{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:29:17Z","timestamp":1790306957603,"version":"4.1.0"},"reference-count":138,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T00:00:00Z","timestamp":1631232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Disability in multiple sclerosis accrues predominantly in the progressive forms of the disease. While disease-modifying treatment of relapsing MS has drastically evolved over the last quarter-century, the development of efficient drugs for preventing or at least delaying disability in progressive MS has proven more challenging. In that way, many drugs (especially disease-modifying treatments) have been researched in the aspect of delaying disability progression in patients with a progressive course of the disease. While there are some disease-modifying treatments approved for progressive multiple sclerosis, their effect is moderate and limited mostly to patients with clinical and\/or radiological signs of disease activity. Several phase III trials have used different primary outcomes with different time frames to define disease progression and to evaluate the efficacy of a disease-modifying treatment. The lack of sufficiently sensitive outcome measures could be a possible explanation for the negative clinical trials in progressive multiple sclerosis. On the other hand, even with a potential outcome measure that would be sensitive enough to determine disease progression and, thus, the efficacy or failure of a disease-modifying treatment, the question of clinical relevance remains unanswered. In this systematic review, we analyzed outcome measures and definitions of disease progression in phase III clinical trials in primary and secondary progressive multiple sclerosis. We discuss advantages and disadvantages of clinical and paraclinical outcome measures aiming for practical ways of combining them to detect disability progression more sensitively both in future clinical trials and current clinical routine.<\/jats:p>","DOI":"10.3390\/biom11091342","type":"journal-article","created":{"date-parts":[[2021,9,12]],"date-time":"2021-09-12T21:45:57Z","timestamp":1631483157000},"page":"1342","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Measuring Treatment Response in Progressive Multiple Sclerosis\u2014Considerations for Adapting to an Era of Multiple Treatment Options"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4146-5870","authenticated-orcid":false,"given":"Nik","family":"Krajnc","sequence":"first","affiliation":[{"name":"Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Department of Neurology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0825-0851","authenticated-orcid":false,"given":"Gabriel","family":"Bsteh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1097\/WCO.0000000000000622","article-title":"Multiple sclerosis: Clinical aspects","volume":"31","author":"Oh","year":"2018","journal-title":"Curr. Opin. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/S1474-4422(07)70243-0","article-title":"Primary-progressive multiple sclerosis","volume":"6","author":"Miller","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"146","DOI":"10.7224\/1537-2073.2012-053","article-title":"Natural History of Multiple Sclerosis Symptoms","volume":"15","author":"Kister","year":"2013","journal-title":"Int. J. MS Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1177\/1352458512451510","article-title":"Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis","volume":"19","author":"Tutuncu","year":"2012","journal-title":"Mult. Scler. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1093\/brain\/112.1.133","article-title":"The natural history of multiple sclerosis: A geographically based study. I. Clinical course and disability","volume":"112","author":"Weinshenker","year":"1989","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1093\/brain\/awg081","article-title":"Early clinical predictors and progression of irreversible disability in multiple sclerosis: An amnesic process","volume":"126","author":"Confavreux","year":"2003","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1093\/brain\/116.1.117","article-title":"Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up","volume":"116","author":"Runmarker","year":"1993","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bsteh, G., Ehling, R., Lutterotti, A., Hegen, H., Di Pauli, F., Auer, M., Deisenhammer, F., Reindl, M., and Berger, T. (2016). Long Term Clinical Prognostic Factors in Relapsing-Remitting Multiple Sclerosis: Insights from a 10-Year Observational Study. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158978"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.clineuro.2014.09.008","article-title":"Relapsing multiple sclerosis patients treated with disease modifying therapy exhibit highly variable disease progression: A predictive model","volume":"127","author":"Scott","year":"2014","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1001\/jama.2018.20588","article-title":"Association of Initial Disease-Modifying Therapy with Later Conversion to Secondary Progressive Multiple Sclerosis","volume":"321","author":"Brown","year":"2019","journal-title":"JAMA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1056\/NEJMoa1606468","article-title":"Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis","volume":"376","author":"Montalban","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/S0140-6736(18)30475-6","article-title":"Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): A