Practice teaching course in MS knowledge...Practice teaching course in MS knowledge Overview New insights into demyelinating diseases pathogenesis, the development of innovative diagnostic

Practice teaching course in MS knowledge13 -14 June 2016 - Barcelona, Spain

PRACTICE TEACHING COURSEFINAL PROGRAMME AND ABSTRACT BOOK

Practice teaching course in MS knowledge

OverviewNew insights into demyelinating diseases pathogenesis, the development of innovative diagnostic tools and the amount of newtreatments available in clinical practice demand that neurologists specialising in multiple sclerosis keep abreast of new developmentsand share best practice. This course will provide a comprehensive update on the most important topics in MS in the setting of a centreof excellence.

Learning objectivesBy attending this practice teaching course, participants will be able to:• Describe the role of the environmental factors in MS onset and the main pathophysiological mechanisms subtending MSpathophysiology

• Illustrate and apply past and present diagnostic criteria for MS• Use clinical and radiological markers of disease severity to define treatment response• Compare the mechanisms of action and safety profile of all MS treatments

Target audienceClinicians recently involved in MS patient management and neurologists interested in entering the MS field.

ChairsXavier Montalban and Jaume Sastre-GarrigaMultiple Sclerosis Centre of Catalonia (Cemcat)Neurology-Neuroimmunology DepartmentVall d’Hebron University Hospital, Barcelona, Spain

EXCEMED designed this programme in partnership with Cemcat (Multiple Sclerosis Centre of Catalonia)

Local scientific and organising coordinationMarga CapellTeaching & Training department Multiple Sclerosis Centre of CataloniaE-mail: [email protected]

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CME ProviderEXCEMED is a non profit foundation dedicated, since the last four decades, to the development of high-quality medical educationprogramme all over the world.

EXCEMED adheres to the guidelines and standards of the European Accreditation Council for Continuing Medical Education (EACCME®)which states that continuing medical education must be balanced, independent, objective, and scientifically rigorous.

Continuing medical educationEXCEMED (www.excemed.org) is accredited by the European Accreditation Council for Continuing Medical Education (EACCME®) toprovide the following CME activity for medical specialists. The EACCME® is an institution of the European Union of MedicalSpecialists (UEMS), www.uems.net

The CME “Practice teaching course in MS knowledge” held on 13-14 June 2016 in Barcelona, Spain, is designated for a maximumof 10 (ten) hours of European CME credits (ECMEC). Each medical specialist should claim only those credits that he/she actuallyspent in the educational activity. EACCME® credits are recognized by the American Medical Association (AMA) towards thePhysician's Recognition Award (PRA). To convert EACCME® credit to AMA PRA category 1 credit, please contact the AMA.

EXCEMED adheres to the principles of the Good CME Practice group (gCMEp).

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General information

LanguageThe official language of this practice teaching course is English.

CME ProviderEXCEMED - Excellence in Medical Education

Programme and Relations Manager: Serena Dell’AricciaT +39 06 420413 251 - F +39 06 420413 [email protected]

Medical Advisor: Doriana [email protected]

For any logistic support please contact:

Meridiano Congress InternationalCongress Coordinator: David H. SlangenT +39 06 88 595 250 - F +39 06 88595 [email protected]

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FormatThis live educational event is accompanied by technological tools allowing participants to express their own views and opinions through

real-time surveys.

Dedicated website Access http://www.excemedpracticecourse2016.org to:√ View the scientific programme √ Fill in the post-event surveys√ Get your certificate of attendance √ Get your EACCME certificate

Practice teaching course in MS knowledge E-mail Password Log in Registration Recover password

Faculty

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Maria Pia AmatoDepartment NEUROFARBAUniversity 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

Wolfgang BrückDepartment of NeuropathologyUniversity Medical Center GöttingenGeorg-August University Göttingen, Germany

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

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

Nicolás FissoloMultiple Sclerosis Centre of Catalonia (Cemcat)Unit of Clinical NeuroimmunologyInstitut de RecercaVall d’Hebron University HospitalBarcelona, Spain

Angelo GhezziMultiple Sclerosis CentreGallarate HospitalGallarate, Italy

Eva HavrdovàMS Centre and Neurology ClinicCharles University Prague, Czech Republic

Bernhard HemmerNeurology ClinicUniversity of MunchenMunchen, Germany

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

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

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

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

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

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

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

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Programme

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14.30 Specific forms of demyelinating diseases

L4: Neuromyelitis optica - NMO Georgina Arrambide (Spain)

L5: Pediatric and juvenile MSAngelo Ghezzi (Italy)

L6: Primary progressive MS Alan J. Thompson (UK)

15.45 Coffee break

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

DiagnosisMaria Pia Amato (Italy)

TreatmentMaría Jesús Arévalo (Spain)

Case presentationÁngela Vidal (Spain)

17.15 Conclusions

Revisiting real-time survey

17.30 End of the first day

Chairpersons: Xavier Montalban and Jaume Sastre-Garriga

Monday, 13 June 2016

08.45 EXCEMED opening

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 MSBernhard Hemmer (Germany)

10.30 L2: Genetics of MSManuel Comabella (Spain)

11.00 Coffee break

11.30 L3: Pathology of MSWolfgang Brück (Germany)

12.00 PD1: Panel discussion on “New revision of McDonald’s criteria”Chair: Lluís Ramió I Torrentà (Spain)

MRI in MS: the radiologist perspectiveAlex Rovira (Spain)

MS diagnosis and differential diagnosisMar Tintoré (Spain)

EPs and OCT in MSLetizia Leocani (Italy)

Discussion

13.00 Working Lunch

Legend: L : Lecture Real-time survey KNS : Key Note Speech PD : Panel Discussion Role-play SS : Snapshot

