et al, Arch Neurol 2003

UHVF ;"3867?" ,5 , $,&D"&#,5" #836&8. 56-G7


1A= "3G8?B"3867?"5T

No lesion or Complete wall

Incomplete wall

Incomplete to complete wallP <0.05

• <X*RI( H>F ')( 1A= Q Y $836B5• K.0860# Z,.. 5-&&8-3G03; B"$850G"&03;• H&8%,%0.067 89 H>F ,6 *) 7",&5

No lesion or Complete wall

Messori et al, Epilepsia 2005

1A= "3G8?B"3867?"5T!>=

Gupta et al, Epilepsia 2005

11/14/2012

3

1,6-&,6083,. ,5?"#65 89 "?0."?57$"#B,305$5

Sanchez & Jensen, Epilepsia 2001

F99"#6 89 ,;" 83 H> 5"0M-&"5-5#"?60%0.067

Adapted form: Jyoti et al, Neurosci Lett 2009

S"6"&8;"3"8-5 56-G7 $"6B8G5

From: Lowenstein, Epilepsia 2009

1"6B8G5• H8?-.,6083

– :040.0,3( $0.06,&7( ,G-.6( ?,"G0,6&0#( 03?,60"36(8-6?,60"36( 6&,-$, #"36&"( &"B,% #"36&"

• :&06"&0,– U.. >E=( :> B",G( K:+ #-6 899( 5?"#090# 56-G7 #&06"&0,

• +"0M-&" G0,;38505– :.030#( [-"560833,0&"( #B,&6( 6"."?B83"( 1!(036"&40"Z"&

– :&06"&0,\ ],6"T F,&.7T F?0."?57T

=$?.0#,60835 98& :.030#,. H&,#60#"

• <"Z %08$,&D"&5 89 &05D ,&" ?&8$0503;( 03?,&60#-.,& 1A= 6"#B30[-"5

• <8 G"9030604" ;"3"60# %08$,&D"&5 7"60 %0.0 9 B G G• L,&0,%0.067 89 $"6B8G5 ?&8G-#"5

B"6"&8;"3"8-5 &"5-.65 89 &05D 89 H>F• U55"55 #,&"9-..7 ZB"3 "560$,603; &05D5 98&03G040G-,. ?,60"365

1

Epileptogenesis and Treatment

Jerome Engel, Jr., MD, PhD

Jonathan Sinay Distinguished Professor of y gNeurology, Neurobiology, and Psychiatry &

Biobehavioral SciencesDavid Geffen School of Medicine at UCLA


DisclosuresNIH NINDS grants R01 NS02808

R01 NS33310P20 80181

Elsevier RoyaltyW lt Kl R ltWolters Kluwer RoyaltyWiley-Blackwell RoyaltyOxford RoyaltyMedNet RoyaltyBest Doctors RoyaltyION ConsultantFDA ConsultantAmerican Epilepsy Society | Annual Meeting 2012

Learning Objectives

1. Understand possible mechanisms of post traumatic epileptogenesis

2. Understand value of biomarkers in developing antiepileptogenic treatments


Epileptogenesis after Trauma

• Cell death• Neuronal reorganization• Enhanced excitation• Decreased and enhanced inhibition• Enhanced tendency to

synchronization

Engel, J Jr. EEG J 76:296-316, 1990 Engel, J Jr. Seizures and Epilepsy. FA Davis, 1989

2

Treatment

• Discovery and validation of antiepilepto-genic interventions are impeded by the prohibitive cost of screening and clinical trials

• The variable incidence of PTE after severeThe variable incidence of PTE after severe head trauma, and the late-onset of seizures that can occur over 10 years after injury make huge animal and patient populations necessary and require exceedingly long follow-up

3

Biomarkers

Dynamic changes that indicate the presence of an epileptogenic process with a sufficiently high degree of reliability to warrant intervention• Biomarkers of epileptogenesis• Biomarkers of epileptogenicity

Biomarkers of Epileptogenesis

• Identify the development of brain tissue capable of generating spontaneous epileptic seizures

• Identify the progression of an epileptic condition after it has developed

Biomarkers of Epilepsy Development

• Predict epilepsy in patients with risk factors- genetic predispositiongenetic predisposition- prolonged febrile seizure- head trauma- intracranial infection- brain lesion

• Institute antiepileptic intervention

Biomarkers of Epilepsy Development

• Create cost-effective rapid-throughput models for screening potential antiepileptogenic interventionsantiepileptogenic interventions

• Identify subjects to enrich clinical trials of potential antiepileptogenic interventions

Target Mechanisms

• Cell loss (e.g., hippocampal atrophy)• Axonal sprouting• Synaptic reorganization• Altered neuronal function (e.g., gene

expression profiles protein products)expression profiles, protein products)• Neurogenesis• Altered glial function and gliosis• Inflammatory changes• Angiogenesis• Altered excitability and synchrony

Potential Biomarkers

• Hippocampal changes on MRI• Interictal spike features, including

fMRI• Pathological high-frequency

oscillations (pHFOs)• Excitability – TMS• AMT-PET imaging• Gene expression profiles

!!"!#"$%!$

!

!"#$%"&' ()*+ , -#$#./)' !0"%)#%12%&'(')*'+ $, $%!$

-.+. -(/+.0'+, 1&1.23+, 4-56, 17

891 :';+3<3=>, ?7 @A0B.A.C3<BD, @:

5)'+B(.A ECB<'CD> -3(B'F> G ,113/$ -%%.#14

5#&2$*&3)%

:3F/BA= F3 0BD(<3D'

5)'+B(.A ECB<'CD> -3(B'F> G ,113/$ -%%.#14 6786

7.D' ?+'D'AF.FB3A

• $H>3 <'IF /.A0'0 ).<' 1.+BA'• -/3F BA F/' /'.0 *> . DABC'+ J/B<' D;CC3+FBA=KC'+.FB3A :'J &.JA BA @+.L -'CF')*'+ $%!%

0 B 0 0 * B0 B• 4A0'+J'AF (+.AB3F3)> .A0 0'*+B0')'AF BAF/'.F'+

• M+'.F'0 JBF/ <'N'FB+.('F.) O%%)= P@& I3+D'BQ;+' C+3C/><.RBD

7.D' ?+'D'AF.FB3A

• M+.ADI'++'0 F3 :.FB3A.< :.N.< 1'0B(.< 7'AF'+.A0 /.0 D'(3A0 (+.AB3F3)>

• S.0 <'IF /')BDC/'+' (+.AB3C<.DF> .F P+33T'5+)> 1'0B(.< 7'AF'+ 8.A;.+> $%!!5+)> 1'0B(.< 7'AF'+ 8.A;.+> $%!!

!!"!#"$%!$

$

7.D' ?+'D'AF.FB3A

• U'DB0;.< 0'IB(BFD 3I DC.DFB( +B=/F /')BC<'=B.,+B=/F /')BD'AD3+> 0'IB(BF, .A0 +B=/FL;.0+.AF.A3CB.

• S.0 IB+DF D'BQ;+' 1.+(/ $%!!• S.0 IB+DF D'BQ;+' 1.+(/ $%!!– UB=/F DB0' DFBII'AD .A0 /'.0 F;+AD F3 +B=/F,I3<<3J'0 *> ='A'+.<BQ'0 (3AN;<DB3A

• V'N'FB+.('F.) 03D' 'D(.<.F'0 3N'+ FB)' 0;' F3+'(;++'AF D'BQ;+'D

• S.0 ! $ D'BQ;+'D C'+ )3AF/ .D 3I 1.+(/ $%!$J/B<' F.TBA= <'N'FB+.('F.) !O%%)= P@&

• KR(.+*.Q'CBA' .00'0 F3 +'=B)'A .A0 FBF+.F'0;C F3 W%%)= P@&;C F3 W%%)= P@&

• &3D' BA(+'.D'0 F3 X%%)= P@& .IF'+ +'(;++'AFD'BQ;+'D 5C+B< $%!$

9+"/2. *1 :$#1#2/$ :/)% /1; <)/2.#2%

• -/3;<0 5E& C+3C/><.RBD *' ;D'0 .IF'+ /'.0F+.;). C+B3+ F3 F/' IB+DF D'BQ;+'Y

• @D 5E& C+3C/><.RBD 'II'(FBN' BAC3DFF+.;).FB( 'CB<'CD>Y

!!"!#"$%!$

!

&'()*'+, -./0 12* 3()(14.,5*.+'*61(7*84.*9 54.:/; 3<

=41(/94) <(.*61/.; >? &'()*'+, @*91*.+ /-& ))&A6*))*96*

5./-*++/. /- =*B./)/C,

D9(7*.+(1, /- @4)(-/.9(4 41 E49 F.496(+6/

?0*.(649 &'()*'+, E/6(*1, G !""#$% &''()"*

?99B4) @/B.+*H E,0'1/041(6 &'()*'+(*+H I.4B04

+),-%.,#/'

• <.J 54.:/ 24+ 9/12(9C 1/ K(+6)/+*

• <(+6)4(0*.H !"# $%#&' #()*#''#+ %, -"%' )*#'#,-.-%/,.*# -"/'# /0 -"# .1-"/* .,+ +/ ,/- *#02#3- /00%3%.2)/2%34 /* )/'%-%/, /0 -"# 5#-#*.,' 600.%*' /* -"#7#).*-8#,- /0 7#0#,'#

?0*.(649 &'()*'+, E/6(*1, G !""#$% &''()"* 0120

3'$/")"* 456'-()7',

!J L7*.7(*M /- 6B..*91 0()(14., I.4B041(6 N.4(9 O9PB.,QINOR

$J &74)B41* 12* '/1*91(4) 04C9(1BK* /- '/+11.4B041(6 *'()*'+, Q5I&R -./0 6B..*91 0()(14., INO

SJ D9K*.+149K 12* +,+1*0 /- 64.* *+14T)(+2*K -/.7*1*.49+ M(12 *'()*'+,

?0*.(649 &'()*'+, E/6(*1, G !""#$% &''()"* 0120

!J L7*.7(*M /- 6B..*91 0()(14., INO

•@/0T41 INO

•U412*.(9C 12* K414•O9 I2*41.* <(4C9/+(+

•349K41*K E6.**9(9C•349K41*K E6.**9(9C

•=*B./)/C, I*)*6/9+B)1•N)4+1 U4BC*

•&A(1 -./0 E*.7(6*•>? E6.**9

?0*.(649 &'()*'+, E/6(*1, G !""#$% &''()"* 0120

Global War on Terror (GWOT)

