2013 CME Annual meeting in multiple sclerosis How to ...On behalf of the Serono Symposia...

2013 CME Annual meeting in multiple sclerosisHow to translate new insights in MSinto clinical practiceIstanbul, Turkey - 31 May - 1 June 2013

ABSTRACT BOOK

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Welcome note

David BatesChairmanNewcastle upon Tyne, UK

Magnhild Sandberg-WollheimCo-ChairLund, Sweden

Dear Colleague,

On behalf of the Serono Symposia International Foundation, it is our pleasure to welcome you to the 2013 annual continuing medical education (CME)-accredited meeting: ‘How to translate new insights in MS into clinical practice’. At this live educational conference, leading international experts will share cutting-edge research on the pathogenesis and treatment of multiple sclerosis (MS) and discuss how best to incorporate our knowledge into the everyday treatment of patients. You will also have the opportunity to earn CME credits.This live educational conference will consist of six interactive sessions. Session I will cover current diagnostic methodology, with advice on how to ensure an accurate and timely diagnosis, and how best to communicate with the patient at this time. In Session II we will detail the rapidly increasing range of treatment options for MS, and in Session III, discuss how these treatments might be best worked into useful treatment algorithms. Session IV will detail the current understanding of brain plasticity and recovery and repair processes in MS, and how these processes might be promoted through treatment. In Session V, presenters will detail the latest research into genetic aspects of MS, and comment on how the findings of this research may affect clinical practice. The final session of the conference, Session VI, will focus on what is known about childhood MS and how best to approach the treatment of paediatric MS.Case studies will be presented, offering you the opportunity to discuss various aspects of clinical practice with the panel of experts. The aims of the 2013 annual conference are: to help learners apply the latest diagnostic tools to achieve a prompt MS diagnosis, to offer objective comparisons of different therapeutic options and identify the most suitable drug for individualized treatment, to review new insights on the genetics and proteomics behind MS, and to facilitate the identification and treatment of juvenile MS.This diverse programme will provide state-of-the-art information for clinicians on current research as well as practical advice on patient management. We hope that you will be able to join us and take part in what we anticipate will be lively discussions.

Yours sincerely,

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Learning objectives

Target audience

Aim of the conference

By attending this live educational conference, learners will be able to:

• apply diagnostic tools to achieve a prompt MS diagnosis;• compare different therapeutic options and identify the most suitable drug for individualized treatment;• review the new insights about genetics and proteomics;• identify the different forms of juvenile MS to apply the right therapeutic intervention.

Clinicians involved in MS management.

New data emerging from imaging, pharmacogenomic and genetic studies have expanded our understanding of multiple sclerosis (MS), making disease management more complex and changing the way in which MS is treated. In this complex scenario, the 2013 SSIF Annual Meeting will give learners the opportunity to learn more about how to apply diagnostic tools to achieve a prompt MS diagnosis, and how to choose the best therapeutic intervention in order to limit inflammatory damage in the early stages of the disease and enhance recovery processes. Moreover, learners will be updated about new insights in genetics and pharmacogenomics, to improve MS management in daily practice. The live educational event will also give an overview of juvenile MS, guiding learners through the diagnosis and therapeutic options for this interesting subset of patients.

Serono Symposia International Foundation (www.seronosymposia.org) is accredited by the European Accreditation Council for Continuing Medical Education (EACCME®) to provide the following CME activity for medical specialists. The EACCME is an institution of the European Union of Medical Specialists (UEMS), www.uems.net. The 2013 CME Annual meeting in multiple sclerosis: “How to translate new insights in MS into clinical practice” held in Istanbul, Turkey on 31 May - 1 June 2013, is designated for a maximum of 9 (nine) hours of European CME credits (ECMEC). Each medical specialist should claim only those credits that he/she actually spent in the educational activity. EACCME® credits are recognized by the American Medical Association towards the Physician’s Recognition Award (PRA). To convert EACCME credit to AMA PRA category 1 credit, please contact the AMA.

Accreditation

Serono Symposia International Foundation adheres to the principlesof the Good CME Practice group.

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Learning effectiveness projectWe value your opinion!

We are continually trying to develop and improve our educational initiative to provide you with cutting-edge learning activities.During this live educational conference you will be asked to answer a real-time survey and after you can answer an online questionnaire to help us better tailor our future educational initiatives.

We thank you for participating!

All Serono Symposia International Foundation programmes are organized solely to promote the exchange and dissemination of scientific and medical information. No forms of promotional activities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of the named speakers, and do not represent an endorsement or recommendation on the part of Serono Symposia International Foundation. This programme is made possible thanks to educational grants received from: Arseus Medical, Besins Healthcare, Bristol-Myers Squibb, Celgene, Centre d’Esclerosi Multiple de Catalunya (Vall d’Hebron University Hospital), Centre Hépato-Biliaire, Hôpital Paul Brousse, ComtecMed, Congrex, Croissance Conseil, Cryo-Save, Datanalysis, Dos33, Esaote, European Society of Endocrinology, Ferring, Fondazione Humanitas, Fundación IVI, GE Healthcare, GlaxoSmithKline Pharmaceuticals, IPSEN, Johnson & Johnson Medical, ISFP International Society for Fertility Preservation, ISMH International Society of Men’s Health, K.I.T.E., Karl Storz, Lumenis, Merck Serono Group, PregLem, Richard Wolf Endoscopie, Sanofi-Aventis, Stallergenes, Stopler, Teva Pharma, Toshiba Medical Systems, Université Catholique de Louvain (UCL), University of Catania.

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VenueCeylan Intercontinental HotelAsker Ocagi Caddesi No. 1 Taksim34435 Istanbul, TurkeyPhone: +90 0212 368 4444

LanguageThe official language of the conferencewill be English.

Scientific organisersChairDavid BatesDepartment of NeurologyRoyal Victoria InfirmaryNewcastle upon Tyne, UK

Co-ChairMagnhild Sandberg-Wollheim Department of NeurologyLund University HospitalLund, Sweden

Scientific SecretariatSerono Symposia International FoundationSalita San Nicola da Tolentino, 1/b00187 Rome, Italy

Neurology team leader: Serena Dell’AricciaProject manager: Alessia AddessiMedical advisor: Federica Cerri

Phone: +39 06 420 413 591Fax: +39 06 420 413 [email protected]

Organising Secretariat Meridiano Congress InternationalVia Sapri, 600185 Rome, Italy

Congress coordinator:Federica RussettiPhone: +39 06 88 595 [email protected]

Scientific programme

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Friday, 31 May 2013

SESSION I MS before MS - differential diagnosis

Moderators: M. Sandberg-Wollheim (Sweden) - A. Siva (Turkey)

Real-time survey

08.50 L1: Early diagnosis (RIS/CIS) X. Montalban (Spain)

09.10 L2: Differential diagnosis: MS and acquired demyelinating disorders G. Comi (Italy)

09.30 L3: McDonald criteria D. Bates (UK)

09.50 L4: Diagnosis communication and patients’ coping strategies D. Langdon (UK)

10.10 C1: Case studies on early diagnosis and differential diagnosis G. Comi (Italy)

10.30 Real-time survey

Question time

10.45 Coffee break

SESSION II Treatment issues management today - part 1

Moderators: G. Comi (Italy) - M. Sandberg-Wollheim (Sweden)

Real-time survey

11.10 L5: Do IFNs and GA still have a role in MS? P. Rieckmann (Germany)

11.30 L6: Oral drugs L. Kappos (Switzerland)

11.50 L7: Antibodies in MS H. P. Hartung (Germany)

12.10 L8: When and how to start a therapy T. Ziemssen (Germany)


Question time

12.45 Lunch

08.30 Serono Symposia International Foundation (SSIF) Opening G. Comi (Italy) Introduction to the conference D. Bates (UK) - M. Sandberg-Wollheim (Sweden)

Day 1

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SESSION III Treatment issues management today - part 2

Moderators: R. Karabudak (Turkey) - M. Sandberg-Wollheim (Sweden)

Real-time survey

13.45 L9: Long-term benefit of current DMDs on disability progression: experience from clinical trials and clinical practice D. Goodin (USA)

14.05 L10: When and how to switch from one therapy to another G. Comi (Italy)

14.25 L11: How to detect and monitor safety issues A. Siva (Turkey)

14.45 C2: Case study presentation on treatment to target: shared decision making D. Bates (UK)


Question time

15.20 Coffee break

SESSION IV How to implement recovery processes and brain plasticity

Moderators: D. Bates (UK) - G. Comi (Italy)

Real-time survey

15.45 L12: New biological basis of rehabilitation J. A. Kleim (USA)

16.05 L13: Neuroprotection B. Kieseier (Germany)

16.25 L14: Cell therapy M. Bacigaluppi (Italy)

16.45 L15: The multidisciplinary approach to patient rehabilitation A. J. Thompson (UK)

17.15 KN1: Symptoms management A. J. Thompson (UK)


Question time

18.00 End of day 1

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Saturday, 1 June 2013Day 2 SESSION V Genetics-genomics-proteomics

Moderators: D. Bates (UK) - M. Sandberg-Wollheim (Sweden)

Real-time survey 08.45 L16: From genotype to biology of MS D. Hafler (USA) 09.05 L17: Beyond genetics: integrating next generation sequencing-based approaches E. Stupka (Italy) 09.25 L18: Pharmacogenetics and pharmacogenomics J. Oksenberg (USA) 09.45 L19: How to translate knowledge into practice G. Giovannoni (UK) 10.05 C3: Case studies presentation on how difficult it is to identify the response to treatment G. Giovannoni (UK) 10.25 Real-time survey Question time 10.40 Coffee break

SESSION VI Paediatric MS

Moderators: D. Bates (UK) - M. Sandberg-Wollheim (Sweden)

Real-time survey

11.00 L20: Environmental and genetic factors/clinical phenotypes A. Yeh (Canada) 11.20 L21: How difficult is the diagnosis of MS in children? S. Tenembaum (Argentina) 11.40 L22: Treatment recommendations for paediatric MS A. Ghezzi (Italy) 12.00 C4: Case studies presentation on juvenile MS/differential diagnosis S. Tenembaum (Argentina) 12.20 KN2: How to interpret results in MS clinical trials: statistical issues M. P. Sormani (Italy) 12.50 Real-time survey Question time

Unsession 13.05 Unsession All faculty members 13.30 End of the conference and closing lunch

Marco BacigaluppiDavid BatesGiancarlo ComiAngelo GhezziGavin GiovannoniDouglas GoodinDavid HaflerHans-Peter HartungLudwig KapposRana KarabudakBernd KieseierJeffrey A. KleimDawn LangdonXavier MontalbanJorge OksenbergPeter RieckmannMagnhild Sandberg-WollheimAksel SivaMaria Pia SormaniElia StupkaSilvia TenembaumAlan J. ThompsonAnn YehTjalf Ziemssen

Faculty members

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Biographies

David Bates

Department of NeurologyRoyal Victoria InfirmaryNewcastle upon Tyne, UK

Magnhild Sandberg-Wollheim

Department of NeurologyLund University HospitalLund, Sweden

David Bates trained in Medicine at Downing College, Cambridge and the Middlesex Hospital, London and in Neurology at theUniversity of Newcastle upon Tyne, UK, and the Mayo Clinic, Rochester, Minnesota, USA. He is Emeritus Professor of Clinical Neurology at the University of Newcastle upon Tyne, Former Editor of the International MS Journal and past Chairman of both the MS Forum and the Medical Research Advisory Committee of the MS Society of Great Britain and Northern Ireland. He is Chairman of the Joint Colleges Working Party on the Vegetative State and Criteria for Brain Stem Death and Chairman of the Consensus Conference on the Epilepsies for the Royal College of Physicians, Edinburgh. His research interests are in vascular disease, coma and the unconscious patient, and in MS. Professor Bates has published more than 150 peer-reviewed papers, edited three textbooks and contributed chapters to more than 20. His current research involvement is predominantly in clinical trials of novel therapy in MS and in the role of mitochondria in protecting and repairing axons in the more chronic phases of that disease.

