FINAL PROGRAMME AND ABSTRACT BOOK

MS Preceptorship “Updating knowledge in multiple sclerosis”10th editionBarcelona, Spain - 5-7 June 2013

General information

VenueThe live educational workshop takes place at the:

Centre d'Esclerosi Múltiple de Catalunya (Cemcat) Edifici CemcatHospital Universitari Vall d'HebronPg. Vall d'Hebron, 119-12908035 Barcelona, Spain

LanguageThe official language of the live educational workshop is English.

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

Project Manager: Alessia AddessiTel.: +39 (0)6 420 413 591Fax: +39 (0)6 420 413 677E-mail: info@seronosymposia.org

Medical Advisor: Federica Cerri

Serono Symposia International Foundation is a Swiss Foundation with headquarters in 14, rue du Rhône, 1204 Geneva, Switzerland

Organising secretariatMeridiano Congress InternationalVia Sapri, 6 - 00185 Rome, ItalyCongress coordinator: David H. SlangenTel.: +39 (0)6 88595 250 - Fax: +39 (0)6 88595 234E-mail: d.slangen@meridiano.it

To know more visit: www.neurology.seronosymposia.org

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MS Preceptorship“Updating knowledge in multiple sclerosis”10th edition

Serono Symposia International Foundation live educational workshop on:

MS Preceptorship“Updating knowledge in multiple sclerosis”10th editionBarcelona, Spain - 5-7 June, 2013

Aims The 2013 Preceptorship in multiple sclerosis (MS) will be hosted in the renewed Cemcat MS center in Barcelona. Since the MSscenario has become even more complex in the last years, an exhaustive mixture of theory and practice will be offered to the learnersin order to help them reach more easily MS diagnosis and choose the most appropriate therapeutic intervention. The programmewill cover all the main topics related to MS, starting from how to apply the diagnostic tools, addressing to how to assess and monitorcognitive impairment in clinical practice and reviewing the up-to-date data about efficacy and safety profile of the MS treatments.The aim of this live educational event is to guide young neurologists in the MS field, taking advantages of the clinical and researchexperience of a worldwide reference MS center.

Learning objectivesBy attending this live educational event the learners will be able to:• Select and apply diagnostic algorithm in order to achieve an early MS diagnosis• Compare the efficacy and safety profile of each drug available for MS treatment• Plan a long-term clinical and neuroradiological monitoring once MS has been diagnosed• Review the specific forms of demyelinating disorders and list the most suitable therapeutic approach for each condition

Target audienceYoung neurologists involved in MS patient management; neurologists interested in entering the MS field.

AccreditationSerono Symposia International Foundation (www.seronosymposia.org) is accredited by the European Accreditation Council forContinuing Medical Education (EACCME®) to provide the following CME activity for medical specialists. The EACCME® is aninstitution of the European Union of Medical Specialists (UEMS), www.uems.net

The CME MS Preceptorship "Updating knowledge in multiple sclerosis" held in Barcelona, Spain on 5-6-7 June 2013, is designatedfor a maximum of 12 (twelve) hours of European CME credits (ECMEC). Each medical specialist should claim only those credits thathe/she actually spent in the educational activity. EACCME® credits are recognized by the American Medical Association (AMA)towards the Physician's Recognition Award (PRA). To convert EACCME® credit to AMA PRA category 1 credit, please contact the AMA.

Serono Symposia International Foundation adheres to the principles of the Good CME Practice Group (gCMEp)

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All Serono Symposia International Foundation programmes are organized solely to promote the exchange and dissemination of scientific and medical information. Noforms of promotional activities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of thenamed speakers, and do not represent an endorsement or recommendation on the part of Serono Symposia International Foundation. This programme is made possiblethanks to educational grants received from: Arseus Medical, Besins Healthcare, Bristol-Myers Squibb, Celgene, Centre d’Esclerosi Multiple de Catalunya (Vall d'HebronUniversity Hospital), Centre Hépato-Biliaire, Hôpital Paul Brousse, ComtecMed, Congrex, Croissance Conseil, Cryo-Save, Datanalysis, Dos33, Esaote, European Societyof Endocrinology, Ferring, Fondazione Humanitas, Fundación IVI, GE Healthcare, GlaxoSmithKline Pharmaceuticals, IPSEN, Johnson & Johnson Medical, ISFPInternational Society for Fertility Preservation, ISMH International Society of Men’s Health, K.I.T.E., Karl Storz, Lumenis, Merck Serono Group, PregLem, Richard WolfEndoscopie, Sanofi-Aventis, Stallergenes, Stopler, Teva Pharma, Toshiba Medical Systems, Université Catholique de Louvain (UCL), University of Catania.

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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 workshop you will be asked to answer a real-time survey and after this live educational workshopyou will be receiving an online survey to help us to better tailor our future educational initiatives.

We thank you for participating!

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Scientific organisersXavier Montalban and Jaume Sastre-GarrigaMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Serono Symposia International Foundation designed this programmein partnership with Cemcat (Multiple Sclerosis Centre of Catalonia)

Local scientific and organising coordinationIlaria LaganàTeaching & training managerMultiple Sclerosis Centre of Catalonia E-mail: formacio@cem-cat.org

List of faculty members

Maria Pia AmatoDepartment of Neurological and Psychiatric SciencesUniversity of FlorenceFlorence, Italy

María Jesús ArévaloMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Georgina ArrambideMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Bruno BrochetDepartment of NeurologyCHU and University Victor SegalenBordeaux, France

Manuel ComabellaMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Giancarlo ComiDepartment of NeurologyInstitute of Experimental Neurology Vita-Salute San Raffaele UniversityMilan, Italy

Carme Costa RiuMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Herena EixarchMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

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Nicolás FissoloMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Angelo GhezziMultiple Sclerosis CentreGallarate HospitalGallarate (VA), Italy

Eva HavrdovàMS Centre and Neurology ClinicCharles University Prague, Czech Republic

Bernard HemmerNeurology ClinicUniversity of MunchenMunchen, Germany

Rosalía HornoMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Letizia LeocaniInstitute of Experimental NeurologyUniversity Vita-Salute IRCCSSan Raffaele HospitalMilan, Italy

Imke MetzInstitute of NeuropathologyUniversitätsmedizin Göttingen Georg-August-UniversitatGöttingen, Germany

Xavier MontalbanMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

List of faculty members

Susana OteroMultiple Sclerosis Center of Catalonia (Cemcat) Department of Epidemiology Vall d'Hebron University HospitalBarcelona, Spain

Lluís Ramió i TorrentàDepartment of NeurologyMultiple Sclerosis Unit“Dr. Josep Trueta” Hospital in GironaGirona, Spain

Marta Renom GuiterasMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Jordi RíoMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Lucía RomeroUnit of Multiple Sclerosis University Hospital of BellvitgeBarcelona, Spain

Alex RoviraUnit of Magnetic ResonanceDepartment of RadiologyVall d’Hebron University Hospital-IDIBarcelona, Spain

Carme SantoyoMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Jaume Sastre-GarrigaMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

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Nuria SolàMultiple Sclerosis UnitNeurology DepartmentHospital Clínic de BarcelonaBarcelona, Spain

Alan J. ThompsonDepartment of Brain Repair and RehabilitationUniversity College LondonNational Hospital for Neurology and NeurosurgeryLondon, UK

Mar TintoréMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Carmen TurMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Angela Vidal Multiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University HospitalBarcelona, Spain

Scientific programme5-7 June 2013

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Chairpersons: Xavier Montalban and Jaume Sastre-Garriga

Wednesday, 5 June

08.45 Serono Symposia International Foundation(SSIF) openingGiancarlo Comi (Italy)

09.00 Introduction to MS Centre of Catalonia(Cemcat)Xavier Montalban (Spain)

Real-time survey

09.30 L1: Epidemiology of MSSusana Otero (Spain)

10.00 KNS1: Immunopathogenesis of MSBernard Hemmer (Germany)

10.30 L2: Genetics of MSManuel Comabella (Spain)

11.00 L3: Pathology of MSImke Metz (Germany)

11.30 Coffee break

12.00 PD1: Panel discussion on “New revision ofMcDonald’s criteria”

MS diagnosis and differential diagnosisMar Tintoré (Spain)

MRI in MS: the radiologist perspectiveAlex Rovira (Spain)

VEPs in MSLetizia Leocani (Spain)

Discussion

Real-time survey

13.30 Working Lunch

14.30 Cemcat – Nuts and boltsCarmen Tur (Spain)

15.00 Cemcat and Vall d’Hebron Hospital premisevisits

17.00 End of day 1

Thursday, 6 June

Real-time survey

08.45 Specific forms of demyelinating diseases

L4: Neuromyelitis optica – NMO Georgina Arrambide (Spain)

L5: Primary progressive MS Alan J. Thompson (UK)

L6: Pediatric and juvenile MSAngelo Ghezzi (Italy)

10.00 L7: Overview on symptomatic therapy andrehabilitationJaume Sastre-Garriga (Spain)

10.30 S1: Symptomatic therapy snapshot #1 on gaitrehabilitationCarme Santoyo (Spain)

10.45 S2: Symptomatic therapy snapshot #2 onmanagement of dysphagiaMarta Renom Guiteras (Spain)

11.00 Coffee break

11.30 PD2: Panel discussion on “Cognition disorders in MS”Chair: Alan J. Thompson (UK)

DiagnosisMaria Pia Amato (Italy)

TreatmentBruno Brochet (France)

Case presentationAngela Vidal (Spain)

12.30 KNS2: Injectable therapies in MSEva Havrdovà (Czech Republic)

13.00 L8: Role of MS nurses in MS patients’managementRosalía Horno (Spain)

Real-time survey

13.30 Working lunch

14.30 CS1: Case study sessionLluís Ramió i Torrentà (Spain)Lucía Romero (Spain)Nuria Solà (Spain)

16.30 End of day 2

Legend: L : Lecture; KNS : Key Note Speech; CS : Case Study; S : Snapshot; PD : Panel Discussion

Scientific programme5-7 June 2013

Friday, 7 June

Real-time survey

08.30 PD3: Panel discussion on “Define treatment success”Chair: Mar Tintoré (Spain)

Define treatment success in present dailypractice with clinical and MRI surrogatesJordi Río (Spain)

Define treatment success in the age ofpharmacogenomicsManuel Comabella (Spain)

Discussion

09.30 L9: Fostering treatment adherence andcompliance: a role-playMaría Jesús Arévalo (Spain)Jaume Sastre-Garriga (Spain)

10.30 KNS3: Oral therapies in MSGiancarlo Comi (Italy)

11.00 Coffee break

11.30 KNS4: Therapy with monoclonal antibodies Xavier Montalban (Spain)

12.00 S3: Snapshot #1 on gene therapy in MSHerena Eixarch (Spain)

12.15 S4: Snapshot #2 on DNA vaccines in MSNicolás Fissolo (Spain)

12.30 S5: Snapshot #3 on stem cell therapy in MSCarme Costa Riu (Spain)

12.45 Course wrap-upXavier Montalban (Spain)

Real-time survey

13.15 Certificate delivery and group picture

13.30 Working lunch and end of the liveeducational workshop

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Disclosure of faculty relationships

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

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

Maria Pia Amato Declared receipt of grants and contracts from Merck Serono, Bayer, Teva, Biogen, Genzyme. She is alsomember of company advisory board or board of directors of Merck Serono, Bayer, Teva, Biogen,Genzyme.