Iraqi-9 years of conflict March 2003-December 2011– Operation Iraqi Freedom (OIF) Began March

2003– Operation New Dawn (OND) Began

September 2010

Afghanistan- Oct 2001

– Operation Enduring Freedom (OEF)

OEF/OIF Patient Characteristics

Long WarMultiple DeploymentsMultiple Blast ExposuresChronic PainUnder Stress for Prolonged Periods of Time

!!"!#"$%!$

$

Current Injury Etiology

Leading cause of combat injuries OIF/OEF– 74% Explosions, primarily improvised

explosive devices– 18-20% Gunshot wounds

Leading causes Vietnam– 65% explosions– 35% Gunshot wounds

Owens et al (2012)

Military vs. Civilian TBI

Combat troops injured by blast explosive brisance– Acute polytrauma, no civilian equivalent– Neurological effects may differ from other causes

of TBIP l ti i diff tPopulation is different– Unique population Unifying characteristics (age,

gender, enlisted, fitness standard, absence of alcohol, illicit drug or criminal behavior, treatment in choreographed continuum of care)

Risk from mild TBI in this setting is unknown

TBI Screening in-theatre practice guidelines

June 2010 Directive Type Memorandum: Policy Guidance for Management of Concussion/Mild Traumatic Brain Injury in the Deployed Setting

Military Leaders required to identify personnel involved in a mandatory event and conduct screening ensure reporting andmandatory event and conduct screening, ensure reporting, and refer anyone with positive screen for full medical evaluation

Mandated Screening using Military Acute Concussion Examination (MACE) – MACE brief screen that combines:

acute injury characteristics and symptomsbrief validated cognitive screening

!!"!#"$%!$

S

Mandatory Events Requiring Evaluation

Any Service Member in a vehicle associated with a blast event, collision or rollover

All within X meters of a blast (inside or outside)outside)

Anyone who sustains a direct blow to the head

Command directed, especially with repeated exposures to blasts

Xydakis et al (2012)

Army Knowledge Online (AKO) teleconsultation

Centralized system for deployed military care providers to receive expert recommendations on triage and disposition

Quantities of Military Teleconsults Requested per Calendar Year

VB.:(*M(6W *1 4) $%!$

Consultant recommendationsDiagnoses, initial and final

VB.:(*M(6W*1 4) $%!$

Blast ExposureDARPA Blast Gauge

• Measures blast exposure• Recording 20 msec per episode and then resets itself

• Measures blast wave form, duration, change in air pressure, head axis acceleration

• Data can be downloaded via mini-USB port• Data stored in a central database• Currently being used on 11,000 service members in AfghanistanActivating status lights

H-strap

PALS Webbing

MACE (Military Acute Concussion Evaluation) only if other indicators

MACEMACE, potentially require evac

Status lights:

Jeff Rogers, PhDMTO, DARPA

!!"!#"$%!$

#

TBI in Veterans who seek VA careApril 2007-August 2012

1,515,707 OEF/OIF/OND Veterans have left active duty and become eligible for VA health care since FY 2002 834,463 (55%) of these Veterans obtained VA , ( )health Care647,197 Screen positive for possible mild TBI128,617 (19.9%) are screen positive for TBI51,159 have diagnosis of TBI (7.9 % of initial possible screens)

http://vssc.med.va.gov/tbireports/comprehensivetbi.aspxhttp://www.publichealth.va.gov/epidemiology/reports/oefoifond/health-care-utilization/index.asp

Sources:

$J &74)B41* 12* '/1*91(4) 04C9(1BK* /-'/+1 1.4B041(6 *'()*'+, Q5I&R -./0

6B..*91 0()(14., INO•5.*74)*96*H X(+1/.(64) *7(K*96* -./00()(14., 1.4B04

•Y41*96, O96(K*96*Y41*96,; O96(K*96*•>(*1940•O.49 O.4Z

•LOF"L&F"L=< *0*.C(9C K414

•@/0T41 3()K INO

?0*.(649 &'()*'+, E/6(*1, G !""#$% &''()"* 0120

Conflict Author(s), year No. of patients

Posttraumatic epilepsy (%)

5 yrs 10–15+ years

WW I Credner, 1930 1990 38 50

WW I Ascroft, 1941 317 35 –

WW I Caviness, 1966 82 – 50

WW II Russell & Whitty 1952 820 43 –

Posttraumatic epilepsy following craniocerebral missile wounds in armed conflicts during the 20th century

WW II Russell & Whitty, 1952 820 43

WW II Walker & Erculei, 1969 739 34 –

Korean War Caveness et al., 1962 211 36 –

Korean War Taylor & Kretschmann, 1971 474 – 50

Vietnam War Caveness et al., 1979 1135 34 –

Vietnam War Salazar et al., 1985, 1987 520 34 51

Iran–Iraq Aarabi, 1990 489 32 –

Lebanon Brandvold et al., 1990 46 22 –

Lowenstein 2009 -adapted from Salazar 1999

Korean and Vietnam War VeteransRisk with other TBI severity

53% risk with penetrating TBI10-25% closed head injury (combat) with positive brain imaging5% i d t CHI ith t i i5% in moderate CHI without imaging findings

Chen et al 2009

Vietnam PTE Latency

• Report of the Vietnam Head Injury Study showed that the overall seizure occurrence 15 years after head injury was 53% with the vast majority developing epilepsy(Salazar 1985)j y p g p p y( )

• Recent Vietnam Head Injury Study showed that 12.6% of Veterans with TBI had initial onset of epilepsy more than 14 years after their injury (Raymont 2010)

Recent Conflict (Iran-Iraq War)

32% with penetrating TBI developed epilepsy during an average of 39.4 months of follow-up489 patients with penetrating head trauma over 8 year period followed for up to 154 months32% (157) developed epilepsy during follow-up period of almost 13 yearsperiod of almost 13 years– Latency

6 months 63 72% in first year12 months-5024 months-1748 months-19 95% in first four years111 months-8

Aarabi et al 2000

!!"!#"$%!$

[

SJ D9K*.+149K 12* +,+1*0 /- 64.**+14T)(+2*K -/. 7*1*.49+ M(12 *'()*'+,

•=B0T*.+ /- >*1*.49+ M(12 *'()*'+,

•&'()*'+, @*91*.+ /- &A6*))*96* Q&@/&R•>*1*.49+ .*6*(7* 64.* -/. *'()*'+,•>*1*.49+ .*6*(7* 64.* -/. *'()*'+,

•</< 49K 6(7()(49

•=/9 *'()*'1(6 +*(WB.*+ (9 7*1*.49+

?0*.(649 &'()*'+, E/6(*1, G !""#$% &''()"* 0120

Increasing Number of VA Seizure Patients

90,000

110,000

of P

atie

nts

50,000

70,000

2000 2002 2004 2006 2008 2010 2012

Num

ber

Fiscal Year

Data Source: Office of Specialty Care TransformationData collected using ICD-09 codes 345.xx, 780.3, 780.33, 780.39, 780.02, 780.09, 649.40, 649.41, 649.43, 649.44

Epilepsy population demographics

About 85,000 Veterans treated at VA are diagnosed with epilepsy or seizures20% were seen within a Medical Center with an Epilepsy Centerp p y75% are age 50 and older7% are femaleMany medically and surgically refractoryNon-epileptic seizures

Non-epileptic seizures within Veterans in the VA

FY 12 EMU diagnosis from 14 Epilepsy Center of Excellence sites652 total EMU admissions192 (29%) fi d di i f PNES192 (29%) confirmed diagnosis of PNES

Establishment of Epilepsy Centers of Excellence (ECoE)

Public Law 110-387: Veterans Mental Health and Other Care Improvements Act of 2008Centers must:– link to existing VHA Polytrauma Centers

link to academic centers and conduct research– link to academic centers and conduct research– be established by a Peer Review Panel– be involved with education and fellowship training

Funding Cycle October 2008-September 2013

!!"!#"$%!$

\

Washington DC

=41(/94) >? &'()*'+, @/9+/.1(B0

Las Vegas

Providence

Kansas City

Bronx

Albany

Pittsburgh

Tomah

Ann Arbor

White River Jcn

PhiladelphiaChicago

Des Moines

NewingtonLebanon

Cincinnati

NY Harbor

San Francisco

West Haven

Portland

Seattle

Madison

Minneapolis

Richmond

BaltimoreCheyenne

Salt Lake City

Sioux Falls

Dayton

Hines North Chicago

Black Hills

Denver

FargoFort Harrison

Boise

Martinsburg

LeavenworthPalo Alto

Iron Mountain

Fresno

Long BeachPhoenix

Birmingham

Little Rock

Nashville

y

Fort Myers

Charleston

Fayetteville

Decatur

Asheville

Dublin

Loma LindaLos Angeles

Albuquerque

Durham

HoustonSan Antonio

>? &'()*'+, @*91*. /- &A6*))*96*

Miami

Gainesville

Tampa

Atlanta

Oklahoma City

Anchorage

Honolulu

ECOE Goals

Delivery the highest quality care to veterans with epilepsy, regardless of their geographic locationStreamline epilepsy referrals to sites with expertise and servicesTake epilepsy care to veterans in remote areasTake epilepsy care to veterans in remote areasPromote outreach and educational effortsProvide an efficient and cost-effective mechanism of care deliveryEstablish a national clinical database

We wish to acknowledge and thank veterans who have made enormous sacrifices for our country

Medical Evacuation runway at Landstuhl Army Hospital, Germany

89:$-( ." ;%)")-$% ;$/' $"< =/$-()-'

• ?.0, 7*1*.49+ M2/ +*.7*K (9 O.4Z(;*+'*6(4)), (9 12* *4.), ,*4.+; 247* +B+14(9*K0/.* INO 1249 /12*. +*.7(6*+

• ](+: /- K*7*)/'(9C 5I& -./0 0()K INO (9L&F"LOF 7*1*.49+ .*04(9+ B9:9/M9

!!"!#"$%!$

!