double-blind, randomised, phase 3 study","volume":"391","author":"Kappos","year":"2018","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1212\/WNL.33.11.1444","article-title":"Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)","volume":"33","author":"Kurtzke","year":"1983","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1002\/ana.21867","article-title":"Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial","volume":"66","author":"Hawker","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/S0140-6736(98)10039-9","article-title":"Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS","volume":"352","author":"Kappos","year":"1998","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/ana.21079","article-title":"Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial","volume":"61","author":"Wolinsky","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"SPECTRIMS Study Group (2001). Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MSSG. Randomized controlled trial of interferon- beta-1a in secondary progressive MS: Clinical results. Neurology, 56, 1496\u20131504.","DOI":"10.1212\/WNL.56.11.1496"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/S0140-6736(15)01314-8","article-title":"Oral fingolimod in primary progressive multiple sclerosis (INFORMS): A phase 3, randomised, double-blind, placebo-controlled trial","volume":"387","author":"Lublin","year":"2016","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1212\/WNL.0000000000000560","article-title":"Defining the clinical course of multiple sclerosis: The 2013 revisions","volume":"83","author":"Lublin","year":"2014","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1016\/S0140-6736(02)12023-X","article-title":"Mitoxantrone in progressive multiple sclerosis: A placebo-controlled, double-blind, randomised, multicentre trial","volume":"360","author":"Hartung","year":"2002","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1111\/ene.14589","article-title":"Detection of disability worsening in relapsing-remitting multiple sclerosis patients: A real-world roving Expanded Disability Status Scale reference analysis from the Italian Multiple Sclerosis Register","volume":"28","author":"Lepore","year":"2020","journal-title":"Eur. J. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1177\/1352458517709619","article-title":"Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study","volume":"24","author":"Kappos","year":"2017","journal-title":"Mult. Scler. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1093\/brain\/awh721","article-title":"The natural history of multiple sclerosis: A geographically based study 9: Observations on the progressive phase of the disease","volume":"129","author":"Kremenchutzky","year":"2006","journal-title":"Brain"},{"key":"ref_24","first-page":"S69","article-title":"What We Learned from The History of Multiple Sclerosis Measurement: Expanded Disability Status Scale","volume":"55","author":"Cinar","year":"2018","journal-title":"Noro. Psikiyatr. Ars."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/brain\/122.1.141","article-title":"The psychometric properties of clinical rating scales used in multiple sclerosis","volume":"122","author":"Sharrack","year":"1999","journal-title":"Brain"},{"key":"ref_26","first-page":"321","article-title":"Responsiveness of the Expanded Disability Status Scale (EDSS) to disease progression and therapeutic intervention in progressive forms of multiple sclerosis","volume":"51","author":"Cadavid","year":"2010","journal-title":"Rev. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1097\/WCO.0b013e3283460542","article-title":"Challenges to clinical trials in multiple sclerosis: Outcome measures in the era of disease-modifying drugs","volume":"24","author":"Hyland","year":"2011","journal-title":"Curr. Opin. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1212\/01.wnl.0000288179.86056.e1","article-title":"Responsiveness and predictive value of EDSS and MSFC in primary progressive MS","volume":"70","author":"Kragt","year":"2008","journal-title":"Neurology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1159\/000322140","article-title":"Integration of Cognitive Impairment in the Expanded Disability Status Scale of 215 Patients with Multiple Sclerosis","volume":"64","author":"Brissart","year":"2010","journal-title":"Eur. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1001\/archneur.1988.00520310052017","article-title":"Interrater Reliability in Assessing Functional Systems and Disability on the Kurtzke Scale in Multiple Sclerosis","volume":"45","author":"Amato","year":"1988","journal-title":"Arch. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1212\/WNL.42.4.859","article-title":"Inter- and intrarater scoring agreement using grades 1.0 to 3.5 of the Kurtzke Expanded Disability Status Scale (EDSS)","volume":"42","author":"Goodkin","year":"1992","journal-title":"Neurology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1212\/WNL.40.6.971","article-title":"Interrater variability with the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. The Canadian Cooperation MS Study Group","volume":"40","author":"Noseworthy","year":"1990","journal-title":"Neurology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/1471-2377-14-58","article-title":"Systematic literature review and validity evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis","volume":"14","author":"Feng","year":"2014","journal-title":"BMC Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1177\/1352458512444498","article-title":"Assessing walking disability in multiple sclerosis","volume":"18","author":"Kieseier","year":"2012","journal-title":"Mult. Scler. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1177\/1352458517690823","article-title":"Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis","volume":"23","author":"Motl","year":"2017","journal-title":"Mult. Scler. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1177\/1352458511419880","article-title":"Clinical scales in progressive MS: Predicting long-term disability","volume":"18","author":"Bosma","year":"2011","journal-title":"Mult. Scler. J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Orbach, R., Zhao, Z., Wang, Y.-C., O\u2019Neill, G., and Cadavid, D. (2012). Comparison of Disease Activity in SPMS and PPMS in the Context of Multicenter Clinical Trials. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045409"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1177\/1545968310397204","article-title":"Comparison of the Timed 25-Foot and the 100-Meter Walk as Performance Measures in Multiple Sclerosis","volume":"25","author":"Pace","year":"2011","journal-title":"Neurorehabilit. Neural Repair"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S1474-4422(18)30069-3","article-title":"Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): A phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension","volume":"17","author":"Kapoor","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1177\/135245850000600411","article-title":"The significant change for the Timed 25-foot Walk in the multiple sclerosis functional composite","volume":"6","author":"Kaufman","year":"2000","journal-title":"Mult. Scler. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1185\/03007995.2011.639752","article-title":"Minimally important clinical difference of the Timed 25-Foot Walk Test: Results from a randomized controlled trial in patients with multiple sclerosis","volume":"28","author":"Coleman","year":"2011","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1177\/1352458506070768","article-title":"Clinical impact of 20% worsening on Timed 25-foot Walk and 9-hole Peg Test in multiple sclerosis","volume":"12","author":"Kragt","year":"2006","journal-title":"Mult. Scler. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1177\/1352458510370464","article-title":"Progression on the Multiple Sclerosis Functional Composite in multiple sclerosis: What is the optimal cut-off for the three components?","volume":"16","author":"Bosma","year":"2010","journal-title":"Mult. Scler. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1212\/WNL.0b013e31828cf7f3","article-title":"Timed 25-Foot Walk: Direct evidence that improving 20% or greater is clinically meaningful in MS","volume":"80","author":"Hobart","year":"2013","journal-title":"Neurology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1177\/1352458519876701","article-title":"Clinical outcome measures in SPMS trials: An analysis of the IMPACT and ASCEND original trial data sets","volume":"26","author":"Koch","year":"2019","journal-title":"Mult. Scler. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.apmr.2019.08.488","article-title":"Quantitative Synthesis of Timed 25-Foot Walk Performance in Multiple Sclerosis","volume":"101","author":"Sikes","year":"2019","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e1921","DOI":"10.1212\/WNL.0000000000008519","article-title":"Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data","volume":"93","author":"Goldman","year":"2019","journal-title":"Neurology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1093\/brain\/122.5.871","article-title":"Development of a multiple sclerosis functional composite as a clinical trial outcome measure","volume":"122","author":"Cutter","year":"1999","journal-title":"Brain"},{"key":"ref_49","first-page":"850","article-title":"Upper extremity function in multiple sclerosis: Improving assessment sensitivity with box-and-block and nine-hole peg tests","volume":"69","author":"Goodkin","year":"1988","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1177\/1352458514567553","article-title":"Unilateral and bilateral upper limb dysfunction at body functions, activity and participation levels in people with multiple sclerosis","volume":"21","author":"Bertoni","year":"2015","journal-title":"Mult. Scler. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2522\/ptj.20130588","article-title":"Associations of Upper Limb Disability Measures on Different Levels of the International Classification of Functioning, Disability and Health in People with Multiple Sclerosis","volume":"95","author":"Lamers","year":"2015","journal-title":"Phys. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.msard.2019.01.043","article-title":"Clinical correlates of 9-hole peg test in a large population of people with multiple sclerosis","volume":"30","author":"Solaro","year":"2019","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/j.1600-0404.2007.00972.x","article-title":"The reliability of the MSFC and its components","volume":"117","author":"Koivisto","year":"2007","journal-title":"Acta Neurol. Scand."