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Tuesday, 14 June 2016

Real-time survey

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

09.00 KNS3: Oral therapies in MSXavier Montalban (Spain)

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

10.00 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

11.00 Coffee break

11.30 Fostering treatment adherence andcompliance: a role-playJaume Sastre-Garriga (Spain)

12.30 SS1: Snapshot #1 on gene therapy in MSHerena Eixarch (Spain)

12.45 SS2: Snapshot #2 on DNA vaccines in MSNicolás Fissolo (Spain)

13.00 Working lunch

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

14.30 SS3: Symptomatic therapy snapshot #3 ongait rehabilitationCarme Santoyo (Spain)

14.45 SS4: Symptomatic therapy snapshot #4 onmanagement of dysphagiaMarta Renom Guiteras (Spain)

15.00 L8: Individualizing therapy in MS. A realistic prospect?Giancarlo Comi (Italy)

Revisiting real-time survey

15.45 Cemcat and Vall d’Hebron Hospital premisevisits

17.00 Certificate delivery and group picture

17.15 Course wrap - up

17.30 End of the course

Disclosure of faculty relationships

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EXCEMED adheres to guidelines of the European Accreditation Council for Continuing Medical Education (EACCME®) and all otherprofessional organizations, as applicable, which state that programmes awarding continuing education credits must be balanced,independent, objective and scientifically rigorous. Investigative and other uses for pharmaceutical agents, medical devices and otherproducts (other than those uses indicated in approved product labeling/package insert for the product) may be presented in theprogramme (which may reflect clinical experience, the professional literature or other clinical sources known to the presenter). We askall presenters to provide participants with information about relationships with pharmaceutical or medical equipment companies thatmay have relevance to their lectures. This policy is not intended to exclude faculty who have relationships with such companies; it isonly intended to inform participants of any potential conflicts so that participants may form their own judgements, based on fulldisclosure of the facts. Further, all opinions and recommendations presented during the programme and all programme-relatedmaterials neither imply an endorsement nor a recommendation on the part of EXCEMED. All presentations represent solely theindependent 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 serves on scientific advisory boards for Biogen Idec, Merck Serono and receives speakerhonoraria and research support from Biogen Idec, Merck Serono, Novartis, Almirall, Teva and Genzyme.

María Jesús Arévalo Declared the receipt of honoraria or consultation fees from Novartis and Biogen.

Georgina Arrambide Declared the receipt of honoraria and consultation fees from Biogen Idec and the receipt of a researchsupport from Novartis.

Wolfgang Brück Declared the receipt of grants and contracts from Teva Pharma, Genzyme, Novartis. Declared the receiptof honoraria or consultation fees from Teva Pharma, Genzyme, Novartis, Bayer, Merck-Serono. Hedeclared to be member of a company advisory board, board of directors or other similar group: TevaPharma, Novartis, Biogen.

Manuel Comabella Declared the receipt of honoraria and consultation fees from Teva, Merck Serono, Biogen, Sanofi,Novartis, Genzyme.

Giancarlo Comi Declared the receipt of honoraria or consultation fees from EXCEMED, Novartis, Teva, Sanofi, Genzyme,Merck, Biogen, Roche, Almirall, Chugai, Forward Pharma.

Herena Eixarch Declared no potential conflict of interests.

Nicolás Fissolo Declared no potential conflict of interests.

Angelo Ghezzi Declared the receipt of honoraria and consultation fees from Biogen, Almirall, Merck Serono, Genzymeand Novartis.

Eva Havrdovà Declared the receipt of grants and contracts from the Czech Ministry of Education, the receipt ofhonoraria and consultation fees from Biogen, Sanofi Genzyme, Merck Serono, Novartis, Actelion.

Bernhard Hemmer Declared the receipt of grants and contracts from Biogen, Chugai, Five Prime, Hoffmann La Roche.Declared the receipt of honoraria or consultation fees from GLG, WebMD, Allergy, Chugai, Biogen, GSK,Merck Serono. He declared to be member of a company advisory board, board of directors or othersimilar group: Novartis, Bayer, Hoffmann La Roche, Genentech.

Letizia Leocani Declared the receipt Research support from Merck Serono and Novartis, she declared the receipt oftravel support from Almirall and Biogen. She also declared to be member of a Biogen advisory board.

Xavier Montalban Declared the receipt of honoraria and consultation fees from: Almirall, Bayer, Biogen, Genzyme, Merck,Novartis, Receptos, Roche, Sanof-Genzyme, Teva.

Susana Otero Declared no potential conflict of interests.

Marta Renom Guiteras Declared no potential conflict of interests.

Jordi Río Declared receipt of honoraria or consultation fees from Biogen, Merck-Serono, Teva, Novartis.

Alex Rovira Declared no potential conflict of interests.

Carme Santoyo Declared no potential conflict of interests.

Jaume Sastre-Garriga Declared the receipt of grants and contracts from Genzyme. He declared to be member of Biogen andNovartis advisory boards, Board of directors or similar groups. He declared the participation in acompany sponsored speakers’ bureau: Almirall, Genzyme, Novartis, Merck, Biogen.

Alan J. Thompson Declared the receipt of honoraria or consultation fees from Biogen, Eisai, MedDay, Novartis (paid to institution).

Ángela Vidal Declared the receipt of honoraria or consultation fees from Novartis, Sanofi and Roche.

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 6 June 2016.

Lluís Ramió i Torrentà

Mar Tintoré

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Availableabstracts

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L1. Epidemiology of MS

Epidemiology is 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 and mortality data, andanalytic epidemiology studies possible risk factors related to the disease.

The first descriptive epidemiological studies on multiple sclerosis (MS) based on available prevalence data concluded that thedisease was not evenly distributed, showing a latitudinal gradient. Despite the methodological limitations, the observedepidemiological pattern strongly suggested a role of the environment acting on genetically predisposed individuals. Recentepidemiological data shows a global increase in MS incidence and prevalence over time and still supports the existence of alatitudinal gradient for prevalence. Prospective incidence studies performed in Europe, America and Asia over the past 20 years showthe classical gradient is disappearing in certain areas, with higher incidence rates in lower latitudinal regions. The increase inprevalence could be explained by longer patient survival and the increase in incidence by improved case ascertainment, due to betterdiagnostic techniques and /or change in environmental factors that increase risk of MS.

Several environmental factors are now being studied for their possible role as risk and prognostic factors. The mirror-image gradientof MS points to a sun related factor such as Vitamin D. On the other hand, an infectious agent acting directly (as a trigger of thedisease) or indirectly (protecting if acquired early in life -hygiene hypothesis-) has also been postulated. Epstein-Bar virus (EBV),seems one of the strongest candidates. Finally, smoking has also been recently linked to MS risk and prognosis.