Georgina Arrambide Declared receipt of grants and contracts from MAGNIMS Fellowship.

Bruno Brochet Declared no potential conflict of interest.

Manuel Comabella Declared receipt of honoraria or consultation fee from Teva, Merck-Serono, Novartis.

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

Carme Costa Riu Declared no potential conflict of interest.

Herena Eixarch Declared no potential conflict of interest.

Nicolás Fissolo Declared no potential conflict of interest.

Angelo Ghezzi Declared receipt of honoraria or consultation fees from Biogen, Merck Serono, Novartis, Sanofi.

Eva Havrdovà Declared receipt of grants and contracts from Czech Ministry of Health, Czech Ministry of Education,Biogen Idec. She declared also receipt of honoraria or consultation fees from Biogen Idec, MerckSerono, Novartis, Teva, Genzyme.

Bernhard Hemmer Declared receipt of grants and contracts from Novartis, Merck Serono, Biogen Idec, Bayer, Metanomics.He declared also receipt of honoraria or consultation fees from: Novartis, Biogen Idec, Bayer, MerckSerono, Roche, Glaxo Smith Kline. He is member of company advisory board, board of directors andother similar groups: Novartis, Biogen Idec, Roche. He declared benefit from a relationship with patentKIR4.1 antibodies.

Rosalia Horno Declared no potential conflict of interest.

Imke Metz Declared receipt of grants and contracts from Biogen Idec. She declared receipt of honoraria orconsultation fees from Biogen Idec and Bayer Healthcare.

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

Susana Otero Declared receipt of honoraria from SSIF.

Lluís Ramió i Torrentà Declared receipt of grants and contracts from Biogen Idec, Merck Serono, Bayer Schering, Teva,Novartis.

Marta Renom Guiteras Declared no potential conflict of interest.

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Disclosure of faculty relationships

Jordi Río Declared no potential conflict of interest.

Lucía Romero Declared no potential conflict of interest.

Alex Rovira Declared to be member of company advisory board, board of directors and other similar groups:Neurotec Pharma, Advance Cell, Bayer Schering, Novartis, OLEA Medical. He declared participation incompany sponsored speaker’s bureau: Bayer, Sanofi Aventis, Merck Serono, Teva, Biogen Idec, OLEAMedical.

Carme Santoyo Declared no potential conflict of interest.

Jaume Sastre-Garriga Declared to be member of company advisory board or board of directors of Biogen. He declared alsoparticipation in company sponsored speaker’s bureau: Novartis, Merck Serono, Teva, SSIF.

Nuria Solà Declared no potential conflict of interest.

Alan J. Thompson Declared receipt of grants and contracts from MS Society of GB, Wellcome Trust, Wolfson Foundation,SRH holding, Medical Research Council, Eisai. Declared receipt of honoraria or consultation fees fromEisai. He is member of company advisory board or board of directors of MSIF, Inspire Raltegravir in MS,Eisai, Imanova, European Charcot. He declared benefits from a relationship with commercialenterprises: Sage Publications.

Mar Tintorè Declared receipt of grants and contracts from Bayer Schering, Biogen Idec, Merck Serono, Teva, SanofiAventis, Genzyme and Novartis. She declared also receipt of honoraria or consultation fees from BayerSchering, Genzyme, Biogen Idec, Merck Serono, Teva, Sanofi Aventis and Novartis. She is member ofcompany advisory board, board of directors and other similar groups: Genzyme, Teva and Biogen Idec.

Carmen Tur Declared receipt of honoraria or consultation fees from Merck Serono, SSIF, Sanofi Aventis, Teva andNovartis.

Angela Vidal Declared no potential conflict of interest.

The following faculty have provided no information regarding significant relationship with commercial supporters and/or discussionof investigational or non-EMEA/FDA approved (off-label) uses of drugs as of 22 May 2013.

Letizia Leocani

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Abstracts

L1. Epidemiology of MS

Epidemiology can be defined as the study of the distribution and determinants of disease from a population perspective, usingquantitative methods. Descriptive epidemiology pictures the distribution and time trends, using prevalence and incidence data, andanalytic epidemiology seeks for possible risk factors related to the disease.

The first descriptive epidemiological studies on multiple sclerosis (MS) used prevalence data to map the distribution of MS aroundthe world. They showed that the disease was not evenly distributed and there was a latitudinal gradient with higher prevalence aswe move away from the equator. It should be noted that these studies had certain limitations that have to be considered whencomparing data. There were differences between studies regarding methodological aspects such as case definition, sources ofinformation, population size and there was data lacking in certain parts of the world.

Despite the methodological limitations, the characteristic distribution led to genetic and environmental pathogenic hypothesis.Considering that MS has an important genetic component of susceptibility, the distribution could be due to the variation of geneticand ethnic backgrounds of the world’s population. Nevertheless, there are reasons to believe that genetics can not explain all of it.The concordance rates for MS of 24% in monozygotic twins reflect other factors acting in uterine or early life environments. Inregions with homogenous population, the latitudinal gradient of MS is still present. According to studies in migrant population, riskof MS can vary when migrating to a different area, particularly when migration occurs early in life. Furthermore, seasonality in therisk of MS has been recently described (“month of birth effect”).

There are several environmental factors that have been postulated. The mirror-image gradient of MS points to a sun related factorsuch as Vitamin D. On the other hand, an infectious agent acting directly (as a trigger of the disease) or indirectly (protecting ifacquired early in life -hygiene hypothesis-) has also been postulated. Epstein-Bar virus (EBV), seems one of the strongestcandidates, as MS in unlikely to develop in a EBV negative individual, there is strong evidence that links epidemiology of infectiousmononycleosis with MS. Smoking has also been recently linked to MS.

Recent data from prospective studies performed in Europe, America and Asia show that MS incidence and prevalence are increasingduring the past 20 years and the classical gradient is disappearing in certain areas. The increase in prevalence could be explainedby longer patient survival and increase in incidence (improved case ascertainment thanks to better diagnostic techniques and /orchange in causal factors that increase risk of MS).

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Susana OteroMultiple Sclerosis Center of Catalonia (Cemcat), Department of Epidemiology, Vall d'Hebron University Hospital, Barcelona, Spain

References:- Kurtzke JF. Geographic distribution of multiple sclerosis: An update with special reference to Europe and the Mediterranean region. Acta Neurol Scand 1980;62:65-80.- Koch-Henriksen N. The Danish Multiple Sclerosis Registry: a 50-year follow-up. Mult Scler 1999;5:293-6.- Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 2008;71:129-35.- Kingwell E, van der Kop M, Zhao Y, Shirani A, Zhu F, Oger et al. Relative mortality and survival in multiple sclerosis: findings from British Columbia, Canada. J NeurolNeurosurg Psychiatry. 2012 Jan;83(1):61-6.

- Koch-Henriksen N, Sørensen PS.The changing demographic pattern of multiple sclerosis epidemiology.Lancet Neurol. 2010 May;9(5):520-32.- Pierrot-Deseilligny C, Souberbielle JC. Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis? Brain. 2010 Jul;133:1869-88.- Dobson R, Giovannoni G, Ramagopalan S.The month of birth effect in multiple sclerosis: systematic review, meta-analysis and effect of latitude. J Neurol NeurosurgPsychiatry. 2013 Apr;84(4):427-32.

- Healy BC, Ali EN, Guttmann CR, Chitnis T, Glanz BI, Buckle G et al. Smoking and disease progression in multiple sclerosis. Arch Neurol. 2009 Jul;66(7):858-64.

KNS1. Immunopathogenesis of MS

Multiple sclerosis (MS) is a commonly occurring inflammatory and demyelinating neurological disease. Based on immunologicaland genetic studies MS has been considered to be an autoimmune disorder mediated by CD4+ type 1 T helper cells.

Recent studies have challenged this idea by indicating a role for other immune cells such as B cells and Th17 cells. So, T- and B-cell responses in the brain of patients with MS involve the clonal expansion of lymphocytes and the antigen-driven maturation of theB-cell receptors, indicating that the immune response in MS engages a broad range of immune cells that target a limited numberof brain antigens. In neuromyelitis optica, Aquaporin-4 was identified as a major target of the autoimmune response. Recent studieshave suggested myelin oligodendrocyte glycoprotein as a target in childhood inflammatory demyelinating diseases and the inwardrectifying potassium channel KIR4.1 as a target in MS.

Here, I summarize recent advances in our understanding of the pathogenesis of MS, and conclude with an outlook on how tocapitalize on this knowledge to develop new therapeutic approaches.