Magnhild Sandberg-Wollheim gained her MD and PhD degrees at the University of Lund in Sweden. She is a specialist in neurology and is director of the MS clinic at the University hospital in Lund. She is a founding member of the Nordic MS Genetic Network. During her career she has combined clinical and laboratory research. She was the first to demonstrate B- and T-cells in the spinal fluid and the intrathecal origin of oligoclonal bands in spinal fluid of MS patients. She identified the association between certain alleles in the HLA region and optic neuritis and has been interested in the natural course of this entity. Dr Sandberg has been a member of steering committees and data safety committees in many international treatment trials and a member of the International Panel on MS Diagnosis.

Chairs

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Marco Bacigaluppi

Neuroimmunology UnitDepartment of NeurologyInstitute of Experimental NeurologyVita-Salute San Raffaele UniversityMilan, Italy

Giancarlo Comi

Department of NeurologyInstitute of Experimental NeurologyVita-Salute San Raffaele UniversityMilan, Italy

Marco Bacigaluppi graduated in medicine from University Vita-Salute in 2004, where he then took up a residency in neurology before commencing a PhD Course in Experimental Neurology in 2010. He is currently researching the role and function of endogenous neurogenesis after experimental stroke as part of his PhD course and also works in the Stroke Unit of the Ospedale San Raffaele in Milan. He is a member of a number of societies including the Italian Neuroimmunology Society and the American Heart Association. He is a reviewer for American Pathology, Neurobiology of Disease and Experimental Neurology and is the author and co-author of a number of publications.

Giancarlo Comi received his degree in medicine in 1973 and neurological certification in 1977, both from the University of Milan, Italy. He joined the Department of Neurology, Scientific Institute San Raffaele, University of Milan, in 1974 as a Clinical Assistant and in 1988 was appointed Assistant Professor in Clinical Neurophysiology. Currently he is Professor of Neurology, Chairman of the Department of Neurology, and Director of the Institute of Experimental Neurology at Vita-Salute San Raffaele University, Scientific Institute San Raffaele, Milan. Professor Comi’s areas of interest are principally directed towards the study of the pathophysiology and treatment of MS. He has authored and co-authored more than 800 articles in peer-reviewed journals and edited eight books. He has a long-standing involvement as an active member of the steering committees and advisory boards of many international clinical trials, mainly in the field of MS. Professor Comi is the Vice President of the European Charcot Foundation and member of the Board of Administration of the Italian Multiple Sclerosis Foundation and the Scientific Committee of the Italian Multiple Sclerosis Association. Professor Comi has also served as President of the European Neurological Society and the Italian Society of Clinical Neurophysiology. He is currently the President of the Italian Society of Neurology. Professor Comi currently sits on the executive boards of various scientific associations and on the editorial boards of Clinical Neurophysiology, European Neurology and Multiple Sclerosis and is the Associate Editor of Neurological Sciences.

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Angelo Ghezzi

Multiple Sclerosis CentreGallarate HospitalGallarate, Italy

Gavin Giovannoni

Department of NeurologyThe Royal London HospitalWhitechapel, London, UK

Angelo Ghezzi is Director of the Department of Neurology 2–Multiple Sclerosis at St Antonio Abate Hospital in Gallarate, Italy, the oldest Italian MS centre. He gained his medical degree at the University of Milan where he specialized in neuropsychiatry. He is a member of the Steering Committee of the International Pediatric MS Study Group, and since 2009 Chair of the MS Study Group of the Italian Neurological Society. Dr Ghezzi is an active researcher, serving as an investigator in many international Phase II and III trials. His research has focused on optic neuritis, MS and pregnancy, MS and sexual disturbances, MS and epilepsy, MS evolution and prognosis, MRI and clinical correlation with MS, and clinical neurophysiology (evoked potentials, pelvic floor neurophysiology). He is especially interested in the clinical and therapeutic aspects of paediatric MS (MS onset in childhood-adolescence, immunomodulatory treatment of juvenile-onset MS). Dr Ghezzi is the editor of 10 books on MS, and author or co-author of about 200 articles published in international journals.

Gavin Giovannoni was appointed to the Chair of Neurology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London and the Department of Neurology, Barts and The London NHS Trust in November 2006. In September 2008 he became the Neuroscience and Trauma Centre Lead in the Blizard Institute. Gavin did his undergraduate medical training at the University of the Witwatersrand, South Africa, where he graduated cum laude in 1987. He was awarded a PhD in immunology from the University of London in 1998. and moved to the Institute of Neurology, Queen Square, London in 1999, being promoted to Reader in Neuroimmunology in 2004. His clinical interests are MS and other inflammatory disorders of the central nervous system. He is particularly interested in clinical issues related to optimizing MS disease-modifying therapies. His current research is focused on Epstein-Barr virus as a possible cause of MS, defining the “multiple sclerosis endophenotype”, MS-related neurodegeneration, multiple sclerosis biomarker discovery, MS clinical outcomes and immune tolerance strategies. His team focus on translational research and therefore have an active clinical trial programme.

Biographies

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Douglas Goodin

UCSF Multiple Sclerosis CenterUniversity of California San FranciscoSan Francisco, CA, USA

David Hafler

Department of NeurologyYale School of MedicineNew Haven, CT, USA

Douglas S. Goodin is a Professor in the Department of Neurology at the University of California, San Francisco (UCSF). He is also the Director of the UCSF Multiple Sclerosis Centre. Professor Goodin is an active member of the American Academy of Neurology (AAN) where he has held several positions. He has been the lead (or a principal) author on numerous AAN position papers including the role of trauma and stress in the pathogenesis of MS, the clinical utility of surface EMG, guidelines on the value of MRI in the diagnosis of suspected MS, the impact of neutralizing antibodies on the efficacy of interferon treatment in MS, and the use of natalizumab in the treatment of MS. He has published over 140 original papers in peer-reviewed journals in the field of neurology. He has also written numerous book chapters for standard texts, and has lectured widely about the diagnosis, management, and epidemiology of MS. In addition, he is a member of the American Neurological Association (ANA). He has served on the editorial boards of Muscle and Nerve, Seminars in Multiple Sclerosis, the International MS Journal, the Journal of Clinical Neurophysiology, and the Journal of Electroencephalography and Clinical Neurophysiology.

David Hafler is Gilbert H. Glaser Professor and Chairman, Department of Neurology, Yale University. He graduated with degrees in both biochemistry and medicine. He was the Breakstone Professor of Neurology at Harvard before moving to Yale and his current post in 2009. He is a member of the American Society of Clinical Investigation, the American Neurological Association and is a member of the editorial boards of the Journal of Clinical Investigation and the Journal of Experimental Medicine. In 2010 he received the American Academy of Neurology’s Dystel Prize for work in MS.David Hafler is a clinical scientist with a research interest in understanding the mechanism of autoimmunity and inflammatory central nervous system diseases, with over 300 publications in the field of autoimmunity and immunology. His laboratory focuses on human autoimmune diseases and the investigation of naturally occurring human diseases which might give insight into the basic processes of T cell regulation. More recently, He has focused on broadly characterizing the molecular pathogenesis of MS at the DNA, mRNA and proteomic level.

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Hans-Peter Hartung

Department of NeurologyHeinrich-Heine-UniversityDüsseldorf, Germany

Ludwig Kappos

Department of BiomedicineUniversity Hospital BaselBasel, Switzerland

Hans-Peter Hartung is Professor and Chairman of the Department of Neurology, Heinrich-Heine-Universitat, Düsseldorf. Following his MD in 1980, he undertook research fellowships in immunology and neuroimmunology in Germany. In 2001, he took up his current position. His research interests are in experimental and clinical neuroimmunology, pathogenesis of and experimental therapies for MS, Guillain-Barré syndrome, CIDP, neuroimaging of demyelinating and ischaemic diseases and neuromuscular diseases. Hans-Peter Hartung heads a 64 bed university department with clinical and research groups including stroke (largest stroke unit in Germany), movement disorders, magnetoencephalography, and MS. He is a member of a number of societies, including the American Academy of Neurology, European Neurological Society and is a Fellow of the Royal College of Physicians in the UK. He reviews publications and is a member of editorial boards covering issues including MS, research, and neurology and neuroimmunology in general. He is involved with a number of international multicentre trials of treatments for MS, Guillain-Barré Syndrome and CIDP. He has peer-reviewed more than 650 articles on the pathogenesis and treatment of neuro-immunological disorders, has written nine books and a hundred book chapters.

Ludwig Kappos is Professor and Chair of Neurology at the University Hospital Basel. Originally from Athens, Greece, he gained his MD and a Diploma in Clinical Psychology from the University of Wurzburg, Germany in 1980, where he then specialized in neurology and neuroimmunology. He went on to become deputy chief, Division of Clinical Neurology, Max Planck Society, Clinical Research Unit for Multiple Sclerosis. In 1990 he was elected Head of the Outpatient Department, Neurology/Neurosurgery and since 2008 has been Chair of Neurology at the University of Basel. His research interests include immunological and molecular studies in neuroimmunological diseases and methodology and conduct of therapeutic studies, mainly in the field of MS. Ludwig Kappos serves as chair or as a member in several steering committees and advisory boards for clinical trials and in organizations active in the field of MS and general neurology. Ludwig Kappos has published more than 450 original papers, reviews and book chapters.

