Download How to translate new insights in MS into clinical practice ABSTRACT BOOK

ABSTRACT BOOK
2013 CME Annual meeting in multiple sclerosis
How to translate new insights in MS
into clinical practice
Istanbul, Turkey - 31 May - 1 June 2013
Welcome note
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,
David Bates
Chairman
Newcastle upon Tyne, UK
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Magnhild Sandberg-Wollheim
Co-Chair
Lund, Sweden
Aim of the conference
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.
Learning objectives
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.
Target audience
Clinicians involved in MS management.
Accreditation
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.
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Serono Symposia International Foundation adheres to the principles
of the Good CME Practice group.
Good
Learning effectiveness project
We 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!
follow us on
SSIF_Neurology
http://twitter.com/SSIF_Neurology#neurology
Follow this code,
login and get access to: updated agenda, faculty members,
question wall, programme evaluation form, certificate of
attendance and CME certificate.
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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Venue
Ceylan Intercontinental Hotel
Asker Ocagi Caddesi No. 1 Taksim
34435 Istanbul, Turkey
Phone: +90 0212 368 4444
Language
The official language of the conference
will be English.
Scientific organisers
Chair
David Bates
Department of Neurology
Royal Victoria Infirmary
Newcastle upon Tyne, UK
Co-Chair
Magnhild Sandberg-Wollheim
Department of Neurology
Lund University Hospital
Lund, Sweden
Scientific Secretariat
Serono Symposia International Foundation
Salita San Nicola da Tolentino, 1/b
00187 Rome, Italy
Neurology team leader: Serena Dell’Ariccia
Project manager: Alessia Addessi
Medical advisor: Federica Cerri
Phone: +39 06 420 413 591
Fax: +39 06 420 413 677
[email protected]
Organising Secretariat
Meridiano Congress International
Via Sapri, 6
00185 Rome, Italy
Congress coordinator:
Federica Russetti
Phone: +39 06 88 595 209
[email protected]
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Scientific programme
Day 1
08.30
Friday, 31 May 2013
Serono Symposia International Foundation (SSIF) Opening
G. Comi (Italy)
Introduction to the conference
D. Bates (UK) - M. Sandberg-Wollheim (Sweden)
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
Moderators:
Treatment issues management today - part 1
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)
12.30
Real-time survey
Question time
12.45
Lunch
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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:
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:
15.05
Long-term benefit of current DMDs on disability progression:
experience from clinical trials and clinical practice
D. Goodin (USA)
Case study presentation on treatment to target:
shared decision making
D. Bates (UK)
Real-time survey
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)
17.45
Real-time survey
Question time
18.00
End of day 1
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Day 2
Saturday, 1 June 2013
SESSION V Genetics-genomics-proteomics
Moderators:
08.45
L16:
09.05
L17:
09.25
L18:
09.45
L19:
10.05
C3:
10.25
10.40
D. Bates (UK) - M. Sandberg-Wollheim (Sweden)
Real-time survey
From genotype to biology of MS
D. Hafler (USA)
Beyond genetics: integrating next generation sequencing-based approaches
E. Stupka (Italy)
Pharmacogenetics and pharmacogenomics
J. Oksenberg (USA)
How to translate knowledge into practice
G. Giovannoni (UK)
Case studies presentation on how difficult it is to identify the response
to treatment
G. Giovannoni (UK)
Real-time survey
Question time
Coffee break
SESSION VI Paediatric MS
Moderators:
D. Bates (UK) - M. Sandberg-Wollheim (Sweden)
Real-time survey
11.00
L20:
11.20
L21:
11.40
L22:
12.00
C4:
12.20
KN2:
12.50
Environmental and genetic factors/clinical phenotypes
A. Yeh (Canada)
How difficult is the diagnosis of MS in children?
S. Tenembaum (Argentina)
Treatment recommendations for paediatric MS
A. Ghezzi (Italy)
Case studies presentation on juvenile MS/differential diagnosis
S. Tenembaum (Argentina)
How to interpret results in MS clinical trials: statistical issues
M. P. Sormani (Italy)
Real-time survey
Question time
Unsession
13.05
13.30
Unsession
All faculty members
End of the conference and closing lunch
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Marco Bacigaluppi
David Bates
Giancarlo Comi
Angelo Ghezzi
Gavin Giovannoni
Douglas Goodin
David Hafler
Hans-Peter Hartung
Ludwig Kappos
Rana Karabudak
Bernd Kieseier
Jeffrey A. Kleim
Dawn Langdon
Xavier Montalban
Jorge Oksenberg
Peter Rieckmann
Magnhild Sandberg-Wollheim
Aksel Siva
Maria Pia Sormani
Elia Stupka
Silvia Tenembaum
Alan J. Thompson
Ann Yeh
Tjalf Ziemssen
Faculty members
Biographies
Chairs
David Bates
Department of Neurology
Royal Victoria Infirmary
Newcastle upon Tyne, UK
David Bates trained in Medicine at Downing College, Cambridge and the Middlesex Hospital, London and in Neurology at the
University 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
Department of Neurology
Lund University Hospital
Lund, Sweden
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 Band 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.
