FINAL PROGRAM AND ABSTRACTS

Your Continuing Medical Education Partnerwww.seronosymposia.org

MS Preceptorship

Updating Knowledge in Multiple Sclerosis

Barcelona, S

pain

- June1-3,2010

GENERAL INFORMATION

VENUEThe workshop will take place at the:

Alimara Hotel Berrugete 126 - 08035 Barcelona

T (34) 935 040 440 - F (34) 934 279 292 www.alimarahotel.com

and

Vall d’Hebron University HospitalUnitat de Neuroimmunologia Clínica

EUI 2ª Pl. Ps. Vall d’Hebron, 119-12908035 Barcelona, Spain

LANGUAGEThe official language of the workshop will be English.

TRAVEL INFORMATIONThe first human settlements in Barcelona date back to Neolithic times. The city

itself was founded by the Romans who set up a colony called Barcino at the end ofthe 1st century BC. The colony had some thousand inhabitants and was bounded

by a defensive wall, the remains of which can still be seen in the old town. For over200 years, Barcelona was under Muslim rule, and, following the Christian

reconquest, it became a county of the Carolingian Empire and one of the mainresidences of the court of the Crown of Aragon. The fruitful medieval periodestablished Barcelona's position as the economic and political centre of the

Western Mediterranean. The city’s Gothic Quarter bears witness to the splendourenjoyed by the city from the 13th to the 15th centuries. From the 15th to 18thcenturies the city entered a period of decline, while it struggled to maintain its

economic and political independence. This struggle ended in 1714, when the cityfell to the Bourbon troops and rights and privileges in Catalonia were suppressed.A period of cultural recovery began in the mid-19th century with the arrival of the

industrial revolution and the development of the textile industry. During this period,which was known as the Renaixença, Catalan regained prominence as a literary

language. The 20th century ushered in widespread urban renewal throughout thecity, culminating in its landmark Eixample district, which showcases some of

Barcelona’s most distinctive Catalan art-nouveau, or modernista, buildings. AntoniGaudí, one of the most eminent architects of the time, designed buildings such asthe Casa Milà (known as La Pedrera, the Catalan for stone quarry), the Casa Batllóand the Sagrada Família church, which have become world-famous landmarks. Thefreedoms achieved during this period were severely restricted during the Civil War

and the fascist dictatorship. With the reinstatement of democracy, Barcelona societyregained its cultural and economic strength. The city's hosting of the 1992 Olympic

Games gave fresh impetus to the city's potential and reaffirmed its status as amajor metropolis. In 2004, the Forum of Cultures reclaimed industrial zones toconvert them into residential districts. An example of the renewed vigour with

which Barcelona is looking towards the 21st century.

MS Preceptorship - Updating Knowledge in Multiple Sclerosis

Serono Symposia International Foundation Workshop on:

MS PRECEPTORSHIPUPDATING KNOWLEDGE IN MULTIPLE SCLEROSISBarcelona, Spain - June 1-3, 2010

AIM OF THE WORKSHOPThe MS Preceptorship offers a balanced mix of comprehensive lectures and interactive sessions that cover all main aspects ofMultiple Sclerosis (MS) scientific background and management. Acquiring the most updated knowledge and sharing theirexperience with top-level experts and highly qualified colleagues, participants will improve competence in patients’management.

LEARNING OBJECTIVESAt the end of the workshop, attendees will have received comprehensive information on the following aspects of MS: • Epidemiology• Genetics• Pathogenic mechanisms• Diagnosis and differential diagnosis• Treatment

TARGET AUDIENCEThis program is designed mainly for neurologists already involved in Multiple Sclerosis management as well as cliniciansinterested in entering this field.

ACCREDITATIONSerono Symposia International Foundation (www.seronosymposia.org) has submitted this program “MS Preceptorship -Updating Knowledge in Multiple Sclerosis” (Barcelona, Spain - June 1-3, 2010) for accreditation by the EuropeanAccreditation Council for Continuing Medical Education (EACCME).

All Serono Symposia International Foundation programs are organized solely to promote the exchange and dissemination of scientific and medical information. No forms of promotionalactivities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of the named speakers, and do not represent anendorsement or recommendation on the part of Serono Symposia International Foundation. This program is made possible thanks to the unrestricted Educational grant received from: Centred’Esclerosi Multiple de Catalunya, Vall d'Hebron University Hospital, ComtecMed, Congrex Sweden, Congrex Switzerland, Cryo-Save, Datanalysis, Esaote, Fundación IVI, ISFP InternationalSociety for Fertility Preservation, ISMH International Society of Men’s Health, K.I.T.E., Merck Serono, Meridiano Viaggi e Turismo, Ministry of Health of the State of Israel, University of Catania.

LOCAL SCIENTIFIC & ORGANIZING COORDINATION

Ilaria Laganàformacio@cem-cat.org

SCIENTIFIC SECRETARIAT

Serono Symposia International FoundationSalita di San Nicola da Tolentino, 1/b00187 Rome, ItalyAssociate Project Manager: Serena Dell’AricciaTel.: +39-06-420413 251Fax: +39-06-420 413 677E-mail: info@seronosymposia.org

Serono Symposia International Foundationis a Swiss Foundation with headquarters in14, rue du Rhône, 1204 Genève, Switzerland

ORGANIZING SECRETARIAT

Meridiano Congress International Via Mentana, 2/B - 00185 Rome - ItalyCongress Coordinator: Debora UrbinelliPhone: +39-06-885 952 32Fax: +39-06-885 952 34E-mail: d.urbinelli@meridiano.it

SCIENTIFIC ORGANIZERS

Xavier Montalban and Jaume Sastre-GarrigaMultiple Sclerosis Centre of CataloniaUnit of Clinical NeuroimmunologyVall d’Hebron University HospitalBarcelona, Spain

LIST OF SPEAKERS AND CHAIRMEN

José Carlos Álvarez-CermeñoService of Neurology Hospital Ramón y Cajal Madrid, Spain

María Jesús ArévaloMultiple Sclerosis Center of CataloniaUnit of Clinical NeuroimmunologyVall d’Hebron University HospitalBarcelona, Spain

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

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

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

Carme CostaMultiple Sclerosis Center of Catalonia Unit of Clinical Neuroimmunology Vall D'Hebron University Hospital Barcelona, Spain

Herena EixarchMultiple Sclerosis Center of Catalonia (CEM-Cat)Unit of Clinical NeuroimmunologyResearch Institute - Vall d'Hebron University HospitalBarcelona, Spain

Oscar FernándezService of NeurologyUniversity Regional Hospital “Carlos Haya”Malaga, Spain

Nicolàs FissoloMultiple Sclerosis Center of Catalonia (CEM-Cat)Unit of Clinical NeuroimmunologyResearch Institute - Vall d'Hebron University HospitalBarcelona, Spain

Angelo GhezziMultiple Sclerosis CentreGallarate HospitalGallarate, Italy

Eva HavrdovàMultiple Sclerosis Centre and Neurology ClinicCharles University Prague, Czech Republic

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

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

Ester MoralDepartment of NeurologyHospital Dos de Maig &Multiple Sclerosis Unit University Hospital BellvitgeBarcelona, Spain

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

Susana OteroMultiple Sclerosis Center of Catalonia Department of EpidemiologyVall d'Hebron University Hospital Barcelona, Spain

Iris Katharina PennerDepartment of Cognitive Psychology University of BaselBasel, Switzerland

Francisco Pérez MirallezMultiple Sclerosis Center of CataloniaUnit of NeurorehabilitationVall d’Hebron University HospitalBarcelona, Spain