Biographies

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Rana Karabudak

Hacettepe University HospitalDepartment of NeurologyNeuroimmunology UnitAnkara, Turkey

Bernd Kieseier

Department of NeurologyHeinrich-Heine UniversityDüsseldorf, Germany

Rana Karabudak has been a professor in the Department of Neurology at the University of Hacettepe since 1999. She founded the Neuroimmunology Unit and Clinical MS Center where she continues to work. Her expertise in MS and clinical neuroimmunology follows extensive experience at UCLA and the University of Chicago in the USA. Professor Karabudak’s interests also include immunological aspects of MS, neuroradiology of MS, and Myasthenia gravis. She has been an investigator in a number of international multicentre drug trials in MS and is one of the founders and board member of the European School of Neurology (ESNI). As well as being the Turkish delegate to EFNS she is also a member of the American Academy of Neurology (AAN) and the European Neurological Society, among the others. She also serves on the Advisory Board of Turkish MS Societies and the Editorial Board of the Turkish Neurological Society Journal. She has authored and co-authored 50 peer-reviewed articles and more than 200 articles, books and book chapters in English and Turkish.

Bernd C.Kieseier is Professor of Neurology at Heinrich-Heine-University. He graduated as an MD in 1994, having trained at Johannes-Gutenberg University of Mainz and the Medical School of West Virginia University, USA. He then worked extensively in the immunology and neurology fields, becoming a Professor of Neurology in 2001, based at Heinrich-Heine University Dusseldorf where he is Vice Chair of the Department and Head of the MS Outpatient Clinic.His major clinical and research interests beyond general neurology are in the field of experimental and clinical neuroimmunology with a focus on MS and immune-mediated neuropathies. He has authored or co-authored more than 250 articles in peer-reviewed journals, written more than 40 book chapters and edited three books on neurology, neuroimmunology, peripheral nerve diseases and MS. Professor Kieseier participated in various clinical trials on MS as principal investigator, and is a member of the medical advisory board of the German MS Society and a member of the German Competence Network Multiple Sclerosis (KKNMS).

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Jeffrey A. Kleim

School of Biological and HealthSystems EngineeringArizona State UniversityTempe, USA

Dawn Langdon

Department of PsychologyRoyal Holloway University of LondonLondon, UK

Jeffrey Kleim, an Associate Professor at the School of Biological and Health Systems Engineering, specializes in the neural substrates underlying motor recovery after stroke and Parkinson’s disease, using both animal models and human patient populations. Following completion of his PhD in Neuroscience at the University of Illinois in 1997 and a postdoctoral fellowship at the Kansas University Medical Center in 1998 he took a faculty position at the Canadian Center for Behavioral Neuroscience at the University of Lethbridge. In 2005 he moved to the Department of Neuroscience and the Brain Rehabilitation Research Center at the University of Florida. He joined the School of Biological and Health Systems Engineering at Arizona State University as an Associate Professor in 2011. Dr Kleim is funded by several national funding agencies to conduct research directed at developing novel therapies for movement disorders based on principles of neural plasticity. He has recently completed a book entitled Neural Plasticity: Foundation For Neurorehabilitation.

Dawn Langdon completed her training as a Clinical Psychologist at Oxford University, Oxford, and the Institute of Psychiatry, London. She worked as a Clinical Neuropsychologist at the National Hospital, Queen Square, London, obtaining a PhD on reasoning in organic brain syndromes. She is a registered Neuropsychologist and a Health Psychologist. Dr Langdon is now a Professor of Neuropsychology at Royal Holloway, University of London and neuropsychology lead on a number of multinational trials. Her research work centres on psychological aspects of MS and current projects include the efficacy of medication in protecting cognition, cognitive rehabilitation, cognitive profiles in clinically isolated syndrome and early MS, and cognition in the later stages of MS, including its relation to early disease status. Dr Langdon is a frequent contributor to international scientific meetings and committees and is a Trustee of the UK MS Trust, with whom she has authored the MS cognition website www.stayingsmart.org.uk. She is co-chair of the BICAMS project.

Biographies

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Xavier Montalban

Multiple Sclerosis Center of CataloniaUnit of Clinical NeuroimmunologyVall d’Hebron University HospitalBarcelona, Spain

Jorge Oksenberg

Department of NeurologyUniversity of California at San Francisco (UCSF)San Francisco, CA, USA

Xavier Montalban is Vice President of the Multiple Sclerosis Foundation, and sits on the advisory board and the scientific committee of the Multiple Sclerosis International Federation and the European Charcot Foundation. Since 2003, he has been a member of the advisory committee on clinical trials of new agents of the National Multiple Sclerosis Society in the United States. He has been a member of ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) since 2009 and is currently Vice President. Professor Montalban is the current director for the Neuroimmunology content of Revista de Neurología, the largest distribution Neurology journal in Spanish, and serves as a member and peer reviewer on several editorial boards of both national and international specialist journals. He has published over 200 original contributions in international journals and has authored a number of book chapters. His current research interests include immune mechanisms in MS, cognitive dysfunction in MS, new intervention strategies, genetic characterization and pharmacogenomics of treatment response and prognostic factors of MS. He has participated both in the design and execution of several Phase II and Phase III clinical trials, and is member of several safety and steering committees.

Jorge Oksenberg holds the G. Zimmermann Endowed Chair in Neurology and is Professor of Neurology at the University of California in San Francisco. He received his PhD in Immunology in 1987 from the Hebrew University of Jerusalem, Israel, and joined the UCSF faculty in 1993 following postdoctoral training at Stanford University, California. Dr. Oksenberg is a leading investigator in the multicentre “Multiple Sclerosis Genetics Group” and the “International Multiple Sclerosis Genetics Consortium”. Dr Oksenberg has published over 200 peer-reviewed articles and scholarly reviews, and serves as associate editor for the Annals of Neurology.

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Peter Rieckmann

Bamberg Hospital and University of ErlangeBamberg, Germany

Aksel Siva

Department of NeurologyIstanbul UniversityIstanbul, Turkey

Peter Rieckmann is currently Director of the Neurological Clinic at the Academic Hospital in Bamberg. He received his MD from the University of Göttingen in 1998. After a postdoctoral fellowship in molecular immunology at the NIH, Bethesda, USA he completed his training in Neurology at the National Institute for Nervous Disease, London, UK and the University of Göttingen, Germany. He was head of the Clinical Research Group for Multiple Sclerosis and Neuroimmunology,at the Julius-Maximilians University of Würzburg and holds several positions as visiting professor across the globe. In 2007 Professor Rieckmann became the MS Society of Canada Research Chair and Director of the MS Program at the University of British Columbia and Vancouver Hospital, Canada. His major research interests are disease-modifying factors and regeneration in MS as well as functional aspects of the blood brain barrier in neuroimmunological diseases. Professor Rieckmann’s clinical goals include enhancing awareness and education about MS, developing effective and properly resourced services for MS outpatient care, and providing more customized treatments for patients. He is chairman of the MS in the 21st century steering group, an international MS stakeholder’s initiative. He serves on steering committees of various international multicentre MS trials (Phase II and III). Professor Rieckmann is a Fellow of the Royal College of Physicians and Surgeons, Canada and has over 200 papers to his credit in peer-reviewed medical journals.

Aksel Siva is Professor of Neurology at the Department of Neurology, Istanbul University. He heads the Clinical Neuro-immunology Unit and Multiple Sclerosis Clinic and is senior advisor to the Headache Clinic. Born in Istanbul, Professor Siva graduated in medicine from the Cerrahpasa School of Medicine in 1978. He has served as President of The Turkish Neurological Society from 2003 to 2009. He is a founding member of The Headache Study Group of the Turkish Neurological Society and is currently president of the Headache and Pain Research Society of Turkey. He is also a founding member of The Turkish Multiple Sclerosis Society and Chairman of the National Scientific Committee. He is a member of, amongst others, the European Neurological Society, American Academy of Neurology and the International Headache Society. Dr Siva has served as an Executive Committee member of ECTRIMS (European Committee on Treatment and Research in Multiple Sclerosis) and currently is a member of The International Medical and Scientific Board of MSIF (Multiple Sclerosis International Federation). Dr Siva has been a member of a number of editorial boards, including the Turkish Pain Journal, the Turkish Neurological Journal; the Journal of Neurological Sciences and the Brazilian Journal of Multiple Sclerosis. His areas of interest and work are, Clinical neuro-immunology (MS and Neuro-Behcet’s Syndrome), headaches and neuro-epidemiology.

Biographies

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Maria Pia Sormani

University of GenoaGenoa, Italy

Elia Stupka

Unit Center for Translational Genomics and BioinformaticsSan Raffaele Scientific InstituteMilan, Italy

Maria Pia Sormani is Professor of Biostatistics at the University of Genoa, Italy. She received her Masters in Biostatistics at the University of Milan, her Master in Biophysics at the University of Pisa and her degrees in Physics at the University of Genoa, in Italy. She collaborated for more than 10 years with the Neuroimaging Research Unit (Dr M Filippi) at the S.Raffaele Hospital in Milan, studying the methodological issues related to the use of magnetic resonance imaging in MS. She has also worked for the National Institute for Cancer Research in Genoa studies. She serves on the National MS Society Clinical Trials Advisory Committee. She is also on the faculty at the University of Genoa, where she teaches Biostatistics and Research Methods to students in medicine. She has published more than 200 papers on peer-reviewed journals.

Elia Stupka started his genomics career as part of the Ensembl group and the core human genome analysis team in Hinxton, where he participated in the completion and analysis of the human genome (Nature, 2001). He then set up and managed the Fugu genome bioinformatics team at IMCB, Singapore where he completed the Fugu genome project (Science, 2003). Dr Stupka then moved to the Telethon Institute of Genetics and Medicine, where he began combining his experience in bioinformatics with a molecular biology lab, working on the understanding of non-coding DNA, and where he also collaborated with the Fantom3 project (Science, 2005). He has been Scientific Director at UCL Genomics, University College London, where he began applying NGS approaches on both rare and complex disease projects and exploring epigenomics approaches to identify novel biomarkers. Since 2011 he has co-directed a new research centre at San Raffaele Research Hospital in Milan, Italy, the first translational genomics and bioinformatics centre of its kind in Italy. It serves a community of over 1,500 clinical and basic scientists across a wide range of clinical applications.

