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Cambridge University Press978-0-521-76627-2 - Multiple Sclerosis Therapeutics: Fourth EditionEdited by Jeffrey A. Cohen and Richard A. Rudick FrontmatterMore information

Multiple Sclerosis TherapeuticsFourth Edition

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Multiple Sclerosis TherapeuticsFourth EditionEdited byJeffrey A. Cohen, MDDirector, Experimental Therapeutics Program, Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Richard A. Rudick, MDDirector, Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA






CAMBRIDGE UNIVERSIT Y PRESSCambridge, New York, Melbourne, Madrid, Cape Town,Singapore, Sao Paulo, Delhi, Tokyo, Mexico City

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Library of Congress Cataloging in Publication dataMultiple sclerosis therapeutics / edited by Jeffrey A. Cohen,Richard A. Rudick. – 4th ed.

p. ; cm.Includes bibliographical references and index.ISBN 978-0-521-76627-2 (hardback)I. Cohen, Jeffrey A. (Jeffrey Alan), 1954– II. Rudick, Richard A.III. Title.[DNLM: 1. Multiple Sclerosis – therapy. 2. Clinical Trials as Topic –methods. 3. Magnetic Resonance Imaging. 4. Multiple Sclerosis –pathology. 5. Outcome Assessment (Health Care) WL 360]LC classification not assigned616.8′34 – dc23 2011030483

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Contents

List of contributors page viiiAbbreviations list xiiiForeword xvStephen C. ReingoldPreface xvii

Section I – Introduction1 Aspects of multiple sclerosis that relate to

experimental therapeutics 1Richard A. Rudick and Jeffrey A. Cohen

2 The pathology of multiple sclerosis 12Ranjan Dutta and Bruce D. Trapp

3 The immunology of multiple sclerosis 20Amit Bar-Or and Peter J. Darlington

4 The genetics of multiple sclerosis 35Jorge R. Oksenberg, Sergio E. Baranzini, andStephen L. Hauser

5 The epidemiology of multiple sclerosis 46Ruth Ann Marrie and Helen Tremlett

Section II – Clinical trial methodology6 Measures of neurological impairment and

disability in multiple sclerosis 56Gary R. Cutter, Charity J. Morgan, Amber R.Salter, Stacey S. Cofield, and Laura J. Balcer

7 Assessment of neuropsychological function inmultiple sclerosis 65Stephen M. Rao

8 Health-related quality of life assessment inmultiple sclerosis 79Deborah M. Miller, Michael W. Kattan, and Alex Z. Fu

9 Measures of acute and chronic lesionsvisualized by conventional magneticresonance imaging 91Jack H. Simon and Jerry S. Wolinsky

10 Measures of magnetization transfer 112Massimo Filippi, Joseph C. McGowan, andMaria A. Rocca

11 Measurement of CNS atrophy 128Elizabeth Fisher

12 Axonal pathology in patients with multiplesclerosis: Evidence from in vivo protonmagnetic resonance spectroscopy 150Sridar Narayanan, Zografos Caramanos, Paul M.Matthews, and Douglas L. Arnold

13 Imaging of gray matter lesions in multiplesclerosis 165Mike P. Wattjes, Jeroen J.G. Geurts, and Frederik Barkhof

14 Functional imaging in multiple sclerosis 175Kyle C. Kern and Nancy L. Sicotte

15 Diffusion imaging in multiple sclerosis 186Stephen E. Jones and Michael D. Phillips

16 The use of MRI in multiple sclerosis clinicaltrials 198Robert A. Bermel, Elizabeth Fisher, Peter B. Imrey,and Jeffrey A. Cohen

17 Optical coherence tomography to monitoraxonal and neuronal integrity in multiplesclerosis 213Kristin M. Galetta and Laura J. Balcer

18 The process of drug development andapproval in the United States, the EuropeanUnion, and Asia 225Nadine Cohen, Ann Dodds-Frerichs, TammyPhinney, and Paula Sandler

19 Selection, interpretation, and development ofend-points in multiple sclerosis clinical trials 232Marc K. Walton

20 The challenge of demonstrating long-termbenefit of disease-modifying therapies inmultiple sclerosis 244Maria Trojano

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Contents

21 The growing need for alternative clinical trialdesigns for multiple sclerosis 253Stephen C. Reingold, Henry F. McFarland, andA. John Petkau

