FINAL PROGRAMME AND ABSTRACT BOOK

Multiple sclerosis: integrating scientificprogress into patient management15-16 November 2013 - Santiago de Chile, Chile

General information

VenueThis live educational conference takes place at the:

SHERATON HOTEL AND CONVENTION CENTER SANTIAGO Av. Santa María 1742, Providencia, Santiago, Chileph: +56 (2) 2233 5000 http://www.starwoodhotels.com/sheraton/property/overview/index.html?propertyID=296&language=en_US

LanguageThe official language of the live educational conference is English.

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

Senior Project Manager: Serena Dell’AricciaTel.: +39 (0)6 420 413 251Fax: +39 (0)6 420 413 677E-mail: info@seronosymposia.org

Medical Advisor: Federica Cerri

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

Organising secretariatMeridiano Congress InternationalVia Sapri, 6 - 00185 Rome, ItalyCongress coordinator: Sara GuglielminiTel.: +39 (0)6 88595 211 - Fax: +39 (0)6 88595 234E-mail: s.guglielmini@meridiano.it

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

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Multiple sclerosis: integrating scientific progress intopatient management

Serono Symposia International Foundation live educational conference on:

Multiple sclerosis: integrating scientific progress into patient management15-16 November 2013 - Santiago de Chile, Chile

Aim of the live educational conferenceMultiple sclerosis (MS) is one of the most frequent neurological disorder in Western European and North American countries. In thelast decades epidemiological studies have been highlighted, despite regional differences, an increasing rate of prevalence of MS alsoin Latin American countries, thus opening new challenging issues concerning disease management also in these countries. A fulldescription of environmental and genetics risk factors and disease variants is still lacking, such as appropriate diagnostic algorithmsand treatment guidelines, tailored on regional health and social services. Despite these limitations, there is a growing interest in themedical community involved in MS patients care to gain more knowledge in this field, sharing knowledge with countries moreexperienced in MS management. This meeting will be a chance to share scientific understandings and practical aspects to betranslate into MS patients care.

Learning objectivesBy attending this live educational conference the learners will be able to:• Outline the most relevant risk factors to develop MS and its clinical variants• Explain how to diagnose and follow up cognitive dysfunction• Compare the effects and disease relapse rate and progression of the available drugs for MS

Target audienceNeurologist involved in MS patients management; physicians with a particular interest in MS.

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

The CME conference on: “Multiple sclerosis: integrating scientific progress into patient management” held on 15-16 November2013 in Santiago de Chile, Chile, is designated for a maximum of 9 (nine) hours of European CME credits (ECMEC). Each medicalspecialist should claim only those credits that he/she actually spent in the educational activity. EACCME® credits are recognized bythe American Medical Association (AMA) towards the Physician's Recognition Award (PRA). To convert EACCME® credit to AMA PRAcategory 1 credit, please contact the AMA.

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

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

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We value your opinion!

We are continually trying to develop and improve our educational initiative to provide you with cutting-edge learning activities.

During this conference you will be asked to answer a real time survey and after this educational event you will be receivingan online survey to help us to better tailor our future educational initiatives.

We thank you for participating!

Scientific organizersEdgardo CristianoMS Center, Department of NeurologyHospital Italiano de Buenos AiresBuenos Aires, Argentina

Óscar FernándezDepartment of Neurology Hospital Regional Universitario Carlos Haya Malaga, Spain

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List of faculty membersJosè Carlos Álvarez-CermeñoService of Neurology Hospital Ramón y CajalMadrid, Spain

Rafael ArroyoService of NeurologyClinical Hospital of San CarlosMartin Lago Madrid, Spain

Jorge Barahona StrauchUniversidad Católica de Chile,Universidad des DesarolloClinica AlemanaSantiago, Chile

Denis Bernardi BichuettiNeurology DepartmentFederal University of São PauloSão Paulo, Brazil

Claudia CárcamoDepartment of Neurology Pontificia Universidad Catolica de ChileSantiago de Chile, Chile

Bonaventura CasanovaDepartment of NeurologyUniversity HospitalLa Fe-Valencia, Spain

Giancarlo Comi Department of Neurology Institute of Experimental Neurology Vita Salute UniversitySan Raffaele Hospital IRCCSMilan, Italy

Jorge Correale Department of NeurologyInstitute for Neurological Research Dr. Raúl Carrea, FLENIBuenos Aires, Argentina

Edgardo CristianoDepartment of Neurology and MS CenterHospital Italiano de Buenos AiresBuenos Aires, Argentina

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Óscar Fernández Department of Neurology Hospital Regional Universitario Carlos Haya Malaga, Spain

José Flores RiveraDemyielinating Diseases Clinic National Institute of Neurology and NeurosurgeryMexico City, Mexico

Juan Raúl García Bonitto Neurology Department Clínica de MarlyBogotá, Colombia

Juan Antonio García-Merino Department of Neurology Hospital Puerta de HierroUniversidad Autonoma de MadridMadrid, Spain

Fernando GraciaNeurology DepartmentHospital Santo TomasPanama City, Republic of Panama, Panama

Hans-Peter HartungDepartment of NeurologyHeinrich-Heine-UniversityDus̈seldorf, Germany

Miguel Ángel Macías Department of Clinical Neurology Centro Médico Nacional de OccidenteIMSS Clinical Research Mexican Multiple Sclerosis Foundation Guadalajara, Mexico

Jorge Nogales-GaeteChile School of MedicineUniversity of ChileNeurology Department Santiago de Chile, Chile

Enedina Maria OliveiraNeuroimmunology Center, MS clinicNeurology & Neurosurgery Department Federal University of São PauloSão Paulo, Brazil

Marcos Papais Alvarenga Department of NeurologyUniversidade Federal do Estado do Rio de Janeiro Centro de Ciências Biológicas e da SaúdeRio de Janeiro, Brazil