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Silvia Tenembaum

Department of NeurologyNational Pediatric Hospital “Dr. Juan Garrahan”Buenos Aires, Argentina

Alan J. Thompson

Department of Brain Repair and Rehabilitation Institute of Neurology University College London National Hospital for Neurology and NeurosurgeryLondon, UK

Sylvia Tenembaum is Staff Neurologist at the National Pediatric Hospital, Buenos Aires, a position she has held since 1989. She is also Chair of the Pediatric chapter of the Latin American Committee for Treatment and Research in Multiple Sclerosis (LACTRIMS). Since 2011 Sylvia Tenembaum has been a member of the International Panel for NMO Diagnostic Criteria Task Force, and Chair of the Pediatric sub committee.She externally reviews for a wide range of publications including Neurology, the European Journal of Pediatric Neurology, Developmental Medicine and Child Neurology and many more.

Alan J. Thompson is Dean of the Faculty of Brain Sciences at University College London. He is the Garfield Weston Professor of Clinical Neurology and Neurorehabilitation at the UCL Institute of Neurology, and a consultant neurologist at the National Hospital for Neurology and Neurosurgery, Queen Square, London. Professor Thompson’s main area of expertise is demyelinating disease, particularly the diagnosis, evaluation and management of MS. His research focuses on the pathological mechanisms that underpin neurological disability and recovery using structural and functional imaging, and developing scientifically sound outcome measures that incorporate the patient’s perspective. He has published extensively in these areas. Through his role with UCL Partners, he has jointly lead innovation in the treatment pathways for stroke and brain cancer. Professor Thompson is Chairman of the International Medical and Scientific Board of the Multiple Sclerosis International Federation (MSIF), Chairman of the Steering Committee of the International Progressive MS Collaborative, Senior Investigator for the National Institute for Health Research, Editor-in-Chief for Multiple Sclerosis Journal, and a Guarantor of Brain.

Biographies

21

Ann Yeh

Division of NeurologyHospital for Sick ChildrenToronto, Canada

Tjalf Ziemssen

MS Center Dresden NeurologicalUniversity ClinicDresden, Germany

Ann Yeh is Associate Professor of Paediatrics (Neurology) at the Hospital for Sick Children, University of Toronto, Canada, where she is the Director of the MS and Demyelinating Disorders Programme and Director of the paediatric neurology training programme. Dr Yeh is a graduate of Harvard University, gained her MD at McMaster University, Hamilton, Ontario and completed her paediatric neurology training at SUNY Buffalo, where she developed and co-directed the Paediatric MS and Demyelinating Disorders Center of Excellence. She currently serves as Director of the Manitoba-Ontario endMS Regional Research and Training Centre. Her research interests are in visual and neuro-cognitive outcomes in pediatric demyelinating conditions, rehabilitative interventions for this population, as well as therapies for paediatric MS.

Tjalf Ziemssen graduated in medicine at the University of Bochum, Germany in 1998. He holds the professorship for Clinical Neurosciences and is Head of the MS Center Dresden, Neurological University Clinic, Dresden Germany. He is also Head of the new autonomic lab and neuroimmunological lab in Dresden.Tjalf Ziemssen is a member of, amongst others, the German Neurological Society, the European Neurological Society and the European Federation of Autonomic societies.

Abstracts

23

Early diagnosis (RIS/CIS)L1

Clinically isolated syndrome (CIS) describes the first episode of an acute or subacute neurological episode caused by inflammation or demyelination in the central nervous system (CNS). The attack may present as a monofocal or multifocal episode, depending on whether there are single or multiple neurological signs or symptoms. Radiologically isolated syndrome (RIS) differs from CIS in that patients present without overt clinical symptoms, the syndrome instead detected by incidental magnetic resonance imaging (MRI) findings.Although most patients diagnosed with multiple sclerosis (MS) initially present with CIS, not all progress to clinically definite MS (CDMS). However, when CIS occurs in tandem with the detection of CNS lesions by MRI, it is highly predictive of developing further inflammation and progression to CDMS within a decade. Likewise, patients with RIS-associated MRI anomalies are highly likely to experience subsequent radiological or clinical events. As with CIS, there is a correlation between the number and location of CNS lesions and the probability of conversion from RIS to CDMS.As treatments for MS are more effective when given early, CIS and RIS present a clinical challenge as to whether or not to initiate treatment, requiring careful assessment of risk factors to determine whether early treatment is warranted or to delay therapy until a more certain diagnosis can be made. Proposed diagnostic criteria and management of RIS will be discussed, with recommendations for the treatment of this patient population. Results from the five large-scale CIS treatment trials - CHAMPS, ETOMS, BENEFIT, PreCISe and REFLEX – will also be reviewed, along with the McDonald criteria and its revisions for the diagnosis of CIS and RIS, and the implications this will have for early treatment approaches.

Xavier Montalban

Multiple Sclerosis Center of CataloniaUnit of Clinical NeuroimmunologyVall d’Hebron University HospitalBarcelona, Spain

24

Differential diagnosis:MS and acquired demyelinating disorders

L2

Early and accurate diagnosis of multiple sclerosis (MS) is key; the importance of starting treatment as early as possible has a large consensus of agreement among MS experts. The new diagnostic criteria have clearly accelerated the diagnosis of MS; nevertheless, diagnosis of a significant proportion of patients remains a challenge. The borders between MS and other inflammatory central nervous system (CNS) disorders, such as acute disseminated encephalomyelitis, neuromyelitis optica with its large variability of phenotypes, primary CNS vasculitis, Balo and Marburg diseases, remain uncertain, at least in the early phases of the manifestations. Additionally, other conditions that may mimic the symptoms of demyelinating disease include vascular disease (vasculitis, vasculopathy or stroke), viral infection, malignancy of the CNS, vitamin B12 deficiency and mitochondrial disease. The diagnostic criteria and clinical features for the physician to be aware of when performing differential diagnosis will be summarized, including consensus definitions, clinical presentations and neuroimaging features. The problem of radiologically isolated syndromes will also be discussed.

Giancarlo Comi


25

McDonald criteriaL3

There is no specific laboratory test to identify multiple sclerosis (MS). The only absolute method for diagnosis is histological examination of tissue obtained from sites within the central nervous system. For the clinician, the diagnosis of MS requires the use of information obtained from the patient’s history, examination and imaging, and the examination of cerebrospinal fluid (CSF). Recent diagnostic criteria have emphasized the importance of identifying dissemination of the disease in space and time, but it remains obligatory for the neurologist to exclude other diagnoses.The first clinical criteria relied heavily upon the history provided by the patient and the examination undertaken by the neurologist. Paraclinical features have been included since the 1980s, initially involving CSF examination and evoked potentials, and since 2000 the McDonald Criteria and its revisions have relied heavily upon magnetic resonance imaging.Much of the development in clinical criteria for diagnosis has been driven by the need for uniformity in clinical trials and is directed towards the goal of allowing earlier diagnosis and treatment with effective therapies at a time when the inflammatory pathology is more likely to be controlled and subsequent long-term effects of the disease reduced or prevented. There is, however, a problem in that the aim of early diagnosis and the search of ever more sensitive tests inevitably carries the problem of loss of specificity of diagnosis. The neurologist must be careful not to allow over-diagnosis of the condition early in the course of the disease, potentially exposing patients to treatments that might be unnecessary and could even be harmful.One of the most evident aspects of improved diagnostic criteria in MS is that the character of the disease is changing. In the latter half of the 20th Century, substantial numbers of patients coming to autopsy were found to have MS without having been diagnosed in their lifetime. It is improbable that such numbers continue today but the result is that the diagnostic process in those now identified earlier and with milder disease might allow people with relatively benign disease to be treated in the longterm, increasing the apparent success of therapies. This presentation will evaluate the recent modifications to the standard international classification and question whether they provide the most effective way to diagnose MS. It will consider differing diagnostic probabilities around the world and the need for varied criteria. The diagnosis and decision about the need for therapy may not be best achieved with a rigid protocol but rather with assessment, evaluation and advice from an experienced neurologist.

References McDonald WI, Compston A, Edan G et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7.

Polman CH, Reingold SC, Edan G et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840–6.

Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292–302.

David Bates


26

Diagnosis communicationand patients’ coping strategies

L4

Diagnosis is a very stressful process for patients with multiple sclerosis (MS). Even with the new diagnostic criteria and early treatment, there is a significant emotional impact. This is reflected in the raised incidence of formal psychiatric syndromes such as anxiety and depression. However, revealing the diagnosis appears to improve emotional status. Professionals involved in diagnostic investigations and communication should make managing patients’ emotions a priority and take care to identify those patients with low resilience who are particularly vulnerable. Patients with early MS rely on positivity and practical strategies to preserve normal life.

References Giordano A, Granella F, Lugaresi A et al. Anxiety and depression in multiple sclerosis patients around diagnosis. J Neurol Sci 2011;307:86–91.

Raphael A, Hawkes CH, Bernat JL. To tell or not to tell? Revealing the diagnosis of multiple sclerosis. MSARD 2013;3:247–51.

Solari A, Martinelli V, Trojano M et al. An information aid for newly diagnosed multiple sclerosis patients improves disease knowledge and satisfaction with care. Mult Scler 2010;16:1393–405.

Dawn Langdon

Department of PsychologyRoyal Holloway University of LondonLondon, UK

27

Case studies on early diagnosisand differential diagnosis

C1

The importance of diagnosing multiple sclerosis (MS) early in the disease course in order to establish a specific treatment and to prevent disability progression is now well known. The recent revision of McDonald’s criteria has simplified the previous sets of criteria to allow a prompt diagnosis of MS even after the first symptoms. Nevertheless, other neurological disorders that can mimic MS but which require a completely different therapeutic approach must still be eliminated from the diagnosis. Here we examine real clinical cases covering all of the challenges related to the diagnosis of MS in the very early phases of the disease.