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

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KNS1. Immunopathogenesis of MS

The immune system plays a central role in the pathogenesis of MS. The presence of lymphocytes and macrophages in MS lesionsand the association of MS with HLA alleles and many genetic variants tagging particular immune genes define the adaptive immunesystem, which consists of T- and B-cells, as a key player in the pathogenesis of disease. Inflammation in MS only affects the CNS.Lymphocytes in the CNS of MS patients show evidence of clonotypic accumulation indicating that single T- and B-cells, whichunderwent extensive clonal expansion in the peripheral immune compartment, selectively enrich in the CNS. This suggests that theCNS in MS is particular prone to inflammation and T- and B-cell are selectively attracted by specific target antigens that are onlyexpressed in the CNS or undergo unique modifications in the CNS. While a CNS infection would be compatible with such a condition,the unsuccessful search for an infectious agent in MS lesions, despite outstanding technological advances in virology andmicrobiology, supports the concept that the immune response in MS targets CNS autoantigens. Unfortunately the search for thetargets of the immune response in MS has remained yet ineffective, although several candidate antigens have been proposed butnone yet confirmed.

Why immune responses are initiated against CNS antigens and maintained in MS is unclear. Generation of specific T-cell and B-cellresponses, which involves the expansion of large numbers of antigen specific lymphocytes from few precursor cells in the lymphnode, requires professional antigen presenting cells (APCs) such as dendritic cells. It is well established that autoreactivelymphocytes, which harbour the potential to induce CNS autoimmunity, are part of the normal lymphocyte repertoire. Two scenarioscould be envisioned how pathogenic immune responses to CNS autoantigens might be initiated. The CNS intrinsic modelhypothesises that the initial event takes place in the CNS, which leads to the release of CNS antigens to the periphery (either bydrainage to the lymph nodes or active carriage by APCs). In the context of a proinflammatory environment, an autoimmune responseis generated, which eventually targets the CNS. This scenario is supported by the observation that oligodendrocyte damage mayprecede immune infiltration in some early MS lesions and oligodendrocyte death may result in immune mediated CNSdemyelination in certain experimental animal models. By contrast, the CNS extrinsic model hypothesizes that the initial event takesplace outside of the CNS (e.g. in the context of a systemic infection) and leads to an aberrant immune response against the CNS.Several mechanisms such as molecular mimicry (crossreactivity between microbial antigens and autoantigens), bystanderactivation (priming of autoreactive T cells in the context of other lymphocyte responses) and break of tolerance (priming autoimmuneresponses by a strong inflammatory stimulus) may account for the initiation of autoimmune responses. The scenario is wellrepresented in the experimental autoimmune encephalomyelitis model, in which an autoimmune response against the CNS is eitherinduced by immunisation with myelin antigens and adjuvants or occurs spontaneously in genetically engineered mice, in whichrodent or human myelin antigen specific T- and B-cell receptors are expressed on the majority of circulating lymphocytes. Bothscenarios will flow into a detrimental circle of events: tissue damage leads to release of antigens to the periphery, which primes newimmune responses in the lymphoid tissue followed by the invasion of lymphocytes into the CNS leading to recruitment ofmacrophages, which execute tissue damage. The sequence is quite compatible with the relapsing-remitting nature of diseases.Since the process is not self-limiting it is likely that immune regulatory mechanisms fail in MS.

During the progressive phase of disease the contribution of the peripheral immune system decreases and immune responses seemto be confined to the CNS compartment. This view is supported by the observation that systemic immune therapies have no or onlyminor effects in progressive MS. CNS pathology changes from focal to diffuse white matter injury associated with microglia activationand diffuse lympho- and monocytic infiltrates and increasing cortical involvement, which seems to be associated with lymphoid likefollicles in the meninges This implies that the immune response is sequestered to the CNS compartment with little contributionfrom the periphery. It is however unclear, whether diffuse tissue injury observed in progressive MS is caused by thecompartmentalized immune response or a consequence of diffuse tissue injury caused by other mechanisms. Likewise more axonalinjury is observed in demyelinated lesion areas and remyelination seems to protect from axonal damage Moreover damage ordysfunction of other glia cells may result in secondary neurodegeneration. Thus the ongoing tissue injury in progressive MS mightbe the consequence of earlier immune mediated damage to glia structures that per see is sufficient to induce secondaryneurodegeneration even in the absence of additional inflammatory damage.

Taken together the peripheral immune system plays a central role during the relapsing-remitting phase of disease. In theprogressive phase injury seems to arise from a compartmentalized immune response in the CNS, immune independentmechanisms of secondary degeneration as a consequence of earlier immune mediated damage or the combination of bothmechanisms.

Bernhard HemmerNeurology Clinic, University of Munchen, Munchen, Germany

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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 thatthanks to the development of new genotyping technologies that additional genes located outside the HLA region have been proposed,although with weaker effects, as solid candidates for MS genetic risk. Most of the genes proposed as risk genes for the disease arerelated with the immune system, and very little are related with the target organ, the central nervous system. In addition, the causalvariants associated with genetic polymorphisms remain to be identified. This presentation will provide an update on the geneticcomponent of MS.

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

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L3. Pathology of MS

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which leads to focal destruction of myelin,acute axonal damage/loss of axons and reactive astrogliosis in the white and grey matter. MS has long time been considered a focalwhite matter disease, however, nowadays it is accepted that MS involves the entire central nervous system (CNS), including the greymatter and the normal-appearing white and grey matter. In the cortical grey matter, three different lesion types are defined withsubpial demyelination being the most frequent lesion type. Pathological changes occur also in the normal appearing white and greymatter including microglial activation as well as neuroaxonal damage.

The presentation discusses the pathological events occurring in the above mentioned three compartments including:

1. White matter lesion type (inflammation, axonal pathology, remyelination)

2. Grey matter involvement (lesion types, neuronal pathology, meningeal inflammation)

3. Normal appearing brain tissue involvement (microglia activation, axonal and neuronal changes)

The major pathological differences between relapsing-remitting and progressive multiple sclerosis are described in detail as wellas the main differential diagnoses of inflammatory demyelinating diseases.