&'() *) +,-+./0*12) 3-,4-)55,*67*528 9+209+)/(9897:9, $; $%!$

& 2 . .<*,8 &= (28.59,; <(; 4.(>?2@9,)25/ -3 49??)/0@*?2*

4.20*A90+.2*; 4&

&79,28*? '+209+)/ B-8295/ C !""#$% &''()"*

!

+),-%.,#/'

D*79 -3 E-779,82*0F?59,9)5D-?9

G/+9 -3 H2?*?82*0I90*52-?).2+

D-?9

&79,28*? '+209+)/ B-8295/ C !""#$% &''()"* 0120 $

3'$/")"* 456'-()7',• 4,9@9?52?J 9+209+)/ 2? 5.-)9 K25. L?-K? ,2)L) M)68. *) GNFO 2)8,2528*00/ 27+-,5*?5

• GNF 7*/ +,-A689 0-8*02P9A 8.*?J9) 2? 5.9 :,*2? 5.*5 8,9*59:,293; 0-8*02P9A )92P6,9); *?A 5.9)9 7*/ :9 )6++,9))2:09 :/)5*?A*,A &'()B 2 A 2 A A A• B92P6,9) 6?A9, )-79 82,867)5*?89) +,-A689 A*7*J9 *?A3-)59, 36,5.9, )92P6,9)

• D9K &'() K25. ?9K 798.*?2)7) -3 *852-? *,9 *@*20*:09 5.*57*/ )6++,9)) 9*,0/ +-)5 GNF )92P6,9)

• &?27*0 A*5* 912)5 5.*5 2?A28*59 5.9 39*)2:2025/ -3 5.2)*++,-*8. 2? -5.9, +*,*A2J7)

&79,28*? '+209+)/ B-8295/ C !""#$% &''()"* 0120 Q

89' $/*#:'"(• B92P6,9) A9@90-+ *359, GNF• G.9 0*59?8/ 2) 6?L?-K? R 86,,9?5 2A9*) *,9 *00 :*)9A -? 802?28*0

)92P6,9 -:)9,@*52-?)• S?9 ./+-5.9)2) 2) 5.*5 GNF 2) *))-82*59A 32,)5 K25. )7*00;

0-8*02P9A )92P6,9) 5.*5 *,9 ?-5 @2)2:09 802?28*00/ -, K25. ,-652?9)8*0+ ''T) *?A 5.*5 5.9)9 )92P6,9) +,-A689 2?8,9*)9A A*7*J9*?A -5.9, 8.*?J9) *))-82*59A K25. 5.9 A9@90-+79?5 -3 4G'

• I9797:9, 5.9 L2?A02?J +*,*A2J7• F5 2) 02L90/ 5.*5 *? *?52 )92P6,9 A,6J 8-60A )6++,9)) 5.9)9• G.9,9 *,9 ?- J--A A*5* 5- )6++-,5 -, ,93659 5.2) *,J679?5• <-,9 5.*? !U 9339852@9 *?A ,90*52@90/ )*39 &'() *,9 *@*20*:09 5-

59)5 5.2) 8-?89+5• F? )9@9,*0 9+209+)/ 7-A90) M?-5 4G'O; 9*,0/ 5,9*579?5 8*?

+,9@9?5 )6:)9V69?5 9+209+)/• F5 2) 89,5*2? 5.*5 A-2?J ?-5.2?J K200 ?-5 )-0@9 5.2) +,-:097

#

Rationale for using anti-seizure drugs now

• &'() *,9 *@*20*:09; K9 .*@9 9159?)2@9 91+9,29?89 6)2?J5.97; *,9 ,90*52@90/ )*39; *,9 L?-K? 5- :9 9339852@9 2?)6++,9))2?J )92P6,9) *5 09*)5; *?A 2? )-79 8*)9); *0)-)6++,9))2?J )-79 9+209+)/ *))-82*59A 8.*?J9)

• 420-5 802?28*0 5,2*0); *?A 9@9? * )7*00 ?95K-,L -3 5,2*0 89?59,);8*? :9 )5*,59A ?-K 5- A9@90-+ 2?3,*)5,6856,9; 598.?2V69)M2?806A2?J 0-?J 59,7 7-?25-,2?J; 958O; +-))2:09 :2-7*,L9,);*?A * :9559, 6?A9,)5*?A2?J -3 5.9 +,-89)) -39+209+5-J9?9)2) 2? 7*? *359, A2339,9?5 ,2)L)

U

;.,( (/$#:$()- '<)%'<,=

G,*67* '+209+)/

D96,-?*0 0-))

&059,9A J9?9 91+,9))2-?F-? 8.*??90)

&852@*52-? -3 728,-J02*

W.28. -3 5.9)9 *,9 8,2528*0 3-, 9+209+5-J9?9)2)X

&1-? )+,-652?J

D9K 82,8625 3-,7*52-?

I989+5-,)49+52A9)'@9,/5.2?J

E.*?J9) 2? *)5,-8/59)

D96,-J9?9)2)

Y

!!"!#"$%!$

$

><)%'<(.*'"',),

'+209+528+,-+

9?)25/

'+209+528+,-+

9?)25/

S?9 .25 S?9 .25

Z*59?5 +9,2-A

E02?28*0B92P6,9)

E02?28*0B92P6,9)

G279

'+209+528+,-+

9?)25/

G279

G279

GK- .25)'+209+528+,-+

9?)25/

G279

<6052+09 .25)E02?28*0B92P6,9)

E02?28*0B92P6,9)

G,*67*

B92P6,9)X

[

;/..?, .? -."-'<(• B-79 *?52 )92P6,9 A,6J) 8*? 2?59,,6+5 L2?A02?J

M4\N; ]4&; ZGT; G4<; Z']; Z&E; ]TN; N^()O• '5.-)61272A9 5,9*579?5 +,9@9?5) 9+209+)/ 2? W&T ,*5)

MN0679?390A 95 *0; '+209+)2* $%%_O• GG` *?A T*:*+9?52? +,9@9?5 ./+9,91825*:2025/ 2? 6?A9,865 8-,591 R *

)02J.50/ A2339,9?5 7-A90M : 0 : 0 3 OMZ2; T,*:9, 95 *0; D96,-:2-0 -3 (2) $%!$O

• E--02?J 8-,591 *,-6?A GNF +,9@9?5) 9+209+)/M(a&7:-)2- 95 *0; &?? D96,-0; $%!$O

• 7GSI 2?.2:25-,) :0-8L 9+209+)/ 2? GB 7289 *?A 7*/ *0)- K-,L 2? )5*56)9+209+5286) 7-A90

M^9?J Z\; `6 Z; T657*?? (\; W-?J <; &?? D96,-0 $%%_OM\6*?J 95 *0; D96,-:2-0 (2) $%!%O

_

@AB ,')C#/', )" B!D /$(,

E-?5,-0

$7

#7

Y7

b092? 95 *0; N,*2? I9); $%%# c

>(9.,#E):)F' (/'$(:'"( G</'7'"(,H '<)%'<,=

D-59 5.*59@9? *359, Q7-?5.);5,9*59A ,*5)A- ?-5 d8*58.A- ?-5 8*58.6+e 5-6?5,9*59A)6:f985)

N0679?390A 95 *0; '+209+)2* $%%_ !%

;.,((/$#:$()- '<)%'<,= )"F#-'F 5= I;J )" (9' /$(

51

2

4

3

4-5

3-5

1-5

2-5

Grade 1 seizure B5*/) 0-8*02P9A

D’Ambrosio et al., Brain 2005

4-5

3-5

1-5

2-5

Grade 2 seizure B+,9*A) 2? 8-,591Z9)2-?

!!

;$)/'F ,-$%< >>D $"F '<)F#/$% >K.DL */$F' 2,')C#/',

D-59g 0*8L -3'E-T )92P6,9

Z27259A 5- 8-,528*0 3-86)

1-5 1-5ECoG ECoG

51

3

2

pt

4

o

Z*8L -3 )8*0+)92P6,9 1s

2-5

4-5

3-5

pt-o

1s

2-5

4-5

3-5

pt-oScalp Scalp

D’Ambrosio et al., Brain 2005 !$

!!"!#"$%!$

Q

1-5

2-5

4-5

3-5

ECoG

F+)20*59,*0

E-?5,*0*59,*0

;$)/'F ,-$%< >>D $"F '<)F#/$% >K.DL ,')C#/',

pt-o

4-1

Scalp

ECoG

Scalp

1s

D’Ambrosio et al, Brain 2009 !Q

tpro

porti

on

0.6

0.8

1.0

*****

Grade1Grade2Grade3

N20*59,*0 *5 -?)95

;/.*/',,)." .? <.,((/$#:$()- '<)%'<,=

EC

o G-e

ven t

0.0

0.2

0.4

Weeks Post Injury0 2-3 4-5 8-9 14-15 17-18 27-28

*** ***

* B+,9*A) 3,-73-86)

(a&7:,-)2- 95 *0; N,*2? ; $%%U !#

!%% !>+, $/' ".( $%)M' )" (9')/ <.,,)5%' $-().",

• E6,,9?5 &'() .*@9 76052+09 798.*?2)7) -3*852-?

• B-79 K-,L K900 3-, ?96,-+*5.28 +*2?• B-79 *,9 )9A*52?Jh -5.9,a) *,9 ?-5B-79 *,9 )9A*52?Jh -5.9, ) *,9 ?-5• B-79 )6++,9)) *:?-,7*0 ?95K-,L *852@25/ 2?&( 7-A90)h -5.9,) *,9 2?9339852@9

• D99A 5- 91*72?9 76052+09 &'() 5- *))9))9339852@9?9)) 2? GNF 7-A90)

![

K."-%#,)."