Giancarlo Comi


28

Do IFNs and GA still have a role in MS?L5

Do interferons (IFNs) and glatiramir acetate (GA) still have a role in multiple sclerosis (MS)? Yes, these injectable drugs have a long-standing record of safe and effective immunomodulatory treatment for relapsing types of MS and offer an excellent choice for patients with early disease – even at the stage of clinically isolated syndrome (CIS). None of the new oral drugs has been approved for the treatment of CIS and in most patients diagnosed with CIS at a young age of early adulthood safety is a major concern when choosing from the available options of effective disease-modifying treatment. Both IFN beta and GA have long-term data on effectiveness, with some almost complete cohort follow-up for over 20 years from their initial pivotal trials. For example, the long-term outcome from the initial subcutaneous IFN beta-1b study suggests that early treatment is associated with a higher survival rate at 21 years‘ follow-up.Another important aspect is the safe use of injectables in children with MS, where young patients, in addition to clinical benefit, demonstrated an excellent safety and tolerance profile using these drugs. In particular for young women of childbearing age who are planning a family, IFN beta and GA offer an excellent opportunity to start on these injectables and continue right into pregnancy, when they can safely take a drug holiday − pregnancy itself has potent immunomodulatory capacity. Several pregnancy registries indicated that taking the injectables right into pregnancy is not associated with a greater risk for negative pregnancy outcome. All these data are incomplete for the new oral medications.An important aspect for making an informed choice for disease-modifying treatment in relapsing forms of MS is the availability of head-to-head trials. With the exception of one study (fingolimod against intramuscular IFN beta-1a), no superiority of the new orals in direct comparison to the ‘old‘ injectables has been demonstrated/published. Based on the afore-mentioned arguments, IFN and GA can still be considered the important baseline drugs to start disease-modifying treatment in CIS and early stages of relapsing-remitting MS.

Peter Rieckmann

Bamberg Hospital and University of ErlangeBamberg, Germany

29

Oral drugsL6

Nearly 20 years after the first approval of interferon beta as treatment for relapsing multiple sclerosis (MS), a new generation of oral disease-modifying drugs has entered, or is entering, daily practice.Over 60,000 patients have been exposed to fingolimod since its introduction as the first oral drug approved for the treatment of relapsing MS, adding growing experience from clinical practice and observational studies to the data from the controlled trials. What is the place of this compound and other recently approved, or waiting to be introduced, agents with different, only partly understood, modes of action like teriflunomide, dimethylfumarate and laquinimod relative to established first- and second-line treatments? The key clinical and paraclinical data from recently completed studies will be reviewed. How far do these new therapeutic principles in addition to a more or less pronounced anti-inflammatory effect also address the unmet need of effective treatments against the more neurodegenerative features of the disease that accompany its steadily progressive phase?With the increasing number of therapeutic options, neurologists are challenged with deciding which of these numerous options (and when in the course of the disease) to select for the individual patient. Evidence to support these decisions is emerging but is still scarce. The different efficacy and adverse event profile of the compounds available as well as accompanying studies of imaging and biomarkers in controlled trials provide first hints towards differential indications that eventually may allow to better balance risks and benefits.Emerging algorithms should benefit and obtain further refinement by well-designed systematic and comprehensive observational cohort studies.

Ludwig Kappos

Department of BiomedicineUniversity Hospital BaselBasel, Switzerland

30

Antibodies in MSL7

While multiple sclerosis (MS) is often well controlled with immunomodulatory disease-modifying therapy, such as the interferons and glatiramer acetate, patients whose treatment is not adequately controlled with these standard therapies may benefit from treatment with monoclonal antibodies. Monoclonal antibodies represent a class of therapies that can be categorized according to their mechanism of action and their molecular targets. The first monoclonal antibody to be approved for the treatment of MS, natalizumab, is targeted against α4-integrin, a cell-adhesion molecule expressed on lymphocytes, preventing auto-aggressive T cells from entering the central nervous system. However, natalizumab carries the risk of serious adverse events, such as progressive multifocal leukoencephalopathy, which occurs in approximately 1:1000 treated patients, the risk increasing with treatment duration. Additionally, persistent neutralizing antibodies against natalizumab develop in approximately 6% of patients, rendering therapy largely ineffective. Other monoclonal antibodies are currently under investigation for the treatment of MS, including the CD52-targeted alemtuzumab, the CD20-targeted rituxumiab, ocrelizumab and ofatumumab, and daclizumab, which is targeted to the alpha subunit of the interleukin-2 receptor of T cells. The mechanisms of action of these antibody therapies will be reviewed, with data from trials in MS. Key to the use of monoclonal antibodies is when to initiate therapy, as these agents are much less effective in chronic progressive MS, suggesting that the optimal window of opportunity exists early in the relapsing course of the disease only. Therefore, careful assessment of current treatments and disease activity are required, weighing the risk:benefit ratio for individual patients to allow identification of those who will benefit the most from this more aggressive type of therapy and who are willing to accept additional risks in exchange for potentially greater clinical efficacy. The question of whether different therapeutic antibodies have better suitability for different subtypes of MS will be discussed, along with the future role of monoclonal antibodies in the evolving therapeutic landscape and treatment algorithm.

Hans-Peter Hartung

Department of NeurologyHeinrich-Heine-UniversityDüsseldorf, Germany

31

When and how to start a therapyL8

It has been possible using the McDonald criteria to diagnose patients with multiple sclerosis (MS) earlier than previously by the integration of magnetic resonance imaging (MRI) parameters into the diagnostic criteria. This provides an earlier window of opportunity to treat patients with disease-modifying drugs before clinically manifest tissue destruction and disability has emerged. Several pivotal clinical trials have demonstrated that interferon beta and glatiramer acetate can effectively reduce the risk of developing clinically definite MS (CDMS) in patients with clinically isolated syndrome (CIS) with a first demyelinating event and positive brain MRI. Histopathological studies have shown significant axonal loss in patients within their first 5 years of disease. Natural history studies could correlate the initial relapse rate within the first few years of the disease to the time to accrued disability. Additionally, longitudinal studies on patients with CIS have shown that patients with even a very small number of baseline MRI lesions carry an increased risk of developing CDMS and, more importantly, that the increase in volume of the lesions seen in the first 5 years correlates with the degree of disability in the longer term. Certainly, when continuing disease activity has been demonstrated clinically or by MRI, the need to initiate treatment is clear. Studies supporting early treatment rely on evidence that shows that the experiences of the first few years are likely to impact on the long-term evolution of the disease. The decision to start treatment should be made jointly by the patient and the physician after reviewing the existing evidence. Facing increasingly complex decisions, patients need up-to-date evidence-based information and decision support systems in order to make informed decisions together with physicians based on their autonomy preferences.

Tjalf Ziemssen

MS Center Dresden NeurologicalUniversity ClinicDresden, Germany

32

Long-term benefit of current DMDs on disability progression: experience from clinical trials and clinical practice

L9

Randomized controlled trials (RCTs) have established the short-term efficacy of current disease-modifying drugs (DMDs) in multiple sclerosis (MS). As with many chronic diseases, however, establishing the effectiveness of therapy in altering long-term outcome is difficult because, in general, RCT designs are ill-equipped for this purpose. Thus, it is not realistic to continue a placebo arm after a drug has been demonstrated to alter clinically relevant short-term outcomes. Most patients will not consent to such a prolonged placebo exposure and few clinicians would recommend it. As a result, establishing long-term efficacy in chronic diseases requires non-randomized observational study designs. The pivotal trial of interferon (IFN) beta-1b, begun in 1988, was the first successful DMD trial in MS. Because this trial occurred so long ago, the patient cohort from this trial offers a unique opportunity to evaluate the efficacy of long-term DMD use. Despite this potential value, however, any such assessment faces several challenges. For example, when patients entered the RCT, they did so at very different points along the continuum of the MS disease course, with respect to both disease duration (i.e. the time since their first clinical symptom) and severity (i.e. their disability level), and there is accumulating evidence that patients respond better to DMD therapy earlier in their disease course. Also complicating any analysis of the long-term impact of therapy will potentially be biased. First, following the trial, the decision to start, to continue, or to switch therapy will be influenced, to a large extent, by the perceived response to therapy. Patients doing well will stay on therapy, whereas patients doing poorly will stop or switch. Therefore, any attempt to perform a longitudinal analysis of exposure to therapy will be contaminated by this bias and statistical adjustments will need to be made to mitigate their effects. Alternatively, the use of intent-to-treat (ITT) principals (i.e. with the groups analysed ‘as-randomized’) will be biased against finding any treatment effect because the difference in exposure will be for the duration of the RCT only and will represent only a small proportion of the overall follow-up period. Because the pivotal IFN beta-1b RCT took place over the course of 5 years, this trial offers a unique opportunity to address both methods of analysis in order to explore the potential long-term benefit of DMD therapy. Therefore, at 16 years we identified 88% of the cohort and did a detailed evaluation on 70% of the cohort. The purpose of this study was to assess the relationship between drug exposure and long-term disability using a variety of bias reduction strategies in patients with MS. This analysis provided consistent evidence that early initiation and sustained use of DMDs resulted in a beneficial impact on long-term outcomes in MS, as measured by fixed disability (Expanded Disability Status Scale ≤6) and conversion to secondary progressive MS. At 21 years we sought to determine the impact of therapy on all-cause mortality using an ITT approach. For this analysis we identified the vital status of 98.4% of the cohort. This study showed that patients who were originally randomized to IFN beta-1b (either at 50 or 250 µg) had a significant reduction in all-cause mortality over the 21-year interval compared with those who were randomized to placebo, with a 46-47% reduction in the hazard ratio for death in either treatment group.These findings indicate that DMD treatment has an important impact on the long-term course and outcome in MS.

Douglas Goodin

UCSF Multiple Sclerosis CenterUniversity of California San FranciscoSan Francisco, CA, USA

33

When and how to switch from one therapy to anotherL10

Individualized treatment is now possible for patients with relapsing multiple sclerosis (MS). Many treatments with different efficacy and safety profiles, modes of action, convenience and tolerability constitute the basis for personalized treatment in a disease characterized by a large interindividual variability of disease course. The availability of prognostic factors and the existence of some predictive factors for response to treatment may contribute to orient treatment decision, both before starting treatment and for an early detection of treatment response. Existing data from clinical trials and post-marketing studies for the classification of treatment responses will be presented, and the contribution of biomarkers will be analysed. In treatment-naive patients the decision for an escalating approach or an induction approach will be based on the benefit/convenience profile. The possibility of shifting among treatments of the same class or from first-line to second-line treatments in patients with suboptimal response or breakthrough disease is a working option. The indication for heroic therapeutic strategies will also be presented. Treatment discontinuation is sometimes necessary for safety or tolerability issues or for patient decision. The problem of disease rebound after discontinuation of natalizumab has recently emerged. How to minimize the risks related to treatment discontinuation in various conditions is becoming an important aspect of MS therapy.