Wolfgang BrückDepartment of Neuropathology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany

1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction6 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 andMetabolism 14, 267-273.

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

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

MRI in MS: the radiologist perspectiveAlex Rovira

Learning objectives of the presentation

• To understand the value of using a standardized imaging protocol and structured reporting in patients with multiple sclerosis

• To learn about recognition patterns that might be helpful in suggesting the diagnosis of multiple sclerosis

• To understand the role of spinal cord imaging and new MR techniques in the differential diagnosis

The exact diagnosis of multiple sclerosis (MS) still remains challenging in some cases, as there is no single test (including biopsy)that can provide a definite diagnosis of this disease. Due to this fact the neurological community has adopted diagnostic criteria forMS, which have been modified in the last 20 years several times following new evidence and experts recommendations. With theavailability of expensive and not completely free from side effects disease modifying treatments, which are particularly effective whenadministered during the early phases of the disease, an early and accurate diagnosis of MS is more imperative than ever. Diagnosticcriteria for MS include clinical and paraclinical assessments emphasizing the need to demonstrate demyelinating lesions within thecentral nervous system disseminated in space (DIS) and time (DIT), and to exclude alternative diagnosis that could mimic MS eitherclinically or radiologically. Although the diagnosis can be made on clinical grounds alone, magnetic resonance imaging (MRI) shouldbe obtained to support the clinical diagnosis and in a significant proportion of patients can even replace some clinical criteria. Thispossibility has been included in the different versions of the McDonald criteria that for the first time integrated MRI features in thediagnostic scheme, allowing an earlier and more accurate diagnosis of the disease. Nevertheless, we should keep in mind that foroptimal application of these MRI criteria, the scans must be technically adequate and neuroradiologist must consider the clinicalinformation to properly interpret the imaging findings, and be expert enough to recognize the full range of brain and spinal cordabnormalities that suggest the diagnosis of MS, as several other disorders can cause white matter lesions with imagingcharacteristics similar to those seen in MS. Focal white matter T2 hyperintense lesions (T2-HI) mimicking those seen in MS can bedetected in a relatively large list of different disorders that may affect middle age and young patients, such as hypoxic-ischemicvasculopathies (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 fulladvantage 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. Detailed description of these features and their interpretation must be translated intoa written and structured radiological report, which should be accurate with inclusion of all relevant positive and negative findings,and clinically focused, in order to properly assist with the further management of these patients. These standardized reports aremore time-efficient than simply dictation, support analysis for research and decision support, and improve communication ofradiology results, which has important clinical implications in the management of patients presenting with T2-HI.

References:- Aliaga ES, Barkhof F. MRI mimics of multiple sclerosis. Handb Clin Neurol. 2014; 122:291-316.- Bakshi et al. MRI in multiple sclerosis: current status and future prospects. Lancet Neurol 2008; 7: 615–25- Charil A, Yousry TA, Rovaris M, Barkhof F, De Stefano N, Fazekas F, Miller DH, Montalban X, Simon JH, Polman C, Filippi M. MRI and the diagnosis of multiplesclerosis: expanding the concept of "no better explanation". Lancet Neurol. 2006;5:841-5

- Filippi M. Rocca MA. MR Imaging of Multiple Sclerosis. Radiology: 2011; 259: 659-681- Haller et al. Magnetic Resonance Imaging in Multiple Sclerosis. Top Magn Reson Imaging 2009; 20: 313-323- Rocha AJ, Littig IA, Nunes RH, Tilbery CP. Central nervous system infectious diseases mimicking multiple sclerosis: recognizing distinguishable features usingMRI. Arq Neuropsiquiatr. 2013;71:738-46.

- Rovira À, Leon A. MR in the diagnosis and monitoring of multiple sclerosis: An overview. European Journal of Radiology 2008; 67:409-414- Rovira À, Wattjes MP, Tintoré M, et al. MAGNIMS study group. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiplesclerosis-clinical implementation in the diagnostic process. Nat Rev Neurol. 2015; 11:471-82

Alex Rovira, Spain 1

Mar Tintoré, Spain 2

Letizia Leocani, Italy 3

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MS diagnosis and differential diagnosisMar Tintoré

Diagnostic criteria for MS rely on the demonstration of CNS disease in space and time and in reasonable exclusion of other causes.Since McDonald 2001, in patients with a first attack, evidence for dissemination in space and time may be provided by MRI. The 2010McDonald criteria selected the Magnims criteria for dissemination in space (DIS). DIS is defined as the presence of ≥1 asymptomaticT2 lesion(s) in at least two of four locations considered characteristic for MS in previous MRI criteria: juxtacortical, periventricular,infratentorial and spinal cord. These criteria simplify the previous Barkhof criteria and highlight the importance of lesion location forMS diagnosis. Controversies regarding the need to exclude the symptomatic lesion will be discussed. The presence of at least oneasymptomatic gadolinium enhancing lesion or the presence of a new T2 irrespective of the timing of the new scan, qualifies fordissemination in time (DIT). In this setting, one single MRI performed at any time, demonstrating DIS and showing at least one ormore asymptomatic gadolinium enhancing would be sufficient to diagnose MS. Although many studies have already shown theimportance of CSF study in the diagnosis and differential diagnosis of MS, the presence of oligoclonal bands has not been includedin the diagnosis algorithm. These criteria have been adapted to other populations such as patients with primary progressive MS orpatients with paediatric MS. An overview of new directions for the future will be considered. Clinical cases to illustrate differentialdiagnoses will be presented.