22 Ethical considerations in multiple sclerosisclinical trials 261Aaron E. Miller, Nada Gligorov, and Stephen C. Krieger

23 Pharmacogenomics and relateddiscovery-driven approaches in multiplesclerosis 272Paulo Fontoura and David Leppert

24 Neutralizing antibodies directed againstbiologic agents to treat multiple sclerosis 287Per Soelberg Sørensen

Section III – Clinical trials of multiplesclerosis therapies

25 Interferon beta to treat multiple sclerosis 300Richard A. Rudick

26 Glatiramer acetate to treat multiplesclerosis 315Jenny Guerre and Corey C. Ford

27 Natalizumab to treat multiple sclerosis 330Chris H. Polman, Joep Killestein, and Richard A. Rudick

28 Mitoxantrone to treat multiple sclerosis 344Gilles Edan and Emmanuelle Le Page

29 Cladribine to treat multiple sclerosis 358Gavin Giovannoni and Stuart D. Cook

30 Fingolimod to treat multiple sclerosis 370Jeffrey A. Cohen

31 Dimethyl fumarate to treat multiple sclerosis 387Robert J. Fox and Ralf Gold

32 Alemtuzumab to treat multiple sclerosis 393Orla Tuohy and Alasdair J. Coles

33 Daclizumab to treat multiple sclerosis 399Jaume Sastre-Garriga and Xavier Montalban

34 Laquinimod to treat multiple sclerosis 405Douglas R. Jeffery

35 Teriflunomide to treat multiple sclerosis 410Paul W. O’Connor

36 High-dose methylprednisolone to treatmultiple sclerosis 418Robert J. Fox and R. Philip Kinkel

37 Use of immunosuppressants to treat multiplesclerosis 436James M. Stankiewicz and Howard L. Weiner

38 Intravenous immunoglobulin to treat multiplesclerosis 444Franz Fazekas, Siegrid Fuchs, Per SoelbergSørensen, and Ralf Gold

39 Plasma exchange treatment for CNSinflammatory demyelinating disease 454Brian G. Weinshenker, B. Mark Keegan, Jeffrey L.Winters, Ichiro Nakashima, and Kazuo Fujihara

40 Statins in multiple sclerosis 465Martin S. Weber, Emmanuelle Waubant, and ScottS. Zamvil

41 T-cell-based therapies for multiplesclerosis 472Tanuja Chitnis and Samia J. Khoury

42 B-cell-based therapies for multiplesclerosis 483Emmanuelle Waubant and Amit Bar-Or

43 Sex hormones and other pregnancy-relatedfactors with therapeutic potential in multiplesclerosis 498Rhonda R. Voskuhl

44 Hematopoietic stem cell transplantation totreat multiple sclerosis 508Richard K. Burt and Francesca Milanetti

45 Mesenchymal stem cell transplantation totreat multiple sclerosis 520Don Mahad, Sarah M. Planchon, and Jeffrey A. Cohen

46 Neuroprotection in multiple sclerosis 535Avindra Nath and Peter A. Calabresi

47 Combination therapy in multiplesclerosis 547Michelle Fabian and Fred D. Lublin

48 Dalfampridine in multiple sclerosis 557Andrew D. Goodman

49 Complementary and alternative treatments inmultiple sclerosis 562Vijayshree Yadav, Lynne Shinto, and Dennis N.Bourdette

50 The role of chronic cerebrospinal venousinsufficiency in multiple sclerosis 574Devon Conway, Soo Hyun Kim, and AlexanderRae-Grant

vi






Contents

Section IV – Therapy in clinical practice51 Disease-modifying therapy for multiple

sclerosis in clinical practice 583Jeffrey A. Cohen and Andrew D. Goodman

52 Treatment for patients with primaryprogressive multiple sclerosis 604Zhaleh Khaleeli and Alan J. Thompson

53 Diagnosis, pathogenesis, and treatment ofneuromyelitis optica (NMO) spectrumdisorders 614Sean J. Pittock

54 Management of pediatric multiplesclerosis 632E. Ann Yeh and Bianca Weinstock-Guttman

55 Use of MRI in the clinical management ofmultiple sclerosis 645J. Theodore Phillips and Lael A. Stone

56 Multiple sclerosis-associated fatigue 654Lauren B. Krupp and Dana J. Serafin

57 Management of spasticity 666Francois A. Bethoux and Matthew Sutliff

58 Management of bladder and sexualdysfunction in multiple sclerosis 676Natasha Frost, Jessica Szpak, Scott Litwiller, andAlexander Rae-Grant

59 Depression in multiple sclerosis 696Adam I. Kaplin and Ryan E. Stagg

60 Assessment and treatment of pain disordersin multiple sclerosis 707Jahangir Maleki and Amy Sullivan

61 Management of medical comorbidities inpatients with multiple sclerosis 714John R. Scagnelli and Myla D. Goldman

62 Rehabilitation in multiple sclerosis 724Francois A. Bethoux and Matthew Sutliff

Index 731Color plates appear between p. 398 and 399

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Contributors

Douglas L. Arnold, MDJames McGill Professor of Neurology; Director, MagneticResonance Spectroscopy Unit, Montreal NeurologicalInstitute, McGill University, Montreal, Quebec, Canada

Laura J. Balcer, MD, MSCEDepartment of Neurology, University of Pennsylvania Schoolof Medicine, Philadelphia, PA, USA