Giancarlo Comi


34

The majority of the current long-term treatments for multiple sclerosis (MS) have immunomodulatory properties with or without an immunosuppressant mode of action, with some having more potent immunosuppressant properties that are associated with significant safety issues. Neurologists need to follow closely their patients with MS who are receiving long-term therapies with regard to safety issues, as well as their response and adherence to treatment. Safety concerns are regarded as general issues for all treatments and drug-specific for each agent. The general issues include the physical, psychological and cognitive status of the patient, as well as the presence of comorbid disorders and laboratory abnormalities. One other important safety concern in patients with MS is that most are at a childbearing age and have no children but who wish for parenthood at the time of diagnosis and/or when their treatment is planned. This necessitates careful decision making and monitoring of therapies in this patient population, which includes both pregnancy and fertility issues. Before initiating a long-term MS treatment, the patient needs to be worked-up both physically and psychologically in order to rule out any safety concern that may contraindicate specific agents and also for awareness of baseline status for follow-up monitoring. As adherence is another essential issue in MS treatment, the potential side effects and safety data need to be studied and discussed with the patient prior to initiation of therapy. In patients with lupus-like serology, interferon (IFN) beta 1-group agents should not be favoured. The most common side effects for the IFN beta 1-group drugs are flu-like symptoms, transient liver enzymes abnormalities, thyroid dysfunction and skin reactions. Injection-site reactions and, although rare, immediate post-injection panic attack-like reactions, are associated with glatiramer acetate use. Patients need to be followed regularly for these relatively common but much less adverse events (AEs). The long-term safety profiles of these drugs are well characterized. However, despite this safety information, patients receiving these drugs need to be monitored at regular intervals.The first oral drug for MS, fingolimod, is now to be followed by the other orals, teriflunomide and oral fumarate (BG-12), which were recently approved. Each drug has its own safety profile, and the practising neurologist must know them in detail in order to inform their patient to be aware of the potential AEs and the expected work up at initiation, and then to have the basic knowledge to follow and monitor their patients properly. The initial work up may cover ophthalmological, cardiac, haematological and biochemistry studies, and dermatological examination for individuals who are planned to be given fingolimod as well as to be monitored at regular intervals, once the drug is started. Teriflunomide currently seems to have a less extensive work up protocol but renal, hepatic and metabolic parameters should not be neglected. BG-12 may cause gastrointestinal side effects at onset and patients should be followed by regular haematological and liver tests. These new drugs currently necessitate more frequent monitoring than the first-line therapies.

How to detect and monitor safety issuesL11

Aksel Siva

Department of NeurologyIstanbul UniversityIstanbul, Turkey

35

L11

The monoclonal antibody natalizumab should be administered in certified centres. In addition to biochemistry and haematological studies, serum JC virus antibody status (a-JCV) is needed when considering natalizumab use and further risk management for progressive multifocal leucoencephalopathy (PML) in patients who are JCV antibody positive. The close monitoring for the development of any new neurological symptom(s) as well as unusual magnetic resonance imaging findings should alert the physician in a high-risk patient for the potential of PML. PML seems to be an evolving issue that may not be limited to natalizumab use and therefore the suspicion rate of MS-treating neurologists should be increased in patients who had received immunosuppressant therapies in the past and are planned to go on to receive one of the new agents that necessitate close monitoring. Some relatively older immunosuppressant agents, such as mitoxantrone, approved as an MS therapy, and cyclophoshamide, although not approved as an official MS therapy but widely used in more aggressive forms of the disease have a limited duration of usage and an upper dosage limit owing to their potentially severe side effects. Mitoxantrone is known to be associated with treatment-related haematological malignancies, cardiomyopathy and reproductive system complications. However, with lower doses the probability of these AEs may be reduced without compromising too much the potential efficacy in the short term. Cyclophoshamide is another ‘ancient’ agent that is still used as an alternative in many centres. It has been associated with bladder malignancies and some other AEs, but with proper management the risks will remain low.Many MS centres now have established programmes to follow their patients, but for the physician who treats such patients the safety issues should not prevent them to withhold such therapies from their patients once they are aware of the initiation and follow-up protocols.The current practice of MS management has changed significantly over the last decade with new options emerging. Although each ‘new drug’ has its own safety and tolerability issues, once the practising neurologist is knowledgeable of them, their application is justified. It should be remembered that MS treatment for some is the balance between accepting disability and reduced quality of life (QoL) versus expecting reduced disability and better QoL, but accepting the probability (relatively low risk) of severe AEs. Proper management of patients with highly active MS is a practice of risk management. In summary, as our alternatives for long-term MS management is expanding and we are entering the era of personalized medicine, we are likely to better understand and detect disease course and severity as well as treatment responses and safety issues. One major issue is to be aware of the current safety issues in order to monitor properly our patients to reduce therapy-related AEs and prevent any harm secondary to therapy.

36

Case study presentation on treatment to target: shared decision making

C2

Thanks to the most recent scientific discoveries, the multiple sclerosis (MS) therapeutic armamentarium available in clinical practice and in clinical trials is continuously growing. This growing armamentarium offers new opportunities for patients but raises questions and concerns. Indeed, even though the new disease-modifying drugs seem to be highly effective, their safety profile and long-term efficacy have still to be examined in depth. The role of the MS patient is becoming more and more relevant and an active role is required in the complicated process of diagnosis and therapeutic decision making. In this case study session, it will be highlighted how difficult it is to choose a treatment, how important it is to know the patient’s thoughts and expectations, and to share the decision-making process from the very beginning of the disease.

David Bates


37

New biological basis of rehabilitationL12

Historically, basic science has had very little impact on clinical neurorehabilitation. However, recent advances in our core understanding of the neural and behavioural signals driving plasticity have begun to impact clinical practice. There is now a wealth of data demonstrating that there are specific behavioural, neurophysiological and molecular signals that drive plasticity both in the intact central nervous system (CNS) during normal learning and in the injured CNS during ‘relearning’. Behavioural signals include repetition, intensity, timing, difficulty and salience.Neural signals include timing, intensity and repetition of neuronal activity along with extra and intracellular signalling pathways. These signals all contribute to the development of several neural strategies that support functional improvement through recovery and/or compensation. Novel rehabilitation interventions are being developed that are based on these principles of neural plasticity and enhance functional improvement. Evidence for the efficacy of these interventions and the role of bioengineering in the development of device-assisted therapies will also be discussed.

Jeffrey Kleim

School of Biological and HealthSystems EngineeringArizona State UniversityTempe, USA

38

NeuroprotectionL13

Multiple sclerosis (MS) is characterized by chronic inflammatorion, demyelination and neurodegeneration in the central nervous system. An emerging body of evidence based on recent findings in histopathology, imaging and other studies is currently changing our understanding of the disease and its underlying pathogenesis. Conceptual shifts have included: first, an appreciation of the extent to which the neuron and its axon are affected in MS; and second, elucidation of how the neurobiology of axon–glial and, particularly, axon–myelin interactions may influence disease progression.This presentation will review the mechanisms leading to axonal loss in acute inflammation and in chronic demylination and discuss how remyelination might prevent axon degeneration. Furthermore, it will speculate about alternatives beyond immune-directed therapeutic approaches and evaluate future perspectives for neuroprotective and neuroregenerative treatment strategies for MS.

Bernd Kieseier

Department of NeurologyHeinrich-Heine UniversityDüsseldorf, Germany

39

Cell therapyL14

Transplantation of stem cells such as neural precursor cells and mesenchymal stem cells has been proposed as a promising therapeutic strategy in various neurological disorders, including multiple sclerosis (MS). Recent evidence consistently shows that transplantation of these cells is aimed mainly at protecting the central nervous system from inflammatory and neurodegenerative damage. Systemically transplanted stem cells, in fact, seem to modify experimental disease progression by releasing a plethora of factors that act as immunomodulatory molecules or as neuroprotectants. Nonetheless, many questions remain regarding the true efficacy and precise mode of action of these stem cell-based therapies.Research on stem cell transplantation in MS is thus advancing on two different fronts. While preclinical research is trying to discover the molecular basis of stem cell therapeutic plasticity, thus advancing knowledge to offer a solid framework for clinical trial design, on the other hand, pilot trials are trying to unravel the safety and feasibility of stem cell transplantation as well as to gain some hints on efficacy. Here we will provide an overview of the current knowledge regarding the rational of stem cell transplantation in MS as well as clinical advances.

Marco Bacigaluppi

Neuroimmunology UnitDepartment of NeurologyInstitute of Experimental NeurologyVita-Salute San Raffaele UniversityMilan, Italy

40

The philosophy underpinning rehabilitation is highly appropriate to the unpredictable and diverse needs of those affected by multiple sclerosis (MS). The key elements of this educational process, which seeks to increase ability, participation and autonomy, is well suited to the management of the multiple symptoms inherent to this condition. Randomized controlled trials provide a reasonable evidence base supporting multidisciplinary rehabilitation in both out- and in-patient settings. There is a need to target specific disabling symptoms such as spasticity, weakness and cognitive impairment and to improve approaches in vocational rehabilitation. These studies are limited by the evaluating tools utilized, which often fail to incorporate the patient’s own perception of benefit. There is a need to develop better, more scientifically sound patient-related outcome measures (PROMS) and to apply newer measurement techniques such as Rasch analysis and item-response theory.A key question is: rather than adapt to disability, can we reduce impairment? Recent studies targeting both MS and optic neuritis suggest a degree of plasticity which may compensate for impairment and indicate that the extent of response may influence recovery. A better understanding of plasticity could be invaluable in reducing impairment and provide an ideal target to guide and enhance the rehabilitation process.

The multidisciplinary approachto patient rehabilitation

L15

Alan J. Thompson


41

Symptoms managementKN1

Management of symptoms in multiple sclerosis (MS) has received relatively little attention compared with disease-modifying treatments. However, the effect of these symptoms on quality of life can be profound. Clinical trials of pharmacological drugs to treat the symptoms of MS have often been underpowered and have used inappropriate measures of outcome. Therefore, the evidence base on which to make clinical decisions has been less than adequate. However, interest in pharmacological and other approaches to symptom management in MS has increased in the last decade and there has been continuing exploration of underlying mechanisms.1 Several large randomized controlled trials have been reported focusing particularly on motor symptoms (including weakness and spasticity), bladder dysfunction, memory, mood and fatigue. Studies have included exercise and agents such as long-acting aminopyridenes, cannabinoids and botulinum toxin. It is important to build on these developments and encourage more definitive trials with scientifically sound clinical outcomes evaluating interventions that address some of the other disabling symptoms affecting those with MS.

References 1. Thompson AJ, Toosy AT, Ciccarelli O. Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions. Lancet Neurol 2010;9:1182–99.