EPs and OCT in MSLetizia Leocani

In Multiple Sclerosis (MS), the underlying pathology may precede by years the clinical presentation. Demyelination andneurodegeneration lead to accumulation or progression of disability, although may be countered by functional reorganization,together with some level of remyelination and neuroregeneration. Indeed, early MS disease course is dependent on the balancebetween demyelination and remyelination, with the clinical manifestation determined by the degree of plasticity offsetting the effectof damage. Although the pathogenesis of demyelination has been well described, the cellular and molecular mechanisms ofneurodegeneration are not fully understood. Among the major factors, ion channel expression and redistribution, together withneuroprotective pathways counteracting oxidative stress and mitochondrial dysfunction have been identified 1 Neurophysiologicalmethods, namely evoked potentials (EP), are currently used for the assessment of functional consequences of demyelination,remyelination and axonal loss occurring in the course of the disease, as well as in pre-clinical testing. The functional informationprovided by evoked potentials accounts for their correlation with disease severity and point to their possible role as paraclinicalmeasure for monitoring disease progression. In particular, they can help assessing the functional impact of the disease on centralsensorimotor and cognitive networks affected by MS, and may reveal subclinical lesions. Visual evoked potential (VEP), combinedwith OCT, provide a complete evaluation of structural and functional damage of the the optic pathway, representing a sensitivesurrogate measure of neurodegeneration e demyelination. 2,3. Furthermore, EP also provide some prediction on the future evolutionof disability, consistently with the hypothesis that early demyelination may prompt future neuronal loss, as shown in longitudinalstudies 3. If further validated, neurophysiological methods may have a role in the early identification of patients who are more likelyto develop future disability and for whom a closer clinical monitoring of treatment response is necessary. Finally, the possibility todemonstrate improved conduction through evoked potentials can represent a key feature in the assessment of efficacy of noveltherapeutic approaches targeting demyelination.

References:1. Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 2014;10:225–38.2. Leocani L, Comi G. Neurophysiological markers. Neurol Sci. 2008;29 Suppl 2:S218–21.3. Leocani L, Comi G. Clinical neurophysiology of multiple sclerosis. Handb Clin Neurol. 2014;122:671–9.

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L4. Neuromyelitis optica - NMO

Neuromyelitis optica (NMO) is a rare and severe inflammatory disease with predominant involvement of the optic nerves and thespinal cord, previously considered to be a variant of multiple sclerosis (MS). The main objective of this talk is to provide a generalupdate on this disease. Over the years, a number of clinical, laboratory, and magnetic resonance imaging studies have provided datato differentiate NMO from MS. The discovery of serum IgG antibodies targeting the water channel aquaporin-4 has not only helpedcategorize NMO as an independent entity from MS, but has also broadened the disease spectrum [NMO spectrum disorders(NMOSD)]. The discovery of these highly specific antibodies, in turn, could potentially aid in finding a more specific treatment aimedat the prevention of recurrences. However, different antibody detection methods with varying degrees of sensitivity are still used,despite recommendations based on recent data pointing to cell-based assays as the most sensitive. And even when using theseassays, 20-30% of results are still negative and, in some instances, other antibodies have been identified. The most relevant to dateis the anti-MOG antibody since its presence appears to indicate a more benign disease course, although such findings should beconfirmed in further studies. Furthermore, despite these improvements, atypical cases with intermediate MS and NMO featuresexist that are still difficult to differentiate early in the disease course. Taking all these issues into account, the International Panelfor NMO Diagnosis (IPND) developed and published a revised version of the diagnostic criteria in 2015. Nevertheless, despite theseimprovements and although we have a better understanding of this disease, there is still plenty to learn from NMOSD.

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

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L5. Pediatric and juvenile MS

Although multiple sclerosis (MS) is typically considered an adult disease, paediatric MS (paed-MS) is increasingly recognised,accounting for ~3-10% of all MS cases, with >90% of cases being relapsing-remitting. Diagnostic criteria for paed-MS have recentlybeen reviewed and defined.1 Compared with adult-onset MS, paed-MS is more likely to involve cerebellar and brainstem dysfunction,moreover it is more frequently associated with a polysymptomatic presentation and with higher relapse rate. In some patients theevolution is aggressive since the onset. Disease progression in paed-MS is slower than in adult-onset MS, but disability milestonesare reached at earlier due to the young onset. Approximately 30% of patients with paed-MS develop cognitive dysfunction early inthe disease course, which negatively impacts on their academic and social functioning.

To date, there have been no randomised controlled interventional clinical trials in paed-MS. However, results from observationalstudies have shown that immunomodulators (beta-interferon and glatiramer acetate) are well tolerated and significantly reduce therelapse rate and the disease progression in this population. European guidance recommends early initiation of immunomodulatingtherapy for relapsing paed-MS.2 The International Pediatric MS Study Group, created to promote and co-ordinate internationalstudies in paed-MS, recommends the use of first-line therapies (beta-interferon or glatiramer acetate) for all patients with paed-MS.3 However, ~30% of patients continue to progress and relapse and may require second-line therapy.

The efficacy and safety of natalizumab in paed-MS have been shown in case reports and many observational studies representingan useful option for active MS patients, however the risk of progressive multifocal leucoencephalopathy must be carefully andminimized by testing anti-JCV antibodies. Cyclophosphamide has been shown to reduce disease activity in a retrospective study of17 patients with paed-MS but it was associated with high incidence of adverse events. Mitoxantrone has shown a beneficial effect infour patients with paed-MS with severe evolution, but the safety profile (risk of leukaemia and cardiomyopathy) is discouraging.International randomised controlled studies are necessary to better define the efficacy and safety profile of new pharmacologicaltreatments in paed-MS.

Angelo GhezziMultiple Sclerosis Centre, Gallarate Hospital, Gallarate, Italy

References:1. Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, andresearch.

2. Lancet Neurol. 2014 Sep;13(9):936-48. doi: 10.1016/S1474-4422(14)70093-6.3. Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediatedcentral nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 2013;19:1261-1267.

4. Ghezzi A, Banwell B, Boyko A, et al. The management of multiple sclerosis in children: a European view. Mult Scler 2010;16:1258-1267.5. Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler2012;18:116-127.

6. Ghezzi A, Moiola L, Pozzilli C, et al. Natalizumab in the pediatric MS population: results of the Italian registry. BMC Neurol. 2015;15:174.