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1177\/1352458517690824","article-title":"The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis","volume":"23","author":"Feys","year":"2017","journal-title":"Mult. Scler. J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.acn.2005.07.006","article-title":"A comprehensive review of the Paced Auditory Serial Addition Test (PASAT)","volume":"21","author":"Tombaugh","year":"2006","journal-title":"Arch. Clin. Neuropsychol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2466\/pms.1977.44.2.367","article-title":"Paced Auditory Serial-Addition Task: A Measure of Recovery from Concussion","volume":"44","author":"Gronwall","year":"1977","journal-title":"Percept. Mot. Ski."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1191\/1352458502ms845oa","article-title":"The multiple sclerosis functional composite: A new clinical outcome measure for multiple sderosis trials","volume":"8","author":"Rudick","year":"2002","journal-title":"Mult. Scler. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1590\/S0004-282X2011000400014","article-title":"Paced auditory serial addition test (PASAT): A very difficult test even for individuals with high intellectual capability","volume":"69","author":"Brooks","year":"2011","journal-title":"Arq. Neuro-Psiquiatria"},{"key":"ref_59","first-page":"1219-e72","article-title":"The Symbol Digit Modalities Test as sentinel test for cognitive impairment in multiple sclerosis","volume":"21","author":"Cleynhens","year":"2014","journal-title":"Eur. J. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1177\/1352458518803785","article-title":"Recommendations for cognitive screening and management in multiple sclerosis care","volume":"24","author":"Kalb","year":"2018","journal-title":"Mult. Scler. J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1177\/1352458518808204","article-title":"Symbol Digit Modalities Test: A valid clinical trial endpoint for measuring cognition in multiple sclerosis","volume":"25","author":"Strober","year":"2018","journal-title":"Mult. Scler. J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1177\/1352458512451512","article-title":"Revisiting the Multiple Sclerosis Functional Composite: Proceedings from the National Multiple Sclerosis Society (NMSS) Task Force on Clinical Disability Measures","volume":"18","author":"Ontaneda","year":"2012","journal-title":"Mult. Scler. J."},{"key":"ref_63","first-page":"1","article-title":"A one-year follow-up study of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) in relapsing-remitting multiple sclerosis: An appraisal of comparative longitudinal sensitivity","volume":"15","author":"Querol","year":"2015","journal-title":"BMC Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e376","DOI":"10.1212\/WNL.0000000000011275","article-title":"Siponimod and cognition in secondary progressive multiple sclerosis: EXPAND secondary analyses","volume":"96","author":"Benedict","year":"2021","journal-title":"Neurology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1177\/1352458517690821","article-title":"Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis","volume":"23","author":"Benedict","year":"2017","journal-title":"Mult. Scler. J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1177\/1352458509354552","article-title":"Psychometrics and normative data for the Multiple Sclerosis Functional Composite: Replacing the PASAT with the Symbol Digit Modalities Test","volume":"16","author":"Drake","year":"2009","journal-title":"Mult. Scler. J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1093\/arclin\/acu055","article-title":"The Symbol Digit Modalities Test: Normative Data from a Large Nationally Representative Sample of Australians","volume":"29","author":"Kiely","year":"2014","journal-title":"Arch. Clin. Neuropsychol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.msard.2016.09.009","article-title":"Practice effect in Symbol Digit Modalities Test in multiple sclerosis patients treated with natalizumab","volume":"10","author":"Roar","year":"2016","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.msard.2012.12.004","article-title":"Measures of visual pathway structure and function in MS: Clinical usefulness and role for MS trials","volume":"2","author":"Galetta","year":"2013","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1177\/1352458517690822","article-title":"Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis","volume":"23","author":"Balcer","year":"2017","journal-title":"Mult. Scler. J."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/ana.22005","article-title":"Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis","volume":"67","author":"Talman","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.ophtha.2011.11.032","article-title":"Ganglion Cell Loss in Relation to Visual Disability in Multiple Sclerosis","volume":"119","author":"Walter","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1001\/archneurol.2009.107","article-title":"Damage to the Optic Radiation in Multiple Sclerosis Is Associated With Retinal Injury and Visual Disability","volume":"66","author":"Reich","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1212\/WNL.59.5.679","article-title":"Benefit of interferon beta-1a on MSFC progression in secondary progressive MS","volume":"59","author":"Cohen","year":"2002","journal-title":"Neurology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1177\/135245850000600305","article-title":"New low-contrast vision charts: Reliability and test characteristics in patients with multiple sclerosis","volume":"6","author":"Balcer","year":"2000","journal-title":"Mult. Scler."