Alan J. Thompson


42

From genotype to biology in MSL16

Multiple sclerosis (MS) is a multifocal demyelinating disease with progressive neurodegeneration caused by an autoimmune response to self-antigens in a genetically susceptible individual. In a collaborative genome-wide association study (GWAS) performed by the International MS Genetics Consortium and involving 9772 cases of European descent, we replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. GWAS in other autoimmune diseases have revealed numerous genetic associations between common single nucleotide polymorphisms (SNPs) and risk of autoimmune diseases, some of which are shared between diseases. Along with clinical evidence, this suggests that some genetic risk factors with their biologic effects may be shared across diseases. We evaluate the extent of this sharing for 107 immune-mediated disease risk SNPs in seven diseases and developed a novel statistic for Cross Phenotype Meta-Analysis, which detects the association of an SNP to multiple, but not necessarily all, phenotypes. We have determined that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple, but not all, immune-mediated diseases (SNP-wise PCPMA< 0.01). Distinct groups of interacting proteins are encoded near SNPs that predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We have begun efforts to identify the biologic effects of disease-causing SNPs at non-coding regions of the genome, where it has been difficult to assign function to DNA sequence, and to compare these effects across different autoimmune diseases. We use fine-mapping genetic data to identify causal mutations and integrate these data with chromatin maps of 10 defined human CD4+ T-cell populations and 56 additional cell types. These investigations identified risk variants disrupting the enhancers of distinct cell types among the different autoimmune diseases. Finally, autoimmune disease results from untoward interactions between genetics and the environment. We recently showed that increased salt (NaCl) concentrations found locally under physiological conditions in vivo dramatically boost the induction of T helper 17 (Th17) cells mediated by serum and glucocorticoid-inducible kinase 1. The Th17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype, characterized by the up-regulation of the proinflammatory cytokines granulocyte-macrophage colony-stimulating factor, tumour necrosis factor alpha and interleukin 2. Mice fed with a high-salt diet develop a more severe form of experimental autoimmune encephalomyelitis, in line with augmented central nervous system-infiltrating and peripherally induced antigen-specific Th17 cells. It was of interest to observe that RNA array analyses of genes induced by NaCl are markedly enhanced among GWAS hits. Identifying specific sites where a single, non-coding nucleotide variant is responsible for disease risk may pinpoint specific disruptions of consensus transcription factor-binding sites that ultimately define disease risk as related to environmental factors.

David Hafler

Department of NeurologyYale School of MedicineNew Haven, CT, USA

43

Beyond genetics: integrating next generationsequencing-based approaches

Sequencing of the human genome was meant to revolutionize the mechanistic understanding of disease and to enable better diagnoses and therapy. The subsequent emphasis on genome-wide association studies has delivered numerous loci of relevance to disease but has fallen short of those promises. Touching on examples spanning from basic science (our recent discovery of a new class of non-coding RNAs) to translational science (biomarker discovery), we show some of the reasons that potentially underlie this failure. Relating to our experience in establishing a translational genomics centre situated within a hospital, with the aim of eventually benefiting patients, we can understand how some of these failed promises still hold great potential for understanding disease, as long as new, more integrated and patient-centric approaches are taken. In this approach, all components and functions of the genome (genetics, epigenetics and gene expression) need to be taken into account together and to be treated as potentially heritable features. By viewing the heritablity of the genome in this way, we might begin to understand better the relationship between the environment and the disease, the partial heritability of complex disease, and, above all, the unique puzzle which makes up a specific disease progression and phenotype within the context of his/her environment and family, as opposed to a ‘blanket’ diagnosis. Recently we have begun integrating these approaches in collaboration with INSPE and the Martinelli Boneschi laboratory in the context of multiple sclerosis (MS), where we have focused on multiplex families with at least three individuals affected with MS, with preliminary results providing insight into how all components (genetics, epigenetics and gene expression) might play important roles in these families.

L17

Elia Stupka

Unit Center for Translational Genomics and BioinformaticsSan Raffaele Scientific InstituteMilan, Italy

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Pharmacogenetics and pharmacogenomicsL18

Genetic polymorphisms and variable expression of drug receptors, metabolizing enzymes and transporters have been linked to interindividual differences in efficacy and toxicity of many therapeutic agents. The term pharmacogenetics, a subclass of pharmacogenomics, was initially coined in 1959 by Friedrich Vogel and is now defined by the US Food and Drug Administration as “the study of variations in DNA sequence as related to drug response.” These variants include single nucleotide and copy number polymorphisms. The contemporary definition of pharmacogenomics extends beyond germline DNA variants to include changes in RNA expression, epistasis and epigenetic regulations. In multiple sclerosis (MS), the combined effect of heterogeneity of disease presentation and the significant variation in clinical response to disease-modifying agents necessitates the definition of pharmacogenomic biomarkers that can a priori predict therapeutic response and define appropriate therapeutic regimens in order to ensure optimal clinical response, patient compliance and protection against the more severe side effects. Achieving adequate predictive specificity and sensitivity will undoubtedly require integration of data from all aspects of MS research, including clinical, genetic and environmental data, coupled to the application of advanced integrative approaches, such as dynamic systems modelling. This effort will be challenged further by the introduction of new therapeutic agents and the establishment of combination therapies. We will critically review the current pharmacogenomics knowledge of MS, addressing DNA variants and gene expression signatures reported to correlate with therapeutic responses, and discuss the options available to incorporate pharmacogenomics into routine clinical practice.

Jorge Oksenberg

Department of NeurologyUniversity of California at San Francisco (UCSF)San Francisco, CA, USA

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How to translate knowledge into practice

Although we have some markers that may predict response to disease-modifying drugs (DMDs) prior to starting treatment, none of these has translated into clinical practice. Therefore, we have to give patients with active multiple sclerosis (MS) a trial of a DMD to see if they respond to therapy or not. The assessment of response, or not, relies on clinical, magnetic resonance imaging and validated body fluid biomarkers. Patients who have breakthrough disease should be switched to another class of treatment; this switch can be horizontally to another platform therapy, or vertically to a more effective second-line agent. The strategy of horizontal or vertical switching depends on individualized treatment decisions that need to take into account patient-related, disease-related and healthcare environmental factors. Individualized treatment decisions need to take into account the risks and benefits of the specific treatments. A large part of the emerging treatment landscape is the development of risk mitigation strategies. An emerging strategy is the concept of treating-2-target to render patients with MS free from disease activity. These strategies will be presented in the context of cases studies.

L19

Gavin Giovannoni


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Case studies presentation on how difficultit is to identify the response to treatment

C3

Once a diagnosis of multiple sclerosis (MS) has been established, clinicians are faced with the complex therapeutic algorithms that could be applied to the different phases of the disease. Different therapeutic approaches have been proposed after a treatment failure, but how to recognize responder and non-responder patients is still a challenge for the neurologist involved in MS management because of the lack of clinically available, approved biomarkers. The identification of non-responders is of central importance in the MS field, as it would lead to changes in therapeutic approach, possibly requiring more aggressive and risky treatment. Few validated serum markers may help physicians in recognizing non-responders, but clinical assessment and longitudinal magnetic resonance imaging scans remain mandatory, despite the identification of several promising biomarkers. All of these issues will be discussed during the course of this clinical case study session.

Gavin Giovannoni


47

Environmental and genetic factors/clinical phenotypes

Paediatric-onset multiple sclerosis (MS) comprises 2–5% of MS cases. Recent years have seen a significant growth in knowledge regarding the clinical manifestations of paediatric MS, as well as the possible environmental and genetic risk factors linked to its development. This presentation will review the clinical features that characterize paediatric MS and explore risk factors for its development, including putative lifestyle and infectious and environmental risk factors.

L20

Ann Yeh

Division of NeurologyHospital for Sick ChildrenToronto, Canada

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How difficult is the diagnosis of MS in children?L21

Multiple sclerosis (MS) is uncommon in adolescents and even rarer in prepubescent children, but there has been an increased recognition of paediatric-onset MS over the past decade. Although the diagnosis of MS classically relies on the demonstration of disease dissemination in space and time, the exclusion of other neurological disorders is essential. Although the well-known clinical criteria for adult-onset MS are widely used, the diagnosis of MS is not simple in the paediatric population, particularly in childhood because of the broad differential diagnosis. Various conditions and diseases may cause similar clinical monofocal or multifocal symptoms, remitting clinical course, and paraclinical signs more or less typical for MS. The limited specificity of abnormalities disclosed by magnetic resonance imaging may increase the likelihood of the diagnosis of MS in patients affected by other disorders.It is important to avoid the misdiagnosis of MS by ruling out demyelinating and non-demyelinating syndromes in children. Acquired demyelinating syndromes of the central nervous system (CNS) have a variety of presentations in childhood. For example, acute disseminated encephalomyelitis is a polysymptomatic disorder associated with encephalopathy. Conversely, other demyelinating conditions can affect only a discrete region within the CNS without any mental status changes, such as clinically isolated syndromes involving the brainstem, spinal cord, optic nerves or both. While these demyelinating syndromes are typically monophasic in childhood, recurrences can occur, raising the possibility of an MS diagnosis. But similar clinical presentations can occur in children suffering from an infectious, neoplastic, metabolic or vascular disease (for instance, CNS vasculitis, systemic lupus erythematosus, mitochondrial disease, antiphospholipid or anticardiolipin syndrome, CADASIL, migraine, CNS malignancy). A prompt and accurate diagnosis of paediatric-onset MS is important to optimize overall management of both the physical and the social impact of the disease. Avoiding misdiagnoses is particularly compelling because there are partially effective treatments for MS as well as different therapies for other disorders that can mimic MS. This presentation will review the main clinical, neuroimaging and laboratory features of MS starting in children and adolescents, with particular emphasis in the atypical features or red flags that may serve to distinguish alternative diagnoses.

Silvia Tenembaum


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Treatment recommendations for paediatric MSL22

Multiple sclerosis (MS) in children and adolescents accounts for about 3–10% of cases of the whole MS patient population. Paediatric or juvenile MS is characterized by a relapsing course in almost all cases, and the frequency of relapses is higher than that in adult-onset MS, at least during the first years of disease evolution.The objective of MS therapy is to speed up recovery after a relapse, to prevent the occurrence of relapses and to prevent disease progression and neurodegeneration. The use of drugs for MS in children and adolescents has not been studied in clinical trials, so their use is mainly based on results from trials in adults and from observational studies.Two consensus papers have recently addressed the topic of treatment in paediatric MS:1,2 high-dose intravenous corticosteroids are, by consensus, the treatment choice for acute relapses, whereas the prevention of relapses and disease progression is based on treatment with immunomodulatory agents. Interferon (IFN) beta and glatiramer acetate (GA) have been demonstrated to be well tolerated in paediatric patients with MS and also reduce relapse rate and disease progression.1,2 Cyclophosphamide and natalizumab could be offered as second-line treatment in patients with a poor response to either IFN beta or GA. Two recent studies have demonstrated that natalizumab is highly efficacious in paediatric patients with active MS.3,4 New oral and injectable drugs will be available in the near future; if safe and well tolerated in the long-term follow up of adults with MS, these drugs could be tested in the paediatric MS population.

