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Background: Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Preventing progressive disability is the key therapeutic goal but there remains no validated definition for its measurement in a trial context. Meanwhile, MS trials continue to shorten and to depend on unvalidated surrogates. Since there have been no treatment claims for improving unremitting disability, worsening of disability in the placebo/control arm must occur for effectiveness on this outcome to be shown., Methods: We examined widely-used clinical surrogates of long-term disability progression in individual patients with MS within a unique database from the placebo arms of 31 randomized clinical trials., Results: Detection of treatment effects in secondary progressive MS trials is undermined by noise in disability measurement. Whereas existing measures can be partially validated in secondary progressive MS, this is not the case in relapsing-remitting MS. Here, examination of widely used definitions of treatment failure demonstrated that disability progression was no more likely than similarly defined improvement. Existing definitions of disease progression in short-term intervention trials in relapsing-remitting patients reflect random variation, measurement error, and remitting relapses., Conclusion: Clinical surrogates of unremitting disability used in trials of relapsing-remitting multiple sclerosis cannot be validated. Trials have been too short or degrees of disability change too small to measure the key outcomes. These analyses highlight the difficulty in determining effectiveness of therapy in chronic diseases.

Background: Quality of life (QOL) is becoming an increasingly important factor in measurement of disease impact as well as an outcome measure in clinical trials., Objectives: To study the QOL of patients with multiple sclerosis (MS) in a population-based prevalence cohort and compare it with the general US population., Design: Population-based prevalence cohort., Setting: Olmsted County, Minn, population., Participants: All patients with definite MS (N = 201) alive and residing in Olmsted County on December 1, 2000., Intervention: None., Main Outcome Measures: The expanded disability status scale (EDSS) and the Multiple Sclerosis Quality of Life Health Survey (MSQOL-54), which consisted of Short Form 36 (SF-36) with an additional 18 items pertinent to MS., Results: The MSQOL-54 form was completed by 185 patients. Patients with MS had worse scores than the general US population with respect to physical functioning, vitality, and general health dimensions of the SF-36 QOL measure. Many QOL domains (pain, role emotional, mental health, and social functioning) were, however, similar for the 2000 MS cohort compared with the general US population. Duration of MS and EDSS score correlated significantly with physical functioning (P<.001). The QOL correlation with EDSS score was less than expected. No significant difference in the scores for the 8 QOL dimensions were found for patients with quick vs slow progression (quick progression defined as <5 years from onset to EDSS score of 3). The majority of patients with MS (77%) were mostly satisfied or delighted with their QOL., Conclusion: Though MS can cause significant disability, most patients with MS in the Olmsted County prevalence cohort continue to report a good QOL.

Objective: S: To study the change in disability over 10 years in individual patients constituting the 1991 Olmsted County, MN, multiple sclerosis (MS) prevalence cohort., Methods: The authors reassessed this 1991 cohort in 2001. The authors determined the Expanded Disability Status Scale scores (EDSS) for each patient still alive, and within the year prior to death for those who died. The authors analyzed determinants of potential prognostic significance on change in disability., Results: Follow-up information was available for 161 of 162 patients in the 1991 cohort. Only 15% had received immunomodulatory therapy. The mean change in EDSS for the entire cohort over 10 years was 1 point and 20% worsened by >or=2 points. For patients with EDSS <3 in 1991 (n = 66), 83% were ambulatory without a cane 10 years later. For patients with EDSS of 3 through 5 in 1991 (n = 33), 51% required a cane to ambulate (48%) or worse (3%). For patients with EDSS 6 to 7 in 1991 (n = 39), 51% required a wheelchair or worse in 2001. Gait impairment at onset, progressive disease, or longer duration of disease were associated with more worsening of disability (p < 0.002). The 10-year survival was decreased compared with the Minnesota white population for both men and women., Conclusions: Although survival was reduced and 30% of patients progressed to needing a cane or wheelchair or worse over the 10-year follow-up period, most remained stable or minimally progressed. Patients within the EDSS 3.0 through 5.0 range are at moderate risk of developing important gait limitations over the 10-year period. The authors did not identify factors strongly predictive of worsening disability in this study.

In this past year, there has only been modest progress in the search for an effective treatment for multiple sclerosis and its complications, although a number of carefully designed trials are in progress. No treatment predictably slows the course of active disease. The marginal benefits previously claimed for azathioprine have been strengthened by a meta-analysis of previously published work. Methylprednisolone may have a minor role in the treatment of very severe, acute optic neuritis but prednisone use may predispose patients to recurrent optic neuritis. 4-Aminopyridine and 3,4-diaminopyridine may prove useful for the symptomatic treatment of some multiple sclerosis patients; pemoline may be an alternative to amantadine for the control of fatigue; and acetazolamide may be an alternative to carbamazepine and phenytoin for the treatment of painful tonic spasms.

We describe the interrater variability in the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. Two physicians blinded to their previous assessments and to each other's scores consecutively examined 168 patients (545 paired examinations). Perfect agreement on the assignment of the disability scores ranged from 48% (cerebellar functional group) to 69% (EDSS and pyramidal functional group). Only 31% to 62% of this agreement occurred independently of that expected by chance (kappa). With the exception of the cerebellar and sensory functional groups, agreement within 1 step occurred in at least 92% of cases. These findings suggest that differences of a single step on these scales may not reflect an important functional change. We recommend that at least a 2-step change (1.0 point on the EDSS and 2 points on the FS) is needed to be confident of an important change in the degree of disability or response to treatment in this disease.