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.jns.2012.03.009","article-title":"Low-contrast acuity measures visual improvement in phase 3 trial of natalizumab in relapsing MS","volume":"318","author":"Balcer","year":"2012","journal-title":"J. Neurol. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1016\/j.ophtha.2007.06.047","article-title":"Visual Acuity as an Outcome Measure in Clinical Trials of Retinal Diseases","volume":"114","author":"Beck","year":"2007","journal-title":"Ophthalmology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1007\/s00415-021-10437-5","article-title":"Visual deficits and cognitive assessment of multiple sclerosis: Confounder, correlate, or both?","volume":"268","author":"Jakimovski","year":"2021","journal-title":"J. Neurol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1093\/brain\/awu335","article-title":"Vision and vision-related outcome measures in multiple sclerosis","volume":"138","author":"Balcer","year":"2014","journal-title":"Brain"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1212\/WNL.34.10.1368","article-title":"A neurologic rating scale (NRS) for use in multiple sclerosis","volume":"34","author":"Sipe","year":"1984","journal-title":"Neurology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1017\/S0317167100000391","article-title":"Responsiveness of the Scripps neurologic rating scale during a multiple sclerosis clinical trial","volume":"26","author":"Koziol","year":"1999","journal-title":"Can. J. Neurol. Sci. J. Can. Sci. Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0140-6736(94)91046-4","article-title":"Cladribine in treatment of chronic progressive multiple sclerosis","volume":"344","author":"Sipe","year":"1994","journal-title":"Lancet"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/ana.25145","article-title":"Deep gray matter volume loss drives disability worsening in multiple sclerosis","volume":"83","author":"Eshaghi","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_84","first-page":"93","article-title":"Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis","volume":"87","author":"Stromillo","year":"2016","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e1348","DOI":"10.1212\/WNL.0000000000008198","article-title":"Cortical atrophy accelerates as cognitive decline worsens in multiple sclerosis","volume":"93","author":"Eijlers","year":"2019","journal-title":"Neurology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1212\/01.WNL.0000150542.16969.CC","article-title":"Dehydration confounds the assessment of brain atrophy","volume":"64","author":"Duning","year":"2005","journal-title":"Neurology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.neuroimage.2015.05.077","article-title":"Diurnal fluctuations in brain volume: Statistical analyses of MRI from large populations","volume":"118","author":"Nakamura","year":"2015","journal-title":"NeuroImage"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1212\/01.WNL.0000161871.83614.BB","article-title":"Risk factors for progression of brain atrophy in aging: Six-year follow-up of normal subjects","volume":"64","author":"Enzinger","year":"2005","journal-title":"Neurology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s40263-014-0140-z","article-title":"Clinical relevance of brain volume measures in multiple sclerosis","volume":"28","author":"Airas","year":"2014","journal-title":"CNS Drugs"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.3174\/ajnr.A4681","article-title":"Autoimmune Comorbidities Are Associated with Brain Injury in Multiple Sclerosis","volume":"37","author":"Zivadinov","year":"2016","journal-title":"Am. J. Neuroradiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1212\/01.wnl.0000316810.01120.05","article-title":"Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis","volume":"71","author":"Zivadinov","year":"2008","journal-title":"Neurology"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"101426","DOI":"10.1016\/j.msard.2019.101426","article-title":"Correlation between EDSS scores and cervical spinal cord atrophy at 3T MRI in multiple sclerosis: A systematic review and meta-analysis","volume":"37","author":"Song","year":"2019","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1111\/jon.12553","article-title":"Spinal Cord Atrophy in Multiple Sclerosis: A Systematic Review and Meta-Analysis","volume":"28","author":"Casserly","year":"2018","journal-title":"J. Neuroimaging"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Moccia, M., Ruggieri, S., Ianniello, A., Toosy, A., Pozzilli, C., and Ciccarelli, O. (2019). Advances in spinal cord imaging in multiple sclerosis. Ther. Adv. Neurol. Disord., 12.","DOI":"10.1177\/1756286419840593"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/ana.410420318","article-title":"Recommendations from the national multiple sclerosis society clinical outcomes assessment task force","volume":"42","author":"Rudick","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1177\/135245859900500409","article-title":"The Multiple Sclerosis Functional Composite Measure (MSFC): An integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force","volume":"5","author":"Fischer","year":"1999","journal-title":"Mult. Scler. J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1177\/1352458516638941","article-title":"The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis","volume":"23","author":"Cadavid","year":"2016","journal-title":"Mult. Scler. J."