• '+209+)/ *359, GNF 2) *? 27+-,5*?5 +,-:097 5.*5?99A) 5- :9 )-0@9A

• <-,9 :*)28 ,9)9*,8. 2) ?99A9A; 2?806A2?J 59)52?J?9K9, &'() 2? GNF 7-A90)

• <-,9 802?28*0 ,9)9*,8. 2) *0)- ?99A9A 5-A 5 2 5. . A . 2A959,72?9 5.9 +.9?-79?* *?A 798.*?2)7)*))-82*59A K25. 5.9 9+209+5-J9?28 +,-89)) 2? 7*?

• &'() 7*/ +,-@9 6)9360 2? )6++,9))2?J9+209+5-J9?9)2) 23 6)9A 9*,0/ *?A *++,-+,2*590/

• S5.9, )5,*59J29) 2?@-0@2?J A,6J) 5.*5 A- ?-5A2,9850/ )6++,9)) )92P6,9) -, A9@289) *,9 02L90/ 5-:9 6)9360 *) K900

!_

K#//'"( </'7'"()." ,(/$('*= $?('/ 8NJ

89), ), #"$--'<($5%'O

!c

J:<$-( ." K%)")-$% K$/' $"F ;/$-()-'

• F?A2@2A6*0) K25. 7-A9,*59 5- )9@9,9 GNF ?99A 5- :97-?25-,9A 3-, 9+209+)/ A9@90-+79?5

• &8659 8-?52?6-6) )8*0+; )6:J*09*0; *?A 2?5,*8,*?2*0''T 7-?25-,2?J 7*/ ,9@9*0 )6:802?28*0 )92P6,9) 5.*5*,9 *79?*:09 5- 5,9*579?5 9*,0/

• '*,0/ 5,9*579?5 K25. &'() 7*/ ,9A689 5.9 2?82A9?89-3 4G'

• <-,9 :*)28 *?A 802?28*0 ,9)9*,8. 2) ?99A9A 2? 5.2) *,9*• (-2?J ?-5.2?J K200 A932?2590/ ?-5 )-0@9 5.2) +,-:097

$%

!!"!#"$%!$

!

AED Prophylaxis Does NOT Work inPosttraumatic Epilepsy

!"#"$%"&'()'(*+(

,-.&/#0'12-3)'4!)',5!

63/7"&8/.9':;'4"<%:=&3")'4"<%:=&3")'>=8.&-</-

?5/3"8"'63/7"&8/.9':;'@:3A'1:3A)'@:3A'1:3A

>$"&/#-3'BC/<"C89'D:#/".9''E''Annual Meeting

+

Disclosure

B/8-/

FD1

,;/G"&

?:38=<.-3#9)'&"8"-&#5 #:3.&-#.

?:38=<.-3#9)'&"8"-&#5'#:3.&-#.

H"8"-&#5'#:3.&-#.

6?I',5-&$-

>$"&/#-3'BC/<"C89'D:#/".9''E''Annual Meeting 2012

DC"-0"&) &"8"-&#5'#:3.&-#.

(

Learning Objectives

• D98."$-./#'&"7/"28':;'#</3/#-<'.&/-<8':;'>B!'C&:C59<-J/8'

;:&'"-&<9'-3K'<-."'C:8..&-=$-./#'8"/G=&"8

• @/A5</A5.8';&:$'/3K/7/K=-<'8.=K/"8

>$"&/#-3'BC/<"C89'D:#/".9''E''Annual Meeting 2012L

?<-88/;/#-./:3':;'MINO&"<-."K'D"/G=&"8

• D"/G=&"8' P'K-9'Q'-#=."'89$C.:$-./#'RC&:7:0"KS'

8"/G=&"8

– T(U'5:=&8'Q'/$$"K/-."'8"/G=&"8

– (U'5&8 .:'P'K-98'Q'"-&<9'8"/G=&"8

• D"/G=&"8'VP'K-98'Q'<-."'R=3C&:7:0"KS'8"/G=&"8'Q'

C:8.O.&-=$-./#'"C/<"C89

I"A5/ BW'BC/<"C8/-'(**LXUURD=CC<W'+*SY(+Z[X'I"A5/ B'".'-<)'BC/<"C8/- (*+*X\+Y[P+Z\W U

]%8"&7-./:3-<'D.=K/"8

^ 2/.5'8"/G=&"8

D.=K9 >B!R8S _:W `:<<:2O=C'R$:S M&"-."K 63.&"-."K

D"&7/. +ab+ ,I)',@M +[b bO+\[ ( (\

c:538 +aPa ,@M [( [OP( +* \*

d:=3A +aPa ,@M bU +( [ (OL+

4=&&/ +ab* ,I bL (U ( O

4=&&/ +aa( ,I La* +( ( PO+[

,&/#"'+ab* e,> +UL (U * +\O\\

I"A5/ BW'BC/<"C8/-'(**LXUURD=CC<W'+*SY(+Z[ \

H?MY',5"39.:/3'.:',&"7"3.',MB

• ,-./"3.8'2/.5'8"7"&"'MIN'RC&"K/#."K'8"/G=&"'&/80' (*^S

• !:=%<"O%</3K'&-3K:$/G-./:3'.:'&"#"/7"'2/.5/3'(U'5&8 :;'/3f=&9

– ,<-#"%:)':&

– ,5"39.:/3'R/W7W .5"3':&-<S';:&'+('$:3.58

• M!4'.:'$-/3.-/3'.5"&-C"=./#'8"&=$'#:3#"3.&-./:3

– 4-/3.-/3"K'/3'VP*^'C-./"3.8

– c/.5/3'.5"&-C"=./#'&-3A"'/3'P\^':;'C-./"3.8'25:'5-K'<-."'8"/G=&"8

M"$0/3 _H'".'-<)'_'B3A< g'4"K'+aa*XL(LYUaPO\*( [

!!"!#"$%!$

$

B-&<9'D"/G=&"8

,T*W**+

M"$0/3 _H'".'-<)'_'B3A< g'4"K'+aa*XL(LYUaPO\*( P

h-."'D"/G=&"8'R,MBS

,V*W*(

M"$0/3 _H'".'-<)'_'B3A< g'4"K'+aa*XL(LYUaPO\*( b

,&:8C"#./7"'?:3.&:<<"K'D.=K/"8':;'>B!';:&'

,&:C59<-J/8':;'D"/G=&"8'-;."&'D"7"&"'@"-K'M&-=$-

M&"-.$"3. A&:=C8 ?:#5&-3" I"A5/ >>_

D.=K9 H-3K:$ >B! R3S ?:3.&:< R3S (**( (**L (**L

4#i=""3 bL d ,@M RbUS ,<-#"%: Rb*S

d:=3A bL d ,@M R++aS ,<-#"%: Ra\S

F<j.G3"& bL i=-8/ ?Ik RP\S ,<-#"%: RP[SF<j.G3"& bL i=-8/ ?Ik RP\S ,<-#"%: RP[S

M"$0/3 a* d ,@M R(*bS ,<-#"%: R+a[S

M"$0/3 aa d e,> R(UPS ,@M +'20 R+L(S

4-3-0-'a( d ,I'R\*S _:3"'RP[S

,"#5-K&" a+ i=-8/ ,@M RLUS _:3" R\(S

D"&7/. b+ _ ,@Ml,I R+ULS _:3" R(US

?IkW'?-&%-$-G"C/3"X'hBe)'<"7"./&-#".-$X',I)'C5"3:%-&%/.-<X',@M)'C5"39.:/3

D#5/"&5:=. -3K'H:%"&.8)'?:#5&-3"'h/%&-&9'(**(X'I"A5/ B) BC/<"C8/-'(**LX'?5-3A'-3K'h:2"8."/3)'_"=&:<:A9'(**L' a

B-&<9',:8.O.&-=$-./#'D"/G=&"8

?5-3A'-3K'h:2"38."/3)'_"=&:<:A9'(**LX[*Y+*Z+[W +*

h-."',:8.O.&-=$-./#'D"/G=&"8

?5-3A'-3K'h:2"38."/3)'_"=&:<:A9'(**LX[*Y+*Z+[W ++

>B!'.:',&"7"3.',MBY'M5"'@:C";=<8

• ,&"7/:=8<9'."8."K'>B!8'5-7"'$-39'-K7"&8"'";;"#.8

• _"2"&'>B!8'5-7"'3:.'%""3'-K"m=-."<9'."8."K

• M5"'n-3./"C/<"C.:A"3/#o'-&A=$"3.C C A A

– D5:=<K'."8.'>B!8'85:23'.:'5-7"'-3./"C/<"C.:A"3/#

";;"#.8'/3'-3/$-<'$:K"<8

+(

!!"!#"$%!$

&

,&:8C"#./7"'?:3.&:<<"K'D.=K/"8':;'>B!';:&'

,&:C59<-J/8':;'D"/G=&"8'-;."&'D"7"&"'@"-K'M&-=$-

M&"-.$"3. A&:=C8

D.=K9 H-3K:$ >B! R3S ?:3.&:< R3S

4#i=""3 bL d ,@M RbUS ,<-#"%: Rb*S

d:=3A bL d ,@M R++aS ,<-#"%: Ra\S

F<j.G3"& bL i=-8/ ?Ik RP\S ,<-#"%: RP[S

M"$0/3 a* d ,@M R(*bS ,<-#"%: R+a[S

M"$0/3 aa d e,> R(UPS ,@M +'20 R+L(S

4-3-0-'a( d ,I'R\*S _:3"'RP[S

,"#5-K&" a+ i=-8/ ,@M RLUS _:3" R\(S

D"&7/. b+ _ ,@Ml,I R+ULS _:3" R(US

g:3"8'(**b _ hBe RL(S @/8.:&/#-< ,@M RU+S

1<"/3 (*+( _ hBe R[[S _:3" R[*S

?IkW'?-&%-$-G"C/3"X'hBe)'<"7"./&-#".-$X',I)'C5"3:%-&%/.-<X',@M)'C5"39.:/3

D#5/"&5:=. -3K'H:%"&.8)'?:#5&-3"'h/%&-&9'(**(X'I"A5/ B) BC/<"C8/-'(**LX'?5-3A'-3K'h:2"8."/3)'_"=&:<:A9'(**L' +L

,5-8"'('_:3&-3K:$/G"K'hBe'D.=K9';:&',MB'

