The Multiple Sclerosis Functional Composite: A clinically meaningful measure of disability

27 April 2010
Volume 74(17_Supplement_3) Supplement 3, New Frontiers in Multiple Sclerosis: Impact of Disease-Modifying Therapies on Nontraditional Measures of Disease Activity
pp S8-S15


Background: The Multiple Sclerosis Functional Composite (MSFC) provides a focused and sensitive evaluation of disability in patients with multiple sclerosis (MS) that may be more responsive to change than that provided by the Expanded Disability Status Scale.

Expert Clinical Opinion: The MSFC is a 3-part quantitative instrument that measures arm, leg, and cognitive function with the 9-Hole Peg Test (arm/hand dexterity), the Timed 25-Foot Walk (leg function), and the Paced Auditory Serial Addition Test (3-second version, PASAT3; cognition). The MSFC has excellent test-retest reliability. Construct validity was supported by expected differences in scores between patients with primary or secondary progressive MS compared with relapsing-remitting MS. Concurrent validity was demonstrated by significant correlations with the Expanded Disability Status Scale, the Sickness Impact Profile, and the Short Form-36, particularly on the physical components of the latter 2 scales. MSFC scores also correlate with MRI changes. Limitations of the MSFC include practice effects with the PASAT and to a lesser extent the 9-Hole Peg Test, variations in the reference populations used to calculate Z-scores, and the lack of an accepted definition of a clinically meaningful change.

Future Directions: Future research should be directed at adding a test that measures visual function (e.g., contrast acuity), at replacing the PASAT by a cognition test that has better measurement characteristics, and at developing methods to better understand the clinical relevance of changes in MSFC scores.

GLOSSARY: 9HPT = 9-Hole Peg Test; CI = confidence interval; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; HR = hazard ratio; IFN = interferon; MS = multiple sclerosis; MSFC = Multiple Sclerosis Functional Composite; PASAT = Paced Auditory Serial Addition Test; RRMS = relapsing-remitting MS; SF-36 = Short Form-36; SIP = Sickness Impact Profile; T25FW = Timed 25-Foot Walk.

Back to top


Precise and standardized assessment of disease progression and treatment response is critical to the design of multiple sclerosis (MS) clinical studies. The Expanded Disability Status Scale (EDSS)1 has long been considered the gold-standard measurement of disability and disease progression in MS.2 The EDSS measures neurologic impairment across 8 functional systems1 and is used routinely as a primary or secondary clinical end point in studies of disease-modifying therapies (DMTs).3-8 Scoring on the EDSS ranges from 0 (normal neurologic examination) to 10.0 (death). Intermediate scores indicate minimal disability (1.0–3.0), moderate disability (3.0–5.0), and more severe disability, such as needing assistance walking (≥6.0) and bed-bound status (≥8.5).1

Despite its widespread use, the EDSS has several limitations, including the need for a neurologist to examine the patient and derive the score. At the lower end of the scale (scores <3.0), the score is derived by rating the severity of impairments determined by neurologic examination to obtain multiple functional systems scores. At that range of the scale, the EDSS becomes imprecise because of subjectivity in determining the scores; it has been argued that the scale does not measure disability at the lower end. In the middle and upper regions of the scale (scores ≥3.0), the EDSS is weighted heavily toward ambulatory disability and is less sensitive to other dimensions of MS such as arm and cognitive function. Nonlinearity, in which a 1.0-point change at 1 point on the scale is not the same as a 1.0-point change at another point on the scale, is another drawback to the use of the EDSS. In some clinical studies, patients with mild to moderate disability (EDSS score <6.0) were grouped with more severely disabled patients (EDSS score ≥6.0), and disease progression was defined as a 1.0- or 0.5-point change. One study2 challenged the notion that these changes were similar and found that a 0.5-point change in EDSS score for more severely disabled patients did not correspond with changes in other instruments that rated disability. In contrast, changes in the EDSS for patients with mild to moderate disease severity more closely corresponded with other outcome measures. These findings suggest that the EDSS is less responsive to changes in more severely ill patients.2