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L6. Primary progressive MS

Primary progressive multiple sclerosis (PPMS) comprises approximately 10-15% of MS cases overall. It is characterized by a laterage of onset (on average 40 years, similar to the age of onset in SPMS) and an equal sex ratio (1). It has a predominantly motorpresentation, usually with an asymmetric spastic paraparesis with occasional cerebellar and brainstem and rarely sensory or visualprogressive disorders. PPMS can be challenging to diagnose - it does not have acute events or relapses, the hallmark of MS, butrather a slowly progressive course which is often very insidious at onset. In a recent longitudinal multicenter cohort of 453 patientswith radiologically isolated syndrome (MRI findings typical of MS without clinical manifestations), followed over a mean of 5.8 years,15 had clinical conversion manifested as gradual progression of disability (2). The proportion of patients and their demographic andclinical characteristics were similar to those of PPMS in the MS population (including the proportion of men and frequency of spinalcord lesions).

PPMS has a variable course with 25% of patients needing assistance to walk at 7.5 years after onset, but with another 25% stillwalking unaided at 25 years. Factors associated with a worse outcome include presentation involving multiple systems, and ashorter time to EDSS 3. Patients who were younger at disease onset take longer to reach EDSS 6.0, but these patients were alsoyounger when reaching EDSS 6.0. (3). Sensory symptoms at presentation were associated with both a longer time to, and an olderage at, EDSS 6.0.

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. The differences in underlying pathology between primaryand secondary progressive MS are thought to be relative rather than absolute (4). Diagnosis is particularly challenging but has beenhelped by new criteria which include MRI evidence of dissemination in time and space (5). A recent meeting to review phenotypes inMS, encouraged a stronger focus on clinical and imaging markers of activity rather than the labels of primary and secondaryprogressive MS (6).

PPMS is usually characterized by fewer and smaller lesions on MRI, compared with relapsing MS. A major study evaluated 145patients with PPMS over 10 years to determine which MRI abnormalities best predict progression. Changes in clinical measures at10 years were predicted by male sex, low brain volume at baseline, and by the number of new T2 lesions and reduced cord volumesat 2 years (7). In early PPMS, progression on the EDSS over 3 years was associated with the mean rate of decrease in grey mattermagnetization transfer ratio (MTF; p=0.032). The combination of grey matter MTR and focal T2 lesions appears to be the strongestpredictor of disability in PPMS, and correlated strongly with cognitive performance (8).

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 in PPMS, and there have been a numberof disappointingly negative trials, a recent positive phase III trial of ocrelizumab, which targets B lymphocytes, was presented atECTRIMS 2015 (9). A comprehensive rehabilitation programme incorporating management of mobility, bladder function and muscletone is important (10). Improved understanding of progression leading to effective treatments for PPMS is a key goal for future MSresearch and is the focus of a major international alliance (11).

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

References:01. Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurology 2007; 6(10): 903-912.02. Kantarci OH, Lebrun C, Siva A, et al. Primary progressive multiple sclerosis evolving from radiologically isolated syndrome. Annals of Neurology 2016; 79(2):

288-294.03. Koch M, Kingwell E, Rieckmann P et al. The natural history of primary progressive multiple sclerosis. Neurology 2009; 73(23):1996-2002.04. Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Progressive multiple sclerosis: prospects for disease therapy, repair and restoration of function. Lancet

Neurology, 2016 in press. 05. Polman C, Reingold SC, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology 2011; 69(2):

292-302.06. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology

2014; 83(3):278-286.07. Khaleeli Z, Ciccarelli O, Manfredonia F et al. Predicting progression in primary progressive multiple sclerosis: a 10-year multicenter study. Annals of Neurology

2008; 63(6):790-793.08. Tur C, Khaleeli Z, Ciccarelli O, Altmann DR, Cercignani M, Miller DH, Thompson AJ. Complementary roles of grey matter MTR and T2 lesions in predicting

progression in early PPMS. Journal of Neurology, Neurosurgery and Psychiatry 2011; 82(4): 423-428.09. Montalban X, Hemmer B, Rammohan K et al. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis - results of the placebo-controlled,

double-blind, phase III ORATORIO study (Abstract 228). Multiple Sclerosis Journal 2015; 21(S11): 781-782.10. Thompson AJ, Toosy AT, Ciccarelli O. Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions. Lancet

Neurology 2010; 9(12): 1182-1199.11. Fox R, Thompson AJ, Baker D et al. Setting a research agenda for progressive multiple sclerosis. Multiple Sclerosis Journal 2012: 18(11):1534-1540.

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PD2. Panel discussion on “Cognition disorders in MS”

1 - Department NEUROFARBA, University of Florence, Florence, Italy2 - Multiple Sclerosis Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department, Vall d’Hebron University Hospital, Barcelona, Spain

DiagnosisMaria Pia Amato

Cognitive dysfunction in multiple sclerosis (MS) presents a considerable burden to patients and to society, due to the negative impacton function, including maintaining employment, activities of daily living, social activity, and the capacity to benefit from in-patientrehabilitation. In some individuals with MS the impact of cognitive impairment can be profound, even if physical functioning remainsrelatively intact. Interventions to ameliorate or reduce cognitive impairment, as part of a comprehensive rehabilitation programme,may benefit patient function and quality of life. To diagnose and quantify the extent of cognitive impairment, appropriate assessmentsare essential but often difficult. Patient report is unreliable and highly correlated with depressive symptomatology. Unfortunately,routine neurological examinations for MS are too insensitive to yield valid information on cognitive function. For example, theexpanded disability status scale (EDSS), does not include an adequate assessment of cognitive dysfunction. The development of theMultiple Sclerosis Functional Composite (MSFC) which includes the Paced Auditory Serial Addition Test (PASAT) was a step forwardtowards incorporating a sensitive measure of cognition into a standardized rapid MS assessment tool. The challenge with moredetailed and comprehensive performance-based cognitive evaluations is that while they are the most reliable, they can be timeconsuming and impractical in many clinical settings. Screening patients to identify those with the highest likelihood of dysfunctionwould be ideal, but validated screening tools have yet to be developed or applied. One assessment approach is to use test batteriesthat range from 30 to 90 min in duration. The goal of these batteries is to capture the core features of MS- associated cognitivedysfunction. The Brief Repeatable neuropsychological Battery (BRNB) assesses those domains most commonly impaired in MS andis most widely used in clinical and research settings. The Minimal Assessment of Cognitive Function in MS (MACFIMS), developedfor a similar purpose, is a more recent battery created by expert consensus and published in 2002. These batteries differ in thespecific auditory/verbal memory and visual/spatial memory tests employed, but assess similar domains, and are comparable in theiroverall sensitivity to disease status. Despite the availability of such batteries, the assessment of cognitive function in research studiesof MS is far from optimal. Methodological shortcomings include the variability of the domains assessed and the instruments used,the handling of common confounds such as fatigue and depression, and the inclusion of heterogeneous groups of patients in whomselection criteria for cognitive impairment were either applied inconsistently across studies or applied at all. More recently the BriefInternational Cognitive Assessment of MS (BICAMS) has been developed and validated to overcome some of the above shortcomingsby an international panel of experts. It tests information processing speed, verbal and visual memory, requires nearly 15 minutes foradministration and minimum training of the assessor. Translation and validation in different countries have provided evidence of itsgood psychometric properties so that this tool seems to be promising for everyday assessment and monitoring of cognition in clinicaland research settings.