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Bernard HemmerNeurology Clinic, University of Munchen, Munchen, Germany

L2. Genetics of MS

During the last two decades, many research groups have dedicated important efforts to identify the individual genes that confersusceptibility to multiple sclerosis (MS). The main conclusion derived from this work is that the HLA-class II region on chromosome6p21, specifically the HLA-DRB1*15 haplotype, contributes by far the most to genetic susceptibility in MS, and results from manyMS genetic studies support this association. Unfortunately, despite the evidence that MS is a complex genetic trait with multiplegenes contributing to disease susceptibility, genetic studies aiming to identify additional risk genes for MS have been ratherdisappointing, as many of the candidate genes identified in one study were not confirmed in others. It has not been until recently thatadditional genes located outside the HLA region have been proposed, although with weaker effects, as solid candidates for MSgenetic risk. In particular, three single-nucleotide polymorphisms (SNPs), two located within the interleukin-2 receptor α (IL2RA)and one located within the interleukin-7 receptor α (IL7RA), were strongly associated with MS. Other SNPs positioned in attractivegenes were also found to be associated with the disease. Most of the genes proposed as risk genes for the disease are related withthe immune system. These latest findings have certainly opened new scenarios in MS genetic research.

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Manuel ComabellaMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

References:1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction

6 1206-1212. 2 - Filicori M, Cognigni GE, Pocognoli P et al. 2003 Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and

Metabolism 14, 267-273.

L3. Pathology of MS

Multiple sclerosis (MS) pathology is complex and not only involves focal lesions known as MS plaques, but also cortical pathology aswell as changes in the normal-appearing white matter. The talk will thus focus on the three topics:1) Focal MS pathology2) Cortical pathology3) Pathology of the normal-appearing white matter.

Focal pathology is characterized by demyelination, inflammation, axonal loss with relative axonal preservation as well as gliosis.However, remyelination as a reparative process may also occur. Remyelinated fibres are characterized by thin and irregular myelinsheaths. Remyelination is extensive in early MS lesions, but limited in chronic MS. Correspondingly, mature oligodendrocytes areabundant in early MS lesions, but lost in chronic MS. In the process of remyelination oligodendrocyte precursor cells (OPCs)differentiate into mature oligodendrocytes that synthesize the new myelin. These OPCs are present in all lesion stages, indicatingthat a differentiation block of OPCs in chronic MS lesions may be responsible for remyelination failure.

The irreversible axonal damage correlates with the clinical disability and is thus of major importance. The acute axonal damage ismost pronounced in early disease stages, but ongoing in chronic MS lesions. Chronic MS lesions thus reveal an axonal reduction ofapproximately 50%. The extent of axon damage correlates with the severity of inflammation during active demyelination. The secondphase of axon degeneration present in chronic demyelinated plaques is also related to inflammation. A range of cellular (e.g. CD8+

T cells), soluble (e.g. nitric oxide, glutamate, perforin) or trophic factors are candidates for mediating the axonal damage.

Cortical lesions are common in MS. Subpial lesions are most frequently observed, followed by leucocortical and intracortical lesions.Cortical lesions occur most often in progressive MS and in patients with long disease duration. They are observed in 90% of autopsycases with chronic MS but are already present in early disease stages (38%). Cortical lesions are associated with pial inflammation.Remyelination can also be observed in cortical lesions and is more frequent than in white matter lesions.

The "normal-appearing white matter" without demyelination shows numerous pathological changes that are most dominant inchronic disease stages. An inflammation consisting of T cells as well as microglial cells is present. An astrocyte activation is not onlyfound in focal lesions, but also in non-demyelinated white matter. Also, a diffuse axonal damage within the normal-appearing whitematter is present. Foci of microglial cells correlate with the axonal damage.

The talk gives insights into some important new aspects of the complex pathology of multiple sclerosis.

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Imke MetzInstitute of Neuropathology, Universitätsmedizin Göttingen, Georg-August-Universitat, Göttingen, Germany

PD1. Panel discussion on “New revision of McDonald’scriteria”

1 - Multiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital, Barcelona, Spain;2 - Unit of Magnetic Resonance, Department of Radiology, Vall d’Hebron University Hospital-IDI, Barcelona, Spain;3 - Institute of Experimental Neurology, University Vita-Salute IRCCS, San Raffaele Hospital, Milan, Italy

MS diagnosis and differential diagnosisMar Tintoré

Diagnostic criteria for MS rely on the demonstration of central nervous system disease dissemination in space and time and inreasonable exclusion of other causes. Since McDonald 2001, in patients with a first attack, evidence of diagnosis for disseminationin space and time may be provided by MRI. The recently published 2010 McDonald criteria selected the Magnims criteria fordissemination in space (DIS). DIS is defined as the presence of ≥1 asymptomatic T2 lesion(s) in at least two of four locationsconsidered characteristic for MS in previous MRI criteria: juxtacortical, periventricular, infratentorial and spinal cord. These criteriasimplify the previous Barkhof criteria and highlight the importance of lesion location for MS diagnosis. Moreover, this new definitionrelies on T2 lesions only. Non-inclusion of gadolinium enhancing lesions seems appropriate since enhancing lesions per se provideinformation on disease activity and not on dissemination in space. For demonstration of dissemination in time (DIT), an MRIperformed at any time demonstrating DIS and showing at least one or more asymptomatic gadolinium enhancing and non-enhancing lesions(s) (this being used as evidence for DIT) would be sufficient to diagnose MS. Although many studies have alreadyshown the importance of cerebro-spinal fluid examination in the diagnosis and differential diagnosis of MS, the presence ofoligoclonal bands has not been included in the diagnostic algorithm. These new criteria have been adapted to other populations suchas patients with primary progressive MS or patients with paediatric MS. An overview of the past diagnostic criteria will also beperformed as well as new directions for the future will be considered (intracortical lesions, 3 Teslas MRI, other). Clinical cases toillustrate differential diagnoses will be presented.

MRI in MS: the radiologist perspectiveAlex Rovira

The exact diagnosis of MS still remains challenging in some cases, as there is no single test that can provide a definite diagnosis ofthis disease, which is based on different diagnostic criteria. The introduction of expensive and not completely free from side effectsof different disease modifying treatments that reduce the number and severity of clinical relapses and may slow progression ofdisability, particularly when administered during the early phases of the disease, makes the accuracy of an early diagnosis moreimperative than ever. Diagnostic criteria for MS include clinical and paraclinical assessments emphasizing the need to demonstratedemyelinating lesions within the central nervous system (CNS), lesions disseminated in space (DIS) and time (DIT), and to excludealternative diagnosis that could mimic MS either clinically or radiologically. Although the diagnosis can be made on clinical groundsalone, MRI is usually required to support the clinical diagnosis and in a significant proportion of patients can even replace someclinical criteria. This possibility has been included in the different versions of the McDonald criteria that for the first time integratedMRI features in the diagnostic scheme, allowing an earlier and more accurate diagnosis of the disease. Nevertheless, we shouldkeep in mind that for optimal application of these MRI criteria, the scans must be technically adequate and neuroradiologist mustconsider the clinical information to properly interpret the imaging findings, and be expert enough to recognize the full range of brainand spinal cord abnormalities that suggest the diagnosis of MS, as several other disorders can cause white matter lesions withimaging characteristics similar to those seen in MS. Focal white matter T2 hyperintense lesions (T2-HI) mimicking those seen in MScan be detected in a relatively large list of different disorders that may affect middle age and young patients, such as hypoxic-ischemic vasculopathies (CADASIL, Fabry’s disease, Susac’s syndrome), primary and systemic vasculitis, sarcoidosis, adult forms ofleukoencephalopathies, and even in healthy subjects. While it is recognized that a combination of findings from clinical history,physical examination, and laboratory tests is commonly required to correctly establish a diagnosis of MS, a detailed analysis ofdifferent MRI features should also be considered essential: e.g. lesions shape, size, and distribution (both in brain and spinal cord);pattern of contrast-uptake. In addition to these conventional MRI based features, non-conventional MR techniques (diffusion-weighted, perfusion-weighted, susceptibility-weighted) may also provide in some cases useful diagnostic information. Knowledge ofthese features, will assist the diagnostic work-up of patients presenting with T2-HI, and should be considered a first step to take full

16

Mar Tintoré, Spain 1

Alex Rovira, Spain 2

Letizia Leocani, Italy 3

advantage of the potential of MRI, and in doing so should result in a reduced chance of misdiagnoses and facilitate the correctdiagnosis of sometimes treatable disorders.

References:- Rovira A, Leon A. MR in the diagnosis and monitoring of multiple sclerosis: An overview. European Journal of Radiology 2008; 67:409-414- Bakshi et al. MRI in multiple sclerosis: current status and future prospects. Lancet Neurol 2008; 7: 615–25- Haller et al. Magnetic Resonance Imaging in Multiple Sclerosis. Top Magn Reson Imaging 2009; 20: 313-323- Fillipi M. Rocca MA. MR Imaging of Multiple Sclerosis. Radiology: 2011; 259: 659-681

VEPs in MSLetizia Leocani

Abstract not in hand at the time of printing.

17

Cemcat - Nuts and bolts

In this talk we will give a practical view of the Cemcat, which is a strategic alliance between the Catalan Health Institute, throughthe University Hospital Vall d’Hebron, the Catalan Health Service and the Multiple Sclerosis Foundation. Functionally, Cemcat is theintegration and fusion of two professional teams dedicated to the comprehensive care of people with multiple sclerosis. All Cemcatactivities are carried out in a new building located within the Vall d’Hebron University Hospital. In this talk, we will discuss the mainpoints related to the clinical, research, and teaching activities that are carried out at Cemcat.

18

Carmen TurMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

References:1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction

6 1206-1212. 2 - Filicori M, Cognigni GE, Pocognoli P et al. 2003 Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and

Metabolism 14, 267-273.

