Diagnosing and Managing Multiple Sclerosis: A Personalized Approach
Spectrum of Multiple Sclerosis and Timely Recognition
In 2017, the International Panel on Diagnosis of MS published its revision of the 2010 McDonald criteria, given the advances in diagnosis during the interim 7 years.8 The update addressed the recognition of clinically isolated syndrome (CIS) and subtypes of MS, on the basis of new clinical, magnetic resonance (MR) imaging, and c erebrospinaluid (CSF) criteria. In addition, the update discussed the potentially controversial entity of radiologically isolated syndrome (RIS). What emerges from the new diagnostic criteria, as well as from recent reports of “prodromal” MS, is a spectrum of disease: from quiescent or subclinical MS to overt clinical manifestations of relapses and progressive disability (Figure 1). The early recognition of MS is critical to instituting DMTs that reduce relapses and clinical and subclinical disease worsening, and prevent long-term disability.15
Multiple sclerosis (MS) is one of the leading causes of disability and many efforts have been implemented to help expediate diagnosis and initiate early, effective treatment. With rapidly changing guidelines and treatment indications, it can be difficult discerning when to start a disease-modifying therapy in the early spectrum of MS, such as clinically and radiologically isolated syndrome; how to discuss MS management in women of childbearing age; or how to use the new guidelines to confirm an MS diagnosis. In this supplement, these topics will be addressed along with recognizing treatment failure, knowing when to switch therapies, and how to incorporate patient preference in treatment-related decisions.
After completing this activity, the participant will demonstrate the ability to:
- Recognize and diagnose the spectrum of multiple sclerosis (MS), from clinically isolated syndrome (CIS) to the various forms of MS (ie, relapsing-remitting and progressive) using established, updated, clinical imaging and laboratory criteria
- Appropriately use available and emerging disease-modifying therapies (DMTs) for MS based on their efficacy, safety, and tolerability profiles, as well as their approved or anticipated indications for the various forms of MS
- Recognize and manage treatment failure, including switching DMTs
- Monitor disease and patient outcomes, including patient adherence, according to recommended protocols
- Use shared decision making when prescribing DMTs to improve treatment adherence and patient outcomes
- Appropriately manage MS in women of child-bearing age
Patricia K. Coyle, MD, FAAN, FANA
Professor and Vice Chair, Clinical Affairs
Department of Neurology
Director, MS Comprehensive Care Center
Stony Brook University Hospital
Stony Brook, NY
JOINT ACCREDITATION STATEMENT
In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and RMEI Medical Education, LLC. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physician Continuing Medical Education
The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Method of Participation and Request for Credit
There are no fees for participating and receiving CME credit for this activity. During the period, September 30, 2019 through September 29, 2020, participants must read the learning objectives and faculty disclosures and study the educational content.
PIM supports Green CME by offering your Request for Credit online. If you wish to receive acknowledgement for completing this activity, please complete the post-test and evaluation on www.cmeuniversity.com. In the “Find Post-test/Evaluation by Course” field at the top of the page, search by course ID 14335. Upon registering and successfully completing the post-test with a score of 70% or better and the activity evaluation, your certificate will be made available immediately. Processing credit requests online will reduce the amount of paper used by nearly 100,000 sheets per year. If you have questions regarding the receipt of your e-mailed certificate, please contact PIM via e-mail at [email protected].
This activity is jointly provided by RMEI Medical Education, LLC and Postgraduate Institute for Medicine.
This activity is supported by an independent educational grant from Genentech.
There is no fee for this educational activity.
Print and Online Journal Supplement
DISCLOSURE OF CONFLICTS OF INTEREST
Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.
The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity.
Patricia K. Coyle, MD, FAAN, FANA, has affiliations with Accordant, Actelion, Alexion, Bayer, Biogen, Celgene, Genentech/Roche, Novartis, Sanofi/Genzyme, Serono, TG Therapeutics (Consulting Fees); Actelion, Genentech/Roche, MedDay, NINDS, Novartis (Contracted Research).