References 1. Ghezzi A, Banwell B, Boyko A et al. The management of multiple sclerosis in children: a European view. Mult Scler 2010;16:1258–67.

2. Chitnis T, Tenembaum S, Banwell B et al; the International Pediatric Multiple Sclerosis Study Group. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler 2012;18:116–27.

3. Kornek B, Aboul-Enein F, Rostasy K et al. Natalizumab therapy for highly active pediatric multiple sclerosis. JAMA Neurol 2013;70:469–75.

4. Ghezzi A, Pozzilli C, Grimaldi L et al; the Italian MS Study Group. Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases. Mult Scler 2013; doi: 10.1177/1352458512471878.

Angelo Ghezzi

Multiple Sclerosis CentreGallarate HospitalGallarate, Italy

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Case studies presentationon juvenile MS/differential diagnosis

C4

Multiple sclerosis (MS) in paediatric patients is a rare condition and its diagnosis is even more difficult than in adults owing of the large number of neurological disorders that can mimic MS and the lack of specific clinical and radiological hallmarks of disease. A careful clinical workout is mandatory in order to guarantee a prompt diagnosis and to apply the most appropriate treatment to limit disease progression. By presenting a clinical case, atypical forms of paediatric MS will be discussed and the ‘red flag’ that may be considered to identify alternative diagnoses highlighted.

Silvia Tenembaum


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How to interpret results in MS clinical trials: statistical issues

KN2

Monitoring the evolution of multiple sclerosis (MS) and detecting the effects of new drugs has always been very challenging, mainly owing to the high variability of the disease. Since the first randomized clinical trial (RCT) demonstrating the efficacy of a drug in MS (1993), the number of RCTs has been increasing exponentially in MS. A standard methodology has now been consolidated, passing through Phase II placebo-controlled trials, typically lasting 6 months with magnetic resonance imaging (MRI) endpoints, and ending up with Phase III placebo-controlled trials, lasting 1–2 years with relapse or disability progression endpoints. This process has brought to the market new drugs, and other therapies will become available in the near future. So we entered a new era of RCT in MS: as patients enrolled in trials have more and more benign disease and the use of placebo has become ethically questionable, new design strategies are required to handle this evolution. A large effort is devoted to study, among other strategies to minimize the exposure to placebo, the validation of surrogate outcomes and the use of time-to-event endpoints as primary outcomes in Phase III trials. An emerging issue is also the development of strategies for clinical trials for paediatric MS populations. As MS is a rare condition in children, clinical trials would be unfeasible if based on clinical endpoints. These points will be examined in detail.

1. Surrogate outcomesMRI markers are widely used as primary outcomes in Phase II trials. Their role as surrogate for clinical endpoints has been closely studied and is still controversial. A recent meta-analysis further validated their role as surrogates at the trial level. The possibility of their use as primary endpoints in Phase III trials is, therefore, possible, even if limited to specific conditions. 2. Time-to-event endpointsA simple alternative to the standard placebo-controlled trial is a design with a time-to-event (relapse, progression) endpoint. With such a design, patients are randomized to receive the active treatment immediately after their entry into the study or after they have the event of interest (a relapse, a progression) after randomization, being forced to stay in placebo only if they have a stable disease course. This possibility mitigates the ethical concerns of keeping patients with MS in the placebo arm for long and fixed periods of time (1 or 2 years).

3. Trials in paediatric MS populationsCalculations based on data from a paediatric cohort have been performed. Six-month Phase II trials using new T2 lesions as an endpoint may be feasible in the paediatric MS population. Achievable sample sizes for Phase III trials powered on relapse rates or time-to-first relapse will need to be 2 years in duration and will require multicentre collaborations.

Maria Pia Sormani

University of GenoaGenoa, Italy

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Disclosure of faculty relationships

Serono Symposia International Foundation adheres to guidelines of the European Accreditation Council for Continuing Medical Education (EACCME) and all other professional organizations, as applicable, which state that programmes awarding continuing education credits must be balanced, independent, objective, and scientifically rigorous. Investigative and other uses for pharmaceutical agents, medical devices, and other products (other than those uses indicated in approved product labeling/package insert for the product) may be presented in the programme (which may reflect clinical experience, the professional literature or other clinical sources known to the presenter). We ask all presenters to provide learners with information about relationships with pharmaceutical or medical equipment companies that may have relevance to their lectures. This policy is not intended to exclude faculty who have relationships with such companies; it is only intended to inform learners of any potential conflicts so participants may form their own judgments, based on full disclosure of the facts. Further, all opinions and recommendations presented during the programme and all programme-related materials neither imply an endorsement, nor a recommendation, on the part of Serono Symposia International Foundation. All presentations solely represent the independent views of the presenters/authors.

The following faculty provided information regarding significant commercial relationships and/or discussions of investigational or non-EMEA/FDA approved (off-label) uses of drugs:

Marco Bacigaluppi Declared no potential conflict of interest.

David Bates Declared no potential conflict of interest.

Giancarlo Comi Declared receipt of honoraria or consultation fees from SSIF, Novartis, Teva, Sanofi, Genzyme, Merck Serono, Bayer, Actelion.

Angelo Ghezzi Declared receipt of honoraria or consultation fees from Merck Serono, Biogen, Teva, Novartis. He declared also participation in company sponsored speaker’s bureau: Merck Serono, Genzyme, Biogen.

Gavin Giovannoni Declared receipt of grants and contracts from Bayer Schering, Biogen Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva, Sanofi Aventis. He declared also receipt of honoraria or consultation fees from Bayer Schering, Biogen Idec, Eisai, Elan, Fiveprime, Genzyme, Genetech, GSK, GW Pharma, Ironwood, Merck Serono, Novartis, Pfizer, Sanofi Aventis, Synthon BV, Teva, UCB Pharma, Vertex Pharmaceuticals. He declared also to be member of company advisory board or similar groups: Nil. He is stakeholder of Canbex. He declared also participation in company sponsored speaker’s bureau: Biogen Idec, Genzyme, GWE Pharma, Ironwood, Merck Serono, Novartis, Roche, Sanofi Aventis, Teva, Vertex Pharmaceuticals. He declared benefit from a relationship with Nil.

Douglas Goodin Declared receipt of grants and contracts from Novartis and Biogen. He declared receipt of honoraria or consultation fees from Teva, Bayer, Merck Serono. He declared also his participation to a company sponsored speaker’s bureau: Teva.

David Hafler Declared receipt of honoraria or consultation fees from Allozyne, Bayer, McKinsey, NKT therapeutics, Novartis, Biogen.

Hans-Peter Hartung Declared receipt of honoraria or consultation fees from: Biogen Idec, MedImmune, Novartis, Genzyme, Teva, Roche. He declared also his participation to company sponsored speakers’ bureau: Biogen Idec, MedImmune, Novartis, Genzyme, Teva, Roche.

Ludwig Kappos Declared receipt of grants, contracts, honoraria, consultation fees and to be member of company advisory board or other similar groups: Actelion, Advancecell, Allozyne, BaroFold, Bayer Healthcare, Bayer Schering, Bayhill, Biogen Idec, Biotica,CLC Behring, Elan, Genmab, GeNeuro, Genmark, GlaxoSmithKline, Genzyme, J&J, Lilly, Merck Serono, Novartis, Novonordisk, Octapharma, Peptimmune, Roche, Sanofi-Aventis, Santhera, Teva, UCB, Xenoport, Wyeth.

Rana Karabudak Declared no potential conflict of interest.

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Bernd Kieseier Declared receipt of grants and contracts from Biogen and Novartis. He declared also receipt of honoraria or consultation fees from Biogen, Genzyme, Novartis.

Jeffrey A. Kleim Declared no potential conflict of interests.

Dawn Langdon Declared receipt of grants and contracts from Bayer Healthcare and of honoraria or consultation fees from Bayer Healthcare, SSIF, Novartis, Merck Serono, Biogen. She declared also participation in company sponsored speaker’s bureau: Bayer Healthcare, SSIF, Novartis, Merck Serono, Biogen.

Xavier Montalban Declared receipt of honoraria or consultation fees from Bayer, Biogen Idec, Merck Serono, Geneuro, Neurotec, Novartis, Teva, Sanofi, Genzyme, Almirall.

Jorge Oksenberg Declared receipt of grants and contracts from USA National Institute of Health, USA National Multiple Sclerosis Society. He declared receipt of honoraria or consultation fees from EU Marie Curies ITN, SSIF. He declared also to be member of a company advisory board or similar groups: Annals of Neurology.

Peter Rieckmann Declared receipt of honoraria or consultation fees from Bayer, Biogen Idec, Merck Serono, Genzyme, Novartis, Teva.

Magnhild Declared receipt of honoraria or consultation fees from Actelion, Almirall, Bayer Health Care, MerckSandberg-Wollheim Serono, Novartis, Roche. She is a member of a company advisory board or similar groups: Active Biotech.

Aksel Siva Declared receipt of grants and contracts from Bayer. He declared receipt of honoraria or consultation fees from Bayer, Biogen, Novartis, Merck Serono, Teva. He declared also his participation to company sponsored speaker’s bureau: Allergan.

Maria Pia Sormani Declared of receipt of honoraria or consultation fees from Merck Serono, Teva, Allozyne. She declared also to be member of company advisory board or similar groups: Merck Serono, Teva, Biogen Idec.

Elia Stupka Declared no potential conflict of interest.

Silvia Tenembaum Declared to be member of advisory boards or similar groups: Biogen, Genzyme, Teva, Merck Serono.

Alan J. Thompson Declared receipt of grants and contracts from Eisai, MS Society UK Research. He declared receipt of honoraria or consultation fees from Novartis, SSIF. He declared also to be member of company advisory board or similar groups: Eisai, IMANOVA, MSIF. He declared benefit from a relationship with a commercial enterprise: Multiple Sclerosis Journal.

Ann Yeh Declared no potential conflict of interest.

Tjalf Ziemssen Declared receipt of grants and contracts from Bayer, Teva, Biogen, Novartis, Merck Serono. He also declared receipt of honoraria or consultation fees from Bayer, Teva, Sanofi, GSK, Novartis, Merck, CSL, Biogen. He is also member of company advisory board or similar groups: Teva, Bayer, Novartis, Sanofi, Biogen.

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Notes

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