L4. Neuromyelitis optica – NMO

Neuromyelitis optica (NMO) is a rare and severe inflammatory demyelinating disease with predominant involvement of the opticnerves and the spinal cord, previously considered to be a variant of multiple sclerosis (MS). Over the years, a number of clinical,laboratory, and magnetic resonance imaging studies have provided data to differentiate NMO from MS. More recently, the discoveryof serum IgG antibodies targeting the water channel aquaporin-4 has not only helped categorize NMO as an independent entity fromMS, but has also broadened the disease spectrum. The discovery of these highly specific antibodies, in turn, could potentially aid infinding a more specific treatment aimed at the prevention of recurrences than those drugs currently supported by clinical guidelines,like rituximab or mofetil mycophenolate. All this information was obtained from adult patients, but now the behavior of NMO is alsostarting to be better understood in special populations, like children and pregnant women. However, a worldwide consensusregarding NMO-IgG detection is still to be obtained since different methods for antibody identification exist, and the initial describedsensitivity of indirect immunofluorescence, the most commonly used assay, has not been reproduced in all centres. This is of utmostimportance when considering that such assays fail to detect approximately 20-30% of NMO cases, or that they yield positive resultsin atypical or MS-like cases, which could delay a proper diagnosis and treatment, especially at disease onset. Each of theabovementioned topics will be reviewed in more detail throughout this talk.

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Georgina ArrambideMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

L5. Primary progressive MS

Primary progressive multiple sclerosis (PPMS) has a number of characteristics which make it more challenging to diagnose andmanage than relapsing/remitting MS. It does not have acute events or relapses, the hallmark of MS, but rather a slowly progressivecourse which is often very insidious at onset. However although overall it has a worse prognosis then RRMS it has a variable coursewith 25% of patients needing assistance to walk at 7.5 years after onset, but with another 25% still walking unaided at 25 years.PPMS comprises approximately 10-15% of MS cases overall. Compared with other forms of MS, PPMS is characterized by a laterage of onset (on average 40 years, similar to the age of onset in SPMS) and an equal sex ratio. PPMS has a predominantly motorpresentation, tending to present with an asymmetric spastic paraparesis with occasional cerebellar and brainstem, but not usuallysensory or visual disorders. PPMS may be a less inflammatory form of MS but there is some evidence to suggest that both the myelin sheath and nerve axonare more vulnerable to damage than is the case in relapsing/remitting MS. There is continuing discussion as to whether it is adistinct condition or simply one end of a spectrum (1). The question arises whether disability progression can be predicted so thosepatients who might be more suitable for therapeutic intervention or enrolment in a clinical trial can be identified. Studies haveshown that gender had no impact on clinical features or natural history of PPMS, although the time from onset of MS to death wasshorter for men (2). Clinical presentation, whether brainstem, motor, sensory or cerebellar, had no impact on survival, althoughpresentation with three or more affected systems was associated with worse outcome. A shorter time to reach EDSS 3.0 also hadan adverse effect on survival. Koch et al showed that patients who were younger at disease onset took longer to reach EDSS 6.0,but these patients were also younger when reaching EDSS 6.0. (3). Sensory symptoms at presentation were associated with both alonger time to, and an older age at, EDSS 6.0.

Diagnosis is particularly challenging but has been helped by new criteria which include MRI evidence of dissemination in time andspace (4). PPMS is usually characterized by fewer and smaller lesions on MRI, compared with relapsing MS. A major study evaluated145 patients with PPMS at 1, 2, 5 and 10 years to determine which MRI abnormalities best predict progression. During this time therewas an increase from baseline in average T2 lesion load at years 1 and 2 (14.6% and 23.3% respectively) and a decrease in brainvolume at the same time points (1.3% and 1.7% respectively), along with a decrease in cervical cord area and some worsening inclinical measures (5-7). However, there was no correlation between changes in clinical and MRI outcomes. Changes in clinicalmeasures at 5 years was predicted by male sex and low brain volume at baseline, and by the number of new T2 lesions and reducedcord volumes at 2 years (8). Similar results were seen at the 10-year follow-up. When brain atrophy is assessed, the most markedchanges are seen in grey matter volume. In early PPMS, progression on the EDSS over 3 years was associated with the mean rateof decrease in grey matter magnetization transfer ratio (MTR; p=0.032), which was also the strongest predictor of the rate of T2 lesionload increase (p=0.024). The combination of grey matter MTR and focal T2 lesions may therefore prove to be the strongest predictorof disability in PPMS, as well as showing a strong correlation with overall cognitive performance (9).

Despite being progressive from onset, the disease course is quite variable and an active management programme incorporating diet,exercise and a healthy life style is crucial. Although there are currently no effective treatments targeting repair and neuroprotection,a comprehensive rehabilitation programme incorporating management of mobility, bladder function and muscle tone is important.Improved understanding of progression leading to improved treatment for PPMS is a key goal for future MS research and is the focusof a major international collaborative effort (10).

20

Alan J. ThompsonDepartment of Brain Repair and Rehabilitation, University College London, National Hospital for Neurology and Neurosurgery,London, UK

References:01. Antel J, Antel S, Caramanos Z et al. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity. Acta Neuropathol

2012;123(5):627-3802. Cottrell DA, Kremenchutzky M, Rice GP et al. The natural history of multiple sclerosis: a geographically based study. 5. The clinical features of primary

progressive multiple sclerosis. Brain 1999; 122 Pt 4:625-639.03. Koch M, Kingwell E, Rieckmann P et al. The natural history of primary progressive multiple sclerosis. Neurology 2009;73: 1996-2002.04. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald Criteria. Annals of Neurology 2011; 69:

292-302.05. Ingle GT, Thompson AJ, Miller DH. Magnetic resonance imaging in primary progressive multiple sclerosis. J Rehabil Res Dev 2002; 39:261-271.06. Stevenson VL, Miller DH. Magnetic resonance imaging in the monitoring of disease progression in multiple sclerosis. Mult Scler 1999; 5:268-272.07. Stevenson VL, Miller DH, Leary MS et al. One year follow up study of primary and transitional progressive multiple sclerosis. J Neurol Neurosurg Psychiatry

2000; 68:713-718.08. Sastre-Garriga J, Ingle GT, Rovaris M et al. Long-term clinical outcome of primary progressive multiple sclerosis: predictive value of clinical and MRI data.

Neurology 2005; 65:633-63509. Khaleeli Z, Ciccarellli O, Manfredonia F et al. Predicting progression in primary progressive multiple sclerosis: a 10-year multicenter study. Ann Neurol 2008;

63:790-793.10. Fox R, Thompson AJ, Baker D et al. Setting a Research Agenda for Progressive Multiple Sclerosis MSJ 2012: 18:1534-1540

L6. Pediatric and juvenile MS

The onset of multiple sclerosis (MS) tipically occurs in adults, however the onset in subjects with less than 18 years of age is beingincreasingly recognized, in about 3-10% of all patients with MS (1). The diagnostic criteria of this form have been reviewed anddefined in a recent paper (2), and, in cases with a typical MS onset and excluding the ADEM-like onset, diagnosis of definite MS canbe made if the new revised MS diagnostic criteria are fulfilled (3).

Some clinical findings seem to be peculiar of pediatric-MS (Ped-MS):

- the onset with cerebellar and brainstem dysfunction (1, 4), specially in subjects with less than 12 years,

- the polysymptomatic presentation, with fever, headache, letargy, meningism, seizures (ADEM-like onset), specially in very youngpatients (1),

- the evolution with a high relapse rate, specially in the first years of the disease, resulting in an annualized relapse rate higherthan observed in adult MS (4-7),

- the evolution with a relapsing-remitting (RR) course in more than 90% of cases (1).

- the progression with a longer interval but a lower age to reach the end-points of mild (EDSS score of 3-4) and severe (EDSSscore of 6) disability, compared to adult onset MS (5, 8). So, at a given age, patients with onset in childhood are more disabledthan those with a later onset.

The frequency of relapses (or the inter-attack interval) in the first few years after disease onset is a negative prognostic factor as itcorrelates with an increased disease severity and with an earlier entry into the secondary progressive phase of MS (1). Moreover,this finding suggests that probably the inflammatory process is more pronounced in children with MS compared to adults. Thefrequent pleocytosis in the CSF (9) and the aspect of MRI lesions seem to confirm this conclusion (10, 11). Recent studies have demonstrated that about 30% of children and adolescents with MS develop cognitive dysfunction early, with anegative impact on academic functioning and on social relationships (12-14).

The objective of MS treatment is to prevent to prevent the occurrence of relapses, to delay the accumulation of disability, and toreduce irreversible brain damage. What is the best treatment of ped-MS? The use of drugs for MS in children and adolescents hasnot been studied in randomised controlled clinical trials, so their use is mainly based on results from trials in adults and onobservational class 3 and 4 studies: however, in spite of methodological limitations, these studies (15, 16) have shown thatimmunomodulators, namely Interferon-Beta and Glatiramer acetate:

- are safe and well tolerated in children and adolescents with MS,

- significantly reduce relapse rate and disease progression in this population.

A panel of European experts (15) has recommend to start early the therapy with IAs in children and adolescents with relapsing MS;subjects at the first demyelinating episode must be monitored clinically and with MRI study, offering the treatment if a new clinicalor subclinical (new T2 or Gadolinium enhancing lesions) episode occurs; moreover the treatment could also be considered inselected cases with an aggressive onset at their first episode.A similar position has been taken by the International pediatric MS Study Group with the following statement “Use of first-linetherapies in pediatric MS (where available) is generally accepted as the standard care. Based on these findings, the IPMSSGrecommends that all pediatric patients with MS, as defined by Krupp et al., should be considered for treatment with either a beta-interferon or glatiramer acetate as first line therapy.

However, in spite of IA tratment about 30% of cases continue to progress and develop relapses. There are no accepted criteria todefine treatment failure, and the decision is made on a clinical basis, taking into account the occurrence of relapses, the increaseof EDSS score, MRI activity (new T2 lesions, Gadolinium-enhancing lesions) (15, 16).For patients with poor tolerability, severe side effects, evidence of clinical activity there are two options:

- to shift from IFNB (in particular if neutralising antibodies to IFNB are present) to GA or vice-versa

- to shift to second line treatments: this option should be considered in particular for cases with a very active form of MS.