Postgraduate Institute for Medicine
The PIM planners and managers have nothing to disclose.
RMEI Medical Education, LLC
The RMEI planners and managers have nothing to disclose.
DISCLOSURE OF UNLABELED USE
This educational activity may contain references to published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
The author would like to thank Barbara J. Martin, MD and Lobna Eldasher, PharmD for their assistance in writing and editing this manuscript. The individuals mentioned report no potential conflicts of interest and have given their written permission to be named.
Please contact PIM via e-mail at [email protected].
- Wallin WT,Culpepper WJ, Campbell JD,et al. The prevalence of MS in the United States. Neurology.2019;92(10):e1029-e1040.
- Wallin M, Culpepper WJ, Campbell, et al. The prevalence of multiple sclerosis in the United States: a population-based healthcare database approach [poster]. Presented at ECTRIMS, Paris, France. October 6, 2017.
- National MS Society. News: Preliminary results of MS prevalence study estimate nearly 1 million living with MS in the US. https://www.nationalmssociety.org/About-the-Society/News/Preliminary-Res.... Accessed April 23, 2019.
- US Department of Health and Human Services, National Institutes of Health. Multiple sclerosis. https://report.nih.gov/nIHfactsheets/ViewFactSheet.aspx?csid=103. Accessed April 23, 2019.
- Scalfari A, Knappertz V, Cutter G, Goodin DS, Ashton R, Ebers GC. Mortality in patients with multiple sclerosis. Neurology. 2013;81(2):184-192.
- Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD. Multiple sclerosis prevalence in the United States commercially insured population. Neurology. 2016;86(11):1014-1021.
- Trapp BD,Vignos M,Dudman J,et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol.2018;17(10):870-884.
- Thompson AJ,Banwell BL,Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol.2018;17(2):162-173.
- Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis—report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788.
- Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline: Disease-modifying therapies for adults with multiple sclerosis—Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology [data supplement]. https://download.lww.com/wolterskluwer_vitalstream_com/PermaLink/WNL/A/W.... Accessed April 23, 2019.
- Rae-Grant A, Day GS, Marrie RA, et al. Comprehensive systematic review summary: disease-modifying therapies for adults with multiple sclerosis—report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):789-800.
- National MS Society. Developing a healthcare team. http://www.nationalmssociety.org/Treating-MS/Comprehensive-Care/Deveopin.... Accessed April 23, 2019.
- Elwyn G, Frosch D, Thomson R, et al. Shared decision making: a model for clinical practice. J Gen Intern Med. 2012;27(10):1361-1367.
- Elwyn G, Durand MA, Song J, et al. A three-talk model for shared decision making: multistage consultation process. BMJ. 2017;359:j4891.
- MS Coalition. The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence. Updated September 2018. http://www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d... /DMT_Consensus_MS_Coalition_color. Accessed April 24, 2019.
- Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286.
- Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009;72(9):800-805.
- Okuda DT, Mowry EM, Cree BAC, et al. Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. Neurology. 2011;76(8):686-692.
- Okuda DT, Siva A, Kantarci O, et al. Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One. 2014;9(3):e90509.
- Kantarci OH, Lebrun C, Siva A, et al. Primary progressive multiple sclerosis evolving from radiologically isolated syndrome. Ann Neurol. 2016;79(2):288-294.
- Giorgio A, Stromillo ML, Rossi F, et al.Cortical lesions in radiologically isolated syndrome. Neurology.2011;77(21):1896-1899.
- Lebrun C, le Page E, Kantarci O, et al. Impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort. Mult Scler J. 2012;18(9):1297-1302.
- Thouvenot E. Should we treat patients with radiologically isolated syndrome (RIS)? Yes. Rev Neurol (Paris). 2018;174(10):689-692.
- Gout O. Should we treat patients with radiologically isolated syndrome (RIS)? No. Rev Neurol (Paris). 2018;174(10):693-695.