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"102512","DOI":"10.1016\/j.autrev.2020.102512","article-title":"Clinical outcome measures in multiple sclerosis: A review","volume":"19","author":"Inojosa","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1080\/03007995.2016.1222516","article-title":"Evaluation of the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite as clinical endpoints in multiple sclerosis clinical trials: Quantitative meta-analyses","volume":"32","author":"Turkistani","year":"2016","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1177\/1352458509102626","article-title":"The search for responsive clinical endpoints in primary progressive multiple sclerosis","volume":"15","author":"Bosma","year":"2009","journal-title":"Mult. Scler. J."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/ana.25313","article-title":"Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial","volume":"84","author":"Wolinsky","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Hegen, H., Bsteh, G., and Berger, T. (2018). \u2018No evidence of disease activity\u2019\u2014Is it an appropriate surrogate in multiple sclerosis?. Eur. J. Neurol., 25.","DOI":"10.1111\/ene.13669"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.amjmed.2014.01.011","article-title":"Individual and Composite Study Endpoints: Separating the Wheat from the Chaff","volume":"127","author":"Goldberg","year":"2014","journal-title":"Am. J. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1093\/brain\/aww173","article-title":"Defining secondary progressive multiple sclerosis","volume":"139","author":"Lorscheider","year":"2016","journal-title":"Brain"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"666868","DOI":"10.3389\/fneur.2021.666868","article-title":"Clinical and Paraclinical Biomarkers and the Hitches to Assess Conversion to Secondary Progressive Multiple Sclerosis: A Systematic Review","volume":"12","author":"Krajnc","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1177\/135245859900500508","article-title":"Disease steps in multiple sclerosis: A longitudinal study comparing disease steps and EDSS to evaluate disease progression","volume":"5","author":"Hohol","year":"1999","journal-title":"Mult. Scler. J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1191\/1352458505ms1120oa","article-title":"Responsiveness of the Multiple Sclerosis Impairment Scale in comparison with the Expanded Disability Status Scale","volume":"11","author":"Ravnborg","year":"2005","journal-title":"Mult. Scler. J."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"University of California SFMSET, Cree BAC, Hollenbach, J.A., Bove, R., Kirkish, G., Sacco, S., Caverzasi, E., Bischof, A., Gundel, T., and Zhu, A.H. (2019). Silent progression in disease activity-free relapsing multiple sclerosis. Ann. Neurol., 85, 653\u2013666.","DOI":"10.1002\/ana.25463"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1177\/1352458519898108","article-title":"Recovery of cognitive function after relapse in multiple sclerosis","volume":"27","author":"Benedict","year":"2020","journal-title":"Mult. Scler. J."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Kalinowski, A., Cutter, G., Bozinov, N., Hinman, J.A., Hittle, M., Motl, R., Odden, M., and Nelson, L.M. (2021). The timed 25-foot walk in a large cohort of multiple sclerosis patients. Mult. Scler. J., 13524585211017013.","DOI":"10.1177\/13524585211017013"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1212\/01.wnl.0000436065.97642.d2","article-title":"Clinically meaningful performance benchmarks in MS: Timed 25-Foot Walk and the real world","volume":"81","author":"Goldman","year":"2013","journal-title":"Neurology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/ane.13152","article-title":"Plasma neurofilaments correlate with disability in progressive multiple sclerosis patients","volume":"141","author":"Ferraro","year":"2019","journal-title":"Acta Neurol. Scand."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1212\/01.wnl.0000313034.46883.16","article-title":"Disability as an outcome in MS clinical trials","volume":"71","author":"Ebers","year":"2008","journal-title":"Neurology"},{"key":"ref_114","first-page":"e111","article-title":"Reliability of Outcome Measures in Clinical Trials in Secondary Progressive Multiple Sclerosis","volume":"96","author":"Koch","year":"2020","journal-title":"Neurology"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1212\/WNL.0000000000011120","article-title":"Has the Time Come to Revisit Our Standard Measures of Disability Progression in Multiple Sclerosis?","volume":"96","author":"Kalincik","year":"2021","journal-title":"Neurology"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1177\/1352458516667568","article-title":"MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study","volume":"22","author":"Tourbah","year":"2016","journal-title":"Mult. Scler. J."