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

Marta Renom GuiterasMultiple Sclerosis Center of CataloniaUnit of NeurorehabilitationVall d’Hebron University HospitalBarcelona, Spain

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

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

Lucia Romero PinelUnit of Multiple Sclerosis University Hospital of BellvitgeBarcelona, Spain

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

Carme SantoyoMultiple Sclerosis Center of CataloniaUnit of NeurorehabilitationVall d’Hebron University HospitalBarcelona, Spain

Jaume Sastre-GarrigaMultiple Sclerosis Center of CataloniaUnit of Clinical NeuroimmunologyVall d’Hebron University HospitalBarcelona, Spain

Alan J. ThompsonDepartment of Brain Repair and RehabilitationNational Hospital for Neurology and NeurosurgeryLondon, UK

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

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

Christiane WegnerInstitute of Neuropathology University Medical Center Georg-August-UniversityGöttingen, Germany

Hartmut WekerleMPI NeuroimmunologyMartinsried, Germany

LIST OF SPEAKERS AND CHAIRMEN

SCIENTIFICPROGRAM

Chairpersons: Xavier Montalban and Jaume Sastre-Garriga, Spain

TUESDAY - JUNE 1, 2010

08.30 Registration at Welcome Desk

08.45 SSIF OpeningGiancarlo Comi, Italy

09.00 Opening and introduction to MS Centre of Catalonia (CEM-Cat)Xavier Montalban, Spain

09.30 L1: Epidemiology of MSSusana Otero, Spain

10.00 KNS1: Immunopathogenesis of MSHartmut Wekerle, Germany

11.00 Coffee Break

11.30 L2: Pathology of MSChristiane Wegner, Germany

12.00 L3: MS Clinical forms and MS variantsOscar Fernández, Spain

12.30 L4: CSF analysis in MSJosé Carlos Álvarez-Cermeño, Spain

13.00 L5: MRI in MS: the radiologist perspectiveAlex Rovira, Spain

13.30 Working lunch

Legend: L : Lecture; KNS : Key Note Speech; WG : Working Group; S : Snapshot; PD : Panel Discussion

14.30 WG1: “ON DEMAND” CASE STUDY SESSION

Group 1: Clinical case on demand #1Group 1: Carmen Tur, Spain

Group 2: Clinical case on demand #2Group 1: Carlos Nos, Spain

Group 3: Clinical case #3Group 1: Georgina Arrambide, Spain

15.30 Visit 1: Visits to MS clinic and laboratory, MRI and FEM

Inside the Vall d’Hebron Hospital

Visit “Clinic”Held in the Ambulatories and Psychological offices with a presentation of patients’ flowwithin the different premises.

Visit “Laboratory”Held in the Laboratories to have an overview of technical equipments and discussprocedures.

Visit “MRI”Held at the MRI unit with a presentation of equipments and procedures and discussionof clinical cases.

At FEM - NRHB Rehabilitation centre

Visit “Rehabilitation”Held at the Day Hospital rehabilitation center with a presentation of approaches

targeted to different levels of disability.

17.30 End of Day 1

WEDNESDAY - JUNE 2, 2010

CLINICAL WORK-UP

08.30 L6: MS diagnosis and differential diagnosisMar Tintoré, Spain

09.00 L7: Juvenile MSAngelo Ghezzi, Italy

09.30 L8: Overview on symptomatic therapy and rehabilitationJaume Sastre-Garriga, Spain

10.00 S1: Symptomatic Therapy Snapshot #1 on Gait rehabilitation Carme Santoyo, Spain

10.15 S2: Symptomatic Therapy Snapshot #2 on Management of dysphagia Marta Renom Guiteras, Spain

10.30 Coffee break

11.00 PD1: PANEL DISCUSSION ON COGNITION IN MSChairman: Alan J. Thompson, UK

Diagnosis - Iris Katharina Penner, Switzerland

Treatment - María Jesús Arévalo, Spain

Clinical Case Presentation - Francisco Pérez Mirallez, Spain

Discussion

12.30 KNS2: Overview of drugs currently registered for MSEva Havrdovà, Czech Republic

13.00 L9: Role of MS nurses in MS patients’ managementRosalía Horno and Gemma Rodríguez, Spain

13.30 Working lunch

14.30 WG2: CASE STUDY SESSION ON DMDs

Group 1: Clinical case: DMDs safetyGroup 1: Ester Moral, Spain

Group 2: Clinical case: DMDs efficacyGroup 1: Lluís Ramió i Torrentá, Spain

Group 3: Clinical case: DMDs and pregnancyGroup 1: Lucia Romero, Spain

15.30 Visit 2: Visits to MS clinic and laboratory, MRI and NRHB UnitsFor visit description, please see details in Day 1

17.30 End of Day 2

THURSDAY - JUNE 3, 2010

08.30 L10: Genetics of MSManuel Comabella, Spain

09.00 PD2: PANEL DISCUSSION ON “DEFINE TREATMENT SUCCESS”Chairwoman: Mar Tintoré, Spain

13.00 Define treatment success in present daily practice with clinical and MRIsurrogates Jordi Río, Spain

12.30 Define treatment success in the age of pharmacogenomics Manuel Comabella, Spain

12.45 Discussion

09.50 L11: Fostering treatment adherence and compliance: a role playMaría Jesús Arévalo and Jaume Sastre-Garriga, Spain

10.40 Coffee Break

11.00 KNS3: Oral therapies in MSGiancarlo Comi, Italy

11.45 KNS4: Future therapeutic targets as glanced from MS immunopathogenesis:Antibodies in MS Xavier Montalban, Spain

12.15 S3: Snapshot #1 on Gene Therapy in MS Herena Eixarch, Spain

12.30 S4: Snapshot #2 on DNA vaccines in MS Nicolàs Fissolo, Spain

12.45 S5: Snapshot #3 on Stem cell therapy in Ms Carme Costa, Spain

13.00 Course Wrap upXavier Montalban, Spain

13.30 End of the workshop and Working lunch

DISCLOSURE OF FACULTY RELATIONSHIPS

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

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

Josè Carlos Álvarez-Cermeño Declared receipt of grants and contracts from Merck Serono, Bayer.Schering, Biogen Idec and receiptof honoraria or consultation fees from Merck Serono, Bayer.Schering, Biogen Idec, Teva, SanofiAventis, to be member of Merck Serono, Bayer.Schering, Biogen Idec advisory board.

María Jesús Arévalo Declared no potential conflict of interest.

Georgina Arrambide Declared receipt of a McDonald Fellowship, Multiple Sclerosis International Federation.

Manuel Comabella Declared no potential conflict of interest.

Giancarlo Comi Declared receipt of honoraria and consultation fees from Serono Symposia International Foundation,Bayer Schering, Merck Serono, Teva Pharmaceuticals INd. Ltd, Sanofi Aventis, Biogen Dompè.

Carme Costa Declared no potential conflict of interest.

Herena Eixarch Declared no potential conflict of interest.

Oscar Fernández Declared no potential conflict of interest.

Nicolàs Fissolo Declared no potential conflict of interest.

Angelo Ghezzi Declared receipt of grant and contract from Teva and Merck Serono and receipt of honoraria fromDompè, Schering, Novartis, Actelion, Merck Serono.

Eva Havrdovà Declared receipt of grants from Czech Republic Ministry of Health and Ministry of Education. Receiptof Honoraria and Consultation fee from Merck Serono, Bayer, Byogen Idec, Teva, Sanofi Aventis,Novartis, GG.