- Wijnands JMA,Kingwell E,Zhu F, et al. Health-care use before a first demyelinating event suggestive of amultiple sclerosisprodrome: a matched cohort study. Lancet Neurol. 2017;16(6):445-451.
- Wijnands JM, Zhu F, Kingwell E, et al. Five years before multiple sclerosis onset: phenotyping the prodrome. Mult Scler.2019;25(8):1092-1101.
- Högg T,Wijnands JMA,Kingwell E, et al. Mining healthcare data for markers of the multiple sclerosis prodrome. Mult Scler Relat Disord.2018;25:232-240.
- Disanto G,Zecca C,MacLachlan S, et al. Prodromal symptoms of multiple sclerosis before diagnosis. Ann Neurol.2018;83(6):1162-1173.
- Wijnands JMA,Zhu F,Kingwell E, et al. Prodrome in relapsing-remitting and primary progressive multiple sclerosis. Eur J Neurol.2019;26(7):1032-1036.
- Miller AE, Wolinsky JS, Kappos L, et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(10):977-986.
- Marcus JF, Waubant EL. Updates on clinically isolated syndrome and diagnostic criteria for multiple sclerosis. Neurohospitalist. 2013;3(2):65-80.
- MS Coalition. The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence. Updated July 2017. https://cdn.ymaws.com/www.mscare.org/resource/collection/A0711E7F-0EFA-4... February 13, 2019.
- Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.
- Brownlee WJ, Swanton JK, Miszkiel KA, Miller DH, Ciccarelli O. Should the symptomatic region be included in dissemination in space in MRI criteria for MS? Neurology. 2016;87(7):680-683.
- Tintoré M, Otero-Romero S, Rio J, et al. Contribution of the symptomatic lesion in establishing MS diagnosis and prognosis. Neurology. 2016;87(13):1368-1374.
- Tintoré M, Rovira A, Brieva L, et al. Isolated demyelinating syndromes: comparison of CSF oligoclonal bands and different MRI criteria to predict conversion to CDMS. Mult Scler. 2001;7(6):359-363.
- Tintoré M, Rovira A, Rio J, et al. Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? Neurology. 2008;70(13 Pt 2):1079-1083.
- Andreadou E, Chatzipanagiotou S, Constantinides VC, Rombos A, Stamboulis E, Nicolaou C. Prevalence of cerebrospinal fluid oligoclonal IgG bands in Greek patients with clinically isolated syndrome and multiple sclerosis. Clin Neurol Neurosurg. 2013;115(10):2094-2098.
- Dobson R, Ramagopalan S, Davis A, Giovannoni G. Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude. J Neurol Neurosurg Psychiatry. 2013;84(8):909-914.
- Kuhle J, Disanto G, Adiutori R, et al. Conversion from clinically isolated syndrome to multiple sclerosis: a large multicentre study. Mult Scler J. 2015;21(8):1013-1024.
- Tintoré M, Rovira A, Rio J, et al. Defining high, medium, and low impact prognostic factors for developing multiple sclerosis. Brain. 2015;138(Pt 7):1863-1874.
- Huss AM, Halbgebauer S, Ockl P, et al. Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically-isolated syndrome. J Neurol. 2016;263(12):2499-2504.
- Martinelli V, Dalla Costa G, Messina MJ, et al. Multiple biomarkers improve prediction of multiple sclerosis in clinically isolated syndromes. Acta Neurol Scand. 2017;136(5):454-461.
- Arrambide G, Tintoré M, Espejo C, et al. The value of oligoclonal bands in the multiple sclerosis diagnostic criteria. Brain. 2018;141(4):1075-1084.
- van der Vuurst de Vries RM, Mescheriakova JY, Wong YYM, et al. Application of the 2017 revised McDonald criteria for multiple sclerosis to patients with a typical clinically isolated syndrome. JAMA Neurol. 2018;75(11):1392-1398.