Natalizumab was demonstrated to be safe and effective in a few case reports and in two studies which have included 19 and 24patients (see ref. 15 and 16), with a mean follow up of 15 and 18 months, respectively (17, 18): in all this studies a strong suppressionof disease activity was found. The risk of PML must be carefully considered, but this risk can now be predicted by the test to detectanti-JCV antibodies (19).Cyclophosphamide has shown to reduce disease activity in a retrospective study of 17 ped-MS subjects with a mean age of 15 yearand a mean disease duration of 3.1 years, but many adverse events were recorded. (20).

21

Angelo GhezziMultiple Sclerosis Centre, Gallarate Hospital, Gallarate (VA), Italy

Mitoxantrone has shown a beneficial effect in 4 ped-MS cases with severe evolution (21), but the safety profile, particularly the ofleukaemia and cardiomyopathy, discourages its use (15, 16). Daclizumab has been proposed as a possible second-line treatment forpediatric cases with an active MS evolution in a study where 6 cases were included (22).Further studies are necessary to better define the efficacy and safety profile of new medications in ped-MS, a registry on aninternational basis could contribute to clarify this issues. The International Pediatric MS Study Group (www.ipmssg.org) has beencreated to promote and coordinate international studies in the field of research, treatment and clinical care of ped-MS.

22

References:01 - Banwell, B., Ghezzi, A., Bar-Or, A., et al. (2007) Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet

Neurology, 6:887-902.02 - Krupp L., Banwell B., Tenembaum S. for the International Pediatric MS Study Group, Consensus definitions proposed for pediatric multiple sclerosis and

related disorders. Neurology 2007, 68 (suppl. 2):S7-S12.03 - Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb; 69(2):292-

302.04 - Ghezzi, A., Pozzilli, C., Liguori, M. et al. (2002) Prospective study of multiple sclerosis with early onset. Mult.Scler. 8:115-8.05 - Renoux, C., Vukusic, S., Mikaeloff, Y. et al. (2007) Natural history of multiple sclerosis with childhood onset. N Engl J Med 365:2603-2613.06 - Gusev, E., Boiko, A., Bikova, O. Et al. (2002) The natural history of early onset multiple sclerosis: comparison of data from Moscow and Vancouver. Clin

Neurol.Neurosurg.104:203-7.07 - Gorman, M.P., Healy, B.C., Polgar-Turcsanyi, M., Chitnis, T. (2009) Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis

Arch. Neurol. 66:54-59.08 - Boiko, A., Vorobeychik, G., Paty, D. et al. (2002) Early onset multiple sclerosis: a longitudinal study. Neurology 59:1006-10.09 - Pohl, D., Rostasy, K., Reiber, H., Hanefeld, F. (2004) CSF characteristics in early-onset multiple sclerosis. Neurology 63:1966-1967.10 - Chabas, D., Castello-Trivino, T., Mowry, E.M. et al. (2008) Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype. Neurology 71:1090-1093.11 - Waubant, E., Chabas, D., Okuda, D. et al. (2009) Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time

of multiple sclerosis onset vs adults. Arch. Neurol. 66:967-71.12 - Banwell, B.L. and Anderson, PE. (2005) The cognitive burden of multiple sclerosis in children. Neurology 64:891-4.13 - MacAllister, W.S., Belman, A.L., Milazzo, M.. et al. (2005) Cognitive functioning in children and adolescents with multiple sclerosis. Neurology 64:1422-5.14 - Amato, M., Goretti, B., Ghezzi, A. et al. (2008) Cognitive and psychosocial features of childhood and juvanile MS. Neurology 70:1891-1897.15 - GhezziA., Banwell B., Boyko A. et al. The management of multiple sclerosis in children: a European view. Mult. Scler. 2010, 16:1258-1267.16 - Chitins T., tenembaum S., Banwell B. et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult. Scler.

2012, 18:116-127.17 - Ghezzi A, Pozzilli C, Grimaldi LM et al. Safety and efficacy of natalizumab in children with multiple sclerosis Neurology. 2010, 75:912-7.18 - Yeh EA., Weinstock-Guttman B. Natalizumab in pediatric multiple sclerosis patients Ther. Adv. Neurol. Disord. 2010, 3:293-299. 19 - Gorelik L, Lerner M, Bixler S. et al. Anti-JC virus antibodies: implications for PML risk stratification Ann Neurol. 2010, 68:295-303.20 - Makhani N., Gorman M.P., Branson H.M. et al. Cyclophosphamide therapy in pediatric multiple sclerosis Neurology 2009; 72:2076-82.21 - Kornek B, Bernert G, Rostasy K, et al. Long-term follow-up of pediatric patients treated with mitoxantrone for multiple sclerosis. Neuropediatrics. 2011, 42:7-12.22 - Gorman MP, Tillema JM, Ciliax Amet al. Daclizumab use in patients with pediatric multiple sclerosis Arch Neurol. 2012 Jan; 69(1):78-81.

L7. Overview on symptomatic therapy and rehabilitation

Multiple Sclerosis (MS) may cause a variety of symptoms: fatigue, cognitive dysfunction, bladder and bowel problems, sexualproblems, tremor, spasticity, speech and swallowing disorders, sensory symptoms including pain, among others. Motor andcoordination symptoms causing gait problems and upper limb dysfunction also need to be considered. These symptoms, in isolation,or more commonly in association, are the ultimate cause of worsening quality of life and therefore must be treated with the sameemphasis as the condition itself. There is a need for an interdisciplinary management of symptoms in MS; this management is thefocus of neurorehabilitation. Neurorehabilitation approaches emphasize education of patients and self-management of symptoms;this approach is ideally suited to meet the evolving needs of people with MS. Thus, symptom management should be performed ona neurorehabilitation setting using an interdisciplinary approach. According to this, clinical trials evaluating the efficacy and safetyof a drug intervention to treat a given symptom lack the added value of interdisciplinary interventions (e.g. drug A may be useful forspasticity, but its combined efficacy together with physiotherapy and occupational therapy has not been investigated; in combinationthey are likely to have a greater impact on quality of life, the final goal of any symptomatic therapy). Clinical trials evaluating theeffectiveness of neurorehabilitation approaches in people with MS have shown that improvements in activities and participation areto be expected. However, modalities of intervention have been usually ill-defined (rehabilitation black box) and clinical trialmethodologies suboptimal. Therefore, further research is needed to improve clinical trial methodology and our ways of evaluatingthe impact of neurorehabilitation by means of goal achievement frameworks and through the use of clinically appropriate andscientifically sound outcome measure tools. In this lecture we will briefly overview current therapies for symptoms of MultipleSclerosis.

23

Jaume Sastre-GarrigaMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

S1. Symptomatic therapy snapshot #1 on gaitrehabilitation

One of the most pronounced incapacitating manifestations of MS are gait abnormalities, resulting from the combined effect ofdecrease in muscle strength, spasticity, cerebellar ataxia, sensory disorders and reduction in aerobic capacity. Pathological gaitpatterns are less functional, secure, and effective which contribute to secondary problems such as increased risk of falls andincreased energy expenditure and affect activity, participation and quality of life.

Physical therapy interventions firstly aim to develop motor recovery and secondly to train compensatory strategies in order toimprove or maintain functional independence and efficacy in deambulation.

In this speech we’ll revise the main rehabilitation strategies for gait impairment in MS: from conventional rehabilitation to the latestrobotic biofeedback devices.

24

Carme SantoyoMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

References:- Perry J. (1992) Gait Analysis. Normal and pathological function. NJ: Slack Incorporated.- Rodgers MM et al. Gait characteristics of individuals with multiple sclerosis before and after a 6-month aerobic training program. J Rehabil Res Dev; 1999. 36:183-88.

- Hobard J, et al. Measuring the impact of MS on walking ability. The 12-items MS walking scale (MSWS-12). Neurology 2003; 60: 31-36.- Givon U, et al. Gait analysisi in multiple sclerosis: characterization of temporal-spatial parameters using GAITrite functional ambulation system. Gait posture2009; 29:138-42

- Martin CL, et al. Gait and balance impairment in early multiple sclerosis in the absence of clinical disability. Mult Scler. 2006; 12:620-8- Gehlsen G, et al. Gait characteristics in multiple sclerosis: progressive changes and effect of exercise on parameters. Arch Phys Med Rehábil.1986; 67:536-39.- Benedetti MG et al. Gait abnormalities in minimally impaired multiple sclerosis patients. Mult Scler.1999; 5: 363-368- Crenshaw SJ et al. Gait variability in people with multiple sclerosis Mult Scler.2006; 12; 613 - Thoumie, P. et al. Motor determinants of gait in 100 ambulatory patients with multiple sclerosis. Mult Scler. 2005; 11; 485- Thoumie P, et al. Relation between walking speed and muscle strength is affected by somatosensory loss in múltiple sclerosis. J Neurol Neurosurg Psychiatry.2002; 73: 313-15.

- Remelius JG, et al. Gait initiation in multiple sclerosis. Motor Control. 2008; 12:93-108.- Holden MK, Gill KM, Magliozzi MR. Gait assessment for neurologically impaired patients. Phys Ther. 1986; 66: 1530-39.- Tesio L, Rota V: Gait analysis on split-belt force treadmills: validation of an instrument. Am J Phys Med Rehabil 2008;87:515-26.- Albrecht H, et al. Day-to-day variability of maximum walking distance in MS patients can mislead to relevant changes in the Expanded Disability Status Scale(EDSS): average walking speed is a more constant parameter. Mult Scler. 2001;7:105-09.