Rosalía Horno Declared no potential conflict of interest.

Xavier Montalban Declared receipt of honoraria and conlutation fee from Bayer Schering, Biogen Idec, Merck-Serono,Novartis, Teva, Sanofi-Aventis, Almirall.

Ester Moral Declared no potential conflict of interest.

Carlos Nos Declared no potential conflict of interest.

Susana Otero Declared no potential conflict of interest.

Iris Katharina Penner Declared receipt of grants and contract from Bayer Schering, receipt of honoraria or consultation feesfrom Bayer Schering, Novartis, Roche, Merck Serono, Biogen Idec, Teva, Sanofi Aventis, to be memberof advisory board, board of directors of Bayer Schering, Novartis, Biogen Nordic.

Francisco Pérez Miralles Declared no potential conflict of interest

All Serono Symposia International Foundation programs are organized solely to promote the exchange and dissemination of scientific and medical information. No forms of promotionalactivities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of the named speakers, and do not represent anendorsement or recommendation on the part of Serono Symposia International Foundation. This program is made possible thanks to the unrestricted Educational grant received from: Centred’Esclerosi Multiple de Catalunya, Vall d'Hebron University Hospital, ComtecMed, Congrex Sweden, Congrex Switzerland, Cryo-Save, Datanalysis, Esaote, Fundación IVI, ISFP InternationalSociety for Fertility Preservation, ISMH International Society of Men’s Health, K.I.T.E., Merck Serono, Meridiano Viaggi e Turismo, Ministry of Health of the State of Israel, University of Catania.

Lluis Ramió i Torrentá Declared receipt of grants and contracts and honoraria or consultation fees from Biogen, Bayer-Schering, Teva, Sanofi-Aventis, Merck Serono and receipt of honoraria and consultation fees fromBiogen, Bayer-Schering, Sanofi-Aventis, Merck Serono.

Marta Renom Guiteras Declared no potential conflict of interest.

Jordi Río Declared no potential conflict of interest.

Gemma Rodriguez Declared no potential conflict of interest.

Lucia Romero Pinel Declared no potential conflict of interest.

Alex Rovira Declared no potential conflict of interest.

Carme Santoyo Declared no potential conflict of interest.

Jaume Sastre-Garriga Declared to be member of a Biogen, Merck Serono, Novartis Teva, Bayer advisory board. He declaredalso participation in a Biogen, Bayer, Merck Serono, Novartis and Sanofi-Aventis Almirall sponsoredspeaker’s bureau.

Alan J. Thompson Declared receipt of fees from Eisai London Research Labs, Merck Serono, DignaBiotech, Novartis.

He declared to be member of Patrick Berthoud Trust (Trustee); National Hospital DevelopmentFoundation (Trustee); MSIF International Medical and Scientific Board (chairman).

He declared also benefits from a relationship with a commercial enterprise: Honorarium as Editor-in-Chief Multiple Sclerosis (Sage publications); free subscription as member Editorial Board for LancetNeurology and for Current Medical Literature - Multiple Sclerosis and receipt of support for travelfrom Biogenidec.

Mar Tintoré Declared receipt of grants and contracts, honoraria and consultation fees from: Schering Bayer,Biogen-Idec, Merck-Serono, Teva, Sanofi-Aventis and Novartis.

Carmen Tur Declared no potential conflict of interest.

Christiane Wegner Declared no potential conflict of interest.

Hartmut Wekerle Declared no potential conflict of interest.

ABSTRACTS

L1EPIDEMIOLOGY OF MS

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

Epidemiology can be defined as the study of the distribution and determinants of disease from a population perspective, using quantitativemethods. Descriptive epidemiology pictures the distribution and time trends, using prevalence and incidence data, and analyticepidemiology 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 around theworld. They showed that the disease was not evenly distributed and there was a latitudinal gradient with higher prevalence as we moveaway from de equator. It should be noted that this studies had certain limitations that have to be considered when comparing data. Therewere differences between studies regarding methodological aspects such as case definition, sources of information, population size andthere was data lacking in certain parts of the world.

Despite the methodological limitations, the characteristic distribution led to genetic and environmental pathogenic hypothesis. Consideringthat MS has an important genetic component of susceptibility, the distribution could be due to the variation of genetic and ethnicbackgrounds of the world’s population. Nevertheless, there are reasons to believe that genetics can not explain all of it. In regions withhomogenous population, this gradient is still present, and according to studies in migrant population, risk of MS can vary when migratingto a different area, particularly when migration occurs early in life. Furthermore, studies conducted in monozygotic twins, showconcordance rates for MS of 24% that would reflect other factors acting in uterine or early life environments.

There are several environmental factors that have been postulated. The mirror-image gradient of MS points to a sun related factor such asVitamin D. On the other hand, an infectious agent acting directly (as a trigger of the disease) or indirectly (protecting if acquired early inlife -hygiene hypothesis-) has also been postulated. Epstein-Bar virus (EBV), seems one of the strongest candidates, as MS in unlikely todevelop in a EBV negative individual, there is strong evidence that links epidemiology of infectious mononuclerosis with MS, and recentstudies have shown an increase in EBV antibodies preceding symptomatic MS.

Recent data from prospective studies performed in Europe, America and Asia show that MS incidence seems to be increasing during thepast 20 years and the classical prevalence gradient is not as clear in certain areas. This phenomenon could be explained by an improvedcase ascertainment thanks to better diagnostic techniques, such as MRI, the emergence of data in areas that had not been studiedpreviously or changes in population composition due to migration. However, it can not be ruled out a true increase in MS risk as a resultin a change in causal factors.

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. - Kurtzke JF. Geographic distribution of multiple sclerosis: An update with special reference to Europe and the Mediterranean region. Acta Neurol Scand1980;62:65-80.

- Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol 2008;7:268-77.- Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci 2001 Apr;22(2):117-39.- Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain2000;123:968-74.

- Koch-Henriksen N. The Danish Multiple Sclerosis Registry: a 50-year follow-up. Mult Scler 1999;5:293-6.- Grytten N, Glad SB, Aarseth JH, Nyland H, Midgard R, Myhr KM. A 50-year follow-up of the incidence of multiple sclerosis in Hordaland County, Norway.Neurology 2006;66:182-6

- Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 2008;71:129-35.

KNS 1IMMUNOPATHOGENESIS OF MS

Hartmut WekerleMPI Neuroimmunology, Martinsried, Germany

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Abstract not in hand at the time of going to press.

ABSTRACTS

L2PATHOLOGY OF MS

Christiane WegnerInstitute of Neuropathology, University Medical Center, Georg-August-University, Göttingen, Germany

Multiple sclerosis is characterized by inflammatory demyelinating lesions in the white and grey matter of the central nervous system. Whitematter lesions display inflammation, demyelination, gliosis and axonal loss. The amount of inflammation decreases during lesion formation.Different patterns of demyelination can be distinguished in early actively demyelinating lesions. These patterns show either similarities toT-cell-mediated autoimmune encephalomyelitis or signs of oligodendrocyte dystrophy [1]. However, these distinct features are not presentin chronic MS lesions anymore, which are characterized by scarce inflammatory infiltrates, demyelination fibrillic gliosis and axonal loss. Inaddition to focal damage to white matter, there is evidence for diffuse white matter changes such as microglial activation and axonaldamage in chronic MS [2].