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1136\/jnnp.68.4.450","article-title":"Disability outcome measures in therapeutic trials of relapsing-remitting multiple sclerosis: Effects of heterogeneity of disease course in placebo cohorts","volume":"68","author":"Liu","year":"2000","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"3287","DOI":"10.1093\/brain\/awv258","article-title":"Defining reliable disability outcomes in multiple sclerosis","volume":"138","author":"Kalincik","year":"2015","journal-title":"Brain"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1177\/1352458517729465","article-title":"Clinical outcome measures for progressive MS trials","volume":"23","author":"Ontaneda","year":"2017","journal-title":"Mult. Scler. J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1001\/jamaneurol.2020.1568","article-title":"Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials","volume":"77","author":"Kappos","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/ana.24487","article-title":"Optical coherence tomography reflects brain atrophy in multiple sclerosis: A four-year study","volume":"78","author":"Saidha","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1001\/jamaneurol.2013.573","article-title":"Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis","volume":"70","author":"Saidha","year":"2013","journal-title":"JAMA Neurol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1177\/1352458517740216","article-title":"Peripapillary retinal nerve fibre layer as measured by optical coherence tomography is a prognostic biomarker not only for physical but also for cognitive disability progression in multiple sclerosis","volume":"25","author":"Bsteh","year":"2017","journal-title":"Mult. Scler. J."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/S1474-4422(16)00068-5","article-title":"Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: A cohort study","volume":"15","author":"Arnow","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1111\/ene.13897","article-title":"Peripapillary retinal nerve fibre layer thinning rate as a biomarker discriminating stable and progressing relapsing\u2013remitting multiple sclerosis","volume":"26","author":"Bsteh","year":"2019","journal-title":"Eur. J. Neurol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1177\/1352458520935724","article-title":"Macular ganglion cell\u2013inner plexiform layer thinning as a biomarker of disability progression in relapsing multiple sclerosis","volume":"27","author":"Bsteh","year":"2020","journal-title":"Mult. Scler. J."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ajo.2016.11.010","article-title":"Estimating Optical Coherence Tomography Structural Measurement Floors to Improve Detection of Progression in Advanced Glaucoma","volume":"175","author":"Bowd","year":"2016","journal-title":"Am. J. Ophthalmol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/ana.24954","article-title":"Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis","volume":"81","author":"Disanto","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1212\/WNL.0000000000004683","article-title":"Monitoring disease activity in multiple sclerosis using serum neurofilament light protein","volume":"89","author":"Novakova","year":"2017","journal-title":"Neurology"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.msard.2019.02.004","article-title":"Clinical and MRI correlates of CSF neurofilament light chain levels in relapsing and progressive MS","volume":"30","author":"Damasceno","year":"2019","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1093\/brain\/awy154","article-title":"Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis","volume":"141","author":"Barro","year":"2018","journal-title":"Brain"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"e1007","DOI":"10.1212\/WNL.0000000000007032","article-title":"Blood neurofilament light chain as a biomarker of MS disease activity and treatment response","volume":"92","author":"Kuhle","year":"2019","journal-title":"Neurology"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1177\/1352458518794308","article-title":"Prognostic value of cerebrospinal fluid neurofilament light chain and chitinase-3-like-1 in newly diagnosed patients with multiple sclerosis","volume":"25","author":"Sellebjerg","year":"2018","journal-title":"Mult. Scler. J."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1212\/WNL.0000000000010346","article-title":"Serum neurofilament light as a biomarker in progressive multiple sclerosis","volume":"95","author":"Kapoor","year":"2020","journal-title":"Neurology"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1212\/01.wnl.0000335765.55346.fc","article-title":"Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis","volume":"72","author":"Altmann","year":"2008","journal-title":"Neurology"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"e1201","DOI":"10.1212\/WNL.0000000000009097","article-title":"Blood neurofilament light levels segregate treatment effects in multiple sclerosis","volume":"94","author":"Delcoigne","year":"2020","journal-title":"Neurology"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fneur.2016.00131","article-title":"Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment","volume":"7","author":"Kosa","year":"2016","journal-title":"Front. Neurol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1111\/ene.13339","article-title":"Patient-reported outcomes in multiple sclerosis: A systematic comparison of available measures","volume":"24","author":"Khurana","year":"2017","journal-title":"Eur. J. 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