Liliana Patrucco Neurology DepartmentItalian Hospital of Buenos AiresBuenos Aires, Argentina

Alfredo Rodríguez Antigüedad Service of Neurology Hospital of BasurtoBilbao, Spain

Vladimiro SinayDemyielinating Diseas ClinicNeurology Department Institute of Neurosciences Fundación FavaloroBuenos Aires, Argentina

Scientific programme15-16 November 2013

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Chairs: E. Cristiano (Argentina) - J. Nogales-Gaete (Chile)

09.00 L1: Epidemiology - risk factors: environment andgeneticsE. Cristiano (Argentina)

09.30 L2: Differential diagnosis: MS variants and MSmimickers F. Gracia (Panama)

10.00 L3: Pathogenesis of MSJ. Correale (Argentina)

10.30 L4: MRI and Mc Donald’s criteria B. Casanova (Spain)

11.00 Coffee break

11.30 L5: CSF BiomarkersJ.C. Álvarez-Cermeño (Spain)

12.00 CC1: Diagnosis and differential diagnosisC. Cárcamo (Chile)

12.30 Lunch

Epidemiological, pathological and clinical aspects Session I

Friday, 15 November

08.45 Serono Symposia International Foundation (SSIF) opening and introductionG. Comi (Italy), E. Cristiano (Argentina), Ó. Fernández (Spain)

Chairs: Ó. Fernández (Spain) - J. Flores Rivera (Mexico)

13.30 L6: Early treatmentG. Comi (Italy)

14.00 L7: Injectable therapiesJ. Flores Rivera (Mexico)

14.30 L8: Oral therapiesJ.A. García-Merino (Spain)

15.00 L9: Antibodies in MSH.P. Hartung (Germany)

15.30 Coffee break

16.00 L10: When and how to switch therapiesL. Patrucco (Argentina)

16.30 L11: Risks and side effects management for DMDs V. Sinay (Argentina)

17.00 KN1: Stem cell therapy: where do we stand?Ó. Fernández (Spain)

17.30 CC2: Treatment algorithmsR. Arroyo (Spain)

18.00 End of day 1

Therapeutic armamentarium: what is new andwhat is knownSession II

Legend: L : Lecture; KN : Key Note; CC : Clinical Cases;

Saturday, 16 November

Chairs: E. Cristiano (Argentina) - M.A. Macías (México)

08.30 L12: Cognitive impairment: the extent of theproblemM.A. Macías (México)

9.00 L13: The role of white and grey matter: MRIfindingsE.M. Oliveira (Brazil)

9.30 L14: “Invisible symptoms” (Fatigue, affectivedisorders)D. Bernardi Bichuetti (Brazil)

10.00 L15: Neuropsychological assessment andtreatment of cognitive dysfunctionJ.R. García Bonitto (Colombia)

10.30 L16: Socio-economic impactA. Rodríguez Antigüedad (Spain)

11.00 Coffee Break

Cognitive dysfunctionsSession III

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Saturday, 16Novemb

Chairs: Ó. Fernández (Spain) - M. Papais Alvarenga (Brazil)

11.30 L17: The role of rehabilitation M. Papais Alvarenga (Brazil)

12.00 L18: Case-based approach to symptommanagementJ. Barahona Strauch

12.30 L19: Perceptions of multiple sclerosis patientsregarding their clinical careJ. Nogales-Gaete (Chile)

13.00 Closing round-up and concluding remarks

Symptoms managementSession IV

Disclosure of faculty relationships

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

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

Josè Carlos Álvarez-Cermeño Declared the receipt of honoraria and consultation fees from: Merck Serono, Biogen Idec, Teva,Bayer. He declared to be member of a company advisory board, board of directors or othersimilar group: Merck Serono, Biogen Idec, Teva, Bayer.

Denis Bernardi Bichuetti Declared the receipt of grants and contracts from: Merck Serono, Biogen-Idec, Bayer HealthcareTeva. He declared the receipt of honoraria and consultation fees from: Merck Serono, Biogen andto be member of a company advisory board, board of directors or other similar group: MerckSerono, Genzyme.

Bonaventura Casanova Declared the receipt of grants and contracts from: Merck Serono, Biogen-Idec, TevaPharmaceuticals, Sanofi-Genzyme, Almirall. He declared the receipt of honoraria andconsultation fees from: Merck Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Genzyme andto be member of a company advisory board, board of directors or other similar group: MerckSerono, Novartis, Biogen Idec, Teva Pharmaceuticals, Sanofi-Genzyme.

Giancarlo Comi Declared the receipt of honoraria and consultation fees from: Serono Symposia InternationalFoundation, Merck Serono, Bayer, Novartis, Teva, Biogen, Genzyme, Sanofi, Actelion, Almirall.

Jorge Correale Declared the receipt of grants and contracts from: Novartis Argentina, Merck Serono Argentina,Biogen-Idec Argentina. He declared the receipt of honoraria and consultation fees from: NovartisArgentina, Merck Serono Argentina, Genzyme Argentina. He declared to be member of acompany advisory board, board of directors or other similar group: Novartis Argentina, GenzymeArgentina and declared the participantion in company sponsored speaker's bureau: NovartisArgentina, Merck Serono Argentina, Biogen-Idec Argentina, Teva-IVAX Argentina, GenzymeArgentina.

Óscar Fernández Declared the receipt of honoraria as consultant in advisory boards, and as chairmen or lecturerin meetings, and has also participated or participates at present in clinical trials and otherresearch projects promoted by Biogen-Idec, Bayer-Schering; Merck-Serono, Teva, Novartis,Actelion, Almirall and Allergan.

José Flores Rivera Declared the receipt of honoraria and consultation fees form: Genzyme, Novartis, Bayer, CaridianBCI, Teva.

