Detecting clinically-relevant changes in progressive multiple sclerosis.

OBJECTIVE: To investigate which changes in different clinical outcome measures contribute most to increased disease impact, as reported by the patient, in progressive multiple sclerosis (MS). METHODS: From a cohort of prospectively-followed MS patients, we selected progressive patients with two visits, 4-6 years apart. We assessed long-term changes on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Guy's Neurological Disability Scale (GNDS). We defined the presence or absence of clinically meaningful change by using the Multiple Sclerosis Impact Scale (MSIS-29) as an anchor measure. We also studied change on recently identified sub-scales of GNDS. RESULTS: Change on GNDS (especially the spinal-plus subscale) contributed most to increased disease impact. Also change on the T25FW contributed largely. Specific profiles of change in T25FW and MSIS seemed to exist (generally, a lower increase in disease impact in patients with longer disease duration and higher baseline impact/disability). In some patients a dissociation existed between increased impact, according to the MSIS-29, and objective physical worsening of the T25FW. CONCLUSION: These results support using GNDS (particularly the spinal-plus domain) and T25FW in outcome measurement in progressive MS. We suggest there is a relation between baseline clinical characteristics and an increased impact at follow-up. This may have implications for patient selection in trials for progressive MS.

Proxy measurements in multiple sclerosis: agreement on different patient-reported outcome scales.

BACKGROUND: Patient-reported outcome (PRO) scales are often used in multiple sclerosis (MS) research. Full understanding of items can be influenced by disease worsening, mood disturbances and cognitive problems of the MS patient. Earlier research with the Multiple Sclerosis Impact Scale (MSIS-29) showed that proxy respondents (i.e. partners of patients) can provide useful information. OBJECTIVE: To determine agreement between patients and proxy respondents on different MS PRO scales. METHODS: 139 Patients and partners completed the MSIS-29 (Physical and Psychological scale), Multiple Sclerosis Walking Scale (MSWS-12), Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) and Guy's Neurological Disability Scale (GNDS). We calculated the mean difference and intra-class correlation coefficients (ICC) on scale level and weighted kappas (κ(w)) on item level. RESULTS: On all scales, except MSNQ, the partner score was higher. ICCs were good for MSWS, GNDS and MSIS Physical, and moderate for MSNQ and MSIS Psychological. κ(w) was excellent for MSWS items, fair to good for GNDS, MSIS Physical and MSIS Psychological items, and poor for MSNQ items. CONCLUSION: Partners of patients with MS can be a useful source of information for several PRO scales, especially when the focus is on physical functioning. For psychological functioning this seems to be less reliable.

Progression on the Multiple Sclerosis Functional Composite in multiple sclerosis: what is the optimal cut-off for the three components?

For the Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT), components of the Multiple Sclerosis Functional Composite (MSFC), cut-off points of 20% change have previously been defined as meaningful endpoints of functional decline. Recently, however, a 15% change of MSFC components was introduced. The objective of this study was to determine optimal cut-offs for all MSFC components to indicate clinical disease progression in a primary progressive (PP) multiple sclerosis (MS) population. T25FW, 9HPT and the Paced Auditory Serial Addition Test (PASAT) were performed in 161 patients with PPMS with a 2-year interval. Absolute and relative differences in test scores were calculated. For each cut-off point of relative change, proportions of patients who progressed (deterioration beyond cut-off value) and improved (improvement beyond cut-off value) were calculated. Further, we calculated the ratio of 'improved' versus 'progressed' patients. Line graphs were created indicating: percentage progressed patients, percentage improved patients, and ratio of improved versus progressed patients. The optimal cut-off was determined by searching the cut-off point with the lowest ratio of improved versus progressed patients, while at the same time capturing a substantial amount of progression. For both T25FW and 9HPT, the ratio between patients that improved and worsened clearly decreased between the cut-offs of 15% and 20%. For the PASAT, the ratio between patients improved and worsened was persistently poor. In conclusion, a cut-off of 20% for both T25FW and 9HPT has a better signal-to-noise ratio than lower values (e.g. 15%) and is therefore preferable for the assessment of disease progression. No satisfactory cut-off point for the PASAT could be determined.

The search for responsive clinical endpoints in primary progressive multiple sclerosis.

OBJECTIVE: To determine whether in primary progressive multiple sclerosis (PPMS) combining scores of Expanded Disability Status Scale (EDSS) with data from Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT) would produce a clinical endpoint that has a higher event rate than EDSS alone. METHODS: In a group of 161 PPMS patients, EDSS, T25FW, and 9HPT were performed at three time points over 2 years. We calculated how many patients showed clinically meaningful deterioration (or improvement) on individual and combined scales. We defined improvements on one scale with deterioration on the other as "opposing changes." We investigated the possible effect of baseline disability on the definition of our endpoint by dividing the population into two subsets of patients determined by baseline EDSS level. RESULTS: On individual scales, event rates were highest on T25FW: 34% and 46% 1 year and 2 years after baseline. On a combination of two scales, at 1 year the event rate was highest on T25FW/9HPT (46%; with a high rate of opposing changes) and at 2 years on T25FW/EDSS (57%; with a lower rate of opposing changes). In both subsets, event rates were highest on T25FW and (at 2 years) on the combination of T25FW/EDSS. CONCLUSIONS: T25FW has the highest event rate as a single scale, independent of baseline disability level. A term of 2 years turned out to be more meaningful to observe than 1 year. "Worsening on either T25FW or EDSS" is the most appropriate composite endpoint in this patient group.