Recent studies have demonstrated extensive demyelination in the neocortex, particularly in patients with chronic MS. Neocortical lesionshave been shown to contain significantly fewer lymphocytes and microglia/macrophages compared to white matter lesions. Within corticallesions adjacent to subcortical white matter lesions there was evidence for substantial glial, neuronal and synaptic loss [3], but only subtledamage to dendrites and synapses was found in non-lesional MS neocortex. Cortical lesions displayed more pronounced remyelinationthan white matter lesions [4]. Demyelination and neuronal loss was also observed in other grey matter areas such as the hippocampus,thalamus, cerebellar cortex and spinal cord [5].

In conclusion, there is evidence for significant white and grey matter damage in MS. Limitation of this pathology is important and mayrequire anti-inflammatory as well as neuroprotective treatment approaches.

References:1 - Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis

of demyelination. Annals of Neurology 2000, 47:707-717.2 - Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H: Cortical demyelination and

diffuse white matter injury in multiple sclerosis. Brain 2005, 128:2705-2712.3 - Wegner C, Esiri MM, Chance SA, Palace J, Matthews PM: Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 2006, 67:960-

967.4 - Albert M, Antel J, Bruck W, Stadelmann C: Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol 2007, 17:129-138.5 - Wegner C, Stadelmann C: Grey matter pathology and multiple sclerosis, Curr Neurol Neurosci Rep 2009, 9: 399-404.

L3MS CLINICAL FORMS AND MS VARIANTS

Oscar FernándezService of Neurology, University Regional Hospital “Carlos Haya”, Malaga, Spain

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Abstract not in hand at the time of going to press.

ABSTRACTS

L4CSF ANALYSIS IN MS

José Carlos Álvarez-CermeñoService of Neurology, Hospital Ramón y Cajal, Madrid, Spain

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Abstract not in hand at the time of going to press.

L5MRI IN MS: THE RADIOLOGIST PERSPECTIVE

Alex RoviraUnit of Magnetic Resonance, Department of Radiology, Vall d’Hebron University Hospital-IDI, Barcelona, Spain

Conventional MRI techniques (cMRI), such as T2-weighted (T2W) sequences and gadolinium-enhanced T1-weighted sequences, which arehighly sensitive for detecting multiple sclerosis (MS) plaques, have become established as the most important paraclinical tool fordiagnosing MS, as well as for understanding the natural history of the disease and monitoring the efficacy of experimental treatments. Infact, cMRI metrics have become common primary endpoints in phase II immunomodulatory drug therapy trials. However, a possible roleof cMRI metrics as surrogate endpoints in phase III trials has been disclaimed because of the poor correlation between cMRI metrics andthe clinical disease course, particularly disability progression, which is driven by the neurodegenerative component of the disease.

Explanations for this clinical-radiological discrepancy include inappropriate clinical rating, neglect of spinal cord involvement,underestimation of damage to the normal appearing brain tissue (both white and gray matter), and compensation by cortical adaptation.However, one of the major contributors to this paradox is the lack of pathological specificity of T2W imaging, which provides only adichotomous type of information; that is, it simply discriminates between MS focal lesions and normal appearing white matter, but notbetween the type and degree of the underlying pathologic substrate (edema, inflammation, demyelination, remyelination, reactive gliosis,and axonal loss), which contribute differently to the development of permanent disability. In the last 20 years, a huge effort has been madeby the MRI research community to overcome the limited pathological specificity of cMRI, by developing new MRI techniques thatselectively measure the more destructive aspects of MS pathology and monitor the reparative mechanisms, such as T1- hypointense lesionsand quantitative analysis of global and regional brain volume (measures of irreversible tissue damage), magnetization transfer MR imaging(a measure that correlates with the extent of demyelination and remyelination), diffusion-weighted MR imaging (a technique that providesinformation about the orientation, size, and geometry of tissue damage in white and gray matter), and proton MR spectroscopy (atechnique which provides details on tissue biochemistry, metabolism, and function). All these non-conventional MR techniques haveincreased our understanding of the pathogenesis of the disease, and appear to be more sensitive biomarkers for measuring the pathologicprocesses underlying the progression of clinical disability (demyelination and axonal loss).

Functional MR imaging (fMRI) can be used to detect the ability of the brain to compensate for tissue impairment or loss, a phenomenonknown as “brain plasticity”, by showing increased magnitude or regional extent of activation during task performance in MS patients ascompared to controls. This abnormal cortical activation pattern may change over time in response to clinical disability, and to rehabilitationand pharmacological agents. Therefore, in the future, fMRI could be used as a monitoring tool in the assessment of the efficacy of therapiesthat promote neuroplasticity.

However proper application of all these MR-based measures to the study of MS requires their optimization and standardization acrosscenters. Moreover, these techniques should demonstrate their feasibility, reproducibility, sensitivity to disease evolution and treatmentchanges, and value in reflecting and predicting the accumulation of irreversible disability. All these required efforts are especially importantnowadays, where there is a growing interest in developing neuroprotective agents in MS, which consequently demand new imagingstrategies for monitoring myelin repair and axonal loss. In this way, MR could serve as a true biological marker of the severity andprogression of this disease.

References:01 - Arnold DL. Evidence for neuroprotection and remyelination using imaging techniques Neurology 2007; 68 (Suppl 3):S83–S9002 - Bakshi R, Minagar A, Jaisani Z, Wolinsky JS. Imaging of multiple sclerosis: role in neurotherapeutics. NeuroRx. 2005; 2:277-303.03 - Barkhof F. The clinico-radiological paradox in multiple sclerosis revisited. Curr Opin Neurol 2002; 15:239 –245.04 - Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol. 2009;

5:256-6605 - Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol. 2006; 5:158-170.06 - Bitsch A, Kuhlmann T, Stadelmann C, Lassmann H, Lucchinetti C, Bruck W. A longitudinal MRI study of histopathologically defined hypointense

multiple sclerosis lesions. Ann Neurol 2001; 49:793-796.

ABSTRACTS

07 - Chen JT, Collins DL, Atkins HL, Freedman MS, Arnold DL; Canadian MS/BMT Study Group. Magnetization transfer ratio evolution with demyelinationand remyelination in multiple sclerosis lesions. Ann Neurol. 2008 ;63:254-62.

08 - Dwyer M, Bergsland N, Hussein S, Durfee J, Wack D, Zivadinov R. A sensitive, noise-resistant method for identifying focal demyelination andremyelination in patients with multiple sclerosis via voxel-wise changes in magnetization transfer ratio. J Neurol Sci. 2009 Jul 15;282(1-2):86-95

09 - Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H. The relation betweeninflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132:1175-89

10 - Giacomini PS, Levesque IR, Ribeiro L, Narayanan S, Francis SJ, Pike GB, Arnold DL. Measuring demyelination and remyelination in acute multiplesclerosis lesion voxels. Arch Neurol. 2009;66:375-81.

11 - Giacomini PS, Arnold DL. Non-conventional MRI techniques for measuring neuroprotection, repair and plasticity in multiple sclerosis Current Opinionin Neurology 2008, 21:272–277

12 - Goodin DS. Magnetic resonance imaging as a surrogate outcome measure of disability in multiple sclerosis: have we been overly harsh in ourassessment? Ann Neurol 2006; 59:597–605.