Juan Raúl García Bonitto Declared receipt of honoraria and consultation fees from: Novartis and Genzyme. He declared tobe member of a company advisory board, board of directors or other similar group: Novartis andGenzyme. He declared also the participation on a company's speakers bureau: Novartis,Genzyme and Merck Serono.

Juan Antonio García-Merino Declared the receipt of honoraria or consultation fees from: Merck, Bayer, Biogen-Idec,Genzyme-Sanofi, Teva, Novartis. He declared to be member of a company advisory board, boardof directors or other similar group: Merck, Bayer, Biogen-Idec, Genzyme-Sanofi, Novartis.

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Fernando Gracia Declared to be member of a Merck Serono sponsored speakers bureau.

Hans-Peter Hartung Declared the receipt of honoraria and consultation fees from: Biogen-Idec GmbH, Merck Serono,Teva, Genzyme, MedImmune, Hoffmann-LaRoche, Novartis, Bayer.

Miguel Ángel Macías Declared receipt of grant and contracts from: Teva Mexico and genzyme. He declared to bemember of a company advisory board, board of directors or other similar group: Teva andGenzyme.

Jorge Nogales-Gaete Declared no potential conflict of interest.

Enedina Maria Oliveira Declared the receipt of honoraria or consultation fees from: MerckSerono Brazil, Bayer Brazil,Novartis Brazil. She declared to be member of a company advisory board, board of directors orother similar group: Novartis Brazil.

Marcos Papais Alvarenga Declared no potential conflict of interest.

Liliana Patrucco Declared no potential conflict of interest.

Alfredo Rodríguez Antigüedad Declared the receipt of honoraria and consultation fees from: Merck Serono, Novartis, Teva,Genzyme, Schering, Biogen.

Vladimiro Sinay Declared the receipt of grants and contracts from: Merck Serono Argentina, Teva IVAX. Hedeclared the receipt of honoraria and consultation fees from: Bayer, Biogen, Novartis, MerckSerono, Ieva IVAX. He declared the participation in company sponsored speaker's bureau: Bayer,Biogen, Novartis, Merck Serono, Teva-IVAX.

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 4 November 2013.

Rafael Arroyo

Jorge Barahona Strauch

Claudia Cárcamo

Edgardo Cristiano

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Abstracts

L1. Epidemiology - risk factors: environment and genetics

Multiple sclerosis has a complex aetiology involving both genetic and environmental factors.

Nowadays, there is evidence that environment has a significantly greater role over genetics. Factors like latitude, ultraviolet radiationexposure, vitamin D levels, EBV previous infection and tobacco smoking may provide more than 75% of the risk of developing multiplesclerosis.

Latin-American countries show a different epidemiological scenario in relation to Europe and North America. During the last decadeseveral investigations began to provide a reasonable estimate of the disease in the region: prevalence and incidence is substantiallylower than previously found in developed countries. Reasons for these differences are unknown; however, some evidence stronglysuggests that solar exposure and subsequent vitamin D levels have been associated with a decreased risk of developing MS. Thismay account for the increased risk observed in areas located at a greater distance from the Equator. It has been proposed thatimproved hygiene, which partially explains the reduced rate of infections in Western countries, might be a starting point to clarify theincreased incidence of allergic and autoimmune diseases in the same population. Regarding genetic factors, LAC populations arevery heterogeneous, and while Argentina and Uruguay have the largest Caucasian influence, numerous LAC inhabitants are raciallyconstituted by mestizos, a complex admixture of Caucasian and Amerindian peoples.

These new insights may contribute to identify potential clues regarding aetiological causing factors.

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Edgardo CristianoMS Center, Department of Neurology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

L2. Differential diagnosis: MS variants and MS mimickers

The diagnosis of Multiple Sclerosis (MS) may be straightforward when typical clinical presentations are observed as optic neuritis,brainstem or spinal syndromes starting as a Clinical Isolated Syndrome (CIS), and neuroimaging findings are suggestive of MSdemyelinating lesions, following the McDonald 2010 criteria. Frequently, this is not the case, and it may be quite challenging, wherethe differential diagnosis of a non-MS demyelinating disease or a non–demyelinating disease can be within a quite broad spectrum.It has been proposed more than 100 entities that can mimics MS or in other cases can be confuse with a variant ( Ex. Shilder, Bago).Special attention must be underline with Neuromyelitis Optica and Acute Disseminated Encephalomyelitis. A systematized processfor alternative diagnosis must be develop for exclusions of other diseases that can better explain the clinical and paraclinicalfindings. Proposed algorithms maybe a helpful aid to evaluate the diagnosis of the three most common presentation of CIS. Themainly areas that must be explore are Ischemic/hemorraghic, inflammatory/infectious, malignancy, toxic/nutritional, central pontinemyelinosis and neuromuscular diseases. Identifying a set of “Red Flags” may suggest alternatives diagnosis early in the process ofthe differential diagnosis and systemic features must be examined. Situations in whom the diagnosis of MS is being considered butthe clinical and imaging presentations are atypical, it would be necessary to accomplish additional studies before the diagnosis isstablished

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Fernando GraciaNeurology Department, Hospital Santo Tomas, Panama City, Republic of Panama, Panama

L3. Pathogenesis of MS

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) of probable autoimmuneetiology. In addition to the characteristic inflammatory process, there is a neurodegenerative phenomenon, probably responsible forthe irreversibility of certain symptoms that patients in certain stages of evolution of the disease.

The immunological abnormalities that mediate myelin damage are initiated by activation of the immune system in the periphery,through the recognition of myelin components. This activation determines: a) clonal expansion of autoreactive cells, b) production of various cytokines and c) expression of adhesion molecules that facilitate the penetration of autoreactive cells within the CNS.

These cells are ultimately responsible for tissue damage. Installed parallel axonal damage, which may be due to: a) autoimmune reaction against axonal components, b) changes in the exchange of Na + and Ca + + which induces axonal activation of apoptotic phenomena, c) loss of trophic factors produced by myelin.