In 1994, the US National Multiple Sclerosis Society convened a task force to develop a multidimensional clinical rating instrument that (1) reflected the varied clinical expression of MS across patients and over time, (2) evaluated each dimension independently of the others, and (3) measured cognitive function and other dimensions not included in other instruments available at the time. The result was the Multiple Sclerosis Functional Composite (MSFC), which is simple to administer regardless of the physician's or technician's prior experience, relevant to clinical studies (i.e., sensitive, reliable, and quantitative), and supplementary to the EDSS.9-12 Herein, we examine the MSFC, discuss its advantages and limitations, and review its use in clinical studies of DMTs in MS.


The MSFC is made up of 3 components that measure arm and hand dexterity, walking speed, and cognition (table 1).9 The 9-Hole Peg Test (9HPT) measures arm and hand function according to the time needed for the patient to insert and remove 9 pegs from a board, first with the dominant hand and then with the nondominant hand. The final score is recorded as the mean time for both hands. The 9HPT is more sensitive than the EDSS in detecting deteriorations in upper extremity function.9,13 The Timed 25-Foot Walk (T25FW) assesses change in ambulatory function. A time increase of 20% or greater indicates a clinically meaningful impairment in gait.9,14 The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function in which patients listen to a series of 61 spoken numbers separated by 3-second (PASAT3) or 2-second (PASAT2) intervals. Each number must be added to the prior number. The final score is the number of correct additions in the series.9,15 Because practice effects have been well described, particularly for the 9HPT and the PASAT3, a run-in to establish a stable baseline is necessary.16-18

Table 1 The 3 components of the Multiple Sclerosis Functional Composite

Click here to enlarge

The 3 components of the MSFC are partially independent of each other and correlate to a similar extent with the composite score.19 Because the components differ in direction of change (deterioration indicated by higher scores on the 9HPT and T25FW vs lower scores on the PASAT3) and units of measurement (time vs number correct), the MSFC composite score is reported as a Z-score that is computed from individual Z-scores for each component. Lower MSFC scores compared with baseline or prior measurements indicate neurologic deterioration.17 A Z-score is a standardized score that compares a patient's performance with that of a reference population. Z-scores are the number of standard deviations between scores for the individual and the reference population.9 The reference population used to create Z-scores can be derived from a standard MS population such as the pooled dataset used to develop the MSFC,9 the entry scores from patients enrolled in a particular study, or healthy controls. Choice of the reference population (e.g., patients with MS vs healthy controls) will influence weighting of the individual components.20


The MSFC was used as the primary efficacy end point in the International Multiple Sclerosis Secondary Progressive Avonex® Controlled Trial.17 Intrarater reliability was tested after the MSFC was administered 3 times before baseline and at baseline. Intraclass correlation coefficients of 0.90 for session 3 compared with session 4 and 0.87 for all 4 sessions combined indicate excellent intrarater reliability. Interrater reliability after 6 months without testing/retraining also was excellent, with an intraclass correlation coefficient of 0.96.

The MSFC has been validated by different investigators and in different patient populations. Construct validity is the ability of an instrument to measure adequately the disease dimensions that it was designed to measure.21 In other words, scores on any given rating scale should, for example, indicate deterioration over time for patients with progressive disease and improvement for patients who respond to treatment. In a cross-sectional study,22 MSFC Z-scores were lower (indicating a higher level of disability) in patients with primary progressive MS (−0.4) or secondary progressive MS (−0.3) vs patients with relapsing-remitting MS (RRMS) (+0.42; p< 0.05).