13 - Miller DH. Biomarkers and Surrogate Outcomes in Neurodegenerative disease: Lessons from Multiple Sclerosis. NeuroRx 2004; 1:284-29414 - Pantano P, Mainero C, Caramia F. Functional brain reorganization in multiple sclerosis: evidence from fMRI studies. J Neuroimaging. 2006;16:104-

114.15 - Rovaris M, Gass A, Bammer R, Hickman SJ, Ciccarelli O, Miller DH, Filippi M. Diffusion MRI in multiple sclerosis. Neurology. 2005;65:1526-1532 16 - Rovira A. Tissue-specific MR imaging in multiple sclerosis. AJNR Am J Neuroradiol. 2009;30:1277-8 17 - Sormani MP, Bonzano L, Roccatagliata L, et al. Magnetic resonance imaging as a potential surrogate for relapse in multiple sclerosis: a meta-analytic

approach. Ann Neurol 2009; 65: 270–277.18 - Zivadinov R. Can imaging techniques measure neuroprotection and remyelination in multiple sclerosis? Neurology 2007; 68 (Suppl 3):S72–S82

WG1“ON DEMAND” CASE STUDY SESSION

Carmen Tur, Carlos Nos and Georgina ArrambideMultiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain

Abstracts not in hand at the time of going to press.

ABSTRACTS

L6MS DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Mar TintoréMultiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain

Diagnostic criteria for MS (McDonald criteria and revised Polman criteria) rely on the demonstration of CNS disease in space and time andin reasonable exclusion of other causes. In patients with a first attack, evidence of diagnosis for dissemination in space and time may beprovided by MRI. The McDonald criteria selected the modified Barkhof criteria to demonstrate dissemination in space. In patients who haveabnormal CSF (detection of oligoclonal bands -OB- or raised IgG index), the presence of two or more lesions is sufficient to demonstratedissemination in space. New gadolinium-enhancing lesions appearing at least three months after the onset of the clinical event wouldcomply with MRI criteria for dissemination in time. Demonstration of dissemination in time in patients with CIS may also be fulfilled whena new MRI scan shows the presence of a new T2 lesion. These MRI criteria for defining dissemination in space and time are consideredover-rigorous by some neurologists and there is controversia about their clinical applications. New dissemination in space and timeproposals for MRI criteria, including those wished-for for pediatric population, will be discussed. Clinical cases to illustrate differentialdiagnoses will be presented.

L7JUVENILE MS

Angelo GhezziMultiple Sclerosis Centre, Gallarate Hospital, Gallarate, Italy

Juvenile Multiple Sclerosis (JMS) is increasingly recognized, raising the question whether it has peculiar aspects compared with the adultform (adult onset MS-AOMS).JMS is defined by the onset of the disease before 16 years of age in most studies, and occurs in about 3 to 5% of all MS cases, with a clearpreponderance of females during the adolescence (f/m ratio about 4) (1,2). The presentation of JMS can be monofocal or polyfocal,sometimes with symptoms consistent with acute demyelinating encephalomyelitis (ADEM) raising the problem of the differential diagnosisfrom this disease, particularly with respect to the recurrent (new event of ADEM with a recurrence of the initial symptoms 3 or more monthsafter the 1st event, without clinical/MRI involvement of new areas) or multiphasic variant (ADEM followed by new clinical events alsomeeting the criteria of ADEM but involving new areas) (3).The evolution of JMS is initially relapsing-remitting in most cases, the primary-progressive course representing less than 4% of cases (2).Relapses are rather frequent in early phases of the disease, with an annualized relapse rate of about 1-1.9 (1,2,4,5), slightly higher thanthat commonly reported in adults.Prognosis is in general less severe than AOMS, as the mean time to reach mild (EDSS4) or severe disability (EDSS6 or 7) as well as the shiftto the secondary progressive phase is longer compared to AOMS, however these landmarks are reached at an age approximately 10 yearsyounger (6-8). Factors related to a poor prognosis are the number/frequency of relapses in the first stages of the disease, the early shift toprogression, early disability. Recent studies have demonstrated that cognitive impairment can occur precociously, with a negative impacton school and social activities (9-10).MRI and CSF examination contribute to the increasing recognition and early diagnosis of JMS, although their sensitivity is lower withrespect to AOMS (1,2).Treatment is currently based on strategies optimised for AOMS. Immunomodulating agents, namely Interferon-Beta and Glatiramer Acetate,have not been evaluated in children with double-blind, placebo-controlled trials, but in open-label, observational studies showing they aresafe and well tolerated, meanwhile reducing relapse rate and disease progression (1,2,11). The overall positive results of IFNB and GA in J-MS has led the European Regulatory Agency to modify the label of drugs including thefollowing statement: “limited published data suggest that safety profile in adolescents from 12 to 16 years of age receiving IFNB or GA issimilar to that seen in adults (…)”, whereas there is not enough information on the use of IFNB or GA in children below 12 years of age.Second-line treatment with cyclophosphamide and now with natalizumab are used off-label and can be proposed in selected cases withan aggressive evolution.

References:01. Ghezzi A. Childhood-juvenile multiple sclerosis: clinical characteristics and treatment. Expert rev Neurotherapeutics 2005, 5:403-41102. Banwell B, Ghezzi A. A. Bar-Or et al. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol. 2007,

6:887-90203. Krupp LB, Banwell B., Tenembaum S. et al. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Nweurology 2007

(suppl2) S7-S1204. Ghezzi A. Pozzilli C., Liguori M. et al. Prospective study of multiple sclerosis with early onset. Multiple Sclerosis 2002, 8:115-11805. Gusev E., Boiko A., Bikova O. et al. The natural history of early onset multiple sclerosis: comparison of data from Moskow and Vancouver. Clin.

Neurology Neurosurg. 2002, 104:203-20706. Simone I.L., Carrara D., Tortorella C. et al. Course and prognosis in early onset MS. Comparison with adult-onset forms. Neurology 2002, 59:1922-192807. Boiko A. Vorobeychik G., Paty D., et al. Early onset multiple sclerosis. A longitudinal study. Neurology 2002, 59:1006-101008. Renoux C., Vukusic S., Mikaeloff Y et al. Natural History of multiple sclerosis with childhood onset. N Engl. J Med. 2007, 356:2603-1309. Amato MP, Goretti B, Ghezzi A Cognitive and psychosocial features of childhood and juvenile MS.Neurology. 2008;70(20):1891-7.10. Ghezzi A, Amato MP, Annovazzi P, et al. Long-term results of immunomodulatory treatment in children and adolescents with multiple sclerosis: the

Italian experience. Neurol Sci. 2009 30(3):193-911. Ghezzi A. Therapeutic strategies in childhood multiple sclerosis. Ther. Adv. Neurol. Disorders, 2010 in press

ABSTRACTS

L8OVERVIEW ON SYMPTOMATIC THERAPY AND REHABILITATION

Jaume Sastre-GarrigaMultiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain

Multiple Sclerosis (MS) may cause a variety of symptoms: fatigue, cognitive dysfunction, bladder and bowel problems, sexual problems,tremor, spasticity, speech and swallowing disorders, sensory symptoms including pain, among others. Motor and coordination symptomscausing gait problems and upper limb dysfunction also need to be considered. These symptoms, in isolation, or more commonly inassociation, are the ultimate cause of quality of life worsening and therefore must be treated with the same emphasis as the conditionitself. There is a need for an interdisciplinary management of symptoms in MS; this management is the focus of neurorehabilitation.Neurorehabilitation approaches emphasize education of patients and self-management of symptoms; this approach is ideally suited tomeet the evolving needs of people with MS. Thus, symptom management should be performed on a neurorehabilitation setting using aninterdisciplinary approach. According to this, clinical trials evaluating the efficacy and safety of a drug intervention to treat a givensymptom lack the added value of interdisciplinary interventions (e.g. drug A may be useful for spasticity, but its combined efficacy togetherwith physiotherapy and occupational therapy has not been investigated; in combination they are likely to have a greater impact on qualityof life, the final goal of any symptomatic therapy). Clinical trials evaluating the effectiveness of neurorehabilitation approaches in peoplewith MS have shown that improvement in activities and participation is to be expected. However, modalities of intervention are ill-defined(rehabilitation black box) and clinical trial methodology is suboptimal. Therefore, further research is needed to improve clinical trialmethodology and our ways of evaluating the impact of neurorehabilitation by means of goal achievement frameworks and through theuse of clinically appropriate and scientifically sound outcome measure tools. In this lecture, we will focus on two specific MS symptoms:fatigue and bladder dysfunction. Several drugs have been proposed for the treatment of MS-related fatigue; amantadine, L-carnitine,modafinil, methylphenidate, 4-aminopyridine have all been shown to hold promise in the treatment of fatigue in small studies; however,their safety and efficacy remains unclear; recent results on fampridine will also be discussed. Energy-saving strategies performed byoccupational therapists alone or in a truly interdisciplinary approach, together with physiotherapists and psychologists, have also beenshown to be useful, although definite proof of efficacy is awaited. Treatment strategies for bladder dysfunction will also be discussed,focusing on the recently published UK consensus for management of the bladder in multiple sclerosis.

S1SYMPTOMATIC THERAPY SNAPSHOT #1 ON GAIT REHABILITATION

Carme SantoyoMultiple Sclerosis Center of Catalonia, Unit of Neurorehabilitation, Vall d’Hebron University Hospital, Barcelona, Spain

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Abstract not in hand at the time of going to press.

ABSTRACTS

S2SYMPTOMATIC THERAPY SNAPSHOT #2 ON MANAGEMENT OF DYSPHAGIA

Marta Renom GuiterasMultiple Sclerosis Center of Catalonia, Unit of Neurorehabilitation, Vall d’Hebron University Hospital, Barcelona, Spain

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

The intervention is interdisciplinary and can involve neurologists, speech and language pathologists, physiotherapists, nurses, radiologistsand 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 include observation ofthe oral anatomy and examination of the cranial nerves involved in swallowing and of the muscular tone, oral reflexes and movementexecution pattern. A functional assessment of chewing, swallowing, phonation and articulation should also be performed. A bedsidescreening examination has been described, which includes the 50-ml water test, pharyngeal sensation examination and pulse oximetry.

Referral to instrumental examination should be done in any case in moderate to severe dysphagia. Videofluoroscopy and fiberopticlaryngoscopy 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 of swallowingand to improve quality of life and social participation. It can include rehabilitation, pharmacological treatment and eventuallyimplementation of enteral feeding. Rehabilitation includes restorative, compensatory and adaptive approaches and also education onsecurity manoeuvres. The restorative approach includes different interventions directed to improve the sensoriomotor control of theswallowing mechanisms. The compensatory approach consists of general advice, strategies and manoeuvres to be taken into account whileeating and drinking. The adaptive approach includes measures involving adaptation of environmental factors, including food consistency.

Family and caregivers should be involved in rehabilitation. Pharmacological treatment may help alleviate associated problems such asHyper-salivation, hiccups or reflux.

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- Poorjavad M, Derakhshandeh F, Etemadifar M, et al. (2010): Oropharyngeal dysphagia in multiple sclerosis. Mult Scler. 16(3):362-5- Bogaardt H, van Dam D, Wever NM, et al. (2009): Use of neuromuscular electrostimulation in the treatment of dysphagia in patients with multiplesclerosis. Ann Otol Rhinol Laryngol. Apr;118(4):241-6.

PD1PANEL DISCUSSION ON COGNITION IN MS

Iris Katharina Penner 1, María Jesús Arevalo 2 and Francisco Pérez Mirallez 3;1. Department of Cognitive Psychology, University of Basel, Basel, Switzerland2. Multiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain3. Multiple Sclerosis Center of Catalonia, Unit of Neurorehabilitation, Vall d’Hebron University Hospital, Barcelona, Spain

TREATMENTMaría Jesús Arevalo

Multiple sclerosis (MS) is a chronic inflammatory disease of central nervous system. The main physiopatological feature of MS isdemyelination. MS is one of three most common causes of severe disability in youngest people. In patients with MS (PwMS), apart fromcomplete psychophysical status and objective neurologic status, a subjective perception of symptoms and signs, known as quality of life,must be considered, too.PwMS have a substantial risk of cognitive dysfunction, even in the earliest stages of the disease, where there is minimum physical disability.Despite the high prevalence rates and the significant impact of cognitive dysfunction on quality of life in this population, cognitivefunctions are not routinely assessed due to the high cost and time consumption. Studies of the cognitive profile of PwMS suggest that some cognitive abilities are more likely to decline than others (e.g. disturbances inmemory, attention, concentration, speed of information processing and executive functions). Although some reduction in self-awarenessof cognitive decline occurs, metacognitive skills and awareness of more concrete impairments appear preserved. Cognitive impairmentscan be extremely disruptive and interfere with PwMS ability to work, engage in social activities, maintain a household and drive. Since theonset and progression of MS typically occurs when PwMS are attempting to establish and maintain cognitively demanding life roles (e.g.parent and worker), their cognitive symptoms can further accentuate the need to successfully maintain functioning.The available immune-modulating agents may reduce the development of new lesions and therefore prevent or minimize the progressionof cognitive decline. There is currently insufficient evidence concerning the efficiency of symptomatic treatment in MS. Donepezil andrivastigmine (AChEls) have demonstrated some specific benefits in PwMS cognitively impaired, but the studies were small. There is alsocurrently no optimal non-pharmacological treatment strategy for cognitive decline in MS, as the studies published to date reportheterogeneous results. Nevertheless, non-pharmacological treatments, such as cognitive rehabilitation, may benefit some MS patients. In the present talk, we will briefly review recent research on non-pharmacological and pharmacological approaches to improve cognitivefunction in our patients.

ABSTRACTS

KNS 2OVERVIEW OF DRUGS CURRENTLY REGISTERED FOR MS

Eva HavrdovàMultiple Sclerosis Centre and Neurology Clinic, Charles University, Prague, Czech Republic

Disease modifying drugs (DMDs) in MS: First line drugs: Three recombinant interferon beta (IFNb) preparations and glatiramer acetate (GA)are currently approved for relapsing-remitting multiple sclerosis (RR MS). Their efficacy is very similar and was proven even in head-to-head trials conducted recently. IFNb-1a i.m. and IFNb-1b s.c. are approved for patients with clinically isolated syndrome (CIS) and high riskfor clinically definite MS, IFNb-1a s.c with extended indication for CIS by McDonald´s criteria, GA was recently also approved for CIS. Insome countries there is extended approval for RR MS under age of 18. There is no proven effect of these drugs for chronic progression ofMS without the presence of relapses. There is not enough publications supporting the idea of combination therapies to start with; andthere is not enough publications on sequential therapy. Long-term follow-ups of clinical trials though systematic have many limitations: nocontrol groups any more, no blinding, and selection bias due to drop-outs. They may be useful in trying to define some prognostic markers.Post marketing follow-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. Extensive patient registries are being established all over the world to provide independent long-termpatient observation though again this is may have limitations like retrospective data collection and suboptimal data quality. Long-term sideeffect profile and tolerability of above mentioned drugs is very good, the adherence to injectable treatments decreases over time, andseems to be a challenge for both the patient and treating physician.