Axonal engagement is followed by the expression of axonal growth inhibitory molecules, which are generically known assemaphorins, and are limiting the intrinsic repair mechanisms.

However, many deleterious factors of the immune system in certain situations may be required in the neuro-repair processes. Thus,macrophages and microglia are necessary to remove residual deposits of myelin facilitating regenerative processes. Similarly,activation of the p75 TNF-α receptor and certain IgM antibodies promote remyelination. Similarly, autoreactive cells can produceneurotrophic factors, sometimes a process mediated by IL-1β (one pro-inflammatory cytokine), also contributing to the repairprocess.

In this context it is clear that the end result of damage or repair of the CNS in MS result of the balance between deleteriousphenomena and repair processes, both mediated by the immune system.

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Jorge CorrealeDepartment of Neurology, Institute for Neurological Research Dr. Raúl Carrea, FLENI, Buenos Aires, Argentina

L4. MRI and Mc Donald’s criteria

MS is a chronic devastating disease of the central nervous system; the more important facts in recent years have been the advancesin treatment and the knowledge of mechanisms that conduce to permanent disability. In this line, the concept of a window ofopportunity to treatment have a more robust basis, this concept have been possible for advances in medical images, mainly the MR,which changes our rules in MS practice.

MRI is a necessary tool to perform a prompt diagnosis of MS, that is with no doubt the more important fact in the natural historycourse of MS, because the early and exact diagnosis permit to begin with appropriate therapy, just at first when the efficacy oftherapy is highest, because the possibility to stop or slow the neurodegenration and the spreading antigen.

The introduction of MRI in the MS diagnosis criteria means that making the diagnosis can be made with high reliability since thefirst outbreak of the disease. From three illustrative cases we will review the application of MRI to MS diagnosis.

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Bonaventura CasanovaDepartment of Neurology, University Hospital, La Fe-Valencia, Spain

L5. CSF Biomarkers

Abstract not in hand at the time of printing.

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

CC1. Diagnosis and differential diagnosis

The diagnostic of multiple sclerosis (MS) is complex and must be done by a clinician with each patient considering the clinical history,MIR and all the paraclinic studies that he considers necessary to exclude other diagnostic. The diagnostic criteria that we used areperiodically reviewed and updated and are a excellent guide to affront our patients, but we never forget that each patient is differentand we must done a special effort in discard other potential diagnostic.

The spectrums of disorders mimicking multiple sclerosis that may cause multiple lesions of the central nervous system and followa relapsing course is wide and depend on the type of presentation. In many patients with a typical presentation of MS the diagnosismay be easy for an experienced neurologist, but in other case the diagnosis is a great challenge. Probably the most difficultdiagnostic is to differentiate MS from the spectrum of neuromyelitis optica and sometimes the evolution is the only way to do it.

We will discuss three clinical cases that exemplify the approach during the diagnostic process with the individual patient.

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Claudia CárcamoDepartment of Neurology, Pontificia Universidad Catolica de Chile, Santiago de Chile, Chile

L6. Early treatment

The importance of early treatment in multiple sclerosis (MS) is definitely accepted as the key factor in the relapsing MS. Many studieshave revealed that the amount of inflammatory activity in the early phase of MS predict the time to reach disease milestones, suchas onset of the progressive phase, EDSS 3/4 and brain atrophy. On the contrary the clinical and MRI signs of inflammatory activityhave much less predictive value if observed in established MS and during the progressive phase of the disease. This is probably themajor reason why treatments targeting inflammation (all treatments available today!) have a decreased efficacy during the advancedrelapsing phase and during the progressive phase of MS.

From a pathological angle, one can argue that axonal damage starts very early in the course of the disease. Likewise, inflammatoryactivity in relapsing-remitting MS is not restricted to episodes of clinical impairment, but typically starts before an initial clinicalrelapse which has led to the concept of “clinically absent syndrome” and generally continuous during remission. Moreover, theimmune-mediated processes that underline MS becomes more compartmentalised in the CNS, driven by pathogeneticmechanisms which are quite different from those dominating the relapsing phase of the disease.

Patients with a first event suggestive of MS (also called: clinically isolated syndrome (CIS)) and an abnormal MRI scan have a highrisk of developing MS. The risk is particularly elevated in the first six months following the first attack and is modulated by manyfactors revealed by epidemiological studies and 7 phase III clinical trials performed in CIS patients. Results of these clinical trialswill be reviewed and predictive factors will be analysed. The 2010 revision of the McDonald criteria allow for a quicker diagnosis inmany of CIS patients and have implications on the decision to start treatment. Since many alternatives now exist for treatment ofCIS patients the various algorithms will be discussed and the benefit to risk profile of individual treatments will be presented.

Extension studies of CIS clinical trials have confirmed the long term benefit of early treatment in preventing the conversion toclinically definite MS and some data emerged also in the prevention of disability accumulation. From studies in relapsing-remittingMS, we already have evidence that late treatment initiation or low-dose regimens do not seem to match the benefit of early, high-dose therapy, at least over an observation period of four years (PRISMS Study, 2001). However, now it has been shown that thisconcept is already applicable at the stage when patients display the first signs of MS, which underline the urgent need to treatpatients rather early than wait for further MS signs to develop.

More recently the problem of the so called radiologically isolated syndromes (RIS), a very bad and confusing definition, has emerged,opening the possibility to consider a disease modifying therapy even before the first clinical attack. If treat or not, at least some RIScases are now the new frontier of early treatment.

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

L7. Injectable therapies

The new therapies in MS make difficult to choice the initial treatment for patients and of course we must be in alert with potentialserious adverse events.

In pivotal studies for interferons was demonstrated that early start of treatment modify natural course of disease and now a dayswe know also that improves quality of life and survival.