Concurrent validity is an assessment of the level of correlation between the instrument under development and other accepted or validated instruments. Moderate to moderately strong correlations between MSFC and EDSS scores indicate some commonality between these scales in their assessment of disability (table 2). One relatively consistent finding across studies was that walking time (but not arm function or cognition) correlates strongly with the EDSS, which is not unexpected given the bias of the EDSS toward ambulation.9,17,22,23 Thus, the MSFC is a good measure of ambulatory disability, and it also includes aspects of neurologic function (e.g., arm function and cognition) not measured well by the EDSS.

Table 2 Spearman rank correlations of MSFC components, MSFC composite score, and EDSS in patients with MS

Click here to enlarge

One study24 compared the MSFC with the EDSS and several different quality of life instruments, including the Sickness Impact Profile (SIP), in 300 patients with MS. The MSFC correlated relatively strongly with the EDSS (r = −0.80) and the overall SIP score (r = −0.62). Correlations between the MSFC, the physical component of the SIP (r = −0.71), and the physical component summary of the Medical Outcomes Study Short Form (SF-36) (r = 0.41) were stronger than those for the SIP psychosocial score (r = −0.34) or the SF-36 mental component summary (r = −0.05).

Concurrent validity of the MSFC also has been shown with MRI findings. Several traditional and nontraditional MRI measures, including T1 and T2 lesion load, brain atrophy, magnetic transference ratio, and mean diffusivity, correlated modestly (r<0.50) but significantly with MSFC scores.25-33 Scores on the 9HPT correlated with functional MRI measures of motor cortex.30 Baseline MSFC scores in patients with RRMS were predictive of brain atrophy 2 and 8 years later.31,32 In addition, other studies have shown that MSFC scores correlated with metabolic and immunologic markers of disease severity in the brain34-36 and chemokine polymorphisms associated with MS.37


The MSFC was developed as a measure of neurologic impairment that would improve on or supplement information gleaned from the EDSS. Because the MSFC can be administered by trained office staff38 rather than a neurologist, it should be less expensive and more convenient to use than the EDSS. The MSFC is a quantitative instrument that uses linear measures resulting in comparable changes across the range of disease severity. In contrast, the EDSS is based on qualitative psychometrics (i.e., an ordinal scale), and deterioration over the range of the scale is nonlinear, resulting in a ceiling effect.1,2,19 Unlike the EDSS, the MSFC includes an assessment of cognitive function and thus measures a broader range of dimensions of disability.9 Finally, results from a prospective study39 showed that the MSFC more precisely measures between-group changes than the EDSS in cohorts of patients with MRI-documented differences in MS severity.

Limitations of the MSFC include the lack of a measure of vision.9 Second, clinical interpretation of the MSFC Z-score change and individual component Z-score changes are difficult. Third, there are significant practice effects on the PASAT3 and the 9-HPT, which result in improving scores that can make interpretation difficult.18 However, in parallel-group studies, the practice and learning effects should be controlled. Fourth, use of particular reference populations introduces weightings to the different components of the MSFC, and this may limit the comparability of results from one study to another.40 Finally, although a 20% change in scores on the T25FW and 9-HPT and a 0.5 SD change on the PASAT3 are considered clinically meaningful,41 similar cut points for the overall MSFC score have not been characterized.42



The value of the MSFC in predicting future disability and MRI status in patients with RRMS was documented in an 8-year follow-up of a phase 3 study of IM interferon (IFN)β-1a (Avonex).31 In a subset of 159 patients, baseline MSFC scores modestly correlated with MSFC scores at 2 years (r = 0.75) and 8 years (r = 0.64); these correlations were stronger somewhat than those between baseline EDSS scores and 2-year (r = 0.54) and 8-year (r = 0.45) EDSS scores. Baseline MSFC scores and MSFC change scores (baseline to year 2) correlated with disability at 8 years (figure 1), and baseline MSFC and MSFC change scores over 2 years predicted severe EDSS scores (EDSS ≥6.0) at 8-year follow-up, with odds ratios of 2.72 (95% confidence interval [CI]: 1.42–5.21; p = 0.002) and 3.05 (95% CI: 1.61–5.78; p< 0.001). Brain atrophy as measured by brain parenchymal fraction on MRI also correlated with MSFC scores at baseline (r = 0.419; p< 0.0001), year 2 (r = 0.498; p< 0.0001), and follow-up (r = 0.481; p< 0.0001).32 In a subset of 30 patients from this study population who were observed for 13 years, the change in T2 lesion volume from baseline to 2 years correlated with MSFC scores at the 13-year follow-up visit (r = −0.50; p = 0.005).43