There may be suboptimal treatment response to each of these drugs defined by the presence of relapses, disability progression and/or MRIactivity (Gd+ lesions or new or enlarging T2 lesions). These patients should be offered the possibility of therapy with natalizumab,monoclonal antibody against adhesion molecules on lymphocytes. The efficacy is double compared to IFNb and GA. It is approved for RRMS if first-line drugs fail to stabilize the disease, or if there is rapidly evolving severe RR MS defined by 2 or more disabling relapses inone year, and with one or more Gd-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared to a previous one.Safety concerns concentrate predominantly on progressive multifocal leukoencefalopathy, DNA JC virus opportunistic infection of the brainwhich occurred in 49 cases out of 70 000 treated patients. Patient and physician information is the basis for sustained pharmaco-surveillance effort.

Mitoxantrone received its marketing approval in 2002 for patiens with secondary progressive (SP) MS or progressing relapsing MS in caseof failure of previous DMDs. It is a cytostatic drug used in haemato-oncology. The activity of the disease may be temporarily shut downfor several months including MRI but the patient must be closely followed for possible side effects which include cardiotoxicity(recommended life-time cumulative dose si 100mg/m2, echocardiography has to be checked regularly not only before and during treatmentbut also for several years after treatment) and malignancy (acute myeloid leukaemia being the most common). Overall risk forcardiomyopathy/leukaemia is 1:250-800. Therefore, the use of mitoxantrone is declining in MS.

L9ROLE OF MS NURSES IN MS PATIENTS’ MANAGEMENT

Rosalía Horno and Gemma RodríguezMultiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain

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Abstract not in hand at the time of going to press.

ABSTRACTS

WG2CASE STUDY SESSION ON DMDs

Ester Moral 1, Lluís Ramió i Torrentá 2 and Lucia Romero 3;1. Department of Neurology, Hospital Dos de Maig & Multiple Sclerosis Unit, University Hospital Bellvitge, Barcelona, Spain; 2. Department of Neurology, Multiple Sclerosis Unit, “Dr. Josep Trueta” Hospital in Girona, Girona, Spain;3. Unit of Multiple Sclerosis, University Hospital of Bellvitge, Barcelona, Spain.

GROUP 1Clinical case: DMDs safetyEster MoralIn 2007 19-year old Caucasian woman without previous clinical history was admitted to the neurological department because of anepisode of paraparesis and numbness in both legs lasting for 10 days. The MRI showed more than 9 T2 hyperintense lesions with somegadolinium enhancement. EDSS was 3.5. Treatment with natalizumab was started after being diagnosed of severe MS. She received thefirst dose of the drug without problems but during the second IV infusion a cutaneous allergic reaction appeared and the treatment wasstopped.

A 15-year

L10GENETICS OF MS

Manuel ComabellaMultiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain

During the last two decades, many research groups have dedicated important efforts to identifying the individual genes that confersusceptibility to multiple sclerosis (MS). The main conclusion derived from this work is that the HLA-class II region on chromosome 6p21,specifically the HLA-DRB1*15 haplotype, contributes, by far the most, to genetic susceptibility in MS, and results from many MS geneticstudies support this association. Unfortunately, despite the evidence that MS is a complex genetic trait with multiple genes contributingto disease susceptibility, genetic studies aiming to identify additional risk genes for MS have been rather disappointing, as many of thecandidate genes identified in one study were not confirmed in others. It has not been until recently that additional genes located outsidethe HLA region have been proposed, although with weaker effects, as solid candidates for MS genetic risk. In particular, three single-nucleotide polymorphisms (SNPs), two located within the interleukin-2 receptor α (IL2RA) and one located within the interleukin-7receptor α (IL7RA), were strongly associated with MS. Other SNPs positioned in attractive genes were also found to be associated withthe disease. These latest findings have certainly opened new scenarios in MS genetic research.

ABSTRACTS

PD2PANEL DISCUSSION ON “DEFINE TREATMENT SUCCESS”

Jordi Río and Manuel Comabella;Multiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain;

DEFINE TREATMENT SUCCESS IN PRESENT DAILY PRACTICE WITH CLINICAL AND MRI SURROGATES Jordi RíoThe objective of the definition of treatment response is to select earlier responders on one hand, and of poor- or non-responders on theother hand. Patient response outcomes should be measured taking into consideration the interfering factors related to the disease itself.MRI offers an advantage in the response evaluation as it produces objective data, however the frequency of evaluation is limited and lowfrequency 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 been validatedand there is no consensus among different investigators. Long-term disability data are crucial, in order to select the most clinicallymeaningful definition. These criteria are based on relapses, disability progression or both. Several factors make difficult the employment ofrelapse outcomes to determine therapeutic response (low predictive value, regression to the mean, etc.). The progression of neurologicalimpairment is another criterium employed to quantify response, however efficacy fluctuations related to depression, fatigue, spasticity,concurrent illness and prolonged relapse need be excluded. Nevertheless, criteria of response to IFNb therapy using disability progressionare 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 for identifyingpatients with a confirmed increase of disability in the next years of therapy. Moreover, the combination of measures of clinical and MRIdisease activity may have a prognostic value for identifiyng patients with a poor outcome during the next years of therapy. Several factors are related to response from MS heterogeneity to genetic load and IFN response genes to poor healing mechanisms. Otherfactors related to suboptimal response are: excess disease activity, poor adherence to therapy, misdiagnosis, “pseudo” failure” or loss ofdrug efficacy.In conclusion, in relation with response to therapy in multiple sclerosis patients, the proportion of non-responders varies depending on thedefinition used, criteria based on relapse measures have poor sensitivity and positive diagnostic value, non-responders have a higherclinical activity at baseline, baseline EDSS predicts long-term disability, there are limited prospective MRI data as predictors of therapeuticresponse and the combination of clinical and MRI measures of disease activity may have a prognostic value for identifiyng patients witha poor response.

DEFINE TREATMENT SUCCESS IN THE AGE OF PHARMACOGENOMICSManuel ComabellaThe mechanisms underlying heterogeneity in the response to treatment in multiple sclerosis (MS) are not completely understood, althoughgenetic factors are most likely to be playing important roles. Moreover, given the complex nature of the disease, this heterogeneity isprobably explained by the contribution of multiple genes. Disease modifying therapies (DMT) are the mainstay of treatment in relapsing-remitting MS and have demonstrated a beneficial effect on disease activity. However, DMT are partially effective, and their long-termimpact on disease progression remains elusive. In addition, not all patients respond to current DMT.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, single nucleotidepolymorphisms (SNP) screens, and proteomics in order to predict response to treatment and toxicity to drugs. Although pharmacogenomicsholds great promise for individualized therapy in MS, big efforts should first be made to identify markers for treatment efficacy.This talk will focus on the current status and future directions of pharmacogenomic studies in MS, mainly in relation with interferon-betatreatment.

ABSTRACTS

L11FOSTERING TREATMENT ADHERENCE AND COMPLIANCE: A ROLE PLAY

María Jesús Arévalo and Jaume Sastre-GarrigaMultiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain

Evidence coming from the pivotal clinical trials and from some other well-performed clinical trials has clearly demonstrated the benefit ofimmunomodulatory therapies in MS. It is also clear that present therapies are not without side effects and mode of administration is stillcumbersome for a number of patients; these factors impact on adherence to treatment, which may render the therapeutic efforts futile.Several studies have shown that most drop-outs occur in the early phases of therapy so especial care needs to be taken when patientsstart their immunomodulating therapy in order to avoid treatment discontinuation. Available evidence suggests that individualized care isan important factor to keep drop-out rates low; in this regard, management of side effects of therapies is crucial, as it is responsible foralmost a half of all discontinuations. Another important factor related to treatment discontinuation seems to be lack of efficacy; therefore,close follow-up of non-adherent patients is highly recommended to increase therapy efficacy and to achieve an early identification ofpatients with poorer prognosis.