Amit Bar-Or, MD, FRCPCAssociate Professor, Neurology & Neurosurgery and AssociateProfessor, Microbiology & Immunology, McGill University;Director, Experimental Therapeutics Program, MontrealNeurological Institute; Staff Neurologist, MontrealNeurological Hospital, McGill University Hospital Center,Montreal, Quebec, Canada

Sergio E. Baranzini, PhDDepartment of Neurology, University of California at SanFrancisco, San Francisco, CA, USA

Frederik Barkhof, MD, PhDProfessor, Department of Diagnostic Radiology, VUUniversity Medical Center, Amsterdam,The Netherlands

Robert A. Bermel, MDMellen Center for Multiple Sclerosis Treatment and Research,Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Francois A. Bethoux, MDMellen Center for Multiple Sclerosis Treatment and Research,Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Dennis N. Bourdette, MDChair and Roy and Eulalia Swank Family Research Professor,Department of Neurology, Oregon Health Sciences University,Portland, OR, USA

Richard K. Burt, MDDivision of Immunotherapy, Department of Medicine,Northwestern University, Feinberg School of Medicine,Chicago, Il, USA

Peter A. Calabresi, MDProfessor of Neurology, Director, The John Hopkins MultipleSclerosis Center, Director, Division of Neuroimmunology andNeuroinfectious Diseases, Department of Neurology, JohnHopkins University, Baltimore, MD, USA

Zografos Caramanos, MAMagnetic Resonance Spectroscopy Unit, MontrealNeurological Institute, McGill University, Montreal, Quebec,Canada

Tanuja Chitnis, MDDepartment of Neurology, Brigham and Women’s Hospital,Center for Neurologic Disease, Partners MS Center, HarvardMedical School, Boston, MA, USA

Stacey S. Cofield, PhDDepartment of Biostatistics, University of Alabama atBirmingham, Birmingham, AL, USA

Jeffrey A. Cohen, MDDirector, Experimental Therapeutics Program, Mellen Centerfor Multiple Sclerosis Treatment and Research, NeurologicalInstitute, Cleveland Clinic, Cleveland, OH, USA

Nadine Cohen, PhDSenior Vice President, Regulatory Affairs, Biogen Idec Inc.,Cambridge, MA, USA

Alasdair J. Coles, PhD, FRCPDepartment of Clinical Neurosciences, University ofCambridge, Addenbrooke’s Hospital, Cambridge, UK

Devon Conway, MD, MSCMellen Center for Multiple Sclerosis Treatment and Research,Neurological Institute, Cleveland Clinic Foundation,Cleveland, OH, USA

Stuart D. Cook, MDUniversity of Medicine and Dentistry, New Jersey MedicalSchool, Newark, NJ, USA

viii






List of contributors

Gary R. Cutter, PhDDepartment of Biostatistics, University of Alabama atBirmingham, Birmingham, AL, USA

Peter J. Darlington, PhDResearch Associate, Montreal Neurological Institute,Neuroimmunology Unit, McGill University, Montreal,Quebec, Canada

Ann Dodds-Frerichs, MBASenior Director, Regulatory Affairs, Biogen Idec Inc.,Cambridge, MA, USA

Ranjan Dutta, PhDProject Staff, Department of Neurosciences, Cleveland Clinic,Cleveland, OH, USA

Gilles Edan, MDChef de Service de Neurolosie Clinique Neurologie, CHUPontchaillou, Rennes, France

Michelle Fabian, MDAssistant Professor of Neurology, Corinne GoldsmithDickinson Center for Multiple Selerosis, Department ofNeurology, Mount Sinai School of Medicine, New York,NY, USA

Franz Fazekas, MDDepartment of Neurology, Medical University of Graz, Graz,Austria

Massimo Filippi, MDNeuroimaging Research Unit, Institute of ExperimentalNeurology, Division of Neuroscience, San Raffaele ScientificInstitute, Vita-Salute, San Raffaele University, Milan, Italy

Elizabeth Fisher, PhDDepartment of Biomedical Engineering, Lerner ResearchInstitute, Cleveland Clinic, Cleveland, OH, USA

Paulo Fontoura, MD, PhDDepartment of Immunology, Faculty of Medical Sciences, NewUniversity of Lisbon, Lisbon, Portugal

Corey C. Ford, MD, PhDDepartment of Neurology, University of New Mexico,Albuquerque, NM, USA

Robert J. Fox, MDMedical Director, Mellen Center for Multiple SclerosisTreatment and Research, Neurological Institute, ClevelandClinic, Cleveland, OH, USA

Natasha Frost, MD, MSCDean Health System, Madison, WI, USA

Alex Z. Fu, PhDDepartment of Quantitative Health Sciences, Cleveland Clinic,Cleveland, OH USA

Siegrid Fuchs, MDDepartment of Neurology, Medical University of Graz, Graz,Austria

Kazuo Fujihara, MDDept of Multiple Sclerosis Therapeutics and Neurology,Tohoku University, Sendai, Japan