It is not rare that MS patients reported a lack of adherence or even treatment suspension by different causes including adverseevents, no efficacy, new therapies, etc., this is a key issue when we talk of efficacy and has important consequences in public health,most in Latin American countries. We know that near of 75% of MS patient changes initial treatment and must be discussed inagreement with local health authorities in view that each country can have different political health issues.

In daily practice there are two main aspects to consider for efficacy of chosen therapy: first, long term efficacy derived of follow upstudies from pivotals and second, safety and tolerability issues related with chronic exposure to disease modifiers therapies. Thesedata are now available from years/patient exposure and we can suggest that interferons and glatiramer acetate can be used beyond15-20 years preserving safety and efficacy.

Now a day, there are a lot of new emerging therapies and in view of this the therapeutic choice for MS patients must be individualizedand decisions must be taken together with patient.

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José Flores RiveraDemyielinating Diseases Clinic, National Institute of Neurology and Neurosurgery, Mexico City, Mexico

L8. Oral therapies

Over the last years multiple sclerosis (MS) therapy has experienced a rapid and profound change. Oral drugs are being incorporatedto the therapeutic armamentarium and will modify significantly the current schemes of patient management. Fingolimod has beenthe first oral drug available and a large clinical experience with its use has been accumulated in the last years worldwide.Teriflunomide, dimethylfumarate (BG12) and laquinimod are the next oral drugs, two of them already available in several countries.Each drug targets different aspects of MS pathogenesis; their modification may have a significant impact on the long-term controlof the disease. In this presentation, their mechanisms of action and the results of clinical trials will be reviewed.

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Juan Antonio García-MerinoDepartment of Neurology, Hospital Puerta de Hierro, Universidad Autonoma de Madrid, Madrid, Spain

L9. Antibodies in MS

While multiple sclerosis (MS) is often well controlled with platform immunomodulatory disease-modifying therapy, the interferonsand glatiramer acetate, patients whose disease is not adequately controlled with these standard therapies may benefit fromtreatment with monoclonal antibodies. Monoclonal antibodies can be categorized according to their mechanism of action and theirmolecular targets. The first monoclonal antibody to be approved for the treatment of MS, natalizumab, is targeted against α4-βintegrin, a cell-adhesion molecule expressed on lymphocytes. Blockade of this molecule prevents auto-aggressive T cells fromentering the central nervous system. While generally tolerated very well, natalizumab carries the risk of serious adverse events, inparticular progressive multifocal leukoencephalopathy, which occurs in overall in about 1:1000 treated patients. That risk increaseswith presence of anti-JC virus antibody as a footprint of JCV infection, treatment duration, and prior exposure toimmunosuppressants. Additionally, persistent neutralizing antibodies against natalizumab develop in approximately 6% of patients,rendering therapy largely ineffective. Very recently, a monoclonal antibody initially used for the treatment of leukemia, has beenapproved in the EU. Alemtuzumabs is directed against the CD52 antigen and causes a precipitous and sustained depletion of Tlymphocytes when applied in short annual courses. B cells which also go down in number recover to normal much more quickly.Treatment with alemtuzumab has been shown to be superior to IFNβ1a reducing relapse rate, disability progression and MR diseaseburden. Significant side effects include thyroid autoimmunity, immune thrombocytopenic purpura and glomerulonephritis.AnotherT cell mediated monoclonal, daclizumab, is directed against the intermediate affinity IL-2 receptor and may act by expanding apopulation of regulatory NK cells that diminish the activity of autoaggressive T cells. Monthly sc injections provided major beneficialeffects in a phase 2b registration trial. B cells can be depleted by CD20-targeted monoclonals rituxumab, ocrelizumab andofatumumab. One major mode of action may be the disruption of antigen presentation by B cells to T lymphocytes. Key to the useof monoclonal antibodies is when to initiate therapy, as these agents are much less effective in chronic progressive MS, suggestingthat the optimal window of opportunity exists early in the relapsing course of the disease only. Therefore, careful assessment ofcurrent treatments and disease activity is required, weighing the risk:benefit ratio for individual patients to allow identification ofthose who will profit most from this more aggressive type of therapy and who are willing to accept additional risks in exchange forpotentially greater clinical efficacy. The question of whether different therapeutic antibodies have better suitability for differentsubtypes of MS will be discussed, along with the future role of monoclonal antibodies in the evolving therapeutic landscape andtreatment algorithm.

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Hans-Peter Hartung Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany

References:- Ali R, Nicholas RS, Muraro PA. Drugs in development for relapsing multiple sclerosis. Drugs. 2013 May;73(7):625-50- Bielekova B. Daclizumab therapy for multiple sclerosis. Neurotherapeutics. 2013 Jan;10(1):55-67- Bourdette D, Yadav V. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. Curr Neurol Neurosci Rep. 2008 Sep;8(5):417-8- Clifford DB et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis:lessons from 28 cases. Lancet Neurol 2010;9: 438–46

- Chanvillard C et al. The role of natural killer cells in multiple sclerosis and their therapeutic implications. Front Immunol. 2013;4:63. doi: 10.3389- Chataway J, Miller DH. Natalizumab therapy for multiple sclerosis. Neurotherapeutics. 2013 Jan;10(1):19-28- Deiß A et al. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013 Mar;13(3):313-35- Fox RJ. In the coming year we should abandon interferons and glatiramer acetate as first-line therapy for MS: yes. Mult Scler. 2013 Jan;19(1):24-5- Gold R et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013Jun 22;381(9884):2167-75

- Havla J et al. Fingolimod reduces recurrence of disease activity after natalizumab withdrawal in multiple sclerosis. J Neurol. 2013 May;260(5):1382-7- Havrdova E et al. Disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study.Mult Scler. 2013 Sep 10