Maria Pia Amato, Italy 1

María Jesús Arévalo, Spain 2

Ángela Vidal, Spain 2

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TreatmentMaría Jesús Arévalo

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), apartfrom complete psychophysical status and objective neurologic status, a subjective perception of symptoms and signs, known asquality 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 physicaldisability. Despite the high prevalence rates and the significant impact of cognitive dysfunction on quality of life in this population,cognitive functions 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. disturbancesin memory, attention, concentration, speed of information processing and executive functions). Although some reduction in self-awareness of cognitive decline occurs, metacognitive skills and awareness of more concrete impairments appear preserved.Cognitive impairments can be extremely disruptive and interfere with PwMS ability to work, engage in social activities, and maintaina household and drive. Since the onset and progression of MS typically occurs when PwMS are attempting to establish and maintaincognitively demanding life roles (e.g. parent and worker), their cognitive symptoms can further accentuate the need to successfullymaintain functioning.The available immune-modulating agents may reduce the development of new lesions and therefore prevent or minimize theprogression of cognitive decline. There is currently insufficient evidence concerning the efficiency of symptomatic treatment in MS.Donepezil and rivastigmine (AChEls) have demonstrated some specific benefits in PwMS cognitively impaired, but the studies weresmall. There is also currently no optimal non-pharmacological treatment strategy for cognitive decline in MS, as the studiespublished to date report heterogeneous results. Nevertheless, non-pharmacological treatments such as cognitive rehabilitation maybenefit some MS patients. In the present talk, we will briefly review recent research on non-pharmacological and pharmacological approaches to improvecognitive function in our patients.

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KNS2. Injectable therapies in MS

Disease modifying drugs (DMDs) in MS: First line drugs: Three recombinant interferon beta (IFNb) preparations and glatirameracetate (GA) are currently approved for relapsing-remitting multiple sclerosis (RR MS). Their efficacy is very similar and was proveneven in head-to-head trials conducted recently. Also 3T MRI confirmed similar efficacy on MR measures. All of them are approvedfor patients with clinically isolated syndrome (CIS) and in high risk for clinically definite MS. In some countries there is extendedapproval for RR MS under age of 18. There is no proven effect of these drugs for chronic progression of MS without the presence ofrelapses. There is not enough publications supporting the idea of combination therapies to start with; and there is not enoughpublications on sequential therapy. Long-term follow-ups of clinical trials 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. New formulations (pegylated interferon beta 1a administered every other week, double dose ofGA administered 3 times a week) may increase the persistence of patients.

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. The brain volume loss correlates with disability progression, thereforeMRI monitoring must be added to clinical follow up. Statistical evaluation of more than 10 000 of patients in clinical trials shows clearsuperiority of second line drugs in achieving less brain damage in comparison with first line injectables.

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

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PD3. Panel discussion on “Define treatment success”

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 surrogatesJordi Río

The objective of the definition of treatment response is to select responders on one hand, and poor- or non-responders on the otherhand. Several criteria for treatment response to treatment have been proposed. Nevertheless, these different criteria have not beenvalidated and there is no consensus among different investigators.These criteria are based on relapses, disability progression or both. Several factors make difficult the employment of relapseoutcomes to determine therapeutic response (low predictive value, regression to the mean, etc.). Whilst long-term disability data arecrucial in order to select the most clinically meaningful definition. Relatively to the progression of neurological impairment, efficacyfluctuations related to depression, fatigue, spasticity, concurrent illness and prolonged relapse need to be excluded. Nevertheless,criteria of response to IFNb therapy using disability progression are more clinically relevant than those based only in relapse rate. MRI offers an advantage in the response evaluation as it produces objective data, however the frequency of evaluation is limited andlow frequency of MRI evaluations leads to poor perspective data. 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. A suboptimal response may be due to several individual features from MS heterogeneity to genetic load and IFN response genes topoor healing mechanisms. Other factors may play a role, such as excess disease activity, poor adherence to therapy, misdiagnosis,“pseudo” failure” or loss of drug efficacy.In conclusion, the proportion of non-responders varies depending on the definition used. Criteria based on relapse measures havepoor sensitivity and positive diagnostic value; there are limited prospective MRI data as predictors of therapeutic response and thecombination of clinical and MRI measures of disease activity may have a prognostic value for identifiying patients with a poorresponse.

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, thisheterogeneity is probably explained by the contribution of multiple genes. Disease Modifying Therapies (DMTs) are the mainstay oftreatment 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.

Jordi Río, Spain 1

Manuel Comabella, Spain 1

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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.

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

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SS1. Snapshot #1 on gene therapy in MS

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 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 and approaches developed to treat EAE are going to be discussed, as well as thenew tools that are being developed in the field of gene therapy.

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

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SS2. 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.

Nicolás FissoloMultiple Sclerosis Centre of Catalonia (Cemcat), Unit of Clinical Neuroimmunology, Institut de Recerca,Vall d’Hebron University Hospital, Barcelona, Spain

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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 provide an overview of the evidence in favor of neurorehabilitationin MS.

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

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SS3. Symptomatic therapy snapshot #3 on gaitrehabilitation

One of the most pronounced incapacitating manifestations of Multiple Sclerosis (MS) are gait abnormalities, resulting from thecombined effect of decrease in muscle strength, spasticity, cerebellar ataxia, sensory disorders and reduction in aerobic capacity.Pathological gait patterns are less functional, secure, and effective. Secondary problems such as increased risk of falls andincreased energy expenditure affect activity, participation and quality of life.