Kristin M. Galetta, MSDepartment of Neurology, University of Pennsylvania Schoolof Medicine, Philadelphia, PA, USA

Jeroen J.G. Geurts, PhDMR Center for MS Research, VU University Medical Center,Amsterdam, The Netherlands

Gavin Giovannoni, MBBCh, PhDBlizard Institute of Cell and Molecular Science, Barts and TheLondon School of Medicine and Dentistry, Queen MaryUniversity of London, London, UK

Nada Gligorov, PhDAssistant Professor of Medical Education, Mount Sinai Schoolof Medicine, New York, NY, USA

Ralf Gold, MDDepartment of Neurology, St. Josef-Hospital andRuhr-University Bochum, Bochum, Germany

Andrew D. Goodman, MDDepartment of Neurology, University of Rochester School ofMedicine and Dentistry, Rochester, NY, USA

Myla D. Goldman, MD, MScDepartment of Neurology, University of Virginia,Charlottesville, VA, USA

Jenny Guerre, MDDepartment of Neurology, University of New Mexico,Albuquerque, NM, USA

Stephen L. Hauser, MDProfessor and Chair, Department of Neurology, University ofCalifornia at San Francisco, San Francisco, CA, USA

Peter B. Imrey, PhDProfessor of Medicine, Department of Quantitative HealthSciences, Cleveland Clinic, Cleveland, OH, USA

Douglas R. Jeffery, MD, PhDThe Multiple Sclerosis Center at Advance Neurology, Advance,NC, USA

Stephen E. Jones, MD, PhDDepartment of Diagnostic Radiology, Imaging Institute,Cleveland Clinic, Cleveland, OH, USA

Adam I. Kaplin, MD, PhDAssistant Professor of Psychiatry and Neurology, Departmentsof Psychiatry and Behavioral Sciences and Neurology, John

ix







Hopkins University School of Medicine, Baltimore, MD,USA

Michael W. Kattan, PhDChair, Department of Quantitative Health Sciences, ClevelandClinic, Cleveland, OH, USA

B. Mark Keegan, MDAssociate Professor and Consultant of Neurology, Departmentof Neurology, School of Medicine, Mayo Clinic, Rochester,MN, USA

Kyle C. Kern, MSStaff Research Associate, Department of Neurology, DavidGeffen School of Medicine, UCLA, Los Angeles, CA, USA

Zhaleh Khaleeli, PhDSpecialist Registrar in Neurology, Institute of Neurology,University College London, Queen Square, London, UK

Samia J. Khoury, MDDepartment of Neurology, Brigham and Women’s Hospital,Center for Neurologic Disease, Partners MS Center, HarvardMedical School, Boston, MA, USA

Joep Killestein, MD, PhDDepartment of Neurology, VU Medical Center, Amsterdam,The Netherlands

Soo Hyun Kim, MDCardiovascular Medicine, Section of Vascular Medicine,Cleveland Clinic, Cleveland, OH, USA

R. Philip Kinkel, MDDirector, Multiple Sclerosis Program, Beth Israel DeaconessMedical Center; Associate Professor of Neurology, HarvardMedical School, Boston, MA, USA

Stephen C. Krieger, MDAssistant Professor of Neurology, Corinne GoldsmithDickinson Center for Multiple Sclerosis, Department ofNeurology, Mount Sinai School of Medicine, New York, NY,USA

Lauren B. Krupp, MDStony Brook University Medical Center, Department ofNeurology, Stony Brook, NY, USA

Emmanuelle Le Page, MDService de Neurologie, Hopital Pontchaillou, Rennes, France

David Leppert, MDAssociate Professor, Department of Neurology, UniversityHospital Basel, Switzerland

Scott Litwiller, MDUrologic Associates of Oklahoma, Tulsa, OK,USA

Fred D. Lublin, MDSaunders Family Professor of Neurology, Corinne GoldsmithDickinson Center for Multiple Sclerosis, Department ofNeurology, Mount Sinai School of Medicine, New York, NY,USA

Henry F. McFarland, MDChief, Neuroimmunology Branch, National Institute ofNeurological Disorders and Stroke, National Institutes ofHealth, Bethesda, MD USA

Joseph C. McGowan, PhDExponent Inc. Philadelphia, PA, USA

Don Mahad, MD, PhDMellen Center for MS Treatment and Research, NeurologicalInstitute, Cleveland Clinic, Cleveland, OH, USA

Jahangir Maleki, MD, PhDNeurological Center for Pain, Neurological Institute,Cleveland Clinic, Cleveland, OH, USA

Ruth Ann Marrie, MD, PhDAssociate Professor of Medicine, Departments of InternalMedicine and Community Health Sciences, University ofManitoba, Winnipeg, Manitoba, Canada

Paul M. Matthews, MD, DPhilCentre for Neurosciences, Division of Experimental Medicineand Toxicology, Imperial College, London; GlaxoSmithKlineClinical Imaging Centre, Hammersmith Hospital, London,UK