Figure 1 Percentage of patients with Expanded Disability Status Scale (EDSS) score ≥6.0 at follow-up by the baseline Multiple Sclerosis Functional Composite (MSFC) score from a phase 3 clinical study of IM interferon beta-1a and the change in MSFC score during the 2 years of the studyThe most favorable quartile is shown to the left and the least favorable to the right. Quartile 1: MSFC baseline ≥0.51, MSFC change <0.35; Quartile 2: MSFC baseline ≥0.06 and <0.51, MSFC change ≥0.08 and <0.35; Quartile 3: MSFC baseline ≥−0.32 and <0.06, MSFC change ≥−0.34 and <0.08; Quartile 4: MSFC baseline <−0.31, MSFC change <−0.34. Reproduced with permission from Rudick et al. Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS. Neurology 2001;56:1324–1330.

Click here to enlarge

In the phase 3 International Multiple Sclerosis Secondary Progressive Avonex® Controlled Trial in patients with secondary progressive MS, IM IFNβ-1a reduced deterioration in MSFC Z-scores by 40.4% (p = 0.033) compared with placebo.44 Over 2 years, changes in MSFC scores correlated with the change in SF-36 mental component summary scores (r = 0.182; p≤ 0.01) in this study.45


The MSFC has been used as a secondary efficacy measure in a long-term study of subcutaneous IFNβ-1b (Betaseron®) in patients with a first neurologic event suggestive of MS and 2 or more clinically silent MRI lesions. The Betaferon/Betaseron in Newly Emerging MS for Initial Treatment study compared IFNβ-1b treatment every other day (n = 292) with placebo (n = 176) for 2 years or until development of clinically evident MS. At that point, patients were eligible to continue open-label IFNβ-1b (early treatment) or switch from placebo to active treatment (delayed treatment) for up to 3 additional years for a total of 5 years. An interim analysis conducted at the 3-year postrandomization point showed that the total MSFC score improved for all patients but that no significant differences were observed between the early- and delayed-treatment groups (p = 0.48). Differences between groups in favor of early treatment were noted on the PASAT (version not specified; p = 0.011) but not on the 9HPT (p = 0.118) or the T25FW (p = 0.792). The authors concluded that the MSFC may not sufficiently be sensitive to detect change in patients with very early-stage disease.46 In addition, the MSFC was used as a secondary outcome measure in the small pilot study of IFNβ-1b in patients with primary progressive MS (n = 49) or transitional MS (n = 24).47 Patients were randomized to IFNβ-1b or placebo for 2 years. Treatment with IFNβ-1b resulted in significant benefit on MSFC scores compared with placebo at the 6-month follow-up (specific data not provided). Data for longer periods of treatment were not reported.

Glatiramer acetate.

To date, the MSFC has not been used in randomized placebo-controlled trials of glatiramer acetate (Copaxone®).