Physical therapy interventions aim firstly 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.

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

References:- Krebs DE, et al. Reliability of the observational kinematic gait analysis. Phys Ther. 1985; 65:1027-33- Holden MK, Gill KM, Magliozzi MR. Gait assessment for neurologically impaired patients. Phys Ther. 1986; 66: 1530-39.- 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.- Perry J. (1992) Gait Analysis. Normal and pathological function. NJ: Slack Incorporated.- Sinkjaer, T. et al. Impaired stretch reflex and joint torque modulation during spastic gait in multiple sclerosis patients. J Neurol.1996; 243:566-74- 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.- Benedetti MG et al. Gait abnormalities in minimally impaired multiple sclerosis patients. Mult Scler.1999; 5: 363-368.- 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.- 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.- 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.- van Uden CJ, et al. Test-retest reliability of temporal and spatial gait characteristics measured with an instrumented walkway system (GAITRite). BMC MusculoskeletDisord. 2004; 5:13- Thoumie, P. et al. Motor determinants of gait in 100 ambulatory patients with multiple sclerosis. Mult Scler. 2005; 11; 485- Crenshaw SJ et al. Gait variability in people with multiple sclerosis Mult Scler.2006; 12; 613 - Martin CL, et al. Gait and balance impairment in early multiple sclerosis in the absence of clinical disability. Mult Scler. 2006; 12:620-8- Baram Y, et al. Virtual Reality Cues for Improvement of Gait in Patients with Multiple Sclerosis. Neurology, 2006; vol.66(2):178-81.- 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- Lünenburger, L. et al. Biofeedback for robotic gait rehabilitation. Journal of Neuro Engineering and Rehabilitation. 2007, 4:1- Remelius JG, et al. Gait initiation in multiple sclerosis. Motor Control. 2008; 12:93-108- Tesio L, Rota V: Gait analysis on split-belt force treadmills: validation of an instrument. Am J Phys Med Rehabil 2008;87:515-26.- Goldman MD, et al. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Mult Scler. 2008; 14: 383-90- Lo, A. et al. Triche Improving Gait in Multiple Sclerosis Using Robot-Assisted, Body Weight Supported Treadmill Training. Neurorehabil Neural Repair 2008; 22; 661- 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 Med Rehabil2008;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- Givon U, et al. Gait analysisi in multiple sclerosis: characterization of temporal-spatial parameters using GAITrite functional ambulation system. Gait posture 2009;29:138-42- 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 2009 Vol. 90,Issue 5, 849-55- Barret CL, et al. A randomized trial to investigate the effects of functional electrical stimulation and therapeutic exercise on walking performance for people with multiplesclerosis. Mult Scler.2009; 15:493-504.- Gijbels D, et al. Predicting habitual walking performance in multiple sclerosis: relevance of capacity and self-report measures. Mult Scler. 2010; 16:618-26- Gijbels D, et al. Which walking capacity tests to use in multiple sclerosis? A multicentre study providing the basis for a core set. Multiple Sclerosis Journal 2012 18 : 364-371- Feys P, et al. Effect of time of day on walking capacity and self-reported fatigue in persons with multiple sclerosis: a multi-center trial Mult Scler 2012 18:351-357- Stevens V, et al. Gait impairment and optimizing mobility in multiple sclerosis. Phys Med Rehabil Clin N Am. 2013 Nov;24(4):573-92.- Wagner JM, et al. Plantarflexor weakness negatively impacts walking in persons with multiple sclerosis more than plantarflexor spasticity. Arch Phys Med Rehabil. 2014Jul;95(7):1358-65- Baert I, et al. “Responsiveness and clinically meaningful improvement, according to disability level, of five walking measures after rehabilitation in multiple sclerosis: aEuropean multicenter study”. Neurorehabil Neural Repair. 2014 Sep;28(7):621-31- Feys P, et al. “Within-day variability of short and long walking tests in persons with multiple sclerosis. J Neurol Sci. 2014 Mar 15;338(1-2):183-7

30

SS4. Symptomatic therapy snapshot #4 on managementof dysphagia

This lecture will offer insight into dysphagia, including proper detection, assessment and treatment of this symptom.

The reported prevalence of dysphagia in MS falls between 33% and 43%. The symptom, which is associated with brainstem andcerebellar impairment, is more frequent in advanced stages of the disease but can also appear in early stages. Dysphagia can leadto serious complications such as bronchopneumonitis, poor nutritional state and a decrease in quality of life. It can affect swallowingof liquids and/or solids -- the latter being more frequent in severe dysphagia.

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

The presence of altered feeding habits and of cough and/or choking during or after meals are the two most commonly reportedsymptoms. 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 muscle tone, oral reflexes and the movementexecution pattern. A functional assessment of chewing, swallowing, phonation and articulation should also be performed. Thevolume-viscosity swallow test (V-VST, Clavé et al. 2008) is a bedside method to screen patients for dysphagia. Referral toinstrumental examination should be done in moderate to severe cases of dysphagia or when there are specific objectives forexamination. Videofluoroscopy and fiberoptic laryngoscopy are the two most commonly used instrumental procedures.

Treatment of dysphagia should begin soon after first symptoms appear as it has the goals of improving security and efficacy ofswallowing as well as supporting quality of life and social participation. Treatments can include rehabilitation, pharmacologicaltreatment and, eventually, implementation of enteral feeding. Rehabilitation includes restorative, compensatory and adaptiveapproaches and also education on security manoeuvres. The restorative approach includes neuromuscular exercises which aredirected at improving the sensoriomotor and praxic-cognitive control of the swallowing mechanisms and can also includeneuromuscular electrostimulation. The compensatory approach consists of general advice as well as strategies and manoeuvres tobe taken into account while eating and drinking. The adaptive approach includes measures involving adaptation of the consistencyof food. Family and caregivers should be involved in rehabilitation. Pharmacological treatment includes use of botulinum toxin -particularly for the treatment of drooling.

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

NOTES

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