Francesca Milanetti, MDDivision of Immunotherapy, Department of Medicine,Northwestern University, Feinberg School of Medicine,Chicago, IL, USA; Division of Clinical Immunology andRheumatology, S. Andrea University Hospital, “Sapienza”University of Rome, II School of Medicine, Rome, Italy

Aaron E. Miller, MD, FAANProfessor of Neurology, Corinne Goldsmith Dickinson Centerfor Multiple Sclerosis, Department of Neurology, Mount SinaiSchool of Medicine, New York, NY, USA

Deborah M. Miller, PhDDirector, Comprehensive Care, Mellen Center for MultipleSclerosis Treatment and Research, Cleveland Clinic,Neurological Institute, Cleveland, OH, USA

Xavier Montalban, MDUnitat de Neuroimmunologia Clınica, Multiple SclerosisCentre of Catalonia (CEM-Cat), Vall d’Hebron UniversityHospital, Barcelona, Spain

Charity J. Morgan, PhDFood and Drug Administration, Silver Spring, MD, USA

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Ichiro Nakashima, MDDepartment of Multiple Sclerosis Therapeutics and Neurology,Tohoku University, Sendai, Japan

Sridar Narayanan, PhDDepartment of Neurology and Neurosurgery, MagneticResonance Spectroscopy Unit, Montreal NeurologicalInstitute, McGill University, Montreal, Quebec, Canada

Avindra Nath, MDThe John Hopkins Multiple Sclerosis Center, Departmentof Neurology, John Hopkins University, Baltimore, MD,USA

Paul W. O’Connor, MD, MScWaugh Family Chair in Multiple Sclerosis Research; Professor,Department of Health Policy, Management and Evaluation,University of Toronto, Toronto, Ontario, Canada

Jorge R. Oksenberg, PhDDepartment of Neurology, University of California at SanFrancisco, San Francisco, CA, USA

A. John Petkau, PhDProfessor, Department of Statistics, University of BritishColumbia, Vancouver, British Columbia, Canada

Michael D. Phillips, MDDepartment of Diagnostic Radiology, Imaging Institute,Cleveland Clinic, Cleveland, OH, USA

J. Theodore Phillips, MD, PhDDirector, Multiple Sclerosis Program, Baylor Institute forImmunology Research, Baylor University Medical Center,Dallas, TX, USA

Tammy Phinney, MSCDirector, Regulatory Affairs, Biogen Idec Inc., Cambridge,MA, USA

Sean J. Pittock, MB, BAO, BCh, MMedSci, MDAssociate Professor of Neurology, Department of Neurology,College of Medicine, Mayo Clinic, Rochester,MN, USA

Sarah M. Planchon, PhDMellen Center for MS Treatment and Research, NeurologicalInstitute, Cleveland Clinic, Cleveland, OH, USA

Chris H. Polman, MD, FRCP, FRCPIProfessor and Chair, Department of Neurology, VU MedicalCenter, Amsterdam, The Netherlands

Alexander Rae-Grant, MDMellen Center for Multiple Sclerosis Treatment and Research,Neurological Institute, Cleveland Clinic Foundation,Cleveland, OH, USA

Stephen M. Rao, PhDDirector, Schey Center for Cognitive Neuroimaging, Lov RuvoCenter for Brain Health, Neurological Institute, ClevelandClinic, Cleveland, OH, USA

Stephen C. Reingold, PhDPresident, Scientific and Clinical Review Associates, LLCSalisbury, Connecticut and New York City, NY, USA

Maria A. Rocca, MDNeuroimaging Research Unit, Institute of ExperimentalNeurology, Division of Neuroscience, San Raffaele ScientificInstitute, Vita-Salute, San Raffaele University, Milan, Italy

Richard A. Rudick, MDDirector, Mellen Center for Multiple Sclerosis Treatment andResearch, Neurological Institute, Cleveland Clinic, Cleveland,OH, USA

Amber R. Salter, MPHDepartment of Biostatistics, University of Alabama atBirmingham, Birmingham, AL, USA

Paula Sandler, PhDVice President, Regulatory Affairs, Biogen Idec Inc.,Cambridge, MA, USA

Jaume Sastre-Garriga, MDUnitat de Neuroimmunologia Clınica, Multiple SclerosisCentre of Catalonia (CEM-Cat), Vall d’Hebron UniversityHospital, Barcelona, Spain

John R. Scagnelli, MDDepartment of Neurology, University of Virginia,Charlottesville, VA, USA

Dana J. Serafin, BAStony Brook University Medical Center, Department ofNeurology, Stony Brook, NY, USA

Lynne Shinto, ND, MPHAssociate Professor, Deparmtent of Neurology, Oregon Healthand Science University, Portland, OR, USA

Nancy L. Sicotte, MDDepartment of Neurology, Cedars-Sinai Medical Center, LosAngeles, CA, USA