The MSFC was used as a measure of disability progression in the phase 3 Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study of natalizumab (Tysabri®) in patients with RRMS.7 Natalizumab improved changes in MSFC Z-scores (p≤ 0.003) at each time point measured from 12 to 120 weeks compared with placebo (figure 2).48,49 Changes in MSFC Z-scores were correlated with changes in EDSS scores from baseline to weeks 48 (r = −0.157; p< 0.001) and 120 (r = −0.27; p< 0.001).50 In addition, natalizumab improved changes in the T25FW (p< 0.001), 9HPT (p< 0.001), and PASAT3 (p = 0.005) Z-scores during the 2-year study compared with placebo (figure 3).49 When disability was defined as a 20% or greater sustained reduction from baseline score, the 9HPT (hazard ratio [HR], 0.55; 95% CI: 0.36–0.84; p = 0.005) and T25FW (HR, 0.66; 95% CI: 0.49–0.89; p = 0.006) were more sensitive to the beneficial effects of natalizumab (vs placebo) during a 2-year time period than was the PASAT3 (HR, 0.78; 95% CI: 0.35–1.72; p = 0.534).48

Figure 2 The effect of natalizumab on disability as measured by the Multiple Sclerosis Functional Composite (MSFC) score48

Click here to enlarge

Figure 3. The effect of natalizumab on Multiple Sclerosis Functional Composite (MSFC) composite and individual component scores49Abbreviation: PASAT = Paced Auditory Serial Addition Test.

Click here to enlarge


The MSFC is unique among the available instruments for assessing neurologic disability because it includes the PASAT, a separate measure of cognition. Cognitive impairment is an important dimension of MS-related disability that can negatively affect quality of life, occupational ability, and rehabilitation. However, measurement of cognitive deterioration can be challenging. Longitudinal PASAT data cannot be interpreted without a control group because of marked practice effects. Moreover, the natural history of the PASAT in MS is highly variable and may be influenced by patient motivation or prior training.

The PASAT was used in several clinical trials of DMTs as a component of the MSFC or as a standalone measure of cognitive function. The PASAT (both the 3-second and 2-second versions, administered every 26 weeks) was 1 of a battery of neuropsychologic tests administered to patients as part of a phase 3 clinical trial of IM IFNβ-1a.51 IM IFNβ-1a prolonged the time to sustained deterioration in the PASAT processing rate compared with placebo (p = 0.023), and fewer patients treated with IM IFNβ-1a (19.5%) showed sustained deterioration vs placebo (36.6%). The PASAT was included in a cognitive testing battery in a phase 3 study of glatiramer acetate in patients with RRMS in which no statistically significant differences were observed between glatiramer acetate and placebo for any of the cognitive tests used (including the PASAT) after 2 years of treatment.52 The PASAT was administered as part of the MSFC in the phase 3 AFFIRM study of natalizumab monotherapy.49,53 Significantly greater improvements in PASAT3 Z-scores were seen over 2 years in the natalizumab group compared with the placebo group (figure 3).


The MSFC is a reliable and well-validated instrument that was developed as a multidimensional quantitative measure of neurologic disability in MS. Moderately strong correlations between the MSFC and the EDSS have been demonstrated, especially for ambulation. In addition, scores on the MSFC strongly correlate with progression of MRI lesions, brain atrophy, biomarkers of MS, and quality of life measurements in patients with MS.

The MSFC enables measurement of arm/hand dexterity and cognitive function that are not measured by the EDSS. Another consideration in favor of the MSFC over the EDSS is that the MSFC can be administered by a trained technician rather than a neurologist, which can be expected to result in lower costs. Findings from several studies suggest that the MSFC is more sensitive than the EDSS,31,44 although there have been observations that the responsiveness and long-term predictive value of the MSFC and the EDSS are relatively weak.54 In addition, clinically significant cut points for changes in the MSFC and its individual component scores, such as a 20% or greater reduction in scores, are not well characterized. Regulatory authorities require that primary clinical outcome measures demonstrate clinically meaningful changes, and currently this requirement poses a problem for the MSFC. Use and interpretation of the MSFC also may be limited by the effect of the reference population on weighting of the different MSFC components.

The MSFC has been incorporated into many recent clinical studies, and it is being used in many ongoing studies. IM IFNβ-1a and natalizumab have shown statistically significant benefits on MSFC composite scores in clinical studies. Over time and with more widespread use, the MSFC is expected to be further refined and to contribute increasingly to outcomes assessments in MS clinical trials.