- Goldman MD, et al. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Mult Scler. 2008; 14: 383-90- Hobart JC, et al. Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology. 2003; 60:31-6- Krebs DE, et al. Reliability of the observational kinematic gait analysis. Phys Ther. 1985; 65:1027-33- Gijbels D, et al. Predicting habitual walking performance in multiple sclerosis: relevance of capacity and self-report measures. Mult Scler. 2010; 16:618-26.- Lo, A. et al. Triche Improving Gait in Multiple Sclerosis Using Robot-Assisted, Body Weight Supported Treadmill Training. Neurorehabil Neural Repair 2008; 22;661

- van Uden CJ, et al. Test-retest reliability of temporal and spatial gait characteristics measured with an instrumented walkway system (GAITRite). BMCMusculoskelet Disord. 2004; 5:13

- Lünenburger, L. et al. Biofeedback for robotic gait rehabilitation. Journal of Neuro Engineering and Rehabilitation. 2007, 4:1- Baram Y, et al. Virtual Reality Cues for Improvement of Gait in Patients with Multiple Sclerosis. Neurology, 2006; vol.66(2):178-81.- Sinkjaer, T. et al. Impaired stretch reflex and joint torque modulation during spastic gait in multiple sclerosis patients. J Neurol.1996; 243:566-74- Sheffler LR, Hennessey MT, Knutson JS, Naples GG, Chae J: Functional effect of an ankle foot orthosis on gait in multiple sclerosis: a pilot study. Am J Phys MedRehabil 2008;87:26-32.

- Paul L, et al. The effect of functional electrical stimulation on the physiological cost of gait in people with multiple sclerosis. Mult Scler. 2008: 14: 954-61- Barret CL, et al. A randomized trial to investigate the effects of functional electrical stimulation and therapeutic exercise on walking performance for people withmultiple sclerosis. Mult Scler.2009; 15:493-504.

- Mount, J. et al. Effects of dorsiflexor endurance exercises on foot drop secondary to multiple sclerosis: A pilot study. NeuroRehabilitation. 2006; Vol 21: 43-50- Levin, M. et al. What Do Motor "Recovery" and "Compensation" Mean in Patients Following Stroke? Neurorehabil Neural Repair.2009; 23: 313-19 - Holsbeeke, L. et al. Capacity, Capability, and Performance: Different Constructs or Three of a Kind? Archives of Physical Medicine and Rehabilitation - May 2009Vol. 90, Issue 5, 849-55.

S2. Symptomatic therapy snapshot #2 on management ofdysphagia

The reported prevalence of dysphagia in MS ranges between 33% and 43%. It is clearly more frequent in advanced stages of thedisease but can also appear in early stages. It is associated to brainstem and cerebellar impairment. Dysphagia can lead to seriouscomplications such as bronchopneumonitis, bad nutritional state and decrease of the quality of life. It can affect swallowing of liquidsand/or solids, the later being more frequent in severe dysphagia.

The intervention is interdisciplinary and can involve neurologists, speech and language pathologists, physiotherapists, nurses,radiologists and dieticians among others.

Assessment: the presence of altered feeding habits and of cough and/or choking during or after meals are the two most commonlyreported symptoms. A questionnaire is currently available to detect dysphagia (DYMUS). Clinical assessment should includeobservation of the oral anatomy and examination of the cranial nerves involved in swallowing and of the muscular tone, oral reflexesand movement execution pattern. A functional assessment of chewing, swallowing, phonation and articulation should also beperformed. The volume-viscosity swallow test (V-VST, Clavé et al. 2008) is a bedside method to screen patients for dysphagia.Referral to instrumental examination should happen in moderate to severe dysphagia and/or when specific objectives of examinationcan be identified. Videofluoroscopy and fiberoptic laryngoscopy are the two most commonly used instrumental procedures.

Treatment of dysphagia should begin soon after appearance of the first symptoms. Its goal is to improve security and efficacy ofswallowing and to improve quality of life and social participation. It can include rehabilitation, pharmacological treatment andeventually implementation of enteral feeding. Rehabilitation includes restorative, compensatory and adaptive approaches and alsoeducation on security manoeuvres. The restorative approach includes neuromuscular exercises without food, directed to improvethe sensoriomotor and praxic-cognitive control of the swallowing mechanisms and can also include neuromuscularelectrostimulation. The compensatory approach consists of general advice, strategies and manoeuvres to be taken into accountwhile eating and drinking. The adaptive approach includes measures involving adaptation of the food consistency. Family andcaregivers should be involved in rehabilitation. Pharmacological treatment includes use of botulinum toxin, especially for thetreatment of drooling.

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Marta Renom GuiterasMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

References:- Abraham S, Scheinberg LC, Smith ChR, La Rocca, NG (1997) Neurologic impairment and disability status in outpatients with multiple sclerosis reportinggdysphagia symptomatology. J Neur Rehab 11:7-13

- De Pauw A, Dejaeger E, D’hooge B, Carton H (2002) Dysphagia in mulitple sclerosis. Clin Neurol Neurosurg 104:345-351- Prosiegel M, Schelling A, Wagner-Sonntag E (2004) Dysphagia and multiple sclerosis. Int MS J 11:22-31- Terré-Bolliart R, Orient-López F, Guevara-Espinosa D et al. (2004) Disfagia orofaríngea en pacientes afectados de esclerosis múltiple. Rev Neurol 39:707-710- Giusti A, Giambuzzi M (2008) Management of dysphagia in MS. Neurol Sci 29:364-366- Tassorelli C, Bergamaschi R, Buscone S et al. (2008) Dysphagia in multiple sclerosis: from pathogenesis to diagnosis. Neurol Sci (2008) 29;360-363- Bergamaschi R, Crivelli P, Rezzani C et al. (2008): The DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis. J Neurol Sci 269:49-53- Clavé P et al. Accuracy of the volume-viscosity swallow test for clinical screening of oropharyngeal dysphagia and aspiration. Clin Nur. 2008 Dec; 27(6):806-15- Bogaardt H et al. (2009) Use of neuromuscular electrostimulation in the treatment of dysphagia in patients with multiple sclerosis. Ann Otol Rhinol Laryngol.Apr;118(4):241-6

- Domenico A. Restivo, Antonino Casabona , Diego Centonze et al. Pharyngeal electrical stimulation for dysphagia associated with multiple sclerosis: A pilot study.Brain Stimulation 2012 xxx 1-6

PD2. Panel discussion on “Cognition disorders in MS”

1 - Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy2 - Department of Neurology, CHU and University Victor Segalen, Bordeaux, France3 - Multiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital, Barcelona, Spain

DiagnosisMaria Pia Amato

Only during the past 20 years clinicians have become aware of the prevalence and functional impact of MS-related cognitiveimpairment and its profound functional impact. Cognitive dysfunction is highly variable and estimates of its frequency range from43% to 65% of the cases. The domains most commonly impaired are episodic memory, complex attention and informationprocessing speed, executive functions and verbal fluency. Language, semantic memory and attention span are less frequentlyinvolved. Cognitive dysfunction can have a dramatic impact on several aspects of quality of life, independently on degree of physicaldisability and is one of the most important predictors of the patient work status.. Current therapeutic approaches include the use ofdisease-modifying drugs, symptomatic drugs for fatigue and donepezil, as well as different rehabilitative programmes. Recent dataon the use of interferon-beta in patients with clinically isolated syndromes and early relapsing-remiting MS have suggested a betterpreservation of cognitive functioning in subjects treated at the very beginning of the disease. Due to the high prevalence and greatfunctional impact of MS-related cognitive imapirment, the search for effective therapeutic strategies is an urgent priority for futureresearch.

TreatmentBruno Brochet

Only Cognitive impairment is common in MS and affects mainly information processing speed, attention, memory and executivefunctions. Deficits can have a significant impact on patients' quality of life and especially have important vocational consequences.Cognitive impairment should be taken into account in the evaluation of the disease. Recently several programmes ofneuropsychological rehabilitation have been tested to reduce cognitive deficits and their consequences in daily living. This panelpresentation will review several trials recently published. These trials showed preliminary positive results for the effectiveness ofneuropsychological rehabilitation in MS to improve memory span, working memory, and immediate visual memory, but the level ofevidence remains low and these studies are hampered by many methodological flaws. The overall quality of the studies was low andthe interventions were heterogeneous. Therefore well-designed high quality studies are needed on the effects of neuropsychologicalrehabilitation in MS. Pharmacological approaches using specific drugs acting on the central nervous system will be also reviewed.

Case presentationAngela Vidal

Abstract not in hand at the time of printing.

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Maria Pia Amato (Italy) 1

Bruno Brochet (France) 2

Angela Vidal (Spain) 3

KNS2. Injectable therapies in MS

Concerning disease modifying drugs (DMDs) in multiple sclerosis (MS), as first line treatment, three recombinant interferon beta(IFNb) preparations and glatiramer acetate (GA) are currently approved for relapsing-remitting multiple sclerosis (RR MS). Theirefficacy is very similar and was proven even in head-to-head trials conducted recently. All of them are approved for patients withclinically isolated syndrome (CIS) and in high risk for clinically definite MS. In some countries there is extended approval for RR MSunder age of 18. There is no proven effect of these drugs for chronic progression of MS without the presence of relapses. There isnot enough publications supporting the idea of combination therapies to start with; and there is not enough publications onsequential therapy. Long-term follow-ups of clinical trials though systematic have many limitations: no control groups any more, noblinding, and selection bias due to drop-outs. They may be useful in trying to define some prognostic markers. Post marketingfollow-ups on long-term efficacy of these drugs show the importance of early treatment as the only tool to slow down thedevelopment of disability in MS. 21-year data from the original trial with IFNB-1b show that delaying the treatment by 5yrs shortenslife expectancy by 10 years. 8-year follow up from BENEFIT trial (IFNB-1b in CIS) shows that with early treatment long term stabilitymeasured by EDSS may be achieved in a substantial number of patients. Long-term side effect profile and tolerability of abovementioned drugs is very good, the adherence to injectable treatments decreases over time, and seems to be a challenge for boththe patient and treating physician.