63.&"-."K

3#"

':;'

,M

B

1<"/3','".'-<)'>&#5'_"=&:< (*+(X[aY+(a*O\W

hBe

?=

$=

<-./7"

'/3

#/K

"3

+U

,5-8"'('_:3&-3K:$/G"K'hBe'D.=K9';:&',MB'

• ,&/$-&/<9'.:'"7-<=-."'8-;".9'-3K';"-8/%/</.9

• [ObP'9"-&8':<K'2/.5'8"7"&"'MINW'><<'A/7"3',@M';:&'+'2""0

• M&"-.$"3.'A&:=C8Y

– ,&"8"3."K' b'5:=&8' hBe'\\$Ap0ApK';:&'L*'K-98'R3Q[[S,&"8"3."K' b'5:=&8' hBe'\\$Ap0ApK';:&'L*'K-98'R3 [[S

– ,&"8"3."K'bO(U'5:=&8' _:'.&"-.$"3.'R3Q[*S

• `:<<:2"K'=C'.:'(U'$:3.58

• +(^'8.:CC"K'hBe'"-&<9

• 4:&.-</.9Y'+*Wa^'.&"-."K'-K=<.8'78W'PW\^'=3.&"-."K'-K=<.8

1<"/3','".'-<)'>&#5'_"=&:< (*+(X[aY+(a*O\W +\

H?M'e,>'.:',&"7"3.',MB

+'2""0',@M'78W'+'$:3.5'e,>':&'['$:3.58'e,>

M"$0/3 _H'".'-<)'g'_"=&:8=&A +aaaXa+Y\aLO[** +[

H?M'e,>'.:',&"7"3.',MBY'_:'F::K

e,>'['$: R3Q+(*S

e,>'+'$: R3Q+(PS

,Q*W+a

M"$0/3 _H'".'-<)'g'_"=&:8=&A +aaaXa+Y\aLO[**

R S

,@M'+'20'R3Q+L(S

+P

H?M'e,>'.:',&"7"3.',MBY'4:&"'@-&$q

+'2""0',@M'78W'+'$:3.5'e,>':&'['$:3.58'e,>

e,>'['$: R3Q+(*S

e,>'+'$: R3Q+(PS

,Q*W*P

M"$0/3 _H'".'-<)'g'_"=&:8=&A +aaaXa+Y\aLO[**

,@M'+'20'R3Q+L(S

+b

!!"!#"$%!$

#

?:3#<=8/:3

• ,&:C59<-#./#'>B!8'&"K=#"K'-#=."'89$C.:$-./#'8"/G=&"8'

-;."&'8"7"&"'MIN'%=.'3:.'C:8..&-=$-./#'"C/<"C89

• >3./"C/<"C.:A"3/# ";;"#.8'/3'-3/$-<'$:K"<8'5-7"'3:.'%""3'

.&-38<-."K'.:'5=$-3'"7/K"3#".&-38<-."K'.:'5=$-3'"7/K"3#"

• ,:."3./-<'5-&$'2/.5'>B!8':=.2"/A58'%"3";/.8

– N3.&/38/#'-K7"&8"'";;"#.8

– !"<"."&/:=8'";;"#.8':3'%&-/3'&"#:7"&9

• >B!'C&:C59<-J/8'K:"8'_]M'2:&0'/3'C:8..&-=$-./#'"C/<"C89

+a

!!"!#"$%!$

!

!"#$% &$'(")*+(, -./0$.#, 1(+2 3("42"&'(')*'+ $, $%!$

-+.( /0 1233244, 5&

62783 /29:.83 /239.;<=

><=;.)2+', 5<+?=<8@

A)'+.(<8 -9.='93? B2(.';? C 5664"0 7$$*/68

9/#)0+#4($

DE;+.(.<, A;:.83DE;+.;.28<=3, -.3<., F7<+=.'G2E8@<;.28, -9.='93?

G @ .

B(.'8;.4.( [email protected]+? >2<+@5')*'+

G2E8@<;.28

A)'+.(<8 -9.='93? B2(.';? C 5664"0 7$$*/68 :;<:

A 3<@=? 82; E8E3E<= (<3'I

• # )28;7 2=@ *2? 37<:'8 *? < *<*?3.;;'+

• B'.JE+'3 K.;7.8 72E+3 24 ;7' .8LE+? ='<@.8M ;27239.;<=.J<;.28

F = . = ;. = @– F28HE=3.H', =<3;.8M 3'H'+<= 3'(28@3• N+'<;'@ K.;7 .8;+<H'82E3 97'82*<+*.;<= K.;7.8.;.<= +'32=E;.28

B'.JE+'3 >'(2)' O8;+<(;<*='

• &<.=? 3'.JE+'3 372+;=? <4;'+ @.3(7<+M'

• B'H'+<= )'@.(<;.283 ;+.'@ 2H'+ ;7' 8'P; 4'K)28;73

7 * *.; = * . = ;. ;– 97'82*<+*.;<=, 2P(<+*<J'9.8', ='H';.+<(';<)

• A; Q )28;73 24 <M', @'H'=293 8'K 283';<;28.( 3'.JE+'3, R!% (=E3;'+3 9'+ @<?

!!"!#"$%!$

$

O84<8;.=' B9<3)3

• N+'<;'@ K.;7 AFN/ ;7'8 ;29.+<)<;' K.;7 28=?)2@'3; *'8'4.;

• S%T +'@E(;.28 .8 39<3)3 E3.8M H<=9+2<;' U #%)M":M"@<?)M":M"@<?

• A@).;;'@ <; $! )28;73 24 <M' ;2 *'M.8 ;7':';2M'8.( @.';

V'('8; F2E+3'

• O)9+2H')'8; 2((E++'@ K.;7 (2)*.8<;.28 @.';<8@ H<=9+2<;' <4;'+ 3'H'+<= )28;73

• --W .)9+2H'3X @.';<+? ;7'+<9? @.3(28;.8E'@ <;# ?'<+3 24 <M'# ?'<+3 24 <M'

• &'H'=29)'8; .)9+2H'@, *E; 3;.== 7<3 )2@'3;)2;2+ <8@ =<8ME<M' @'=<?3

=53 "6> ?6'"6*#% @/8A &/#B +' -./0$.#,

Y.'3')'+ '; <=0 ! "#$%&'%($)( $%!!Z$QX[SS [\$0

?2.")* +6 !0/6/)"0 !"($ "6> C(")*/)$

• A=K<?3 (283.@'+ <*E3' .8 <8? .84<8; K.;78'K 283'; 3'.JE+'3 <8@ 3E*@E+<=7')2++7<M'0

• B'.JE+'3 (<8 *' *2;7 +'4+<(;2+? <8@ )<?@'H'=29 .8;2 .84<8;.=' 39<3)30

• F283.@'+ 82897<+)<(2=2M.( <99+2<(7'3 .4)'@.(<;.28 ;+.<=3 <+' E83E(('334E=0

11/14/2012

1

!"#$%&$ #&' (() %&*+,- -.#/"#-%0 (1%231,4

Michael R. Sperling, M.D.Thomas Jefferson University

Philadelphia, PA

!"#$%&'( )*%+#*,- ./&%#0- 1 5&&/#2 633-%&$

7%,02+,/.3

2'"#3*,4#$ ."%04

. % )% % 356

2'07$# /8 9#+'0%/(,4%*5/(,7+0%(:

.7(/;%/(< )%,'%< 356=4'$"'< 2#7$/(#><

?#$0#>< 3*,4#$ ."%04<@7(AB#&C< 2#7$/*'&#<

D#A0$/(%&,

!"#$%&'( )*%+#*,- ./&%#0- 1 5&&/#2 633-%&$ 89:8

9#,#'$&4 5/(0$'&0, E%047(%;#$,%0-

;3#.&%&$ <=>30-%?3,

F%,&7,, 04# 70%+%0- /8 ))G '(A (#7$/%"':%(:0#&4(%H7#, %( A%':(/,%(: */,0 0$'7"'0%& #*%+#*,-

Di h EEG d i i d tDiscuss how EEG and neuroimaging are used to assess prognosis in post-traumatic epilepsy

!"#$%&'( )*%+#*,- ./&%#0- 1 5&&/#2 633-%&$ 89:8

Diagnosis

Diagnosis is clinically driven Reliance upon history Interictal EEG may aid in confirming clinical suspicionsuspicion

Interictal spikes, focal slow waves, normal

Ictal EEG may be necessary to establish diagnosis

Verify diagnosis of epileptic seizureVerify diagnosis of psychogenic seizure or other non-epileptic event, e.g., syncope

Interictal EEG

Interictal spikes consistent with frontal or temporal contusions

Interictal EEG

EEG may suggest another etiology

11/14/2012

2

Ictal EEG-Video MRI

Provides evidence for the presence of a structural lesion

Supports presumed diagnosis of post-traumatic epilepsyLocation of lesion may be typical for PTE

Frontal, temporal or occipital poleBeneath a depressed skull fractureEstablishes presence of blood or hemisiderinIf atypical, may lead to questioning diagnosis

CT: Contusion MRI: Contusion

MRI

Certain MRI findings may lead to questioning diagnosis of PTE

Multimodal Imaging

Storti et al. Magn Reson Mater Phy 2012High density EEG, fMRI

11/14/2012

3

MRI Lesion and PTE

Lesion location and development of PTECortical vs subcortical vs bothSingle vs multiple lesionsSubdural hematoma vs intraparenchymalSubdural hematoma vs intraparenchymal lesion