- Hawker K. B-cell-targeted treatment for multiple sclerosis: mechanism of action and clinical data. Curr Opin Neurol. 2008 Apr;21 Suppl 1:S19-25- Hillert J. In the coming year we should abandon interferons and glatiramer acetate as first line therapy for MS: no. Mult Scler. 2013 Jan;19(1):26-8- Kappos L et al. Clinical effects of natalizumab on multiple sclerosis appear early in treatment course. J Neurol. 2013 May;260(5):1388-95- Klotz L, Wiendl H. Monoclonal antibodies in neuroinflammatory diseases. Expert Opin Biol Ther. 2013 Jun;13(6):831-46- Leussink VI et al. Rituximab induces clinical stabilization in a patient with fulminant multiple sclerosis not responding to natalizumab. Evidence for diseaseheterogeneity. J Neurol. 2008 Sep;255(9):1436-8

- Oh J, Calabresi PA.Emerging injectable therapies for multiple sclerosis. Lancet Neurol. 2013 Nov;12(11):1115-26- Oleen-Burkey M, Cyhaniuk A, Swallow E. Treatment patterns in multiple sclerosis: administrative claims analysis over 10 years. J Med Econ. 2013;16(3):397-406- Reardon J, Perumal JS.Review of daclizumab and its therapeutic potential in the treatment of relapsing-remitting multiple sclerosis. Drug Des Devel Ther. 2013 Oct9;7:1187-1193

- Rommer P et al. Monoclonal Antibodies in Treatment of Multiple Sclerosis. Clin Exp Immunol. 2013 Sep 4. doi: 10.1111- Saidha S, Calabresi PA. Anti-interleukin-2 receptor alpha for multiple sclerosis? Lancet. 2013 Jun 22;381(9884):2141-3- Yousry TA et al. Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2012 Nov;72(5):779-87- Vidal-Jordana A et al. Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes. Mult Scler. 2013 Aug;19(9):1175-81- Wiendl H, Gross CC.Modulation of IL-2Rα with daclizumab for treatment of multiple sclerosis. Nat Rev Neurol. 2013 Jul;9(7):394-404

L10. When and How to switch therapies

While no curative treatment exists for multiple sclerosis (MS), several disease-modifying therapies (DMTs) have been developed toreduce relapse rates, slow disability progression, and modify the overall disease course.

There is a variable response to MS disease-modifying therapies on an individual basis ranging from the super responder, withvirtually no disease activity, to a whole spectrum of partial responders to even the biological non-responders.

Approximately 30% of patients show a suboptimal therapeutic response during the early treatment years.

The issue becomes the definition of unacceptable breakthrough activity.

Measures used to identify patients with breakthrough disease include clinical measures (compliance with treatment, relapses andprogression on the expanded disability status scale), MRI measures (gadolinium-enhancing lesions and new T2 hyperintenselesions), and biological markers of therapy.

These measures have been used to identify the proportion of patients with breakthrough disease, to quantify the level ofbreakthrough disease, and to identify patients at risk for poor prognosis.

The most common approach to unacceptable treatment response is to switch therapy.

Optimal time to switch should be early when there is breakthrough activity, because of the risk for permanent damage incurred thelonger a patient remains on suboptimal therapy.

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Liliana PatruccoNeurology Department, Italian Hospital of Buenos Aires, Buenos Aires, Argentina

L11. Risks and side effects management for DMDs

Risk communication is not a simple task, and one should consider many aspects when addressing this issue.

New therapies for multiple sclerosis have opened new opportunities but at the same time have made neurologists confront newsituations.

Over the last years a group of next-generation therapies have been approved in different parts of the world. These are Natalizumab,Fingolimod, Teriflunomide, Dimethyl Fumarate and Alemtuzumab.

Natalizumab has been released to the market years ago and has a well known safety profile. A relatively common side effect includesinfusion reaction, but usually does not involve serious risk. The issue that must be taken into account is the presence of JC virus andthe possibility of developing progressive multifocal leukoencephalopathy. The pharmaceutical company has developed a riskstratification that is updated regularly for better monitoring and communication with patients.

Fingolimod was the first oral medication for the disease. It opened a new window of treatment. It is mandatory to monitor cardiacfunction during the first dose, as well as visual functions, hepatic, hematologic and search for infections during follow up.

Teriflunomide has been approved in the current year in Argentina. It is a medication with a very good tolerability and safety profile,but certain precautions should be taken into account regarding contraception methods.

Dimethyl fumarate has been marketed in some countries of the world proving to be a fairly safe drug. But unlike the abovementioned drug, it is not always well tolerated. Finally, Alemtuzumab has recently been approved in Europe. It is a drug with a highlevel of efficacy, but requires monitoring of autoimmunity, infections and infusion reactions.

The monitoring and therapeutic risk management involves warning, permanent controls, corrective and preventive actions. Far frombeing a passive process, we must take an active roll to face the security challenges of new therapies for multiple sclerosis.

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Vladimiro SinayDemyielinating Diseas Clinic, Neurology Department, Institute of Neurosciences, Fundación Favaloro, Buenos Aires, Argentina

KN1. Stem cell therapy: where do we stand?

Multiple sclerosis (MS) is considered an autoimmune disease that affects persons genetically susceptible, over which acts someenvironmental unknown factor, causing an altered immune response, directed against myelin antigens of the central nervoussystem, giving rise to an inflammatory, demyelinating and neurodegenerative disease.

MS can be treated, with immunomodulators, which reduce around 30% of disease activity. In non-responders, therapy escalates toa second line comprised by immunosuppressants which are able to reduce around 60-70% of MS clinical activity. Some MS casesare really aggressive and can be treated with bone marrow transplantation, but this exceptional therapy is associated with 1-2%mortality.

There are patients in whom all therapies fail and clinical and magnetic resonance (MR) activity are maintained. Spontaneousremyelination does occur in MS, but it is limited, and decreases with disease progression. The failure of remyelination can be due toa failure of recruiting or migration of endogenous oligodendrocyte precursors (OPCs), failure of OPC differentiation to remyelinatingoligodendrocytes or to the existence of a deregulated signaling environment.