Jack H. Simon, MD, PhDProfessor, Department of Diagnostic Radiology, OregonHealth and Science University; Chief, Imaging, Portland VAMedical Center, Portland, OR, USA

Per Soelberg Sørensen, MD, DMScDanish Multiple Sclerosis Center, Department of Neurology,Copenhagen University Hospital Rigshospitalet, Copenhagen,Denmark

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Ryan E. Stagg, MDDepartment of Psychiatry and Behavioral, Sciences, JohnHopkins University School of Medicine, Baltimore, MD, USA

James M. Stankiewicz, MDDepartment of Neurology, Brigham and Women’s Hospital,Center for Neurologic Disease, Partners MS Center, HarvardMedical School, Boston, MA, USA

Lael A. Stone, MDMellen Center for Multiple Sclerosis Treatment andResearch, Neurological Institute, Cleveland Clinic, Cleveland,OH, USA

Amy Sullivan, PsyDMellen Center for Multiple Sclerosis Treatment and Research,Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Matthew Sutliff, PTMellen Center for Multiple Sclerosis Treatment and Research,Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

Jessica SzpakDean Health System, Madison, WI, USA

Alan J. Thompson, MD, FRCP, FRCPI, FAANDean, University College London, Faculty of Brain Sciences,London, UK

Bruce D. Trapp, PhDChairman, Department of Neuroscience, Lerner ResearchInstitute, Cleveland Clinic, Cleveland, OH, USA

Helen Tremlett, BPharm, MRPharmS, PhDFaculty of Medicine, Division of Neurology, Brain ResearchCentre, Faculty of Medicine University of British Columbia,Vancouver, British Columbia, Canada

Maria Trojano, MDProfessor of Neurology, Department of Neurological andPsychiatric Sciences, University of Bari, Bari Italy

Orla Tuohy, MBDepartment of Clinical Neurosciences, University ofCambridge, Addenbrooke’s Hospital, Cambridge, UK

Rhonda R. Voskuhl, MDProfessor, Department of Neurology; Director, MultipleSclerosis Program, UCLA, Los Angeles, USA

Marc K. Walton, MD, PhDAssociate Director for Translational Medicine, Office ofTranslational Sciences, Center for Drug Evaluation andResearch, FDA, Silver Spring, MD, USA

Mike P. Wattjes, MDMS Center Amsterdam, Department of Radiology,VU University Medical Center, Amsterdam, TheNetherlands

Emmanuelle Waubant, MD, PhDDepartment of Neurology, University of California at SanFrancisco, San Francisco, CA, USA

Martin S. WeberDepartment of Neurology, Technische Universitat Munchen,Munich, Germany

Howard L Weiner, MDDepartment of Neurology, Brigham and Women’s Hospital,Center for Neurologic Disease, Partners MS Center, HarvardMedical School, Boston, MA, USA

Brian G. Weinshenker, MDProfessor of Neurology, Department of Neurology, College ofMedicine, Mayo Clinic, Rochester, MN, USA

Bianca Weinstock-Guttman, MDDepartment of Neurology, State University of New York,Buffalo; Buffalo General Hospital, Buffalo, NY,USA

Jeffrey L. Winters, MD,Department of Laboratory Medicine and Pathology, MayoClinic, Rochester, MN, USA

Jerry S. Wolinsky, MDProfessor, Department of Neurology; Bartels FamilyProfessorship; Opal C. Rankin Professorship, The University ofTexas Health Science Center at Houston, Houston, TX,USA

Vijayshree Yadav, MD, MCRAssistant Professor, Department of Neurology, Oregon Healthand Science University, Portland, OR, USA

E. Ann Yeh, MDPediatric MS and Demyelinating Disorders Center of the JNI,Women and Children’s Hospital of Buffalo, Buffalo, NY,USA

Scott S. Zamvil, MDDepartment of Neurology, University of California at SanFrancisco, San Francisco, CA, USA

xii






Abbreviations list

This list includes abbreviations that were utilized in multiple chapters.

Abbreviation Full name9HPT Nine-Hole Peg TestAA African AmericanAE adverse eventAPC antigen presenting cellAQP4 aquaporin-4ARR annualized relapse rateB-cell B lymphocyteBBB blood–brain barrierBDNF brain-derived neurotrophic factorBPF brain parenchymal fractionCD clinically definiteCDMS clinically definite multiple sclerosisCI confidence intervalCIS clinically isolated syndromecMRI conventional magetic resonance

imagingCNS central nervous systemCSF cerebrospinal fluidDMT disease-modifying therapyDTI diffusion tensor imagingEAE experimental autoimmune encephalomyelitisEBV Epstein Barr virusEDSS Expanded Disability Status ScaleELISA enzyme-linked immunosorbent assayEMA European Medicines AgencyFDA Food and Drug AdministrationFSS Functional System ScoreGA glatiramer acetate, CopaxoneGABA gamma-aminobutyric acidGd-enhancing gadolinium-enhancingGM gray matterHLA human leukocyte antigenHR hazard ratioHRQoL health-related quality of lifeIFN� interferon betaIFN�-1b interferon beta-1bIFN�-1a(IM) interferon beta-1a by intramuscular injectionIFN�-1a(SC) interferon beta-1a by subcutaneous injection