Presence of hemosiderin and development of PTE

Location and prevalence impair accurate assessmentWalled vs incompletely walled lesions

Cumulative Probability of Developing PTE at 60 Months (20/184)

Variables N

No. with PTE

Prob at 60 mo (%) 95% CI (%)

p Value (log-rank test)

Sequelae of sSDH-C

Yes 23 9 39 13 19 19 59 08 <0 001Yes 23 9 39.13 19.19-59.08 <0.001No 112 11 9.82 4.31-15.33

No MRI lesion verses 21 1 4.76 0-13.87HG lesions only 29 7 24.14 8.56-39.71 0.067G only 9 1 11.11 0-31.64 0.508H only 33 2 6.06 0-14.2 0.824HG lesions + H 34 6 17.65 4.83-30.46 0.167

SDH-C: subdural/contusion; H: hemosiderin; G: gliosis Messori et al 2005

Incomplete vs Complete Wall Around Hemosiderin Deposit

Complete wall around hemosiderin Incomplete wall around hemosiderin

Incomplete wall lesions (and IW that later transform to CW lesions) have greater probability of developing PTE Messori et al 2005

Blood-Brain Barrier and PTE

sLORETA identified delta and contrast enhancement with MRITomkins et al. JNNP 2012

Diffuse Axonal Injury

Paterakis. J Trauma 2000Effect on cortical connections

MRI Ascertainment of LesionsArfanakis et al. AJNR 2002

A. Small hemorrhagic lesion in left occipital lobeB. DWI shows same lesionC. Trace map of diffusion shows same lesionD. Lattice index (fractional anisotropy) shows decreased anisotropy in left internal capsule and anterior callosum

11/14/2012

4

Blood-Brain Barrier Disruption and PTE

32 patients with head trauma – 17 had PTEPatients studied at varying intervals after trauma – 5 days to 18 years, though most late80% of patients with PTE had MRI lesion

Tomkins et al. JNNP 2012

p30.8% of patients without PTE had MRI lesion76.9% of patients with PTE had BBB disruption vs. 33.3% of patients without PTE (p < 0.05)Volume of BBB disruption was significantly larger in patients with PTE (9.8 + 2.6 vs 1.7 + 0.6 cm3, p = 0.001

Prognosis for Developing PTEn = 137

Angeleri F et al. Epilepsia 1999

Relative Risk of PTE in 137 Patients

Variables Relative risk 95% CI

Early seizures 8.58 2.87-25.65Single CT lesion 3.43 1.23-9.57Focal EEG 3 49 1 10-11 05Focal EEG 3.49 1.10 11.05GCS 0.93 0.30-2.96

Angeleri F et al. Epilepsia 1999

EEG and Brain Volume Loss in mlVietnam Series

EEG Total 0-25 25-50 50-75 > 75

Abnormally slow 173 62 51 24 36(36%) (30%) (14%) (21%)

Epileptiform with 49 8 11 7 23or without slowing (14%) (22%) (14%) (47%)

Jabbari et al Electroenceph Clin Neurophys 1986

EEG and Seizures in PTEVietnam Series

Measure NormalN = 239

Gen/foc slow

N = 173

Epileptiform

N = 49

P value

T t l V l 26 50 76 0 0001Total Volume Loss (mean in

ml)

26 50 76 0.0001

Seizure 35% 63% 84% 0.0001

Jabbari et al Electroenceph Clin Neurophys 1986

Management

Antiepileptic drugs – mainstay of therapySurgery – for medically refractory cases

Best prognosis with single lesionMultifocal EEG probably worse prognosisMultifocal EEG probably worse prognosisHistory of trauma or other injury in adults associated with better surgical outcome (Mathern et al)Role of multimodal assessment tools to be defined

11/14/2012

5

Impact on Clinical Care and Practice

EEG and MRI are used to aid in diagnosis of postraumatic epilepsyDifferent techniques elucidate different lesion types

– Lesion type influences risk of PTE– Provide data to identify those at risk for

developing PTE

May be used to identify candidates for therapeutic intervention, e.g., anti-epileptogenesis

1

Page 1

Traumatic Brain Injury and Traumatic Brain Injury and Psychogenic Psychogenic SeizuresSeizures12/2/2012

Martin Martin SalinskySalinsky M.D. M.D. Portland VAMC Epilepsy Center of ExcellencePortland VAMC Epilepsy Center of ExcellencePortland VAMC Epilepsy Center of ExcellencePortland VAMC Epilepsy Center of Excellence

Oregon Health & Science Oregon Health & Science UniversityUniversityPortland, OregonPortland, Oregon


Psychogenic Non-Epileptic Seizures (PNES)

Transient alterations in behavior resembling an epileptic seizure but not due to paroxysmal neuronal discharges;

» without other physiologic abnormalities» without other physiologic abnormalities» with probable psychological origin

PNESImpact on the Patient

Antiepileptic Drug therapy (90%)» Side effects

Disability» Restrictions on driving

R i i k» Restrictions on workPsychological/Social effectsCost of assessment and treatment

Psychogenic Seizures (PNES)Frequency

King et al 1982 20%Bowman et al 1996 33%Martin et al 2003 32%Benbadis et al 2004 30%

inpatient video-EEG evaluations (% of admissions)

Benbadis et al 2004 30%Salinsky et al 2011 26%

King DW et al; Neurology; 1982Bowman ES, Markand ON Am J Psychiatry; 1996Martin R et al, Neurology; 2003Benbadis SR et al, Epilepsia; 2004Salinsky MC, Neurology; 2011

Post-traumatic Epilepsy

Population-based studies» Chart review, administrative databases1,2

» Seizures assumed to be epilepticFew cases confirmed by monitoringy g

1Annegars JF et al; NEJM 19982Pugh MJ, Amuan A, Neurology 78:S06.001; 2012

TraumaticBrain Injury

SeizuresPostPost--traumatictraumaticseizuresseizures

PNESPNES

2

Page 2

Head Injury and Psychogenic Seizures (PNES)

Author Type # of PNES patients

Percent with documented head injury

Mean age (range)

Barry et al,Epilepsia 1998

Retrospective; video-EEG monitoring

157 24% 34 (15-56)

monitoring

Westbrook et al, Epilepsia 1998

Retrospective; video-EEG monitoring

102 32% 34 (17-57)

PNESSeverity of Head Injury

60

80

100

of p

atie

nts

Barry et alWestbrook et alAnnegars et al

0

20

40

Mild Moderate Severe

Perc

ent o

Severity of TBI

Annegars et al, NEJM; 1998

TBI Severity and SeizuresU.S. Veterans

Hx of mildmild TBI as cause of seizures »» 82% with PNES82% with PNES

HX of severesevere TBI as cause of seizuresHX of severesevere TBI as cause of seizures»» 90% with epilepsy90% with epilepsy

Seizures after moderate-severe TBI

18%27%

Result of video-EEG monitoring (n=127)

Psychogenic

55%

Epileptic

Nondiagnostic

Hudek et al, J Head Trauma Rehabil; 2004

TBI and PNESU.S. Veterans

seizure risk (post-traumatic)>50% with severesevere military TBI1

rates of mild TBI (15-19%)2,3

Associated with PNESAssociated with PNES

post-traumatic stress disorder (PTSD)Associated with PNES in civilian studies4

33-65% in mild military TBI 2,3

(Less in moderate-severe TBI)6

1Raymont et al, Neurology; 20102Hoge et al, NEJM; 20083Pietrzak et al, J Nerv Ment Dis; 2009

4Bowman and Markand, Am J Psychiatry; 19965Zatzick et al, Arch Gen Psychiatry; 2010

18% 25%

4%

12%41%

Veterans(N=203)

40%

26%

4%

3%

Civilians(N=726)

18% 25%

4%

12%41%

Veterans(N=203)

40%

26%

4%

3%

Civilians(N=726)

Discharge Diagnoses

PNES PNES

12%41% 3%

27%A B

Epilepsy PNES Mixed NES Other Nondiagnostic

12%41% 3%

27%A B

Epilepsy PNES Mixed NES Other Nondiagnostic

PNES – Psychogenic non-epileptic seizuresES – Epileptic seizuresNES other – Syncope, parasomnia, other

Salinsky et al, Neurology; 2011

3

Page 3

TBI as Cause of PNES Civilians vs. Veterans

56%

40%

60% % with proposed TBI etiology

p<0.01

26%

0%

20%

Civilian PNES Veteran PNES

For veterans - 50% of TBIs were military TBIs

Veterans with PNES vs. ESMental Health Evaluations

PNESPNES ESES ppN 68 54

Age at Admission 48.4 49.9 NS

Any Axis 1 Diagnosis (%) 77 9 66 7 NSAny Axis 1 Diagnosis (%) 77.9 66.7 NS

Number of Axis 1 Diagnoses 3 (0-8) 2(0-6) 0.01

Any Axis 2 Diagnosis (%) 27.9 16.7 NS

20

40

60

rcen

t of p

atie

nts

Axis I Diagnoses by Seizure TypePsychogenicEpileptic

******

0

20

PTSD Major Depression

ETOH abuse

Substance abuse

Other Depression

Adjustment d/o

Per

*** p<0.001

Salinsky et al, Epilepsy and Behavior; 2012

Psychiatric HistoricalTotal Axis I diagnoses Age at admissionAny Axis II diagnosis Sex PTSD Duration of seizuresMajor depression

Veterans with PNES vs. ESMultivariate AnalysisVeterans with PNES vs. ESMultivariate Analysis

Other depressionAlcohol abuseSubstance abuseAdjustment d/oBipolar d/oAny Psychiatric AdmitNumber of Psychiatric Admits

Variables Odds Ratio p>Chi-square

PTSD 5.7 <0.001

TBI

PTSD

TBI PNES(mild)

Hoge et al, NEJM; 2008Pietrzak et al, J Nerv Ment Dis; 2009

TBI and Psychogenic Seizures Key Points

1.1. Traumatic Brain Injury Traumatic Brain Injury ++ seizuresseizures= = epilepsy

» Some have PNES

22 Mild TBIMild TBI2.2. Mild TBI Mild TBI » Strong association with PNES» Weak association with epilepsy

3.3. PTSDPTSD is strongly associated with PNES

!!"!#"$%!$

!