Stem cell can be obtained from embryos, fetal or adult tissues. Cell from embryos or fetal tissues have, on one hand, ethicalproblems, and on the other hand its use can originate problems of oncogenesis. Due to these problems it has been preferred toinitiate this kind of therapy in humans using autologous mesenchymal stem cells (MSC), which can be found in adult tissues (fat,skin, bone marrow, etc.). These cells are capable to grow, differentiate and repair. Also these cells have regulatory functions in thedifferent organs, and can migrate to other places to develop their regulatory and regenerative activities.

Experimental studies performed in all models of Experimental Autoimmune Encephalomyelitis, using either animal or human MSChave shown that the treatment with MSC is able to produce remyelination and even neurogenesis. Both in mice and humans, it hasbeen possible to demonstrate the occurrence of transdifferentiation of MSC into cells expressing oligodendrocyte and neuronalmarkers. Those cells can produce remyelination when administered by intravenous, intrathecal or local routes.

At present, there are many clinical trials in MS, only one has shown some hints of efficacy, but all of them have shown this therapyto be safe. The treatment of MS with stem cell must be considered, by now, as a treatment exclusively experimental.

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Óscar FernándezDepartment of Neurology, Hospital Regional Universitario Carlos Haya, Malaga, Spain

CC2. Treatment algorithms

Abstract not in hand at the time of printing.

24

Rafael ArroyoService of Neurology, Clinical Hospital of San Carlos, Martin Lago Madrid, Spain

L12. Cognitive impairment: the extent of the problem

Multiple sclerosis (MS) is a chronic immflamatory and demyelinating disease of the central nervous system and axonal damage hasalso been showed. MS is associated with discapacity and negatively affects quality of life.

Even when motor dysfunction is a major characteristic of MS, cognitive impairment (CI) is one of the most relevant findings in MS.It may occur early in the course of disease worsening with progression and represent a heavy load to patients and society.

Several epidemiological studies showed a frequency of 45 to 60 percent of CI in different populations. The cognitive domains morefrequently affected includes atention, memory and speed of information processing.

Although CI is usually observed late in the course of the disease, it has been describe to be present in Isolated Clinical Syndromeand also in Radiological Isolated Syndrome.

The mechanisms of damage in the CI are those related with axonal loss. White and Grey matter involvement has been demonstrated.CI is related with brain atrophy and underscore in neuropsychological examination. Sophisticated techniques in Magnetic ResonanceImaging (MRI) and validated cognitive batteries studies show interesting findings including subcortical and cortical damage.

Initial pivotal and head-to-head trials of disease modifying drugs did not include CI as a primary end-point and the impact ofinterferons and glatiramer acetate as secondary or tertiary out-comes is not well evaluated. Recent intravenous and oral drugsincludes cognitive evaluation as a relevant end point and some had shown modest effect on CI.

Less than four percent of MS published papers are related to CI. Middle and Low income countries deals with a worse situation.Latinamerica recently has validated cognitive batteries and published cognitive profiles of this large pòpulation. Concluding: It ismandatory to establish an homogeneus approach to CI assessment in order to have early diagnosis and more effective treatments.

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Miguel Ángel MacíasDepartment of Clinical Neurology, Centro Médico Nacional de Occidente, IMSS Clinical Research Mexican, Multiple Sclerosis Foundation, Guadalajara, Mexico

L13. The role of white and grey matter: MRI findings

Cognitive symptoms are very frequent in multiple sclerosis and may be present since after the first relapse. Conventional magneticresonance imaging (MRI) techniques support the hypothesis that cognitive impairment correlates with white matter lesion burden.Also, non-conventional MRI techniques such as magnetization transfer MRI, showed that the location of lesions in eloquent sitesmay have a central role in the pathogenesis of MS neuropsychological impairment.

It has been demonstrated that gray matter disease in MS is associated to disability and cognitive dysfunction, as well. Corticaldemyelinating lesions are long recognized in MS, represent up to 26% of total number of plaques and in some patients, precede theappearing of white matter plaques. In the last ten years, new MRI techniques allowed for a better understanding of gray matterlesion development and progression and several studies correlated disability, fatigue and EDSS progression to the extent of thecortical damage.

Recently it has been demonstrated that the presence of intracortical lesions may be used as criterion for establishing disseminationin space and improving accuracy of the available diagnostic criteria when used in combination.

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Enedina Maria OliveiraNeuroimmunology Center, MS clinic, Neurology & Neurosurgery Department, Federal University of São Paulo, São Paulo, Brazil

L14. “Invisible symptoms” (Fatigue, affective disorders)

The treatment of multiple sclerosis (MS) can be divided into immunomodulatory and symptomatic treatment. While research madein the past 20 years has provided doctors and patients with drugs that exert effect on the immune system and disease progression,many patients still suffer with the consequences of neurologic disability and request for complementary treatment in order toimprove their quality of life.

Fatigue is the most common symptom in MS, albeit it is multifactorial and its pathophysiology not well understood. It is typicallyviewed as a subjective feeling experienced by an individual but can also be conceptualized as fatigability consisting of either a motoror cognitive behavioral performance decrement over time during a specific task (such as walking, doing housekeeping or on aworking environment). The presence and degree of fatigue can be influenced by disease factors, such motor disability, cognitivedecline, disease duration comorbidities, such as depression, poor sleep quality, and external factors, such as medications, infectionsand temperature changes, and influences quality of life and employment status. The treatment of fatigue is also multifactorial, andinvolves avoiding precipitating factors, treatment of comorbidities and relapses, adequate use of disease modifying drugs,programed physical exercise and specific drugs to treat fatigue, amongst which amantadine and modofanil are the most used.