Abbreviation Full nameIg immunoglobulinIL-# interleukin, e.g. IL-2IM intramuscularIMD immunomodulatory drugIRIS immune reconstitution inflammatory

syndromei.v. intravenousIVIg intravenous immunoglobulinMBP myelin basic proteinMHC major histocompatibility complexMMP matrix metalloproteinaseMOG myelin oligodendrocytes glycoproteinMP methylprednisoloneMRI magnetic resonance imagingMRS magnetic resonance spectroscopyMS multiple sclerosisMSFC Multiple Sclerosis Functional CompositeMSQLI Multiple Sclerosis Quality of Life InventoryMSSS Multiple Sclerosis Severity ScaleMxA Myxovirus resistance protein ANAA N-acetyl aspartateNAb neutralizing antibodyNABT normal-appearing brain tissueNAWM normal-appearing white matterNMO neuromyelitis opticaNP neuropsychologicalOCBs oligoclonal bandsOCT optical coherence tomographyON optic neuritisOR odds ratioPASAT Paced Auditory Serial Addition TestPLEX plasma exhangePLP proteolipid proteinPML progressive multifocal leukoencephalopathyPP primary progressivePPMS primary progressive multiple sclerosisQoL quality of lifeRCT randomized controlled trial

xiii






List of abbreviations

RNFL retinal nerve fiber layerROC receiver operating characteristicRR relapsing–remittingRRMS relapsing–remitting multiple sclerosisSAE serious adverse events.c. subcutaneousSDMT Symbol Digits Modalities TestSNP single nucleotide polymorphism

SP secondary progressiveSPMS secondary progressive multiple sclerosisT25FW Timed 25-Foot WalkT-cell T lymphocyteTCR T-cell receptorTGF� transforming growth factor-betaTNF� tumor necrosis factor-alphaWM white matter

xiv






Foreword

Multiple Sclerosis Therapeutics is now in its fourth edition andremains the definitive source of information about the theoryand art of clinical trials for this complex disorder. The first edi-tion of the book appeared in 1999, only a few years after regu-latory approval of the first agents to modify the multiple scle-rosis (MS) disease course. Subsequent editions have appearedevery 3 to 5 years, attesting to the rapid progress that has beenmade over the past decade. However, this fourth edition servesas a reminder that we still have only partially effective thera-pies for only some forms of the disease, that available therapieshave problematic side effects and remain extremely expensive,and that there remains a strong demand for safer, more effec-tive, more tolerable, and more affordable therapeutic agents forall forms of MS. An interesting irony to the progress that hasbeen made is that our past success has created new problemsin clinical trial theory, design, and conduct. The availability ofmultiple relatively safe and effective immunomodulatory thera-pies stresses the need to identify new biological modes of actionthat might be useful for MS, thus underscoring the problem thatwe still do not know entirely what causes the disease. And, withmany patients worldwide having access to available therapy, thepractical and ethical challenges of testing the next generation(s)of therapies require entirely new ways of thinking about trialdesign and interpretation.

Compared with prior editions, the current volume containsexpansive chapters on the biology and demographics of MS,including separate chapters on disease pathology, immunology,genetics, and epidemiology. New MS treatments will requireour ability to better target the etiopathology of the disease. Thus,this emphasis on the fundamentals of the disease process helpsto chart progress in disease pathology that will surely result innew therapeutic modalities.

An extensive treatment of clinical trial methodology is pro-vided in 19 chapters, providing updated information on clinicalassessment, imaging outcomes, biological markers, and evolv-ing developments in regulatory review. New information aboutcortical lesions in MS – previously a relatively underappreciatedlocus of disease pathology – points to modalities such as dou-ble inversion recovery imaging and other measures of corticalpathology that should be in the “mix” of assessments done totrack changes in the brain by MRI. A review of data on neutral-izing antibodies that often develop in subjects using interferontherapy has been moved from the prior edition’s section on

specific therapeutic modalities to the current section on trialdesign considerations, a reflection perhaps of the need to payattention to the complexities of evaluating long-term efficacyand of combining new experimental therapies with availabletherapies which may no longer be effective in some subjects.

The fourth edition contains 27 separate chapters devoted tospecific available or experimental therapies for MS, a signifi-cant increase over the prior edition. Significantly, there are newchapters on therapies that were not particularly visible at thetime of the prior edition 5 years ago: cladribine, fingolimod,fumarate, laquinimod, and teriflunomide, all represent a newera of oral therapy for MS; and alemtuzumab and daclizumabmay represent the next steps for monoclonal antibody therapy.A new chapter on mesenchymal and neural stem cell trans-plantation represents a “brave new world” for MS therapeuticsand would not have been possible to include previously. Finally,no discussion of MS therapies today would be complete with-out a review of the current knowledge and controversy aboutchronic cerebrospinal venous insufficiency, its detection, preva-lence, relevance, and treatment.