!"#$%&'( )'*'$+,+*- ./ 0.1-2#'",'-%& 34%(+415

!"#$%&'()(&* +,-&*(".* /.,01%)(2"3/%()4&'(')*'+ $ $%!$&'(')*'+ $, $%!$

6+//#+5 07 8(."*- )9&-.-/-01 02 3'4+0/4+5'+6

71-.'+/-86 02 9:;*;); ;8 <-+)-15=;)>=-:?+'1@/ 02 9:;*;);

9)'+-(;1 AB-:'B/6 C0(-'86 D :**"'( )++-%*$

9%1&(.1"#+

30 2-1;1(-;:?-/(:0/4+'/

9)'+-(;1 AB-:'B/6 C0(-'86 D :**"'( )++-%*$ ;<=;

>+'#*%*$ ?@A+&-%B+1

• E4*:-/='? /4+5-(;: 'FB'+-'1('"048(0)'/ -1 EGA -/:-)-8'?• H1='+'18 :-)-8;8-01 ?-224/' 1;84+' 02 -1I4+6 -1 G<H41:-J':6 80 +'/4:8 -1 'B-:'B/6 02 20(;: 01/'841:-J':6 80 +'/4:8 -1 'B-:'B/6 02 20(;: 01/'8• H1.;/-.' -1.'/8-5;8-01 02 EGA 028'1 (=;::'15'?":-)-8'?*6 ;?='/-01/"K'*/ K-8=-1 ;+';/ 02 '1('B=;:0);:;(-;• &'/B-8' :-)-8;8-01/ :-)-8'? '.-?'1(' /455'/8/'22'(8-.'1'// ;1? B+0)-/' 02 /4+5-(;: -18'+.'18-01 20+EGA

9)'+-(;1 AB-:'B/6 C0(-'86 D :**"'( )++-%*$ ;<=;

H1/'+8 .-?'0 02 K;8'+ /:-?'

C-:'18 'B-?')-( 02 =';? -1I4+6

• G+;4);8-( <+;-1 H1I4+-'/L28CM (0))01– !N$ !NO )-::-01 ;?4:8 (;/'/ G<H"6+ -1 A7"7C9– P%%Q =0/B-8;:-R;8-01/ ;1? S%Q ;?4:8 ?';8=/"6';+– #OS,%%% (=-:?+'1 K-8= G<H"6+ -1 7C9– T0/8 (0))01 -1 60415 L);:'/M ;1? ':?'+:6

• E0/8 8+;4);8-( 'B-:'B/6 L023M 2+'U4'18 ;28'+ G<H– !% $%V /'.'+' G<H B;8-'18/ ?'.':0B EGA– G<H ;((8/ 20+ #V 02 ;:: 20(;: 'B-:'B/6 ;1? SV 02 ;::'B-:'B/6 +'2'++'? 80 /B'(-;:-R'? ('18'+/

– W0415'+ ;5' ;1? =-5='+ G<H /'.'+-86 -1(+';/' +-/J

X-/J 2;(80+/ 20+ +'2+;(80+6 /'-R4+'/ B0/8=';? -1I4+6

• A;+:6 /'-R4+'/• E'1'8+;8-15 -1I4+6• &'B+'//'? /J4:: 2+;(84+'• C4* ?4+;: =');80);

5.%4 /6"1) 789:, "2 $/)(&.)* ;()- <=> :&*$".,#&,(3/%%4

!!"!#"$%!$

$

!%%Q /'.'+' G<H"6';+

!S%%% ?'.':0B EGA B0/8 G<H

YS%%% *+D (;/'/ 02)'?-(;::6 +'/-/8;18 EGA

4+# 5+'# -1 7C

?-/) (* /$$:"$:(/)& :"%& 2": *1:@&:4AA

G+';8)'18 02 AB-:'B/6• T'?-(;: G+';8)'18 K-8= ;18- 'B-:'B8-( ?+45/ L9A&/M K-::

(018+0: ;*048 $"P+?/ 02 (=-:?+'1 K-8= 'B-:'B/6• H2 )'?-(;: 8+';8)'18 -1'22'(8-.'Z– C4+5'+6 022'+/ +';: :-J':-=00? 02 -)B+0.')'18 ;1?"0+(4+'(4 '

– C4+5-(;: '22'(8-.'1'// (018-14'/ 80 -1(+';/'– [-?' .;+-'86 02 /4+5-(;: 0B8-01/ )';1/ );16 ?-22'+'18(;1?-?;8'/ 20+ 'B-:'B/6 /4+5'+6

• C4+5'+6 10K +'B+'/'18/ ; =-5=:6 '22'(8-.' :0K +-/J8+';8)'18 20+ );16 (=-:?+'1 K-8= TXA\*48\

• C4+5-(;: ?'(-/-01 );J-15 ?'B'1?'18 01 'F8'18 02(.&'(%E'-%.* 02 K='+' 8=' 'B-:'B/6 ;+-/'/ 2+0)\

>=;::'15'/ 80 /4+5-(;: ;BB+0;(= 80 EGA

• ]0(;:-R;8-01" B08'18-;: 20+ )4:8- 20(;:-86– G+;4);8-( -1I4+6 (=;+;(8'+-/8-(;::6 F%//"1+ (+11(%G+(5 -. %,4'#- /.&'( #+$%.* ./ +4%(+4-.$+*+1%1 HIJ

– K'#+ -. L'B+ 1%*$(+ /.&'( %*A"#5K'#+ -. L'B+ 1%*$(+ /.&'( %*A"#5

• C(;++-15";?='/-01/– X'5-01/ 02 B0/8 8+;4);8-( ;+;(=10-? /(;+ ;1?;?='/-01/ -)B;-+ ;*-:-86 80 B0/-8-01 /4*?4+;: 5+-?':'(8+0?' ;++;6/

&'B8= ':'(8+0?'/

H18'+=')-/B='+-(':'(8+0?'/

]0(;:-R;8-01 -1 EGA• >:0/'? =';? -1I4+6

• E;8=0B=6/-0:056 F%//"1+ ?':-.'+6 02 );//-.' '1'+56L;((':'+;8-01"?'(':'+;8-01 0+ *:;/8M 80 *+;-1B;+'1(=6);– >0184/-01/– ^')0++=;5'/– 9F01;: /=';+-15, '?'); ;1? -/(=')-;

• E'1'8+;8-15 =';? -1I4+6• E;8=0B=6/-0:056 *:;/8 (01' 02 '1'+56 B+0?4('/ (-(;8+-F-1 8=' (0+8'F

!!"!#"$%!$

P

!_`$ !__$ ;8 W3^ $S B;8-'18/ K-8= EGA /84?-'? :0(;:-R;8-01"B;8=0:056!_`$ !__$ ;8 W3^ $S B;8-'18/ K-8= EGA /84?-'? :0(;:-R;8-01"B;8=0:056TXH, 1'4+0B/6(=, AAa, $!"$S -(AAa!O B;8-'18/ 8')B0+;: 3:K>M NOC ;//0(-;8'? K-8= TGC ;1? abb&/4+5-(;: 048(0)'` B;8-'18/ 1'0(0+8-(;: ?-? K':: -2 K:9C?PK:0OCN >3!C?Q '.-?'18

B/* / @:"1$ *&(C1:& 2"3( *&3".,/:4 )" -&/, ):/1#/ /:& ,(22(31%))" %"3/%(C& /331:/)&%4 /., )-(* *-"1%, ,&)&: *1:@(3/%(.)&:D&.)(".E

)3P /=0K-15 'F8'1/-.' ?-B0:' (:4/8'+ ;:015 );+5-102 B0/8 8+;4);8-( +'5-01 02 B0+'1('B=;:6N X'/'(8-01+'1?'+'? B;8-'18 /R+ 2+''N

HC9C L!(8;: H18'+-(8;: "EA>G #1;:6/-/ *6 "8;8-/8-(;:E;+;)'8+-( T;BB-15 cFETdM

T(3;::6 Q9, E;-5' 9], e;+5='/' a, f=;15 ^, 30.0816 Ag g+, CB'1('+ CC, f4*;:Ha, <:4)'12':? ^N ]0(;:-R-15 .;:4' 02 -(8;: -18'+-(8;: CEA>G ;1;:6R'? *6 CETLHC9CMN AB-:'B/-;N $%%S C'Bh#iL_MZ!#S% i#

9+;(=10-? /(;++-15"2-*+0/-/• X'5-01/ 02'1('B=;:0);:;(-; 8=;8;BB';+ .;(;18 01 /(;1/;(84;::6 2-::'? K-8= ?'1/'6K'* :-J' /(;+

• G=-/ ?'1/' /(;+ ?-224/':6;?='+'/ 80 B-; "/4+2;('.'-1/ );J'/ B;//-15/4*?4+;: ':'(8+0?'/?-22-(4:8" B'+-:04/

C(;++-15 .-?'0 02 ?-22-(4:86 0B'1-15?4+; ='+'B;//K0+?

!!"!#"$%!$

#

!# 6+ 0:? 2');:' j B'1'8+;8-15 *-=')-/B='+-( L8+'' *+;1(=M -1I4+6/'.'+' EGAh AAa ?-224/' K-8= ]B+'?0)-1;1('N

^')-/B='+'(80)6 K-8=048-)B+0.')'18

&'1/' ;?='/-01/ ;1? ;.;/(4:;+ 8-//4'2041? ;8 /4+5'+6

•$! B;8-'18/"!O 6';+ -18'+.;: K-8= EGAN•i"$! /'-R4+' 2+'' L$`VM 93& i =;? k$/R+/")018=N•S"$# =;? /'-R4+' +'?4(8-01

abb& bX Al>A]]A3G b7G>bTAC H3 `PV

SO EGA B;8-'18/ 0.'+ !% 6+ B'+-0? +'.-'K'?NP%"SO =;? 8')B0+;: :0*' 01/'8N T0/8 (0))01 '8-0:056m *:4188+;4);

!_"P% A15': >:;// !