This supplement was supported by funding from Biogen Idec, Inc. and Elan Pharmaceuticals, Inc. The authors thank Paul Benfield, Ann Marie Galioto, Matthew Hasson, Colleen Hedge, and Michael Theisen of Scientific Connexions, Newtown, Pennsylvania, for editorial assistance in preparing this manuscript. Mr. Benfield, Mr. Hasson, and Mr. Theisen were responsible for technical and mechanical editing of the manuscript for non-intellectual content and preparing electronic files for submission to the publisher. Ms. Hedge provided word processing and copyediting for the manuscript, ensured compliance with Neurology journal style, and obtained copyright permissions on behalf of the authors where appropriate. Ms. Galioto provided medical writing on the first draft of the manuscript based on a content outline provided by the authors. Subsequent drafts and the final manuscript were reviewed, revised, and approved by the authors. This support was funded by Biogen Idec and Elan Pharmaceuticals.


Dr. Polman has served on steering committees or independent data safety monitoring boards for Actelion, Antisense Therapeutics, Bayer-Schering, Biogen Idec, GlaxoSmithKline, Merck-Serono, Roche, Teva, and UCB Pharma; serves on the editorial boards of Multiple Sclerosis and Lancet Neurology; received honoraria from Bayer-Schering, Biogen Idec, Novartis Pharmaceuticals, and Teva; received research support from Bayer-Schering, Biogen Idec, GlaxoSmithKline, Merck-Serono, Novartis, Teva, and UCB Pharma; and received grant support from the NABINMS (Neutralizing Antibodies on Interferon Beta in Multiple Sclerosis) project/EEC and the Dutch Multiple Sclerosis Society. Dr. Rudick has served on scientific advisory boards for Bayhill Pharmaceuticals, Genzyme, Novartis Pharmaceuticals, and Wyeth Pharmaceuticals; received compensation for travel/honoraria from Biogen Idec, Genzyme, Novartis, Teva, and Wyeth; received royalties from publishing for the text Multiple Sclerosis Therapeutics (Informa Healthcare, UK); and received research funding from the National Institutes of Health.


Back to top

1. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–1452.

2. Kragt JJ, Nielsen JM, van der Linden FA, Uitdehaag BM, Polman CH. How similar are commonly combined criteria for EDSS progression in multiple sclerosis? Mult Scler 2006;12:782–786.

3. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology 1993;43:655–661.

4. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45:1268–1276.

5. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39:285–294.

6. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998;352:1498–1504.

7. Polman CH, O'Connor PW, Havrdova E, et al; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899–910.

8. Rudick RA, Stuart WH, Calabresi PA, et al; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911–923.

9. Cutter GR, Baier ML, Rudick RA, et al. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999;122(Pt 5):871–882.

10. Rudick R, Antel J, Confavreux C, et al. Clinical outcomes assessment in multiple sclerosis. Ann Neurol 1996;40:469–479.

11. Rudick R, Antel J, Confavreux C, et al. Recommendations from the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force. Ann Neurol 1997;42:379–382.

12. Whitaker JN, McFarland HF, Rudge P, Reingold SC. Outcomes assessment in multiple sclerosis clinical trials: a critical analysis. Mult Scler 1995;1:37–47.

13. Goodkin DE, Hertsgaard D, Seminary J. Upper extremity function in multiple sclerosis: improving assessment sensitivity with box-and-block and nine-hole peg tests. Arch Phys Med Rehabil 1988;69:850–854.

14. Kaufman M, Moyer D, Norton J. The significant change for the Timed 25-foot Walk in the multiple sclerosis functional composite. Mult Scler 2000;6:286–290.