As the new goal for treatment in MS has been proposed being freedom from measurable disease activity, it is of great importancenot only to start treatment early but also to check regularly the effect of treatment not to miss the window of opportunity forescalating treatment in patients with suboptimal response.

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Eva HavrdovàMS Centre and Neurology Clinic, Charles University, Prague, Czech Republic

L8. Role of MS nurses in MS patients’ management

MS nurse has multiple roles within the MS team. We would like to point these different roles and explain how they are developed.

Traditionally nurses have had a cooperative role but during the last decades nurses have taken also independent roles which provea growth of knowledge.

At the end of the 90s is when the idea of having a specialist nurse starts to take shape, mostly because of the introduction of immunemodulators. This MS specialist nurse comes with the idea to perform Sanitary Education not only for the manage of the medicationbut also for the disease. That’s why this type of patient will need a follow up to feel cared for and looked after and if some problemor question comes out, patient can have a direct contact with the nurse by telephone call or by visiting the hospital.

It has been very difficult to start this in the hospital, therefore some sites still have part time nurses. Because in our country doesn’texist this as a speciality, this nurse has had to self train on her time off.

MS nurse has also taken a Research role being involvedin all the clinical research as an important part of the team. On a clinicaltrial MS nurse may actas a reference for the patient, as a data collector, in takings samples of patients under study.

Other function of MS nurse is to administrate intravenous therapy which can be symptomatic treatment, commercialized medicationor IV Clinical Trial study drugs. Some of these medications are getting more and more popular as a second option of treatment, likeNatalizumab, for the easy administration and the short period of time the patients have to stay in the Day Hospital.

A Day Hospital allows the MS nurse to observe the patient through the infusion and also check vital signs anytime as per protocolor whenever MS nurse considers on the basis of MS Nurses’ professional criteria. People with MS are treated as outpatients and itdoesn’t require hospital admission.

From the traditional cooperative role, MS nurse assist Neurologist when performing a Lumbar Puncture, when filling up asubcutaneous reservoir with Baclophen for an intratecal infusion by internal pump.

The future new oral therapies for MS won’t represent any impairment for the MS nurse to continue being a reference in themanagement of people with MS. Even though the new oral drugs management will most probably require a multidisciplinary teamfocus.

In our center we have a very low rate of therapy abandon, partly because of medical and nursing work, together with themultidisciplinary team, making the patients feel cared for. Nevertheless MS is still a disease without a cure so it’s a chronic diseasewith an high risk of complications and disability progression.

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Rosalía HornoMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

CS1. Case study session

1 - Department of Neurology, Multiple Sclerosis Unit, “Dr. Josep Trueta” Hospital in Girona, Girona, Spain2 - Unit of Multiple Sclerosis, University Hospital of Bellvitge, Barcelona, Spain3 - Neuroimmunology group, Neurology department, Hospital Clinic of Barcelona, Barcelona, Spain

Clinical caseNuria Solà, Sara Llufriu, Maria Sepúlveda, Yolanda Blanco, Albert Saiz

Summary of the presentation: A 32 year-old woman was admitted to our Hospital because of an acute urinary retention.Neurological examination revealed muscular weakness in her right arm with a global muscle balance 4 out of 5, impairment ofsensation to temperature and pain below thoracic T4 level and hypopalestesia in lower extremities. Deep tendon reflexes wereglobally hyperactive and right plantar response was extensor. The spinal MRI showed T2 signal alteration between C4-C7, T4-T6 andT8-T9 with diffuse contrast enhancement. CSF showed pleocytosis (10 cells/mm3) and absence of oligoclonal bands. MRI brain,visual evoked potentials and coherence optical tomography were normal. She had been controlled by Internal medicine departmentsince 2010 due to the presence of ANA (>640URF), anti-double-stranded DNA (11U/ mL, nv<10U/mL) and slightly positive Crithidialucillae indirect immunoflourescence (IF) determination. At admission, these non-organ specific antibodies were clearly positive(ANA>640 URF, anti-dDNA 91.7 U/mL and Crithidia lucillae IF positive) but NMO-IgG were negative by immunohistochemistry andcell-based assay. The diagnosis of longitudinal extensive transverse myelitis (LETM) associated with a probable systemic lupuserythematosus disease (SLE) was established. 3-days cycle of high dose of methylprednisolone and 6 cycles of cyclophosphamide(CFM) were done. Retrospectively, the serum was reanalyzed by an assay of transfect cells with the isoform M23 of AQP-4 and NMO-IgG resulted positive. This led to the final diagnosis of NMO spectrum disorder. The patient’s clinical status and spinal MRI lesionsimproved after the established treatment. The titer of serologic non-organ specific Ab decreased (anti-dDNA 39.4 U/mL and Crithidialucillae IF negative) and new serum determination of NMO-IgG was also negative after the immunosuppressive treatment. LETM isa heterogeneous syndrome defined by the existence of more than a three-vertebral-segment spinal cord lesion seen in MRI andproduced by an inflammatory process that may occur in the context of multiple sclerosis, NMO or as an uncommon manifestationof systemic autoimmune diseases, such as SLE. NMO often leads to severe disability and its diagnosis is crucial due to its worseprognosis. Although the coexistence of clinical and/or serological markers of non organ-specific disease is well-established, IgGautoantibody recognizing the water channel aquaporin-4 represents a highly specific biomarker for NMO. Its existence predictsfuture relapse and development of definite NMO. The improvement of IgG-NMO determination has been crucial in the improvementof the diagnosis and to establish an early treatment.

References:1. Pittock SJ, Lennon VA, de Seze J, Vermersch P, Homburger HA, Wingerchuk DM, Lucchinetti CF, Zéphir H, Moder K, Weinshenker BG. Neuromyelitis optica andnon organ-specific autoimmunity. Arch Neurol. 2008;65:78-83.

2. Trebst C, Raab P, Voss EV, Rommer P, Abu-Mugheisib M, Zettl UK, Stangel M. Longitudinal extensive transverse myelitis--it's not all neuromyelitis optica. NatRev Neurol. 2011;7:688-98.

3. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66:1485-9.4. Saiz A, Zuliani L, Blanco Y, Tavolato B, Giometto B, Graus F; Spanish-Italian NMO Study Group. Revised diagnostic criteria for neuromyelitis optica (NMO).Application in a series of suspected patients. J Neurol. 2007;254(9):1233-7.

5. Sellner J, Boggild M, Clanet M, Hintzen RQ, Illes Z, Montalban X, Du Pasquier RA, Polman CH, Sorensen PS, Hemmer B. EFNS guidelines on diagnosis andmanagement of neuromyelitis optica. Eur J Neurol. 2010;17:1019-32.

6. Sepúlveda M, Blanco Y, Rovira A, Rio J, Mendibe M, Llufriu S, Gabilondo I, Villoslada P, Castilló J, Corral J, Ayuso T, Iñiguez C, Santos S, Guijarro C, Ramió-Torrentà L, Sempere AP, Olascoaga J, Graus F, Montalban X, Saiz A. Analysis of prognostic factors associated with longitudinally extensive transverse myelitis.Mult Scler. 2012 Oct 4.

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Lluís Ramió i Torrentà (Spain) 1

Lucía Romero (Spain) 2

Nuria Solà, Sara Llufriu, Maria Sepúlveda, Yolanda Blanco, Albert Saiz (Spain) 3

PD3. Panel discussion on “Define treatment success”

1 - Multiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital, Barcelona, Spain

Define treatment success in present daily practice with clinical and MRI surrogateJordi Río

The objective of the definition of treatment response is to select earlier responders on one hand, and poor- or non-responders onthe other hand. Patient response outcomes should be measured taking into consideration the interfering factors related to thedisease itself. MRI offers an advantage in the response evaluation as it produces objective data, however the frequency of evaluationis limited and low frequency of MRI evaluations leads to poor perspective data. Several criteria for treatment response to interferon beta have been proposed. Nevertheless, these different criteria have not beenvalidated and there is no consensus among different investigators. Long-term disability data are crucial in order to select the mostclinically meaningful definition. These criteria are based on relapses, disability progression or both. Several factors make difficultthe employment of relapse outcomes to determine therapeutic response (low predictive value, regression to the mean, etc.). Theprogression of neurological impairment is another criterion employed to quantify response, however efficacy fluctuations related todepression, fatigue, spasticity, concurrent illness and prolonged relapse need be excluded. Nevertheless, criteria of response toIFNb therapy using disability progression are more clinically relevant than those based only in relapse rate.On the other hand, there are limited prospective data to validate MRI measures of disease activity as reliable prognostic factors ofsuboptimal response to therapy, but MRI changes which occurred during the first months of IFN may have a prognostic value foridentifying patients with a confirmed increase of disability in the next years of therapy. Moreover, the combination of measures ofclinical and MRI disease activity may have a prognostic value for identifiyng patients with a poor outcome during the next years oftherapy. Several factors are related to response from MS heterogeneity to genetic load and IFN response genes to poor healing mechanisms.Other factors related to suboptimal response are: excess disease activity, poor adherence to therapy, misdiagnosis, “pseudo” failure”or loss of drug efficacy.In conclusion, in relation with response to therapy in multiple sclerosis patients, the proportion of non-responders varies dependingon the definition used, criteria based on relapse measures have poor sensitivity and positive diagnostic value, non-responders havea higher clinical activity at baseline, baseline EDSS predicts long-term disability, there are limited prospective MRI data as predictorsof therapeutic response and the combination of clinical and MRI measures of disease activity may have a prognostic value foridentifiyng patients with a poor response.