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Marco Bacigaluppi
Neuroimmunology Unit
Department of Neurology
Institute of Experimental Neurology
Vita-Salute San Raffaele University
Milan, 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
Department of Neurology
Institute of Experimental Neurology
Vita-Salute San Raffaele University
Milan, Italy
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 VitaSalute 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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Biographies
Angelo Ghezzi
Multiple Sclerosis Centre
Gallarate Hospital
Gallarate, Italy
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
Department of Neurology
The Royal London Hospital
Whitechapel, London, UK
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.
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Douglas Goodin
UCSF Multiple Sclerosis Center
University of California San Francisco
San Francisco, CA, 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
Department of Neurology
Yale School of Medicine
New Haven, CT, USA
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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Biographies
Hans-Peter Hartung
Department of Neurology
Heinrich-Heine-University
Düsseldorf, Germany
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
Department of Biomedicine
University Hospital Basel
Basel, Switzerland
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.
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Rana Karabudak
Hacettepe University Hospital
Department of Neurology
Neuroimmunology Unit
Ankara, Turkey
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 peerreviewed articles and more than 200 articles, books and book chapters in English and Turkish.
Bernd Kieseier
Department of Neurology
Heinrich-Heine University
Düsseldorf, Germany
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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Biographies
Jeffrey A. Kleim
School of Biological and Health
Systems Engineering
Arizona State University
Tempe, USA
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
Department of Psychology
Royal Holloway University of London
London, UK
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.
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Xavier Montalban
Multiple Sclerosis Center of Catalonia
Unit of Clinical Neuroimmunology
Vall d’Hebron University Hospital
Barcelona, Spain
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
Department of Neurology
University of California at San Francisco (UCSF)
San Francisco, CA, USA
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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Biographies
Peter Rieckmann
Bamberg Hospital and University of Erlange
Bamberg, Germany
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 JuliusMaximilians 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
Department of Neurology
Istanbul University
Istanbul, Turkey
Aksel Siva is Professor of Neurology at the Department of Neurology, Istanbul University. He heads the Clinical Neuroimmunology 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.
18
Maria Pia Sormani
University of Genoa
Genoa, 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
Unit Center for Translational Genomics and Bioinformatics
San Raffaele Scientific Institute
Milan, Italy
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.
19
Biographies
Silvia Tenembaum
Department of Neurology
National Pediatric Hospital “Dr. Juan Garrahan”
Buenos Aires, Argentina
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
Department of Brain Repair and Rehabilitation
Institute of Neurology University College London
National Hospital for Neurology and Neurosurgery
London, UK
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.
20
Ann Yeh
Division of Neurology
Hospital for Sick Children
Toronto, Canada
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
MS Center Dresden Neurological
University Clinic
Dresden, Germany
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.
21
Abstracts
L1
Early diagnosis (RIS/CIS)
Xavier Montalban
Multiple Sclerosis Center of Catalonia
Unit of Clinical Neuroimmunology
Vall d’Hebron University Hospital
Barcelona, Spain
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.
23
L2
Differential diagnosis:
MS and acquired demyelinating disorders
Giancarlo Comi
Department of Neurology
Institute of Experimental Neurology
Vita-Salute San Raffaele University
Milan, Italy
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.
24
L3
McDonald criteria
David Bates
Department of Neurology
Royal Victoria Infirmary
Newcastle upon Tyne, UK
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.
25
L4
Diagnosis communication
and patients’ coping strategies
Dawn Langdon
Department of Psychology
Royal Holloway University of London
London, UK
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.
26
C1
Case studies on early diagnosis
and differential diagnosis
Giancarlo Comi
Department of Neurology
Institute of Experimental Neurology
Vita-Salute San Raffaele University
Milan, Italy
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.
27
L5
Do IFNs and GA still have a role in MS?
Peter Rieckmann
Bamberg Hospital and University of Erlange
Bamberg, Germany
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 relapsingremitting MS.
28
L6
Oral drugs
Ludwig Kappos
Department of Biomedicine
University Hospital Basel
Basel, Switzerland
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.