- Lee DH, Peschke M, Utz KS, Linker RA. Diagnostic value of the 2017 McDonald criteria in patients with a first demyelinating event suggestive of relapsing-remitting multiple sclerosis. Eur J Neurol.2019;26(3):540-545.
- US FDA. FDA news release: FDA approves new oral drug to treat multiple sclerosis. March 26, 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-new-ora.... Accessed April 29, 2019.
- Mayzent (siponimod) prescribing information. East Hanover, NJ; Novartis AG: April 2019. https://www.mayzent.com/index.jsp?utm_source=google&utm_medium=paid&utm_... r a n d_Go o g l e _ 4 . 2 0 1 9&utm_ t e rm=ma y z e n t & u tm_content=paidsearch&gclid=CNj4_JGtheMCFUTmswodb2QMsA.June 25, 2019.
- Mavenclad (cladribine) prescribing information. Rockland, MA; EMD Serano: March2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf. Accessed June 25, 2019.
- Lemtrada (alemtuzumab) prescribing information. Cambridge, MA; Genzyme Corp: January 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103948s5158lbl.... Accessed June 25, 2019.
- US FDA. FDA news release: FDA approves new oral drug to treat multiple sclerosis. March 29, 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-new-ora.... Accessed April 29, 2019.
- Fox R, Salter A, Alster J, et al. Risk tolerance in MS patients: survey results from the NARCOMS registry. Mult Scler Relat Disord. 2015;4(3):241-249.
- Rudick RA, Polman CH. Current approaches to the identification and management of breakthrough disease in patients with multiple sclerosis. Lancet Neurol. 2009;8(6):545-559.
- Cascione M, Tenenbaum N, Wendt J, et al. Treatment retention on fingolimod compared with injectable multiple sclerosis therapies in African-American patients: a subgroup analysis of a randomized phase 4 study. Mult Scler Relat Disord. 2018;25:50-56.
- Miller AE, Xu X, Macdonell R, et al. Efficacy and safety of teriflunomide in Asian patients with relapsing forms ofmultiple sclerosis: a subgroup analysis of the phase 3 TOWER study. J Clin Neurosci. 2019;59:229-231.
- Saida T, Yamamura T, Kondo T, et al. A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsingremitting multiple sclerosis from East Asia and other countries.BMC Neurol. 2019;19(1):5.
- De Angelis F, Chataway J. Novel multiple sclerosis drugs in the pipeline. Clin Pharmacol Ther. 2019;105(5):1082-1090.
- RyersonLZ,FoleyJ,ChangI, et al. Natalizumab extended interval dosing (EID) is associated with a significant reduction in progressive multifocal leukoencephalopathy (PML) risk compared with standard interval dosing (SID) in the TOUCH Prescribing Program. J Neurol Neurosurg Psychiatry.2018;89:A29.
- Bomprezzi R,Pawate S. Extended interval dosing of natalizumab: a twocenter, 7-year experience. Ther Adv Neurol Disord.2014;7(5):227-231.
- Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry.2016;87(8):885-889.
- Hodel J, Outteryck O, Verclytte S, et al. Brain magnetic susceptibility changes in patients with natalizumab-associated progressive multifocal leukoencephalopathy. Am J Neuroradiol. 2015;36(12):2296-2302.
- Consortium of MS Centers. MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-up of MS. February 2018. https://cdn.ymaws.com/mscare.site-ym.com/resource/collection/9C5F19B9-34.... Accessed May 1, 2019.
- Dalla Costa G, Martinelli V, Moiola L, et al. Serum neurofilaments increase at progressive multifocal leukoencephalopathy onset in natalizumab-treated multiple sclerosis patients. Ann Neurol.2019;85(4):606-610.
- Ho PR, Koendgen H, Campbell N, Haddock B, Richman S, Chang I. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol.2017;16(11):925-933.
- van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013;368(17):1658-1659.