Of highly practical impact is the final section of the volume,on “Therapy in Clinical Practice.” Recent therapeutic achieve-ments dictate the need for practical advice to practitionersaround the world and the expansion of treatment-focus fellow-ship programs for MS physicians and allied health profession-als is an indication of the need for “texts” like Multiple SclerosisTherapeutics. Diagnosis and treatment of neuromyelitis optica(NMO) is given a new chapter, emphasizing both the recentdevelopment of a biological marker for the disease (the aqua-porin 4 autoantibody assay) and the prominent role that NMOand NMO spectrum disorders play in the differential diagnosisfor MS. Many clinicians are newly focused on diagnosis, treat-ment, and management of pediatric-onset MS and this topicas well is given a new chapter in the present edition. Also pre-viously not addressed is the topic of comorbidities in patientswith MS, which highlights the need to consider and treat non-MS pathologies as well as MS itself, whether these be associatedwith the underlying autoimmune nature of the disease, a symp-tomatic consequence of the disease or its treatments, or are sim-ply coincidental.

This will not be the final edition of Multiple Sclero-sis Therapeutics. Fundamental and applied research relatedto MS is burgeoning and will result in new, especially

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Foreword

non-immunomodulatory, interventions with novel modes ofaction that may be used to combine with, or replace, currenttherapies. Ongoing clinical studies described in this fourth edi-tion will be completed in the next few years and some, at least,will be added to our mix of available therapies with the con-sequent need for new perspectives on patient management forrelapsing and likely progressive forms of MS. Increased focuson biomarkers – cellular, biochemical and imaging – and theirpotential as valid clinical surrogates will alter the outcomes thatwe monitor in MS trials. A better understanding of the geneticbasis for MS and its subtypes and a better, biologically baseddefinition of MS phenotypes and more efficient and accuratediagnostic procedures will result in more targeted clinical trialrecruitment based on rational objective data and might wellusher in an era of “personalized medicine.” Regulatory agenciesworldwide have already begun to stress the importance of head-to-head comparisons of new agents against available agents to

provide a sense of relative safety and efficacy to guide physi-cians, patients, and third-party payers. And regulators are onthe cusp of providing formal guidance for adaptive trial designin an effort to streamline current trial and statistical protocolsand guidelines for the development of biosimilar agents, creat-ing the possibility of “generic” products for MS with all of theirchallenges.

For any practitioner, clinical investigator, or fundamental orapplied scientist who hopes his or her work will have an impacton new treatments for MS, Multiple Sclerosis Therapeutics is aninvaluable resource. Its regular updating has provided an ongo-ing MS history for more than a decade and will serve to guideand prepare us all for the exciting developments to come.

Stephen C. Reingold, PhDPresident, Scientific and Clinical Review Associates,LLC Salisbury, Connecticut and New York City, NY, USA

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Preface

The field of multiple sclerosis therapeutics is rapidly changing.Understanding of the disease is improving, leading to new con-cepts with major diagnostic and therapeutic implications. Clini-cal trial methodology is evolving, and there are numerous ongo-ing or recently completed clinical trials for novel therapeuticstrategies in all categories of the disease. As a result, a vari-ety of new therapeutic options are emerging. Multiple sclero-sis therapy is now proactive – there is general consensus thatearly diagnosis and initiation of disease-modifying drug ther-apy, and active monitoring of patients during therapy are essen-tial to delay or prevent neurological disability. For all these rea-sons, we felt a single text, providing a comprehensive summaryof the dynamic field of multiple sclerosis therapeutics, would bevaluable.

This book has been substantially updated from the prioredition: over 50% of the material is new, including new chap-ters on pathology, epidemiology, gray matter imaging, neu-romyelitis optica, pediatric multiple sclerosis, medical comor-bidities, chronic cerebrospinal venous insufficiency, and a wide

range of emerging therapies. All chapters have been substan-tially revised to provide current information, particularly onrapidly evolving topics such as genetics, magnetic resonanceimaging and other endpoints, drug mechanism of action andpotential adverse effects, and neuroprotection and repair strate-gies. The current status of recently approved disease-modifyingand symptomatic drugs for multiple sclerosis is summarized.Experts provide overviews on disease and symptom manage-ment. This book will be an essential reference for practitionerscaring for patients with multiple sclerosis, investigators plan-ning or conducting clinical trials, clinical and research trainees,and clinical trial sponsors.

We thank the authors and co-authors who provided currentand comprehensive chapters. We also gratefully acknowledgeCassandra Talerico, PhD for expert assistance in compiling thebook. Finally, we dedicate this book to our wives and familiesfor their patience and support.

J. A. Cohen and R. A. Rudick

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