Side effects 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 asgradual dose increase and anti-inflammatory therapy administration schemes. Other side effects such as injection site reactions, flushingand laboratory abnormalities also need to be closely monitored. Nurse-led patient education at onset of therapy may be helpful to managepatients’ expectations from therapy and to anticipate and diminish the impact of side effects on adherence to treatment.

Finally, even though results from clinical trials are the keystone to our clinical practice, measuring efficacy of therapy in clinical practice inan appropriate manner is crucial to obtain the most from available therapies. Clinical daily practice individualized monitoring of treatmentresponse, treatment adherence, and side effects profile is therefore highly recommended if clinical trials efficacy results are to be met inour clinics.

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

ABSTRACTS

KNS3ORAL THERAPIES IN MS

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

Actually approved disease modifying drugs (DMDs) for relapsing-remitting multiple sclerosis include recombinant interferon (IFN-beta) andglatiramer acetate (GA). All these immunomodulatory treatments have been shown to reduce the frequency and severity of relapses, aswell as reducing progression of neurological disability. However all DMDs are administered parenterally and need frequent injections whichmay be inconvenient and uncomfortable for patients. In addition, not all patients respond adequately and common side effects associatedwith these therapies may reduce adherence. The development of drugs with easier administration, such as oral agents, would furtherpromote adherence, increase patient satisfaction and thereby improve efficacy. Two phase III clinical trials CLARITY and TRANSFORM haveprovided 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 significant increasein the proportion of patients who remained relapse-free. Overall, the frequencies of adverse events in both cladribine treatment groupswere 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 fatalviral infections occurred. Moreover, the FREEDOMS study demonstrated a significant reduction of disease activity of both doses offingolimod against interferon beta 1a i.m.. The safety profile of the drug open some concern for the risk herpes infections andcardiovascular problems.

Other oral drugs in earlier phase of the development include BG12, teriflunomide and laquinimod For all these three drugs, a preliminaryefficacy emerged from Phase II studies and phase III studies are ongoing.

ABSTRACTS

KNS4FUTURE THERAPEUTIC TARGETS AS GLANCED FROM MSIMMUNOPATHOGENESIS: ANTIBODIES IN MS

Xavier MontalbanMultiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall d’Hebron University Hospital, Barcelona, Spain

XXXX of non-disjunction during meiosis is a rare event in most organisms, with the exception of the human species where approximately30% of oocytes carry a chromosomal imbalance. This condition has severe clinical consequences, as approximately one-third ofspontaneous abortions are aneuploid.

The most obvious oocytes recovered are well-known risk factors. The following measures can be considered in these cases.

1. Adapting the ovarian stimulation protocol according to the patient’s individual profile and the experience from her previousstimulation cycles.

2. Reducing FSH and compensating with LH in the stimulation protocol to selectively stimulate the greatest follicles and prevent thegrowth of smaller ones.

Learning ObjectivesBy the end of the programme participants should appreciate: • International Variation in Assisted Reproduction Practice• Need to collect data to reflect practice• Value of e-Learning to facilitate best practice

IntroductionXxxx xxx

MethodsXxxx xxx

ResultsXxxx xxx

ConclusionsXxxx xxx

References:1. Teigen K, McKinney JA, Haavik J, Martinez A. Selectivity and affinity determinants for ligand binding to the aromatic amino Acid hydroxylases. Curr Med

Chem 2007; 14: 455-467.2. Thony

Abstract not in hand at the time of going to press.

ABSTRACTS

S3SNAPSHOT #1 ON GENE THERAPY IN MS

Herena EixarchMultiple Sclerosis Center of Catalonia (CEM-Cat), Unit of Clinical Neuroimmunology, Research Institute - Vall d'Hebron University Hospital, Barcelona, Spain

Gene therapy is a group of techniques that involve 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 their innatecapability of viruses to introduce their genetic material into host cells. Gene therapy is a relatively new field in biomedicine since the firstclinical trial was approved in 1989. From then on, the amount of trials increased exponentially, indeed, from the late 90’s until nowapproximately 100 clinical trials are approved each year worldwide.

Although gene therapy is generally understood as a replacement approach,directed to treat genetic diseases, several approaches based ongene therapy have been made in the animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE). Theseexperimental approaches include the delivery of immunomodulatory molecules in the CNS, enhancement of neuroprotection or inductionof antigen-specific immune tolerance. Moreover, our work is being focused in antigen-specific approaches. In the last years, we have beendeveloping a strategy to induce immune tolerance using retroviral gene transfer into the hematopoietic system. To this end, we used aretroviral vector that expressed a chimeric protein in order to target the autoantigen MOG40-55 into the MHC class II compartment toprevent or reduce susceptibility to the disease, thus restoring the tolerance to the autoantigen. We have shown that this strategyconstitutes a powerful tool to induce antigen-specific immune tolerance both preventively and therapeutically.

In summary, in the present talk we will review general aspects of gene therapy, how this technology can be applied in the treatment ofMS and the advantages and disadvantages of using viral vectors as gene-delivery systems.

ABSTRACTS

S4SNAPSHOT #2 ON DNA VACCINES IN MS

Nicolàs FissoloMultiple Sclerosis Center of Catalonia (CEM-Cat), Unit of Clinical Neuroimmunology, Research Institute - Vall d'Hebron University Hospital, Barcelona, Spain

Since the discovery, over a decade and a half ago, that genetically engineered DNA can be delivered in vaccine form and elicit an immuneresponse, 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 years differentstudies have shown the potential use of DNA vaccines to modulate autoimmune diseases, like multiple sclerosis (MS), inducing tolerancerather than stimulation of an immune response.Compared to traditional immunization procedures, DNA vaccination offers several advantages: for instance, expression of native antigensin situ, prolonged in vivo antigen production, increased availability of antigenic peptides because of the endogenous and long-termsynthesis of the gene product and the modification of the vaccination protocol that could induce either Th1 or Th2 immune responses The design of DNA vaccines includes not only the development of vectors coding for relevant auto-antigens but also antigen expressionand immunogenicity optimization via use of adjuvants, through formulation and by using next-generation delivery strategies

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

So far, two clinical trials of DNA vaccines have been reported in MS. From these studies, it can be concluded that the vaccine was welltolerated and did not induce significant anti-inflammatory antigen-specific immune changes.

ABSTRACTS

S5SNAPSHOT #3 ON STEM CELL THERAPY IN MS

Carme CostaMultiple Sclerosis Center of Catalonia, Unit of Clinical Neuroimmunology, Vall D'Hebron University Hospital, Barcelona, Spain

Stem cells are found in all multicellular organisms. They are characterized by the ability to renew themselves trough mitotic cell divisionand differentiated 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 cell of theorganism, they are pluripotent. The adults also have stem cells, which can only give rise cells closely related to their organ or tissue oforigin, they are multipotent. Recently, researchers have created induced stem cells, they are a type of pluripotent stem cells artificiallyderived 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 damage tissue, the therapies with stem cells were originally conceivedas replacement therapies. But it has been shown that stem cells affect the recovery by an additional mechanism, they also have the abilityto regulate the immune system.

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

Treatments with haematopoietic or mesenchymal stem cells have been used to treat multiple sclerosis patients. The results have beenapparently positives, but there still are controversial and further studies are necessary.

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