- Nieuwkamp DJ, Murk JL, van Oosten BW, et al. PML in a patient without severe lymphocytopenia receiving dimethyl fumarate. N Engl J Med. 2015;372(15):1474-1476.
- Baharnoori M, Lyons J, Dastagir A, Koralnik I, Stankiewicz JM. Nonfatal PML in a patient with multiple sclerosis treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e274.
- Gyang TV, Hamel J, Goodman AD, Gross RA, Samkoff L. Fingolimodassociated PML in a patient with prior immunosuppression. Neurology. 2016;86(19):1843-1845.
- Major EO, Yousry TA, Clifford DB. Pathogenesis of progressive multifocal leukoencephalopathy and risks associatedwithtreatmentsformultiplesclerosis: a decade of lessons learned. Lancet Neurol.2018;17(5):467-480.
- McGuigan C, Craner M, Guadagno J, et al. Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry.2015;87(2):117-125.
- Krämer J, Tenberge JG, Kleiter I, et al. Is the risk of progressive multifocal leukoencephalopathy the real reason for natalizumab discontinuation in patients with multiple sclerosis?PLoS One. 2017;12(4):e0174858.
- Menzin J, Caon C, Nichols C, White LA, Friedman M, Pill MW. Narrative review of the literature on adherence to disease-modifying therapies among patients with multiple sclerosis. J Manag Care Pharm JMCP. 2013;19(1 suppl A):S24-S40.
- Farber RS, Sand IK. Optimizing the initial choice and timing of therapy in relapsing-remitting multiple sclerosis. Ther Adv Neurol Disord. 2015;8(5):212-223.
- Armstrong MJ, Shulman LM, Vandigo J, et al. Patient engagement and shared decision-making: what do they look like in neurology practice? Neurol Clin Pract. 2016;6(2):190-197.
- Colligan E, Metzler A, Tiryaki E. Shared decision-making in multiple sclerosis. Mult Scler J. 2017;23(2):185-190.
- Barry MJ, Edgman-Levitan S. Shared decision making: pinnacle of patientcentered care. N Engl J Med. 2012;366(9):780-781.
- Elwyn G. Durand MA, Song J, et al. A three-talk model for shared decision making: multistage consultation process. BMJ. 2017;359:j4891.
- Berger JR, Markowitz C. Deciding the best multiple sclerosis therapy: tough choices. JAMA Neurology. 2018;75(12):1461-1462.
- Ben-Zacharia A, Adamson M, Boyd A, et al. Impact of shared decision making on disease-modifying drug adherence in multiple sclerosis.Int J MS Care. 2018;20(6):287-297.
- National MS Society. Who gets MS (epidemiology)? http://www.nationalms society.org/What-is-MS/Who-Gets-MS. Accessed May 5, 2019.
- Sandberg-Wollheim M, Neudorfer O, Grinspan A, et al. Pregnancy outcomes from the Branded Glatiramer Acetate Pregnancy Database. Int J MS Care.2018;20(1):9-14.
- Coyle PK, Oh J, Magyari M, Oreja-Guevara C, Houtchens M. Management strategies for female patients of reproductive potential with multiple sclerosis: an evidence-based review. Mult Scler Relat Disord. 2019;32:54-63.
- Coyle, PK. Management of women with multiple sclerosis through pregnancy and after childbirth. Ther Adv Neurol Disord. 2016;9(3):198-210.
- Houtchens MK, Edwards NC, Phillips AL. Relapses and disease-modifying drug treatment in pregnancy and live birth in US women with MS. Neurology. 2018;91(17):e1570-e1578.
- Gould AL, et al. 71st Annual Meeting Abstract. Pregnancy-related Relapses in a Large, Contemporary Multiple Sclerosis Cohort: No Increased Risk in the Postpartum Period. American Academy of Neurology. March 7, 2019.
- A Guide to the Accelerated Elimination Procedure for Aubagio (teriflunomide). https://www.aubagiohcp.com/content/pdf/drug_elimination_guide.pdf. Accessed June 18, 2019.