The prevalence of major depression in MS patients ranges from 15-30% and the lifetime prevalence of 40-60%. Interestingly, the rateof depression in MS is higher than other chronic illness, including other neurological diseases, which suggests that factors relatedto brain inflammation and lesions exerts influence in the development of depression rather than the patient’s environmentalsituation itself. Depression can develop regardless of MS subtype, disease duration and disability status, and also influences patient’squality of life, employment status, marital status, adherence to immunomodulatory treatment and longevity, thus its identificationand adequate treatment must be implement by anyone involved in MS care. Broadly any antidepressant can be used by MS patients,but the choice of treatment must individualized, since anticholinergic drugs can worsen bowel immobility and serotoninergic drugscan worsen spasticity and some can worsen fatigue, for example, but also some drugs can exert influence on sleep quality, urinaryincontinence and pain, and thus can be adjunctive to other symptoms. Psychotherapy should be used solely or complementary todrug interventions for the treatment of depression and comorbid anxiety, as both may coexist in many patients. Emotional lability,such as pathological laughing and crying, can happen even in the absence of depressive symptoms, and can be treated withserotoninergic drugs or neuroleptics.

Although there are many standardized questionnaires used to screen fatigue, depression and anxiety, it remains to the clinician’sbest judgment to perceive its diagnosis and discuss therapeutics option with each patient.

27

Denis Bernardi BichuettiNeurology Department, Federal University of São Paulo, São Paulo, Brazil

L15. Neuropsychological assessment and treatment ofcognitive dysfunction

Abstract not in hand at the time of printing.

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Juan Raúl García BonittoNeurology Department, Clínica de Marly, Bogotá, Colombia

L16. Socio-economic impact

Abstract not in hand at the time of printing.

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Alfredo Rodríguez AntigüedadService of Neurology, Hospital of Basurto, Bilbao, Spain

L17. The role of rehabilitation

The goal of rehabilitation is to improve and maintain function.MS patients with no disability, normally on early phases of the disease,should be advised by physicians to practice physical exercises as routine to promote good health and general conditioning, reducingfatigue, helping the patient to fell and function at best. If symptoms begin to interfere with everyday activities, a rehab team canaddress problems with mobility, dressing and personal care, role performance at home and work, and overall fitness. They alsoprovide evaluation and treatment of speech and swallowing difficulties and problems with thinking and memory. Rehabilitation isconsidered a necessary component of comprehensive, quality health care for people with MS, at all stages of the disease.

In this lecture we will present a review about the “Types of Rehabilitation Therapies”, focusing the main frequent dysfunctions in MSpatients: spasticity, cognitive rehabilitation, disorders of mood and affect, ataxia and imbalance, sexual and bladder dysfunction andbulbar dysfunctions.

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Marcos Papais AlvarengaDepartment of Neurology, Universidade Federal do Estado do Rio de Janeiro, Centro de Ciências Biológicas e da Saúde,Rio de Janeiro, Brazil

L18. Case-based approach to symptom management

Abstract not in hand at the time of printing.

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Jorge Barahona StrauchUniversidad Católica de Chile, Universidad des Desarollo, Clinica Alemana, Santiago, Chile

L19. Perceptions of multiple sclerosis patients regardingtheir clinical care

1 - Neurologist, Neurology Service, Hospital Barros Luco, South Neurology Department, Universidad de Chile, Santiago de Chile, Chile;2 - Sociologist, associate consultant, National Reference Center for the Diagnosis and Treatment of MS of the public health system of Chile, Santiago

de Chile, Chile.

The knowledge by the health care team concerning to the perceptions of patients with multiple sclerosis (MS) is an ethical andclinical imperative. Even though these ones have a very dynamic and diverse expression depending on biographical and psychosocialcharacteristics of the patient, time and course of the disease and impact of this on quality of life, you may recognize some commonelements.

MS is usually experienced as a "biographical permanent disruption" that is, it is lived as a dramatic and unexpected change in allthe dimensions of the life, establishing a "before and after". The coexistence of relapsing remitting clinical events with changingsymptoms and sometimes complete absence of them, with a chronic and degenerative unpredictable prognosis process, configurea permanent perception of uncertainty for the patient, making difficult their ability to accept and adapt to an ever-changing disease.

It is a common report in MS patients, the difficulty they lived to reach a definitive medical diagnosis. This is even more remarkablein the case of the clinical isolated syndrome, especially when it is presented with few and mild symptoms, because it involvesassuming something, this is not strictly MS and treat it with the same strength as if it were. This setting makes the diagnosis processbe a favorable space for doubt and mistrust towards treatment, determining a complex and variable disposition of MS patientsregarding treatment.

This perception of facing something generally unknown and of a chronic character in a stage of life, without culture or experiencein chronic diseases because they are mostly young individuals, generates greater difficulty in assuming the disease, in many casesgenerating an initial "denial", fed back by a disease with periods of "normal" clinical appearance inter outbreaks. The overalluncertainty of the new situation usually leads to a compulsive search for information primarily on the internet, finding data that cansometimes give a clear answer, but most of the times are alarming and contradictory. This recurring situation requires explicitsupport and guidance of the health care team.

During the disease, four invisible elements to laboratory control tests appear in a spontaneous way, as central to the impacts in thequality of life: general fatigue, which transversely occurs throughout all dimensions of everyday life. Progressive loss of physical andcognitive autonomy. Gradual loss of activity in the social networks that previously belonged. Sexual and sphincters dysfunction.

Regarding health care, the characteristics best valued by patients are: professional knowledge of the MS subject which is bettervalued if it is accompanied with direct experience with a significant number MS patients. Experience is evaluated as the way of feelingconcerned with some of the patient´s worries or problems which are often, not even, understood by other doctors. Patients thankthe information if it is proposed in schematic and understandable form privileging the everyday problems, over a big quantity ofinformation related with clinical or technical aspects.

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Jorge Nogales-Gaete, Santiago de Chile, Chile 1

Alejandra Nogales-Collao, Santiago de Chile, Chile 2

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