EbCG GX97T9GH> G]A >9CAC &b 9C [A]] C7XaH>9]]W9C 3b3 GX97T9GH> AGHb]baW GATEbX9] ]b<A

>9CAC

$%%S $%%i !!B8/ L;.5 ;5' P%h i ),S 2M K-8= TX EGA41?'+K'18 e3C

i )0/ O#V /'-R4+' +'?4(8-01!$ )0/ `SV /'-R4+' +'?4(8-01$# )0/ _OV /'-R4+' +'?4(8-01

$"!! B;8-'18/ EGA XF K-8= e3C *08= *'(;)' CfX nXAA

K'*'((% '*F >%,@#%&G +-7 '(7

• K+-#.14+&-%B+ #+B%+D '- !>NO '*F NNO

• )+F%&'((5 #+/#'&-.#5 +4%(+415 R 14.*-'*+."1#+&"##+*- &L#.*%& 1+%E"#+1 F+14%-+ .4-%,'(#+&"##+*- &L#.*%& 1+%E"#+1 F+14%-+ .4-%,'(F.1%*$ ./ ; .# ,.#+ '*-%&.*B"(1'*-1

• =S 4'-%+*-1 H;< 1"#$+#%+1J /.# 023 =TTU ;<=<

!!"!#"$%!$

S

!"#$+#5 254+1

]0*'(80)6 #%V^')-/B='+080)6 P%V>;::0/080)6 $%Ve;54/ 3'+.' C8-)4:;80+ !%V

3*$+( N('11

!%

!$

!#

>:;// He:

%

$

#

i

`

C'-R4+' n+'' X;+' &-/;*:-15 [0+8=K=-:' 30 <'1'2-8

>:;// HHH>:;// HH>:;// H

N.*&("1%.*1

• !"#$+#5 %1 ./ @+*+/%- %* 1+(+&-+F %*F%B%F"'(1D%-L 023

– VWX L'F 1%$*%/%&'*- %,4#.B+,+*- %* 1+%E"#+."-&.,+1 H3*$+( C '*F CCJ."-&.,+1 H3*$+( C '*F CCJ

– YWX L'F D.#-LDL%(+ %,4#.B+,+*- %* 1+%E"#+."-&.,+1 H3*$+( C CCCJ

• N.#4"1 &'((.1.-.,5 %1 1"&&+11/"( '1 ' 4'((%'-%B+4#.&+F"#+Z '&L%+B%*$ ' [D.#-LDL%(+\ ."-&.,+%* SWX ./ &'1+1

0"@(%1L+F !"#$%&'( ?"-&.,+1 %* 023

• ^;J-)-;1 500? 0+ 'F('::'18 048(0)'/ -1 `PV• ^;+8R2-':? EGA 8')B :0*' (;/'/ ?0 ;/ K':: ;/

101 EGA 8')B :0*' (;/'/• g-;15 i!V L!!"!`M 8+';8'? /4+5-(;::6 =;?

? :: 8 8500? 'F('::'18 048(0)'/

• ]'' $"$ K-8= EGA C'-R4+' 2+'' K-8= e3C• X;11;::- ;1? ]-)*+-(J #S iSV /'-R4+' 2+''h OSV

-)B+0.'? K-8= >>C

!".3%1,&G $:&$".,&:/.3& "2 2/D":/6%& "1)3"#&

C,4'&- .* N(%*%&'( N'#+ '*F 0#'&-%&+

•]0(;:-R;8-01 02 EGA -/ ?-22-(4:8 ?4' 80 ?-224/' ;1?K-?'/B+';? 1;84+' 02 -1I4+6•>018')B0+;+6 101 -1.;/-.' 241(8-01;: -);5-15 /84?-'/LTAa HCM );6 (018+-*48' 80 :0(;:-R;8-01LTAa, HCM );6 (018+-*48' 80 :0(;:-R;8-01

•H1.;/-.' ':'(8+0?' B:;(')'18 -/ )0+' :;*0+-04/, 8-)'(01/4)-15 ;1? B+0*;*:6 ;//0(-;8'? K-8= 5+';8'+ +-/J 02/4+5-(;: (0)B:-(;8-01/•E+0)-/-15 +'/4:8/ =;.' *''1 0*8;-1'? K-8= /4+5-(;:8+';8)'18 02 EGA ;1? /=04:? *' (01/-?'+'? 20+ 8=0/'B;8-'18/ ?')01/8+;8-15 )'?-(;: +'/-/8;1(' 80 EGA

!!"!#"$%!$

!

!"#$ %&'()'$*+ ,-*./-#012"3+.(#*"3# '34 5.6"&*$7)

&'(')*'+ $, $%!$

-./'01 23 45+6'7, 8&9 : ; <1 59+.:'//.+ =7; <1=5+)=7&'0=+>)'7> .: ?'@+.A.BC

8=C. <A575( D+5E.7=91.'75F, D+5E.7= G4D

D)'+5(=7 H05A'0/C 4.(5'>C I 533('. 8//$*36

9*#+."#(&/

H5/=5, 8D9, J'+>'F,G0/1'+ 4)5>1, K@7;*'(L,G<M, ?'@+.0=(', ?2N

O'/'=+(1 P+=7>/

D)'+5(=7 H05A'0/C 4.(5'>C I 533('. 8//$*36 :;<:

=/'&3*36 >?@/+$*A/#

• Q. /@))=+5E' >1' )=57 0.57>/ :+.) >15/=:>'+7..7R/ /'//5.7•Q. 0+'/'7> =7 =AB.+5>1) :.+ )=7=B')'7> .: 9./>>+=@)=>5( '05A'0/C

D)'+5(=7 H05A'0/C 4.(5'>C I 533('. 8//$*36 :;<:

SA=/1 9=7'A

• 27(+'=/'; +5/L .: '05A'0/C 5/ A5)5>'; >.).;'+=>' =7; /'6'+' (565A5=7 QM2 T15(1(.)0+5/'/ UV .: =AA (=/'/

• 27 0'.0A' @7;'+ =B' WU C'=+/ QM2 57(+'=/'/• 27 0'.0A' @7;'+ =B' WU C'=+/, QM2 57(+'=/'/>1' +5/L :.+ PQ<4, <94

• O5/L S=(>.+/ 57(A@;'X *+=57 (.7>@/5.7, 4&N,A57'=+ .+ ;'0+'//'; :+=(>@+', KY< Z $# 1.@+/,=B' .6'+ [U C'=+/

SA=/1 9=7'A

• O5/L :.+ '05A'0/C =:>'+ (565A5=7 QM2 5/ B+'=>'/> 57>1' :5+/> >T. C'=+/ =:>'+ QM2 57 )./> />@;5'/'F('0> :.+ .7' />@;C /@BB'/>57B >1=> /'6'+'QM2 >1' +5/L 0'+/5/>/ :.+ !% C'=+/QM2 >1' +5/L 0'+/5/>/ :.+ !% C'=+/

D7>5'05A'0>.B'7'/5/

• ?'T *5.)=+L'+/ .: +5/L =+' 0+.)5/57BX 8O2>'(175\@'/– N500.(=)0=A (1=7B'/27>'+5(>=A /05L' :'=>@+'/ :8O2– 27>'+5(>=A /05L' :'=>@+'/, :8O2

• HHP– 9NSY/ 9=>1.A.B5(=A 15B1 :+'\@'7(C ./(5AA=>5.7/

• D8Q 9HQ 5)=B57B• ?. ;':575>56' B'7'>5( *5.)=+L'+/

!!"!#"$%!$

$

&'*=>'

• 9+.01CA=(>5( DH&/ +';@('; =(@>' /C)0>.)=>5(/'5E@+'/ =:>'+ /'6'+' QM2 *@> 7.> '05A'0/C– DH&/ )=C 0+.6' @/':@A 57 /@00+'//57B'05A'0>.B'7/5/'05A'0>.B'7/5/

2)=B57B =7; HHP 57 9./> Q+=@)=>5(H05A'0/C

• HHP =7; 8O2 =+' 5)0.+>=7> 57 >1' ;5=B7./5/ .:9./> >+=@)=>5( '05A'0/C ]9QH^

• &5::'+'7> >'(175\@'/ 'A@(5;=>' ;5::'+'7> A'/5.7>C0'/C0– K'/5.7 >C0'– 9+.65;' ;=>= >. 5;'7>5:C >1./' => +5/L :.+;'6'A.057B 9QH

• 8=C *' 5)0.+>=7> >. 5;'7>5:C (=7;5;=>'/ :.+>1'+=0'@>5( 57>'+6'7>5.7

9./> Q+=@)=>5( H05A'0/C Q+'=>)'7>

• DH&/ )=57/>=C .: >1'+=0C• 4@+B'+C– M'/> 0+.B7./5/ T5>1 = /57BA' A'/5.7

A 5: A P 1 5–8@A>5:.(=A HHP 1=/ = T.+/' 0+.B7./5/– O.A' .: )@A>5).;=A =//'//)'7> >..A/

Q+=@)=>5( M+=57 27_@+C =7; 40'AA/

• Q+=@)=>5( *+=57 57_@+C =7; /0'AA/ ;. 7.> 5)0AC'05A'0/C– 4.)' T5AA 1=6' 9/C(1.B'75( ?.7'05A'0>5( 4'5E@+'/] 9?H4^

• 85A; .+ )575)=A QM2– 4>+.7B =//.(5=>5.7 T5>1 9?H4–`'=L =//.(5=>5.7 T5>1 '05A'0/C

• 9./> >+@)=>5( />+'// ;5/.+;'+ 5/ =//.(5=>';T5>1 9?H4

Documents

Managing Common Complex Symptomatic Epilepsies - Hope4Harper