29
L7
Antibodies in MS
Hans-Peter Hartung
Department of Neurology
Heinrich-Heine-University
Düsseldorf, Germany
While multiple sclerosis (MS) is often well controlled with immunomodulatory diseasemodifying 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.
30
L8
When and how to start a therapy
Tjalf Ziemssen
MS Center Dresden Neurological
University Clinic
Dresden, Germany
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.
31
L9
Long-term benefit of current DMDs on disability
progression: experience from clinical trials and
clinical practice
Douglas Goodin
UCSF Multiple Sclerosis Center
University of California San Francisco
San Francisco, CA, USA
Randomized controlled trials (RCTs) have established the short-term efficacy of current diseasemodifying 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 nonrandomized 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 longterm 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.
32
L10
When and how to switch from one therapy to another
Giancarlo Comi
Department of Neurology
Institute of Experimental Neurology
Vita-Salute San Raffaele University
Milan, Italy
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.
33
L11
How to detect and monitor safety issues
Aksel Siva
Department of Neurology
Istanbul University
Istanbul, Turkey
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.
34
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.
35
C2
Case study presentation on treatment to target:
shared decision making
David Bates
Department of Neurology
Royal Victoria Infirmary
Newcastle upon Tyne, UK
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.
36
L12
New biological basis of rehabilitation
Jeffrey Kleim
School of Biological and Health
Systems Engineering
Arizona State University
Tempe, USA
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.
37
L13
Neuroprotection
Bernd Kieseier
Department of Neurology
Heinrich-Heine University
Düsseldorf, Germany
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.
38
L14
Cell therapy
Marco Bacigaluppi
Neuroimmunology Unit
Department of Neurology
Institute of Experimental Neurology
Vita-Salute San Raffaele University
Milan, Italy
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.
39
L15
The multidisciplinary approach
to patient rehabilitation
Alan J. Thompson
Department of Brain Repair and Rehabilitation
Institute of Neurology University College London
National Hospital for Neurology and Neurosurgery
London, UK
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.
40
KN1
Symptoms management
Alan J. Thompson
Department of Brain Repair and Rehabilitation
Institute of Neurology University College London
National Hospital for Neurology and Neurosurgery
London, UK
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.
41
L16
From genotype to biology in MS
David Hafler
Department of Neurology
Yale School of Medicine
New Haven, CT, USA
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 noncoding 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 highsalt conditions display a highly pathogenic and stable phenotype, characterized by
the up-regulation of the proinflammatory cytokines granulocyte-macrophage colonystimulating factor, tumour necrosis factor alpha and interleukin 2. Mice fed with a highsalt 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.
42
L17
Beyond genetics: integrating next generation
sequencing-based approaches
Elia Stupka
Unit Center for Translational Genomics and Bioinformatics
San Raffaele Scientific Institute
Milan, Italy
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.
43
L18
Pharmacogenetics and pharmacogenomics
Jorge Oksenberg
Department of Neurology
University of California at San Francisco (UCSF)
San Francisco, CA, USA
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.
44
L19
How to translate knowledge into practice
Gavin Giovannoni
Department of Neurology
The Royal London Hospital
Whitechapel, London, UK
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.
45
C3
Case studies presentation on how difficult
it is to identify the response to treatment
Gavin Giovannoni
Department of Neurology
The Royal London Hospital
Whitechapel, London, UK
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.
46
L20
Environmental and genetic factors/clinical
phenotypes
Ann Yeh
Division of Neurology
Hospital for Sick Children
Toronto, Canada
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.
47
L21
How difficult is the diagnosis of MS in children?
Silvia Tenembaum
Department of Neurology
National Pediatric Hospital “Dr. Juan Garrahan”
Buenos Aires, Argentina
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 nondemyelinating 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.
48
L22
Treatment recommendations for paediatric MS
Angelo Ghezzi
Multiple Sclerosis Centre
Gallarate Hospital
Gallarate, Italy
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.
49
C4
Case studies presentation
on juvenile MS/differential diagnosis
Silvia Tenembaum
Department of Neurology
National Pediatric Hospital “Dr. Juan Garrahan”
Buenos Aires, Argentina
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.
50
KN2
How to interpret results in MS clinical trials:
statistical issues
Maria Pia Sormani
University of Genoa
Genoa, Italy
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 outcomes
MRI 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 metaanalysis 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 endpoints
A simple alternative to the standard placebo-controlled trial is a design with a time-toevent (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 populations
Calculations 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-tofirst relapse will need to be 2 years in duration and will require multicentre collaborations.
51
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.
52
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
Sandberg-Wollheim
Declared receipt of honoraria or consultation fees from Actelion, Almirall, Bayer Health Care, Merck
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.
53
Notes
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