Multiple Sclerosis
Measuring Disability Progression with the Multiple Sclerosis Functional Composite
Kristen M Krysko1 and Paul W O’Connor2
1. Medical Student, Class of 2012, University of Toronto; 2. Neurologist and Director, Multiple Sclerosis Clinic and Multiple Sclerosis Research, St Michael’s Hospital and Professor of Medicine (Neurology), University of Toronto
Abstract
The multiple sclerosis functional composite (MSFC) is a three-part quantitative objective measure of neurologic function, measuring leg (Timed 25-foot Walk [25FTW]), arm (Nine-hole Peg Test [9HPT]) and cognitive (Three-second Paced Auditory Serial Addition Test [PASAT3]) function. The MSFC was developed to be a more sensitive measure of disability than the expanded disability status scale (EDSS) and has excellent reliability. Validity is supported by moderately strong correlations with EDSS, brain atrophy and quality of life. Advantages of the MSFC include its continuous scale and inclusion of several disease dimensions. Limitations include practice effects, the lack of a visual function component, variations in reference populations and limited understanding of clinically relevant MSFC z-score changes. MSFC z-score change has been used as a secondary end-point in MS trials, but EDSS progression remains the primary disability outcome. A new approach to MSFC data involves defining MSFC progression as worsening in an MSFC component by 15–20% over three months. With further study, this could be used as a primary disability outcome in future clinical trials.
Keywords
Multiple sclerosis, multiple sclerosis functional composite (MSFC), expanded disability status scale (EDSS), outcome measures, end-point, disability, clinical trials
Disclosure: Kristen M Krysko has no conflicts of interest to declare. Paul W O’Connor has received honoraria from Biogen Idec, sanofi-aventis, Novartis, EMD Serono, Bayer, Teva Neuroscience and Genentech. He has also received research support for clinical trials from Biogen Idec, BioMS, sanofi-aventis, Novartis, Bayer and Genentech. Received: 2 August 2010 Accepted: 8 November 2010 Citation: European Neurological Review, 2011;6(1):31–5 Correspondence: Paul W O’Connor, 30 Bond St #3007S, St Michael’s Hospital, Toronto, ON, Canada, M5B 1W8. E:
oconnorp@smh.ca
Evaluation of new treatments in clinical trials of multiple sclerosis (MS) requires valid and reliable measures of disability and disease progression. It is also important to monitor clinical outcomes in individual patients to optimise care. There are different kinds of outcome measure, including physician-oriented measures such as those based on the neurologic examination and quantitative tests of neurologic function, as well as patient-oriented self-report measures.1 Physician-oriented outcomes tend to be more objective compared with patient self-report measures, whereas quantitative tests of neurologic function are more standardised and reliable than measures based on the neurologic examination. However, physicians tend to be more familiar with the latter measures, whereas the clinical relevance of changes in objective tests of neurologic function are unclear.1
The expanded disability status scale (EDSS)2 used measure in assessing disability and progression in MS.1
is the most universally The EDSS
is based on the neurologic examination and measures impairment in eight functional systems, with EDSS scores in steps of 0.5, ranging from zero (normal neurologic examination) to 10 (death).2
The EDSS
has been used as a primary or secondary efficacy end-point in clinical trials of disease-modifying therapies (DMTs) in MS.3–12
The main strengths of the EDSS are its familiarity and widespread use, which enable comparisons between different trials. In addition, data have been collected on its reliability and validity.1,13
However, over the © TOUCH BRIEFINGS 2011
First, the scale is ordinal rather than equal interval, requiring non-parametric analyses. The mean staying time is different at each level of the scale, with longer mean staying times at the upper and lower ends of the scale than at scores of three, four or five.14 Second, there is subjectivity in determining scores of ambulation and bowel and bladder dysfunction.1
There is also interexaminer variability
in rating functional system scores as mild, moderate or severe, resulting in lower reliability at low EDSS scores.13
Finally, higher EDSS
scores are fully dependent upon ambulatory disability, so new changes in functional system scores do not affect upper-range EDSS scores. Additionally, the EDSS is relatively insensitive to arm function, cognitive function, and fatigue, which are important dimensions of MS.1
Development of the Multiple Sclerosis Functional Composite
Owing to known limitations of the EDSS and the increasing number of clinical trials in MS, the National Multiple Sclerosis Society (NMSS) sponsored a workshop in 1994 to evaluate currently available outcome tools. At this workshop, participants agreed that there was no optimal assessment measure available and recommended the development of a multidimensional assessment tool incorporating multiple clinically independent dimensions of MS, including cognitive function.15
A task
force was then appointed to recommend improved clinical outcome measures. This task force published important criteria for MS clinical
31
past few years there has been discussion regarding the limitations of the EDSS.1,13
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