15. Gronwall DM. Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 1977;44:367–373.

16. Cohen JA, Fischer JS, Bolibrush DM, et al. Intrarater and interrater reliability of the MS functional composite outcome measure. Neurology 2000;54:802–806.

17. Cohen JA, Cutter GR, Fischer JS, et al, for the IMPACT Investigators. Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial. Arch Neurol 2001;58:961–967.

18. Solari A, Radice D, Manneschi L, Motti L, Montanari E. The multiple sclerosis functional composite: different practice effects in the three test components. J Neurol Sci 2005;228:71–74.

19. Fischer JS, Rudick RA, Cutter GR, Reingold SC. The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. The National MS Society Clinical Outcomes Assessment Task Force. Mult Scler 1999;5:244–250.

20. Fox RJ, Lee JC, Rudick RA. Optimal reference population for the multiple sclerosis functional composite. Mult Scler 2007;13:909–914.

21. Ford HL, Gerry E, Tennant A, Whalley D, Haigh R, Johnson MH. Developing a disease-specific quality of life measure for people with multiple sclerosis. Clin Rehabil 2001;15:247–258.

22. Kalkers NK, de Groot V, Lazeron RH, et al. MS functional composite: relation to disease phenotype and disability strata. Neurology 2000;54:1233–1239.

23. Hoogervorst EL, Kalkers NF, Uitdehaag BM, Polman CH. A study validating changes in the multiple sclerosis functional composite. Arch Neurol 2002;59:113–116.

24. Miller DM, Rudick RA, Cutter G, Baier M, Fischer JS. Clinical significance of the multiple sclerosis functional composite: relationship to patient-reported quality of life. Arch Neurol 2000;57:1319–1324.

25. Kalkers NF, Bergers L, de Groot V, et al. Concurrent validity of the MS Functional Composite using MRI as a biological disease marker. Neurology 2001;56:215–219.

26. Kalkers NF, Bergers E, Castelijns JA, et al. Optimizing the association between disability and biological markers in MS. Neurology 2001;57:1253–1258.

27. Vrenken H, Pouwels PJ, Ropele S, et al. Magnetization transfer ratio measurement in multiple sclerosis normal-appearing brain tissue: limited differences with controls but relationships with clinical and MR measures of disease. Mult Scler 2007;13:708–716.

28. Khaleeli Z, Cercignani M, Audoin B, Ciccarelli O, Miller DH, Thompson AJ. Localized grey matter damage in early primary progressive multiple sclerosis contributes to disability. Neuroimage 2007;37:253–261.

29. Khaleeli Z, Sastre-Garriga J, Ciccarelli O, Miller DH, Thompson AJ. Magnetisation transfer ratio in the normal appearing white matter predicts progression of disability over 1 year in early primary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2007;78:1076–1082.

30. Lowe MJ, Horenstein C, Hirsch JG, et al. Functional pathway-defined MRI diffusion measures reveal increased transverse diffusivity of water in multiple sclerosis. Neuroimage 2006;32:1127–1133.

31. Rudick RA, Cutter G, Baier M, et al. Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS. Neurology 2001;56:1324–1330.

32. Fisher E, Rudick RA, Cutter G, et al. Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients. Mult Scler 2000;6:373–377.

33. Sastre-Garriga J, Ingle GT, Chard DT, Ramió-Torrentà L, Miller DH, Thompson AJ. Grey and white matter atrophy in early clinical stages of primary progressive multiple sclerosis. Neuroimage 2004;22:353–359.

34. Chard DT, Griffin CM, McLean MA, et al. Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis. Brain 2002;125(Pt 10):2342–2352.

35. Jasperse B, Jakobs C, Eikelenboom MJ, et al. N- acetylaspartic acid in cerebrospinal fluid of multiple sclerosis patients determined by gas-chromatography-mass spectrometry. J Neurol 2007;254:631–637.