Define treatment success in the age of pharmacogenomicsManuel Comabella

The mechanisms underlying heterogeneity in the response to treatment in multiple sclerosis (MS) are not completely understood,although genetic factors are most likely to be playing important roles. Moreover, given the complex nature of the disease,this heterogeneity is probably explained by the contribution of multiple genes. Disease Modifying Therapies (DMTs) are the mainstayof treatment in relapsing-remitting MS and have demonstrated a beneficial effect on disease activity. However, DMTs are partiallyeffective, and their long-term impact on disease progression remains elusive. In addition, not all patients respond to current DMTs.The increasing number of new therapies for MS and the potential risk for a lack of response and/or serious adverse reactions makeindividualized therapy a high-priority for MS. Pharmacogenomics applies technologies such as gene expression profiling, singlenucleotide polymorphisms (SNP) screens, and proteomics in order to predict response to treatment and toxicity to drugs. Althoughpharmacogenomics holds great promise for individualized therapy in MS, big efforts should first be made to identify markers fortreatment efficacy.This talk will focus on the current status and future directions of pharmacogenomic studies in MS, mainly in relation withinterferonbeta treatment.

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Jordi Río, Spain 1

Manuel Comabella, Spain 1

L9. Fostering treatment adherence and compliance: a role-play

Evidence coming from the pivotal clinical trials and from some other well-performed clinical trials has clearly demonstrated thebenefit of immunomodulatory therapies in MS. It is also clear that present therapies are not without side effects and mode ofadministration is still cumbersome for a number of patients; these factors impact on adherence to treatment, which may render thetherapeutic efforts futile. Several studies have shown that most drop-outs occur in the early phases of therapy so especial careneeds to be taken when patients start their immunomodulating therapy in order to avoid treatment discontinuation. Availableevidence suggests that individualized care is an important factor to keep drop-out rates low; in this regard, management of sideeffects of therapies is crucial, as it is responsible for almost a half of all discontinuations. Another important factor related totreatment discontinuation seems to be perceived lack of efficacy as a consequence of wrong expectations about treatment effects;therefore, adequate setting of expectations about therapy is crucial from outset of treatment with disease-modifying drugs. Sideeffects profile of IFNbeta preparations and GA are not entirely overlapping. In the case of IFNbeta preparations, it is especiallyimportant to manage flu-like symptoms at onset of therapy. Several strategies can be implemented to diminish patient discomfort,such as gradual dose increase and anti-inflammatory therapy administration schemes. Other side effects such as injection sitereactions, flushing and laboratory abnormalities also need to be closely monitored. Nurse-led patient education at onset of therapymay be helpful to manage patients’ expectations from therapy and to anticipate and diminish the impact of side effects on adherenceto treatment. Finally, even though results from clinical trials are the keystone to our clinical practice, measuring efficacy of therapyin clinical practice in an appropriate manner is crucial to obtain the most from available therapies. Clinical daily practiceindividualized monitoring of treatment response, treatment adherence, and side effects profile is therefore highly recommended ifclinical trials efficacy results are to be met in our clinics.

In the present talk, we will briefly review these issues and in the role playing that will ensue, we will put into practice ourinterpersonal skills so as to maximize patients’ adherence to treatment in order to make the most of the available therapies.

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María Jesús Arévalo and Jaume Sastre-GarrigaMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

KNS3. Oral therapies in MS

Actually approved disease modifying drugs (DMDs) for relapsing-remitting multiple sclerosis include recombinant interferon (IFN-beta) and glatiramer acetate (GA). All these immunomodulatory treatments have been shown to reduce the frequency and severityof relapses, as well as reducing progression of neurological disability. However all DMDs are administered parenterally and needfrequent injections which may be inconvenient and uncomfortable for patients. In addition, not all patients respond adequately andcommon side effects associated with these therapies may reduce adherence. The development of drugs with easier administration,such as oral agents, would further promote adherence, increase patient satisfaction and thereby improve efficacy. Two phase IIIclinical trials CLARITY and TRANSFORM have provided promising results for Cladribine and fingolimod respectively.

The results of the CLARITY study show that annual short-course treatment with both doses (3,5 mg/kg and 5,25 mg/kg) of cladribinetablets led to a significant reduction in the rate of clinical relapses, disability progression and brain lesions, as well as a significantincrease in the proportion of patients who remained relapse-free. Overall, the frequencies of adverse events in both Cladribinetreatment groups were comparable to those observed in the placebo group dose.

The results of TRANSFORM study, also show a significant reduction in annualized relapses rate and MRI activity. During this study,two fatal viral infections occurred. Moreover, the FREEDOMS study demonstrated a significant reduction of disease activity of bothdoses of Fingolimod against Interferon beta 1a . The safety profile of the drug open some concern for the risk of herpes infectionsand cardiovascular problems.

Other oral drugs in earlier phase of the development include BG12, Teriflunomide and Laquinimod For all these three drugs, apreliminary efficacy emerged from Phase II studies and phase III studies are ongoing.

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Giancarlo ComiDepartment of Neurology, Institute of Experimental Neurology, Vita-Salute San Raffaele University, Milan, Italy

References:1. Comi G, Abramsky O, Arbizu T, Boyko A, Gold R, Havrdovà E, Komoly S, Selmaj K, Sharrack B, Filippi M; LAQ/5063 Study Group. Oral laquinimod in patients with

relapsing-remitting multiple sclerosis: 36 week double-blind active extension of the multicentre, randomized, double-blind, parallel-group placebo-controlledstudy. Mult Scler 2010;16:1360-1366

2. Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol 2011;69:759-7773. Duddy M, Haghikia A, Cocco E, Eggers C, Drulovic J, Carmona O, Zéphir H, Gold R. Managing MS in a changing treatment landscape. J Neurol 2011;258:728-

7394. Hartung HP, Montalban X, Sorensen PS, Vermersch P. Olsson T. Principles of a new treatment algorithm in multiple sclerosis. Expert Rev Neurother

2011;11:351-362

KNS4. Therapy with monoclonal antibodies

Abstract not in hand at the time of printing.

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Xavier MontalbanMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

References:1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction

6 1206-1212. 2 - Filicori M, Cognigni GE, Pocognoli P et al. 2003 Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and

Metabolism 14, 267-273.

S3. Snapshot #1 on gene therapy in MS

Gene therapy is a group of techniques that involves an individual's modification of genetic makeup to treat acquired and hereditarydiseases. Among all the different vehicles used to deliver genes into an individual's cells, viral vectors are the most used due to theinnate capability of viruses to introduce their genetic material into a host cell. Gene therapy is a relatively new field in biomedicinesince the first clinical trial was approved in 1989. From then on, the amount of trials increased exponentially, indeed, from the late90’s until now approximately 100 clinical trials are approved each year worldwide.

Several approaches to treat multiple sclerosis have been made in its animal model (experimental autoimmune encephalomyelitis,EAE), including delivery of immunomodulatory molecules in the CNS, enhancement of neuroprotection or induction of antigen-specific immune tolerance. The different strategies developed to treat EAE are going to be discussed, as well as the new tools thatare being developed in the field of gene therapy that in the future could be useful to overcome the neurodegenerative processes thattake place in MS patients.

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Herena EixarchMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

S4. Snapshot #2 on DNA vaccines in MS

Since the discovery, over a decade and a half ago, that genetically engineered DNA can be delivered in vaccine form and elicit animmune response, there has been much progress in understanding the basic biology of this technology.

DNA vaccination is a strategy of immunization based on the injection of a gene encoding a target protein with the goal of eliciting apotentially protective immune response in the host. Classically, DNA vaccines have been successful at generating protective immuneresponses in various cancer models and infectious diseases, due to an activation of the immune system. Although, in the last yearsdifferent studies have shown the potential use of DNA vaccines to modulate autoimmune diseases, like multiple sclerosis (MS),inducing tolerance rather than stimulation of an immune response.

Compared to traditional immunization procedures, DNA vaccination offers several advantages: for instance, expression of nativeantigens in situ, prolonged in vivo antigen production, increased availability of antigenic peptides because of the endogenous andlong-term synthesis of the gene product and the modification of the vaccination protocol that could induce either Th1 or Th2 immuneresponses

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, probably of autoimmune aetiology,in which auto-reactive T cells play an essential role in the pathogenesis of the disease through the attack of myelin components. Atpresent, there is not an effective treatment for the disease. Most of the currently used drugs for the treatment of MS target theimmune response, but are not selective for the auto-reactive T cells

The application of DNA vaccination to the treatment of the animal model of MS, experimental autoimmune encephalomyelitis (EAE),has demonstrated the great potential of this procedure for therapeutic purposes. The protection appears to be highly influenced bythe capacity of DNA vaccination to modulate immune responses affecting the Th1, Th2 and, importantly, the T cell immunoregulatoryarms.

So far, two clinical trials of DNA vaccines have been reported in MS. From these studies, it can be concluded that the vaccine wassafe, well-tolerated, and caused antigen-specific immune tolerance.

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Nicolás FissoloMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

S5. Snapshot #3 on Stem cell therapy in MS

Stem cells are found in all multicellular organisms. They are characterized by the ability to renew themselves through mitotic celldivision and differentiate into a diverse range of specialized cell types.

There are different kinds of stem cells. The embryonic stem cells are obtained from embryos and can differentiate into whatever cellof the organism, they are pluripotent. The adults also have stem cells, which can only give rise to cells closely related to their organor tissue of origin, they are multipotent. Recently, researchers have created induced stem cells that are a type of pluripotent stemcells artificially derived from an adult somatic cell by inducing a forced expression of certain genes.

Since the stem cells have the ability to repair and regenerate the damaged tissue, the therapies with stem cells were originallyconceived as replacement therapies. Howeverit has been shown that stem cells affect the recovery by an additional mechanism, theyalso have the ability to regulate the immune system.

Several studies with stem cells have been undertaken in animal models of multiple sclerosis with encouraging results. They haveshown that stem cells can contribute to repair the tissue damage, but they play a more important role in modulating the immunesystem.

Treatments with haematopoietic or mesenchymal stem cells have been used to treat multiple sclerosis patients. The results havebeen apparently positive, but they are still controversial and further studies are necessary.

36

Carme Costa RiuMultiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department,Vall d’Hebron University Hospital,Barcelona, Spain

References:1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction

6 1206-1212. 2 - Filicori M, Cognigni GE, Pocognoli P et al. 2003 Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and

Metabolism 14, 267-273.

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