36. Moldovan IR, Rudick RA, Cotleur AC, et al. Interferon gamma responses to myelin peptides in multiple sclerosis correlate with a new clinical measure of disease progression. J Neuroimmunol 2003;141:132–140.

37. van Veen T, Nielsen J, Berkhof J, et al. CCL5 and CCR5 genotypes modify clinical, radiological and pathological features of multiple sclerosis. J Neuroimmunol 2007;190:157–164.

38. Fischer JS, Jak AJ, Kniker JE, Rudick RA, Cutter G. Multiple Sclerosis Functional Composite (MSFC): Administration and Scoring Manual. National Multiple Sclerosis Society: New York; 2001.

39. Hobart J, Kalkers N, Barkhof F, Uitdehaag B, Polman C, Thompson A. Outcome measures for multiple sclerosis clinical trials: relative measurement precision of the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite. Mult Scler 2004;10:41–46.

40. Uitdehaag BM, Adèr HJ, Roosma TJA, de Groot V, Kalkers NF, Polman CH. Multiple sclerosis functional composite: impact of reference population and interpretation of changes. Mult Scler 2002;8:366–371.

41. Schwid SR, Goodman AD, McDermott MP, Bever CF, Cook SD. Quantitative functional measures in MS: what is a reliable change? Neurology 2002;58:1294–1296.

42. Uitdehaag BM, Adèr HJ, Kalkers NF, Polman CH. Quantitative functional measures in MS: what is a reliable change? Neurology 2002;59:648–649.

43. Rudick RA, Lee JC, Simon J, Fisher E. Significance of T2 lesions in multiple sclerosis: a 13-year longitudinal study. Ann Neurol 2006;60:236–242.

44. Cohen JA, Cutter GR, Fischer JS, et al. IMPACT Investigators. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002;59:679–687.

45. Miller DM, Cohen JA, Kooijmans M, Tsao E, Cutter G, Baier M. Change in clinician-assessed measures of multiple sclerosis and subject-reported quality of life: results from the IMPACT study. Mult Scler 2006;12:180–186.

46. Kappos L, Freedman MS, Polman CH, et al. BENEFIT Study Group. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007;370:389–397.

47. Montalban X. Overview of European pilot study of interferon beta-1b in primary progressive multiple sclerosis. Mult Scler 2004;10(suppl 1):S62–S64.

48. Polman CH, Rudick RA, Balcer LJ, et al. Sustained disability progression using scores from the Multiple Sclerosis Functional Composite. Presented at the 59th Annual Meeting of the American Academy of Neurology; April 28–May 5, 2007; Boston.

49. Phillips JT, Kappos L, O'Connor PW, et al; for the AFFIRM Investigators. The effects of natalizumab monotherapy on multiple sclerosis measures of disability progression in patients with multiple sclerosis. Presented at the 58th Annual Meeting of the American Academy of Neurology; April 1–8, 2006; San Diego, CA.

50. Lublin FD, O'Connor PW, Havrdova E, et al; for the AFFIRM Investigators. The effects of natalizumab on disability progression in the AFFIRM study: correlation between changes in Multiple Sclerosis Functional Composite and Expanded Disability Status Scale scores (poster P580). Presented at the 21st Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 28–October 1, 2005; Thessaloniki, Greece.

51. Fischer JS, Priore RL, Jacobs LD, et al. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Ann Neurol 2000;48:885–892.

52. Weinstein A, Schwid SR, Schiffer RB, McDermott MP, Giang DW, Goodman AD. Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Arch Neurol 1999;56:319–324.

53. Fisher E, O'Connor PW, Havrdova E, et al; for the AFFIRM Investigators. The effects of natalizumab on brain atrophy and cognitive function: results from the AFFIRM study (poster P383). Presented at the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27–30, 2006; Madrid, Spain.

54. Kragt JJ, Thompson AJ, Montalban X, et al. Responsiveness and predictive value of EDSS and MSFC in primary progressive MS. Neurology 2008;70:1084–1091.